Roger

Artemisinin is the elixir of immortality for humans. Artemisinin is too inexpensive, but it's being prevented from use by dark forces, just like how penicillin was. Scientists from the NEW FEDERAL STATE OF CHINA in Europe say that if the world's doctors openly discuss and research artemisinin, it would definitely be the elixir of immortality for humanity. Cancer, AIDS, and all diseases essentially disrupt the body's immune system, causing blockages in all blood vessels. Artemisinin completely cleanses and clears the body's blood vessels, fundamentally resolving human diseases. 青蒿素就是人类长生不老药 青蒿素这个药太便宜，是黑暗势力不让用的，就像伊维菌素一样。新中国联邦在欧洲的科字家说，如果能让世界医生公开讲青蒿素、研究青蒿素，青蒿素绝对是人间的长生不老药。癌症、艾滋病、所有疾病本质就是把人的免疫力打乱，所有血管堵塞，青蒿素就是把人体的血管完全清理、疏通，从根本上解决人类的疾病。 Long COVID may be caused by the vaccine, long-term vaccine sequelae. 长新冠，可能是因疫苗导致的 长期疫苗后遗症。 At Long Covid Clinic, 70% of Patients Have Long Vax Refer to: https://expose-news.com/2024/04/07/the-era-of-long-vax-has-quietly-arrived/ The main message of the video is: The three main antidotes for vaccines are: 1. Artemisinin and its derivatives (recent feedback suggests that artemether is the best choice), 2. Ivermectin, 3. Vitamin D3 injections (testing for deficiency is required first, as the efficacy of injections and oral dosage forms are completely different). 视频主要表达的意思是： 疫苗的三个主要解药是： 1.青蒿素及其衍生物（最近两年的反馈来看，青蒿琥脂最佳）， 2.伊维菌素 3.维生素D3针剂（需先测试是否缺乏，针剂和口服的药剂效果完全不同） Observations on the anti-disease effects of Artemisia annua leaves being higher than artemisinin align with the practical efficacy in Africa during the pandemic and observations by American scientists. However, the mechanism of its efficacy awaits clarification. The timing of ferrous sulfate intake before Artemisia administration is valuable experiential knowledge and worthy of consideration. However, the discussion on the pharmacokinetics of artemisinin and artemether seems to generalize. After intravenous injection of artemether, blood drug concentration quickly decreases, with a half-life (t1/2) of only about 30 minutes; the half-life of oral artemether tablets is approximately 1.3-3.2 hours. The half-life of artemisinin in the human body is just over 1 hour (there is an error in the article!). Since the effective blood drug half-life and bioavailability are crucial for the anti-malarial efficacy, the development of artemisinin-based anti-malarial drugs in the past 40-50 years has mainly focused on improving these shortcomings of artemisinin. However, this literature review seems to create confusion on this crucial issue. 其中的黄花蒿植物叶的抗许多病症效果高于青蒿素的观察，符合疫情期在非洲的应用实效及美国科学家的观察发现。但其疗效有别的机理有待明确；亚铁在青蒿给药前的服用时间经验很有价值，值得借鉴考虑。 但，药物代谢动力学中的青蒿素与青蒿琥酯血药半衰期信息有点以偏概全。琥酯静脉注射后血药浓度很快下降，半衰期(t1/2)仅为30分钟左右；口服青蒿琥酯片剂半衰期约为1.3-3.2小时。而青蒿素在人体内半衰期仅1小时余（文章中的信息有错误！）。因有效血药半衰期和生物利用度是抗疟疗效的关键，故过去40-50年的青蒿抗疟药开发主要就是围绕改进青蒿素的这些缺陷而展开。而这篇文献总结似乎在这个关键问题上给人混淆迷惑的映像。 Blood-brain barrier 血脑屏障 Gynecological diseases 妇科疾病, prostate diseases 前列腺疾病, neurological diseases 脑部疾病. Lipid solubility characteristics. 脂溶性特点 To reach the nerve endings 到达神经末梢 Half-life of 1 hour. 半衰期 1小时。 Clearing vascular debris 清理血管垃圾 Invention patent 发明专利 The essence of the content is written in the patent 精华的内容写在专利里。

CN101569601A具有祛痘功能的组合物及其应用 CN101569601A Compound with acne-removing function and its application 具有祛痘功能的组合物及其应用 本发明公开了一种具有祛痘功能的组合物及其应用，该组合物按重量份计由下述组分组成：青蒿素母液1～10份、乳木果油5～100份；其能平衡油脂分泌，去除老化角质，疏通毛孔，杀菌消炎，并能促进细胞新陈代谢，修复受损肌肤，在祛痘的同时除印、平疤，长期使用可以有效抑制痤疮生成，还原健康肌肤，且安全无毒；以本发明组合物为活性成分，与一种或多种化妆品可接受的载体按照常规制备方法可以制成各种剂型的祛痘化妆品，满足广大痤疮患者的迫切需要，具有良好的应用前景；此外，本发明将青蒿素母液变废为宝，充分回收利用资源，可以提高经济效益和社会效益。 具有祛痘功能的组合物及其应用 技术领域 本发明涉及组合物，特别涉及一种具有祛痘功能的组合物及其应用。 背景技术 痤疮俗名粉刺、青春痘，是由于毛囊及皮脂腺阻塞、发炎所引发的一种皮肤病，好发于面部、前胸和上背部等皮脂分泌旺盛的部位，主要表现为白头粉刺、黑头粉刺和炎性丘疹，严重的可以有结节和囊肿。痤疮是青年人群中最常见的影响美容的皮肤病，患者容易出现自尊心、自信心受损、尴尬、抑郁、紧张等社会心理问题，造成社交和就业障碍等。目前，市面上的祛痘化妆品种类繁多，但大多治愈率低，停药后容易反复发作，而且大多为化学制剂和激素类药物，使用后容易产生副作用。因此，高效、安全的祛痘化妆品的研制是痤疮患者的迫切需求。 青蒿素母液是青蒿植物提取青蒿素后的残余物。青蒿素是从青蒿中分离得到的一种抗疟有效成分，以青蒿素为基础的联合疗法已被WHO列为治疗疟疾的首选方法；近年来科学家们还发现青蒿素及其衍生物对多种癌细胞具有选择性毒性。青蒿素虽然可以化学合成，但成本很高，无法工业化生产，目前的主要来源仍然是从青蒿植物中提取。从青蒿中提取青蒿素的方法有多种，其中有机溶剂提取法操作简便、成本低廉，是目前大多数厂家广泛采用的方法。该法将青蒿叶用有机溶剂如石油醚、汽油、环己烷、乙酸乙酯等浸取，所得浸取液经柱层析分离、浓缩结晶等步骤分离出青蒿素，剩余提取液回收溶剂即得青蒿素母液。文献报道，青蒿素母液中含有青蒿素，青蒿甲、乙、丙、丁、戊素，青蒿酸，蒿酸甲酯，挥发油，黄酮类，香豆素类，油脂类，蜡质，脂肪烃类等多种成分，具有止血、抗炎、抑制真菌等作用。但青蒿素母液目前大多数被废弃或仅作为燃料使用，造成资源的极大浪费。 乳木果油(Shea Butter)是从产于非洲的乳木果树的果仁中萃取得到的油脂。其与人体皮脂腺分泌油脂的各项指标最为接近，蕴含丰富的非皂化成分，能迅速被皮肤吸收，具有保湿、防晒、抗衰老、消炎等功效，对皮炎、湿疹、晒伤、冻伤、烫伤、裂口和伤痕皮肤等有明显的促进愈合作用。 迄今为止，尚未见以青蒿素母液和乳木果油为主要原料制备祛痘化妆品的研究报道。 发明内容 有鉴于此，为克服现有技术的不足，本发明的目的在于提供一种具有祛痘功能的天然组合物，能平衡油脂分泌，去除老化角质，疏通毛孔，杀菌消炎，并能促进细胞新陈代谢，修复受损肌肤，在祛痘的同时除印、平疤，长期使用可以有效抑制痤疮生成，还原健康肌肤，且安全无毒。 为达到此目的，本发明提供了一种具有祛痘功能的组合物，按重量份计由下述组分组成：青蒿素母液1～10份、乳木果油5～100份。 进一步，各组分的重量配比为：青蒿素母液2～7份、乳木果油5～70份； 进一步，所述青蒿素母液由下述方法得到： a、将青蒿叶用有机溶剂提取，得提取液； b、将步骤a所得提取液进行柱层析，使青蒿素吸附在层析柱上，洗涤除去未吸附在层析柱上的提取物，收集洗涤液，回收溶剂，得母液I； c、将步骤b中吸附在层析柱上的青蒿素洗脱下来，收集洗脱液，浓缩结晶，过滤，分别得青蒿素粗晶和滤液，滤液回收溶剂，得母液II； d、将步骤b所得母液I和步骤c所得母液II混合，即得青蒿素母液； 进一步，所述有机溶剂为石油醚。 本发明的另一目的在于提供所述具有祛痘功能的组合物的应用。 为达到此目的，本发明提供了所述具有祛痘功能的组合物在制备祛痘化妆品中的应用。 进一步，所述具有祛痘功能的组合物与化妆品可接受的载体按照常规制备方法制成各种剂型的祛痘化妆品。 上述化妆品可接受的载体是指化妆品领域的常规载体，包括但不限于：油质载体如油脂、蜡类、烃类、高级脂肪醇、高级脂肪酸、酯类等；粉质载体如滑石粉、高岭土、膨润土、钛白粉、硬脂酸镁、聚乙烯粉、聚苯乙烯粉、纤维素微珠等；胶质载体如明胶、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟乙基纤维素、聚乙二醇、聚乙烯醇、聚乙烯吡咯烷酮、丙烯酸聚合物等；表面活性剂如阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂和非离子性表面活性剂等；以及保湿剂、粘结剂、防腐剂、抗氧剂、着色剂和香料等。上述各种剂型是指化妆品领域的常规剂型，包括但不限于：水剂、乳剂、霜剂、凝胶剂、膏剂、面膜剂等。 本发明的有益效果在于：本发明提供了一种具有祛痘功能的天然组合物，经上百例痤疮患者使用证实，其能平衡油脂分泌，去除老化角质，疏通毛孔，杀菌消炎，并能促进细胞新陈代谢，修复受损肌肤，在祛痘的同时除印、平疤，长期使用可以有效抑制痤疮生成，还原健康肌肤，且安全无毒。以本发明组合物为活性成分，与一种或多种化妆品可接受的载体按照常规制备方法可以制成各种剂型的祛痘化妆品，满足广大痤疮患者的迫切需要，具有良好的应用前景。此外，本发明将废弃的青蒿素母液变废为宝，充分回收利用资源，可以提高经济效益和社会效益。 具体实施方式 为了使本发明的目的、技术方案和优点更加清楚，下面对本发明的优选实施例进行详细的描述。 在优选实施例中使用的乳木果油购自加纳PURE LTD公司；青蒿素母液购自重庆华立药业股份有限公司，由下述方法制得： a、将青蒿叶干燥后粉碎，取青蒿叶粉，加入石油醚冷浸提取，每24小时更换新的石油醚至提取液呈无色，合并多次提取液，浓缩至适当体积，得浓缩提取液； b、将步骤a所得浓缩提取液进行硅胶柱层析，使青蒿素吸附在层析柱上，洗涤除去未吸附在层析柱上的提取物，收集洗涤液，回收溶剂，得母液I； c、将步骤b中吸附在层析柱上的青蒿素洗脱下来，收集洗脱液，浓缩结晶，过滤，分别得青蒿素粗晶和滤液，滤液回收溶剂，得母液II； d、将步骤b所得母液I和步骤c所得母液II混合，即得青蒿素母液。 实施例1～5、祛痘膏剂的制备 主要原料及重量配比：见表1。 表1、祛痘膏剂的主要原料及重量配比 制备方法：取青蒿素母液，加入5倍量水，加热至温度50℃使溶解，过滤，取滤液，备用；取适量水，加入甘油、聚氧乙烯醚磷酸三酯和羟苯乙酯，加热使溶解，再加入上述青蒿素母液的滤液，混合均匀，作为水相；取乳木果油，加热使熔化，作为油相；将水相缓缓加至油相中，不断搅拌至冷凝，即得祛痘膏剂。 使用方法：先清洁面部，再将祛痘膏剂点涂或敷于痤疮处，每天2～6次。具体次数依据患者皮肤情况、痤疮部位以及严重程度而定，通常需要使用2～7天，严重情形可能需要几周甚至更长的时间。 上述实施例1～8制备的祛痘膏剂经上百例痤疮患者试用，结果证实：其能平衡油脂分泌，去除老化角质，疏通毛孔，杀菌消炎，并能促进细胞新陈代谢，修复受损肌肤，在祛痘的同时除印、平疤，疗效确切，治疗有效率达95％以上，患者使用后均未出现不良反应。 当然，除膏剂外，本发明的组合物还可以与化妆品可接受的载体按照常规制备方法制成多种剂型的系列祛痘化妆品，如水剂、乳剂、霜剂、凝胶剂、面膜剂等，单独或配套使用，全脸或患处局部使用，不仅可以达到高效、安全地治疗痤疮的目的，还可以有效预防痤疮的生成。 最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管通过参照本发明的优选实施例已经对本发明进行了描述，但本领域的普通技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离所附权利要求书所限定的本发明的精神和范围。 1、具有祛痘功能的组合物，其特征在于：按重量份计由下述组分组成：青蒿素母液1～10份、乳木果油5～100份。 2、根据权利要求1所述的具有祛痘功能的组合物，其特征在于：各组分的重量配比为：青蒿素母液2～7份、乳木果油5～70份。 3、根据权利要求1或2所述的具有祛痘功能的组合物，其特征在于：所述青蒿素母液由下述方法得到： a、将青蒿叶用有机溶剂提取，得提取液； b、将步骤a所得提取液进行柱层析，使青蒿素吸附在层析柱上，洗涤除去未吸附在层析柱上的提取物，收集洗涤液，回收溶剂，得母液I； c、将步骤b中吸附在层析柱上的青蒿素洗脱下来，收集洗脱液，浓缩结晶，过滤，分别得青蒿素粗晶和滤液，滤液回收溶剂，得母液II； d、将步骤b所得母液I和步骤c所得母液II混合，即得青蒿素母液。 4、根据权利要求3所述的具有祛痘功能的组合物，其特征在于：所述有机溶剂为石油醚。 5、权利要求1所述的具有祛痘功能的组合物在制备祛痘化妆品中的应用。 6、根据权利要求5所述的应用，其特征在于：所述具有祛痘功能的组合物与化妆品可接受的载体按照常规制备方法制成各种剂型的祛痘化妆品。 Composition with anti-acne function and application thereof The invention discloses a composition with anti-acne function and an application thereof. The composition comprises the following components according to parts by weight: 1-10 parts of artemisinin mother solution and 5-100 parts of shea butter. The composition can balance soil secretion, remove aged horniness, unblock pores, sterilize and diminish inflammation; and the composition can promote cell metabolism, repair damaged skin, remove prints, and level scars while removing acnes; the composition can effectively prevent acnes and furuncles from being generated in long term use, restore healthy skin, and is safe and non-toxic. The composition of the invention is taken as active ingredient, which is capable of being prepared into anti-acne cosmetics by conventional preparation method together with various dosage forms with one or more carriers acceptable to cosmetics, satisfies the desperate needs of wide patients with acne, and has favorable application prospect; in addition, the invention changes the waste of artemisinin mother solution into valuable, fully recycles resources, and can improve economic and social benefits. Compositions and application thereof with acne-removal function Technical field The present invention relates to compositions, particularly a kind of compositions and application thereof with acne-removal function. Background technology Acne popular name acne, comedo, be because a kind of dermatosis that hair follicle and sebaceous gland are blocked, inflammation caused, good sending out in vigorous positions of sebum secretion such as face, shirtfront and last backs mainly shows as hoary hair's acne, blackhead and inflammatory pimple, and serious can nodosity and cyst.Acne is the dermatosis of modal influence beauty treatment among the young crowd, and social mentality's problems such as sense of personal worth, self-confidence are impaired, awkward, depressed, anxiety appear in patient easily, cause social and the obstacle etc. of obtaining employment.At present, acne-eliminating cosmetic on the market is of a great variety, but cure rate is low mostly, outbreak repeatedly easily after the drug withdrawal, and mostly be chemicals and hormone medicine greatly, be easy to generate side effect after the use.Therefore, the development of efficient, safe acne-eliminating cosmetic is the urgent needs of patients with acne. Artemisinin mother liquid is the residue after sweet wormwood herb extracts arteannuin.Arteannuin is to separate a kind of malaria effective ingredient that obtains from Herba Artemisiae Annuae, has been classified as the prefered method of treatment malaria by WHO based on the conjoint therapy of arteannuin; Scientists finds that also arteannuin and derivant thereof have selective toxicity to multiple cancerous cell in recent years.Though arteannuin can chemosynthesis, cost is very high, can't suitability for industrialized production, and present main source remains from sweet wormwood herb and extracts.The method of extracting arteannuin from Herba Artemisiae Annuae has multiple, and wherein the organic solvent extraction method is easy and simple to handle, with low cost, is the method that present most of producer extensively adopts.With leachings such as organic solvent such as petroleum ether, gasoline, cyclohexane extraction, ethyl acetate, the gained leaching liquid is isolated arteannuin through steps such as column chromatography for separation, condensing crystallizings to this method with artemisia leaf, and the residue extracting solution reclaims solvent and promptly gets artemisinin mother liquid.Bibliographical information contains arteannuin in the artemisinin mother liquid, Herba Artemisiae Annuae first, second, third, fourth, penta element, and artelinic acid, the artemisic acid methyl ester, volatile oil, flavonoid, Coumarins, oils, waxiness, multiple composition such as fat hydrocarbon has effects such as hemostasis, antiinflammatory, inhibition fungus.The use but the present great majority of artemisinin mother liquid go out of use or only act as a fuel causes the significant wastage of resource. Shea butter (Shea Butter) is the oils and fats that extraction obtains from the kernel of the RUMUGUO tree that originates in Africa.Itself and the greasy every index of human body smegma are the most approaching, contain abundant non-saponification composition, can be rapidly by skin absorbs, have preserve moisture, effect such as sun-proof, defying age, antiinflammatory, dermatitis, eczema, sunburn, cold injury, scald, breach and scar skin etc. are had tangible promotion healing effect. Up to now, Shang Weijian is the research report that primary raw material prepares acne-eliminating cosmetic with artemisinin mother liquid and shea butter. Summary of the invention In view of this, for overcoming the deficiencies in the prior art, the object of the present invention is to provide a kind of natural composition with acne-removal function, the energy Bergamot Mint Extract, remove aging cutin, dredging pore, bactericidal antiphlogistic, and can promote cell metabolism, repair impaired skin, remove seal, flat scar in anti-acne, life-time service can effectively suppress acne and generate, reduce healthy skin and safety non-toxic. For reaching this purpose, the invention provides a kind of compositions with acne-removal function, form by following component by weight: 1～10 part of artemisinin mother liquid, 5～100 parts of shea butters. Further, the weight proportion of each component is: 2～7 parts of artemisinin mother liquid, 5～70 parts of shea butters; Further, described artemisinin mother liquid is obtained by following method: A, with the artemisia leaf organic solvent extraction, extracting solution; B, step a gained extracting solution is carried out column chromatography, arteannuin is adsorbed on the chromatographic column, the extract that is not adsorbed on the chromatographic column is removed in washing, collects cleaning mixture, reclaims solvent, mother solution I; C, the arteannuin that is adsorbed on the chromatographic column among the step b is eluted, collect eluent, condensing crystallizing filters, respectively arteannuin coarse-grain and filtrate, filtrate is reclaimed solvent, mother solution II; D, the mother liquid obtained II of the mother liquid obtained I of step b and step c is mixed, promptly get artemisinin mother liquid; Further, described organic solvent is a petroleum ether. Another object of the present invention is to provide described application with compositions of acne-removal function. For reaching this purpose, the invention provides the described application of compositions in the preparation acne-eliminating cosmetic with acne-removal function. Further, described have the compositions of acne-removal function and the cosmetics acceptable carrier is made various dosage forms according to conventional preparation method a acne-eliminating cosmetic. Above-mentioned cosmetics acceptable carrier is meant the conventional carrier of cosmetic field, includes but not limited to: oily carrier such as oils and fats, wax class, hydro carbons, high fatty alcohol, higher fatty acids, esters etc.; Opaque carrier such as Pulvis Talci, Kaolin, bentonite, titanium dioxide, magnesium stearate, polyethylene powder, polystyrene powder, cellulose bead etc.; Colloid bearer such as gelatin, methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, acrylate copolymer etc.; Surfactant such as anion surfactant, cationic surfactant, amphoteric surfactant and nonionic surfactant etc.; And wetting agent, binding agent, antiseptic, antioxidant, coloring agent and spice etc.Above-mentioned various dosage form is meant the regular dosage form of cosmetic field, includes but not limited to: water preparation, Emulsion, cream, gel, unguentum, face film agent etc. Beneficial effect of the present invention is: the invention provides a kind of natural composition with acne-removal function, use confirmation through routine patients with acne up to a hundred, its energy Bergamot Mint Extract is removed aging cutin, dredging pore, bactericidal antiphlogistic, and can promote cell metabolism, repair impaired skin, in anti-acne, remove seal, flat scar, life-time service can effectively suppress acne and generate, and reduces healthy skin and safety non-toxic.With the present composition is active component, can make the acne-eliminating cosmetic of various dosage forms with one or more cosmetics acceptable carriers according to conventional preparation method, satisfies pressing for of vast patients with acne, has a good application prospect.In addition, depleted artemisinin mother liquid is turned waste into wealth in the present invention, fully recycles resource, can improve the economic and social benefits. The specific embodiment In order to make the purpose, technical solutions and advantages of the present invention clearer, below the preferred embodiments of the present invention are described in detail. The shea butter of Shi Yonging is available from Ghana PURE LTD company in a preferred embodiment; Artemisinin mother liquid is made by following method available from Chongqing Holley Pharmaceutical limited company: A, with the artemisia leaf crushed after being dried, get the artemisia leaf powder, add the petroleum ether merceration and extract, per petroleum ether that more renewed in 24 hours is colourless to extracting solution, merges multiple extraction liquid, is concentrated into proper volume, concentrated extracting solution; B, step a gained concentrated extracting solution is carried out silica gel column chromatography, arteannuin is adsorbed on the chromatographic column, the extract that is not adsorbed on the chromatographic column is removed in washing, collects cleaning mixture, reclaims solvent, mother solution I; C, the arteannuin that is adsorbed on the chromatographic column among the step b is eluted, collect eluent, condensing crystallizing filters, respectively arteannuin coarse-grain and filtrate, filtrate is reclaimed solvent, mother solution II; D, the mother liquid obtained II of the mother liquid obtained I of step b and step c is mixed, promptly get artemisinin mother liquid. The preparation of embodiment 1～5, anti-acne unguentum Primary raw material and weight proportion: see Table 1. The primary raw material of table 1, anti-acne unguentum and weight proportion Preparation method: get artemisinin mother liquid, add 5 times of water gagings, be heated to temperature and make dissolving for 50 ℃, filter, get filtrate, standby; Get suitable quantity of water, add glycerol, polyoxyethylene ether phosphotriester and ethyl hydroxybenzoate, heating makes dissolving, adds the filtrate of above-mentioned artemisinin mother liquid again, and mix homogeneously is as water; Get shea butter, heating makes fusing, as oil phase; Water is slowly added in the oil phase, constantly be stirred to condensation, promptly get the anti-acne unguentum. Using method: earlier cleaning is facial, again with anti-acne unguentum spot printing or spread on the acne place, every day 2～6 times.Concrete number of times is decided according to patient skin situation, acne position and the order of severity, needs usually to use 2～7 days, and severe case may need several weeks even longer time. The anti-acne unguentum of the foregoing description 1～8 preparation is on probation through routine patients with acne up to a hundred, the result confirms: its energy Bergamot Mint Extract, remove aging cutin, dredging pore, bactericidal antiphlogistic, and can promote cell metabolism, repair impaired skin, in anti-acne, remove seal, flat scar, determined curative effect, the treatment effective percentage reaches more than 95%, and the patient untoward reaction all do not occur after using. Certainly, except that unguentum, compositions of the present invention can also be made the serial acne-eliminating cosmetic of multiple dosage form with the cosmetics acceptable carrier according to conventional preparation method, as water preparation, Emulsion, cream, gel, face film agent etc., independent or supporting use, full face or affected part are local uses, and not only can reach the purpose for the treatment of acne efficiently and safely, can also effectively prevent the generation of acne. Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and the spirit and scope of the present invention that do not depart from appended claims and limited. 1, has the compositions of acne-removal function, it is characterized in that: form by following component by weight: 1～10 part of artemisinin mother liquid, 5～100 parts of shea butters. 2, the compositions with acne-removal function according to claim 1, it is characterized in that: the weight proportion of each component is: 2～7 parts of artemisinin mother liquid, 5～70 parts of shea butters. 3, the compositions with acne-removal function according to claim 1 and 2, it is characterized in that: described artemisinin mother liquid is obtained by following method: A, with the artemisia leaf organic solvent extraction, extracting solution; B, step a gained extracting solution is carried out column chromatography, arteannuin is adsorbed on the chromatographic column, the extract that is not adsorbed on the chromatographic column is removed in washing, collects cleaning mixture, reclaims solvent, mother solution I; C, the arteannuin that is adsorbed on the chromatographic column among the step b is eluted, collect eluent, condensing crystallizing filters, respectively arteannuin coarse-grain and filtrate, filtrate is reclaimed solvent, mother solution II; D, the mother liquid obtained II of the mother liquid obtained I of step b and step c is mixed, promptly get artemisinin mother liquid. 4, the compositions with acne-removal function according to claim 3 is characterized in that: described organic solvent is a petroleum ether. 5, the described application of compositions in the preparation acne-eliminating cosmetic of claim 1 with acne-removal function. 6, application according to claim 5 is characterized in that: described have the compositions of acne-removal function and the cosmetics acceptable carrier is made various dosage forms according to conventional preparation method a acne-eliminating cosmetic. 本文短链接|Short link to this article: gettr.ink/HdNftC

CN101428034A增减毒抗肿瘤复方药物 CN101428034A Compound medicine for increasing and decreasing toxicity and anti-tumor effect 具有增效减毒特点的抗肿瘤组合药物 本发明涉及一种具有增效减毒效果的抗肿瘤组合药物，该组合药物是主要由替尼泊苷和青蒿素的衍生物组成的，这种组合药物由于在抑制特定肿瘤细胞生长时具有的增效减毒效果，适合于制备抗肿瘤药物，特别适合于制备治疗脑神经胶质瘤、肝癌、宫颈癌的药物。 具有增效减毒特点的抗肿瘤组合药物 技术领域 本发明涉及一种具有增效减毒特点的抗肿瘤组合药物，特别涉及到用于制备治疗脑神经胶质瘤、肝癌和宫颈癌的药物的抗肿瘤组合药物，属于抗癌药物技术领域。 背景技术 神经胶质瘤亦称胶质细胞瘤。对神经胶质瘤的治疗以手术治疗为主，但由于肿瘤呈浸润性生长，与脑组织间无明显边界，除早期肿瘤小且位于适当部位者外，难以作到全部切除，一般都主张综合治疗，即术后配合以放射治疗、化学治疗等，可延缓复发及延长生存期。神经胶质瘤是脑部肿瘤的主要类型之一，由于血脑屏障的因素，主要化疗药物有替莫唑胺和替尼泊苷等化疗剂，这些化疗剂都有高脂溶性并能通过血脑屏障的性质。但是，替莫唑胺(英文Temozolomide)有包括致癌、致畸和生殖毒性在内的明显毒副作用；替尼泊苷(英文Teniposide)或类似的依托泊苷(英文Etoposide)在治疗脑肿瘤中也存在恶心、呕吐等消化道副作用，以及骨髓抑制毒性，不宜长期和大剂量使用。肝癌亦称肝细胞癌，是一种极具侵袭性的恶性肿瘤，愈后较差，其发生发展与我国流行的乙型和丙型肝炎病毒感染密切相关。由于肝癌发生时肝细胞已受到严重损害，致使治疗手段极为有限。迄今尚无正式获准有效治疗药物。现行肝癌治疗药物阿霉素、氟尿嘧啶等治疗有效率过低，且无明显延命效果。宫颈癌约占恶性肿瘤的2％，属于发病率较高的妇科恶性肿瘤。目前，由于单一治疗手段的局限性，宫颈癌的治疗是以手术、放疗、化疗为主要手段。常用顺铂类(如卡铂)、氟尿嘧啶类(如卡培他滨)作为化疗药物，有一定疗效，但存在比较明显的毒副作用。研发新型药物，增效减毒，是肿瘤化疗药物长期而艰巨工作。 替尼泊苷是一种周期特异性的细胞毒药物，其作用机制是DNA拓扑异构酶II特异性抑制剂，临床用于中枢神经系统恶性肿瘤神经母细胞瘤，胶质瘤和星形细胞瘤及转移瘤，以及恶性淋巴瘤，急性淋巴细胞白血病的治疗。替尼泊苷是小分子化合物，分子量是656.6，而且脂溶性极强，油水分配系数P的对数值log10 P是1.96，是其易于透过血脑屏障治疗脑细胞肿瘤的关键性质。 1993年就有青蒿素类化合物对Ehrlich腹水癌细胞的细胞毒活性的报道：MTT法测得青蒿素的半数毒性浓度IC50是29.8μM，双氢青蒿素、青蒿琥酯、蒿甲醚和蒿乙醚等化合物的IC50则是12.2-19.9μM[Woerdenbag H.J.et al.Cytotoxicity of artemisinin-related endoperoxidesto Ehrlich ascites tumor cells.J.Nat.Prod.1993；56：849-56]。另有文献报道，双氢青蒿素(又名二氢青蒿素)对人乳腺癌MCF-7细胞有很强的抑制作用，利用SRB法测得IC50为0.26μM，抑制MCF—7细胞增殖的机制之一，是将细胞滞留在G0+G1期；青蒿素对MCF-7细胞增殖仅有微弱抑制作用，但青蒿琥酯却有显著的抑制作用。利用SRB法测得青蒿琥酯对MCF—7细胞增殖的半数抑制浓度IC50为0.31μM，在1μM引起的细胞凋亡和直接的细胞毒作用明显强于10μM青蒿素的作用[林芳，等.(1)二氢青蒿素对人乳腺癌MCF-7细胞的体外抑制作用.中国新药杂志2002，11：934-936；(2)青蒿素和青蒿琥酯对人乳腺癌MCF-7细胞的体外抑制作用比较研究.中草药2003，34：347-349]。研究还发现，经青蒿琥酯或双氢青蒿素体外作用48小时，宫颈癌Hela细胞、子宫绒毛膜瘤JAR细胞、胚肌瘤RD细胞、卵巢癌HO-8910细胞等四种肿瘤细胞生长受到显著抑制，用MTT法测得的半数抑制浓度IC50分别是15.4-49.7μM(青蒿琥酯)或8.5-32.9μM(双氢青蒿素)(Chen H.H.，et al.Inhibition of human cancer cellline growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives invitro.Pharmacol Res 2003；48：231-236)。说明青蒿素的衍生物是潜在的抗肿瘤药物。 青蒿素的衍生物，特别是已经被开发成为药物的青蒿素、双氢青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯，不论是口服制剂，还是注射剂和栓剂，都已经被药理和临床研究证明是当前用于治疗疟疾的特效药。但是这类药物还有两个方面的特性——脂溶性和安全性尚未被充分应用于抗肿瘤组合药物的研究开发。第一方面的特点是，青蒿素衍生物属于小分子化合物并且具有特别强的脂溶性。例如，青蒿素、双氢青蒿素和蒿甲醚的分子量依次是282.3、284.3、298.4，油水分配系数P的对数值log10 P依次是1.68、1.78和2.24，确保使其能够顺利通过血脑屏障，由循环系统进入中枢神经系统和脑细胞，有助于其抑制脑部肿瘤细胞的生长，成为为数有限的抗脑肿瘤药物之一。第二方面的特点在于，本发明涉及的青蒿素的衍生物药物的使用，不论在细胞水平，还是在整体动物包括临床患者治疗水平；不论是按照疟疾治疗规范给药还是按照癌症治疗规范要求，在所使用的治疗用量下，都已经被证明有良好的用药安全性：毒副作用都远比常规抗肿瘤化疗药带来的毒性和毒副作用都要小很多。因此，在证明青蒿素的衍生物具有抗肿瘤作用，并且与某种常规肿瘤化疗药联用时能够产生药效相加或药效协同作用的情况下，就有理由说明二者合用对该常规肿瘤化疗药的抗肿瘤治疗具有增效作用或减毒作用，或者具有既增效又减毒的比较理想的作用。公开发表的研究文献已说明青蒿素的衍生物是潜在的抗肿瘤药物。本发明所说的青蒿素的衍生物，即青蒿素、双氢青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯因为都有与青蒿素相同的倍半萜母核和过氧桥基本结构，而且都有不同程度的抗肿瘤作用。 发明内容 本发明的目的在于提供了一种具有增效减毒特点的抗肿瘤组合药物。这种组合药物是由替尼泊苷和青蒿素的一种衍生物组成，不仅具有增强抗肿瘤的效果，而其还可以降低药物对人体的毒害。 本发明所采用的技术方案是： 一种具有增效减毒特点的抗肿瘤组合药物，它是由替尼泊苷和青蒿素的一种衍生物作为活性成分组成，在药物制剂中同时含有替尼泊苷和青蒿素的一种衍生物作为抗肿瘤活性成分，其中替尼泊苷的质量占质量分数的1％-99％，优选10％—50％；青蒿素的一种衍生物的质量占质量分数的1％-99％，优选50％—90％。青蒿素的一种衍生物是青蒿素、双氢青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯中的一种；优选使用双氢青蒿素。将药物活性成分替尼泊苷和青蒿素的一种衍生物制成药物制剂。 抗肿瘤组合药药物制剂中，至少同时含有替尼泊苷和青蒿素的一种衍生物作为抗肿瘤活性成分，也就是说，还可以含有其他抗肿瘤活性成分。 本发明还公开该抗肿瘤组合物用于制备恶性肿瘤即癌症，特别是脑神经胶质瘤、肝癌和宫颈癌药物的用途。 以本发明公开的抗肿瘤组合药物作为活性成分，可以制成药学上可接受的剂型，包括注射剂、片剂、胶囊、颗粒剂、缓释制剂、控释制剂和纳米制剂，应用于临床。 本发明的发明人证实了青蒿素的衍生物对宫颈癌、脑神经胶质瘤、肝癌、肺癌和乳腺癌等多种肿瘤细胞的生长有显著抑制作用，这是本发明的一个重要前提条件。 将青蒿素的衍生物与抗肿瘤药替尼泊苷联合使用，可以在一些肿瘤细胞上产生抑制作用“相加”和“协同”的效应。 不同类型的肿瘤，其肿瘤细胞的发生发展机理和影响因素存在差异，对治疗药物的敏感性也存在差异。本发明公开了由替尼泊苷和青蒿素的衍生物如双氢青蒿素组成的抗肿瘤组合药物，优选开发成为治疗宫颈癌、脑肿瘤特别是神经胶质瘤和肝细胞肿瘤的药物制剂，最适于在治疗中表现出增效减毒效果。蒿甲醚、蒿乙醚和青蒿琥酯在人和动物体内都经过代谢和生物转化形成双氢青蒿素，因此，本发明所说的抗肿瘤组合药物是指替尼泊苷与青蒿素、双氢青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯中的任意一种衍生物组成的药物。 本发明相对于现有技术具有如下优点：由替尼泊苷和青蒿素的衍生物组成的抗肿瘤组合药物在抑制肿瘤细胞生长时具有增效减毒效果；可以用于制造恶性肿瘤即癌症，特别是脑神经胶质瘤、肝癌和宫颈癌的治疗药物。 具体实施方式 以下结合实施例对本发明做进一步地详细说明，应该理解的是，这些实施例仅用来说明本发明，并不限制本发明的范围。 实施例1 肿瘤细胞种类及其细胞培养方法 细胞株及细胞培养：实验所用细胞包括宫颈癌Hela细胞、脑神经胶质瘤SWO-38细胞、肝癌HepG2细胞、肺癌LAC细胞和乳腺癌MCF-7细胞。所有细胞的培养条件如下：在二氧化碳细胞培养箱中(37℃、饱和湿度、CO2含量5％)，生长于含10％胎牛血清和100U/mL抗生素的RPMI-1640培养液中。每3到4天细胞传代一次。 实施例2 双氢青蒿素及替尼泊苷对肿瘤细胞生长的抑制作用 药物作用：收集处于对数生长期的细胞，在培养液中分散成每毫升含5×104细胞的单个细胞悬液。细胞悬液按每孔100微升接种于96孔细胞培养板，于二氧化碳细胞培养箱中培养24小时。弃去原有培养液，按每3个孔为一个检测浓度加入含有待测试药物的培养液100微升，继续培养72小时，观察药物对细胞生长的作用。实验中另设培养液空白对照及未加药处理的细胞对照。用MTT法测定药物对细胞生长的半数抑制浓度。 所用的MTT法基本操作：96孔板中的细胞经药物处理68小时后，每孔加入浓度为5毫克/毫升的MTT溶液10微升，于二氧化碳细胞培养箱中反应4小时。取出96孔细胞培养板，小心吸出培养液弃去，孔中残留的色素沉淀用150微升二甲基亚砜溶解后，在490纳米处用酶标仪测定光密度值。此时每孔的光密度值与活细胞数量成正比。 细胞存活率(％)＝(实验孔光密度值-培养空白组光密度值)/(细胞对照组光密度值-培养液空白组光密度值)×100％ 药物对细胞生长的半数抑制浓度IC50即细胞存活率为50％时的药物浓度。 结果如表1和表2所示： 表1 双氢青蒿素对肿瘤细胞生长的抑制作用* *细胞生长抑制试验至少重复三次，结果以平均值(x)±标准偏差(SD)表示；以溶剂和培养液作为药物空白对照。IC50：半数抑制浓度(μM) 表2 替尼泊苷对肿瘤细胞生长的抑制作用* *细胞生长抑制试验至少重复三次，结果以平均值(x)±标准偏差(SD)表示；以溶剂和培养液作为药物空白对照。IC50：半数抑制浓度(μM) 实施例3 双氢青蒿素联用替尼泊苷抑制某些肿瘤细胞生长时具有的协同作用或增效作用 实验过程同上。结果见表3： 表3 双氢青蒿素(A)与替尼泊苷(B)抑制肿瘤细胞生长的协同或增效作用* *细胞生长抑制试验至少重复三次，结果以平均值(x)±标准偏差(SD)表示；以溶剂和培养液作为药物空白对照。IC50：半数抑制浓度(μM) 实验结果表明：第一，用占IC50数量的9.4％的双氢青蒿素，加上占IC50数量的30％的替尼泊苷，能够对宫颈癌Hela细胞的生长产生半数抑制效果(疗效相加或协同作用)；用占IC50数量的3％的双氢青蒿素，加上占IC50数量的35％的替尼泊苷，能够对脑神经胶质瘤SWO-38细胞的生长产生半数抑制效果(疗效协同作用)；用占IC50数量的15.7％的双氢青蒿素，加上占IC50数量的4.7％的替尼泊苷，能够对肝癌HepG2细胞的生长产生半数抑制效果(疗效协同作用)。第二，在化疗实践中，在使用青蒿素衍生物的同时，适当减少替尼泊苷的药量也能获得所需要的抗肿瘤效果，这样也就减少了由替尼泊苷引起的毒副作用。 1.一种抗肿瘤组合药物，其特征是：含有替尼泊苷和青蒿素的一种衍生物的抗肿瘤组合药物。 2.根据权利要求1所述的抗肿瘤组合药物，其特征是：含有替尼泊苷与青蒿素的一种衍生物作为抗肿瘤活性成分。 3.根据权利要求1或2所述的抗肿瘤组合药物，其特征是：所述活性成分青蒿素的一种衍生物是指青蒿素、双氢青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯中的一种，优选使用双氢青蒿素。 4.根据权利要求1—3任意一项所述的抗肿瘤组合药物，其特征是：在所述活性成分中，替尼泊苷的质量占质量分数的1％-99％，优选10％—50％；青蒿素的一种衍生物的质量占质量分数的1％-99％，优选50％—90％。 5.根据权利要求1—4任意一项所述的抗肿瘤组合药物，其特征是：将药物活性成分替尼泊苷和青蒿素的一种衍生物制成药物制剂。 6.根据权利要求5所述的抗肿瘤组合药物，其特征是：在药物制剂中，至少同时含有替尼泊苷和青蒿素的一种衍生物作为抗肿瘤活性成分。 7.根据权利要求1—6任意一项所述的抗肿瘤组合药物，其特征是：用于制备恶性肿瘤即癌症，特别是脑神经胶质瘤、肝癌和宫颈癌药物。 8.根据权利要求1—6任意一项所述的抗肿瘤组合药物，其特征是：所述的药物被制成药学上可接受的剂型，包括注射剂、片剂、胶囊、颗粒剂、缓释制剂、控释制剂和纳米制剂。 Antineoplastic combined medicament with enhancing and poison-reducing character The invention relates to an antineoplastic compound medicine having synergism and attenuation effects. The compound medicine mainly comprises teniposide and derivant of arteannuin. Owing to the synergism and attenuation effects in inhibiting the growth of specific tumor cells, the compound medicine is suitable for preparing antineoplastic medicine, particularly for preparing medicines for treating cerebral glioma, liver cancer and cervical carcinoma. Antineoplastic combined medicament with enhancing and poison-reducing character Technical field The present invention relates to a kind of antineoplastic combined medicament, specially refer to the antineoplastic combined medicament that is used to prepare the medicine for the treatment of glioma brain tumour, hepatocarcinoma and cervical cancer, belong to the cancer therapy drug technical field with enhancing and poison-reducing character. Background technology Glioma also claims glioma.To gliomatous treatment based on operative treatment, but because tumor is infiltrative growth, and no obvious border between cerebral tissue, except that infantile tumour the little and person that is positioned in the suitable position, be difficult to accomplish complete resection, generally all advocate Comprehensive Treatment, promptly postoperative cooperates with radiotherapy, chemotherapy etc., can delay recurrence and prolong life cycle.Glioma is one of main type of brain tumor, because the factor of blood brain barrier, main chemotherapeutics has chemotherapeutics such as temozolomide and teniposide, and these chemotherapeutics all have fat-solubility and can be by the character of blood brain barrier.But temozolomide (English Temozolomide) has the obvious toxic-side effects that comprises carcinogenic, teratogenesis and genotoxicity; Teniposide (English Teniposide) or similarly etoposide (English Etoposide) in the treatment cerebral tumor, also exist feel sick, digestive tract side effects such as vomiting, and bone marrow depression toxicity, unsuitable long-term and heavy dose of the use.Hepatocarcinoma also claims hepatocarcinoma, is a kind of invasive malignant tumor that has, and the back of healing is relatively poor, and it is popular B-mode closely related with infection with hepatitis C virus with China that development takes place for it.Because hepatocyte had been subjected to grievous injury when hepatocarcinoma took place, and caused treatment means very limited.Still do not have so far and formally get permission effective medicine.Treatment such as existing cancer treatment drug amycin, fluorouracil effective percentage is low excessively, and does not have obvious life prolongation effect.Cervical cancer accounts for 2% of malignant tumor, belongs to the higher gynecologic malignant tumor of sickness rate.At present, because the limitation of single therapy means, the treatment of cervical cancer is to be main means with operation, radiotherapy, chemotherapy.Cisplatin class (as carboplatin) commonly used, fluorouracil (as capecitabine) have certain curative effect, but have apparent in view toxic and side effects as chemotherapeutics.The research and development newtype drug, efficacy enhancing and toxicity reducing is the long-term and arduous work of tumor chemotherapeutic drug. Teniposide is a kind of cell toxicity medicament of period specific, its mechanism of action is a DNA topoisomerase II specific inhibitor, clinical central nervous system's malignant tumor neuroblastoma that is used for, glioma and astrocytoma and metastatic tumor, and malignant lymphoma, the treatment of acute lymphoblastic leukemia.Teniposide is a micromolecular compound, and molecular weight is 656.6, and fat-soluble extremely strong, the logarithm value log of profit partition coefficient P 10P is 1.96, is its key property that is easy to see through blood brain barrier treatment brain cell tumor. The report of artemisine compounds to the cytotoxic activity of Ehrlich ascites cells just arranged in 1993: mtt assay records the half toxic concentration IC of arteannuin 50Be 29.8 μ M, the IC of chemical compounds such as dihydroarteannuin, artesunate, Artemether and arteether 50Then be 12.2-19.9 μ M[Woerdenbag H.J.et al.Cytotoxicity of artemisinin-related endoperoxidesto Ehrlich ascites tumor cells.J.Nat.Prod.1993; 56:849-56].Other has bibliographical information, and dihydroarteannuin (having another name called dihydroartemisinine) has very strong inhibitory action to human breast carcinoma MCF-7 cell, utilizes srb assay to record IC 50Being 0.26 μ M, suppressing one of mechanism of MCF-7 cell proliferation, is that cell is trapped in the G0+G1 phase; Arteannuin only has faint inhibitory action to the MCF-7 cell proliferation, but artesunate has significant inhibitory effect.Utilize srb assay to record the half-inhibition concentration IC of artesunate to MCF-7 cell proliferation 50Be 0.31 μ M, the apoptosis that causes at 1 μ M and directly cytotoxicity obviously be better than the effect [Lin Fang of 10 μ M arteannuin, Deng. (1) dihydroartemisinine is to human breast carcinoma MCF-7 cells in vitro inhibitory action. Chinese Journal of New Drugs 2002,11:934-936; (2) arteannuin and artesunate are to the comparative study of human breast carcinoma MCF-7 cells in vitro inhibitory action. Chinese herbal medicine 2003,34:347-349].Research is also found, through artesunate or dihydroarteannuin interaction in vitro 48 hours, four kinds of growth of tumour cell such as s, uterus choriocarcinoma jar cell, embryo muscular tumor RD cell, ovarian cancer HO-8910 cell are subjected to remarkable inhibition, the half-inhibition concentration IC that records with mtt assay 50Be respectively 15.4-49.7 μ M (artesunate) or 8.5-32.9 μ M (dihydroarteannuin) (Chen H.H., et al.Inhibition of human cancer cellline growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives invitro.Pharmacol Res 2003; 48:231-236).The derivant that arteannuin is described is potential antitumor drug. The derivant of arteannuin, arteannuin, dihydroarteannuin, Artemether, arteether and artesunate particularly have been developed to into medicine, no matter be oral formulations, or injection and suppository, all proved the current specific drug that is used for the treatment of malaria by pharmacology and clinical research.But this class medicine also has the characteristic of two aspects---fat-soluble and safety fully is not applied to the research and development of antineoplastic combined medicament as yet.The characteristics of first aspect are, artemisinin derivative belongs to micromolecular compound and has strong especially fat-soluble.For example, the molecular weight of arteannuin, dihydroarteannuin and Artemether is 282.3,284.3,298.4 successively, the logarithm value log of profit partition coefficient P 10P is 1.68,1.78 and 2.24 successively, guarantees to make it can pass through blood brain barrier smoothly, enters the central nervous system brain cell of unifying by blood circulation, helps it to suppress the growth of brain tumor cell, becomes one of a limited number of anti-cerebral tumor medicines.The characteristics of second aspect are, no matter the use of the derivant medicine of the arteannuin that the present invention relates at cellular level, still comprises the clinical patients treatment level in whole animal; No matter be according to the administration of malaria treatment standard or according to the treatment of cancer code requirement, under employed treatment consumption, all be proved to be good drug safety: toxic and side effects is all much smaller more than toxicity and toxic and side effects that conventional anti-tumor chemotherapeutic medicine brings.Therefore, derivant at the proof arteannuin has antitumor action, and can produce under drug effect addition or the synergistic situation of drug effect during with certain conventional chemotherapy of tumors medicine coupling, illustrate that with regard to having reason the two antineoplaston that share this routine chemotherapy of tumors medicine has potentiation or Attenuation, perhaps have the more satisfactory effect of not only potentiation but also attenuation.The research document of publishing has illustrated that the derivant of arteannuin is potential antitumor drug.The derivant of the said arteannuin of the present invention, promptly arteannuin, dihydroarteannuin, Artemether, arteether and artesunate be because all have sesquiterpene parent nucleus identical with arteannuin and peroxide bridge basic structure, and antitumor action is in various degree all arranged. Summary of the invention The object of the present invention is to provide a kind of antineoplastic combined medicament with enhancing and poison-reducing character.This composition of medicine is made up of a kind of derivant of teniposide and arteannuin, not only have the antineoplastic of enhancing effect, and it can also reduce the murder by poisoning of medicine to human body. The technical solution adopted in the present invention is: A kind of antineoplastic combined medicament with enhancing and poison-reducing character, it is made up of as active component a kind of derivant of teniposide and arteannuin, a kind of derivant that contains teniposide and arteannuin in pharmaceutical preparation simultaneously is as anti-tumor active ingredient, wherein the quality of teniposide accounts for the 1%-99% of mass fraction, preferred 10%-50%; The quality of a kind of derivant of arteannuin accounts for the 1%-99% of mass fraction, preferred 50%-90%.A kind of derivant of arteannuin is a kind of in arteannuin, dihydroarteannuin, Artemether, arteether and the artesunate; The preferred dihydroarteannuin that uses.A kind of derivant of active constituents of medicine teniposide and arteannuin is made pharmaceutical preparation. In the pharmaceutical preparation of antitumor combination medicine, a kind of derivant that contains teniposide and arteannuin at least simultaneously that is to say as anti-tumor active ingredient, can also contain other anti-tumor active ingredients. The present invention also discloses this anti-tumor compositions, and to be used to prepare malignant tumor be cancer, particularly the purposes of glioma brain tumour, hepatocarcinoma and cervical cancer medicine. As active component, can make pharmaceutically acceptable dosage form with antineoplastic combined medicament disclosed by the invention, comprise injection, tablet, capsule, granule, slow releasing preparation, controlled release preparation and nanometer formulation, be applied to clinical. The derivant that the present inventor has confirmed arteannuin has remarkable inhibitory action to the growth of kinds of tumor cells such as cervical cancer, glioma brain tumour, hepatocarcinoma, pulmonary carcinoma and breast carcinoma, and this is an important prerequisite condition of the present invention. The derivant and the antineoplastic agent teniposide of arteannuin are united use, can on some tumor cells, produce the effect of inhibitory action " addition " and " working in coordination with ". Different types of tumors, the generation development mechanism and the influence factor of its tumor cell there are differences, and the sensitivity of medicine also be there are differences.The invention discloses the antineoplastic combined medicament of forming by the derivant such as the dihydroarteannuin of teniposide and arteannuin, preferred development becomes the particularly pharmaceutical preparation of glioma and liver cell tumor of treatment cervical cancer, the cerebral tumor, is suitable for showing in treatment the efficacy enhancing and toxicity reducing effect most.Artemether, arteether and artesunate all pass through metabolism in the humans and animals body and biotransformation forms dihydroarteannuin, therefore, the said antineoplastic combined medicament of the present invention is meant the medicine that any one derivant in teniposide and arteannuin, dihydroarteannuin, Artemether, arteether and the artesunate is formed. The present invention has following advantage with respect to prior art: the antineoplastic combined medicament of being made up of the derivant of teniposide and arteannuin has the efficacy enhancing and toxicity reducing effect when suppressing growth of tumour cell; Can be used to make malignant tumor is cancer, particularly the medicine of glioma brain tumour, hepatocarcinoma and cervical cancer. The specific embodiment Below in conjunction with embodiment the present invention is done further to describe in detail, it should be understood that these embodiment only are used for illustrating the present invention, do not limit the scope of the invention. Embodiment 1 tumor cell kind and cell culture processes thereof Cell strain and cell culture: test used cell and comprise s, glioma brain tumour SWO-38 cell, hepatocarcinoma HepG2 cell, pulmonary carcinoma LAC cell and breast carcinoma MCF-7 cell.The condition of culture of all cells is as follows: (37 ℃, saturated humidity, CO in carbon dioxide cell incubator 2Content 5%), grow in and contain in 10% hyclone and the antibiotic RPMI-1640 culture fluid of 100U/mL.Per 3 to 4 days passages once. Embodiment 2 dihydroarteannuins and teniposide are to the inhibitory action of growth of tumour cell Drug effect: collect the cell that is in exponential phase, in culture fluid, be dispersed into every milliliter and contain 5 * 10 4The individual cells suspension of cell.Cell suspension is inoculated in 96 porocyte culture plates by every hole 100 microlitres, cultivates 24 hours in carbon dioxide cell incubator.Discard original culture fluid, add culture fluid 100 microlitres that contain medicine to be tested, continue to cultivate 72 hours, observe the effect of medicine cell growth by per 3 Kong Weiyi detectable concentrations.Establish culture fluid blank and the not cell contrast of dosing processing in the experiment in addition.Measure the half-inhibition concentration of medicine cell growth with mtt assay. Used mtt assay basic operation: after 68 hours, it is MTT solution 10 microlitres of 5 mg/ml that every hole adds concentration to the cell in 96 orifice plates through drug treating, and reaction is 4 hours in carbon dioxide cell incubator.Take out 96 porocyte culture plates, careful sucking-off culture fluid discards, in the hole residual pigementation with 150 microlitre dmso solutions after, measure optical density value in 490 nanometers with microplate reader.This moment, the optical density value in every hole was directly proportional with living cells quantity. Cell survival rate (%)=(the blank group of experimental port optical density value-cultivation optical density value)/(the blank group of cell matched group optical density value-culture fluid optical density value) * 100% The half-inhibition concentration IC of medicine cell growth 50Be that cell survival rate is 50% o'clock a drug level. The result is as shown in Table 1 and Table 2: Table 1 dihydroarteannuin is to the inhibitory action of growth of tumour cell * *Cell growth inhibition test is triplicate at least, and the result is with meansigma methods (x) ± standard deviation (SD) expression; With solvent and culture fluid as the medicine blank.IC 50: half-inhibition concentration (μ M) Table 2 teniposide is to the inhibitory action of growth of tumour cell * *Cell growth inhibition test is triplicate at least, and the result is with meansigma methods (x) ± standard deviation (SD) expression; With solvent and culture fluid as the medicine blank.IC 50: half-inhibition concentration (μ M) Synergism or potentiation that embodiment 3 dihydroarteannuin coupling teniposides have when suppressing some growth of tumour cell Experimentation is the same.The results are shown in Table 3: Table 3 dihydroarteannuin (A) suppresses working in coordination with or potentiation of growth of tumour cell with teniposide (B) * *Cell growth inhibition test is triplicate at least, and the result is with meansigma methods (x) ± standard deviation (SD) expression; With solvent and culture fluid as the medicine blank.IC 50: half-inhibition concentration (μ M) Experimental result shows: the first, and with accounting for IC 509.4% dihydroarteannuin of quantity adds to account for IC 5030% teniposide of quantity can produce half and suppress effect (curative effect addition or synergism) to the growth of s; With accounting for IC 503% dihydroarteannuin of quantity adds to account for IC 5035% teniposide of quantity can produce half and suppress effect (curative effect synergism) to the growth of glioma brain tumour SWO-38 cell; With accounting for IC 5015.7% dihydroarteannuin of quantity adds to account for IC 504.7% teniposide of quantity can produce half and suppress effect (curative effect synergism) to the growth of hepatocarcinoma HepG2 cell.The second, in the chemotherapy practice, when using artemisinin derivative, the dose that suitably reduces teniposide also can obtain needed antitumous effect, has so also just reduced the toxic and side effects that is caused by teniposide. 1. an antineoplastic combined medicament is characterized in that: the antineoplastic combined medicament that contains a kind of derivant of teniposide and arteannuin. 2. antineoplastic combined medicament according to claim 1 is characterized in that: a kind of derivant that contains teniposide and arteannuin is as anti-tumor active ingredient. 3. antineoplastic combined medicament according to claim 1 and 2 is characterized in that: a kind of derivant of described active component arteannuin is meant a kind of in arteannuin, dihydroarteannuin, Artemether, arteether and the artesunate preferably uses dihydroarteannuin. 4. according to any described antineoplastic combined medicament of claim 1-3, it is characterized in that: in described active component, the quality of teniposide accounts for the 1%-99% of mass fraction, preferred 10%-50%; The quality of a kind of derivant of arteannuin accounts for the 1%-99% of mass fraction, preferred 50%-90%. 5. according to any described antineoplastic combined medicament of claim 1-4, it is characterized in that: a kind of derivant of active constituents of medicine teniposide and arteannuin is made pharmaceutical preparation. 6. antineoplastic combined medicament according to claim 5 is characterized in that: in pharmaceutical preparation, a kind of derivant that contains teniposide and arteannuin at least simultaneously is as anti-tumor active ingredient. 7. according to any described antineoplastic combined medicament of claim 1-6, it is characterized in that: being used to prepare malignant tumor is cancer, particularly glioma brain tumour, hepatocarcinoma and cervical cancer medicine. 8. according to any described antineoplastic combined medicament of claim 1-6, it is characterized in that: described medicine is made into pharmaceutically acceptable dosage form, comprises injection, tablet, capsule, granule, slow releasing preparation, controlled release preparation and nanometer formulation.

CN101282722A使用青蒿素及其衍生物治疗和预防良性色素痣（痣）---所述制剂对治疗痣细胞痣最适，对黑素细胞痣特别有效，从而也可用于预防皮肤癌 用青蒿素及其衍生物治疗和预防良性色素斑（痣） 皮肤良性色素痣或脚癣或甲真菌病可用局部给药的、特别是式(I)的局部用配方活性成分来治疗，式中X代表CO、CHOZ或CHNRZ，Z选自氢、直链或支链(C1－C6)烷基、直链或支链(C2－C6)烯基、直链或支链(C2－C6)炔基、(C3－C8)环烷基、(C6－C24)芳基、(C7－C24)芳烷基、间－CH2(C6H4)COOM和对－CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O－蒿素基；SO2NH－蒿素基；POR4R5和PSR4R5；R3代表直链或支链(C1－C6)烷基、直链或支链(C1－C6)烷氧基；直链或支链(C2－C6)烯基；直链或支链(C2－C6)炔基；(C3－C8)环烷基；(C6－C24)芳基；(C6－C10)芳氧基；(C7－C24)芳烷基；－(CH2)n－COOM，其中n代表1和6之间的整数；或者10α－二氢蒿素基；R4和R5单独选自直链或支链(C1－C6)烷基；直链或支链(C2－C6)烯基；直链或支链(C2－C6)炔基；(C3－C8)环烷基；(C6－C24)芳基；(C7－C24)芳烷基；OM；直链或支链(C1－C6)烷氧基；(C6－C10)芳氧基以及NR7R8；R6选自直链或支链(C1－C6)烷基；直链或支链(C2－C6)烯基；直链或支链(C2－C6)炔基；(C3－C8)环烷基；(C6－C24)芳基和(C7－C24)芳烷基；M代表氢或药学可接受的阳离子；而R7和R8各自代表氢或直链或支链(C1－C6)烷基，或者R7和R8共同形成亚烃基桥键(C4－C6)；同时R选自氢和对R6所举的那些基团。所述化合物对预防后天痣细胞痣也有效。 用青蒿素及其衍生物治疗和预防良性色素斑（痣） 本发明涉及局部给药特别是用局部用配方治疗皮肤和黏膜上良性色素斑(痣)；特别是痣细胞色素痣、着色斑病和黏膜色素斑的治疗。此外，本发明还涉及适宜于此种治疗的局部用配方。 术语痣细胞痣指的是各种微观组织上由所谓痣细胞构成的良性皮肤病变，色素痣(胎痣、肝色痣)。痣细胞是正常色素带有缺陷形成的细胞，即黑素细胞。几乎每个人身上都会出现不同数目、不同大小和不同颜色强度的黑素细胞痣。痣的外表现型可以是很不相同的。它可为与皮肤齐平面的或者高于皮肤平面的色素痣(球形、有蒂或者平放在皮肤上的)点状也如大平面的、疣状的、隆起的或者光滑的，而着色则从肤色经褐色至黑色。后天性黑素细胞痣的数目随生命过程而增加。具有奇特结构的痣细胞色素痣，有高恶变的危险，并被称为发育异常的或者非典型的痣细胞色素痣。 由痣细胞色素痣也许会发展成恶性黑素瘤，也即黑皮肤癌。在60％以上的情况下，它由痣细胞色素痣形成。在近几十年中，人们注意到，黑素瘤发病率明显上升。1960年在美国寿命风险约1∶600，而当今人们观察到寿命风险为1∶100。因此，举例来说，根据Prof.Dr.Matthias Volkenandt(Klinikfür Dermatologie und Allergologie der Ludwig-Maximilians- München，Frauenlobstrasse 9，80337München)所说，黑素瘤在巴伐利亚州地区的发病率为每100000个居民每年约14(也即14个新病例)。这相当于寿命风险约1％(每100个居民在一生中有一个患黑素瘤)。就这个数字来说，黑素瘤并不是人类最频繁发生的肿瘤，不过，按照Volkenandt所述，发病率上升之高，没有别的肿瘤与之相提并论。 按照现今的知识状况，还没有克服痣细胞色素痣变质的预防性诊治和疗法。具有高危险的痣的变质首先要手术切除。早些时候，激光处理在美容方面，发挥作用。所有两种方法都是侵入性的、带有一定风险(瘢痕形成、皮肤变色等)并且与高费用相联系。 后天性痣的出现，总是一种小的、有时候小得用显微镜才能看见的红小点(出血或血管瘤)。从这种痣最初阶段开始，往往发展成较大的红色、有点隆起的斑点。然后，从这些痣最初阶段起始，形成大小、棕褐色度和结构不同的褐色痣细胞色素痣。 青蒿素(也称Qinghaosu)是一种具有过氧化物基团的倍半萜烯内酯，迄今为止它主要作为对全身起作用的抗疟疾剂来研究和使用。青蒿素很难溶于水；但是青蒿素的水溶性衍生物已被研制出来。在EP-A-0 428 773中，记叙了全身性或局部应用青蒿素及其衍生物来治疗牛皮癣、病毒性疾病(疣、触染性软疣和羊痘)、紫外线诱发的疾病(多形的光致皮肤病、“胶原质脉管疾病”、恶化前的角化病( Keratosen)、癌前期皮炎、恶性小痣、基底细胞癌、颞鳞小房癌和恶性黑素瘤)、起疱性皮肤病和痔。 本发明的目的是提供局部起作用的、但优选局部用药的配方制剂，该制剂对治疗良性色素痣，特别是对黑素细胞痣有效，因而也可用来预防皮肤癌。 按本发明，该发明目的得以实现的方法是，用选自式(I)的一类化合物来制备局部应用的，特别是局部给药的配方制剂来治疗良性色素痣： 在该式(I)中，X为CO、CHOZ或CHNRZ，其中Z选自： 氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM和对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5； 其中R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)nCOOM，其中n为1至6的整数；或者为10α-二氢蒿素基； R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8； R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基； M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或者直链或支链(C1-C6)烷基，或者R7和R8共同构成一个(C4-C6)亚烷基桥键；以及 R选自氢和对R6所列举的基团。 现已意外发现，用上述生物活性物质，特别是用局部(例如在皮肤上)用药的配制品处理可以很早成功治疗皮肤色素痣，特别是那些起源于黑素细胞的色素痣。也曾发现，经用式(I)化合物治疗痣细胞色素痣，还可能预防皮肤癌(特别是基底细胞瘤或者黑素瘤)。此外，还发现，这种活性物质在局部应用的情况下，在预防良性色素斑方面，特别是预防后天性痣细胞色素痣方面也是有效的。 在本专利申请范围内，“良性色素痣”特别理解成： -痣，特别是痣细胞色素痣(普通的或者发育异常的；痣细胞色素痣也常被称为黑素细胞痣)；其下按发生位置可分三个小类，即交界痣细胞色素痣(界层表皮/真皮)、混合痣细胞色素痣(真皮结缔组织)以及真皮痣细胞色素痣(真皮深层)，并按发生时机可区别的小类为先天性痣细胞色素痣(＝胎痣)和后天性痣细胞色素痣。后天性痣细胞色素痣的一个小类是复发痣，它是在外科切除一种其他良性母斑后形成的。先天性交界痣细胞色素痣的一个例子是斑痣，后天性交界痣细胞色素痣或者混合痣细胞色素痣的一个实例是乳晕痣(萨顿氏痣)；而后天性黑素细胞交界痣细胞色素痣、混合痣细胞色素痣或者真皮痣细胞色素痣的例子则是Spitz痣和里德氏痣。先天性真皮痣细胞色素痣的一个例子是mongolenfleck(＝Naevus Bleu)，而先天性交界痣细胞色素痣、混合痣细胞色素痣或者真皮的痣细胞色素痣的一个例子则是先天性Riesenpigmentnaevus(Naevus giganteus)； -着色斑病(例如肝色痣＝Lentigo simplex、Sonnenflecken＝Lentigosolaris、老年斑＝Lentigo senilis、PUVA-Lentigines)； -黑色素沉着紊乱(例如雀斑＝ephelides)；以及 -黏膜色素痣(例如眼结膜痣、唇痣、口腔黏膜痣及性器官痣)。 式(I)化合物在诊治所有上述良性色素痣方面，特别是后天性或者先天性痣细胞色素痣方面是有效的。上述这些痣中，发育异常的(非典型的)痣细胞色素痣具有变质成皮肤癌的高可能性，因此，为了预防皮肤癌，优选用式(I)化合物来治疗痣。 (C1-C6)烷基优选是甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、仲戊基、新戊基、正己基、仲己基以及新己基。更为优选的是直链(C1-C3)烷基，而特别优选的是甲基或者乙基。直链或者支链(C2-C6)烯基优选的是(C2-C4)烯基，例如乙烯基、烯丙基、1-甲基乙烯基、2-甲基乙烯基、丁-1-烯-1-基、丁-2-烯-1-基、丁-3-烯-1-基、丁-1-烯-2-基、丁-2-烯-2-基、丁-3-烯-2-基、2，2-二甲基乙烯基和1，2-二甲基乙烯基。直链或支链(C2-C6)炔基优选的是乙炔基、炔丙基、丙-1-炔-1-基、丁-1-炔-1-基、丁-2-炔-1-基、丁-3-炔-1-基、丁-3-炔-2-基、3-甲基丁-1-炔-1-基、3，3-二甲基丁-1-炔-1-基、1，1-二甲基丁-2-炔-1-基和1，1-二甲基丙-2-炔-1-基。(C3-C8)环烷基优选的是环丙基、环丁基、环戊基和环己基。(C6-C24)芳基优选的是(C6-C10)芳基，例如苯基、萘-1-基和萘-2-基。(C7-C24)芳烷基优选的是(C7-C12)芳烷基，例如苯甲基、苯乙基、(萘-1-基)甲基和(萘-2-基)甲基。(C1-C6)烷氧基中的烷基，是上面对(C1-C6)烷基举例说明的同样基团。优选的是(C1-C3)烷氧基、而更为优选的则是甲氧基、乙氧基或者正丙氧基。(C6-C10)芳氧基中的芳基，是上面对(C6-C24)芳基举例说明的同样基团。更为优选的是苯氧基或者α-萘氧基或β-萘氧基。 在本申请范围内，术语“蒿素基”表示一个具有X＝CH-的式(I)所示的基团，该基团可通过碳的自由价连到氧或氮上。在本申请范围内，术语“10-α-二氢蒿素基”意指-O-蒿素基，其中蒿素基的含义同前所述。 式(I)中，Z优选为氢；直链或支链(C1-C6)烷基；间-CH2(C6H4)COOM和对-CH2(C6H4)COOM；COR3；SOR4；SO2OM；SO2NR7R8；SO2NH-蒿素基和POR4R5。 就符合制药学要求的作为M的阳离子而言，可提及的是，示例性的碱金属阳离子如锂、钠或者钾的阳离子，碱土金属阳离子如镁及钙的阳离子，铵以及H+N(RXRYRZ)，其中Rx、Ry、Rz各自可单独为甲基或者乙基。 当R3是直链或支链(C1-C6)烷基、直链或支链(C1-C6)烷氧基、-(CH2)n-COOM或者蒿素基时，Z优选为COR3。此时特别是，M优选为氢、钠、钾或铵。 当M是碱金属、碱土金属或铵时，Z优选为SO2OM。 当R4和R5选自OM和直链或支链(C1-C6)烷氧基时，Z优选为POR4R5。更为优选的是，R4和R5中之一为OM，其中M特别是钠、钾或铵，以及是其他的直链或支链(C1-C6)烷氧基或者OH。 式(I)所示的化合物已为人所知，或者可制成类似于式(I)所示的已知化合物。在此情况下，X＝CO的这个化合物是青蒿素，而X＝CHOH的化合物是二氢青蒿素。X＝CHOZ且Z不同于氢的化合物，或者X＝CHNRZ的化合物，以下称之为“二氢青蒿素的衍生物”。 式(I)所示的化合物可以如下方法制得： -青蒿素(X＝CO)可如已知的那样，从植物黄花蒿(ArtemisiaAnnua)植物中分离出来。 -二氢青蒿素(X＝CHOH)是已知的，并可例如在约0℃下，使青蒿素在甲醇中用硼氢化钠还原来制备。 -X＝CHOZ的二氢青蒿素的衍生物，其中Z为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基，可用二氢青蒿素通过以下方法来制备：首先使二氢青蒿素用氯化三甲硅转化成二氢青蒿素的三甲基甲硅烷基醚，使三甲基甲硅烷氧基同溴化三甲硅交换溴(按照US-A-2005/0119232的实施例1)，然后在碱存在下，使溴原子再按所要求使用过量HOZ进行取代，其中Z的含义已予说明。在这些衍生物之中，蒿甲醚(Z＝Me)和蒿乙醚(Z＝Et)是已知的化合物。 -X＝CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明，Z＝氢、直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基者，可用二氢青蒿素通过以下方法来制备：首先使二氢青蒿素用氯化三甲硅转化成二氢青蒿素的三甲基甲硅烷基醚，使三甲基甲硅烷氧基同溴化三甲硅交换溴(按照US-A-2005/0119232的实施例1)，然后在碱存在下，使溴原子再按所要求使用过量的胺HNRZ进行取代，其中R和Z的含义已予说明。 -X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明，而Z＝间-CH2(C6H4)COOM或者对-CH2(C6H4)COOM(M的定义正如在式(I)中所指出)，可由二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物作原料来制取，其方法是，在碱存在下，用间-溴代甲基苯甲酸甲酯或者对-溴代甲基苯甲酸甲酯使所述原料烷基化、继而使甲基酯水解，并当M不应为氢时形成相宜的盐。在这些衍生物之中，X＝CHOZ和Z＝对-CH2(C6H4)COOH的衍生物已知为“蒿酸” -X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝COR3或CSR3以及R3为直链或支链(C1-C6)烷氧基或者(C6-C10)芳氧基，可以通过二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物与适宜的氯代羧酸(C1-C6)烷基酯或者氯代羧酸(C6-C10)芳基酯或者氯硫代羧酸(C1-C6)烷基酯或氯硫代羧酸(C6-C10)芳基酯和一种碱来制备。 -X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝COR3以及R3为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基；(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基；可以通过二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物与酰基氯和碱的反应来制备，其中酰基氯与适宜的R3进行取代。 -X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝CSR3以及R3为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基；(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基；可以通过Z＝COR3的上述相应衍生物与Lawesson′s试剂发生反应来制取。 -X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)中已予说明，Z＝COR3和R3-(CH2)n-COOM(其中M的含义已在式(I)中作了说明)，可以通过二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物与环状酸酐反应(当n＝2或者3时)或者与MeOOC(CH2)n-COOMe反应来制取。在后一种情况下，X＝CHOZ时，也可一起加入碱性催化剂如NEt3，而且酯交换反应时释出的甲醇可例如通过减压蒸浓从平衡状态中抽出。当M不是氢时，可以形成相应的盐，其方法是：使残留的甲酯基裂解，例如用M氰化物。在这些衍生物之中，X＝CHOZ、n＝2和M＝氢的已知为“青蒿酯”。 -X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝CSR3和R3-(CH2)n-COOM(其中M的含义在式(I)中已予说明)是可制得的，其方法是：用Lawesson′s试剂使MeOOC(CH2)n-COOMe中的一个或两个羰基氧被硫替代，并使所得半硫代二酯与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物进行反应，继而使其仍为游离的COOMe基团水解成COOH，并当M不是氢时形成相应的盐。 -可以制得X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝C(NR6)R3(其中R6的含义在式(I)中已予说明)以及R3为直链或支链(C1-C6)烷氧基或者(C6-C10)芳氧基，其方法是：使R6含义已如上说明的异氰酸酯R6-NCO与相应(C1-C6)醇或者(C6-C10)芳醇进行反应，并使这样得到的氨基甲酸乙酯与POCl3反应，然后在碱存在下与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物进行反应。 -可以制得X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝C(NR6)R3(其中R6的含义在式(I)中已予说明)以及R3为直链或支链(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基；(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基，其方法是：使R6含义已如上说明的异氰酸酯R6-NCO与相应格氏试剂R3MgBr进行反应，其中R3的含义已予说明，并使这样得到的酰胺与POCl3进行反应，然后在碱存在下，与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物进行反应。 -X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)中已予说明、Z＝C(NR6)R3和R3-(CH2)n-COOM(其中M和R6的含义在式(I)中已予说明)可用这样的方法来制取：使n和R6的含义已如上说明的化合物MeOOC-(CH2)n-CONHR6与POCl3进行反应，然后与二氢青蒿素或X＝CHNRH的二氢青蒿素衍生物在碱存在下进行反应，并使甲基酯进行水解，并且如果M不是氢，则形成相宜的盐。 -具有Z＝SOR4和R4＝OMe的X＝CHOZ或CHNRZ的二氢青蒿素衍生物(其中R的含义在式(I)中已予说明)可有选择地在碱性催化剂存在下，通过二氢青蒿素与过量亚硫酸二甲酯(DRP 487253)的反应，馏除释出的甲醇，并接着减压馏除过剩的亚硫酸二甲酯来制取。 -X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)已予说明，且Z＝SOR4(其中R4为直链或支链(C1-C6)烷氧基或者(C6-C10)芳氧基)，可以通过X＝CHOH或者CHNRH的相应衍生物与过量亚硫酰(二)氯和适宜的碱如吡啶进行反应，除掉过量亚硫酰(二)氯，并接着使得到的亚硫酸衍生物与相应直链或者支链(C1-C6)醇或者(C6-C10)芳醇在适宜的碱如吡啶存在下进行反应而制得。-X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中R的含义在式(I)已予说明，且Z＝SOR4(其中R4为(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基)，可以通过格氏试剂R4MgBr(其中R4的含义已予说明)与过量亚硫酰(二)氯反应，除掉过量亚硫酰(二)氯，并接着使得到的R4-SOCl与X＝CHOH或者CHNRH的相应二氢青蒿素衍生物在适宜的碱如吡啶存在下进行反应而制得。 -X＝CHOZ或CHNRZ的二氢青蒿素衍生物，其中R的含义在式(I)已予说明，且Z＝SOR4(其中R4为NR7R8、R7和R8的含义在式(I)中已予说明)，可以通过胺HNR7R8与过量亚硫酰(二)氯进行反应，除掉过量亚硫酰(二)氯，并接着使所得的RR7R8NSOCl与X＝CHOH或者CHNRH的相应二氢青蒿素衍生物在适宜的碱如吡啶存在下进行反应而制得。 -X＝CHOZ或CHNRZ的二氢青蒿素的衍生物，其中Z＝SO2OM(M的含义在式(I)中已予说明)，可以通过X＝CHOH或CHNRH的相应衍生物与吡啶-三氧化硫-络合物进行反应，并将所得磺酸盐的吡啶鎓抗衡离子交换成M而制得。 -X＝CHOZ或CNHRZ的二氢青蒿素的衍生物，其中Z＝SO2NR7R8，而且R、R7和R8的含义在式(I)中已予说明，可以通过X＝CHOH或CHNRH的二氢青蒿素衍生物与与1eq.硫酰氯在碱如吡啶存在下进行反应，并接着在碱如吡啶存在下与1eq.胺HNR7R8(其中R7和R8的含义已予说明)进行反应而制得。 -X＝CHOZ且Z＝SO2O-蒿素基的二氢青蒿素衍生物，可通过2eq.二氢青蒿素与1eq.硫酰氯在碱如吡啶存在下进行反应而制得。 -X＝CHOZ且Z＝SO2NH-蒿素基的二氢青蒿素衍生物，可在碱如吡啶存在下，通过二氢青蒿素与1eq.硫酰氯进行反应，并接着在碱如吡啶存在下，与1eq X＝CHNH2的青蒿素衍生物进行反应而制得。这样得到的衍生物与X＝CHNHZ且Z＝SO2O-蒿素基的衍生物是同一种衍生物。而后，由如此所得的衍生物可以通过对磺氨基氮上进行脱质子化，并用烷基溴RBr(其中R的含义已予说明)进行烷基化，来制备X＝CHNRZ、其中R的含义在式(I)已予说明(但除氢以外)的二氢青蒿素衍生物。 -X＝CHNHZ且Z＝SO2NH-蒿素基的二氢青蒿素的衍生物，可以按照US-A-2005/0119232中的实施例2来制备。由该衍生物又可通过脱除两个磺氨基氮中一个上的质子，并用烷基溴RBr(其中R的含义已予说明)进行烷基化，来制备X＝CHNRZ、其中R的含义在式(I)已予说明(但除氢以外)的二氢青蒿素衍生物。 -可以制得X＝CHOZ或CNHRZ、其中Z＝POR4R5或者PSR4R5(R、R4和R5的含义在式(I)中已予说明)的二氢青蒿素衍生物，其方法是：首先使二氢青蒿素或者X＝CHNRH的二氢青蒿素衍生物与与过量POCl3(或PSCl3)进行反应，并馏除过量POCl3(或PSCl3)。向所得X＝CHOPOCl2(或CHOPSCl2)或者CHNRPOCl2(或CHNRPSCl2)的粗产物中，视待引入基团R4和R5的种类而定，作为格氏试剂R4MgBr/R5MgBr(当R4及/或者R5应当为(C1-C6)烷基、直链或支链(C2-C6)烯基、直链或支链(C2-C6)炔基、(C3-C8)环烷基、(C6-C24)芳基或者(C7-C24)芳烷基时)的形式、以醇化物R4O-/R5O-的形式(当R4及/或R5应该为直链或支链(C2-C6)烷氧基或者(C6-C10)芳氧基时)、或者以胺HNR7R8的形式或者以水或氢氧化物的形式引入基团R4和R5；条件是这些试剂优选按亲核性增加的顺序添加，而且在至少是R4及/或R5OM中之一时、将对此必需的MOH是作为最后试剂添加。. 在X＝CHOZ或CHNRZ的化合物的情况下，碳原子(也即倍半萜烯构架上C10-原子)的构型可以是(R)或者(S)。式(I)所示的化合物也可以C10-差向异构体混合物的形式来使用，其中两种差向异构体的比例可以通过青蒿素的在前还原及/或通过C10-羟基对其他源自水的羟基或者对合成时所用亲核体进行置换来加以改变。 优选的是上述式(I)所示的那些活性物质，它们选自青蒿素、二氢青蒿素、含羧基的衍生物(特别是青蒿酯)、蒿甲醚(Artemeter)、蒿乙醚、二氢青蒿素的碳酸丙酯和蒿酸 特别优选的是青蒿素、二氢青蒿素和青蒿酯。 式(I)所示的化合物可以单独使用，或者以两种或多种这些化合物的组合形式来使用。 式(I)的化合物，特别是青蒿酯，对预防后天性痣细胞色素痣也有效。为预防痣细胞色素痣起见，将式(I)的化合物，特别是青蒿酯，大面积涂到整个皮肤上，涂到具有形成痣的高可能性的皮肤痛觉过敏带上，或者涂到已看得见的早期痣上。具有形成痣的高可能性的皮肤痛觉过敏带，一方面是频繁暴露于紫外线照射的皮肤局部。另一方面，这种皮肤痛觉过敏带，常存在于已形成痣细胞色素痣的周围(例如典型地以多达5cm的半径围绕已存在的痣)。此外，式(I)所示的化合物，特别是青蒿酯，还具有其他有利的特性，即它们显然已存在早期痣，但还如此微小使得凭裸眼几乎辨别不出。在式(I)所示化合物的作用下，这种仍辨认不清的早期痣首先形成小红点，数日之后变成深色至黑色，而且部分像深色、具有位于微孔中的结晶体。在一些有利的情况下，顶射显微镜检查法预先检查成问题的皮肤部位就成为不必要。 为应用起见，可将式(I)的活性物质配制成适于局部使用，特别是适于局部表面(皮肤)应用的配方制剂。所制配方制剂(配制品)中的活性物质浓度并不特别关键。以配方制剂的总重量计可以制备浓度约0.1％(重量)至约40％(重量)的配方制剂。为了治疗痣细胞色素痣(先天性＝胎痣，或者后天性)，以配方制剂的总重量计，配方制剂优选含有约5％(重量)至约20％(重量)的活性物质，特别优选含有约10％(重量)。为预防后天性痣细胞色素痣起见，以配方制剂的总重量计配方制剂优选含有至多约5％(重量)的式(I)所示化合物；更确切地说，优选含有约1％(重量)至约5％(重量)。生物活性物质的确切治疗所需量，取决于有效物质本身、所用的基料(Grundlage)、所制盖伦剂型(例如软膏、悬浮液、药膏、硬膏、乳膏剂、凝胶、溶液)以及所用的添加剂，而且可以由技术人员通过简单的效果试验来确定。 存在的痣细胞色素痣(先天性＝胎痣，或者后天性)的治疗时间取决于痣的种类、大小、结构、色素沉着以及年代。优选以高浓度的式(I)所示化合物进行周期性的治疗。第一疗程(Behandlungstagen)后，第一反应通常是明显的。直到明显好转或者变化，即表现出痣细胞色素痣逐渐退色或者消失，可以持续二至数月。就陈旧性患者而言，此时间段会更长一些，因为表皮更新随陈旧性增加而持续得更长一些。 就预防后天性痣细胞色素痣而言，应用2～3次即足矣。较大的早期痣最好治疗更长一些时间，直到早期痣逐渐退色或消失为止。 式(I)所示的活性物质应该视治疗措施(Therapieansatz)而定，不同程度地深深侵入皮肤： -就治疗痣细胞色素痣(先天性＝胎痣，或者后天性)而言，应视痣的类型及陈旧程度而定，活性物质优选进入上真皮。 -就预防后天性痣细胞色素痣而言，活性物质最好通过真皮直抵表皮及真皮间边界的交界区域。 对惰性的通常用于局部配方制剂的底料来说，作为式(I)活性物质的配方制剂底料适于所有这些活性物质。特别是用于局部配方制剂的这种底料：凡士林、脂肪、蜡、脂肪酸酯、石蜡、油、硅酮及其聚合物。优选是将活性物质和约60％(重量)至约99.9％(重量)，更优选与约％(重量)80至约95％(重量)以制成的配方制剂计的配方制剂底料一起进行配制。如果使用亲水/含水局部配方制剂底料如水凝胶、乳膏剂，则活性物质可借助纳米胶囊封装，包封在脂质体内(Einschluss in Liposomen)或者例如与环糊精形成络合物，来防止其分解。关于青蒿素及其衍生物与环糊精的络合，举例来说，请参见US-A-2005/187189。 按照德国药典，具有非水单相底料如无水纯脂肪相的局部配方制剂被称作软膏。其中使用了本发明式(I)活性物质的软膏，由这样一种软膏底料组成，该软膏底料可含有一种或多种细微分散的活性物质，以在皮肤上应用。 当该局部配方制剂应为软膏时，该配方制剂底料可优选由室温下具有正辛醇/水的分配系数约1至约105，更优选约10至约105，特别优选约50至约104的亲油组分组成。在此场合下，该配方制剂底料的例子是凡士林、脂肪、蜡、脂肪酸酯、石蜡、油、硅酮及其聚合物(例如聚二烷基硅氧烷、硅酮弹性体、硅酮-蜡、硅酮乳化剂)。 涂敷软膏时，式(I)活性物质从包围它的局部制剂底料中出来，并进入皮肤中。该亲脂性底料与皮肤粘附得非常牢固，并向外形成拒水层。此层同样还阻止了水分从皮肤向外逸出(阻碍作用)。由于这种作用，皮肤被保持湿润，并变得暖和，因为可以蒸发的水不多。由于湿度提高，皮肤也更具弹性，这促进了活性物质的吸收。 跟软膏相反，二相体系(水相和脂肪相)被命名为乳膏。式(I)所示的化合物也可配制成乳膏。就脂肪相而言，可以采用诸如上面对软膏底料举例说明的同一类物质。水相中除水之外也可有选择地含有各种能使皮肤耐受的水相pH的缓冲剂物质，或者也可含有已知的成凝胶聚合物如羟基丙基甲基纤维素、羧甲基纤维素、含有交联剂(例如硼砂或者诸如Mg2+或者Ca2+的多价金属阳离子)的聚乙烯醇以及以及类似物质。为了进行乳化，可以使用常用的皮肤耐受性表面活性物质，例如脂肪酸一甘油酯和脂肪酸二甘油酯、聚氧乙烯(40)氢化的蓖麻油(Cremophor )或者卵磷脂。 作为局部配方制剂的辅料，可以是常用的渗透促进剂(诸如二甲基乙酰胺、二甲基甲酰胺、丙二醇、脂肪醇、三乙醇胺、二甲亚砜、氮酮以及其他)、改进效果的角质层分离药(例如水杨酸、尿素、类维生素A)和防腐剂。添加剂一般用于改进盖伦剂型的效果、稳定性、持久性和坚度。 优选将式(I)所示的化合物配制成基本上不含增强渗透的材料的局部配方制剂。还优选配制式(I)所示的化合物，使之基本上不含(C5-C19)一元羧酸、其酯及其酰胺。在本专利申请范围内，“基本上不含”应理解为，局部配方制剂以配方制剂的总量计含有小于1％(重量)，优选小于0.1％(重量)的增渗材料。 用于糊剂、软膏、乳膏剂、溶液、凝胶、喷雾剂或者悬浮液的式(I)化合物，优选是所有含有一个羧基的衍生物，特别是青蒿酯。在此情况下，羧基可以有选择地以碱金属盐、碱土金属盐或铵盐的形式存在。 为在皮肤上应用或者应用到皮肤中，将式(I)活性物质以局部配方制剂形式、特别是以糊剂、软膏、悬浮液、溶液、凝胶、喷雾剂或者乳膏的形式、特别优选以软膏的形式、涂到硬膏(Pflaster)上。硬膏可以有选择地是一种吸收或吸入局部配方制剂的材料。活性物质当然也可直接悬浮于或者溶于硬膏的惰性粘合剂中；在类似于先前已知的硬膏中，例如用于东莨菪碱(例如“Scopoderm TTS”)或者用于雌二醇(例如“Estraderm TTS”)中的硬膏。以此方式，活性物质可直接并且在长时间内与待处理部位接触。另外还产生闭塞作用，该作用改进了活性物质的渗透。 式(I)活性物质的其他给药方式是糊剂、溶液、悬浮液、凝胶与乳膏剂以及喷雾剂。所列举活性物质的半固态或者液态配方，也可以栓(Stift)的形式(例如类似毡棒那样 以精确剂量)或者以卷(Roller)(在相宜的底料(Grundlage)、溶液、悬浮液、软膏、乳膏剂中含有活性物质)的形式存在。 其他局部的、可按本发明使用式(I)化合物的用药形式实例是涂药器，该涂药器借助超声波、借助电场或者借助微型针来促进式(I)化合物渗入皮肤或黏膜。使用超声波并按本发明可使用的先前已知的涂药器，例如在US-B6,908,448中已予公开，特此一并资作参考。使用电场投药活性物质(因此，其采用离子电渗疗法原理)的涂药器，久已为人所知。按本发明，它们适用于那些属盐类的式(I)活性物质，即如式中X为CHOZ或者CHNRZ，其中Z选自间-CH2(C6H4)COOM和对-CH2(C6H4)COOM、SO2OM和POR4R5，式中R4和R5中之一为OM，并为其他直链或支链的(C1-C6)烷氧基或OH，而M则为药学上可接受的阳离子。就用于将本发明活性物质局部投药到皮肤上的、带微型针的先前已知涂药器而言，请参阅US-A-2005/065463，该文件同样特此一并资作参考。 按本发明可以使用的局部投药方式的另一个实例是一项技术，其中借助吸盘将待处理部位的皮肤吸起，并在皮肤的提高部位上，将真皮的部分层厚用机械方式切除，例如用刀刃。部分切除真皮的皮肤部位，对式(I)所示化合物来说是渗透性的，并允许在这些部位上，进行深入真皮下层的局部治疗。为此必需的器械已描述于作为参考而包括在本申请内的WO-A-95/15783中。 用蒿素及其衍生物(二氢青蒿素，蒿乙醚，蒿甲醚，青蒿酯及其半合成衍生物和合成的类似化合物)进行一种少风险、非侵入的预防性或治疗性处理后天性痣细胞色素痣或者后天性或先天性痣细胞色素痣(＝胎痣)，是处理痣细胞色素痣中的一个巨大进步，并能有力减少皮癌危险。因此，本发明不仅在医学上而且在社会经济学上都具有巨大意义。在所记载的、用式(I)所示化合物，特别是青蒿酯进行的局部治疗中，未观察到该化合物对皮肤的变应性反应。值得注意的还有，健康组织不受损害，而且治疗是无痛、简易的。 鉴于迄今为止获得结果，可看出：用青蒿素及其衍生物进行的局部治疗(lokale Therapie)，特别是局部定位治疗(topische Therapie)非常有效，而且作为痣的预防和治疗，在更长时间内可注意到，比传统的介入性医治方法费用不大，而且风险更小。 现在以下面各实施例来进一步阐明本发明。 实施例1：局部配方制剂 将3g青蒿酯同27g Excipial 油脂的软膏均匀拌和。 实施例2a～8h：局部配方制剂 将不同量青蒿酯(见表1)加到不同底料中。有的也向配方制剂添加表面活性材料。 表1： 实施例编号 青蒿酯(g) 添加剂 底料足量，加至100g 2a～2h 2a：0.12b：0.52c：1.02d：5.02e：10.02f：15.02g：302h：40 - 白凡士林 3a～3h 3a：0.13b：0.53c：1.03d：5.03e：10.03f：15.03g：303h：40 聚山梨醇酯0.5g；聚乙二醇(2000)硬脂酸酯0.5g聚氧乙烯(40)失水山梨醇醚油酸酯0.5g 白凡士林 4a～4h 4a：0.14b：0.54c：1.04d：5.04e：10.04f：15.0 蜂蜡 4g：304h：40 5a～5h 5a：0.15b：0.55c：1.05d：5.05e：10.05f：15.05g：305h：40 大豆卵磷脂2g 石蜡 6a～6h 6a：0.16b：0.56c：1.06d：5.06e：10.06f：15.06g：306h：40 聚乙二醇(2000)硬脂酸酯2g 菜籽油 7a～7h 7a：0.17b：0.57c：1.07d：5.07e：10.07f：15.0 肉豆蔻酸异丙酯1g 十甲基环戊硅氧烷(19g)硅酮高弹体凝胶(加至100g) 8a～8h 8a：0.18b：0.58c：1.08d：5.08e：10.08f：15.0 十甲基环戊硅氧烷25g矿物油加至100g 实施例9a～9i：治疗或预防色素痣中的局部(皮肤)应用 a)一名13岁男孩，有深褐色隆起胎痣(发育异常的胸痣细胞痣)，结构不平整，直径约1.2厘米，用实施例2a的10％青蒿酯凡士林软膏每周治疗2～3次。2周后，胎痣为淡褐色，带有一对深色、小点状部位，看起来像“结晶出来的”染料。所述胎痣是干燥的并有鳞屑，看起来象从“内部”开始萎缩。 b)一名妇女，在皮肤表面有3个黑色隆起的胎痣(躯干交界痣)，直径为0.5至1.0cm，应用实施例2a的10％青蒿酯凡士林软膏，在闭塞的条件下(以硬膏形式)，每周3次过夜。一周后，在每一胎痣上，可辨认出深色部位。3周后，皮肤连同深色晶体样形成物一起脱落。留下三处浅色母斑，带有无色素部位，该部位不再突起于皮肤平面。继续治疗导致所处理部位皮肤上的母斑逐渐退色并成鳞片状脱落。 c)治疗2颗早期痣细胞痣，也即称为皮下淤血，皮肤部位隆起直径0.3～0.4cm：三次应用实施例2a的含10％青蒿酯软膏的硬膏过夜，两周后颜色发生变化，浅红色形成物带有深色小点。可将隆起的有变化皮肤部位揭下。留下两个小伤口，由于提前揭下，伤口痊愈了。 d)一名女受检者，有一颗痣直径约3～4cm(基底细胞癌)，用实施例1的10％青蒿酯软膏超过3月(周期性的，晚上，每隔2周)。该痣表示初期的(类似炎症过程的)发红。3个月后，可以看得出来萎缩(关于颜色和结构)约90％。约5个月后，该痣不再可见。 e)一名女性受检者，臂上有一颗痣(交界痣)，同样用实施例1的10％青蒿酯软膏。因为该女性受检者未注意观察，故而不能在此精确说明给药频繁程度；但给软膏持续数周以上。而今该痣勉强还能看得出来。 f)一名13岁男性受检者，在鼻根-眼区有一颗先天性痣，在闭塞(硬膏)的条件下，两个月内每周用实施例1的10％青蒿酯软膏2至3次。该痣有初期的许多深色小点。它反应得很慢。然而，最初的成功已经呈现。它总起来变浅许多，而且具有多个肤色的区域。 g)一名13岁女患者，有一颗真皮痣，3日内用实施例1的10％青蒿酯软膏。发生立即集中在痣中形成的3个深色部位，而且剩余范围几乎无色。 h)一名女性受检者，在已有大量痣细胞色素痣(交界痣)的腹部，大面积使用实施例1的10％青蒿酯软膏两次(每隔2天1次)。早在第2个治疗日，除了已经存在的痣之外，红色的、初期所述种类的部分早期痣，以细微小点形式可见，它们不均匀地分布在整个已处理的表面上。该早期痣本身是已有，但仅仅由于用软膏治疗而首次可见。2～3日后它们变为深色至黑色。在有些部分上，它们看来象深色、位于微孔中的晶体。在2～3周内，当用指甲在其上稍稍搔刮时，它们随同表皮角质层脱落或剥离。 i)一名女性受检者，用实施例1的软膏处理了其手背，手背上有一些大小不等的色素痣(肝色痣)。这些已有的痣和早期痣明显退色，并随着处理时间延长(7或者10天)逐渐消失。停止治疗后，色素痣颜色变浅。4周后，它们勉强还可见至不再可见。 实施例10：局部应用于甲真菌感染治疗 甲真菌侵袭中足趾和大足趾：半数大足趾的指甲遭侵害。用常规药物如Lamisil进行治疗，成效甚微。实施例2a的10％青蒿酯凡士林软膏每周用3～4次。该软膏主要应用于甲床和指甲下。2周后，早已可观察到明显好转。4周后，中足趾上的变色完全消失，或者不再变深。坏死的大足趾甲部剥落。其余指甲的治疗，更容易且更有效。活性物质无阻碍地达到健康甲部的交界部位。重新长出来的指甲是正常的，没有浅的色变。在真菌感染时，特别在指甲感染真菌时，可预期，没有必要用抗真菌药进行另外的全身性治疗，从而不仅该费用低，而且抗真菌治疗的副作用危险也低微。 1.式(I)化合物的应用，其用于制备可局部使用的、优选治疗良性色素痣或者治疗脚癣或甲癣的局部配方制剂， 在该式(I)中，X为CO、CHOZ或CHNRZ，其中Z选自： 氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM及对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；其中 R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)n-COOM，其中n为1至6的整数；或者为10α-二氢蒿素基； R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8； R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基； M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或直链或支链(C1-C6)烷基，或者R7和R8共同构成(C4-C6)烷基桥键； 而R选自氢和对R6所举的那些基团。 2.权利要求1所述的应用，其特征在于，所述良性色素痣选自后天性痣细胞色素痣；先天性痣细胞色素痣，也即胎痣；着色斑病，特别是肝色痣、日晒斑或老年斑；黑色素沉着紊乱，例如雀斑；以及黏膜色素斑。 3.权利要求2所述的应用，其特征在于，所述色素痣是后天性痣细胞色素痣、先天性痣细胞色素痣(也即胎痣)或者肝色痣。 4.权利要求3所述的应用，其特征在于，所述配方制剂也用于预防皮肤癌。 5.权利要求1中所定义式(I)化合物的应用，其用于制备后天性痣细胞色素痣预防用的局部，特别是局部配方制剂。 6.前列各权利要求中任何一项所述的应用，其特征在于，式(I)化合物选自青蒿素；二氢青蒿素；式(I)所示含羧基的衍生物，特别是青蒿酯；蒿甲醚；蒿乙醚；二氢青蒿素的碳酸丙酯以及蒿酸。 7.权利要求6所述的应用，其特征在于，式(I)化合物是青蒿素、二氢青蒿素或者青蒿酯。 8.包含局部用配方制剂的硬膏，该配方制剂含有式(I)的活性物质： 在该式(I)中，X为CHOZ或者CHNRZ，其中Z选自： 氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM和对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8；SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；其中 R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)n-COOM，其中n为1至6的整数；或者为10α-二氢蒿素基； R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8； R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基； M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或直链或支链(C1-C6)烷基，或者R7和R8共同构成一个(C4-C6)亚烷基桥键；而R选自氢和对R6所举的基团； 而且该局部用配方制剂基本不含渗透增强物质。 9.权利要求8所述的硬膏，其特征在于，X为CHOZ，Z选自间-CH2(C6H4)COOM与对-CH2(C6H4)COOM以及COR3，其中R3为-(CH2)n-COOM。 10.权利要求9所述的硬膏，其特征在于，式(I)化合物是青蒿酯。 11.权利要求10所述的硬膏，其特征在于，该局部配方制剂为糊剂、软膏、糊剂、悬浮液、溶液、凝胶、喷雾剂或者乳膏剂，特别是软膏。 12.治疗人类患者身上良性色素斑或皮肤霉菌病的方法，其特征在于，将式(I)所示化合物以治疗色素痣或治疗皮肤霉菌病有效的量涂到色素痣或皮肤霉菌病局部部位，特别是局部表面： 在该式(I)中，X为CO、CHOZ或CHNRZ，其中Z选自： 氢；直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；间-CH2(C6H4)COOM及对-CH2(C6H4)COOM；COR3；CSR3；C(NR6)R3；SOR4；SO2OM；SO2NR7R8； SO2O-蒿素基；SO2NH-蒿素基；POR4R5和PSR4R5；其中 R3为直链或支链(C1-C6)烷基；直链或支链(C1-C6)烷氧基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C6-C10)芳氧基；(C7-C24)芳烷基；-(CH2)n-COOM，其中n为1至6的整数；或者为10α-二氢蒿素基； R4和R5各自单独选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基；(C7-C24)芳烷基；OM；直链或支链(C1-C6)烷氧基；(C6-C10)芳氧基和NR7R8； R6选自直链或支链(C1-C6)烷基；直链或支链(C2-C6)烯基；直链或支链(C2-C6)炔基；(C3-C8)环烷基；(C6-C24)芳基和(C7-C24)芳烷基； M为氢或药学可接受的阳离子；以及R7和R8各自单独为氢或者直链或支链(C1-C6)烷基，或者R7和R8共同构成一个(C4-C6)亚烷基桥键；以及R选自氢和对R6所举的基团。 13.权利要求12所述的方法，其特征在于，所述良性色素痣选自后天性痣细胞色素痣；先天性痣细胞色素痣，也即胎痣；着色斑病，特别是肝色痣、日晒斑或老年斑；黑色素沉着紊乱，例如雀斑；以及黏膜色素斑。 14.权利要求13所述的方法，其特征在于，所述色素痣是后天性痣细胞色素痣、先天性痣细胞色素痣(也即胎痣)或者肝色痣。 15.预防后天性痣细胞色素痣的方法，其特征在于，将权利要求1所定义的式(I)化合物以预防后天性痣细胞色素痣有效的量在有痣处，优选在局部给药。 16.权利要求12至15中任何一项所述的方法，其特征在于，将式(I)化合物以一种糊剂、软膏、悬浮液、溶液、凝胶、喷雾剂或者乳膏剂，特别以软膏制剂来施用。 17.权利要求16所述的方法，其特征在于，将式(I)所示的化合物制成软膏，并阻止水份经涂抹软膏而从皮肤中逸出。 18.权利要求12至17中任何一项所述的方法，其特征在于，将该配方制剂和橡皮膏一起敷覆。 19.权利要求12至18中任何一项所述的方法，其特征在于，式(I)所示的化合物选自青蒿素；二氢青蒿素；式(I)所示含羧基的衍生物，特别是青蒿酯；蒿甲醚；蒿乙醚；二氢青蒿素的碳酸丙酯以及蒿酸。 20.权利要求19所述的方法，其特征在于，式(I)所示的化合物是青蒿素、二氢青蒿素或者青蒿酯。 21.权利要求14所述的方法，其特征在于，也用于预防皮肤癌。 Treatment and prevention of benign pigmented moles (naevi) using artemisinine and the derivatives thereof Benign pigmented moles or athlete's foot or ringworm of the nails can be treated with locally applicable, especially topically formulated active ingredients of formula (I) wherein X represents CO, CHOZ or CHNRZ, Z is selected from hydrogen, linear or branched (C1-C6) alkyl, linear or branched (C2-C6) alkenyl, linear or branched (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C6-C24) aryl, (C7-C24) aralkyl, m- und p- represent CH2(C6H4)COOM; COR<3>; CSR<3>; C (NR<6>) R<3>; SOR<4>; SO2OM; SO2NR<7>R<8>; SO2O- artemisinyl; SO2NH-artemisinyl; POR<4>R<5> and PSR<4>R<5>; R<3> represents a linear or branched (C1-C6) alkyl, a linear or branched (C1-C6) alkoxy; a linear or branched (C2-C6) alkenyl; a linear or branched (C2-C6) alkynyl; (C3-C8) cycloalkyl; (C6-C24) aryl; (C6-C10) aryloxy; (C7-C24) aralkyl; -(CH2)n-COOM, where n represents a whole number between 1 and 6; or 10a-dihydroartemisinyl; R<4> and R<5> are independently selected from linear or branched (C1-C6) alkyl; linear or branched (C2-C6) alkenyl; linear or branched (C2-C6) alkynyl; (C3-C8) cycloalkyl; (C6-C24) aryl; (C7-C24) aralkyl; OM; linear or branched (C1-C6) alkoxy; (C6-C10) aryloxy and NR<7>R<8>; R<6> is selected from linear or branched (C1-C6) alkyl; linear or branched (C2-C6) alkenyl; linear or branched (C2-C6) alkynyl; (C3-C8) cycloalkyl; (C6-C24) aryl and (C7-C24) aralkyl; M represents hydrogen or a pharmaceutically acceptable cation; and R<7> and R<8> independnetly represent hydrogen or a linear or branched (C1-C6) alkyl, or R<7> and R<8> together form am alkylene bridge (C4-C6); and R is selected from hydrogen and the groups cited for R<6>. Said compounds are also effective in the prevention of acquired Naevus cell naevi. With arteannuin and derivatives for treatment and prevention of benign pigmented moles (nevus) The present invention relates to topical and particularly treat benign pigmented moles (nevus) on skin and the mucosa with prescription with local; The particularly treatment of nevus cytochrome nevus, lentiginosis and mucosa pigmented spots.In addition, the invention still further relates to the part prescription that is suitable for this kind treatment. The term nevus cell nevus refers on the various microstructures the optimum dermatosis by so-called nevus cellularity, nevus cell nevus (birthmark, Hepatic nevus).The nevus cell is that normal pegmentation has the cell that defective forms, i.e. melanocyte.Almost everyone can occur the melanocytic nevus of different numbers, different size and different colours intensity on one's body.The outer Phenotype of nevus can be very inequality.It can be with the nevus cell nevus skin flush or that be higher than skin plane (spherical, the base of a fruit is arranged or lie on the skin) point-like also as planar greatly, verrucose, protuberance or slick, painted then from the colour of skin through brown to black.The number of posteriority melanocytic nevus increases with life process.Nevus cytochrome nevus with fanciful structures, the danger that has height to cancerate, and be called as dysplastic or atypical nevus cytochrome nevus. Perhaps can develop into malignant melanoma by nevus cytochrome nevus, also be the casting skin cancer.Under the situation more than 60%, it is formed by nevus cytochrome nevus.In nearly decades, it should be noted that the melanoma sickness rate obviously rises.Nineteen sixty is about 1: 600 of U.S.'s life-span risk, and current people to observe the life-span risk be 1: 100.Therefore, for instance, according to Prof.Dr.Matthias Volkenandt (Klinikf ü r Dermatologie und Allergologie der Ludwig-Maximilians- M ü nchen, Frauenlobstrasse 9,80337M ü nchen) said, melanoma is annual about 14 (they also being 14 new cases) of per 100000 residents at the geographic sickness rate in state, Bavaria.This is equivalent to about 1% (per 100 residents are having a trouble melanoma in life) of life-span risk.With regard to this numeral, melanoma is not the tumor of human the most frequent generation, and but described according to Volkenandt, the height of sickness rate rising does not have other tumor to mention in the same breath with it. According to knowledge situation now, also do not overcome nevus cytochrome nevus rotten preventative diagnosis and treatment and therapy.The rotten excision of at first wanting with nevus of high-risk.In early time, laser treatment plays a role aspect beauty treatment.All two kinds of methods all be invasive, have certain risk (cicatrization, dyschromasia etc.) and interrelate with high cost. The appearance of posteriority nevus, always a kind of red point (hemorrhage or hemangioma) little, that sometimes little handy microscope just can be seen.From this nevus initial period, the speckle that often develop into bigger redness, a bit swells.Then, initial from these nevus initial periods, form the brown nevus cytochrome nevus big or small, that brown colourity is different with structure. Arteannuin (also claiming Qinghaosu) is a kind of Sesquiterpene with peroxide group, and it is studied mainly as the antimalaric that whole body is worked and uses up to now.Arteannuin is difficult to water-soluble; But the soluble derivative of arteannuin is developed out.In EP-A-0 428 773, narrated general or topical application arteannuin and derivant thereof treat the disease that psoriasis, viral disease (wart, molluscum contagiosum and sheep pox), ultraviolet bring out (the photic dermatosis of multiform, " collagen vascular disease ", premalignant keratosis ( Keratosen), precancer dermatitis, malignant lentigo, basal cell carcinoma, temporo squama houselet cancer and malignant melanoma), blister dermatoses and hemorrhoid. The purpose of this invention is to provide pharmaceutical formulation that work in the part but preferred local application, said preparation is to treating optimum nevus cell nevus, and is particularly effective to melanocytic nevus, thereby also can be used to prevent skin carcinoma. By the present invention, the method that this goal of the invention is achieved is, prepares topical application with a compounds that is selected from formula (I), and particularly the pharmaceutical formulation of topical is treated optimum nevus cell nevus: In this formula (I), X is CO, CHOZ or CHNRZ, and wherein Z is selected from: Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5 R wherein 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) nCOOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base; R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8 R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl; M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8(C of common formation 4-C 6) the alkylidene bridged bond; And R is selected from hydrogen and to R 6Cited group. Now unexpected the discovery used above-mentioned bioactive substance, particularly uses the preparation of part (for example on skin) medication to handle and can successfully treat pigmented vevus of skin very early, and particularly those originate from melanocytic nevus cell nevus.Also once found,, also may prevent skin carcinoma (particularly basal cell tumor or melanoma) through with formula (I) compounds for treating nevus cytochrome nevus.In addition, find that also this active substance is under the situation of topical application, aspect prevention of benign pigmented moles, it also is effective particularly preventing posteriority nevus cytochrome nevus aspect. In the present patent application scope, " optimum nevus cell nevus " is understood as especially: -nevus, particularly nevus cytochrome nevus are (common or dysplastic; Nevus cytochrome nevus also often is called as melanocytic nevus); It can divide three groups by occurrence positions down, be junctional nevus cytochrome nevus (interlayer epidermis/corium), compound nevus cytochrome nevus (corium connective tissue) and dermal nevus cytochrome nevus (corium deep layer), and be congenital nevus cytochrome nevus (=birthmark) and posteriority nevus cytochrome nevus by the diacritic group of occurrence time.The group of posteriority nevus cytochrome nevus is the recurrence nevus, and it forms behind a kind of other optimum mother's marks of surgical excision.The example of congenital junctional nevus cytochrome nevus is a macle, and the example of posteriority junctional nevus cytochrome nevus or compound nevus cytochrome nevus is halo naevus (a Sa Dun Shi nevus); The example of posteriority melanocyte junctional nevus cytochrome nevus, compound nevus cytochrome nevus or dermal nevus cytochrome nevus then is Spitz nevus and Li Deshi nevus.The example of congenital dermal nevus cytochrome nevus is mongolenfleck (=Naevus Bleu), and the example of the nevus cytochrome nevus of congenital junctional nevus cytochrome nevus, compound nevus cytochrome nevus or corium then is congenital Riesenpigmentnaevus (Naevus giganteus); -lentiginosis (for example Hepatic nevus=Lentigo simplex, Sonnenflecken=Lentigosolaris, senile plaque=Lentigo senilis, PUVA-Lentigines); -melanin pigmentation disorder (freckle=ephelides) for example; And -mucosa nevus cell nevus (for example eye conjunctiva nevus, lip nevus, oral mucosa nevus and sexual organ nevus). Formula (I) chemical compound is aspect all above-mentioned optimum nevus cell nevuss of diagnosis and treatment, and particularly posteriority or congenital nevus cytochrome nevus aspect are effective.In above-mentioned these nevuss, dysplastic (atypical) nevus cytochrome nevus has the high likelihood that goes bad into skin carcinoma, therefore, in order to prevent skin carcinoma, preferably uses formula (I) compounds for treating nevus. (C 1-C 6) alkyl preferably methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, sec-amyl, neopentyl, n-hexyl, Sec-Hexyl and new hexyl.Straight chain (C more preferably 1-C 3) alkyl, and particularly preferably be methyl or ethyl.Straight chain or side chain (C 2-C 6) thiazolinyl (C preferably 2-C 4) thiazolinyl, for example vinyl, pi-allyl, 1-methyl ethylene, 2-methyl ethylene, but-1-ene-1-base, but-2-ene-1-base, fourth-3-alkene-1-base, but-1-ene-2-base, but-2-ene-2-base, fourth-3-alkene-2-base, 2,2-dimethyl vinyl and 1,2-dimethyl vinyl.Straight or branched (C 2-C 6) alkynyl preferably acetenyl, propargyl, third-1-alkynes-1-base, fourth-1-alkynes-1-base, fourth-2-alkynes-1-base, fourth-3-alkynes-1-base, fourth-3-alkynes-2-base, 3-methyl fourth-1-alkynes-1-base, 3,3-dimethyl butyrate-1-alkynes-1-base, 1,1-dimethyl butyrate-2-alkynes-1-base and 1,1-dimethyl propylene-2-alkynes-1-base.(C 3-C 8) cycloalkyl preferably cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.(C 6-C 24) aryl (C preferably 6-C 10) aryl, for example phenyl, naphthalene-1-base and naphthalene-2-base.(C 7-C 24) aralkyl (C preferably 7-C 12) aralkyl, for example benzyl, phenethyl, (naphthalene-1-yl) methyl and (naphthalene-2-yl) methyl.(C 1-C 6) alkyl in the alkoxyl, be top to (C 1-C 6) the illustrational same group of alkyl.(C preferably 1-C 3) alkoxyl more preferably then is methoxyl group, ethyoxyl or positive propoxy.(C 6-C 10) aryl in the aryloxy group, be top to (C 6-C 24) the illustrational same group of aryl.More preferably phenoxy group or alpha-naphthoxy base or β-naphthoxy. In the application's scope, one of term " artemisin base " expression has the group shown in the formula (I) of X=CH-, and this group can be linked on oxygen or the nitrogen by the free valency of carbon.In the application's scope, term " 10-α-dihydro artemisin base " means-O-artemisin base, and wherein the implication of artemisin base is ditto described. In the formula (I), Z is preferably hydrogen; Straight or branched (C 1-C 6) alkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3SOR 4SO 2OM; SO 2NR 7R 8SO 2NH-artemisin base and POR 4R 5 With regard to meet the pharmacopedics requirement as with regard to the cation of M, that can mention is the cation of exemplary alkali metal cation such as lithium, sodium or potassium, the cation of alkaline earth metal cation such as magnesium and calcium, ammonium and H +N (R XR YR Z), R wherein x, R y, R zCan be separately methyl or ethyl separately. Work as R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 1-C 6) alkoxyl ,-(CH 2) nWhen-COOM or artemisin base, Z is preferably COR 3This moment, particularly M was preferably hydrogen, sodium, potassium or ammonium. When M was alkali metal, alkaline-earth metal or ammonium, Z was preferably SO 2OM. Work as R 4And R 5Be selected from OM and straight or branched (C 1-C 6) during alkoxyl, Z is preferably POR 4R 5More preferably, R 4And R 5In one of be OM, particularly sodium, potassium or ammonium of M wherein, and be other straight or branched (C 1-C 6) alkoxyl or OH. Chemical compound shown in the formula (I) is known, perhaps can be made into the known compound shown in the formula of being similar to (I).In the case, this chemical compound of X=CO is an arteannuin, and the chemical compound of X=CHOH is a dihydroartemisinine.X=CHOZ and Z are different from the chemical compound of hydrogen, and perhaps the chemical compound of X=CHNRZ below is referred to as " derivant of dihydroartemisinine ". Chemical compound shown in the formula (I) can following method make: -arteannuin (X=CO) can be separated from plant Artemisia annua (ArtemisiaAnnua) plant as known. -dihydroartemisinine (X=CHOH) is known, and can for example under about 0 ℃ arteannuin be prepared in methanol with sodium borohydride reduction. The derivant of the dihydroartemisinine of-X=CHOZ, wherein Z is straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl, available dihydroartemisinine prepares by the following method: at first make dihydroartemisinine change into the trimethyl silyl ether of dihydroartemisinine with chlorination front three silicon, make trimethylsiloxy with bromination front three silicon exchange bromine (according to the embodiment 1 of US-A-2005/0119232), then in the presence of alkali, make bromine atoms use excessive HOZ to replace by institute's requirement again, wherein the implication of Z has been given explanation.Among these derivants, Artemether (Z=Me) and arteether (Z=Et) are compound known. The derivant of the dihydroartemisinine of-X=CHNRZ, wherein the implication of R has been given explanation in formula (I), Z=hydrogen, straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) the aralkyl person, available dihydroartemisinine prepares by the following method: at first make dihydroartemisinine change into the trimethyl silyl ether of dihydroartemisinine with chlorination front three silicon, make trimethylsiloxy with bromination front three silicon exchange bromine (according to the embodiment 1 of US-A-2005/0119232), then in the presence of alkali, make bromine atoms again by requirement use excessive amine HNRZ to replace, wherein the implication of R and Z has been given explanation. The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and between Z=-CH 2(C 6H 4) COOM or right-CH 2(C 6H 4) COOM (definition of M is as pointed in formula (I)), can produce as raw material by the dihydroqinghaosu of dihydroartemisinine or X=CHNRH, its method is, in the presence of alkali, with-bromomethyl essence of Niobe or right-bromomethyl essence of Niobe make described raw material alkylation, make the methyl ester hydrolysis then, and form suitable salt when M not should be hydrogen.Among these derivants, X=CHOZ and Z=be right-CH 2(C 6H 4) derivant of COOH is known as " artemisic acid " The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=COR in formula (I) 3Or CSR 3And R 3Be straight or branched (C 1-C 6) alkoxyl or (C 6-C 10) aryloxy group, can be by the dihydroqinghaosu and suitable chlorinated carboxylic acid (C of dihydroartemisinine or X=CHNRH 1-C 6) Arrcostab or chlorinated carboxylic acid (C 6-C 10) aryl ester or chlorothio carboxylic acid (C 1-C 6) Arrcostab or chlorothio carboxylic acid (C 6-C 10) aryl ester and a kind of alkali prepares. The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=COR in formula (I) 3And R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl; Can prepare by the dihydroqinghaosu of dihydroartemisinine or X=CHNRH and the reaction of acid chloride and alkali, wherein acid chloride and suitable R 3Replace. The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=CSR in formula (I) 3And R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl; Can pass through Z=COR 3Above-mentioned corresponding derivative and Lawesson ' s reagent react and produce. The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=COR in formula (I) 3And R 3-(CH 2) n-COOM (wherein the implication of M is described in formula (I)), dihydroqinghaosu that can be by dihydroartemisinine or X=CHNRH and cyclic acid anhydride react (when n=2 or 3) or with MeOOC (CH 2) n-COOMe reacts and produces.Under latter event, during X=CHOZ, also can add base catalyst such as NEt together 3, and the methanol that disengages during ester exchange reaction can for example be extracted out from poised state by decompression inspissation.When M is not hydrogen, can form corresponding salt, its method is: make residual carbomethoxy cracking, for example use the M cyanide.Among these derivants, being known as of X=CHOZ, n=2 and M=hydrogen " artesunate ". The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=CSR in formula (I) 3And R 3-(CH 2) n-COOM (wherein the implication of M has been given explanation in formula (I)) can make, and its method is: make MeOOC (CH with Lawesson ' s reagent 2) nOne or two ketonic oxygen among the-COOMe is substituted by sulfur, and the dihydroqinghaosu of gained half sulfo-diester and dihydroartemisinine or X=CHNRH is reacted, then make it still be hydrolyzed into COOH, and when M is not hydrogen, form corresponding salt for free COOMe group. -can make the derivant of the dihydroartemisinine of X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=C (NR in formula (I) 6) R 3(R wherein 6Implication in formula (I), given explanation) and R 3Be straight or branched (C 1-C 6) alkoxyl or (C 6-C 10) aryloxy group, its method is: make R 6The isocyanates R that implication as above illustrates 6-NCO and corresponding (C 1-C 6) alcohol or (C 6-C 10) the fragrant and mellow reaction, and make urethanes and the POCl that obtains like this 3Reaction is reacted with the dihydroqinghaosu of dihydroartemisinine or X=CHNRH in the presence of alkali then. -can make the derivant of the dihydroartemisinine of X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=C (NR in formula (I) 6) R 3(R wherein 6Implication in formula (I), given explanation) and R 3Be straight or branched (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl, its method is: make R 6The isocyanates R that implication as above illustrates 6-NCO and corresponding Grignard reagent R 3MgBr reacts, wherein R 3Implication given explanation, and make amide and the POCl that obtains like this 3React, then in the presence of alkali, react with the dihydroqinghaosu of dihydroartemisinine or X=CHNRH. The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation, Z=C (NR in formula (I) 6) R 3And R 3-(CH 2) n-COOM (wherein M and R 6Implication in formula (I), given explanation) available such method produces: make n and R 6The chemical compound MeOOC-(CH that as above illustrates of implication 2) n-CONHR 6With POCl 3React, the dihydroqinghaosu with dihydroartemisinine or X=CHNRH reacts in the presence of alkali then, and methyl ester is hydrolyzed, and if M be not hydrogen, then form suitable salt. -have a Z=SOR 4And R 4The X=CHOZ of=OMe or the dihydroqinghaosu of CHNRZ (wherein the implication of R has been given explanation in formula (I)) can be selectively in the presence of base catalysts, reaction by dihydroartemisinine and excessive dimethyl sulfite (DRP 487253), heat up in a steamer and remove the methanol that disengages, and the dimethyl sulfite that heats up in a steamer except that superfluous that then reduces pressure is produced. The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and Z=SOR 4(R wherein 4Be straight or branched (C 1-C 6) alkoxyl or (C 6-C 10) aryloxy group), can react with the alkali such as the pyridine that suit by corresponding derivative and excessive thionyl (two) chlorine of X=CHOH or CHNRH, remove excessive thionyl (two) chlorine, and then make sulfurous acid derivant and corresponding straight chain or the side chain (C that obtains 1-C 6) alcohol or (C 6-C 10) fragrant and mellow in the presence of suitable alkali such as pyridine, the reaction and making.The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and Z=SOR 4(R wherein 4Be (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) aralkyl), can pass through Grignard reagent R 4MgBr (R wherein 4Implication given explanation) with excessive thionyl (two) chlorine reaction, remove excessive thionyl (two) chlorine, and then make the R that obtains 4The corresponding dihydroqinghaosu of-SOCl and X=CHOH or CHNRH reacts in the presence of suitable alkali such as pyridine and makes. The dihydroqinghaosu of-X=CHOZ or CHNRZ, wherein the implication of R has been given explanation in formula (I), and Z=SOR 4(R wherein 4Be NR 7R 8, R 7And R 8Implication in formula (I), given explanation), can pass through amine HNR 7R 8React with excessive thionyl (two) chlorine, remove excessive thionyl (two) chlorine, and then make the RR of gained 7R 8The corresponding dihydroqinghaosu of NSOCl and X=CHOH or CHNRH reacts in the presence of suitable alkali such as pyridine and makes. The derivant of the dihydroartemisinine of-X=CHOZ or CHNRZ, wherein Z=SO 2OM (implication of M has been given explanation in formula (I)) can react by corresponding derivative and the pyridine-sulfur trioxide-complex of X=CHOH or CHNRH, and the pyridine counter ion counterionsl gegenions of gained sulfonate are exchanged into M and make. The derivant of the dihydroartemisinine of-X=CHOZ or CNHRZ, wherein Z=SO 2NR 7R 8, and R, R 7And R 8Implication in formula (I), given explanation, dihydroqinghaosu that can be by X=CHOH or CHNRH with react in the presence of alkali such as pyridine with the 1eq. chlorosulfuric acid, and follow in the presence of alkali such as pyridine and 1eq. amine HNR 7R 8(R wherein 7And R 8Implication given explanation) react and make. -X=CHOZ and Z=SO 2The dihydroqinghaosu of O-artemisin base can react in the presence of alkali such as pyridine by 2eq. dihydroartemisinine and 1eq. chlorosulfuric acid and makes. -X=CHOZ and Z=SO 2The dihydroqinghaosu of NH-artemisin base can react by dihydroartemisinine and 1eq. chlorosulfuric acid in the presence of alkali such as pyridine, and then in the presence of alkali such as pyridine, with 1eq X=CHNH 2Artemisinin derivative react and make.Derivant that obtains like this and X=CHNHZ and Z=SO 2The derivant of O-artemisin base is with a kind of derivant.Then, can be by to carrying out deprotonation on the sulfoamino-group nitrogen by the derivant of gained like this, and carry out alkylation with alkyl bromide RBr (wherein the implication of R has been given explanation), prepare X=CHNRZ, the implication of the R dihydroqinghaosu that given explanation (but beyond dehydrogenation) in formula (I) wherein. -X=CHNHZ and Z=SO 2The derivant of the dihydroartemisinine of NH-artemisin base can prepare according to the embodiment among the US-A-2005/0119232 2.Again can be by this derivant by removing the proton in two sulfoamino-group nitrogen, and carry out alkylation with alkyl bromide RBr (wherein the implication of R has been given explanation), prepare X=CHNRZ, the implication of the R dihydroqinghaosu that given explanation (but beyond dehydrogenation) in formula (I) wherein. -can make X=CHOZ or CNHRZ, Z=POR wherein 4R 5Perhaps PSR 4R 5(R, R 4And R 5Implication in formula (I), given explanation) dihydroqinghaosu, its method is: the dihydroqinghaosu that at first makes dihydroartemisinine or X=CHNRH with excessive POCl 3(or PSCl 3) react, and heat up in a steamer and remove excessive POCl 3(or PSCl 3).To gained X=CHOPOCl 2(or CHOPSCl 2) or CHNRPOCl 2(or CHNRPSCl 2) crude product in, look radicals R to be introduced 4And R 5Kind and decide, as Grignard reagent R 4MgBr/R 5MgBr (works as R 4And/or person R 5Should be (C 1-C 6) alkyl, straight or branched (C 2-C 6) thiazolinyl, straight or branched (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 6-C 24) aryl or (C 7-C 24) during aralkyl) and form, with alcoholates R 4O-/R 5The form of O-(is worked as R 4And/or R 5Should be straight or branched (C 2-C 6) alkoxyl or (C 6-C 10) during aryloxy group) or with amine HNR 7R 8Form or introduce radicals R with the form of water or hydroxide 4And R 5Condition is that these reagent preferably add by the order that nucleophilicity increases, and is being R at least 4And/or R 5In the time of one of among the OM, will be to add this essential MOH as last reagent.. Under the situation of the chemical compound of X=CHOZ or CHNRZ, carbon atom (also is C on the sesquiterpene framework 10-atom) configuration can be (R) or (S).Chemical compound shown in the formula (I) also can C 10The form of-epimer mixture is used, wherein the ratio of two kinds of epimers can by arteannuin at pre reduction and/or pass through C 10-hydroxyl other are derived from the hydroxyl of water or when synthetic used nucleophile replace change. Those active substances shown in the preferably above-mentioned formula (I), they are selected from the propyl carbonate and the artemisic acid of arteannuin, dihydroartemisinine, carboxylic derivant (particularly artesunate), Artemether (Artemeter), arteether, dihydroartemisinine Particularly preferably be arteannuin, dihydroartemisinine and artesunate. Chemical compound shown in the formula (I) can use separately, perhaps uses with two or more these combination of compounds forms. The chemical compound, particularly artesunate of formula (I), also effective to prevention posteriority nevus cytochrome nevus.For the purpose of prevention nevus cytochrome nevus, with the chemical compound of formula (I), particularly artesunate, large tracts of land is coated onto on the whole skin, is coated onto on the head zone with the high likelihood that forms nevus, perhaps is coated onto on the observable early stage nevus.Head zone with the high likelihood that forms nevus is the local skin that frequently is exposed to ultraviolet radiation on the one hand.On the other hand, this head zone, often be present in formed nevus cytochrome nevus around (for example typically with the radius of 5cm nearly around already present nevus).In addition, the chemical compound, particularly artesunate shown in the formula (I) also has other favourable characteristics, and promptly obviously there has been early stage nevus in they, but also so small making almost can not distinguished with bore hole.Under the effect of chemical compound shown in the formula (I), thisly recognize that still unclear early stage nevus at first forms small red dot, become after a few days dark to black, and the part picture dark, have a crystalline solid that is arranged in micropore.Under some favourable situations, microscopy is penetrated on the top, and to check that in advance debatable skin part just becomes unnecessary. For the purpose of using, the active substance of formula (I) can be mixed with and be suitable for local the use, particularly be suitable for the pharmaceutical formulation that local surfaces (skin) is used.Active material concentration in the made pharmaceutical formulation (preparation) is not crucial especially.Gross weight in pharmaceutical formulation can prepare the pharmaceutical formulation of about 0.1% (weight) of concentration to about 40% (weight).In order to treat nevus cytochrome nevus (congenital=birthmark, perhaps posteriority), in the gross weight of pharmaceutical formulation, pharmaceutical formulation preferably contains 5% (weight) of having an appointment to the active substance of about 20% (weight), especially preferably contains 10% (weight) of having an appointment.For the purpose of prevention posteriority nevus cytochrome nevus, preferably contain chemical compound shown in the formula (I) of about at the most 5% (weight) in the gross weight pharmaceutical formulation of pharmaceutical formulation; Or rather, preferably contain 1% (weight) of having an appointment to about 5% (weight).The definite treatment aequum of bioactive substance, depend on active substance itself, used base material (Grundlage), made lid human relations dosage form (for example ointment, suspension, ointment, plaster, ointment, gel, solution) and used additive, and can determine by simple effect test by the technical staff. The treatment time of the nevus cytochrome nevus that exists (congenital=birthmark, perhaps posteriority) is depended on kind, size, structure, pigmentation and the age of nevus.Preferably periodically treat with chemical compound shown in the formula (I) of high concentration.After first course of treatment (Behandlungstagen), first reaction is normally tangible.Up to being clearly better or changing, promptly show nevus cytochrome nevus and fade gradually or disappear, can continue two to the several months.With regard to the old patient, this time period can be more longer, continues more longerly because epidermal renewal increases with old. With regard to prevention posteriority nevus cytochrome nevus, promptly it is enough to use 2～3 times.Bigger early stage nevus is preferably treated the more longer time, till early stage nevus is faded gradually or disappears. Active substance shown in the formula (I) should be decided on treatment measure (Therapieansatz), invades skin to some extent deeply: -just treating nevus cytochrome nevus (congenital=birthmark, perhaps posteriority), should decide on type and the outmoded degree of nevus, active substance preferably enters corium. -with regard to prevention posteriority nevus cytochrome nevus, active substance preferably directes reach the juncture area on border between epidermis and corium by corium. Concerning the inert bed material that is generally used for the local prescription preparation, be suitable for all these active substances as the pharmaceutical formulation bed material of formula (I) active substance.This bed material especially for the local prescription preparation: vaseline, fat, wax, fatty acid ester, paraffin, oil, silicone and polymer thereof.Preferably with active substance and about 60% (weight) to about 99.9% (weight), more preferably prepare in the pharmaceutical formulation bed material of the pharmaceutical formulation made with about % (weight) 80 to about 95% (weight).If use hydrophilic/aqueous topical pharmaceutical formulation bed material such as hydrogel, ointment, then active substance can encapsulate by Nano capsule, be encapsulated in liposome interior (Einschluss in Liposomen) or for example form complex, prevent its decomposition with cyclodextrin.Complexation about arteannuin and derivant and cyclodextrin for instance, sees also US-A-2005/187189. According to Deutscher Arzneibucs, the local prescription preparation with the single-phase bed material of non-water such as anhydrous pure fat phase is known as ointment.Wherein used the ointment of formula of the present invention (I) active substance, be made up of a kind of like this ointment bed material, this ointment bed material can contain the active substance of one or more fine dispersion, to use on skin. When this local prescription preparation should be ointment, this pharmaceutical formulation bed material can be preferably by the partition coefficient that has n-octyl alcohol/water under the room temperature about 1 to about 10 5, more preferably from about 10 to about 10 5, preferred especially about 50 to about 10 4Lipophilic ingredient form.Under this occasion, the example of this pharmaceutical formulation bed material is vaseline, fat, wax, fatty acid ester, paraffin, oil, silicone and polymer thereof (for example polydialkysiloxane, silicone elastomer, silicone-wax, silicone emulsifier). During coating ointment, formula (I) active substance comes out from the topical formulations bed material that surrounds it, and enters in the skin.This lipotropy bed material and skin adherence get very firm, and outwards form water repellent layer.This layer has equally also stoped moisture from skin outwards overflow (inhibition).Because this effect, it is moistening that skin is held, and become warm, because the water that can evaporate is few.Because humidity improves, skin also has more elasticity, and this has promoted absorption of active agents. Opposite with ointment, two phase systems (water is with mutually fatty) are named as emulsifiable paste.Chemical compound shown in the formula (I) also can be mixed with emulsifiable paste.With regard to the fat phase, can adopt such as top the illustrational same class material of ointment bed material.Also can contain the various buffer material that can make the water pH of skin tolerance outside aqueous phase dewaters selectively, perhaps also can contain known one-tenth gelatin polymer such as HYDROXY PROPYL METHYLCELLULOSE, carboxymethyl cellulose, contain cross-linking agent (Borax or for example such as Mg 2+Perhaps Ca 2+Multivalent metal cation) polyvinyl alcohol and and similar substance.In order to carry out emulsifying, can use skin-tolerant surfactant commonly used, for example fatty acid monoglyceryl ester and fatty acid two glyceride, the hydrogenant Oleum Ricini (Cremophor of polyoxyethylene (40) ) or lecithin. As the adjuvant of local prescription preparation, can be the keratolytic (for example salicylic acid, carbamide, biostearin) and the antiseptic of the penetration enhancer used always (such as dimethyl acetylamide, dimethyl formamide, propylene glycol, aliphatic alcohol, triethanolamine, dimethyl sulfoxine, azone and other), improvement effect.Additive generally is used to improve effect, stability, persistency and the firmness that covers the human relations dosage form. Preferably the chemical compound shown in the formula (I) is mixed with the local prescription preparation that is substantially free of the material that strengthens infiltration.Also preferably prepare the chemical compound shown in the formula (I), make it to be substantially free of (C 5-C 19) monocarboxylic acid, its ester and amide thereof.In the present patent application scope, " being substantially free of " is interpreted as, and the local prescription preparation contains less than 1% (weight) in the total amount of pharmaceutical formulation, preferably less than the anatonosis material of 0.1% (weight). Be used for formula (I) chemical compound of paste, ointment, ointment, solution, gel, spray or suspension, preferably all contain the derivant of a carboxyl, particularly artesunate.In the case, carboxyl can be selectively exists with the form of alkali metal salt, alkali salt or ammonium salt. For on skin, using or be applied in the skin, with formula (I) active substance with the local prescription dosage form, particularly with the form of paste, ointment, suspension, solution, gel, spray or emulsifiable paste, especially preferably with ointment form, be coated onto on the plaster (Pflaster).Plaster can be a kind of material that absorbs or suck the local prescription preparation selectively.Active substance also can directly be suspended in or be dissolved in the inert binder of plaster certainly; In being similar to the plaster of previously known, for example being used for scopolamine (for example " Scopoderm TTS ") or being used for the plaster of estradiol (for example " Estraderm TTS ").In this way, active substance can directly and in long-time contact with pending position.Also produce blocking action in addition, this effect has improved the infiltration of active substance. Other administering modes of formula (I) active substance are paste, solution, suspension, gel and ointment and spray.The semisolid of cited active substance or liquid formulation, (for example similar felt rod like that for form that also can bolt (Stift) With exact dose) or with the volume form existence of (Roller) (in suitable bed material (Grundlage), solution, suspension, ointment, ointment, containing active substance). Other are partial, can use the administration form example of formula (I) chemical compound by the present invention is applicator, and this applicator is by ultrasound wave, come promotion formula (I) chemical compound to infiltrate skin or mucosa by electric field or by microneedle.Use ultrasound wave and by the applicator of the spendable previously known of the present invention,, given in 908,448 openly, support for referencial use hereby in the lump for example at US-B6.Use the applicator of electric field dispensing active substance (therefore, it adopts the ionotherapy principle), known for a long time.By the present invention, they are applicable to that those belong to formula (I) active substance of salt, are CHOZ or CHNRZ suc as formula middle X promptly, between wherein Z is selected from-and CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM, SO 2OM and POR 4R 5, R in the formula 4And R 5In one of be OM, and be (the C of other straight or brancheds 1-C 6) alkoxyl or OH, M then is pharmaceutically acceptable cation.See also US-A-2005/065463 with regard to being used for with regard to the active substance topical administration of the present invention previously known applicator to the skin, the band microneedle, this document is supported for referencial use equally hereby in the lump. Another example by the operable topical administration mode of the present invention is a technology, wherein picks up by the skin of sucker with pending position, and on the raising position of skin, and the part bed thickness of corium is excised with mechanical system, for example uses blade.Part is excised the skin part of corium, is infiltrative to chemical compound shown in the formula (I), and allows to go deep into the topical therapeutic of subcutis on these positions.Essential for this reason apparatus has been described among the WO-A-95/15783 that is included in as a reference in the application. With artemisin and derivant (dihydroartemisinine thereof, arteether, Artemether, artesunate and semi-synthetic derivant thereof and synthetic similar compound) carry out a kind of few risk, non-invasive preventative or therapeutic treatment posteriority nevus cytochrome nevus or posteriority or congenital nevus cytochrome nevus (=birthmark), be a huge advance made of handling in the nevus cytochrome nevus, and can reduce canceroderm danger effectively.Therefore, the present invention not only medically but also on socioeconomic has huge meaning.In the topical therapeutic of being put down in writing, carry out, do not observe the atopic reaction of this chemical compound to skin with chemical compound, particularly artesunate shown in the formula (I).Noticeable also have, and health tissues is without prejudice, and treatment is painless, easy. In view of obtaining the result up to now, can find out: the topical therapeutic (lokale Therapie) that carries out with arteannuin and derivant thereof, particularly local positioning treatment (topische Therapie) is very effective, and as prevention and the treatment of nevus, in the longer time, can notice, more little than traditional intervention treatment method expense, and risk is littler. Further illustrate the present invention with following each embodiment now. Embodiment 1: the local prescription preparation With the 3g artesunate with 27g Excipial Greasy ointment evenly mixes and stirs. Embodiment 2a～8h: local prescription preparation Not commensurability artesunate (seeing Table 1) is added in the different bed materials.What have also adds surface active material to pharmaceutical formulation. Table 1: The embodiment numbering Artesunate (g) Additive The bed material capacity adds to 100g 2a～2h 2a：0.1 2b：0.5 2c：1.0 2d：5.0 2e：10.0 2f：15.0 2g：30 2h：40 - White vaseline 3a～3h 3a：0.1 3b：0.5 3c：1.0 3d：5.0 3e：10.0 3f：15.0 3g：30 3h：40 Polysorbate 0.5g; Polyethylene Glycol (2000) stearate 0.5g polyoxyethylene (40) anhydrous sorbitol oleic acid ester 0.5g White vaseline 4a～4h 4a：0.1 4b：0.5 4c：1.0 4d：5.0 4e：10.0 4f：15.0 Cera Flava 4g：30 4h：40 5a～5h 5a：0.1 5b：0.5 5c：1.0 5d：5.0 5e：10.0 5f：15.0 5g：30 5h：40 Soybean lecithin 2g Paraffin 6a～6h 6a：0.1 6b：0.5 6c：1.0 6d：5.0 6e：10.0 6f：15.0 6g：30 6h：40 Polyethylene Glycol (2000) stearate 2g Oleum Brassicae campestris 7a～7h 7a：0.1 7b：0.5 7c：1.0 7d：5.0 7e：10.0 7f：15.0 Isopropyl myristate 1g Decamethylcyclopentasiloxane (19g) silicone elastomer gel (adding to 100g) 8a～8h 8a：0.1 8b：0.5 8c：1.0 8d：5.0 8e：10.0 8f：15.0 Decamethylcyclopentasiloxane 25 g mineral oil add to 100g Embodiment 9a～9i: use the part (skin) in treatment or the prevention nevus cell nevus A) 13 years old boy has dark brown protuberance birthmark (dysplastic breast nevus cell nevus), the structure out-of-flatness, and about 1.2 centimetres of diameter is treated weekly 2～3 times with the 10% artesunate soft petroleum ointment of embodiment 2a.After 2 weeks, birthmark is filbert, has a pair of dark color, point shape position, looks like " crystallizing out " dyestuff.Described birthmark is exsiccant and squama is arranged, and looks like from " inside " beginning atrophy. B) women, at skin surface the birthmark (trunk junctional nevus) of 3 black protuberance, diameter being arranged is 0.5 to 1.0cm, the 10% artesunate soft petroleum ointment of Application Example 2a under the condition of obturation (with the plaster form), spends the night for 3 times weekly.After one week, on each birthmark, can recognize dark position.After 3 weeks, skin forms thing together with dark crystal sample and comes off.Stay three places light color mother's mark, have the non-pigment position, this position no longer is projected on skin plane.Continuing treatment causes the mother's mark on the skin of position handled to fade gradually and becomes flakey to come off. C) 2 early stage nevus cell nevuss of treatment also promptly are called subcutaneous extvavasated blood, and skin part protuberance diameter 0.3～0.4cm: the plaster that contains 10% artesunate ointment of three Application Example 2a spends the night, and color changes after two weeks, and light red forms thing and has dark point.The skin part that changes of protuberance can be taken off.Stay two minor cut or wounds, owing to take off in advance, wound healing. D) women person under inspection has about a 3～4cm of nevus diameter (basal cell carcinoma), uses the 10% artesunate ointment of embodiment 1 to surpass March (periodic, evening is every 2 weeks).This nevus represents that the initial stage (similar inflammatory process) is rubescent.After 3 months, can see to draw atrophy (about color and structure) about 90%.After about 5 months, this nevus no longer as seen. E) women person under inspection has a nevus (junctional nevus) on the arm, use the 10% artesunate ointment of embodiment 1 equally.Because this women person under inspection does not note observing, so can not the frequent degree of administration accurately be described at this; But to ointment more than lasting several weeks.Now this nevus can also see reluctantly and draw. F) 13 years old male person under inspection, there is a congenital nevus in the district at the nasion-eye, under the condition of inaccessible (plaster), uses the 10% artesunate ointment 2 to 3 times of embodiment 1 in two months weekly.This nevus has the many dark point at initial stage.It reacts very slowly.Yet initial success presents.Its stack up shoals many, and has the zone of a plurality of colours of skin. G) 13 years old women patient has a dermal nevus, uses the 10% artesunate ointment of embodiment 1 in 3 days.Take place to concentrate on 3 dark positions that form in the nevus immediately, and remaining range is almost colourless. H) women person under inspection, at the abdominal part of existing a large amount of nevus cytochrome nevuss (junctional nevus), large tracts of land is used the 10% artesunate ointment twice (every 2 days 1 time) of embodiment 1.As far back as the 2nd treatment day, except the nevus that has existed, the early stage nevus of part red, described kind of initial stage, with trickle point form as seen, they are distributed on the whole surface of having handled unevenly.This early stage nevus itself is existing, but only owing to use Ointment in Treatment first as seen.They become dark to black after 2～3 days.On some part, they it seems the crystal that resembles dark color, is arranged in micropore.In 2～3 weeks, when scratching slightly thereon with fingernail when scraping, they come off in company with horny layer of epidermis or peel off. I) a women person under inspection has handled its back of the hand with the ointment of embodiment 1, and some nevus cell nevuss that differ in size (Hepatic nevus) are arranged on the back of the hand.These existing nevuss and early stage nevus are obviously faded, and along with processing time prolongation (7 or 10 days) fades away.After stopping treatment, the nevus cell nevus color shoals.After 4 weeks, they are also shown in reluctantly to no longer as seen. Embodiment 10: be applied topically to the fungal infection of nail treatment Toes and big toes in the first fungal attack: the fingernail of the big toes of half is encroached on.Treat with conventional medicine such as Lamisil, effect is very little.The 10% artesunate soft petroleum ointment of embodiment 2a is used weekly 3～4 times.This ointment is mainly used under nail matrix and the fingernail.After 2 weeks, can be observed already and be clearly better.After 4 weeks, the variable color complete obiteration on the middle toes perhaps no longer deepens.Downright bad big toes first portion peels off.The treatment of all the other fingernails is easier and more effective.Active substance unhinderedly reaches the position, boundary of healthy first portion.Again Chang Chulai fingernail is normal, does not have shallow complexion changed.When fungal infection, when the nail infection fungus, can expect especially, there is no need to carry out other systemic treatment, thereby not only this expense is low, and the danger of side effects of antifungal therapy is also humble with antifungal agent. 1. formula (I) application of compound, it is used to prepare the local prescription preparation of can be local that use, the optimum nevus cell nevus of preferred therapeutic or treatment tinea pedis or tinea unguium, In this formula (I), X is CO, CHOZ or CHNRZ, and wherein Z is selected from: Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5Wherein R 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) n-COOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base; R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8 R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl; M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8Common formation (C 4-C 6) the alkyl bridged bond; And R is selected from hydrogen and to R 6Those groups of being lifted. 2. the described application of claim 1 is characterized in that, described optimum nevus cell nevus is selected from posteriority nevus cytochrome nevus; Congenital nevus cytochrome nevus also is a birthmark; Lentiginosis, particularly Hepatic nevus, day sunburn or senile plaque; Melanin pigmentation disorder, for example passeris montani saturati speckle; And mucosa pigmented spots. 3. the described application of claim 2 is characterized in that, described nevus cell nevus is posteriority nevus cytochrome nevus, congenital nevus cytochrome nevus (also being birthmark) or Hepatic nevus. 4. the described application of claim 3 is characterized in that described pharmaceutical formulation also is used to prevent skin carcinoma. 5. institute's definition (I) application of compound in the claim 1, it is used to prepare the part, particularly local prescription preparation of posteriority nevus cytochrome nevus prevention usefulness. 6. any one described application in each claim of prostatitis is characterized in that, formula (I) chemical compound is selected from arteannuin; Dihydroartemisinine; Carboxylic derivant, particularly artesunate shown in the formula (I); Artemether; Arteether; The propyl carbonate of dihydroartemisinine and artemisic acid. 7. the described application of claim 6 is characterized in that, formula (I) chemical compound is arteannuin, dihydroartemisinine or artesunate. 8. comprise local plaster with pharmaceutical formulation, this pharmaceutical formulation contains the active substance of formula (I): In this formula (I), X is CHOZ or CHNRZ, and wherein Z is selected from: Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5Wherein R 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) n-COOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base; R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8 R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl; M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8(C of common formation 4-C 6) the alkylidene bridged bond; And R is selected from hydrogen and to R 6The group of being lifted; And should not contain the infiltration enhancing substance substantially with pharmaceutical formulation in the part. 9. the described plaster of claim 8 is characterized in that, X is CHOZ, between Z is selected from-and CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM and COR 3, R wherein 3For-(CH 2) n-COOM. 10. the described plaster of claim 9 is characterized in that, formula (I) chemical compound is an artesunate. 11. the described plaster of claim 10 is characterized in that, this local prescription preparation is paste, ointment, paste, suspension, solution, gel, spray or ointment, particularly ointment. 12. the treatment human patients is the method for benign pigmented moles or skin fungus disease on one's body, it is characterized in that, chemical compound shown in the formula (I) is coated onto nevus cell nevus or skin fungus sick part, particularly local surfaces with treatment nevus cell nevus or the sick effectively amount of treatment skin fungus: In this formula (I), X is CO, CHOZ or CHNRZ, and wherein Z is selected from: Hydrogen; Straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; Between-CH 2(C 6H 4) COOM and right-CH 2(C 6H 4) COOM; COR 3CSR 3C (NR 6) R 3SOR 4SO 2OM; SO 2NR 7R 8 SO 2O-artemisin base; SO 2NH-artemisin base; POR 4R 5And PSR 4R 5Wherein R 3Be straight or branched (C 1-C 6) alkyl; Straight or branched (C 1-C 6) alkoxyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 6-C 10) aryloxy group; (C 7-C 24) aralkyl;-(CH 2) n-COOM, wherein n is 1 to 6 integer; It perhaps is 10 α-dihydro artemisin base; R 4And R 5Be selected from straight or branched (C separately separately 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl; (C 7-C 24) aralkyl; OM; Straight or branched (C 1-C 6) alkoxyl; (C 6-C 10) aryloxy group and NR 7R 8 R 6Be selected from straight or branched (C 1-C 6) alkyl; Straight or branched (C 2-C 6) thiazolinyl; Straight or branched (C 2-C 6) alkynyl; (C 3-C 8) cycloalkyl; (C 6-C 24) aryl and (C 7-C 24) aralkyl; M is hydrogen or the acceptable cation of pharmacy; And R 7And R 8Be separately hydrogen or straight or branched (C separately 1-C 6) alkyl, perhaps R 7And R 8(C of common formation 4-C 6) the alkylidene bridged bond; And R is selected from hydrogen and to R 6The group of being lifted. 13. the described method of claim 12 is characterized in that, described optimum nevus cell nevus is selected from posteriority nevus cytochrome nevus; Congenital nevus cytochrome nevus also is a birthmark; Lentiginosis, particularly Hepatic nevus, day sunburn or senile plaque; Melanin pigmentation disorder, for example passeris montani saturati speckle; And mucosa pigmented spots. 14. the described method of claim 13 is characterized in that, described nevus cell nevus is posteriority nevus cytochrome nevus, congenital nevus cytochrome nevus (also being birthmark) or Hepatic nevus. 15. the method for prevention posteriority nevus cytochrome nevus is characterized in that, the defined formula of claim 1 (I) chemical compound is effectively measured in that the nevus place is arranged, preferably at topical with prevention posteriority nevus cytochrome nevus. 16. any one described method is characterized in that in the claim 12 to 15, and formula (I) chemical compound is used with ointment formulation especially with a kind of paste, ointment, suspension, solution, gel, spray or ointment. 17. the described method of claim 16 is characterized in that, the chemical compound shown in the formula (I) is made ointment, and stops moisture content to be overflowed from skin through smearing ointment. 18. any one described method is characterized in that in the claim 12 to 17, this pharmaceutical formulation and rubber plaster is applied together cover. 19. any one described method is characterized in that in the claim 12 to 18, the chemical compound shown in the formula (I) is selected from arteannuin; Dihydroartemisinine; Carboxylic derivant, particularly artesunate shown in the formula (I); Artemether; Arteether; The propyl carbonate of dihydroartemisinine and artemisic acid. 20. the described method of claim 19 is characterized in that, the chemical compound shown in the formula (I) is arteannuin, dihydroartemisinine or artesunate. 21. the described method of claim 14 is characterized in that, also is used to prevent skin carcinoma. 本文短链接|Short link to this article: gettr.ink/j36f3c

CN101244027A治疗皮肤病的蒿甲醚经皮给药制剂---可用于多形性日光疹、 植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗 CN101244027A: Artemether Transdermal Administration Formulation for Treating Skin Diseases - Suitable for Treating Skin Diseases Such as Polymorphic Light Eruption, Phytophotodermatitis, Atopic Dermatitis, and Eczema 治疗皮肤病的蒿甲醚经皮给药制剂 本发明涉及一种蒿甲醚的经皮给药制剂，由主药蒿甲醚、透皮吸收促进剂或透皮吸收载体及其他药用辅料组成。研究表明，抗疟药蒿甲醚作为一种新型的免疫调节剂可用于某些皮肤类疾病的治疗。本发明所述经皮给药制剂中的蒿甲醚可直接作用于患处皮肤表面，并能透过表皮进入真皮层及皮下组织，与蒿甲醚其他给药途径相比，可大大增加蒿甲醚在患处皮肤中的药量，以提高疗效，减小剂量。本发明提供了一种蒿甲醚的新剂型，具有给药方便，靶向性强，无皮肤刺激性且制备简便等优点，可用于多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗。 治疗皮肤病的蒿甲醚经皮给药制剂 技术领域 本发明涉及药品技术领域，具体地说是治疗多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的蒿甲醚经皮给药制剂。 背景技术 青蒿素是我国药学工作者1971年从菊科植物黄花蒿叶中提取分离到的一种具有过氧桥的倍半萜内酯类化合物。在此基础上，我国医药界自主研发了青蒿素系列衍生药物如双氢青蒿素、蒿甲醚与青蒿琥酯。青蒿素类药具有高效、速效、低毒的抗疟活性，特别是对脑型疟和抗氯喹恶性疟的疗效尤为突出，被世界卫生组织称为“治疗疟疾的最大希望”。 近年来，药理研究发现青蒿素类药还具有免疫调节作用，可对朗格罕氏细胞产生影响。皮肤及皮下的朗格罕氏细胞具有摄取、加工、处理抗原的作用，作为特异性免疫的启动者，其在免疫过程中扮演着极为重要的角色，而青蒿素类药能抑制朗格罕氏细胞的活性，达到阻断皮肤过度免疫反应的效果。此外，青蒿素类药还可抑制成纤维细胞的增殖，并降低细胞外胶原合成量，使瘢痕明显软化、变平，从而发挥抗瘢痕作用。因此，青蒿素类药物有望增加新的适应症，即应用于一些皮肤类疾病的治疗。 相关临床研究已有报道，邓丹琪等通过口服蒿甲醚胶囊治疗多形性日光疹(32例，有效率84.4％)及慢性光化性皮炎(63例，有效率85.7％)，与阳性对照药硫酸羟氯喹片相比，疗效无显著性差异，且未发现副作用。进一步的实验研究也证实，蒿甲醚对紫外线照射后受损的永生化角质形成细胞株-HaCaT细胞具有一定的保护作用。 发明内容 本发明的目的是提供一种可直接作用于患处皮肤表面，并能透过表皮进入真皮层及皮下组织、提高疗效的治疗皮肤病的蒿甲醚经皮给药制剂。 本发明选择青蒿素衍生物中脂溶性较强(易透皮)且具有一定临床应用基础的蒿甲醚，将其制成经皮给药制剂。 本发明的蒿甲醚经皮给药制剂由主药蒿甲醚、透皮吸收促进剂或透皮吸收载体及其他药用辅料组成，蒿甲醚的重量百分比为0.1～20％。 制剂中蒿甲醚的重量百分比优选范围为0.2～10％。 本发明的蒿甲醚经皮给药制剂包括可供临床使用的各种外用剂型，如：软膏剂、贴剂、凝胶剂、气雾剂、粉雾剂、喷雾剂、散剂、洗剂、搽剂、涂剂、涂膜剂等。 本发明的蒿甲醚经皮给药制剂中所用透皮吸收促进剂包括表面活性剂、二甲基亚砜及其类似物、氮酮类化合物、脂肪酸及其酯、脂肪醇、角质保湿及软化剂、环糊精类、萜类、醇类化合物及植物挥发油中的一种或几种。 本发明的蒿甲醚经皮给药制剂中所用透皮吸收载体包括脂质体、传递体、醇质体、微乳、固体脂质纳米粒、环糊精包合物及非离子表面活性剂囊泡中的一种或几种。 本发明的蒿甲醚经皮给药制剂可根据制备的需要加入其他药用辅料，如：赋形剂、防腐剂等。 本发明的蒿甲醚经皮给药制剂可用于多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗。 本发明的蒿甲醚经皮给药制剂相关实验及结果如下： 1、不同透皮吸收促进剂对蒿甲醚经皮渗透的影响 采用改良Franz扩散池法进行体外透皮试验。将处理好的大鼠腹部皮肤固定于扩散池的接口处，有效扩散面积为2.8cm2，接受池容积7.0mL，30％乙醇为接受液，透皮扩散试验仪的磁力搅拌转速为200r·min-1，水浴温度为32±0.2℃。向供给池中加入2.0mL含不同促透剂(0.5％)的蒿甲醚SDS(1％十二烷基硫酸钠)饱和溶液。分别于1，2，4，6，8，10，12及24h从接受池中取样0.2mL，同时补加等温等体积接受介质。样品用HPLC法测定含量，计算累计透过量(Q)，将Q对渗透时间(t)作图得附图1，二者进行线性回归所得斜率即为渗透速率常数(Js)，24h累计透过量为Qr。24h时，取下皮肤，用棉签蘸取30％乙醇擦去皮肤内外表面残留药物，剪碎，再用无水乙醇提取，测定其中药物含量，得24h皮肤滞留量(Qs)。以蒿甲醚SDS饱和溶液(原药)为对照，不同透皮吸收促进剂对蒿甲醚经皮渗透的影响结果见表1，表明这几种常用促透剂可不同程度地增加蒿甲醚的经皮渗透速率、透过量及皮肤滞留量。 表1不同透皮吸收促进剂组的经皮渗透特性(n＝5) 2、不同透皮吸收载体对蒿甲醚经皮渗透的影响 体外透皮试验方法同上，供给池内分别加入蒿甲醚的各种透皮吸收载体，蒿甲醚SDS饱和溶液(原药)为对照，结果见附图2与表2，表明微乳、醇质体等透皮吸收载体也可使蒿甲醚的经皮渗透速率、透过量及皮肤滞留量显著提高。 表2不同透皮吸收载体组的经皮渗透特性(n＝5) 3、家兔皮肤刺激性试验 取健康雄性家兔12只，体重2.0～2.5kg，随机分为6组，分别为蒿甲醚SDS溶液组、蒿甲醚脂质体组、蒿甲醚传递体组、蒿甲醚醇质体组、蒿甲醚微乳组及蒿甲醚固体脂质纳米粒组。试验前24h，将家兔背部脊柱两侧毛剪短后用10％硫化钠脱去，每侧脱毛面积约为50cm2。分别于左侧皮肤涂以不含药基质作空白对照，右侧涂以等量含药供试制剂，然后用两层纱布覆盖，并用自制兔套固定。给药24h后，去除覆盖物并清除皮肤上残留物后，观察给药部位出现红斑和水肿情况，按表3，4中的标准进行评价，每日给药1次，连续7 d，结果见表5，表明供试蒿甲醚经皮给药制剂无明显的皮肤刺激性。 表3皮肤刺激反应评分标准 表4皮肤刺激强度分级 表5家兔皮肤刺激性试验 本发明的蒿甲醚经皮给药制剂给药后蒿甲醚可直接作用于患处皮肤表面，并能透过表皮进入真皮层及皮下组织，与蒿甲醚现有给药途径(口服与注射)相比，可大大增加蒿甲醚在患处皮肤(靶部位)中的药量，以提高疗效，减小剂量。 附图说明 图1是本发明的不同透皮吸收促进剂组的经皮渗透曲线。 图2是本发明的不同透皮吸收载体组的经皮渗透曲线。 具体实施方式 实施例1 处方： 蒿甲醚 10g 75％乙醇 加至100mL 制法：取蒿甲醚用75％乙醇溶解并定容，即得用于经皮给药的蒿甲醚搽剂，其中乙醇溶液既是溶剂也是消毒剂同时还具有促透作用。 实施例2 处方： 蒿甲醚 20g 氧化锌 20g 冰片 2g 滑石粉 加至100g 制法：取蒿甲醚、氧化锌、薄荷脑及滑石粉细粉(过100目筛)，采用等量递增法充分混合，即得用于经皮给药的蒿甲醚散剂。 实施例3 处方： 蒿甲醚 1g 聚乙烯醇-124 30g 薄荷脑 10g 乙醇 500mL 甘油 100mL 纯化水 加至1000mL 制法：取聚乙烯醇-124加入甘油和水中充分膨胀后，加热使完全溶解；另取蒿甲醚与薄荷脑用乙醇溶解，并在搅拌下缓缓加至聚乙烯醇-124溶液中，再加水至全量，搅匀后迅速分装，密闭，即得用于经皮给药的蒿甲醚涂膜剂。 实施例4 处方： 蒿甲醚 50g 硬脂酸甘油酯 70g 硬脂酸 100g 白凡士林 120g 液状石蜡 100g 甘油 120g 十二烷基硫酸钠 10g 羟苯乙酯 1g 纯化水 480mL 制法：取硬脂酸甘油酯、硬脂酸、白凡士林及液状石蜡加热熔化为油相；另将甘油及水加热至90℃，再加入十二烷基硫酸钠及羟苯乙酯溶解为水相；然后将水相缓缓倒入油相中，边加边搅，直至冷凝；最后将蒿甲醚细粉(过100目筛)加入上述基质中，搅拌均匀，即得用于经皮给药的蒿甲醚乳膏剂。 实施例5 处方： 蒿甲醚 2g 聚丙烯酸树脂Eudragit E100 30g 琥珀酸 2g 癸二酸二丁酯 10g 肉豆蔻酸异丙酯 6g 制法：取处方中的药物及辅料，用适量丙酮-乙醇(2∶1)溶解，将混合液均匀涂布于背衬材料上，自然挥干溶媒，在60℃烘箱中固化10min，冷却后盖上防粘材料，切片，即得用于经皮给药的蒿甲醚贴片。 实施例6 处方： 蒿甲醚 5g 卵磷脂 20g 胆固醇 5g 纯化水 500mL 制法：取蒿甲醚、卵磷脂、胆固醇用适量乙醚溶解，并置于圆底烧瓶中，37℃下减压蒸去乙醚，再加入水，37℃下旋转水合30min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚脂质体。 实施例7 处方： 蒿甲醚 5g 卵磷脂 14g 去氧胆酸钠 4g 纯化水 500mL 制法：取蒿甲醚、卵磷脂、去氧胆酸钠用适量乙醚溶解，并置于圆底烧瓶中，37℃下减压蒸去乙醚，再加入水，37℃下旋转水合30min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚传递体。 实施例8 处方： 蒿甲醚 5g 卵磷脂 15g 乙醇 200mL 纯化水 300mL 制法：取蒿甲醚、卵磷脂溶于乙醇中，将该乙醇液在搅拌下缓慢滴入水中，滴完后持续搅拌10min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚醇质体。 实施例9 处方： 蒿甲醚 16g 油酸 25g 吐温-80 90g 乙醇 135g 纯化水 250mL 制法：取蒿甲醚、油酸、吐温-80及乙醇，充分混匀，搅拌下滴入水，即得用于经皮给药的蒿甲醚微乳。 实施例10 处方： 蒿甲醚 5g 硬脂酸 10g 大豆磷脂 11g 纯化水 500mL 制法：取蒿甲醚、硬脂酸、大豆磷脂，于70℃水浴中用适量无水乙醇溶解得有机相；另取水作为水相，加热至相同温度，将有机相注入水相中，80℃搅拌2h，形成初乳；然后将初乳冰浴探头超声300s，即得用于经皮给药的蒿甲醚固体脂质纳米粒。 实施例11 处方： 蒿甲醚 5g 羟丙基-β-环糊精 30g 制法：取羟丙基-β-环糊精用60mL纯化水溶解，蒿甲醚用适量无水乙醇溶解后在搅拌下滴入羟丙基-β-环糊精溶液中，包合温度为45℃，恒温搅拌5h后停止加热，继续搅拌冷却至室温得包合物溶液，冷冻干燥后研细，过80目筛，即得用于经皮给药的蒿甲醚羟丙基-β-环糊精包合物。 实施例12 处方： 蒿甲醚 1g 司盘-80 20g 胆固醇 10g 纯化水 500mL 制法：将蒿甲醚、司盘-80、胆固醇用适量乙醚溶解，并置于圆底烧瓶中，37℃下减压蒸去乙醚，再加入水，37℃下旋转水合30min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚非离子表面活性剂囊泡。 发明效果 鉴于建立动物模型的困难，以及蒿甲醚注射、口服制剂几十年临床应用的安全性，采用自愿受试者对本发明产品进行试验，结果如下： 本发明不限于以上实施例。 1、一种治疗皮肤病的蒿甲醚经皮给药制剂，其特征在于所述制剂由主药蒿甲醚、透皮吸收促进剂或透皮吸收载体及其他药用辅料组成，蒿甲醚的重量百分比为0.1～20％。 2、根据权利要求1所述的治疗皮肤病的蒿甲醚经皮给药制剂，其特征在于所述的制剂中蒿甲醚的重量百分比为0.2～10％。 3、根据权利要求1或2所述的治疗皮肤病的蒿甲醚经皮给药制剂，其特征在于该制剂包括可供临床使用的各种外用剂型：软膏剂、贴剂、凝胶剂、气雾剂、粉雾剂、喷雾剂、散剂、洗剂、搽剂、涂剂、涂膜剂。 4、根据权利要求1或2所述的蒿甲醚经皮给药制剂，其特征在于该制剂中所用透皮吸收促进剂包括表面活性剂、二甲基亚砜及其类似物、氮酮类化合物、脂肪酸及其酯、脂肪醇、角质保湿及软化剂、环糊精类、萜类、醇类化合物及植物挥发油中的一种或几种。 5、根据权利要求1或2所述的蒿甲醚经皮给药制剂，其特征在于该制剂中所用透皮吸收载体包括脂质体、传递体、醇质体、微乳、固体脂质纳米粒、环糊精包合物及非离子表面活性剂囊泡中的一种或几种。 6、权利要求1或2所述的蒿甲醚经皮给药制剂，其特征在于可用于多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗。 Artemether percutaneous drug administration preparation for treating dermatosis The invention relates to a transdermal medication preparation of artemether, which comprises artemether as the main drug, transdermal absorption enhancer or percutaneous absorption carrier and other pharmaceutical adjuvants. Antimalarial artemether can be used as a new immunomodulator and can be used for treating certain skin disease as studies show. The artemether of the transdermal medication preparation can directly act on skin surface of patients and enter dermis layer and subcutaneous tissue through penetrating through epidermis. The transdermal medication preparation of artemether can greatly increase dosage of artemether in skin of patients to increase therapeutic effect at lower dosage compared with other administration mode of artemether. The transdermal medication preparation of artemether has the advantages of convenient administration, strong targeting, no skin irritation and simple preparation. The transdermal medication preparation of artemether can be used for treating skin diseases such as polymorphous light eruption, vegetable-solar dermatitis, atopic dermatitis and eczema. Treat dermopathic artemether percutaneous drug administration preparation Technical field The present invention relates to field of pharmaceutical technology, specifically treat the artemether percutaneous drug administration preparation of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema. Background technology Arteannuin be China pharmacy worker 1971 from feverfew Hemerocallis citrina Baroni mugwort extraction separation to a kind of sesquiterpene lactones compounds with peroxide bridge.On this basis, the independent research of China the world of medicine arteannuin series derivatives medicine such as dihydroarteannuin, Artemether and artesunate.That arteannuin medicine has is efficient, quick-acting, the antimalarial active of low toxicity, and particularly the curative effect to cerebral malaria and anti-chloroquine subtertian malaria is particularly outstanding, is called " maximum of treatment malaria is wished " by World Health Organization (WHO). In recent years, pharmacological research finds that arteannuin medicine also has immunoregulation effect, can exert an influence to langerhans' cells.Skin and subcutaneous langerhans' cells have picked-up, process, handle antigenic effect, startup person as specific immunity, it is playing the part of very important role in immunologic process, and arteannuin medicine can suppress the activity of langerhans' cells, reaches the excessive immunoreactive effect of blocking-up skin.In addition, arteannuin medicine also can suppress fibroblasts proliferation, and reduces extracellular collagen synthetic quantity, makes cicatrix obviously soften, flatten, thereby brings into play anti-cicatrix effect.Therefore, artemisinin-based drug is expected to increase new indication, promptly is applied to some skin class treatment of diseases. The existing report of relevant clinical research, Deng Danqi etc. are by oral Artemether capsule for treating polymorphous light eruption (32 examples, effective percentage 84.4%) and farmersskin (63 examples, effective percentage 85.7%), compare with positive control drug hydroxychloroquine sulfate sheet, the curative effect there was no significant difference, and do not find side effect.Further experimentation also confirms, Artemether to ultraviolet radiation after impaired immortalization keratinocyte strain-HaCaT cell have the certain protection effect. Summary of the invention The purpose of this invention is to provide a kind of illing skin surface that directly acts on, and can see through the dermopathic artemether percutaneous drug administration preparation of treatment that epidermis enters skin corium and subcutaneous tissue, raising curative effect. The present invention selects fat-soluble strong (easily transdermal) in the artemisinin derivative and has the Artemether on certain clinical practice basis, is made into percutaneous drug administration preparation. Artemether percutaneous drug administration preparation of the present invention is made up of principal agent Artemether, Percutaneous absorption enhancer or Transdermal absorption carrier and other pharmaceutic adjuvants, and the percentage by weight of Artemether is 0.1～20%. The percentage by weight preferable range of Artemether is 0.2～10% in the preparation. Artemether percutaneous drug administration preparation of the present invention comprises can be for the various exterior-applied formulations of clinical use, as: ointment, patch, gel, aerosol, powder spray, spray, powder, lotion, liniment, varnish, liniment etc. Used Percutaneous absorption enhancer comprises surfactant, dimethyl sulfoxide and analog thereof, azone compounds, fatty acid and ester thereof, aliphatic alcohol in the artemether percutaneous drug administration preparation of the present invention, cutin is preserved moisture and softening agent, cyclodextrin, terpenoid, alcohol compound and plant volatile oil in one or more. Used Transdermal absorption carrier comprises one or more in liposome, carrier, ethosome, microemulsion, solid lipid nanoparticle, cyclodextrin clathrate and the nonionic surfactant vesicle in the artemether percutaneous drug administration preparation of the present invention. Artemether percutaneous drug administration preparation of the present invention can add other pharmaceutic adjuvants according to the needs of preparation, as: excipient, antiseptic etc. Artemether percutaneous drug administration preparation of the present invention can be used for the treatment of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema. Artemether percutaneous drug administration preparation related experiment of the present invention and result are as follows: 1, different Percutaneous absorption enhancers are to the influence of artemether percutaneous infiltration Adopt improvement Franz diffusion cell method to carry out the transdermal test in vitro test.The rat abdomen skin of handling well is fixed in the seam of diffusion cell, and effectively diffusion area is 2.8cm 2, accept pool volume 7.0mL, 30% ethanol is acceptable solution, the magnetic agitation rotating speed of transdermal diffusion test instrument is 200rmin -1, bath temperature is 32 ± 0.2 ℃.In supply pool, add Artemether SDS (1% sodium lauryl sulphate) saturated solution that 2.0mL contains different penetration enhancer (0.5%).Respectively at 1,2,4,6,8,10,12 and the 24h 0.2mL that from accept the pond, takes a sample, add the isothermal equal-volume simultaneously and accept medium.Sample is measured content with the HPLC method, calculates accumulative total transit dose (Q), with Q to time of penetration (t) map accompanying drawing 1, the two carries out linear regression gained slope and is infiltration rate constant (Js), 24h accumulative total transit dose is Qr.During 24h, take off skin, dip in cotton swab and get 30% ethanol and wipe skin surfaces externally and internally left drug, shred, the reuse dehydrated alcohol extraction is measured wherein medicament contg, 24h skin hold-up (Qs).With Artemether SDS saturated solution (former medicine) is contrast, different Percutaneous absorption enhancers the results are shown in Table 1 to the influence of artemether percutaneous infiltration, show that these several penetration enhancer commonly used can increase transdermal penetration speed, transit dose and the skin hold-up of Artemether to some extent. The transdermal penetration characteristic (n=5) of the different Percutaneous absorption enhancer groups of table 1 2, different Transdermal absorption carriers are to the influence of artemether percutaneous infiltration The transdermal test in vitro test method is the same, the various Transdermal absorption carriers that add Artemether in the supply pool respectively, Artemether SDS saturated solution (former medicine) is contrast, the results are shown in accompanying drawing 2 and table 2, show that Transdermal absorption carriers such as microemulsion, ethosome also can make transdermal penetration speed, transit dose and the skin hold-up of Artemether significantly improve. The transdermal penetration characteristic (n=5) of the different Transdermal absorption vehicle group of table 2 3, rabbit skin irritation test Get 12 of healthy male rabbits, body weight 2.0～2.5kg is divided into 6 groups at random, is respectively Artemether SDS solution group, Artemether liposome group, Artemether carrier group, Artemether ethosome group, Artemether microemulsion group and Artemether solid lipid nanoparticle group.24h before the test cuts short the back with tame rabbit back spinal column diamond wool and sloughs with 10% sodium sulfide, and every side depilation area is about 50cm 2Be coated with pastille substrate not respectively at left side skin and make blank, the right side is coated with the equivalent pastille for test preparation, covers with two-layer gauze then, and overlaps with the self-control rabbit and to fix.Behind the administration 24h, dismantle and remove on the skin behind the residue, observe medicine-feeding part and erythema and edema situation occur, press table 3, the standard in 4 is estimated administration every day 1 time, continuous 7 D the results are shown in Table 5, and showing for the examination artemether percutaneous drug administration preparation does not have tangible skin irritation. Table 3 skin irritation reaction standards of grading Table 4 skin irritation strength grading Table 5 rabbit skin irritation test Artemether can directly act on the illing skin surface after the artemether percutaneous drug administration preparation administration of the present invention, and can enter skin corium and subcutaneous tissue through epidermis, compare with the existing route of administration of Artemether (oral with inject), can increase the dose of Artemether in illing skin (target site) greatly, to improve curative effect, reduce dosage. Description of drawings Fig. 1 is the transdermal penetration curve of different Percutaneous absorption enhancer groups of the present invention. Fig. 2 is the transdermal penetration curve of different Transdermal absorption vehicle group of the present invention. The specific embodiment Embodiment 1 Prescription: Artemether 10g 75% ethanol adds to 100mL Method for making: get Artemether with 75% dissolve with ethanol and standardize solution, promptly get the Artemether liniment that is used for percutaneous dosing, wherein alcoholic solution be solvent also be that disinfectant also has transdermal enhancing effect simultaneously. Embodiment 2 Prescription: Artemether 20g zinc oxide 20g Borneolum Syntheticum 2g Pulvis Talci adds to 100g Method for making: get Artemether, zinc oxide, Mentholum and Pulvis Talci fine powder (crossing 100 mesh sieves), adopt the equivalent incremental method fully to mix, promptly get the Artemether powder that is used for percutaneous dosing. Embodiment 3 Prescription: Artemether 1g polyvinyl alcohol-124 30g Mentholum 10g ethanol 500mL Glycerol 100mL purified water adds to 1000mL Method for making: get polyvinyl alcohol-124 add fully expand in the G ﹠ W after, heating makes dissolving fully; Other gets Artemether and Mentholum dissolve with ethanol, and under agitation slowly adds in polyvinyl alcohol-124 solution, adds water to full dose again, stirs evenly back packing rapidly, and is airtight, promptly gets the Artemether liniment that is used for percutaneous dosing. Embodiment 4 Prescription: Artemether 50g tristerin 70g Stearic acid 100g white vaseline 120g Liquid Paraffin 100g glycerol 120g Sodium lauryl sulphate 10g ethyl hydroxybenzoate 1g Purified water 480mL Method for making: getting tristerin, stearic acid, white vaseline and liquid Paraffin heat fused is oil phase; In addition glycerol and water are heated to 90 ℃, add sodium lauryl sulphate again and ethyl hydroxybenzoate is dissolved as water; Then water is slowly poured in the oil phase, the limit edged stirs, until condensation; At last Artemether fine powder (crossing 100 mesh sieves) is added in the above-mentioned substrate, stir, promptly get the Artemether ointment that is used for percutaneous dosing. Embodiment 5 Prescription: Artemether 2g polyacrylic resin Eudragit E 10030g Succinic acid 2g dibutyl sebacate 10g Isopropyl myristate 6g Method for making: get medicine and adjuvant in the prescription,, evenly coat mixed liquor on the back lining materials with proper amount of acetone-ethanol (2: 1) dissolving, naturally volatilize solvent, in 60 ℃ of baking ovens, solidify 10min, adhesive on the cooling bonnet, section promptly gets the Artemether paster that is used for percutaneous dosing. Embodiment 6 Prescription: Artemether 5g lecithin 20g Cholesterol 5g purified water 500mL Method for making: get Artemether, lecithin, an amount of ether dissolution of cholesterol, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether add entry again, and 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether liposome that is used for percutaneous dosing. Embodiment 7 Prescription: Artemether 5g lecithin 14g Sodium deoxycholate 4g purified water 500mL Method for making: get Artemether, lecithin, an amount of ether dissolution of sodium deoxycholate, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether, add entry again, 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether carrier that is used for percutaneous dosing. Embodiment 8 Prescription: Artemether 5g lecithin 15g Ethanol 200mL purified water 300mL Method for making: get Artemether, lecithin is dissolved in the ethanol, and this ethanol liquid is under agitation slowly splashed in the water, drip off the back and continue to stir 10min, the ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether ethosome that is used for percutaneous dosing. Embodiment 9 Prescription: Artemether 16g oleic acid 25g Tween 80 90g ethanol 135g Purified water 250mL Method for making: get Artemether, oleic acid, tween 80 and ethanol, fully mixing splashes into water under stirring, and promptly gets the Artemether microemulsion that is used for percutaneous dosing. Embodiment 10 Prescription: Artemether 5g stearic acid 10g Soybean phospholipid 11g purified water 500mL Method for making: get Artemether, stearic acid, soybean phospholipid, in 70 ℃ of water-baths, get organic facies with an amount of anhydrous alcohol solution; Water intaking is heated to uniform temp as water in addition, and organic facies is injected aqueous phase, and 80 ℃ are stirred 2h, form colostrum; The ultrasonic 300s that then the colostrum ice bath popped one's head in promptly gets the Artemether solid lipid nanoparticle that is used for percutaneous dosing. Embodiment 11 Prescription: Artemether 5g HP-30g Method for making: get HP-and dissolve with the 60mL purified water, Artemether under agitation splashes in the HP-solution after with an amount of anhydrous alcohol solution, the enclose temperature is 45 ℃, constant temperature stops heating after stirring 5h, the continuation stirring is cooled to room temperature and gets inclusion complex in solution, porphyrize after the lyophilization is crossed 80 mesh sieves, promptly gets the Artemether hydroxypropyl-beta-cyclodextrin inclusion that is used for percutaneous dosing. Embodiment 12 Prescription: Artemether 1g Arlacel-80 20g Cholesterol 10g purified water 500mL Method for making: with an amount of ether dissolution of Artemether, Arlacel-80, cholesterol, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether, add entry again, 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether nonionic surfactant vesicle that is used for percutaneous dosing. The invention effect In view of the difficulty of setting up animal model, and Artemether is injected, the safety of oral formulations clinical practice decades, adopts the volunteer that product of the present invention is tested, and the result is as follows: The invention is not restricted to above embodiment. 1, the dermopathic artemether percutaneous drug administration preparation of a kind of treatment is characterized in that described preparation is made up of principal agent Artemether, Percutaneous absorption enhancer or Transdermal absorption carrier and other pharmaceutic adjuvants, and the percentage by weight of Artemether is 0.1～20%. 2, the dermopathic artemether percutaneous drug administration preparation of treatment according to claim 1, the percentage by weight that it is characterized in that Artemether in the described preparation is 0.2～10%. 3, the dermopathic artemether percutaneous drug administration preparation of treatment according to claim 1 and 2, it is characterized in that said preparation comprises can be for the various exterior-applied formulation of clinical use: ointment, patch, gel, aerosol, powder spray, spray, powder, lotion, liniment, varnish, liniment. 4, artemether percutaneous drug administration preparation according to claim 1 and 2, it is characterized in that used Percutaneous absorption enhancer comprises surfactant, dimethyl sulfoxide and analog thereof, azone compounds, fatty acid and ester thereof, aliphatic alcohol in the said preparation, cutin is preserved moisture and softening agent, cyclodextrin, terpenoid, alcohol compound and plant volatile oil in one or more. 5, artemether percutaneous drug administration preparation according to claim 1 and 2 is characterized in that used Transdermal absorption carrier in the said preparation comprises one or more in liposome, carrier, ethosome, microemulsion, solid lipid nanoparticle, cyclodextrin clathrate and the nonionic surfactant vesicle. 6, claim 1 or 2 described artemether percutaneous drug administration preparations is characterized in that can be used for the treatment of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.

CN101223177A水溶性青蒿素衍生物 CN101223177A: Water-Soluble Derivatives of Artemisinin 水溶性青蒿素衍生物、制法、药物组合物及用途 本发明公开了一类水溶性青蒿素衍生物、制备方法、药物组合物及它的用途。该类衍生物的结构如右，经药理试验证明该类化合物及药物组合物具有明显的免疫抑制活性作用，可开发成为治疗人体免疫功能亢进引起的疾病(红斑狼疮、类风湿关节炎，多发性硬化症等自身免疫性疾病)，以及细胞器官移植后抗移植物排斥反应的新型免疫抑制药物。 PCT国内申请，说明书已公开。 Water-soluble arteannuin derivant, production method, medicine composition and usage Water-soluble artemisinin derivatives, their preparation methods, the pharmaceutical compositions containing them and the use thereof are disclosed. The artemisinin derivatives have the structure as following: These compounds and compositions have immuno-suppressive activities which has been proved by pharmacological test, and may be used to prepare novel immuno-suppressants for treating the diseases caused by hypofunction of human immunity( e. g. auto-immune diseases such as lupus erythematosus, rheumatoid arthritis, multiple sclerosis and the like), and may be useful as anti-rejection agentsin organ transplantation. Water-soluble arteannuin derivant, preparation method, pharmaceutical composition and purposes Ice dissolubility artemisinin derivative, preparation method, pharmaceutical composition and purposes Technical field The present invention relates to the chemical synthesis of terpenoid and its immunosuppressive action, and in particular to new artemisine compounds and preparation method thereof and the pharmaceutical composition as immunodepressant.Background technology Qinghaosu is from Chinese medicine sweet wormwood（Plant Artemisia annua Artemisia a draw a L.) the antimalarial active ingredient that extracts, a kind of rare sesquiterpene lactone containing peroxy-radical.It not only has remarkable anti-Zuo effects, it was found that have immunosuppressive action.Its derivative Artesunate has stronger immunosuppressive action, can treat lupus erythematosus and some skin diseases, obtains good therapeutic effect [remaining its refined etc., Artesunate lupus hung classes 56, Chinese journal of dermatology, 1997,39： 51；Chen Hua etc., Artesunate eczema-dermatitis and light sensitive dermatoses clinical observation, institute of Bengbu Medical College report, 1991,16： 251].But patient needs long-term intravenous to inject, the sodium-salt aqueous solution of Artesunate will be in prepared before use, using being inconvenient.Present clinical is often expensive and toxic to kidney, liver with immune suppressive cyclosporin A, causes some patients to adhere to medication.Therefore, present inventor expands the research for finding more efficient, safer immunodepressant. Qinghaosu Artesunate present inventor, which once studies, finds that the artemisinin derivative that a class contains carboxylic acid functional has stronger immunosuppressive action（Chinese invention patent, application number： 200510023824.1 ).But theirs is water-soluble small, and possible bioavilability is undesirable.Thus continually look for more preferably immunodepressant. It is an object of the invention to provide a class water-soluble arteannuin derivant for the content of the invention. Another object of the present invention is to provide the preparation method of the analog derivative. It is yet another object of the invention to provide the purposes of the analog derivative. It is a further object to provide the pharmaceutical composition of the analog derivative.The present invention provides such as following formula（1) compound shown in, its isomers and pharmaceutical salts: (1) Formula（1) in As n=0, X=Y=H, Z=NH2 As n=l, X=OH, Y=H, Z=NH2, NHMe, NHEt, NHPr(n), NHBu, As n=l, X=OH, Y=CH3, phenyl etc. Z - NH2, NHR (R = d-C4Alkyl), NHCH2CH2OH, NR,2(R ,=d-C4Alkyl, NH(CH2)2.3NMe2 NQ -CH, 3 Formula（L) isomers of compound shown in includes but is not limited to stereoisomer and optical isomer. Formula（1) pharmaceutical salts of compound shown in include but is not limited to the addition salts with hydrochloric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, maleic acid, oxalic acid, tartaric acid, citric acid etc.. The formula of the present invention（1) it is preferably such as following formula in compound（1) compound, wherein, n = 0, X = Y=H,Z = NH2; n= l;X Offer formula α of the present invention) shown in compound, its isomers and pharmaceutical salts.They are with dihydroartemisinine（2) it is raw material, is reacted under acid catalysed conditions with substituted alcohols.Such as substituted alcohols are halohydrin, then and then with amine react, generate target compound（1, η=0).Such as substituted alcohols are dihydric alcohol, then first generate hydroxyl qinghaosu ether, are then translated into p-methyl benzenesulfonic acid ester, then are reacted with amine, generate target compound（1, η=0 such as substituted alcohols are epoxy prapanol, and obtained sweet wormwood glycidyl ethers react with amine, generate target compound（1, η=1).As substituted alcohols are propenyls, it is necessary to be further oxidized to sweet wormwood glycidyl ethers；Reacted again with amine, generate target compound（1, η=1).In the organic solvents such as alcohol with inorganic acid or organic acid corresponding salt can be made in target compound containing unhindered amina.Formula obtained by the inventive method（1) compound can be refined with conventional technique. Some specific preparation methods can refer to the patent of present inventor（12454.9) and the paper J. Med. Chem. 2000,43 (8) that have delivered ZL 89 1 09562.4, ZL 93 1:1635-1640 includes the formula in safely, effectively dosage range the present invention further provides a kind of pharmaceutical composition with immunosuppressive action, described pharmaceutical composition（1) compound or pharmaceutically acceptable salt thereof shown in and pharmaceutically acceptable carrier. " safely, effectively dosage " is referred to：The amount of compound is enough to be obviously improved the state of an illness, and is unlikely to produce serious side effect.The safely, effectively dosage of compound is determined according to concrete conditions such as treatment target Elderly, body weight, treatment indication, method of administration, the course for the treatment of and any related treatments.Adult generally 10 mg/ days to 800 mg/ days, in single or divided doses.Children are cut down according to the circumstance. Substituted amino qinghaosu ether（By weight percentage） 1-55 % Excipient（By weight percentage） 15-40% Adjuvant（By weight percentage） 20-65% The composition of the present invention can be used for oral, parenteral, intranasal, is administered through tongue, through eye, through respiratory tract or per rectum, especially tablet or enteric coated pill, liquid drugs injection, sublingual tablets, patch, suppository, creme, ointment, skin gel etc.. " pharmaceutically acceptable carrier " is referred to：One or more biocompatible solid or liquid fillers or excipient, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity.In " compatibility " referred to herein as composition each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmaceutically acceptable carrier part example has sugar（Such as glucose, sucrose, lactose）, starch（Such as cornstarch, farina）, cellulose and its derivates（Such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate, microcrystalline cellulose）, polyethylene glycol, gelatin, talcum powder, stearic acid, magnesium stearate, calcium sulfate, Plant gentry（Such as soya-bean oil, sesame oil, peanut oil, olive oil）.It can also be emulsifying agent（Such as tween), wetting agent (such as 12 protective embankment base sodium sulphate）, colouring agent, flavor enhancement, stabilizer, preservative, apirogen water etc..Selection of the composition of the present invention to carrier depends on the administering mode of compound. Present inventor uses following method, and the screening and research of the immunosuppressive activity of in vitro and in vivo have been carried out to compound of the invention.（Reference book：Modern pharmacology experimental method, Zhang Juntian chief editors, Beijing Medical University/combined publication society of China Concord Medical Science University publishes for 1998）.One, experiment material experimental animals:It is sheerly Balb/c male mices, 6-8 week old. RPMI- 1640 culture mediums (Gibco, pH7.2) add 10% hyclone (FBS), 100'U/ml penicillin, lOO g/ml streptomysins, 10mM HEPES, the and-Μ Ε of 50 μ Μ 2.Stimulant：ConA（), ConA bacteria lipopolysaccharide（LPS, Lai Zi ＆ceric sCbJ/055:B5), suitable concn is diluted to RPMI- 1640 culture mediums before use.Two, experimental methods [one] lymphocytotoxicity is tested 1. vertebra puts to death mouse, sterile to take its spleen, grind and single cell suspension is made, use MTT lysates（10%SDS, 50% dimethylformamide；PH7.2) remove after red blood cell, cell concentration is tuned into 5xl0 with the RPMI-1640 nutrient solutions containing 10%FBS6/ml。 . 80 μ 1 cell suspension, 40 u 1 sample, 40 nutrient solutions of the μ 1 containing 10%FBS are added in 2.96 well culture plates；Control plus the nutrient solutions of 80 μ 1, cumulative volume are 160 μ 1.And set blank control. 3. it is put into 37 °C, 5% C02Cultivated 48 hours in incubator.6-7 hours before culture is terminated, add the μ 1 of 5mg/ml MTT 16 per hole. 4. terminate culture, add the MTT lysates of 80 μ 1 per hole（10%SDS, 50% dimethylformamide；PH7.2), after being placed 6-7 hours in incubator, 0D is determined at 570nm with ELIASA57.Value. [two] lymphocyte proliferation assay 1. de- vertebra puts to death mouse, sterile to take spleen that single cell suspension is made, cell concentration is tuned into 4xl07ml with the nutrient solutions of RPMI- 1640 containing 10%FBS. 2. adding 100 μ 1 cell suspension in 96 orifice plates, 50 μ 1 sample solution, ConA the or LPS solution of 50 μ 1, control wells add 50 nutrient solutions of the μ 1 containing 10%FBS.Cumulative volume is 200 μ 1. 3. in 37 °C, 5% C02Cultivated 48 hours in incubator.7-8 hours before culture is terminated, add 0. 5 Ci []-thymidine per hole（The holes of 25 μ 1/）. 4. terminating culture, cell collector is used（HARVESTER96, Τ Ο Μ Τ Ε Ο collect cell on glass fibre membrane, add scintillation solution, with liquid scintillation numeration instrument（MicroBeta Trilux, PerkinElmer) detection cell DNA in []-thymidine incorporation, reflect cell proliferative conditions. [three] Allogeneic Mixed Lymphocyte breeder reaction (MLR) 1. de- vertebra puts to death C57BL/6 and Balb/c mouse, sterile to take its spleen, grind and single cell suspension is made, remove after red blood cell, cell concentration is tuned into 6xl0 with the RPMI-1640 nutrient solutions containing 10% calf serum6/ml。 2. C57BL/6 splenocytes are reacting cells, Balb/c splenocytes（Irradiated through Co 60,3000 rads) to stimulate cell, two kinds of cells are mixed in equal volume. 3. the μ 1 of cell mixture 100, the μ 1 of sample 100 are added in 96 orifice plates, the nutrient solution of control plus 100 μ 1 containing 10% serum.And do the independent culture control of two kinds of cells. 4. 37 °C, 5% C02Cultivated in incubator 3,4,5 days.Terminate first 1 day of culture, add (that is, 3. 8xl0 of 25 μ of dilution 11DBq []-thymidine）. 5. terminate culture, culture plate is frozen in -20 °C of refrigerators. 6. cell collector（HARVESTER96, T0MTEC cell) is collected on glass fibre membrane, incorporations of numeration instrument (MicroBeta Trilux, PerkinElmer) the detection DNA to []-thymidine is dodged with liquid, reflects cell proliferative conditions. [four] delayed type hypersensitivity, DTH animal model（DTH) 1. DayO, Balb/c mouse（Female, 6-8 weeks Elderly）Every group ten, every rear foot is with 20 1 0. 5% DNFB sensitization.Next day is strengthened.（DNFB is dissolved in [acetone：Olive oil=4:1] in finish）； 2. each DNFB of 10 μ 1 0. 4% are attacked inside and outside Day (7-9), mouse auris dextra； 3. the preceding 1 day abdominal cavity gavage of attack is once, attacks preceding abdominal cavity gavage once, after 24 hours, then be administered once； 4. 30-48 hours after attack, detect each index. [five] the mouse arthritis animal model ox II Collagen Type VIs of ox II Collagen Type VIs induction（CII, Collagen Research Center, Tokyo, Japan) 0. IN acetums are dissolved in, in 4 °C of refrigerator overnights.Experimental day is by the strain of tuberculosis containing Mycobacterium H37Rv CFA (Walco Pure Chemical industries Ltd., Osaka, Japan) with CII it is isometric it is fully emulsified hook, (the μ containing CII 125 of 25 μ of emulsifying agent 1 are subcutaneously injected in DBA/1 mouse tails§) sensitization is carried out, it is immunized again in afterbody with the emulsifying agent of same dose after 3 weeks, this time adjuvant uses IFA.Begin to be administered second of immune the previous day Jian（Intraperitoneal injection or gavage）, successive administration 2 weeks to 3 months.Using rank scores method. 0:Without redness； 1 :Toe joint slightly swells； 2：Toe joint and pedal swelling； 3 :Sufficient pawl swelling below ankle-joint； 4:Whole sufficient pawl swellings including ankle-joint.The summation of every animal foot scoring represents the CIA order of severity. Three, experimental results [one] the effect performance of lymphopoiesis and toxicity test immune response process is mainly made up of the humoral immune reaction of cell immune response and the B cell mediation mediated with T cell.The activated dissociation of cell and cell is directly stimulated to breed to evaluate the inhibitory activity of medicine lymphproliferation response with T cell mitogen ConA and B cell mitogen LPS in vitro；Screening repeatedly has been carried out on 10 μ Μ, Ι μ Μ, 0. 1 concentration of μ Μ tri- first.Wherein three compounds with obvious immunosuppressive activity are embodiment 1, embodiment 11, embodiment 14, and they are not having cytotoxic concentration, breed the inhibiting rate of (Con A) to Τ cells respectively up to 65%, 48%, 52%；To B cell proliferation（LPS inhibiting rate) is respectively up to 73%, 99%, 81%；Embodiment 2, embodiment 3, embodiment 12 are not having cytotoxic concentration, T cell is bred the inhibiting rate of (Con A) respectively up to 48%, 47%, 47 °/., to B cell proliferation（LPS inhibiting rate) is respectively up to 48%, 51%, 47%；Embodiment 8, embodiment 16, embodiment 17, embodiment 18 are not having cytotoxic concentration, and T cell is bred（Con A) inhibiting rate be 13%, 0%, 6%, 9% respectively, to B cell proliferation（LPS as a result inhibiting rate) shows that this four compounds are stronger to the inhibitory activity of B cell proliferation respectively up to 42%, 51%, 24%, 26%, but has in no cytotoxicity seldom or without inhibitory action to T cell.Based on the above results, embodiment 1, embodiment 11, embodiment 14 are selected in vivo and external its immunosupress pharmacology of further inspection Check is active. [two] Allogeneic Mixed Lymphocyte breeder reaction (MLR) alloantigen is the main cause for causing body rejection after blood transfusion, organ transplant.When response lymphocyte and the co-cultivation of heterologous lymphocyte, the alloantigen on heterologous lymphocyte, mainly histocompatibility antigen are expressed MHC- 1, MHC- II molecules, stimulation responses T cell trigger immunoproliferation reaction.Medicine is evaluated to the pharmacological action closer to physiological immune system response to MLR effect by medicine.As illustrated, embodiment 1, embodiment 11, embodiment 14 significantly inhibit the propagation of response lymphocyte in MLR, their EC50 is respectively： 3. 48 ±0. 72 μ Μ 、 0. 59 ±0. 066 μ Μ、 0. 67±0. 012 μ Μ. [three] delayed type hypersensitivity, DTH animal model（DTH) - Wei Jin mono- Walk check embodiment 1, embodiment 11, the immunopharmacological activity of embodiment 14 in vivo, show that embodiment 1, embodiment 11, embodiment 14 respectively can significantly suppress mice ear degree in oral 50mg/kg, 100mg/kg, 50mg/kg from classical mouse DTH reaction model results（P<0. 01) the inhibiting rate difference 56. 5% compared with control group, is 50. 5%, 52. 2%, with ciclosporin A (CsA) 5mg/kg 40. 6 ° of inhibiting rate/.Pharmacological activity is suitable. [four] mouse arthritis animal model Embodiment 1 and embodiment 14 further examine its immunopharmacological activity of Check on mouse arthritis animal model.As a result show that embodiment 1 and embodiment 14 can significantly suppress mouse arthroncus degree (P in oral lmg/kg, 0. 5mg/kg respectively<05) 0. illustrate Fig. 1 is that to significantly reduce DTH mice ears thickness chart 2 be that auricle weight difference embodiment 1, embodiment 11, embodiment 14 significantly reduce DTH mouse swelling auricle weight for ear swelling thickness difference embodiment 1, embodiment 11, embodiment 14 Fig. 3 is the arthritis score of embodiment 1. The mouse arthritis of the preventing and treating ox Type Ⅱ collagen induction of embodiment 11, suppress morbidity arthroncus Fig. 4 is the arthritis score of embodiment 14. The mouse arthritis of the preventing and treating ox Type Ⅱ collagen induction of embodiment 14, suppress morbidity arthroncus embodiment With reference to embodiment, the present invention is further elaborated, but these embodiments are definitely not any limitation of the invention.（Composition is by weight percentage in the following example） Qinghaosu parent nucleus is represented with Q in the examples below that (Q) wave molding（One）Represent β substitution or/and α substitution ' straight line（One "1) represent β substitutions Dotted line（) represent α substitution embodiments 12 ,-amino arteether（β types） With maleic acid into salt.White crystals.Fusing point： 139— 141°C.Elementary analysis（C21H33N09): Calculated value：The N3.16 measured values of 56.87 H of C 7.50：3'- amino -2'- hydroxyl wormwood artemisia the propyl ether of 56.84 H of C, 7.59 N3.10. embodiments 2（β types） Η Q-0-C-C-C-NH. Η Shang HQ 2 OH 2With maleic acid into salt.White crystals.Fusing point： 146— 147°C.Elementary analysis (C22H35O10N): Calculated value：The measured values of 55.80 H of C, 7.45 N 2.96：The light base wormwood artemisia propyl ether of 3'- methylaminos -2'- of 55.92 H of C, 7.43 N 2.94. embodiments 3（β types） Q-0-C-C-C H I I 2 OHNHMe and maleic acid are into salt.White crystals.Fusing point： 145— 146°C.Elementary analysis（C23H37O10N): Calculated value：The measured values of 56.66 H of C, 7.65 N 2.87：3'- methylamino -2'- hydroxyl wormwood artemisia the butyl ether of 56.67 H of C, 7.63 N 2.89. embodiments 4（β types） Η Η Q-0-C-C-C-Me H I I 2 OH NHMe and maleic acid are into salt.White amorphous solid. Elementary analysis（C24H39 O10N): Calculated value：3'- amino -2'- hydroxyl wormwood artemisia the butyl ether of 7.66 N 2.67. embodiments of C 57.47 H, 7.84 N, 2.79 measured value C, 57.72 H 5（β types） With maleic acid into salt.White amorphous solid. Elementary analysis（C23 H3701()N): Calculated value：The measured values of 56.66 H of C, 7.65 N 2.87：3'- hydroxyethylamino -2'- hydroxyl wormwood artemisia the propyl ether of 56.64 H of C, 7.74 N 2.71. embodiments 6（β types） With maleic acid into salt.White amorphous solid. Elementary analysis（C24 H39 OuN): Calculated value：The measured values of 55.70 H of C, 7.59 N 2.71：3'- phenyl -3'- methylamino -2'- hydroxyl wormwood artemisia the propyl ether of 55.69 H of C, 7.89 N 2.58. embodiments 7（β types） It is sour into salt with horse Come.White amorphous solid Elementary analysis (C29l-l4iO10N): Calculated value：The measured values of 61.80 H of C, 7.33 N 2.49：3'- phenyl -3'- amino -2'- hydroxyl wormwood artemisia the propyl ether of 61.64 H of C, 7.41 N 2.48. embodiments 8（β types) It is sour into salt with horse Come.White amorphous solid. Elementary analysis（C28H3901()N): Calculated value：The N measured values of 61.19 H of C 7.15：3'- hydroxyethylamino -2'- hydroxyls the third butyl ether of wormwood artemisia of 61.29 H of C, 7.23 N embodiments 9（β types) With maleic acid into salt.White amorphous solid. Elementary analysis (C25H41OnN): Calculated value：The N measured values of 56.49 H of C 7.77：3'- dimethylamino -2'- hydroxyl wormwood artemisia the butyl ether of 56.21 H of C, 7.94 N embodiments 10（β types） With maleic acid into salt.White amorphous solid. Elementary analysis（C25H4101()N): Calculated value：The measured values of 58.24 H of C 8.02： C 58.06 H 7.99 The 3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether types of embodiment 11） With maleic acid into salt.White crystals.Fusing point： 158- 160 °Co (J. Med. Chem. 2000, 43 (8):1635-1640 reports that the melting point compound is 148-152 °C) Elementary analysis（C26H4101()N): Calculated value： C 59.19 H 7.83 N 2.65 Measured value： C 59.14 H 7.86 N 2.66. 3'- piperidyl -2'- hydroxyl wormwood artemisia the propyl ether of embodiment 12（β types） With maleic acid into salt.White crystals.Fusing point： 157— 159 °C. Elementary analysis（C27H43(½N): Calculated value： C 59.87 H 8.00 N 2.59 Measured value： C 59.86 H 8.02 N 2.58. Light base wormwood artemisia butyl ether (the α types of the 3'- methylaminos -2'- of embodiment 13） With maleic acid into salt.White amorphous solid. Elementary analysis（C24H39 O10N): Calculated value： C 57.47 H 7.84 N 2.79 Measured value： C 57.62 H 7.51 N 2.61. The 3'- tert-butylamine base -2'- hydroxyl wormwood artemisia propyl ether of embodiment 14（β types） With maleic acid into salt.White crystals.Fusing point： 171— 173 °C. Elementary analysis（C26H4301()N): Calculated value： C 58.96 H 8.18 N 2.64 Measured value： C 58.92 H 7.91 N 2.59. 3'- phenyl -3'- nafoxidine base -2'- hydroxyl wormwood artemisia the propyl ether of embodiment 15（β types) With maleic acid into salt.White amorphous solid. Elementary analysis (C32H45O10N): Calculated value：The measured values of 63.67 H of C, 7.51 N 2.32：3'- phenyl -3'- piperidyl -2'- hydroxyl wormwood artemisia the propyl ether of 63.36 H of C, 7.09 N 2.04. embodiments 16（β types） With maleic acid into salt.White crystals.Fusing point： 163— 165 °C.Elementary analysis（C33H47O10N): Calculated value：The measured values of 64.16 H of C, 7.67 N 2.27：The light base wormwood artemisia propyl ether of 3'- phenyl -3'- dimethylaminos -2'- of 64.43 H of C, 7.68 N 2.18. embodiments 17（6 types） It is sour into salt with horse Come.White crystals.Fusing point： 166— 168 °C.Elementary analysis（C^i^C QN): Calculated value：The measured values of 62.38 H of C, 7.50 N 2.42：The tertiary fourth amino -2'- hydroxyls wormwood artemisia propyl ether of 3'- phenyl -3'- diformazans of 62.05 H of C, 7.68 N 2.41. embodiments 18（β types) With maleic acid into salt.White crystals.Fusing point： 167— 169 °C.Elementary analysis (C32H47O10N): Calculated value： C 63.45 H 7.82 N 2.31 Measured value：The N embodiments 19 2 of 63.70 H of C 7.83 ,-amino arteether ^ types) maleate tablet formulation is as follows： 2'- amino arteethers（β types) 35 % starch of maleate, 25 % sodium cellulose glycolates 30 % starch slurries (10 %) 9 % stearic acid 1 % active component is crushed, 100 mesh sieve, mixed with sodium cellulose glycolate, 10% starch slurry, pelletize, dry, add dried starch, lubricant to mix, tabletting. The 3'- tert-butylamine base -2'- hydroxyl wormwood artemisia propyl ether of embodiment 20（β types）Maleate tablet Prescription is as follows： 3'- tert-butylamine base -2'- hydroxyl wormwood artemisia propyl ether（β types） 30 % The % of Macrogol 4000 5 of the % of microcrystalline cellulose 65 micronizings crushes active component, sieves, with microcrystalline cellulose, the uniform rear direct tablet compressing of mix lubricant.Embodiment 21 2 ,-amino arteether（β types) citrate casing piece Prescription is as follows： 2 ,-amino arteether type) 35% starch of citrate, 20 % dried starch 35 % starch slurries (10 %) 8 % talcum powder, 2 % Active component and starch are well mixed, plus softwood is made in 10 % starch slurries, pelletizes, and dries, whole grain, adds dried starch, talcum powder and mixes, tabletting is enteric coated. The light base wormwood artemisia propyl ether of 3'- nafoxidine bases -2'- of embodiment 22（β types）The ebonite Nang of oxalates Prescription is as follows： 3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether（β types）The % of 50% microcrystalline cellulose of oxalates, 30% polyethylene glycol 1500 20 is sufficiently mixed active component and auxiliary material uniformly, is fitted into capsulae vacuus.The 3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether types of embodiment 23）Gel ' prescription is as follows： 3'- nafoxidine base -2'- hydroxyl wormwood artemisia propyl ether（β types）The % of 35 %-polyethylene glycol 65 is by Liquid Macrogol and polyethylene glycol 1500 (1：1) agitating and heating, after fusion, adds the active component of grinding sieving, is sufficiently stirred for into gel.The 2'- amino arteethers of embodiment 24（β types) maleate liquid drugs injection dissolves active component water for injection, filters, embedding, sterilizing. Claim 1st, a class has water-soluble arteannuin derivant, stereoisomer and the optical isomer and pharmaceutically acceptable salt of following structural formula (1) Wherein： As n=0, X=Y=H, Z=NH2 ' as n=1, X=OH, Y=H, Z=NH2, NHMe, NHEt, NHPr(n), NHBu, As n=l, X=OH, Y=C, phenyl, Z = N¾, NHR (R = Ci-C4Protective embankment base), NHCH2CH2OH, NR'2(R ,=C C4Alkyl), 2nd, water-soluble arteannuin derivant according to claim 1, it is characterised in that As n=0, X=Y=H, Z=N is 2 ,-amino arteether（β types) and its can hyoscine acid-addition salts. 3rd, water-soluble arteannuin according to claim 1 derives plain thing, it is characterised in that As n=l, X=OH, Y=H, Z=NH2, NHMe, NHEt, NHPr(n), NHBu, Particularly 3'- tert-butylamines base -2'- hydroxyls wormwood artemisia propyl ether（β types) and its can hyoscine acid-addition salts and 3'- nafoxidine base -2'- footpaths base wormwood artemisia propyl ether type）And its can hyoscine acid-addition salts. 4th, water-soluble arteannuin derivant according to claim 1, it is characterised in that As n=l, X=OH, Y=CH3)Phenyl, Z = NH2, NHR (R=C C alkyl), NHCH2CH2OH, NR'2(R ,=d-C4Alkyl), 5th, the preparation method of water-soluble arteannuin derivant as claimed in claim 1, comprises the following steps：A. dihydroartemisinine is that raw material is halohydrin reaction, gained compound and aminated compounds reaction generation target compound with substituted alcohols in acid condition（1, n=0); B. dihydroartemisinine is that raw material is in acid condition diol reaction with substituted alcohols, then first generates hydroxyl qinghaosu ether, be then then converted to p-methyl benzenesulfonic acid ester, finally with amine reaction generation target compound（1, n=0); C. dihydroartemisinine is raw material when being epoxy prapanol reaction with substituted alcohols in acid condition, and obtained qinghaosu reacts with amine, generates target compound（1, n=l); D. dihydroartemisinine be raw material be with substituted alcohols in acid condition propenyl reaction when, be first oxidized to qinghaosu glycidyl ethers, then with amine reaction generation target compound（1, n=l). 6th, the composition of water-soluble arteannuin derivant as claimed in claim 1, it is characterised in that be made up of following composition（By weight percentage）： Substituted amino qinghaosu ether 1-55% Excipient 15-40% Adjuvant 20-65%. 7th, the composition of water-soluble arteannuin derivant according to claim 6, it is characterised in that pharmaceutically acceptable excipient is sugar（Glucose, sucrose, lactose), starch（Cornstarch, farina), cellulose and its derivates（Sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate, microcrystalline cellulose）, it is poly- ^ glycol, bright Glue, talcum powder, stearic acid, magnesium stearate, calcium sulfate, vegetable oil（Soya-bean oil, sesame oil, peanut oil, olive oil）；It can also be emulsifying agent（Tween), wetting agent（Lauryl sodium sulfate）, colouring agent, flavor enhancement, stabilizer, preservative, apirogen water. 8th, the purposes of water-soluble arteannuin derivant as claimed in claim 1, prepare prevention, treat because of immune function of human body it is hyperfunction caused by apply in disease, including the medicine of autoimmune disease such as lupus erythematosus, rheumatoid arthritis, multiple sclerosis. 9th, the purposes of water-soluble arteannuin derivant according to claim 11, it is characterised in that applied in the immunosuppressive drug of anti-rejection after preparing organelle transplanting.

CN101125142A青蒿素在制备抗肿瘤多药耐药药物中的应用 CN101125142A: Application of Artemisinin in the Preparation of Anti-Tumor Multidrug-Resistant Drugs 青蒿素在制备抗肿瘤多药耐药药物中的应用 本发明公开了青蒿素、二氢青蒿素、青蒿琥酯在制备抗肿瘤多药耐药药物中的应用，公开了青蒿素、二氢青蒿素、青蒿琥酯在制备作为长春新碱抗肿瘤增效剂药物中的应用，公开了青蒿素、二氢青蒿素、青蒿琥酯在制备治疗口腔鳞上皮癌药物中的应用，通过实验证实上述应用具有重要的临床意义。 青蒿素在制备抗肿瘤多药耐药药物中的应用 技术领域 本发明涉及青蒿素在制备抗肿瘤多药耐药药物中的应用，属于医药领域。 背景技术 肿瘤多药耐药是导致肿瘤化疗失败的重要原因之一。多药耐药性(multidrug Resistance，MDR)是指肿瘤细胞在接受抗癌药物治疗过程中对一种抗肿瘤药物产生抗药性的同时，对结构和作用完全不同的抗肿瘤药物产生交叉抗药性。导致肿瘤多药耐药机制复杂，肿瘤细胞可以通过不同途径获得多药耐药性。目前认为，导致MDR机制包括：①存在于肿瘤细胞膜上的P糖蛋白，多药耐药性相关蛋白，肺耐药相关蛋白异常表达；②磷酸激酶C、DNA拓扑异构酶II、谷胱甘肽(GSH)与谷胱甘肽-S-转移酶等细胞内酶异常改变。此外，胸苷的合成酶(TS)、醛脱氢酶(ALDH)的增加及二氢叶酸还原酶(DHFR)的变异也可导致细胞的耐药性的发生；③细胞调亡(Apoptosis)基因与细胞因子改变。④DNA修复异常；⑤器官微环境及其他因素等。 近几年来，随着对肿瘤耐药机制研究的不断深入，已经发现一些肿瘤多药耐药逆转剂及其活性成分。主要有：①钙通道阻滞剂，如为维拉帕米；②免疫抑制剂，如环胞霉素A；③谷胱甘肽转移酶(GST)及TOP异构酶II抑制剂；④激素及抗激素类化合物；⑤蛋白激酶抑制剂；⑥DNA修复相关酶活性抑制剂等。但能进入临床研究的只有异博定、环孢菌素A、SDZPSC833、它莫西芬等极少数，而且临床逆转效果不尽人意。其主要有以下原因：①毒副作用限制了用药剂量；②多机制参与形成的临床耐药使作用靶点单一的逆转剂难以发挥作用；③生物制剂在体内不稳定，半衰期短，难以作用到靶点部位，且副反应多。 近些年来，发现了许多中药及其中药活性成分能够逆转肿瘤多药耐药，特别是中药逆转肿瘤耐药性在P-gP介导的MDR经典机制被公认后以及肯定了钙拮抗剂异博定等对MDR的逆转作用后，国内外肿瘤研究者们开始有意识地从具有钙通道拮抗活性的中药中研究鉴定作用强、毒性小的MDR逆转剂。研究结果发现：①中药大黄主要成份大黄素/大黄酸在低剂量下能增加抗肿瘤药物的细胞毒作用，并能部分逆转肿瘤细胞的MDR；②粉防已碱、蝙蝠葛碱、莲心碱、左旋四氢马汀和人参皂甙Rb1的逆转肿瘤多药耐药作用明显，逆转倍数为8.2-13.0并且苦参碱、乌头碱对耐药细胞株的药性有不同程度的逆转作用；③中药汉防己提取物汉防己甲素在一定程度上能抑制耐药细胞的MDR特性；④化痰中药贝母中的主要活性成份贝母甲素和贝母乙素在逆转肿瘤多药耐药方面独具特色，其化学结构隶属于异甾生物碱的瑟文类生物碱，完全不同于钙离子拮抗剂、免疫抑制剂和其他现有耐药逆转剂，并且可以作用耐药机制不同(P-gP或MDR)的肿瘤细胞，很有临床应用前景。⑤理气类中药玄胡、补骨脂抽提剂的复方中药制剂R3、中药方剂(由川芎、莪术、鸡血藤等活血化瘀药组成)提取液R1等具有逆转耐药作用⑥浙贝母散剂可逆转急性白血病多药耐药。但这些药物/活性成份或停留于实验室阶段，或提纯后毒性较大，或逆转倍数较低而难以实现逆转耐药效果。 青蒿是临床常用中药，味苦辛、性寒，归肝、胆经。具有清热、解暑、除蒸、截疟之功效。临床上常与其他中药配伍治疗暑邪发热、阴虚发热、夜热早凉、骨蒸劳热、疟疾寒热、湿热黄疸等症。其主要成份为青蒿素，同时青蒿素也是其抗疟的主要活性成份。青蒿素及其衍生物是我国自主研制开发的特效抗疟新药，它具有快速、安全高效、无抗药性的优点，更因为其结构特殊，药理作用广泛，在防治肿瘤、艾滋病等多种疾病方面具有潜在诱人的前景而备受国内外医药界关注。青蒿素是含有一个过氧桥的倍半萜的酯化合物，由于其结构的独特性，而使它的抗疟作用机理与已知抗疟药迥然不同。实验研究表明，青蒿素对疟原虫清除作用主要是通过损伤疟原虫的膜系统，而肿瘤多药耐药产生的一个重要机制与肿瘤细胞膜蛋白异常有密切关系，这就启示蒿素抗疟疾的药理机制，可能对肿瘤多药耐药治疗有效。 发明内容 本发明目的在于提供青蒿素在制备抗肿瘤多药耐药药物中的应用； 本发明目的在于提供二氢青蒿素在制备抗肿瘤多药耐药药物中的应用； 本发明目的在于提供青蒿琥酯在制备抗肿瘤多药耐药药物中的应用； 本发明目的在于提供青蒿提取物在制备抗肿瘤多药耐药药物中的应用； 本发明的技术方案为： 青蒿素在制备抗肿瘤多药耐药药物中的应用； 二氢青蒿素在制备抗肿瘤多药耐药药物中的应用； 青蒿琥酯在制备抗肿瘤多药耐药药物中的应用； 青蒿提取物在制备抗肿瘤多药耐药药物中的应用； 青蒿素在制备作为长春新碱抗肿瘤增效剂药物中的应用。 二氢青蒿素在制备作为长春新碱抗肿瘤增效剂药物中的应用。 青蒿琥酯在制备作为长春新碱抗肿瘤增效剂药物中的应用。 青蒿提取物在制备作为长春新碱抗肿瘤增效剂药物中的应用。 青蒿素在制备治疗口腔鳞上皮癌药物中的应用。 二氢青蒿素在制备治疗口腔鳞上皮癌药物中的应用。 青蒿琥酯在制备治疗口腔鳞上皮癌药物中的应用。 青蒿提取物在制备治疗口腔鳞上皮癌药物中的应用。 所述青蒿提取物采用现有技术制备。 下述实验例用于进一步说明本发明： 本发明实验表明：在体外通过细胞杀伤增敏试验，证实在无明显的细胞毒剂量下，青蒿素和青蒿提取物可部分逆转长春新碱耐药KBV200细胞的耐药性。青蒿琥酯和二氢青蒿素对VCR杀伤KBV200有一定的增敏作用，且四者对VCR杀伤KBV200的增敏作用有剂量依赖效应，随其浓渡的升高，其RI相应升高。 实验例1青蒿素、二氢青蒿素、青蒿琥酯和青蒿提取物对KBV200的抑制实验 1材料 1.1细胞系 KBV200细胞由中国人民解放军军事医学科学院放射医学研究所提供。其由人口腔麟状上皮癌细胞(KB)经长春新碱诱导的多药耐药细胞系。经测定耐药倍数约175倍，以MDR1基因、Pgp糖蛋白高表达为主要耐药机制。该细胞株对其他抗癌药物具有交叉耐药性，对紫杉醇耐药约156倍；对秋水仙素和阿霉素耐药约15倍；但对高三尖杉酯、鬼臼乙叉甙、5-氟脲嘧啶的耐药性较低。 1.2药物 实验药物有：①青蒿素、二氢青蒿素、青蒿琥酯由中国科学院上海药物研究所李英研究员馈赠；青蒿提取物由北京中医院中医研究所制剂室提取。青蒿素、青蒿提取物、二氢青蒿素以少量DMSO溶解，配成浓度为0.2mol/l的母液，超声助溶，-20℃保存。实验前用无血清的培养基(pH＝7.2)稀释至所需浓度DMSO＜0.1％。青蒿琥酯实验前配制，用5％NaHCO3配成浓度为0.2mol/l的母液，超声助溶，再用无血清的培养基(pH＝7.2)稀释至所需浓度DMSO＜0.1％。②长春新碱(VCR)由北京第二制药厂生产(批号0208001)。注射用水配制，100μg/ml，分装，-20℃保存。 1.3试剂 主要包括：①四氮唑蓝(MTT)系瑞士Fluka公司产品，用时以PBS现配制，5mg/ml，过滤除菌，4℃避光保存。②胰蛋白酶系美国GIBCO公司产品，PBS溶液配制，浓度为0.25％，过滤除菌，4℃避光保存。③RPMI1640培养基由美国GIBCOBRL生产。④小牛血清由天津H&Y生物有限公司生产。 ⑤二甲基亚砜(DMSO)系美国Biomol公司产品。 1.4仪器 主要有：①恒温CO2培养箱由日本SANYO公司生产(型号MCO-15AC)。②酶标仪系奥地利ASYA-HITECH公司产品(型号Digiscan SA100)。③高速低温离心机系日本SANYO公司产品。④微量振荡器由北京海淀电子医疗仪器厂生产(型号WZ-2A)。⑤月坛牌洁净工作台由北京半导体设备厂生产。⑥倒置显微镜系日本Nikon公司产品。⑦显微镜BX60由日本(OLYMPUS公司)生产。⑧恒温水浴槽由北京医疗设备厂生产。 2方法 2.1细胞培养及耐药性维持 将保存于液氮中的KBV200细胞(细胞冻存液含10％二甲基亚砜，90％小牛血清)取出，于37℃-40℃水浴中迅速融化，1000rpm离心5min后弃上清，用含10％小牛血清的RPMI1640完全培养基重悬细胞，加入200nmol/L VCR维持耐药，置37℃含5％CO2的恒温培养箱中培养。当细胞贴壁生长至80％融合时，再以0.25％Trypsin/1mM EDTA消化传代。实验前一天更换培养液。 2.2细胞毒实验 取对数生长期的耐药细胞，用含10％小牛血清的RPMI1640培养液制成一定浓度的细胞悬液，加入96孔细胞培养板，每孔180μl实验用药溶液(青蒿素、二氢青蒿素、青蒿琥酯、青蒿提取物，下同)或160μl(逆转耐药组)，使每孔细胞数为0.6×104。或加入不同浓度的青蒿素溶液(二氢青蒿素溶液、青蒿琥酯溶液或青蒿提取物溶液)20μl或青蒿素溶液(二氢青蒿素溶液、青蒿琥酯溶液或青蒿提取物溶液)与VCR合剂40μl(终浓度)，设培养液调零组、不加药细胞空白组，每组设六个平行孔，置37℃含5％CO2的恒温培养箱中培养72小时。每孔加入5mg/ml MTT液15μl，继续培养4小时。离心去上清，每孔加入DMSO 150μl，充分振荡，酶标仪检测570nm下光密度值(OD值)。 实验重复4次。 2.3分组方法 实验分为细胞毒实验与逆转耐药实验两部分。实验内容包括：①测定不同浓度的长春新碱对KBv200细胞抑制率，并依据抑制率计算IC50(即细胞生长抑制率为50％时的药物浓度)。②分别测定实验用药青蒿素、青蒿琥酯、二氢青蒿素、青蒿提取物对KBv200的生长抑制率，依据抑制率计算IC50，并分别选择实验用药对KBV200细胞生长抑制率小于10％、20％、30％的药物浓度与长春新碱伍用对KBV200细胞的生长抑制率。并依据公式计算其逆转KBV200细胞倍数。 2.4计算方法 细胞生长抑制率IR(％)＝[1-(用药组OD值-调零空OD值/对照组OD值-调零空OD值)×100％。逆转倍数RI＝耐药细胞株的IC50/耐药细胞株加逆转剂的IC50。IC50应用加权线性回归计算(用POMS-36计算机软件处理)，并利用Excel软件绘图。 3结果 1长春新碱对KBV200细胞抑制率 依据细胞毒实验方法，观察不同浓度的长春新碱(VCR)对KBV200细胞的抑制效应。不同浓度的4次实验数据的平均值显示，VCR对KBV200细胞均有不同的抑制效应，结果见表1、图1(VCR对KBV200细胞生长抑制率标准折线图)。 表1、VCR对KBV200细胞生长抑制率 长春新碱(μg/ml) IR(％) 0.1250.2500.5001.0002.000 6.51±2.599.06±3.1313.9±3.5425.6±1.7166.3±0.01 注：VCR对KBV200抑制的IC50浓度为1.58±1.22μg/ml 从表1与图1可以看出，以对KBV200细胞抑制的IC50为基准，当VCR浓度在1μg/ml以下时对KBV200细胞抑制效应并不明显。当VCR浓度大于1.58μg/ml以上浓度时才具有较为明显的抑制效应。 2青蒿提取物及其活性成分对KBV200细胞抑制率 按照细胞毒实验方法，青蒿素、二氢青蒿素、青蒿琥酯和青蒿提取物对KBV200的抑制率效应，4次实验数据平均值显示，其对KBV200细胞均有一定抑制效应。其结果见表2-5与图2-5。 表2、青蒿素对KBV200细胞生长抑制率 青蒿素(μmol/l) IR(％) 1.252.505.0010.020.040.080.0160 0.040±2.011.140±2.852.690±4.365.870±3.9012.70±2.5319.22±5.5928.47±2.7343.57±5.20 注：青蒿素对KBV200抑制的IC50浓度为172.4±4.54umol/l 从表2与图2可以看出，当青蒿素浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。青蒿素浓度在160umol/l以下时对KBV200细胞抑制效应并不明显；当青蒿素浓度大于172.4umol/l以上浓度时，其对KBV200细胞的抑制率大于50％；小于80umol/l时对KBV200细胞的抑制率低于30％；小于40umol/l时对KBV200细胞的抑制率低于20％。 表3、青蒿琥酯对KBV200细胞生长抑制率 青蒿琥酯(μmol/l) IR(％) 0.03900.07800.01560.31300.62501.25002.50005.000010.00020.000 1.640±3.5208.650±7.0609.520±4.91018.41±4.42035.25±10.5247.56±1.25057.67±1.11069.85±6.90084.47±0.60095.02±6.560 注：青蒿琥脂对KBV200抑制的IC50浓度为1.466±3.75umol/l 从表3与图3可以看出，当青蒿琥酯浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。青蒿琥酯浓度在1.25umol/l以下时对KBV200细胞抑制效应并不明显；当浓度青蒿琥酯大于1.466umol/l以上浓度时，其对KBV200细胞的抑制率大于50％；小于0.313umol/l时对KBV200细胞的抑制率低于20％；小于0.039umol/l时对KBV200细胞的抑制率几乎无抑制效应。 表4、二氢青蒿素对KBV200细胞生长抑制率 二氢青蒿素(μmol/l) IR(％) 0.1560.3130.6251.2502.5005.00010.0020.0040.00 0.680±0.840.940±3.876.770±6.0310.00±3.3118.50±4.8832.30±10.148.69±6.5371.98±7.1689.99±4.39 注：二氢青蒿素对KBV200抑制的IC50浓度为11.16±5.48umol/l 从表4与图4可以看出，当与二氢青蒿素浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。二氢青蒿素浓度在10umol/l以下时对KBV200细胞抑制效应并不明显；当浓度二氢青蒿素大于11.16umol/l以上浓度时，其对KBV200细胞的抑制率大于50％；小于2.5umol/l时对KBV200细胞的抑制率低于20％；小于0.313umol/l时对KBV200细胞的抑制率几乎无抑制效应。 表5、青蒿提取物对KBV200细胞生长抑制率 青蒿提取物(μg/ml) IR(％) 0.5551.1102.2204.4408.88017.7535.5071.00142.0284.0 2.210±0.435.060±3.485.190±6.319.350±4.9614.68±5.7129.68±4.9666.23±7.8976.49±3.2889.94±1.9699.61±9.82 注：青蒿提取物对KBV200抑制的IC50浓度为29.25±6.14ug/ml 从表5与图5可以看出，当青蒿提取物浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。青蒿提取物浓度在17.75ug/ml以下时对KBV200细胞抑制效应并不明显；当青蒿提取物浓度大于29.25ug/ml以上浓度时，其对KBV200细胞的抑制率大于50％；小于17.75ug/ml时对KBV200细胞的抑制率低于30％；小于0.555ug/ml时对KBV200细胞的抑制率几乎无抑制效应. 实验例2青蒿素、二氢青蒿素、青蒿琥酯和青蒿提取物与VCR伍用对KBV200的抑制实验 (材料和方法同实验例1) 选择青蒿提取物及其活性成分对KBV200细胞抑制率小于10％、20％、30％药物浓度与VCR配伍使用，观察对KBV200细胞抑制率。其中，青蒿素浓度分别为10μmol/l、20μmol/l与40μmol/l；青蒿琥脂浓度分别为0.078μmol/l、0.156μmol/l与0.313μmol/l；二氢青蒿素浓度分别为0.625μmol/l、1.25μmol/与2.5μmol/l；青蒿提取物浓度分别为4.44μg/ml、8.88μg/ml与17.75μg/ml。研究结果见6-9与图6-9。 表6、青蒿素与VCR伍用对KBV200细胞生长抑制率 VCR浓度(μg/ml) VCR(％) VCR+青蒿素(％) VCR+青蒿素(％) VCR+青蒿素(％) 0.1250.2500.5001.0002.000 6.51±2.599.06±3.1313.9±3.5425.6±1.7166.3±0.01 28.92±3.8631.44±3.9937.69±4.7160.23±1.6486.33±3.76 28.98±8.2931.91±0.9640.37±4.6261.78±1.6289.72±5.78 32.36±4.8432.69±6.6543.91±3.9671.71±3.4291.36±7.58 注：当VCR浓度不变时，不同浓度的青蒿素与VCR伍用时具有不同的逆转KBV200耐药效应，10umol/l、20umol/l与40umol/l浓度的逆转倍数分别为2.29、2.68与3.0。 从表6与图6可以看出，VCR浓度不变，与对KBV200细胞的抑制率低于20％的10umol/l、20umol/l与40umol/l三个浓度的青蒿素抑制率配伍使用后，其对KBV200细胞的抑制率明显提高。其中，以40umol/l效果最佳。说明青蒿素可部分逆转长春新碱耐药KBV200细胞的耐药性。 表7、青蒿琥酯与VCR伍用对KBV200细胞生长抑制率 VCR(μg/ml) VCR(％) VCR+青蒿琥酯(％) VCR+青蒿琥酯(％) VCR+青蒿琥酯(％) 0.1250.2500.5001.0002.000 6.51±2.599.06±3.1313.9±3.5425.6±1.7166.3±0.01 13.65±0.2414.54±0.6217.62±0.0523.46±3.7273.01±0.54 25.52±1.0127.61±2.6729.72±6.7852.97±1.1977.09±1.06 37.42±7.2937.47±6.0940.86±7.6767.59±8.2582.24±1.84 注：当VCR浓度不变时，不同浓度的青蒿琥脂与VCR伍用时对VCR杀伤KBV200有一定的增敏作用。0.078umol/l、0.156umol/l与0.313umol/l浓度的逆转倍数分别为1.19、1.79与2.57。 从表7与图7可以看出，VCR浓度不变，与对KBV200细胞的抑制率低于20％的0.078umol/l、0.156umol/l与0.313umol/l三个浓度的青蒿琥酯抑制率伍用后，对KBV200细胞的抑制率略有提高。其中，以0.313umol/l效果最佳。说明青蒿琥酯对VCR杀伤KBV200有一定的增敏作用。 表8、二氢青蒿素与VCR伍用对KBV200细胞生长抑制率 VCR(μg/ml) VCR(％) VCR+二氢青蒿素(％) VCR+二氢青蒿素(％) VCR+二氢青蒿素(％) 0.1250.2500.5001.0002.000 6.510±2.599.060±3.1313.96±3.5425.65±1.7166.31±0.01 9.69±7.20020.92±7.9121.96±0.6135.35±3.8271.34±4.38 20.60±4.4021.30±5.4227.62±5.6549.56±1.1172.90±3.22 29.50±1.433.15±5.5636.43±7.6552.39±5.3176.62±6.29 注：当VCR浓度不变时，不同浓度的二氢青蒿素与VCR伍用时对VCR杀伤KBV200有一定的增敏作用，0.625umol/l、1.25umol/l与2.5umol/l浓度的逆转倍数分别为1.35、1.515与1.74。 从表8与图8可以看出，VCR浓度不变，与对KBV200细胞的抑制率低于20％0.625umol/l、1.25umol/l与2.5umol/l的三个浓度的二氢青蒿素抑制率伍用后，对KBV200细胞的抑制率略有提高。其中，以2.5umol/l效果最佳。说明二氢青蒿素对VCR杀伤KBV200有一定的增敏作用。 表9、青蒿提取物与VCR伍用对KBV200细胞生长抑制率 VCR(μg/ml) VCR(％) VCR+青蒿提取物(％) VCR+青蒿提取物(％) VCR+青蒿提取物(％) 0.1250.2500.5001.0002.000 6.51±2.599.06±3.1313.9±3.5425.6±1.7166.3±0.01 22.21±7.5622.89±1.3424.51±4.9572.14±4.2683.12±1.26 24.28±2.2926.71±0.1249.94±5.6274.52±4.7182.12±2.54 51.20±5.9452.68±5.4271.68±8.1281.59±3.4782.12±1.68 注：当VCR浓度不变时，不同浓度的青蒿提取物与VCR伍用时具有不同的逆转KBV200耐药效应，4.44μg/ml、8.88μg/ml mol/l与17.75μg/ml浓度的逆转倍数分别为2.11、2.98与12.74。 从表9与图9可以看出，VCR浓度不变，与对KBV200细胞的抑制率低于30％的4.44μg/ml、8.88μg/ml与17.75μg/ml三个浓度的青蒿提取物抑制率伍用后，对KBV200细胞的抑制率明显提高。其中，以17.75μg/ml效果最佳。说明青蒿提取物可部分逆转长春新碱耐药KBV200细胞的耐药性。 本发明的研究结果： ①当VCR与青蒿素浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。同时，当VCR小于1.58±1.22μg/ml时，其对KBV200细胞的抑制率小于50％；当青蒿素浓度大于172.4umol/l以上浓度时，其对KBV200细胞的抑制率大于50％；小于80umol/l时对KBV200细胞的抑制率低于30％；小于40umol/l时对KBV200细胞的抑制率低于20％；小于2.50umol/l时对KBV200细胞的抑制率几乎无抑制效应。上述研究证实，青蒿素大浓度具有一定的抑制KBV200细胞增殖效应。②当VCR与青蒿琥酯浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。同时，当青蒿琥酯浓度大于1.466umol/l以上浓度时，其对KBV200细胞的抑制率大于50％；小于0.313umol/时对KBV200细胞的抑制率低于20％；小于0.039umol/l时对KBV200细胞的抑制率几乎无抑制效应.上述研究证实，青蒿琥酯大浓度具有一定的抑制KBV200细胞增殖效应。③当VCR与二氢青蒿素浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。同时，当二氢青蒿素浓度大于11.16umol/l以上浓度时，其对KBV200细胞的抑制率大于50％；小于2.5umol/l时对KBV200细胞的抑制率低于20％；小于0.313umol/l时对KBV200细胞的抑制率几乎无抑制效应。上述研究证实，二氢青蒿素大浓度具有一定的抑制KBV200细胞增殖效应。④当VCR与青蒿提取物浓度呈梯度稀释时，其对KBV200细胞的抑制作用也逐渐减低。同时，当青蒿提取物浓度大于29.25ug/ml以上浓度时，其对KBV200细胞的抑制率大于50％；小于17.75ug/ml时对KBV200细胞的抑制率低于30％；小于0.555ug/ml时对KBV200细胞的抑制率几乎无抑制效应。上述研究证实，青蒿提取物浓度大浓度具有一定的抑制KBV200细胞增殖效应。 本实验中青蒿琥酯对KBV200细胞的IC50为1.466μmol/l(0.563μg/ml)，实验结果说明青蒿琥酯对KBV200细胞有选择性杀伤作用。 本实验结果对青蒿素骨架上12-C上内酯环为羰基(第12位上)进行衍生化处理后的青蒿琥酯IC50为1.466μmol/l(0.563μg/ml)，对肿瘤细胞的抑制作用比青蒿素显著增强，青蒿素IC50为172.4μmol/l(48.58μg/ml)，而酮基被还原后的产物二氢青蒿素对肿瘤细胞的抑制作用较青蒿琥酯次之，二氢青蒿素IC50为11.16μmol/l(3.18μg/ml)。 青蒿提取物，取200g的生药(产地：河北)，提取成22.9g的乙醇粗提物。本实验用的青蒿提取物约含青蒿素为0.83％，而本实验中青蒿提取物对KBV200细胞IC50为29.25μg/ml。 本发明的研究结果发现：①当VCR浓度不变时，与对KBV200细胞抑制率低于20％的10umol/l、20umol/l与40umol/l三个浓度的青蒿素抑制率伍用后，逆转倍数分别为2.29、2.68与3.0。对KBV200细胞的抑制率明显提高。实验结果证明，青蒿素可部分逆转长春新碱耐药KBV200细胞的耐药性且逆转长春新碱耐药KBV200细胞效应与用药剂量成正比。②当VCR浓度不变时，与对KBV200细胞抑制率低于20％的0.078umol/l、0.156umol/l与0.313umol/l三个浓度的青蒿琥酯抑制率伍用后，逆转倍数分别为1.19、1.79与2.57。对KBV200细胞的抑制率略有提高。实验结果证明，青蒿琥酯对VCR杀伤KBV200有一定的增敏作用且对VCR杀伤KBV200的增敏作用与用药剂量成正比。③当VCR浓度不变时，与对KBV200细胞抑制率低于20％的0.625umol/l、1.25umol/l与2.5umol/l三个浓度的二氢青蒿素抑制率伍用后，逆转倍数分别为1.35、1.515与1.74。对KBV200细胞的抑制率略有提高。实验结果证明，二氢青蒿素对VCR杀伤KBV200有一定的增敏作用且对VCR杀伤KBV200的增敏作用与用药剂量成正比。④当VCR浓度不变时，与对KBV200细胞抑制率低于30％的4.44μg/ml、8.88μg/ml与17.75μg/ml三个浓度的青蒿提取物抑制率伍用后，逆转倍数分别为2.11、2.98与12.74。对KBV200细胞的抑制率明显提高。实验结果证明，青蒿提取物可逆转长春新碱耐药KBV200细胞的耐药性且逆转长春新碱耐药KBV200细胞效应与用药剂量成正比。 英文缩写 OD(Opitical density) 吸光度 RPMI1640(RPMI mediμm 1640) RPMI1640培养基 DMSO(Dimethyl Sμlfoxide) 二甲基亚砜 MTT(3-4，5-dimethylthiazol-2-y1) 四氮唑蓝 VCR(Vincristine) 长春新碱 KB 口腔鳞上皮癌状细胞系 KBV200 耐药口腔鳞上皮癌状细胞系 IR(Inhibitory rate) 抑制率 IC10(10％Inhibitory concentration) 抑制率为10％药物浓度 IC20(20％Inhibitory concentration) 抑制率为20％药物浓度 IC30(30％Inhibitory concentration) 抑制率为30％药物浓度 IC50(50％inhibitory concentration) 抑制率为50％药物浓度 MDR(mμltidrμg resistance) 多药耐药 RI(Reversal index) 逆转指数 附图说明： 将上述实验中涉及的图在此作为附图进行说明 图1：VCR对KBV200细胞生长抑制率标准折线图 图2、青蒿素对KBV200细胞生长抑制率标准折线图 图3、青蒿琥酯对KBV200细胞生长抑制率标准折线图 图4、二氢青蒿素对KBV200细胞生长抑制率标准折线图 图5、青蒿提取物对KBV200细胞生长抑制率折线图 图6、青蒿素与VCR伍用后对KBV200细胞生长率标准折线图 图7、青蒿琥酯与VCR伍用对KBV200细胞生长抑制率折线图 图8、二氢青蒿素与VCR伍用对KBV200细胞生长抑制折线图 图9、青蒿提取物与VCR伍用对KBV200细胞生长抑制折线图 下述实施例均能够实现上述实验所述的效果 具体实施方式 实施例1：青蒿素片剂 口服剂量30-50mg。每日2次。 实施例2：二氢青蒿素片剂 口服剂量30-50mg。每日2次。 实施例3：青蒿琥酯片剂 口服剂量50-100mg。每日2次。 实施例4：青蒿提取物片剂 青蒿提取物，取200g的生药提取成22.9g的乙醇粗提物，加入常规辅料，压片，制得100片。口服剂量2-3片。每日2次。 1.青蒿素在制备抗肿瘤多药耐药药物中的应用。 2.二氢青蒿素在制备抗肿瘤多药耐药药物中的应用。 3.青蒿琥酯在制备抗肿瘤多药耐药药物中的应用。 4.青蒿提取物在制备抗肿瘤多药耐药药物中的应用。 5.青蒿素在制备作为长春新碱抗肿瘤增效剂药物中的应用。 6.二氢青蒿素在制备作为长春新碱抗肿瘤增效剂药物中的应用。 7.青蒿琥酯在制备作为长春新碱抗肿瘤增效剂药物中的应用。 8.青蒿提取物在制备作为长春新碱抗肿瘤增效剂药物中的应用。 9.青蒿素在制备治疗口腔鳞上皮癌药物中的应用。 10.二氢青蒿素、青蒿琥酯或青蒿提取物中的任一中药物在制备治疗口腔鳞上皮癌药物中的应用。 Application of artemisine in preparing artitumor multi-medicine-resistant medicine The present invention discloses an application of artemisinin, dihydroartemisinin and artesunate in the preparation of anti-tumor multi-drug resistant drugs, discloses an application of artemisinin, dihydroartemisinin and artesunate in the preparation of the drugs which are taken as the vincristine anti-tumor synergists and discloses an application of artemisinin, dihydroartemisinin and artesunate in the preparation of the drugs for treating oral squamous cell carcinoma, the applications of the present invention are proven to have great clinical significance by the trials. The application of arteannuin in the preparation artitumor multi-medicine-resistant medicine Technical field The present invention relates to the application of arteannuin in the preparation artitumor multi-medicine-resistant medicine, belong to field of medicaments. Background technology Tumor multi-medicine drug-resistant is one of major reason that causes the chemotherapy of tumors failure.Multidrug resistance (multidrug Resistance, MDR) be meant that tumor cell develops immunity to drugs to a kind of antitumor drug in accepting the cancer drug therapy process in, to structure and the diverse antineoplastic agent deposits yields cross-resistance of effect.Cause tumor multi-medicine drug-resistant mechanism complicated, tumor cell can obtain multidrug resistance by different approaches.Think at present, cause MDR mechanism to comprise: 1. be present in the P glycoprotein on the tumor cell membrane, multidrug-associated protein, lung resistance-related protein unconventionality expression; 2. desmoenzyme abnormal changes such as phosphokinase C, DNA topoisomerase II, glutathion (GSH) and glutathione-S-transferase.In addition, the variation of the increase of the synzyme of thymidine (TS), aldehyde dehydrogenase (ALDH) and dihydrofolate reductase (DHFR) also can cause the chemical sproof generation of cell; 3. natural death of cerebral cells (Apoptosis) gene and cytokine change.4. DNA repairs unusual; 5. organ microenvironment and other factors etc. In recent years, along with to the deepening continuously of tumor drug resistance Mechanism Study, had been found that some multidrug resistance reversing agent and active component thereof.Mainly contain: 1. calcium channel blocker, as be verapamil; 2. immunosuppressant is as Ciclosporin A; 3. glutathione transferase (GST) and TOP isomerase II inhibitor; 4. hormone and hormone antagonist compounds; 5. kinases inhibitor; 6. DNA repairs related enzyme activity inhibitor etc.But what can enter clinical research has only only a fews such as isoptin, cyclosporin A, SDZPSC833, zitazonium, and clinical reversing effect is unsatisfactory.It mainly contains following reason: 1. toxic and side effects has limited dosage; 2. the clinical drug-resistant of multimachine system participation formation makes the single inversion agent of action target spot be difficult to play a role; 3. biological preparation is unstable in vivo, and the half-life is short, be difficult to affact the target spot position, and side reaction is many. In the last few years, found that many Chinese medicines and active ingredient of Chinese herbs thereof can reverse multiple drug resistance of tumor, particularly Chinese medicine reversing tumor drug resistance is after the classical mechanism of the MDR of P-gP mediation is generally acknowledged the back and affirmed the reverse effect to MDR such as calcium antagonist isoptin, and the tumor research persons begin the MDR reversal agents that research evaluation effect is strong from the Chinese medicine with calcium channel antagonistic activity consciously, toxicity is little both at home and abroad.Result of study is found: 1. Chinese herb rhubarb Main Ingredients and Appearance emodin/chrysophanic acid can increase the cytotoxicity of antitumor drug under low dosage, and can partly reverse the MDR of tumor cell; 2. Tetrandrine, Dauricine, liensinine, left-handed tetrahydrochysene Ma Ting and ginsenoside Rb1's reverse multiple drug resistance of tumor effect is obvious, and reversing multiple and be 8.2-13.0 and matrine, aconitine has in various degree reverse effect to the property of medicine of drug-resistant cell strain; 3. Chinese medicine Radix Stephaniae Tetrandrae extract tetrandrine can suppress the MDR characteristic of mdr cell to a certain extent; 4. the main active ingredient Peimine and the Peiminine that reduce phlegm in the Chinese medicine Bulbus Fritillariae Uninbracteatae show unique characteristics aspect reverse multiple drug resistance of tumor, its chemical constitution is under the jurisdiction of the cevine Alkaloid of different steroidal alkaloid, be different from calcium ion antagonist, immunosuppressant and other existing reversal agent of drug resistance fully, and can act on the tumor cell of resistance mechanism difference (P-gP or MDR), potential applicability in clinical practice is arranged very much.The Chinese traditional compound medicine R3 of the class of 5. regulating the flow of vital energy Chinese medicine Rhizoma Corydalis, Fructus Psoraleae extractant, Chinese medicinal formulae (forming) by drug for invigorating blood circulation and eliminating stasis such as Rhizoma Chuanxiong, Rhizoma Curcumae, Caulis Spatholobis but extracting solution R1 etc. have 6. Bulbus Fritillariae Thunbergii powder reversing acute leukemia multidrug resistance of reversing drug resistance effect.But these medicine/active ingredients or stay in laboratory stage, or the back toxicity of purifying is bigger, or it is lower and be difficult to realize the reversing drug resistance effect to reverse multiple. Herba Artemisiae Annuae is clinical conventional Chinese medicine, and bitter in the mouth suffering, cold in nature is returned liver, gallbladder meridian.Have heat clearing away, expelling summer-heat, remove steam, the effect of preventing the attack (or recurrence) of malaria.Diseases such as pathogenic summer-heat heatings, fever due to yin deficiency, night fever abating at dawn, hectic fever due to YIN-deficiency consumptive fever, malaria cold and heat, jaundice due to damp-heat are treated in normal clinically and other drug matchings.Its Main Ingredients and Appearance is an arteannuin, and arteannuin also is its antimalarial main active ingredient simultaneously.Arteannuin and derivant thereof are the specially good effect new antimalarial agents of China's independent development exploitation, it has advantage quick, safe and efficient, no Drug resistance, more because its structure is special, pharmacological action is extensive, enjoys domestic and international the world of medicine to pay close attention to having potential tempting prospect aspect the multiple diseases such as anti-curing oncoma, acquired immune deficiency syndrome (AIDS).Arteannuin is the ester compounds that contains the sesquiterpene of a peroxide bridge, because the uniqueness of its structure, and makes its malaria mechanism of action and known antimalarial far different.Experimentation shows, arteannuin mainly is by damaging plasmodial film system to the plasmodium scavenging action, and tumor multi-medicine drug-resistant produces important mechanisms and tumor cell membrane abnormal protein have substantial connection, this just enlightens the antimalarial pharmacological mechanism of artemisin, may be to the tumor multi-medicine drug-resistant treatment effectively. Summary of the invention The object of the invention is to provide the application of arteannuin in the preparation artitumor multi-medicine-resistant medicine; The object of the invention is to provide the application of dihydroartemisinine in the preparation artitumor multi-medicine-resistant medicine; The object of the invention is to provide the application of artesunate in the preparation artitumor multi-medicine-resistant medicine; The object of the invention is to provide the application of Herba Artemisiae Annuae extract in the preparation artitumor multi-medicine-resistant medicine; Technical scheme of the present invention is: The application of arteannuin in the preparation artitumor multi-medicine-resistant medicine; The application of dihydroartemisinine in the preparation artitumor multi-medicine-resistant medicine; The application of artesunate in the preparation artitumor multi-medicine-resistant medicine; The application of Herba Artemisiae Annuae extract in the preparation artitumor multi-medicine-resistant medicine; Arteannuin is preparing as the application in the vincristine antitumor synergist medicine. Dihydroartemisinine is preparing as the application in the vincristine antitumor synergist medicine. Artesunate is preparing as the application in the vincristine antitumor synergist medicine. Herba Artemisiae Annuae extract is preparing as the application in the vincristine antitumor synergist medicine. The application of arteannuin in the squama epithelial cancer medicine of preparation treatment oral cavity. The application of dihydroartemisinine in the squama epithelial cancer medicine of preparation treatment oral cavity. The application of artesunate in the squama epithelial cancer medicine of preparation treatment oral cavity. The application of Herba Artemisiae Annuae extract in the squama epithelial cancer medicine of preparation treatment oral cavity. Described Herba Artemisiae Annuae extract adopts prior art for preparing. Following experimental example is used to further specify the present invention: The present invention's experiment shows: by the test of cell killing enhanced sensitivity, confirm that arteannuin and Herba Artemisiae Annuae extract can partly reverse vincristine drug resistance KB under no tangible cell toxic amount external V200The drug resistance of cell.Artesunate and dihydroartemisinine kill and wound KB to VCR V200Certain sensitization is arranged, and four kill and wound KB to VCR V200Sensitization dose-dependent effect is arranged, with its dense rising of crossing, the corresponding rising of its RI. Experimental example 1 arteannuin, dihydroartemisinine, artesunate and Herba Artemisiae Annuae extract are to KB V200Inhibition experiment 1 material 1.1 cell line KB V200Cell is provided by Institute of Radiation Medicine, Academy of Military Medical Sciences, PLA.Its by human mouth unicorn columnar epithelium cancerous cell (KB) through the inductive multiple medicine-resistant cell line of vincristine.The drug resistance multiple is about 175 times after measured, with MDR 1Gene, Pgp glycoprotein high expressed are main resistance mechanism.This cell strain has cross resistance to other cancer therapy drugs, about 156 times to taxol resistance; To about 15 times of Colchicine and amycin drug resistance; But the drug resistance to high Folium et Ramulus Cephalotaxi ester, etoposide, 5-fluorouracil is lower. 1.2 medicine The experiment medicine has: 1. arteannuin, dihydroartemisinine, artesunate are presented by the Li Ying researcher of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences; Herba Artemisiae Annuae extract is extracted by Beijing Drug Manufacturing Room of institute of traditional Chinese medicine Academy of Traditional Chinese Medicine.Arteannuin, Herba Artemisiae Annuae extract, dihydroartemisinine dissolve with a small amount of DMSO, are made into the mother solution that concentration is 0.2mol/l, ultrasonic hydrotropy ,-20 ℃ of preservations.Culture medium (pH=7.2) with serum-free before the experiment is diluted to desired concn DMSO＜0.1%.5%NaHCO is used in preparation before the artesunate experiment 3Be made into the mother solution that concentration is 0.2mol/l, ultrasonic hydrotropy, the culture medium of reuse serum-free (pH=7.2) is diluted to desired concn DMSO＜0.1%.2. vincristine (VCR) is produced (lot number 0208001) by Beijing No.2 Pharmaceutical Factory.The water for injection preparation, 100 μ g/ml, packing ,-20 ℃ of preservations. 1.3 reagent Mainly comprise: 1. tetrazole indigo plant (MTT) is Switzerland Fluka company product, and the time spent now prepares with PBS, 5mg/ml, and filtration sterilization, 4 ℃ keep in Dark Place.2. trypsin is a U.S. GIBCO company product, the preparation of PBS solution, and concentration is 0.25%, filtration sterilization, 4 ℃ keep in Dark Place.3. the RPMI1640 culture medium is produced by U.S. GIBCOBRL.4. calf serum is by Tianjin H﹠amp; The biological company limited production of Y. 5. dimethyl sulfoxide (DMSO) is a U.S. Biomol company product. 1.4 instrument Mainly contain: 1. constant temperature CO 2Incubator is by Japanese SANYO company's production (model MCO-15AC).2. microplate reader is Austrian ASYA-HITECH company's product (model Digiscan SA100).3. high speed low temperature centrifugal machine is a Japanese SANYO company product.4. micro oscillator is produced (model WZ-2A) by Haidian, Beijing electronic medical instruments factory.5. the Temple of Moon board clean bench is produced by Beijing semiconductor equipment factory.6. inverted microscope is a Japanese Nikon company product.7. microscope BX60 is produced by Japan (OLYMPUS company).8. constant temperature water bath is produced by Beijing Medical Equipment Plant. 2 methods 2.1 cell culture and drug resistance are kept With the KB that is stored in the liquid nitrogen V200(cells frozen storing liquid contains 10% dimethyl sulfoxide to cell, 90% calf serum) takes out, in 37 ℃ of-40 ℃ of water-baths, melt rapidly, abandon supernatant behind the centrifugal 5min of 1000rpm, with the RPMI1640 complete medium re-suspended cell that contains 10% calf serum, add 200nmol/L VCR and keep drug resistance, put 37 ℃ and contain 5%CO 2Constant incubator in cultivate.When cell attachment grows to 80% fusion, again with 0.25%Trypsin/1mM EDTA had digestive transfer culture.Test and change culture fluid the previous day. 2.2 cellulotoxic experiment The take the logarithm mdr cell of trophophase, make certain density cell suspension with the RPMI1640 culture fluid that contains 10% calf serum, add 96 porocyte culture plates, every hole 180 μ l experimental drug solution (arteannuin, dihydroartemisinine, artesunate, Herba Artemisiae Annuae extract, together following) or 160 μ l (reversing drug resistance group), making every porocyte number is 0.6 * 10 4Or arteannuin solution (dihydroartemisinine solution, artesunate solution or Herba Artemisiae Annuae extract solution) the 20 μ l of adding variable concentrations or arteannuin solution (dihydroartemisinine solution, artesunate solution or Herba Artemisiae Annuae extract solution) and VCR mixture 40 μ l (final concentration), if culture fluid zeroing group, not dosing cell blank group, establish six parallel holes for every group, put 37 ℃ and contain 5%CO 2Constant incubator in cultivated 72 hours.Every hole adds 5mg/ml MTT liquid 15 μ l, continues to cultivate 4 hours.The centrifugal supernatant that goes, every hole adds DMSO 150 μ l, fully vibration, microplate reader detects optical density value (OD value) under the 570nm. Experiment repeats 4 times. 2.3 group technology Experiment is divided into cellulotoxic experiment and reversing drug resistance experiment two parts.Experiment content comprises: the vincristine of 1. measuring variable concentrations is to KB V200Cell inhibitory rate, and according to suppression ratio calculating IC 50(being that inhibitory rate of cell growth is 50% o'clock a drug level).2. distinguish determination experiment medication arteannuin, artesunate, dihydroartemisinine, Herba Artemisiae Annuae extract to KB V200Growth inhibition ratio, calculate IC according to suppression ratio 50, and select experimental drug respectively to KB V200Inhibitory rate of cell growth less than 10%, 20%, 30% drug level and vincristine 5 usefulness to KB V200The growth inhibition ratio of cell.And calculate it according to formula and reverse KB V200The cell multiple. 2.4 computational methods Inhibitory rate of cell growth IR (%)=[1-(the empty OD value of the medication group OD value-zeroing/empty OD value of matched group OD value-zeroing) * 100%.Reverse the IC of multiple RI=drug-resistant cell strain 50/ drug-resistant cell strain adds the IC of inversion agent 50IC 50Use weighted linear regression Calculation (using the POMS-36 software processing), and utilize Excel software to draw. 3 results 1 vincristine is to KB V200Cell inhibitory rate According to the cellulotoxic experiment method, the vincristine (VCR) of observing variable concentrations is to KB V200The cell inhibiting effect.The meansigma methods of 4 experimental datas of variable concentrations shows that VCR is to KB V200Cell all has different depression effects, the results are shown in Table 1, (VCR is to KB for Fig. 1 V200Inhibitory rate of cell growth standard broken line graph). Table 1, VCR are to KB V200Inhibitory rate of cell growth Vincristine (μ g/ml) IR(％) 0.125 0.250 0.500 1.000 2.000 6.51±2.59 9.06±3.13 13.9±3.54 25.6±1.71 66.3±0.01 Annotate: VCR is to KB V200The IC that suppresses 50Concentration is 1.58 ± 1.22 μ g/ml From table 1 and Fig. 1 as can be seen, with to KB V200The IC that cell suppresses 50Be benchmark, when VCR concentration when 1 μ g/ml is following to KB V200The cell depression effect is also not obvious.When VCR concentration just has comparatively obvious suppression effect during greater than the above concentration of 1.58 μ g/ml. 2 Herba Artemisiae Annuae extract and active component thereof are to KB V200Cell inhibitory rate According to the cellulotoxic experiment method, arteannuin, dihydroartemisinine, artesunate and Herba Artemisiae Annuae extract are to KB V200The suppression ratio effect, 4 experimental data meansigma methodss show that it is to KB V200Cell all has certain depression effect.It the results are shown in Table 2-5 and Fig. 2-5. Table 2, arteannuin are to KB V200Inhibitory rate of cell growth Arteannuin (μ mol/l) IR(％) 1.25 2.50 5.00 10.0 20.0 40.0 80.0 160 0.040±2.01 1.140±2.85 2.690±4.36 5.870±3.90 12.70±2.53 19.22±5.59 28.47±2.73 43.57±5.20 Annotate: arteannuin is to KB V200The IC that suppresses 50Concentration is 172.4 ± 4.54umol/l From table 2 and Fig. 2 as can be seen, when the arteannuin concentration in gradient diluted, it was to KB V200The cell inhibiting effect is also lowered gradually.Arteannuin concentration when 160umol/l is following to KB V200The cell depression effect is also not obvious; When arteannuin concentration during greater than the above concentration of 172.4umol/l, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 80umol/l to KB V200The cell inhibiting rate is lower than 30%; During less than 40umol/l to KB V200The cell inhibiting rate is lower than 20%. Table 3, artesunate are to KB V200Inhibitory rate of cell growth Artesunate (μ mol/l) IR(％) 0.0390 0.0780 0.0156 0.3130 0.6250 1.2500 2.5000 5.0000 10.000 20.000 1.640±3.520 8.650±7.060 9.520±4.910 18.41±4.420 35.25±10.52 47.56±1.250 57.67±1.110 69.85±6.900 84.47±0.600 95.02±6.560 Annotate: artesunate is to KB V200The IC that suppresses 50Concentration is 1.466 ± 3.75umol/l From table 3 and Fig. 3 as can be seen, when the artesunate concentration in gradient diluted, it was to KB V200The cell inhibiting effect is also lowered gradually.Artesunate concentration when 1.25umol/l is following to KB V200The cell depression effect is also not obvious; When concentration artesunate during greater than the above concentration of 1.466umol/l, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 0.313umol/l to KB V200The cell inhibiting rate is lower than 20%; During less than 0.039umol/l to KB V200Almost unrestraint effect of cell inhibiting rate. Table 4, dihydroartemisinine are to KB V200Inhibitory rate of cell growth Dihydroartemisinine (μ mol/l) IR(％) 0.156 0.313 0.625 1.250 2.500 5.000 10.00 20.00 40.00 0.680±0.84 0.940±3.87 6.770±6.03 10.00±3.31 18.50±4.88 32.30±10.1 48.69±6.53 71.98±7.16 89.99±4.39 Annotate: dihydroartemisinine is to KB V200The IC that suppresses 50Concentration is 11.16 ± 5.48umol/l From table 4 and Fig. 4 as can be seen, when diluting with the dihydroartemisinine concentration in gradient, it is to KB V200The cell inhibiting effect is also lowered gradually.Dihydroartemisinine concentration when 10umol/l is following to KB V200The cell depression effect is also not obvious; When concentration dihydroartemisinine during greater than the above concentration of 11.16umol/l, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 2.5umol/l to KB V200The cell inhibiting rate is lower than 20%; During less than 0.313umol/l to KB V200Almost unrestraint effect of cell inhibiting rate. Table 5, Herba Artemisiae Annuae extract are to KB V200Inhibitory rate of cell growth Herba Artemisiae Annuae extract (μ g/ml) IR(％) 0.555 1.110 2.220 4.440 8.880 17.75 35.50 71.00 142.0 284.0 2.210±0.43 5.060±3.48 5.190±6.31 9.350±4.96 14.68±5.71 29.68±4.96 66.23±7.89 76.49±3.28 89.94±1.96 99.61±9.82 Annotate: Herba Artemisiae Annuae extract is to KB V200The IC that suppresses 50Concentration is 29.25 ± 6.14ug/ml From table 5 and Fig. 5 as can be seen, when the Herba Artemisiae Annuae extract concentration in gradient diluted, it was to KB V200The cell inhibiting effect is also lowered gradually.Herba Artemisiae Annuae extract concentration when 17.75ug/ml is following to KB V200The cell depression effect is also not obvious; When Herba Artemisiae Annuae extract concentration during greater than the above concentration of 29.25ug/ml, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 17.75ug/ml to KB V200The cell inhibiting rate is lower than 30%; During less than 0.555ug/ml to KB V200Almost unrestraint effect of cell inhibiting rate. Experimental example 2 arteannuin, dihydroartemisinine, artesunate and Herba Artemisiae Annuae extract and VCR 5 usefulness are to KB V200Inhibition experiment (material and method are with experimental example 1) Select Herba Artemisiae Annuae extract and active component thereof to KB V200Cell inhibitory rate uses less than 10%, 20%, 30% drug level and VCR compatibility, observes KB V200Cell inhibitory rate.Wherein, arteannuin concentration is respectively 10 μ mol/l, 20 μ mol/l and 40 μ mol/l; Artesunate concentration is respectively 0.078 μ mol/l, 0.156 μ mol/l and 0.313 μ mol/l; Dihydroartemisinine concentration is respectively 0.625 μ mol/l, 1.25 μ mol/ and 2.5 μ mol/l; Herba Artemisiae Annuae extract concentration is respectively 4.44 μ g/ml, 8.88 μ g/ml and 17.75 μ g/ml.Result of study is seen 6-9 and Fig. 6-9. Table 6, arteannuin and VCR 5 usefulness are to KB V200Inhibitory rate of cell growth VCR concentration (μ g/ml) VCR (％) VCR+ arteannuin (%) VCR+ arteannuin (%) VCR+ arteannuin (%) 0.125 0.250 0.500 1.000 2.000 6.51±2.59 9.06±3.13 13.9±3.54 25.6±1.71 66.3±0.01 28.92±3.86 31.44±3.99 37.69±4.71 60.23±1.64 86.33±3.76 28.98±8.29 31.91±0.96 40.37±4.62 61.78±1.62 89.72±5.78 32.36±4.84 32.69±6.65 43.91±3.96 71.71±3.42 91.36±7.58 Annotate: when VCR concentration was constant, the arteannuin of variable concentrations had different reverse KB with 5 times spent of VCR V200The drug resistance effect, the reverse multiple of 10umol/l, 20umol/l and 40umol/l concentration is respectively 2.29,2.68 and 3.0. From table 6 and Fig. 6 as can be seen, VCR concentration is constant, and to KB V200After the arteannuin suppression ratio compatibility that the cell inhibiting rate is lower than 20% 10umol/l, 20umol/l and three concentration of 40umol/l used, it was to KB V200The cell inhibiting rate obviously improves.Wherein, with the 40umol/l best results.Illustrate that arteannuin can partly reverse vincristine drug resistance KB V200The drug resistance of cell. Table 7, artesunate and VCR 5 usefulness are to KB V200Inhibitory rate of cell growth VCR(μg/ml) VCR (％) VCR+ artesunate (%) VCR+ artesunate (%) VCR+ artesunate (%) 0.125 0.250 0.500 1.000 2.000 6.51±2.59 9.06±3.13 13.9±3.54 25.6±1.71 66.3±0.01 13.65±0.24 14.54±0.62 17.62±0.05 23.46±3.72 73.01±0.54 25.52±1.01 27.61±2.67 29.72±6.78 52.97±1.19 77.09±1.06 37.42±7.29 37.47±6.09 40.86±7.67 67.59±8.25 82.24±1.84 Annotate: when VCR concentration was constant, the artesunate of variable concentrations and 5 times spent of VCR were killed and wounded KB to VCR V200Certain sensitization is arranged.0.078umol/l, the reverse multiple of 0.156umol/l and 0.313umol/l concentration is respectively 1.19,1.79 and 2.57. From table 7 and Fig. 7 as can be seen, VCR concentration is constant, and to KB V200After the cell inhibiting rate is lower than artesunate suppression ratio 5 usefulness of 20% 0.078umol/l, 0.156umol/l and three concentration of 0.313umol/l, to KB V200The cell inhibiting rate slightly improves.Wherein, with the 0.313umol/l best results.Illustrate that artesunate kills and wounds KB to VCR V200Certain sensitization is arranged. Table 8, dihydroartemisinine and VCR 5 usefulness are to KB V200Inhibitory rate of cell growth VCR(μg/ml) VCR (％) VCR+ dihydroartemisinine (%) VCR+ dihydroartemisinine (%) VCR+ dihydroartemisinine (%) 0.125 0.250 0.500 1.000 2.000 6.510±2.59 9.060±3.13 13.96±3.54 25.65±1.71 66.31±0.01 9.69±7.200 20.92±7.91 21.96±0.61 35.35±3.82 71.34±4.38 20.60±4.40 21.30±5.42 27.62±5.65 49.56±1.11 72.90±3.22 29.50±1.4 33.15±5.56 36.43±7.65 52.39±5.31 76.62±6.29 Annotate: when VCR concentration was constant, the dihydroartemisinine of variable concentrations and 5 times spent of VCR were killed and wounded KB to VCR V200Certain sensitization is arranged, and the reverse multiple of 0.625umol/l, 1.25umol/l and 2.5umol/l concentration is respectively 1.35,1.515 and 1.74. From table 8 and Fig. 8 as can be seen, VCR concentration is constant, and to KB V200After the cell inhibiting rate is lower than dihydroartemisinine suppression ratio 5 usefulness of three concentration of 20%0.625umol/l, 1.25umol/l and 2.5umol/l, to KB V200The cell inhibiting rate slightly improves.Wherein, with the 2.5umol/l best results.Illustrate that dihydroartemisinine kills and wounds KB to VCR V200Certain sensitization is arranged. Table 9, Herba Artemisiae Annuae extract and VCR 5 usefulness are to KB V200Inhibitory rate of cell growth VCR(μg/ml) VCR (％) VCR+ Herba Artemisiae Annuae extract (%) VCR+ Herba Artemisiae Annuae extract (%) VCR+ Herba Artemisiae Annuae extract (%) 0.125 0.250 0.500 1.000 2.000 6.51±2.59 9.06±3.13 13.9±3.54 25.6±1.71 66.3±0.01 22.21±7.56 22.89±1.34 24.51±4.95 72.14±4.26 83.12±1.26 24.28±2.29 26.71±0.12 49.94±5.62 74.52±4.71 82.12±2.54 51.20±5.94 52.68±5.42 71.68±8.12 81.59±3.47 82.12±1.68 Annotate: when VCR concentration was constant, the Herba Artemisiae Annuae extract of variable concentrations had different reverse KB with 5 times spent of VCR V200The drug resistance effect, the reverse multiple of 4.44 μ g/ml, 8.88 μ g/ml mol/l and 17.75 μ g/ml concentration is respectively 2.11,2.98 and 12.74. From table 9 and Fig. 9 as can be seen, VCR concentration is constant, and to KB V200After the cell inhibiting rate is lower than Herba Artemisiae Annuae extract suppression ratio 5 usefulness of 30% 4.44 μ g/ml, 8.88 μ g/ml and three concentration of 17.75 μ g/ml, to KB V200The cell inhibiting rate obviously improves.Wherein, with 17.75 μ g/ml best results.Illustrate that Herba Artemisiae Annuae extract can partly reverse vincristine drug resistance KB V200The drug resistance of cell. Result of study of the present invention: 1. when VCR and the dilution of arteannuin concentration in gradient, it is to KB V200The cell inhibiting effect is also lowered gradually.Simultaneously, as VCR during less than 1.58 ± 1.22 μ g/ml, it is to KB V200The cell inhibiting rate is less than 50%; When arteannuin concentration during greater than the above concentration of 172.4umol/l, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 80umol/l to KB V200The cell inhibiting rate is lower than 30%; During less than 40umol/l to KB V200The cell inhibiting rate is lower than 20%; During less than 2.50umol/l to KB V200Almost unrestraint effect of cell inhibiting rate.Above-mentioned studies confirm that, the big concentration of arteannuin has certain inhibition KB V200Cell propagation effect.2. when VCR and the dilution of artesunate concentration in gradient, it is to KB V200The cell inhibiting effect is also lowered gradually.Simultaneously, when artesunate concentration during greater than the above concentration of 1.466umol/l, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 0.313umol/ to KB V200The cell inhibiting rate is lower than 20%; During less than 0.039umol/l to KB V200Almost unrestraint effect of cell inhibiting rate. above-mentioned studies confirm that, the big concentration of artesunate has certain inhibition KB V200Cell propagation effect.3. when VCR and the dilution of dihydroartemisinine concentration in gradient, it is to KB V200The cell inhibiting effect is also lowered gradually.Simultaneously, when dihydroartemisinine concentration during greater than the above concentration of 11.16umol/l, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 2.5umol/l to KB V200The cell inhibiting rate is lower than 20%; During less than 0.313umol/l to KB V200Almost unrestraint effect of cell inhibiting rate.Above-mentioned studies confirm that, the big concentration of dihydroartemisinine has certain inhibition KB V200Cell propagation effect.4. when VCR and the dilution of Herba Artemisiae Annuae extract concentration in gradient, it is to KB V200The cell inhibiting effect is also lowered gradually.Simultaneously, when Herba Artemisiae Annuae extract concentration during greater than the above concentration of 29.25ug/ml, it is to KB V200The cell inhibiting rate is greater than 50%; During less than 17.75ug/ml to KB V200The cell inhibiting rate is lower than 30%; During less than 0.555ug/ml to KB V200Almost unrestraint effect of cell inhibiting rate.Above-mentioned studies confirm that, the big concentration of Herba Artemisiae Annuae extract concentration has certain inhibition KB V200Cell propagation effect. Artesunate is to KB in this experiment V200The IC of cell 50Be 1.466 μ mol/l (0.563 μ g/ml), experimental result explanation artesunate is to KB V200The selective lethal effect of cell. It is artesunate IC after carbonyl (on the 12nd) carries out derivatization treatment that this experimental result goes up lactonic ring to 12-C on the arteannuin skeleton 50Be 1.466 μ mol/l (0.563 μ g/ml), to the inhibitory action of tumor cell than the remarkable enhancing of arteannuin, arteannuin IC 50Be 172.4 μ mol/l (48.58 μ g/ml), and the product dihydroartemisinine of ketone group after being reduced take second place dihydroartemisinine IC than artesunate to the inhibitory action of tumor cell 50Be 11.16 μ mol/l (3.18 μ g/ml). Herba Artemisiae Annuae extract, the crude drug (place of production: Hebei), be extracted into the ethanol crude extract of 22.9g of getting 200g.It is 0.83% that the Herba Artemisiae Annuae extract of this experiment usefulness contains arteannuin approximately, and in this experiment Herba Artemisiae Annuae extract to KB V200Cell IC50 is 29.25 μ g/ml. Result of study of the present invention is found: 1. when VCR concentration is constant, and to KB V200After cell inhibitory rate is lower than arteannuin suppression ratio 5 usefulness of 20% 10umol/l, 20umol/l and three concentration of 40umol/l, reverses multiple and be respectively 2.29,2.68 and 3.0.To KB V200The cell inhibiting rate obviously improves.Experimental result proves that arteannuin can partly reverse vincristine drug resistance KB V200The drug resistance of cell and reverse vincristine drug resistance KB V200Cytological effect is directly proportional with dosage.2. when VCR concentration is constant, and to KB V200After cell inhibitory rate is lower than artesunate suppression ratio 5 usefulness of 20% 0.078umol/l, 0.156umol/l and three concentration of 0.313umol/l, reverses multiple and be respectively 1.19,1.79 and 2.57.To KB V200The cell inhibiting rate slightly improves.Experimental result proves that artesunate kills and wounds KB to VCR V200Certain sensitization is arranged and VCR is killed and wounded KB V200Sensitization be directly proportional with dosage.3. when VCR concentration is constant, and to KB V200After cell inhibitory rate is lower than dihydroartemisinine suppression ratio 5 usefulness of 20% 0.625umol/l, 1.25umol/l and three concentration of 2.5umol/l, reverses multiple and be respectively 1.35,1.515 and 1.74.To KB V200The cell inhibiting rate slightly improves.Experimental result proves that dihydroartemisinine kills and wounds KB to VCR V200Certain sensitization is arranged and VCR is killed and wounded KB V200Sensitization be directly proportional with dosage.4. when VCR concentration is constant, and to KB V200After cell inhibitory rate is lower than Herba Artemisiae Annuae extract suppression ratio 5 usefulness of 30% 4.44 μ g/ml, 8.88 μ g/ml and three concentration of 17.75 μ g/ml, reverses multiple and be respectively 2.11,2.98 and 12.74.To KB V200The cell inhibiting rate obviously improves.Experimental result proves that Herba Artemisiae Annuae extract can reverse vincristine drug resistance KB V200The drug resistance of cell and reverse vincristine drug resistance KB V200Cytological effect is directly proportional with dosage. English abbreviation OD (Opitical density) absorbance RPMI1640 (RPMI medi μ m 1640) RPMI1640 culture medium DMSO (Dimethyl S μ lfoxide) dimethyl sulfoxide MTT (3-4,5-dimethylthiazol-2-y1) tetrazole indigo plant VCR (Vincristine) vincristine KB oral cavity squama epithelial cancer shape cell line KB V200Drug resistance oral cavity squama epithelial cancer shape cell line IR (Inhibitory rate) suppression ratio IC 10(10%Inhibitory concentration) suppression ratio is 10% drug level IC 20(20%Inhibitory concentration) suppression ratio is 20% drug level IC 30(30%Inhibitory concentration) suppression ratio is 30% drug level IC 50(50%inhibitory concentration) suppression ratio is 50% drug level MDR (m μ ltidr μ g resistance) multidrug resistance RI (Reversal index) reverses index Description of drawings: The figure that relates in the above-mentioned experiment is described as accompanying drawing at this Fig. 1: VCR is to KB V200Inhibitory rate of cell growth standard broken line graph Fig. 2, arteannuin are to KB V200Inhibitory rate of cell growth standard broken line graph Fig. 3, artesunate are to KB V200Inhibitory rate of cell growth standard broken line graph Fig. 4, dihydroartemisinine are to KB V200Inhibitory rate of cell growth standard broken line graph Fig. 5, Herba Artemisiae Annuae extract are to KB V200The inhibitory rate of cell growth broken line graph Fig. 6, arteannuin and VCR 5 usefulness back are to KB V200Cell growth rate standard broken line graph Fig. 7, artesunate and VCR 5 usefulness are to KB V200The inhibitory rate of cell growth broken line graph Fig. 8, dihydroartemisinine and VCR 5 usefulness are to KB V200Cell growth inhibited broken line graph Fig. 9, Herba Artemisiae Annuae extract and VCR 5 usefulness are to KB V200Cell growth inhibited broken line graph Following embodiment all can realize the described effect of above-mentioned experiment The specific embodiment Embodiment 1: the arteannuin tablet Oral dose 30-50mg.Every day 2 times. Embodiment 2: the dihydroartemisinine tablet Oral dose 30-50mg.Every day 2 times. Embodiment 3: the artesunate tablet Oral dose 50-100mg.Every day 2 times. Embodiment 4: the Herba Artemisiae Annuae extract tablet Herba Artemisiae Annuae extract, the crude drug of getting 200g is extracted into the ethanol crude extract of 22.9g, adds conventional adjuvant, and tabletting makes 100.Oral dose 2-3 sheet.Every day 2 times. 1. the application of arteannuin in the preparation artitumor multi-medicine-resistant medicine. 2. the application of dihydroartemisinine in the preparation artitumor multi-medicine-resistant medicine. 3. the application of artesunate in the preparation artitumor multi-medicine-resistant medicine. 4. the application of Herba Artemisiae Annuae extract in the preparation artitumor multi-medicine-resistant medicine. 5. arteannuin is preparing as the application in the vincristine antitumor synergist medicine. 6. dihydroartemisinine is preparing as the application in the vincristine antitumor synergist medicine. 7. artesunate is preparing as the application in the vincristine antitumor synergist medicine. 8. Herba Artemisiae Annuae extract is preparing as the application in the vincristine antitumor synergist medicine. 9. the application of arteannuin in the squama epithelial cancer medicine of preparation treatment oral cavity. 10. the application of the arbitrary Chinese medicine in dihydroartemisinine, artesunate or the Herba Artemisiae Annuae extract in the squama epithelial cancer medicine of preparation treatment oral cavity.

CN100586477C青蒿素及其衍生物与抗菌药物---预防及治疗细菌感染性疾病 CN100586477C: Artemisinin and Its Derivatives Combined with Antibacterial Drugs for the Prevention and Treatment of Bacterial Infectious Diseases 青蒿素及其衍生物与抗菌药物的联合应用 本发明公开了一种现有的抗疟药青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯新的用途，即，与抗菌药物联合应用抑制细菌生长，增强抗菌药物抗菌效力。尤其是使得青蒿琥酯除作为治疗疟疾药物外，能够在预防及治疗细菌感染性疾病中得到应用。 青蒿素及其衍生物与抗菌药物的联合应用 技术领域 本发明涉及药物应用领域，尤其涉及青蒿素及其衍生物的抗菌应用。 背景技术 感染性疾病是由于病原微生物侵入体内，在体内大量地繁殖所引起的疾病，是临床病人死亡的重要原因之一。造成患者死亡的原因其一是细菌大量繁殖释放毒素导致组织器官的损伤；其二是细菌成分通过激活免疫细胞，诱导TNF-α、IL-1、IL-6、NO等致炎细胞因子释放，引起多种炎症介质所形成的瀑布效应，可使炎症反应扩大甚至失去控制，最终导致以细胞自身性破坏为特征的全身性炎症即脓毒症的发生。细菌感染曾是人类第一死因，抗生素的发明带给了人类希望之光。但抗生素的普遍使用使越来越多的细菌产生了耐药性，如果不解决抗生素滥用的问题，等待人类的将是下一次黑暗。 青蒿提取物用来治疗疟疾相关的发热已经有一千多年的历史，除传统的抗疟作用外，青蒿类物质还具有其它方面的作用，如平喘、抗癌、抗血吸虫及对免疫系统的调节等。国内外有关青蒿素及其衍生物的研究很多，但研究范围主要集中在抗疟、抗癌、抗血吸虫的作用及其机制上。 青蒿琥酯(Artesunate)，化学名为二氢青蒿素-1，2-α-琥珀酸单酯，分子式为C19O8 H28，分子量384，是具有倍半萜结构的抗疟药青蒿素的衍生物。青蒿琥酯是新型的抗疟药，较之青蒿素，青蒿琥酯可配制成任何常规的制剂形式，包括固体和液体形式，给药非常方便。青蒿琥酯作为抗疟药，不但效价高，而且不易产生耐受性。 对青蒿素及其衍生物的抗炎作用已有报道，研究发现青蒿素可抑制LPS/TNF-α诱导性NO合酶的合成及NF-κB的激活；青蒿琥酯对LPS及合并干扰素刺激小鼠腹腔巨噬细胞NO的合成有明显的抑制作用；青蒿琥酯对LPS刺激的小鼠巨噬细胞RAW264.7也具有相似的保护作用；谭余庆等还发现青蒿提取物、青蒿素可降低内毒素休克小鼠LPO、ACP、内毒素、TNF-α、P450浓度，升高SOD活性，降低小鼠死亡率，延长小鼠的平均生存时间，对小鼠肝、肺组织形态也有一定的保护作用；王俊等发现青蒿素能抑制CpG ODN、LPS、热灭活的EC诱导细胞释放炎症因子，并对脓毒症模型小鼠具有显著保护作用。但是青蒿琥酯是否具有抗菌作用，是否能改善细菌对抗生素的耐药，增强抗生素的抗菌效力和对细菌导致的感染是否有效，未见报告。我国是青蒿素和其衍生物的主要生产地，由于该药物疗效高、毒性低，WHO已经将青蒿素列为世界治疗疟疾的主要药物，我国正在扩大青蒿种植和青蒿素生产，因此扩宽青蒿素类衍生物的适应症，将其应用于细菌感染疾病的防治，无疑对提高青蒿素类衍生物的利用、增加其经济价值并改善抗生素滥用所导致的耐药现象具有重要意义。 发明内容 本发明的目的在于将青蒿素及其衍生物，特别是青蒿琥酯应用到抗菌领域，不仅拓宽青蒿素及其衍生物，特别是青蒿琥酯的用途，而且可以减轻现有抗菌药物的滥用及其导致的耐药现象。 基于上述目的，本发明使用的技术方案是将青蒿素及其衍生物中的一种与抗菌药物中的一种进行联合应用，该应用不是做为疾病的治疗方法的应用，而是在配备治疗疾病(抗菌)的药物中的应用，其中上述两种成分的比例为1∶1～4096∶1，上两种成分可以制备成组合物，也可以是两种单独的药剂。上述两种成分能够产生协同抗菌效力，能够降低抗菌药物的最低抑菌浓度(MIC)和最低杀菌浓度(MBC)。 上述菌包括革兰氏阳性菌和革兰氏阴性菌；上述衍生物包括二氢青蒿素、蒿甲醚、蒿乙醚和青蒿琥酯；上述抗菌药物包括β-内酰胺类抗生素(青霉素类、头孢菌素类、非典型β-内酰胺类抗生素)、氨基糖苷类、克林霉素类、喹诺酮类的药物，在一较佳实施例中，上述抗菌药物为青霉素G、氨苄西林、头孢呋辛、头孢匹胺、庆大霉素、克林霉素、洛美沙星、加替沙星、舒氨西林和泰能，优选为庆大霉素、舒氨西林、头孢匹胺和加替沙星。 上述应用优选为青蒿琥酯与抗菌药物的联合应用。 青蒿琥酯单独使用可抑制革兰阴性菌和革兰阳性菌的生长，与抗菌药物联合应用后可明显增强抗菌药物的抗菌效力，减少抗菌药物的使用剂量；实验表明青蒿素及青蒿琥酯与抗菌药物联合应用可明显降低细菌(包括革兰阴性、阳性菌)攻击小鼠死亡率，显著抑制小鼠血清LPS含量和细胞因子TNF-α释放。 本发现人对青蒿琥酯体内外的抗菌和抗炎作用进行了研究。 首先，本研究人员对本青蒿琥酯的体外抗菌作用进行了药理学分析，并与抗生素联合应用后发现青蒿琥酯单独使用可抑制革兰阴性菌和革兰阳性菌的生长，与抗生素联合应用后可明显增强抗生素的抗菌效力，减少抗生素的使用剂量；其次，青蒿琥酯与抗生素联合应用和可明显降低细菌(包括革兰阴性、阳性菌)攻击小鼠死亡率，显著抑制小鼠血清LPS含量和细胞因子TNF-α释放。 因此本发明拓宽了青蒿素及其衍生物，特别是青蒿琥酯的用途，提高了抗菌药物的抗菌效力，减轻了抗菌药物滥用和导致的耐药现象。 附图说明 图1表示青蒿琥酯协同庆大霉素、头孢匹胺、舒氨西林对大肠埃希菌ATCC35218的联合抑菌曲线； 图2表示青蒿琥酯协同氨苄西林、加替沙星、舒氨西林对金葡菌ATCC25923的联合抑菌曲线； 图3表示青蒿琥酯协同庆大霉素、加替沙星、舒氨西林对大肠埃希菌临床分离株的联合抑菌曲线。 具体实施方式 下面结合实施例对本发明作进一步的说明，但所述实施例仅用于说明本发明而不是限制本发明。 青蒿琥酯(AS)与抗菌药物按照表1、表2中的配比，能够产生协同抗菌效力，降低抗菌药物的最低抑菌浓度和最低杀菌浓度。 实验例1 本实验例在于研究青蒿琥酯与十种抗菌药物对不同细菌的MIC(最低抑菌浓度)和MBC(最低杀菌浓度) 采用微孔稀释法，调整细菌浓度为105CFU/ml，接种于96孔无菌培养板内，青蒿琥酯和青霉素钠、氨苄西林等10种抗菌药物分别以生理盐水稀释为5.14mg/ml。加入各种药物至含细菌培养孔内，依次倍比稀释，第1～10孔药物的最终浓度依次为256、128、64、32、16、8、4、2、1、0.5ug/ml。置37℃培养箱孵育24h和48h，读取阳性和阴性对照孔，阴性对照孔清亮，阳性对照孔混浊。药物对细菌的MIC为24h后抑制细菌肉眼可见生长的最低药物浓度，药物对细菌的MBC为48h后抑制细菌肉眼可见生长的最低药物浓度。此次实验结果表明青蒿琥酯单独使用不能完全抑制细菌生长，并观察了不同抗菌药物对该五种细菌的抑菌效力。(见表3)。 表3 10种抗菌药物和AS的单独使用时对不同细菌的MIC及MBC 实验例2 本实验例在于研究青蒿琥酯与抗菌药物联合应用后对大肠埃希菌MIC和MBC的影响。 采用棋盘式微孔稀释法，调整细菌浓度为105CFU/ml，接种于96孔无菌培养板内，将对五种细菌中等敏感的抗菌药物用低于MIC的剂量与不同浓度青蒿琥酯分别配伍，观察配伍后的药物对大肠埃希菌的MIC和MBC。此次实验结果表明青蒿琥酯单独使用虽不能完全抑制细菌生长，但与抗菌药物联合应用后可明显降低抗菌药物的MIC和MBC，说明青蒿琥酯与抗菌药物协同后对细菌有协同的抑菌效力。(见表4)。 表4 各抗菌药物与青蒿琥酯协同后的最低抑菌浓度 实验例3 本实验例在于研究青蒿琥酯与1/2 MIC浓度的不同抗菌药物协同后对大肠埃希菌生长的抑制强度。 调整细菌浓度为106CFU/ml，测定菌液OD600为0.002(1OD＝5×108CFU/ml)，参照实验例1结果，分别单独加入终浓度为256μg/ml青蒿琥酯或1/2 MIC浓度的抗菌药物，以及同时加入256μg/ml青蒿琥酯和1/2MIC浓度的抗菌药物后，至于37℃恒温摇床150rpm振摇，分别测定1、3、5、7、9、12、16、24h时菌液的OD值，计算各时间点的细菌量。研究结果表明青蒿琥酯256μg/ml可使大肠埃希菌ATCC35218，金黄色葡萄球菌ATCC25923和大肠埃希菌临床分离株生长速度明显减慢，与单独使用抗菌药物相比，联合了青蒿琥酯后明显抑制细菌生长，抑制程度比单独使用抗菌药物或青蒿琥酯均强(图1、2、3)。 实验例4 本实验例在于研究青蒿琥酯联合应用抗菌药物对革兰阴性细菌攻击小鼠的保护作用 清洁级昆明种小白鼠70只(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿琥酯组、大肠埃希菌组，大肠埃希菌+庆大霉素组，青蒿琥酯(1.5、5、15mg/kg)+庆大霉素+大肠埃希菌组。每组10只动物。对照不给予任何试剂；青蒿素组肌肉注射15mg/kg的青蒿琥酯；大肠埃希菌组，给予0.8×106/kg活的大肠埃希菌ATCC35218；大肠埃希菌+庆大霉素组，给予庆大霉素0.5mg/kg肌肉注射后给予活大肠埃希菌ATCC35218；庆大霉素+青蒿琥酯+大肠埃希菌组，在给予青蒿琥酯后，立即给予庆大霉素及大肠埃希菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表5)。结果显示青蒿琥酯协同抗菌药物后可明显降低小鼠的死亡率，表明对青蒿琥酯与抗菌药物联合后出现协同保护作用。 表5 青蒿琥酯协同庆大霉素对大肠埃希菌ATCC35218攻击小鼠的保护作用 实验例5 本实验例在于研究青蒿琥酯联合应用抗菌药物对革兰阳性细菌攻击小鼠的保护作用 清洁级昆明种小白鼠70只(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿琥酯组、金葡菌组，金葡菌+加替沙星组，青蒿琥酯(5、15、45mg/kg)+加替沙星+金葡菌组。每组10只动物。对照不给予任何试剂；青蒿素组肌肉注射45mg/kg的青蒿琥酯；金葡菌组，给予1.0×107/kg活的金葡菌ATCC25923；金葡菌+加替沙星组，给予加替沙星0.5mg/kg肌肉注射后给予活金葡菌ATCC25923；加替沙星+青蒿琥酯+金葡菌组，在给予青蒿琥酯后，立即给予加替沙星及金葡菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表6)。结果显示青蒿琥酯协同抗菌药物后可明显降低小鼠的死亡率，表明对青蒿琥酯与抗菌药物联合后出现协同保护作用。 表6 青蒿琥酯协同加替沙星对金葡菌ATCC25923攻击小鼠的保护作用 实验例6 本实验例在于研究青蒿琥酯对灭活大肠埃希菌攻击小鼠的保护作用。 清洁级昆明种小白鼠60只(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿琥酯组、灭活大肠埃希菌组，青蒿琥酯(5、15、45mg/ml)+灭活大肠埃希菌组。每组8只动物。对照不给予任何试剂；青蒿琥酯组肌肉注射给予45mg/kg的青蒿琥酯，4h，24h，48h后重复给药一次；灭活大肠埃希菌组，给予1.25×1011/kg的灭活大肠埃希菌ATCC35218；青蒿琥酯+灭活大肠埃希菌组，在肌肉注射给予青蒿琥酯后，立即给予灭活大肠埃希菌ATCC35218，4h、24h、48h后重复肌肉注射给药青蒿琥酯1次。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表7)。结果显示青蒿琥酯可降低小鼠的死亡率，表明对致炎因子攻击的小鼠具有保护作用。 表7 青蒿琥酯对灭活大肠埃希菌攻击小鼠的保护作用 *p＜0.5；**p＜0.01 vs E.coli 实验例7 本实验例在于研究青蒿琥酯对灭活大肠埃希菌攻击小鼠血清细胞因子释放影响 清洁级昆明种小白鼠40只(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿琥酯组、灭活大肠埃希菌组、青蒿琥酯(5、15、45mg/kg)+灭活大肠埃希菌组，每组动物3只。对照不给予任何试剂。青蒿琥酯组肌肉注射给予45mg/kg的青蒿琥酯；青蒿琥酯(5、15、45mg/kg)+灭活大肠埃希菌组给予青蒿琥酯后立即给予灭活大肠埃希菌ATCC35218；给药完毕4h后摘眼球取血立即离心留置上清保存于-20℃，待测定细胞因子TNF-α(表8)。结果显示青蒿琥酯可显著降低灭活大肠埃希菌攻击小鼠血清细胞因子释放。 表8 青蒿琥酯降低灭活大肠埃希菌ATCC35218攻击小鼠血清细胞因子TNF-α释放(n＝6，x±SD) *p＜0.5；**p＜0.01 vs E.coli 本发明将青蒿琥酯与抗菌药物的联合应用，提高了抗生素的抗菌效力，将青蒿琥酯与抗生素联合应用还可以预防、治疗细菌感染。 本领域技术人员可以根据本发明所述内容，将青蒿素及其衍生物与抗菌药物的联合同样可以达到本发明所述效果。 1.青蒿琥酯与选自庆大霉素、头孢匹胺、舒氨西林、氨苄西林和加替沙星中的一种在制备抗菌药物中的应用。 2.根据权利要求1所述的应用，上述菌为革兰阳性菌或革兰阴性菌。 Combined application of artemisinin and its derivative and antibiotic medicine The present invention discloses the new use of available antimalarial arteannuin and its derivatives dihydro arteannuin, antiannuic methyl ether, antiannuic ethyl ether and antiannuic amber. Arteannuin and its derivatives are used through combination with antibiotic medicine to inhibit bacterial growth and enhance the antibiotic effect of available antibiotic medicine. Especially, antiannuic amberis applied in preventing and treating bacterial infection diseases except being used as antimalarial. The use in conjunction of arteannuin and derivant thereof and antibacterials Technical field The present invention relates to the medicinal application field, relate in particular to the antibacterial applications of arteannuin and derivant thereof. Background technology Infectious disease is owing in the pathogenic microorganism intrusive body, breed caused disease in vivo in large quantities, is one of major reason of clinical patient death.Cause the reason first antibacterial of death to breed the damage that the release toxin causes histoorgan in a large number; It two is that the antibacterial composition passes through immune cell activated, induce proinflammatory cytokines such as TNF-α, IL-1, IL-6, NO to discharge, cause the formed water fall effect of multiple inflammatory mediator, inflammatory reaction is enlarged even out of hand, finally causing with cell self property destruction is that the systemic inflammatory of feature is pyemic generation.Bacterial infection once was human first cause of the death, and antibiotic invention has brought human light of hope.But antibioticly generally make increasing antibacterial produce drug resistance,, wait for that human will be dark next time if do not solve the problem of antibiotic abuse. Herba Artemisiae Annuae extract is used for treating the relevant heating of malaria the history in more than 1,000 year, and except that traditional malaria effect, Herba Artemisiae Annuae class material also has the effect of others, as relieving asthma, anticancer, schistosomicide and to immune adjusting etc.The research of relevant arteannuin and derivant thereof both at home and abroad is a lot, but research range mainly concentrates on malaria, anticancer, antischistosomal effect and the mechanism thereof. Artesunate (Artesunate), chemistry dihydroartemisinine-1 by name, 2-α-monomester succinate, molecular formula is C19O8 H28, molecular weight 384 is the derivants with antimalarial arteannuin of sesquiterpene structure.Artesunate is novel antimalarial, and than arteannuin, artesunate can be mixed with the dosage form of any routine, comprises solid and liquid form, and administration is very convenient.Artesunate is as antimalarial, the height of not only tiring, and be difficult for producing toleration. To the existing report of the antiinflammatory action of arteannuin and derivant thereof, discover that arteannuin can suppress the activation of the synthetic and NF-κ B of LPS/TNF-α inductivity NO synthase; Artesunate to LPS and merge that interferon stimulates Turnover of Mouse Peritoneal Macrophages NO synthetic the obvious suppression effect arranged; Artesunate also has similar protective effect to the mouse macrophage RAW264.7 that LPS stimulates; Tan Yuqing etc. find that also Herba Artemisiae Annuae extract, arteannuin can reduce endotoxin shock mice LPO, ACP, endotoxin, TNF-α, P450 concentration, the increased SOD activity, reduce mouse death rate, prolong the mean survival time of mice, Mouse Liver, lung tissue form are also had the certain protection effect; Discovery arteannuin such as Wang Jun can suppress CpG ODN, LPS, heat-inactivated EC inducing cell discharges inflammatory factor, and the sepsis model mice is had remarkable protective effect.But whether artesunate has antibacterial action, whether can improve the drug resistance of bacterial antibiotic, strengthen antibiotic antibacterial efficacy and infection that antibacterial is caused whether effective, announcement does not appear in the newspapers.China is the main grown place of arteannuin and its derivant, because this curative effect of medication height, toxicity are low, WHO has classified arteannuin as the main medicine of world's treatment malaria, China is enlarging Herba Artemisiae Annuae plantation and arteannuin production, therefore widen the indication of artemisinin derivatives, be applied to the control of bacterial infective diseases, undoubtedly to the utilization that improves artemisinin derivatives, increase its economic worth and improve the drug resistance phenomenon that the antibiotic abuse caused significant. Summary of the invention The objective of the invention is to arteannuin and derivant thereof, particularly artesunate is applied to antibiotic field, not only widen the purposes of arteannuin and derivant thereof, particularly artesunate, and can alleviate the abuse of existing antibacterials and the drug resistance phenomenon that causes thereof. Based on above-mentioned purpose, the technical scheme that the present invention uses is with a kind of use in conjunction of carrying out in a kind of and antibacterials in arteannuin and the derivant thereof, this application is not the application as the treatment of diseases method, but the application in the medicine that is equipped with treatment disease (antibiotic), wherein above-mentioned two kinds of components in proportions are 1: 1～4096: 1, last two kinds of compositions can be prepared into compositions, also can be two kinds of independent medicaments.Above-mentioned two kinds of compositions can produce Synergistic antimicrobial and render a service, and can reduce the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of antibacterials. Above-mentioned bacterium comprises gram positive bacteria and gram negative bacteria; Said derivative comprises dihydroartemisinine, Artemether, arteether and artesunate; Above-mentioned antibacterials comprise the medicine of beta-lactam antibiotic (penicillins, cephalosporins, atypia beta-lactam antibiotic), aminoglycoside, clindamycin class, quinolones, in a preferred embodiment, above-mentioned antibacterials are benzylpenicillin, ampicillin, cefuroxime, cefpiramide, gentamycin, clindamycin, lomefloxacin, Gatifloxacin, ampicillin sodium-sulbactam sodium and safe energy, are preferably gentamycin, ampicillin sodium-sulbactam sodium, cefpiramide and Gatifloxacin. Above-mentioned application is preferably the use in conjunction of artesunate and antibacterials. The independent use of artesunate can suppress the growth of gram-negative bacteria and gram positive bacteria, with the antibacterial efficacy that can obviously strengthen antibacterials after the antibacterials use in conjunction, reduces the using dosage of antibacterials; Experiment shows that arteannuin and artesunate and antibacterials use in conjunction can obviously reduce antibacterial (comprising Grain-negative, positive bacteria) and attack mouse death rate, significantly suppresses mice serum LPS content and cytokine TNF-α and discharges. This finder studies the antibiotic and antiinflammatory action of artesunate inside and outside. At first, this research worker has been carried out pharmacology's analysis to the vitro antibacterial activity of this artesunate, and with the antibiotic use in conjunction after find that the independent use of artesunate can suppress the growth of gram-negative bacteria and gram positive bacteria, with can obviously strengthen antibiotic antibacterial efficacy after the antibiotic use in conjunction, reduce antibiotic using dosage; Secondly, artesunate and antibiotic use in conjunction and can obviously reduce antibacterial (comprising Grain-negative, positive bacteria) and attack mouse death rate significantly suppress mice serum LPS content and cytokine TNF-α release. Therefore the present invention has widened the purposes of arteannuin and derivant thereof, particularly artesunate, has improved the antibacterial efficacy of antibacterials, the drug resistance phenomenon that has alleviated the antibacterials abuse and caused. Description of drawings Fig. 1 represents that artesunate works in coordination with gentamycin, cefpiramide, ampicillin sodium-sulbactam sodium to the antibacterial curve of the associating of escherichia coli ATCC35218; Fig. 2 represents that artesunate works in coordination with ampicillin, Gatifloxacin, the ampicillin sodium-sulbactam sodium antibacterial curve of associating to the golden bacterium ATCC25923 of Portugal; Fig. 3 represents that artesunate works in coordination with gentamycin, Gatifloxacin, ampicillin sodium-sulbactam sodium to the antibacterial curve of the associating of escherichia coli clinical separation strain. The specific embodiment The present invention is further illustrated below in conjunction with embodiment, but described embodiment only is used to illustrate the present invention rather than restriction the present invention. Artesunate (AS) and antibacterials can produce Synergistic antimicrobial and render a service according to the proportioning in table 1, the table 2, reduce the minimum inhibitory concentration and the minimum bactericidal concentration of antibacterials. Experimental example 1 This experimental example is to study artesunate and ten kinds of antibacterials MIC (minimum inhibitory concentration) and the MBC (minimum bactericidal concentration) to different bacterium Adopt the micropore dilution method, the adjustment bacterial concentration is 105CFU/ml, is inoculated in the 96 hole aseptic culture plates, and 10 kinds of antibacterials such as artesunate and penicillin sodium, ampicillin etc. are 5.14mg/ml with the normal saline dilution respectively.Add various medicines to containing in the antibacterial culturing hole, doubling dilution successively, the ultimate density of the 1st～10 hole medicine is followed successively by 256,128,64,32,16,8,4,2,1,0.5ug/ml.Put 37 ℃ of incubators and hatch 24h and 48h, read the positive and negative control hole, negative control hole is limpid, positive control hole muddiness.Medicine is the lowest concentration of drug that suppresses antibacterial naked eyes visible growth behind the 24h to the MIC of antibacterial, and medicine is the lowest concentration of drug that suppresses antibacterial naked eyes visible growth behind the 48h to the MBC of antibacterial.This time experimental result shows the independent use of artesunate bacteria growing inhibiting fully, and has observed the inhibitory effect of different antibacterials to these five kinds of antibacterials.(seeing Table 3). During independent use of 10 kinds of antibacterials of table 3 and AS to the MIC and the MBC of different bacterium Experimental example 2 This experimental example is to study after artesunate and the antibacterials use in conjunction influence to escherichia coli MIC and MBC. Adopt checkerboard type micropore dilution method, the adjustment bacterial concentration is 105CFU/ml, be inoculated in the 96 hole aseptic culture plates, will be to the antibacterials of five kinds of medium sensitivities of antibacterial dosage and the variable concentrations artesunate difference compatibility that is lower than MIC, the medicine behind the observation compatibility is to the MIC and the MBC of escherichia coli.Though this time experimental result shows that artesunate uses bacteria growing inhibiting fully separately,, illustrate that there is collaborative inhibitory effect the collaborative back of artesunate and antibacterials to antibacterial with the MIC and the MBC that can obviously reduce antibacterials after the antibacterials use in conjunction.(seeing Table 4). Minimum inhibitory concentration after each antibacterials of table 4 and artesunate are collaborative Experimental example 3 This experimental example is to study artesunate and the inhibition strength of the collaborative back of the different antibacterials of 1/2 MIC concentration to the escherichia coli growth. The adjustment bacterial concentration is 106CFU/ml, and measuring bacterium liquid OD600 is 0.002 (1OD=5 * 10 8CFU/ml), with reference to experimental example 1 result, adding final concentration respectively separately is the antibacterials of 256 μ g/ml artesunate or 1/2 MIC concentration, and after adding the antibacterials of 256 μ g/ml artesunate and 1/2MIC concentration simultaneously, as for 37 ℃ of constant temperature shaking table 150rpm jolting, measure 1,3,5,7,9,12,16 respectively, the OD value of bacterium liquid during 24h, calculate the amount of bacteria of each time point.Result of study shows that artesunate 256 μ g/ml can make escherichia coli ATCC35218, the staphylococcus aureus ATCC25923 and the escherichia coli clinical separation strain speed of growth obviously slow down, compare with independent use antibacterials, united behind the artesunate obviously bacteria growing inhibiting, the inhibition degree is than using antibacterials or artesunate all strong (Fig. 1,2,3) separately. Experimental example 4 This experimental example is to study artesunate use in conjunction antibacterials are attacked mice to gram-negative bacteria protective effect Cleaning level 70 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half, be divided into matched group, artesunate group, escherichia coli group at random, escherichia coli+gentamycin group, artesunate (1.5,5,15mg/kg)+gentamycin+escherichia coli group.Every group of 10 animals.Contrast does not give any reagent; The artesunate of arteannuin group intramuscular injection 15mg/kg; The escherichia coli group gives 0.8 * 10 6The escherichia coli ATCC35218 that/kg lives; Escherichia coli+gentamycin group gives the escherichia coli ATCC35218 that lives after the gentamycin 0.5mg/kg intramuscular injection; Gentamycin+artesunate+escherichia coli group after giving artesunate, gives gentamycin and escherichia coli immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 5) in 7 days.The result can obviously reduce mortality of mice after showing artesunate Synergistic antimicrobial medicine, shows the coordinating protection effect occurring after artesunate and the antibacterials associating. The collaborative gentamycin of table 5 artesunate is attacked mice to escherichia coli ATCC35218 protective effect Experimental example 5 This experimental example is to study artesunate use in conjunction antibacterials are attacked mice to gram-positive bacteria protective effect Cleaning level 70 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half, be divided into matched group, artesunate group, golden Portugal bacterium group at random, gold Portugal bacterium+Gatifloxacin group, artesunate (5,15,45mg/kg)+Gatifloxacin+golden Portugal bacterium group.Every group of 10 animals.Contrast does not give any reagent; The artesunate of arteannuin group intramuscular injection 45mg/kg; Gold Portugal bacterium group gives 1.0 * 10 7The golden bacterium ATCC25923 of Portugal that/kg lives; Gold Portugal bacterium+Gatifloxacin group gives the golden bacterium ATCC25923 of Portugal that lives after the Gatifloxacin 0.5mg/kg intramuscular injection; Gatifloxacin+artesunate+golden Portugal bacterium group after giving artesunate, gives Gatifloxacin and golden Portugal bacterium immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 6) in 7 days.The result can obviously reduce mortality of mice after showing artesunate Synergistic antimicrobial medicine, shows the coordinating protection effect occurring after artesunate and the antibacterials associating. The collaborative Gatifloxacin of table 6 artesunate is attacked mice to the golden bacterium ATCC25923 of Portugal protective effect Experimental example 6 This experimental example is to study artesunate is attacked mice to the deactivation escherichia coli protective effect. Cleaning level 60 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half are divided into matched group, artesunate group, deactivation escherichia coli group at random, artesunate (5,15,45mg/ml)+deactivation escherichia coli group.Every group of 8 animals.Contrast does not give any reagent; The intramuscular injection of artesunate group gives the artesunate of 45mg/kg, 4h, and 24h, repeat administration is once behind the 48h; Deactivation escherichia coli group gives 1.25 * 10 11The deactivation escherichia coli ATCC35218 of/kg; Artesunate+deactivation escherichia coli group after intramuscular injection gives artesunate, gives deactivation escherichia coli ATCC35218 immediately, repeats administered intramuscular artesunate 1 time behind 4h, 24h, the 48h.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 7) in 7 days.The result shows that artesunate can reduce mortality of mice, shows that the mice that pro-inflammatory cytokine is attacked has protective effect. Table 7 artesunate is attacked the protective effect of mice to the deactivation escherichia coli *p＜0.5；**p＜0.01?vs?E.coli Experimental example 7 This experimental example is to study artesunate the deactivation escherichia coli is attacked the influence of mice serum release of cytokines Cleaning level 40 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half, be divided into matched group, artesunate group, deactivation escherichia coli group, artesunate (5,15,45mg/kg)+deactivation escherichia coli group at random, 3 of every treated animals.Contrast does not give any reagent.The intramuscular injection of artesunate group gives the artesunate of 45mg/kg; Artesunate (5,15,45mg/kg)+deactivation escherichia coli group gives to give deactivation escherichia coli ATCC35218 immediately behind the artesunate; Administration finishes and plucks eyeball behind the 4h and get the centrifugal immediately indwelling supernatant of blood and be stored in-20 ℃, cytokine TNF-α to be determined (table 8).The result shows that artesunate can significantly reduce the deactivation escherichia coli and attack the mice serum release of cytokines. Table 8 artesunate reduction deactivation escherichia coli ATCC35218 attack mice serum cytokine TNF-α release (n=6, x ± SD) *p＜0.5；**p＜0.01?vs?E.coli The present invention has improved antibiotic antibacterial efficacy with the use in conjunction of artesunate and antibacterials, and artesunate and antibiotic use in conjunction can also be prevented, treat bacterial infection. Those skilled in the art can be according to content of the present invention, and the associating of arteannuin and derivant and antibacterials can be reached effect of the present invention equally. 1. Artesunate be selected from a kind of in gentamycin, cefpiramide, ampicillin sodium-sulbactam sodium, ampicillin and the Gatifloxacin in the application of preparation in the antibacterials. 2. application according to claim 1, above-mentioned bacterium are gram positive bacteria or gram-negative bacteria.

CN100430061C使用内过氧化物治疗黄病毒科引起的感染，包括丙型肝炎、牛病毒性腹泻和经典猪瘟病毒---内过氧化物和青蒿素更具体地具有治疗丙型肝炎病毒感染的功效 CN100430061C Use of peroxides to treat infections caused by Flaviviridae, including hepatitis C, bovine viral diarrhea, and classical swine fever viruses--- Peroxides and artemisinin specifically have the effect of treating hepatitis C virus infection. 内过氧化物在制备治疗由黄病毒科病毒(包括丙型肝炎病毒、牛病毒性腹泻病毒和猪瘟病毒)引起的感染的药物中的应用 倍半萜类，特别是倍半萜内酯内过氧化物，例如青蒿素及其类似物，在治疗丙型肝炎病毒感染中的应用。对青蒿素、青蒿素的类似物和一些蒿的粗提取物进行了体外抗DNA病毒、逆转录病毒和黄病毒科病毒(一种重要的人和动物RNA病原体科)的测试。筛选了这些化合物的抗肿瘤活性。观察到青蒿素具有抗牛病毒性腹泻病毒的强活性。由于瘟病毒(如BVDV)与丙型肝炎病毒(HCV)具有许多相似性，我们能够得出结论，在治疗丙型肝炎病毒感染方面，内过氧化物具有一般的效果，青蒿素具有更特异的效果。 内过氧化物在制备治疗由黄病毒科病毒(包括丙型肝炎病毒、牛病毒性腹泻病毒和猪瘟病毒)引起的感染的药物中的应用 发明背景 本发明大体上涉及倍半萜内酯类(sesquiterpene lactones)在治疗由黄病毒科(Flaviviridae)引起的感染中的应用，特别是倍半萜内酯内过氧化物在治疗丙型肝炎感染、黄热病、登革热、牛病毒性腹泻和猪瘟(classical swine fever)中的应用。 慢性丙型肝炎病毒感染是一个影响全世界1.8亿人(总人口的3％)的一个重要的公共健康问题，这里面包括美国的4百万人，而且是导致肝慢性病的一个主要原因。有人预期美国的HCV感染将继续增加，到2010年感染者将达到现在的3倍。丙型肝炎病毒的感染可能引起严重的，在一些病例中可能是威胁生命的慢性肝病，包括肝衰竭和肝癌。 在美国，慢性肝病是导致成人死亡的第十位原因，并且导致8每年接近25000例或接近1％的死亡人数。人口基础上的研究表明：40％的慢性肝病是HCV相关的，导致每年大约8000-10000的死亡。HCV相关的急性和慢性肝病的医疗和工作损失估计每年要超过6亿美元。并且HCV相关的晚期肝病是成人肝移植最常见的原因。因为大多数的HCV感染者的年龄在30-49岁之间，由与HCV相关的慢性肝病引起的死亡数可能在未来的10-20年间大幅增加，这时候这组感染者将达到慢性肝病的并发症通常发生的年龄。 HCV的传播主要是通过皮肤与血的大量或重复的直接接触。在美国，与HCV传播有关的两种最常见的接触是输血和注射毒品。丙型肝炎的治疗是临床实践中变化快速的一个领域。干扰素和利巴韦林(一种核酸类似物)的联合治疗已被批准用于慢性丙型肝炎的首次治疗。对应用利巴韦林和干扰素的联合治疗的患者的研究证实，与单独应用干扰素治疗的反应率15-25％相比，其持久的反应率有显著增加，达到40-50％。多数患者在治疗早期有干扰素一过性感冒样症状，但是这些症状在继续治疗中减轻。随后的副作用有疲劳、骨髓抑制和中枢精神作用(例如，淡漠、认知变化、暴躁和抑郁)。由于严重的副作用，10-40％的患者的干扰素的剂量必须减少，5-15％的患者必须间断使用。利巴韦林能引起溶血性贫血，并且对于患者原来存在的贫血、骨髓抑制或肾衰竭来说也是有问题的。在这些患者，应避免联合治疗，或应该试图纠正贫血。利巴韦林引起的溶血性贫血对有缺血性心脏疾病或脑血管疾病的患者也可能是威胁生命的。利巴韦林是引起畸形的，女性患者在治疗过程中要避免妊娠。其他治疗，包括皮质类固醇、脱氧熊胆酸(ursodiol)和胸腺素，是无效的。肝脏的高铁水平可降低干扰素的药效。去铁治疗(静脉切开放血术或螯合术)与干扰素的联合应用已经研究了，但是，还尚无结论(www.cdc.gov)。所以，在医学领域迫切需要发现和发展可以用来治疗HCV感染、同时具有较少或者能够减少副作用的、并且与现有的治疗相比有更好疗效的新的生物活性分子。 发明内容 已经发现具有以下通式的倍半萜内酯： 具有对抗由黄病毒科，包括丙型肝炎病毒、牛病毒性腹泻病毒和猪瘟病毒引起的感染的活性。本申请描述了一些具有代表性的、目前优选的倍半萜内酯类，不过，本领域人员显然能够理解，公知技术中其他倍半萜内酯化合物在由黄病毒科引起的感染的治疗中也是有效的。还包括此类化合物的药学上可接受的盐。 优先选用的倍半萜内酯是倍半萜内酯内过氧化物青蒿素(artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(artensunate)和蒿甲醚(artemether)。 附图说明 图1是对青蒿素、双氢青蒿素、青蒿琥酯和蒿甲醚化学结构的图解说明。 具体实施方式 本申请中，我们将介绍倍半萜内酯类的抗病毒效应，特别是倍半萜内酯内过氧化物，例如青蒿素、双氢青蒿素、青蒿琥酯和蒿甲醚对特定的黄病毒科病毒例如丙型肝炎病毒的抗病毒作用。 本发明的优选的倍半萜化合物包含具有以下通式的化合物： 其中：X1和X2选自O、S、Se和NH；Y选自O、S、Se和NH；Z选自O、NH、S和Se，且Q选自CO、CHOH、CHOCH3、CHOC2H5、CHOC3H7和CHOCOCCH2CH2COOH及其药物可接受盐。 本发明特别优选的倍半萜化合物包括青蒿素，其X1和X2是O、Y是O、Z是O、并且Q是C＝O；双氢青蒿素(同青蒿素，但Q为CHOH)；蒿甲醚(同青蒿素，但Q为CHOCH3)；蒿乙醚(arteether)(同青蒿素，但Q为COC2H5)；一种丙基产品(同青蒿素，但Q为CHOC3H7)；及青蒿琥酯(artesunate)(同青蒿素，但Q为CHOCOCH2CH2COOH)。本发明的最优选的倍半萜化合物是双氢青蒿素。 内过氧化物有一个二氧键(peroxo linkage)(-O-O)，这个结构被认为对这些产物具有抗疟疾活性是很重要的。用-S-S-(二硫键)，或-Se-Se-(二硒键)，或-N-O-或-NH-NH-(肼)，以及上述键的不同组合，会产生新的化合物，也可能具有活性。 黄病毒科是人类和动物一个重要的RNA病毒病原体科(Rice CM.1996.Flaviviridae：the viruses and their replication.In：Fields BN，Knipe DM，Howley PM，eds.Fields virology.Philadelphia：Lippincott-Raven Publishers.Pp 931-960)。目前已发现的黄病毒科的属在传播途径、宿主范围和发病机理方面表现不同。典型的黄病毒成员是黄热病毒、登革病毒和瘟病毒(pestiviruses)，例如牛病毒性腹泻病毒(BVDV)和猪瘟病毒(CSFV)。该家族最新的最具特征的成员是人的常见的且专有的病原体，即丙型肝炎病毒(HCV)。黄病毒是具有(+)有义RNA基因组极性的单链RNA病毒。其他具有(+)有义RNA的病毒科包括小核糖核酸病毒科(Picornaviridae)、披膜病毒科(Togaviridae)、杯状病毒科(Caliciviridae)和冠状病毒科(Coronaviridae)。 本发明化合物可以应用它们的原形或它们的盐。在一些情况，这些化合物由足够的碱性或酸性能够形成稳定的无毒的酸或碱的盐，这些化合物以盐的形式施用是适合的。药学可接受的盐的例子是与形成的生理学可接受阴离子的有机酸形成的有机酸盐，例如抗坏血酸醋酸盐，安息香酸盐，柠檬酸盐，etoglutarate，甘油磷酸盐，丙二酸盐，甲磺酸盐，琥珀酸盐和酒石酸盐。合适的无机酸盐也可以被合成，包括重碳酸盐，碳酸盐，盐酸盐，硝酸盐，和硫酸盐。 本发明可以含有所述化合物以及合适的赋形剂的药物组合物而常规给药，该组合物对抗病毒感染是有用的。根据所治疗的是内或外病毒感染，本发明的化合物和组合物可以经胃肠外，局部，阴道内，口服或直肠给药。 对胃肠外给药，活性成分或它的盐溶液可以用水制备，任选地和无毒的表面活性剂混合。也可以在甘油，液体聚乙二醇，三乙酰甘油酯和上述试剂的混合物和在油剂里制备。 化合物可使用的剂量可以通过在体外比较其活性而决定。对人的有效量的外推方法是本领域已知的。 本化合物可以单位剂量的形式常规给药；例如每单位剂量形式包含活性成分0.1-2000mg，优选为100-1000mg，最优选为100-500mg。所需药量可以常规地一次性给药或以合适的间隔分次给药，例如每天可分2，3，4或更多次给药。每次的亚剂量还可以进一步分开，例如分成一些分散的松散分隔的施用形式；例如多次从送药器吸入或多次点眼给药。 对体内感染，组合物可以按游离药物计算的剂量水平通过口服或胃肠外给药，大约为1-30mg/kg(哺乳动物体重)，优选1-10mg/kg(哺乳动物体重)。 在此揭示的化合物和组合物的给药的精确的方案将必须依赖于被治疗的个体的需要，治疗的类型，当然还有主治医师的判定。本发明的化合物可用于有该治疗需求的动物。大多情况下，是用于人，但是家畜和宠物也可以特别地预期属于本发明的应用范围。 材料和方法 青蒿素购于Aldrich。洋艾(Artemisia absinthum)KE-4、黄花蒿(Artemisia annua)KE-5和龙蒿(Artemisia dracunculus)KE-6的植物粗提取物从美国Des Moines，Kemin工业有限公司获得。为了制备KE-4、-5和-6样品，将2g干的磨碎的苦艾、甜苦艾或龙蒿在200ml己烷中室温搅拌8小时，然后，悬浮液经过G3玻璃滤器过滤和低压下蒸发。残留的黑的滤渣用于生物筛选。蒿甲醚、双氢青蒿素和青蒿琥酯购于Dafra Pharma。上述化合物都进行了抗不同致病病毒的筛选，例如人免疫缺陷病毒(HIV)、单纯疱疹病毒(HSV)、水痘病毒(VV)、带状疱疹病毒(VZV)和人巨细胞病毒(CMV)。对所有的病毒，除了CMV外，检测了EC50(对HIV在人CEM细胞培养物中诱导的致细胞病性、HSV和VV在人胚胎成纤维细胞E6SM细胞培养物中诱导的致细胞病性、和VZV在人胚胎肺(HEL)细胞培养物中诱导的噬斑形成达到50％的抑制所需的有效化合物的浓度)。为了检测抗病毒活性，抗CMV用IC50表示，人胚胎肺成纤维(HEL)细胞用96孔板培养，每孔用20PFU病毒感染。 在37℃培养2小时后，感染的细胞中加入0.1ml含测试化合物的梯度稀释的培养液。第7天经细胞Giemsa染色后在显微镜下计数噬斑。最小抗病毒浓度以抑制病毒诱导的噬斑形成达到50％所需的剂量表示。 对这些化合物也进行了抗黄病毒的筛选。因为事实上没有足够的体外分析用于抗HCV筛选，所以决定筛选抗牛病毒性腹泻病毒(BVDV)，因为它与丙型肝炎病毒有很多相似性(Frolovl，McBride S and Rice CM.Cis-acting RNA elements required for replication of bovine.Viral diarrheavirus-hepatitis C virus 5’non-translated region chimeras.RNA 4，1418-1435(1998))。进一步对蒿甲醚抗BVDV的不同株的作用进行了筛选。 对这些化合物也进行了抗肿瘤活性的检测，通过对鼠白血病细胞(L1210/0)、鼠乳腺癌细胞(FM3A)和人T淋巴细胞(Molt4/C8，CEM/0)的增殖(的检测)进行。观察到的对CMV和VZV的最好的抗病毒活性来自KE-6。其次是青蒿素对HSV-2和VV的抗病毒活性。 结果和讨论 在第一批筛选中(见表1)，检测了青蒿素和一些蒿属粗提取物(KE-4、KE-5和KE-6)对HIV-1、HIV-2、HSV-1、HSV-2、VV、CMV和VZV的抗病毒活性。 表1：抗HIV-1、HIV-2、HSV-1、HSV-2、VV、CMV和VZV的筛选结果 a50％对HIV在人淋巴细胞CEM细胞培养物中诱导的致细胞病性、HSV和VV在人胚胎成纤维细胞E6SM细胞培养物中诱导的致细胞病性、和CMV和VZV在人胚胎肺HEL细胞培养物中诱导的噬斑形成达到50％的抑制所需的有效的化合物浓度。 另外进行了第二个筛选(表2)，以便检测在牛肾(MDBK)细胞中抗牛病毒性腹泻病毒的活性。 表2：在MDBK细胞中抗BVDV的筛选结果 抗病毒活性用BVDV的Pe515株在MDBK细胞上来评估。抗病毒活性和细胞毒性的检测都应用MTS方法。 EC50是降低病毒引起的细胞毒性效果50％时所需要的浓度。MTC(最小毒性浓度)定义为引起细胞代谢降低＞＝20％的浓度。 当用蒿甲醚、青蒿素、KE4和KE5处理MDBK细胞时，在最高浓度(100μg/ml)仍没有达到MTC。本试验中观察到内过氧化物青蒿素、双氢青蒿素、蒿甲醚和青蒿琥酯具有很强的抗黄病毒BVDV的活性，同时具有低细胞毒性。所以，这些产品可以用于治疗由黄病毒引起的感染。 以蒿甲醚进行了抗不同BVDV株，和抗BDV(边界病病毒)的筛选(表3) 表3：蒿甲醚抗BVDV和BDV的筛选结果 蒿甲醚 100μg/ml 20μg/ml 4μg/ml 800ng/ml 160ng/ml 32ng/ml 6.4ng/ml 1.28ng/ml 0.512ng/ml 0.256ng/ml 非感染 毒性 BVDVII ncp 毒性 ++ ++ ++ +++ +++ +++ +++ +++ +++ BVDVI cp 毒性 + + + + ++ ++ ++ ++ ++ BVDVI ncp 毒性 + + + ++ +++ +++ +++ +++ +++ BDV 毒性 + + + ++ ++ ++ ++ ++ ++ +++ 所有细胞都是阳性的 ++ +/-50％细胞是阳性的 + +/-10％细胞是阳性的 BVDV 牛病毒性腹泻病毒 BDV 边界病病毒 cp 致细胞病变株 ncp 非致细胞病变株 特别地抗BVDVIcp(与HCV最相似的BVDV株)，可以清楚地看到蒿甲醚的效果。该产品的EC90＝0.16μg/ml。这些实验中发现的毒性浓度在100μg/ml附近。也可以观察到抗BDV的效果(EC90＝0.8μg/ml)。 青蒿素和蒿属粗提取物(KE-4、KE-5和KE-6)都进行了抗肿瘤细胞株L12 10/0、FM3A/0、Molt4/C8和CEM/0的筛选，但没有发现有益结果。 结论 在最初的抗DNA病毒和逆转录病毒的筛选中我们没有发现任何明显的抗病毒活性。在第二次抗BVDV(RNA病毒)的筛选中我们清楚地显示青蒿素、青蒿琥酯、蒿甲醚和双氢青蒿素的强抗病毒活性。这些产品都是内过氧化物，与检测过的蒿属粗提取物相比较，显示明显更好的抗BVDV活性。因为BVDV与HCV有许多相似性，青蒿素、青蒿琥酯、蒿甲醚、双氢青蒿素及其他可能的过氧化物可能具有强的和选择性的抗HCV的抗病毒性质。 尽管本发明按期望已经描述了优选的具体实施方式，但可以理解的是，本发明并不仅仅局限于此，因为对其作出的变化和修饰也属于所附权利要求书中所定义的本发明完整范围内。 1、倍半萜或其药学可接受的盐在制备一种用于治疗由黄病毒科病毒引起的感染的药物中的用途，所述倍半萜具有以下通式： 其中： Q选自CO、CHOH、CHOCH3、CHOC2H5、和CHOCOCCH2CH2COOH。 2、权利要求1的用途，其中所述感染是丙型肝炎。 3、权利要求1的用途，其中所述感染是牛病毒性腹泻或猪瘟。 The use of endoperoxides for the treatment of infections caused by flaviviridae, including hepatitis c, bovine viral diarrhea and classical swine fever virus The use of sesquiterpenes and, in particular sesquiterpene lactone endoperoxides, such as artemisinin and analogs thereof, for the treatment of hepatitis C virus infections. Artemisinin, analogs of artemsisnin and some crude Artemisia extracts were tested in vitro against DNA-viruses, retro-viruses and Flavivirida, (an important family of human and animal RNA pathogens). These compounds were also screened for anti-tumor activity. Strong activity of artemisinin was noticed against the bovine viral diarrhea virus (BVDV). As pestiviruses, such as BVDV, share many similarities with hepatitis C virus (HCV), we can conclude that endoperoxides in general and artemisinin more specificly have efficacy as treatments for hepatitis C viral infections. The application of endoperoxide in the medicine of the infection that the preparation treatment is caused by flaviviridae (comprising hepatitis C virus, bovine viral diarrhea virus and swine fever virus) Background of invention The present invention relates generally to the application of the application, particularly sesquiterpene lactones endoperoxide of sesquiterpene lactones class (sesquiterpene lactones) in the infection that treatment is caused by flaviviridae (Flaviviridae) in treatment hepatitis C infection, yellow fever, dengue fever, bovine viral diarrhoea and swine fever (classical swine fever). Chronic hcv infection is an important public health problem that influences the whole world 1.8 hundred million people (total population 3%), comprises 4 million peoples of the U.S. here, and is a main cause that causes the liver chronic disease.Someone expects that the HCV infection of the U.S. will continue to increase, and will reach present 3 times to the infected in 2010.The infection of hepatitis C virus may cause serious, may be life-threatening chronic hepatopathy in some cases, comprises liver failure and hepatocarcinoma. In the U.S., chronic hepatopathy is to cause being grown up the tenth dead reason, and causes for 8 every year near 25000 examples or near 1% death toll.Studies show that on the population-based: 40% chronic hepatopathy is that HCV is relevant, causes the annual approximately death of 8000-10000.The medical treatment of the acute and chronic hepatopathy that HCV is relevant and work estimated amount of damage every year will be above 600,000,000 dollars.And the hepatopathy in late period that HCV is relevant is the modal reason of adult orthotopic liver transplantation.Because most HCV the infected's age, the death toll that is caused by the chronic hepatopathy relevant with HCV may significantly increase in the period of the 10-20 in future between 30-49 year, at this time this group the infected will reach the age that the complication of chronic hepatopathy takes place usually. The propagation of HCV mainly is a large amount of or repeated direct by skin and blood.In the U.S., propagating two kinds of relevant modal contacts with HCV is blood transfusion and shoot up.Therapy for hepatitis C is to change field fast in the clinical practice.The therapeutic alliance of interferon and ribavirin (a kind of nucleic acid analog) has been approved for the treatment first of chronic hepatitis C.The patient of the therapeutic alliance of using ribavirin and interferon be studies confirm that compare with the response rate 15-25% of independent application of interference extract for treating, its persistent response rate has remarkable increase, reaches 40-50%.Most of patients has interferon one property crossed cold like symptoms in early days in treatment, but these symptoms alleviate in continuing treatment.Side effect subsequently has fatigue, bone marrow depression and maincenter mentation (for example, indifferent, cognitive variation, irascible and depressed).Because serious adverse, the dosage of the patient's of 10-40% interferon must reduce, and the patient of 5-15% must be interrupted use.Ribavirin can cause hemolytic anemia, and also is problematic for the unborn anemia of patient, bone marrow depression or renal failure.These patients, should avoid therapeutic alliance, maybe should attempt to correct anemia.The hemolytic anemia that ribavirin causes also may be life-threatening to the patient that ischemic heart disease or cerebrovascular disease are arranged.Ribavirin be cause odd-shaped, female patient in therapeutic process, to avoid gestation.Other treatment comprises corticosteroid, ursodeoxycholic acid (ursodiol) and thymosin, is invalid.The high iron level of liver can reduce the drug effect of interferon.The use in conjunction of de-iron treatment (venotomy or chelating art) and interferon after deliberation, still, also still do not have conclusion ( Www.cdc.gov).So, medical domain press for find with development can be used for treating HCV infect, have simultaneously less or can reduce side effect and compare the new bioactive molecule that better curative effect is arranged with existing treatment. Summary of the invention Have been found that sesquiterpene lactones with following general formula: Have antagonism by flaviviridae, comprise the activity of the infection that hepatitis C virus, bovine viral diarrhea virus and swine fever virus cause.The application has described some representative, at present preferred sesquiterpene lactones classes, and but, those skilled in the art obviously can understand, and other sesquiterpene lactones chemical compounds also are effective in the treatment of the infection that is caused by flaviviridae in the known technology.The pharmaceutically acceptable salt that also comprises this compounds. The sesquiterpene lactones of preferentially selecting for use is sesquiterpene lactones endoperoxides artemisinin (artemisinin), dihydroarteannuin (dihydroartemisinin), artesunate (artensunate) and Artemether (artemether). Description of drawings Fig. 1 is the graphic extension to arteannuin, dihydroarteannuin, artesunate and Artemether chemical constitution. The specific embodiment Among the application, we will introduce the antiviral effect of sesquiterpene lactones class, sesquiterpene lactones endoperoxide particularly, for example arteannuin, dihydroarteannuin, artesunate and Artemether are to the specific flaviviridae antivirus action of hepatitis C virus for example. Preferred sesquiterpenoid of the present invention comprises the chemical compound with following general formula: Wherein: X 1And X 2Be selected from O, S, Se and NH; Y is selected from O, S, Se and NH; Z is selected from O, NH, S and Se, and Q is selected from CO, CHOH, CHOCH 3, CHOC 2H 5, CHOC 3H 7And CHOCOCCH 2CH 2COOH and drug acceptable salt thereof. The particularly preferred sesquiterpenoid of the present invention comprises arteannuin, its X 1And X 2Be that O, Y are that O, Z are that O and Q are C=O; Dihydroarteannuin (same arteannuin, but Q is CHOH); Artemether (same arteannuin, but Q is CHOCH 3); Arteether (arteether) (same arteannuin, but Q is COC 2H 5); A kind of propyl group product (same arteannuin, but Q is CHOC 3H 7); And artesunate (artesunate) (same arteannuin, but Q is CHOCOCH 2CH 2COOH).Most preferred sesquiterpenoid of the present invention is a dihydroarteannuin. Endoperoxide has a dioxy key (peroxo linkage), and (O-O), to be considered to that these products are had the malaria activity be very important to this structure.With-S-S-(disulfide bond), or-Se-Se-(two selenium keys), or-N-O-or-NH-NH-(hydrazine), and the various combination of above-mentioned key can produce new chemical compound, also may have activity. Flaviviridae is (the Rice CM.1996.Flaviviridae:the viruses and their replication.In:Fields BN of important RNA viruses pathogen section of human and animal, Knipe DM, Howley PM, eds.Fields virology.Philadelphia:Lippincott-Raven Publishers.Pp 931-960).The genus of the flaviviridae of having found at present shows different aspect route of transmission, host range and pathogeny.Typical banzi virus member is yellow fever virus, dengue virus and Pestivirus (pestiviruses), for example bovine viral diarrhea virus (BVDV) and swine fever virus (CSFV).The member of the tool feature that this family is up-to-date is people's a common and proprietary pathogen, i.e. hepatitis C virus (HCV).Banzi virus is to have (+) the polar single strand RNA virus of adopted rna gene group is arranged.Other have (+) has the Viraceae of adopted RNA to comprise Picornaviridae (Picornaviridae), Togaviridae (Togaviridae), Caliciviridae (Caliciviridae) and coronaviridae (Coronaviridae). The compounds of this invention can be used their original shape or their salt.In certain situation, these chemical compounds can form the stable nontoxic acid or the salt of alkali by enough alkalescence or acidity, and these chemical compounds are used with the form of salt and are fit to.The example of the acceptable salt of pharmacy is can accept the acylate that anionic organic acid forms with the physiology who forms, ascorbic acid acetate for example, benzoate, citrate, etoglutarate, glycerophosphate, malonate, mesylate, succinate and tartrate.Suitable inorganic acid salt also can be synthesized, and comprises heavy carbonate, carbonate, hydrochlorate, nitrate, and sulfate. The present invention can contain the pharmaceutical composition of described chemical compound and suitable excipient and conventional administration, and said composition antagonism viral infection is useful.According to what treat is interior or outer viral infection, and chemical compound of the present invention and compositions can be through parenteral, part, intravaginal, oral or rectally. To parenteral, active component or its saline solution can prepare by water, randomly mix with nontoxic surfactant.Also can be at glycerol, liquid macrogol, the mixture of triacetin and mentioned reagent and in oil preparation, preparing. The spendable dosage of chemical compound can be by determining in its activity of external comparison.Extrapolation method to people's effective dose is known in the art. This chemical compound can unit dose the conventional administration of form; For example the per unit dosage form comprises active component 0.1-2000mg, is preferably 100-1000mg, most preferably is 100-500mg.Required dose can disposable routinely administration or with suitable interval gradation administration, for example can divide 2,3,4 or more times administration every day.Each sub-doses can also further separately for example be divided into the administration form of some dispersive loose separations; For example repeatedly suck or repeatedly put ocular administration from medicine feeding machine. To infecting in the body, compositions can be passed through oral or parenteral by the dosage level that free drug calculates, and is approximately 1-30mg/kg (weight of mammal), preferred 1-10mg/kg (weight of mammal). Must depend on the needs of the individuality of being treated in the accurate scheme of the administration of the chemical compound of this announcement and compositions, the type of treatment also has attending doctor's judgement certainly.Chemical compound of the present invention can be used for having the animal of this treatment demand.Under the situation, be to be used for the people mostly, but domestic animal and house pet also can be expected especially and belonged to range of application of the present invention. Material and method Arteannuin is purchased in Aldrich.The plant crude extract of Absinthium (Artemisia absinthum) KE-4, Herba Artemisiae annuae (Artemisia annua) KE-5 and tarragon (Artemisia dracunculus) KE-6 is from U.S. Des Moines, and Kemin Industrial Co., Ltd obtains.In order to prepare KE-4 ,-5 and-6 samples, ground Artemisia absinihium L, sweetness and bitterness Chinese mugwort or the tarragon that 2g is done stirring at room 8 hours in the 200ml hexane, then, suspension filter through the G3 glass filter and low pressure under evaporate.Residual black filtering residue is used for biological screening.Artemether, dihydroarteannuin and artesunate are purchased the Pharma in Dafra.Above-claimed cpd has all carried out the screening of anti-different Causative viruss, for example human immunodeficiency virus (HIV), herpes simplex virus (HSV), chickenpox virus (VV), varicella zoster virus (VZV) and human cytomegalic inclusion disease virus (CMV).To all virus, except CMV, detected EC 50(to HIV in people's cem cell culture inductive cytopathogenicity, HSV and VV at human embryonic fibroblast E 6Inductive cytopathogenicity and VZV inductive plaque in human embryonic lung (HEL) cell culture forms the concentration that reaches the required active compound of 50% inhibition in the SM cell culture).For determination of antiviral activity, anti-CMV IC 50Expression, the human embryonic lung becomes fiber (HEL) cell to cultivate every hole 20PFU viral infection with 96 orifice plates. After 2 hours, add the culture fluid that 0.1ml contains the gradient dilution of test compounds 37 ℃ of cultivations in the cell of infection.After cell Giemsa dyeing, counted plaque on the 7th day at microscopically.Minimum antiviral concentration reaches 50% required dosage with the plaque formation that suppresses virus induction and represents. These chemical compounds have also been carried out the screening of anti-flavivirus.Because in fact there are not enough analyzed in vitro to be used for anti-HCV screening, so decision screening anti-bovine viral diarrhea virus (BVDV), because it and hepatitis C virus have a lot of similarity (Frolovl, McBride S and Rice CM.Cis-acting RNA elements required for replication of bovine.Viral diarrheavirus-hepatitis C virus 5 ' non-translated region chimeras.RNA 4,1418-1435 (1998)).Further the effect of the not homophyletic of the anti-BVDV of Artemether is screened. These chemical compounds have also been carried out the detection of anti-tumor activity, by (Molt4/C8, propagation CEM/0) (detection) is carried out to murine leukemia cell (L1210/0), molluscum contagiosum adenocarcinoma cell (FM3A) and human T lymphocyte.Observed best antiviral activity to CMV and VZV is from KE-6.Next is the antiviral activity of arteannuin to HSV-2 and VV. Result and discussion In first screening (seeing Table 1), detected arteannuin and some artemisia crude extract (KE-4, KE-5 and KE-6) antiviral activity to HIV-1, HIV-2, HSV-1, HSV-2, VV, CMV and VZV. Table 1: the The selection result of anti-HIV-1, HIV-2, HSV-1, HSV-2, VV, CMV and VZV aThe 50% couple of HIV in human lymphocyte cem cell culture inductive cytopathogenicity, HSV and VV at human embryonic fibroblast E 6Inductive cytopathogenicity and CMV and VZV inductive plaque in human embryonic lung's hel cell culture forms and reaches 50% the required compounds effective concentration of inhibition in the SM cell culture. Carried out second screening (table 2) in addition, so that detect the activity of anti-bovine viral diarrhea virus in Ren Bovis seu Bubali (MDBK) cell. Table 2: the The selection result of anti-BVDV in the MDBK cell Antiviral activity is assessed on the MDBK cell with the Pe515 strain of BVDV.The MTS method is all used in antiviral activity and Cytotoxic detection. EC 50Be needed concentration when reducing the cytotoxic effect 50% that virus causes.MTC (minimum toxic concentration) is defined as and causes that cellular metabolism reduces＞=20% concentration. When handling the MDBK cell with Artemether, arteannuin, KE4 and KE5, (100 μ g/ml) still do not reach MTC at maximum concentration.Observe the activity that endoperoxides artemisinin, dihydroarteannuin, Artemether and artesunate have very strong anti-flavivirus BVDV in this test, have low cytotoxicity simultaneously.So these products can be used for the treatment of the infection that is caused by banzi virus. Carried out the screening (table 3) of anti-different B VDV strain and anti-BDV (border disease virus) with Artemether Table 3: the The selection result of anti-BVDV of Artemether and BDV Artemether 100 μg/ml 20 μg/ml 4 μg/ml 800 ng/ml 160 ng/ml 32 ng/ml 6.4 ng/ml 1.28 ng/ml 0.512 ng/ml 0.256 ng/ml Non-infection Toxicity BVDVII ncp Toxicity ++ ++ ++ +++ +++ +++ +++ +++ +++ BVDVI cp Toxicity + + + + ++ ++ ++ ++ ++ BVDVI ncp Toxicity + + + ++ +++ +++ +++ +++ +++ BDV Toxicity + + + ++ ++ ++ ++ ++ ++ +++all cells all is male +++/-50% cell is male ++/-10% cell is male The BVDV bovine viral diarrhea virus The BDV border disease virus The strain of cp cytopathogenic effect The non-cytopathogenic effect strain of ncp Anti-especially BVDVIcp (the BVDV strain the most similar to HCV) can be clear that the effect of Artemether.The EC of this product 90=0.16 μ g/ml.The toxic concentration of finding in these experiments is near 100 μ g/ml.Also can observe the effect (EC of anti-BDV 90=0.8 μ g/ml). Arteannuin and artemisia crude extract (KE-4, KE-5 and KE-6) have all been carried out the screening of antitumor cell strain L12 10/0, FM3A/0, Molt4/C8 and CEM/0, but do not find useful result. Conclusion We do not find any tangible antiviral activity in initial resisting DNA virus and retroviral screening.We clearly illustrate the strong antiviral activity of arteannuin, artesunate, Artemether and dihydroarteannuin in the screening of the anti-BVDV second time (RNA viruses).These products all are endoperoxides, compare with the artemisia crude extract that detected, and show obviously better anti-BVDV activity.Because BVDV and HCV have many similaritys, arteannuin, artesunate, Artemether, dihydroarteannuin and other possible peroxide may have strong and the antiviral properties of anti-HCV optionally. Although the present invention has described the preferred specific embodiment by expectation, be understandable that the present invention is not limited only to this, because to its variation made from modify and also to belong in the appended claims in the defined full breadth of the present invention. 1, sesquiterpene or the acceptable salt of its pharmacy purposes in a kind of medicine that is used for the treatment of the infection that causes by flaviviridae of preparation, described sesquiterpene has following general formula: Wherein: Q is selected from CO, CHOH, CHOCH 3, CHOC 2H 5, and CHOCOCCH 2CH 2COOH. 2, the purposes of claim 1, wherein said infection is a hepatitis C. 3, the purposes of claim 1, wherein said infection are bovine viral diarrhoea or swine fever.

CN1833644B青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药中的应用---预防或治疗细菌和CpG ODN引发的脓毒症药物中的应用 CN1833644B Application of artemisinin and its derivatives dihydroartemisinin, artemether, arteether, and artemotil in pharmaceuticals---The application in drugs for preventing or treating sepsis caused by bacteria and CpG ODN. 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药中的应用 本发明涉及青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的新用途。该物质具有显著的体内和体外抗炎作用，可以显著抑制灭活大肠杆菌诱导的人THP-1细胞系及小鼠RAW264.7细胞系释放细胞因子TNF-α与IL-6。该物质原料来源广泛，价格低廉。可用于治疗或预防CpG ODN和细菌引起的脓毒症。 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药中的应用 技术领域 本发明涉及青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的用途，尤其涉及在制药领域中的用途。 背景技术 细菌感染是现在临床病人死亡的主要原因。机体感染时，细菌菌体成分如基因组DNA及细菌内毒素(LPS)通过激活哺乳动物单核/巨噬细胞、树突状细胞等多种免疫细胞，诱导TNF-α、IL-1、IL-6、NO等致炎细胞因子的释放，导致组织器官的损伤，引起脓毒症的发生。 青蒿属菊科植物，1972年我国科研人员最早从中药青蒿中分离得到抗疟有效单体，命名为青蒿素。青蒿素分子式为C15H22O5，根据化学反应，光谱数据和x-射线单品衍射方法，证明青蒿素是一种具有过氧基的新型倍半萜内酯。其衍生物主要有二氢青蒿素、蒿甲醚、蒿乙醚及青蒿琥酯的化学结构式为： 青蒿素及其衍生物用来治疗疟疾相关的发热已经有一千多年的历史，现在临床上主要用于耐药恶性疟疾。Efferth TM，Wang X，Huong SM，Hauber I等在其文章《Antiviral activity of artesunate towards wild-type，recombinantandganciclovir-resistant human cytomegalovimses》(J Mol Med.2002；80(4)：p223-224)中描述了青蒿类物质还具有其它方面的作用，如平喘、抗癌、抗血吸虫及对免疫系统的调节等。国内外有关青蒿素及其衍生物的研究主要集中在抗疟、抗癌、抗血吸虫的作用及其机制上。 对青蒿素及其衍生物的抗内毒素的作用已有研究，Aldieri E，Bergandi L，RigantiC，Costamagna C，Bosia A，Ghigo D等在其文章《Artemisinin inhibits inducible nitricoxide synthase and nuclear factor NF-kB activation》(FEBS Lett.2003；552(2-3)：p141-144)中描述了青蒿素可抑制LPS/TNF-α诱导性NO合酶的合成及NF-κB的激活；梁爱华，薛宝云，李春英等在其文章《青蒿琥酯对内毒素诱导的一氧化氮合成的抑制作用》(中国中药杂志.2001；26(11)：p770-773.)中描述了青蒿素衍生物青蒿琥酯对LPS及合并干扰素刺激小鼠腹腔巨噬细胞NO的合成有明显的抑制作用，对LPS刺激的小鼠腹腔巨噬细胞RAW264.7也具有相似的保护作用，而且随着青蒿琥酯浓度的增加青蒿琥酯对NO合成的抑制作用也增强，梁爱华、薛宝云、王金华等在其文章《青蒿琥酯对内毒素诱导的炎症因子合成抑制作用的研究》(中国中西医结合急救杂志.2001；8(5)：p262.-265)中描述了青蒿琥酯在25～100mg/L对LPS诱导的TNF-α产生具有明显的抑制作用，与LPS单独应用比较抑制率为43％～58％；谭余庆等在其文章《青蒿素提取物抗内毒素作用的实研究》(中国中药杂志.1999；24(3)：p166-171)还发现青蒿提取物、青蒿素可降低内毒素休克小鼠LPO、ACP、内毒素、TNF-α、P450浓度，升高SOD活性，降低小鼠死亡率，延长小鼠的平均生存时间，对小鼠肝、肺组织形态也有一定的保护作用。但是青蒿素及其衍生物对细菌DNA以及细菌(革兰阳性菌和革兰阴性菌)导致的脓毒症是否有效，未见报道。 发明内容 本发明的目的是提供一种青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的新用途，即在制药中的新应用。 实际上，本发明涉青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯作为制备预防或治疗细菌引发的脓毒症药物中的应用。 涉及青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯作为制备预防或治疗CpG ODN引发的脓毒症药物中的应用。 本发明涉青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯作为制备预防或治疗细菌和CpG ODN引发的脓毒症药物中的应用。 所述CpG ODN是指包含有CpG基序的寡核苷酸，是细菌DNA活性的最小单位。 申请人对青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的体外抗炎作用进行了药理学分析，发现青蒿素、二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均具有显著的体外抗炎作用。青蒿素、二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种都可以显著抑制灭活大肠杆菌诱导的人THP-1细胞系及小鼠RAW264.7细胞系释放细胞因子TNF-α与IL-6，而且在治疗剂量内，随着青蒿素、二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种物质浓度的增加，抑制作用也随之增强，提前给予青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种都可以具有预防作用。 申请人对青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯体内抗炎作用进行了药理学分析，发现青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种都能降低灭活大肠杆菌、细菌(包括革兰阴性、阳性菌)攻击小鼠的死亡率，都可以显著抑制小鼠血清细胞因子TNF-α与IL-6释放，并对灭活大肠杆菌、细菌攻击小鼠的主要脏器(心、肝、肠、肺、肾)具有显著保护作用；青蒿素联合抗生素治疗细菌感染效果更佳。 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯使用常规制剂的方法加上医学上可以接受的载体后可以制备成药剂学上的各种剂型。 本发明的优点在于： (1)本发明对已知的青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯发掘了新的医疗用途，开拓了一个新的应用领域。 (2)本发明的青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯安全无毒，药理作用强，有着良好的药用前景。 (3)我国青蒿素及其衍生物的生产大国，本发明拓宽了青蒿素及其衍生物的适应范围，具有良好的社会与经济效益。 (4)由于目前脓毒症的治疗缺乏有效的药物，因此青蒿素及其衍生物的应用对提高脓毒症的救治率具有重要意义。 (5)本发明的物质制备的药物具有显著的体内和体外抗炎作用，能够有效的预防或治疗脓毒症。 具体实施方式 下面例子为进一步描述本发明而不是限制本发明。 实验例1.青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制CpG-ODN诱导细胞因子释放的量-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃ CO2孵箱培养4h后使细胞贴壁，加入不同浓度的青蒿素(5、10、20、40、80μg/ml)或双氢青蒿素、蒿甲醚、青蒿琥酯，2小时后再加入10μg/ml的刺激性CpG ODN(5′-TCC ATG ACG TTC CTG ACG TT-3′)，置37℃、CO2孵箱培养4h后取细胞培养上清待测细胞因子TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。采用双抗体夹心ELISA法测定细胞培养上清中TNF-α和IL-6的浓度，明确青蒿素或衍生物抑制CpG ODN诱导RAW264.7释放细胞因子的作用。 表1青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制CpG ODN诱导RAW264.7细胞释放细胞因子的量效关系(n＝3，x±SD) **p＜0.01 vs CpG ODN 此次实验结果表明青蒿素显著抑制CpG ODN诱导RAW264.7释放细胞因子，随青蒿素浓度增加，其抑制作用增强(p＜0.01，见表1)；双氢青蒿素、蒿甲醚及青蒿琥酯也对CpG ODN诱导RAW264.7释放细胞因子也有显著抑制作用。 实验例2.青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制热灭活大肠杆菌诱导细胞因子释放的量-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃ CO2孵箱培养4h后使细胞贴壁，加入不同浓度的青蒿素(5、10、20、40、80μg/ml)或40μg/ml的双氢青蒿素、蒿甲醚或青蒿琥酯，2小时后再加入1×106/ml热灭活大肠杆菌，置37℃、CO2孵箱培养4h后取细胞培养上清待测细胞因子TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。采用双抗体夹心ELISA法测定细胞培养上清中TNF-α和IL-6的浓度，明确青蒿素或衍生物抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子的作用。 表2青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制热灭活大肠杆菌诱导RAW264.7细胞释放TNF-α的量效关系(n＝3，x±SD) **p＜0.01 vs E.coli 此次实验结果表明青蒿素显著抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子，随青蒿素浓度增加，其抑制作用增强(p＜0.01，见表2)；双氢青蒿素、蒿甲醚及青蒿琥酯也对热灭活大肠杆菌诱导RAW264.7释放细胞因子有抑制作用。。 实验例3.青蒿素抑制CpG ODN诱导细胞因子释放的时-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃、CO2孵箱培养4h后使细胞贴壁，以加入CpG ODN时间为0时相点，分别在-4、-2、-1、0、1、2小时加入20μg/ml青蒿素，置37℃、CO2孵箱培养4h后取细胞培养上清待测定TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。明确青蒿素抑制CpG ODN诱导RAW264.7释放细胞因子的能力。 表3青蒿素抑制CpG ODN诱导RAW264.7释放TNF-的时-效关系(x±SD) **p＜0.01 vs CpG 此次实验结果表明青蒿素显著抑制CpG ODN诱导RAW264.7释放细胞因子，提前加入青蒿素及在加入CpG ODN后加入青蒿素，均能抑制细胞因子释放，但提前加入抑制作用更强(p＜0.01，见表3)。 实验例4.青蒿素抑制热灭活大肠杆菌诱导细胞因子释放的时-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃ CO2孵箱培养4h后使细胞贴壁，以加入热灭活大肠杆菌时间为0时相点，分别在-4、-2、-1、0、1、2小时加入20μg/ml青蒿素，置37℃、CO2孵箱培养4h后取细胞培养上清待测定TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。明确青蒿素抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子的能力。 表4青蒿素抑制热灭活大肠杆菌诱导RAW264.7释放TNF-α的时-效关系(n＝3，x±SD) **p＜0.01 vs E.coli 此次实验结果表明青蒿素显著抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子，提前加入青蒿素或加入热灭活大肠杆菌后给予青蒿素，均能抑制细胞因子释放，但提前加入青蒿素抑制作用更强(p＜0.01，见表4)。 实验例5.青蒿素及其衍生物对CpG-ODN攻击小鼠的保护作用。 清洁级昆明种小白鼠60只(重庆医科大学实验动物中心提供)，体重18.6±0.5g/只，雌雄各半，随机分为对照组、青蒿素组(100mg/kg)、CpG ODN组(4mg/kg)，青蒿素(50、100、200mg/kg)或青蒿素衍生物+CpG-ODN。每组10只动物。含CpG ODN组动物提前1小时给予D氨基半乳糖。对照不给予任何试剂；青蒿素组给予200mg/kg的青蒿素，给药方式为灌胃给药；CpG ODN组，给予4mg/kg体重的CpG ODN，给药方式为尾静脉注射；青蒿素或其衍生物+CpG ODN组，在灌胃给予不同剂量青蒿素后，立即给予4mg/kg体重的CpG ODN。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表5)。 表5青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯对CpG ODN攻击小鼠的保护作用 *p＜0.05，**p＜0.01 vs CpG 本实验表明，青蒿素、双氢青蒿素和蒿甲醚均可以可降低CpG ODN攻击小鼠的死亡率，表明对致炎因子攻击的小鼠具有保护作用。 实验例6.青蒿素及其衍生物对热灭活大肠杆菌攻击小鼠的保护作用。 清洁级昆明种小白鼠60只(重庆医科大学实验动物中心提供)，体重19.9±0.4g/只，雌雄各半，随机分为对照组、青蒿素组、热灭活大肠杆菌组，青蒿素(50、100、200mg/kg)或衍生物(40mg/kg)+热灭活大肠杆菌组。每组10只动物。对照不给予任何试剂；青蒿素或衍生物组灌胃给予青蒿素或衍生物；热灭活大肠杆菌组，给予1.1×1011/kg的热灭活大肠杆菌35218；青蒿素或衍生物+热灭活大肠杆菌组，在灌胃给予青蒿素后，立即给予热灭活大肠杆菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表6)。 表6青蒿素对热灭活大肠杆菌攻击小鼠的保护作用 *p＜0.05；**p＜0.01 vs E.coli 本实验结果显示：青蒿素及衍生物均可以可降低小鼠的死亡率，对致炎因子攻击的小鼠具有保护作用。 实验例7.青蒿素及其衍生物对大肠杆菌35218攻击小鼠的保护作用。 清洁级昆明种小白鼠(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿素组、大肠杆菌组，青蒿素(50、100、200mg/ml)或衍生物+大肠杆菌组。对照不给予任何试剂；青蒿素或衍生物组灌胃给予200mg/kg的青蒿素或衍生物；大肠杆菌组，给予1.1×105/kg活的大肠杆菌；青蒿素或衍生物+大肠杆菌组，在灌胃给予青蒿素或衍生物后，立即给予大肠杆菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表7)。 表7青蒿素对大肠杆菌35218攻击小鼠的保护作用 *p＜0.5；**p＜0.01 vs E.coli 本实验结果显示：青蒿素及其衍生物均可以可降低小鼠的死亡率，对致炎因子攻击的小鼠具有保护作用。 实验例8.青蒿素及其衍生物对热灭活金黄色葡萄球菌攻击小鼠的保护作用。 清洁级昆明种小白鼠(重庆医科大学实验动物中心提供)，体重20.1±0.4g/只，雌雄各半，随机分为对照组、青蒿素组、大肠杆菌组，青蒿素(50、100、200mg/kg)或衍生物(40mg/kg)+热灭活金黄色葡萄球菌组。对照不给予任何试剂；青蒿素或衍生物组灌胃给予200mg/kg的青蒿素；热灭活大肠杆菌组，给予1.1×104/kg热灭活金黄色葡萄球菌；青蒿素或衍生物+热灭活金黄色葡萄球菌组，在灌胃给予青蒿素或衍生物后，立即给予热灭活金黄色葡萄球菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表8)。 表8青蒿素及其衍生物对金黄色葡萄球菌攻击小鼠的保护作用 *p＜0.5；**p＜0.01 vs E.coli 本实验结果显示：青蒿素及其衍生物均可以降低小鼠的死亡率，对致炎因子攻击的小鼠具有保护作用。 实验例9.青蒿素对CpG ODN、热灭活大肠杆菌攻击小鼠血清细胞因子表达影响 清洁级昆明种小白鼠48只(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿素组、CpG ODN组，青蒿素+CpG-ODN组、热灭活大肠杆菌组、青蒿素+热灭活大肠杆菌组，每组动物10只。对照不给予任何试剂。青蒿素组给予200mg/kg的青蒿素，给药方式为灌胃给药；CpG ODN组、热灭活大肠杆菌组，分别给予4mg/kg体重的CpG ODN、1.1×1011/kg体重的热灭活大肠杆菌组，给药方式均为尾静脉注射；青蒿素+CpG ODN组，在灌胃给予青蒿素后，立即给予CpG ODN、热灭活大肠杆菌组。给药完毕后摘眼球取血立即离心留置上清保存于-20℃，待测定细胞因子TNF-α(表9)。 表9青蒿素降低CpG ODN、热灭活大肠杆菌攻击小鼠血清细胞因子TNF-α(pg/ml)表达 *p＜0.5 vs NO ART 本实验结果显示：青蒿素可以可显著降低CpG ODN、热灭活大肠杆菌攻击小鼠血清细胞因子表达。 实验例10.青蒿素在治疗因细菌导致的脓毒症的临床研究 选择细菌脓毒症病人50例，其中30人作为治疗组，其中男19例，女11例，年龄在19-70岁，平均38.6±13.1岁，治疗组在常规治疗的基础上均口服青蒿素进行治疗，观察到治疗组病人的细菌清除率明显提高，脓毒症得到明显的控制。另外20人仅给予常规治疗，不采用青蒿素进行治疗。效果判定标准按照有效、无效2级评定，有效：(1)脓毒症症状得到控制，病情明显好转；(2)血清TNF-α浓度显著降低。无效：(1)用药3天后脓毒症病情无好转或加重；(2)血清TNF-α浓度浓度无显著降低。不良反应评定将病人在用药过程中及用药后5d内出现的不良反应及异常化验结果按照与药物有关、可能有关、无关、可能无关、无法确定5级进行评定，有关及可能有关列人不良反应。 用药方法：200mg的青蒿素片剂口服，12小时1次，疗程5-7d。 用药后的治疗脓毒症的效果如下表所示： 表1.预防和治疗脓毒症临床观察情况 组别 n 有效 无效 有效率 青蒿素治疗组 30 28 2 93 常规治疗组 20 15 5 75 合计 50 43 7 86 表2.治疗组和对照组血清TNF-α浓度 组别 n 显著降低 无显著降低 有效率 青蒿素治疗组 30 29 1 97 常规治疗组 20 13 7 65 合计 50 42 8 84 不良反应：有2例病人出现轻度恶心、头晕等，进食后症状消失，其余无其它不良。 从以上实验可以得到结论：青蒿素在治疗因细菌引起的脓毒症方面具有比较好的疗效。 同理，口服200mg的青蒿素片剂口服，12小时1次，疗程5-7d可以预防或治疗因CpG ODN导致的脓毒症。 同样的，二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以达到同样的药理效果。 实施例1 取已经天然提取的青蒿素200克(纯度98％)，乳糖50克，淀粉糊适量，硬脂酸镁适量，混合均匀后，用直接压片法制备成1000片，然后包装即可得到规格为200mg的片剂，所用设备均为本领域的常规设备。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例1制备成200mg规格的片剂。 实施例2 取已经天然提取的青蒿素100克(纯度98％)，乳糖50克，淀粉糊适量，硬脂酸镁适量，混合均匀后，用直接压片法制备成1000片，然后包装即可得到规格为100mg的片剂，所用设备均为目前生产的常规设备。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例2制备成100mg规格的片剂。 实施例3 取已经天然提取的青蒿素50克(纯度98％)，乳糖50克，淀粉糊适量，硬脂酸镁适量，混合均匀后，用直接压片法制备成1000片，然后包装即可得到规格为50mg的片剂，所用设备均为目前生产的常规设备。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例3制备成50mg规格的片剂。 实施例4 取已经天然提取的青蒿素200克(纯度98％)，淀粉30克，糊精5克，硬脂酸镁适量混合均匀，装入1000粒1号胶囊，然后分装入瓶或加工成盒即得。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例4制备成200mg的胶囊剂。 实施例5 取已经天然提取的青蒿素200克100克(纯度98％)，淀粉30克，糊精5克，硬脂酸镁适量混合均匀，装入1000粒1号胶囊，然后分装入瓶或加工成盒即得。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例5制备成100mg规格的胶囊剂。 实施例6 取已经天然提取的青蒿素50克(纯度98％)，淀粉30克，糊精5克，硬脂酸镁适量混合均匀，装入1000粒1号胶囊，然后分装入瓶或加工成盒即得。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例6制备成50mg规格的胶囊剂。 实施例7 取已经天然提取的青蒿素200克，加入注射用水和本领域常用的润湿剂如吐温-80、本领域常用的助悬剂如甲基纤维素，使润湿剂的含量为0.1-0.2％克每升，使助悬剂的含量为0.5-1％克每升，然后用超声波处理使分散均匀，滤过，调PH值、灌封、灭菌得到1000支浑悬剂。所用设备均为本领域通用设备。 同理，根据实施例7，可以得到100mg和50mg规格的青蒿素浑悬剂。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例7制备成50mg、100mg、200mg规格的浑悬剂。 Abrotine, its derivative dihydro-abrotine, artemether, arteether and arte sunate in use of pharmacy An application of arteannuin and its derivatives (dihydroarteannuin, artemether, arteether and artesunate) in preparing the medicines for preventing and treating the sepsis caused by CpG-ODN and bacteria is disclosed. The application in pharmacy of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate Technical field The present invention relates to the purposes of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, relate in particular to the purposes in pharmaceutical field. Background technology Bacterial infection is present clinical patient main causes of death.During organism infection, antibacterial thalline composition such as genomic DNA and bacterial endotoxin (LPS) are by activating panimmunity cells such as mammal Monocytes, dendritic cell, induce the release of proinflammatory cytokines such as TNF-α, IL-1, IL-6, NO, cause the damage of histoorgan, cause pyemic generation. Herba Artemisiae Annuae belongs to feverfew, and China scientific research personnel in 1972 separates from the Chinese medicine Herba Artemisiae Annuae the earliest and obtains malaria effective monomer, called after arteannuin.The arteannuin molecular formula is C15H22O5, and according to chemical reaction, spectroscopic data and x-ray list product diffraction method prove that arteannuin is a kind of sesquiterpene lactone with peroxy.The chemical structural formula that its derivant mainly contains dihydroartemisinine, Artemether, arteether and artesunate is: Arteannuin and derivant thereof are used for treating the relevant heating of malaria the history in more than 1,000 year, is mainly used in the drug resistance pernicious malaria now clinically.Efferth TM, Wang X, Huong SM, Hauber I etc. are at its article " Antiviral activity of artesunate towards wild-type, recombinantandganciclovir-resistant human cytomegalovimses " (J Mol Med.2002; 80 (4): described Herba Artemisiae Annuae class material p223-224) and also had the effect of others, as relieving asthma, anticancer, schistosomicide and to immune adjusting etc.The research of relevant arteannuin and derivant thereof both at home and abroad mainly concentrates on malaria, anticancer, antischistosomal effect and the mechanism thereof. To the existing research of the antiendotoxic effect of arteannuin and derivant thereof, Aldieri E, Bergandi L, RigantiC, Costamagna C, Bosia A, Ghigo D etc. are at its article " Artemisinin inhibits inducible nitricoxide synthase and nuclear factor NF-kB activation " (FEBS Lett.2003; 552 (2-3): described the activation that arteannuin can suppress the synthetic and NF-κ B of LPS/TNF-α inductivity NO synthase p141-144); The beam Aiwa, Xue Baoyun, Li Chunying etc. are at its article " artesunate is to the synthetic inhibitory action of the nitric oxide of endotaxin induction " (CHINA JOURNAL OF CHINESE MATERIA MEDICA .2001; 26 (11): described p770-773.) the artemisinin derivative artesunate to LPS and merge that interferon stimulates Turnover of Mouse Peritoneal Macrophages NO synthetic the obvious suppression effect arranged, the Turnover of Mouse Peritoneal Macrophages RAW264.7 that LPS is stimulated also has similar protective effect, and along with the increase artesunate of artesunate concentration also strengthens the synthetic inhibitory action of NO, beam Aiwa, Xue Baoyun, Wang Jinhua etc. are at its article " artesunate is to the synthetic inhibiting research of the inflammatory factor of endotaxin induction " (Chinese combination of Chinese and Western medicine first aid magazine .2001; 8 (5): inductive TNF-α generation has the obvious suppression effect to LPS at 25～100mg/L to have described artesunate p262.-265), and using the comparison suppression ratio separately with LPS is 43%～58%; Tan Yuqing etc. are at its article " the real research of arteannuin extract anti-endotoxin effect " (CHINA JOURNAL OF CHINESE MATERIA MEDICA .1999; 24 (3): p166-171) find that also Herba Artemisiae Annuae extract, arteannuin can reduce endotoxin shock mice LPO, ACP, endotoxin, TNF-α, P450 concentration; the increased SOD activity; reduce mouse death rate; prolong the mean survival time of mice, Mouse Liver, lung tissue form are also had the certain protection effect.But whether arteannuin and derivant thereof be effective to the sepsis that DNA of bacteria and antibacterial (gram positive bacteria and gram-negative bacteria) cause, and do not appear in the newspapers. Summary of the invention The new purposes that the purpose of this invention is to provide a kind of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, i.e. new application in pharmacy. In fact, the present invention relates to the application in the medication for treating pyemia that arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate cause as preparation prevention or treatment antibacterial. Relate to arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate as the application in the medication for treating pyemia of preparation prevention or treatment CpG ODN initiation. The present invention relates to the application in the medication for treating pyemia that arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate cause as preparation prevention or treatment antibacterial and CpG ODN. Described CpG ODN is meant the oligonucleotide that includes the CpG motif, is the active least unit of DNA of bacteria. The applicant has carried out pharmacology's analysis to the extracorporeal anti-inflammatory effect of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, finds that arteannuin, dihydroartemisinine, Artemether, arteether, artesunate all have the remarkable vitro antiinflammatory action.Arteannuin, dihydroartemisinine, Artemether, arteether, any in the artesunate can significantly suppress colibacillus deactivating inductive people THP-1 cell line and mice RAW264.7 cell line discharges cytokine TNF-α and IL-6, and in therapeutic dose, along with arteannuin, dihydroartemisinine, Artemether, arteether, the increase of any material concentration in the artesunate, inhibitory action also strengthens thereupon, gives arteannuin and derivative dihydro-abrotine thereof in advance, Artemether, arteether, any in the artesunate can have preventive effect. The applicant is to arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, antiinflammatory action has carried out pharmacology's analysis in the artesunate body, find arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, any in the artesunate can both reduce colibacillus deactivating, antibacterial (comprises Grain-negative, positive bacteria) attacks mortality of mice, can significantly suppress mice serum cytokine TNF-α and IL-6 and discharge, and to colibacillus deactivating, main organs (the heart of germ attack mice, liver, intestinal, lung, kidney) has remarkable protective effect; Arteannuin combined with antibiotic treatment bacterial infection effect is better. Arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate use the method for conventional formulation to add the various dosage forms that can be prepared into behind the acceptable carrier medically on the pharmaceutics. The invention has the advantages that: (1) the present invention has excavated new medical application to known arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, has opened up a new application. (2) arteannuin of the present invention and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate safety non-toxic, pharmacological action is strong, and good prospect in medicine is arranged. (3) big producing country of China's arteannuin and derivant thereof, the present invention has widened the subject range of arteannuin and derivant thereof, has good society and economy benefit. (4) because present pyemic treatment lacks effective medicine, so the application of arteannuin and derivant thereof is significant to improving pyemic treatment rate. (5) medicine of material preparation of the present invention has in the significant body and the extracorporeal anti-inflammatory effect, can effectively prevent or treat sepsis. The specific embodiment Following example is for further describing the present invention rather than restriction the present invention. Experimental example 1. arteannuin, dihydroarteannuin, Artemether and artesunate suppress the amount-result relation that the CpG-ODN inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃ of CO 2Incubator makes cell attachment after cultivating 4h, the arteannuin (5,10,20,40,80 μ g/ml) of adding variable concentrations or dihydroarteannuin, Artemether, artesunate, the zest CpG ODN (5 '-TCC ATG ACG TTC CTG ACG TT-3 ') that adds 10 μ g/ml after 2 hours again, put and get cells and supernatant cytokine TNF-α to be measured after 37 ℃, CO2 incubator are cultivated 4h, after 4 hours, get cells and supernatant cytokine IL-6 to be measured.The concentration of TNF-α and IL-6 in the employing double-antibody sandwich elisa method mensuration cells and supernatant, clear and definite arteannuin or derivant suppress CpG ODN and induce RAW264.7 to discharge effect of cytokines. Table 1 arteannuin, dihydroarteannuin, Artemether and artesunate suppress CpG ODN and induce the RAW264.7 cell to discharge dose-effect relationship (n=3, the x ± SD) of cytokine **p＜0.01 vs CpG ODN This time experimental result shows that arteannuin significantly suppresses CpG ODN and induces RAW264.7 to discharge cytokine, increases with arteannuin concentration, and its inhibitory action strengthens (p＜0.01 sees Table 1); Dihydroarteannuin, Artemether and artesunate also induce RAW264.7 to discharge cytokine to CpG ODN also remarkable inhibitory action. Experimental example 2. arteannuin, dihydroarteannuin, Artemether and artesunate suppress the amount-result relation that the hot colibacillus deactivating inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃ of CO 2Incubator makes cell attachment after cultivating 4h, adds the arteannuin (5,10,20,40,80 μ g/ml) of variable concentrations or dihydroarteannuin, Artemether or the artesunate of 40 μ g/ml, adds 1 * 10 again after 2 hours 6The hot colibacillus deactivating of/ml is put and is got cells and supernatant cytokine TNF-α to be measured after 37 ℃, CO2 incubator are cultivated 4h, gets cells and supernatant cytokine IL-6 to be measured after 4 hours.The concentration of TNF-α and IL-6 in the employing double-antibody sandwich elisa method mensuration cells and supernatant, clear and definite arteannuin or derivant suppress hot colibacillus deactivating and induce RAW264.7 to discharge effect of cytokines. Table 2 arteannuin, dihydroarteannuin, Artemether and artesunate suppress hot colibacillus deactivating and induce the RAW264.7 cell to discharge dose-effect relationship (n=3, the x ± SD) of TNF-α **p＜0.01 vs E.coli This time experimental result shows that arteannuin significantly suppresses hot colibacillus deactivating and induces RAW264.7 to discharge cytokine, increases with arteannuin concentration, and its inhibitory action strengthens (p＜0.01 sees Table 2); Dihydroarteannuin, Artemether and artesunate also induce RAW264.7 to discharge cytokine to hot colibacillus deactivating inhibitory action.。 Experimental example 3. arteannuin suppress the time-effect relationship that the CpG ODN inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃, CO 2Incubator makes cell attachment after cultivating 4h, to add the CpG ODN time is 0 o'clock point mutually, added 20 μ g/ml arteannuin respectively at-4 ,-2 ,-1,0,1,2 hours, put and get cells and supernatant TNF-α to be determined after 37 ℃, CO2 incubator are cultivated 4h, after 4 hours, get cells and supernatant cytokine IL-6 to be measured.Clear and definite arteannuin suppresses CpG ODN and induces RAW264.7 to discharge the ability of cytokine. Table 3 arteannuin suppresses CpG ODN and induces RAW264.7 to discharge the time-effect relationship (x ± SD) of TNF- **p＜0.01 vs CpG This time experimental result shows that arteannuin significantly suppresses CpG ODN and induces RAW264.7 to discharge cytokine, add arteannuin in advance and after adding CpG ODN, add arteannuin, all can suppress release of cytokines, but add inhibitory action stronger (p＜0.01 sees Table 3) in advance. Experimental example 4. arteannuin suppress the time-effect relationship that the hot colibacillus deactivating inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃ of CO 2Incubator makes cell attachment after cultivating 4h, to add the hot colibacillus deactivating time is 0 o'clock point mutually, added 20 μ g/ml arteannuin respectively at-4 ,-2 ,-1,0,1,2 hours, put and get cells and supernatant TNF-α to be determined after 37 ℃, CO2 incubator are cultivated 4h, after 4 hours, get cells and supernatant cytokine IL-6 to be measured.Clear and definite arteannuin suppresses hot colibacillus deactivating and induces RAW264.7 to discharge the ability of cytokine. Table 4 arteannuin suppresses hot colibacillus deactivating and induces RAW264.7 to discharge time-effect relationship (n=3, the x ± SD) of TNF-α **p＜0.01 vs E.coli This time experimental result shows that arteannuin significantly suppresses hot colibacillus deactivating and induces RAW264.7 to discharge cytokine, give arteannuin after adding arteannuin in advance or adding hot colibacillus deactivating, all can suppress release of cytokines, but add arteannuin inhibitory action stronger (p＜0.01 sees Table 4) in advance. Experimental example 5. arteannuin and derivant thereof are attacked the protective effect of mice to CpG-ODN. Cleaning level 60 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 18.6 ± 0.5g/ only, male and female half and half, be divided into matched group, arteannuin group (100mg/kg), CpG ODN at random and organize (4mg/kg), arteannuin (50,100,200mg/kg) or artemisinin derivative+CpG-ODN.Every group of 10 animals.Contain CpG ODN treated animal and gave D aminogalactose in 1 hour in advance.Contrast does not give any reagent; The arteannuin group gives the arteannuin of 200mg/kg, and administering mode is a gastric infusion; CpG ODN organizes, and gives the CpG ODN of 4mg/kg body weight, and administering mode is a tail vein injection; Arteannuin or derivatives thereof+CpG ODN group after the filling stomach gives the various dose arteannuin, gives the CpG ODN of 4mg/kg body weight immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 5) in 7 days. Table 5 arteannuin, dihydroarteannuin, Artemether and artesunate are attacked the protective effect of mice to CpG ODN *p＜0.05， **p＜0.01 vs CpG This experiment shows that arteannuin, dihydroarteannuin and Artemether all can reduce CpG ODN and attack mortality of mice, shows that the mice that pro-inflammatory cytokine is attacked has protective effect. Experimental example 6. arteannuin and derivant thereof are attacked the protective effect of mice to hot colibacillus deactivating. Cleaning level 60 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.4g/ only, male and female half and half, be divided into matched group, arteannuin group, hot colibacillus deactivating group at random, arteannuin (50,100,200mg/kg) or derivant (40mg/kg)+hot colibacillus deactivating group.Every group of 10 animals.Contrast does not give any reagent; Arteannuin or derivant group are irritated stomach and are given arteannuin or derivant; Hot colibacillus deactivating group gives 1.1 * 10 11The hot colibacillus deactivating 35218 of/kg; Arteannuin or derivant+hot colibacillus deactivating group after the filling stomach gives arteannuin, gives hot colibacillus deactivating immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 6) in 7 days. Table 6 arteannuin is attacked the protective effect of mice to hot colibacillus deactivating *p＜0.05； **p＜0.01 vs E.coli This experimental result shows: arteannuin and derivant all can reduce mortality of mice, and the mice that pro-inflammatory cytokine is attacked has protective effect. The protective effect that experimental example 7. arteannuin and derivant thereof are attacked mice to escherichia coli 35218. Cleaning level Kunming kind white mice (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half are divided into matched group, arteannuin group, escherichia coli group at random, arteannuin (50,100,200mg/ml) or derivant+escherichia coli group.Contrast does not give any reagent; Arteannuin or derivant group are irritated arteannuin or the derivant that stomach gives 200mg/kg; The escherichia coli group gives 1.1 * 10 5The escherichia coli that/kg lives; Arteannuin or derivant+escherichia coli group after the filling stomach gives arteannuin or derivant, gives escherichia coli immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 7) in 7 days. The protective effect that table 7 arteannuin is attacked mice to escherichia coli 35218 *p＜0.5； **p＜0.01 vs E.coli This experimental result shows: arteannuin and derivant thereof all can reduce mortality of mice, and the mice that pro-inflammatory cytokine is attacked has protective effect. Experimental example 8. arteannuin and derivant thereof are attacked the protective effect of mice to hot deactivation staphylococcus aureus. Cleaning level Kunming kind white mice (Medical University Of Chongqing's Experimental Animal Center provides), body weight 20.1 ± 0.4g/ only, male and female half and half, be divided into matched group, arteannuin group, escherichia coli group at random, arteannuin (50,100,200mg/kg) or derivant (40mg/kg)+hot deactivation staphylococcus aureus group.Contrast does not give any reagent; Arteannuin or derivant group are irritated the arteannuin that stomach gives 200mg/kg; Hot colibacillus deactivating group gives 1.1 * 10 4The hot deactivation staphylococcus aureus of/kg; Arteannuin or derivant+hot deactivation staphylococcus aureus group after the filling stomach gives arteannuin or derivant, gives hot deactivation staphylococcus aureus immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table in 7 days. Table 8 arteannuin and derivant thereof are attacked the protective effect of mice to staphylococcus aureus *p＜0.5； **p＜0.01 vs E.coli This experimental result shows: arteannuin and derivant thereof all can reduce mortality of mice, and the mice that pro-inflammatory cytokine is attacked has protective effect. Experimental example 9. arteannuin are attacked the influence of mice serum cytokine-expressing to CpG ODN, hot colibacillus deactivating Cleaning level 48 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half, be divided into matched group, arteannuin group, CpG ODN group at random, arteannuin+CpG-ODN group, hot colibacillus deactivating group, arteannuin+hot colibacillus deactivating group, 10 of every treated animals.Contrast does not give any reagent.The arteannuin group gives the arteannuin of 200mg/kg, and administering mode is a gastric infusion; CpG ODN organizes, hot colibacillus deactivating group, gives the CpG ODN, 1.1 * 10 of 4mg/kg body weight respectively 11The hot colibacillus deactivating group of/kg body weight, administering mode is tail vein injection; Arteannuin+CpG ODN group after the filling stomach gives arteannuin, gives CpG ODN, hot colibacillus deactivating group immediately.Plucking eyeball after administration finishes gets the centrifugal immediately indwelling supernatant of blood and is stored in-20 ℃, cytokine TNF-α to be determined (table 9). Table 9 arteannuin reduces CpG ODN, hot colibacillus deactivating is attacked mice serum cytokine TNF-α (pg/ml) and expressed *p＜0.5 vs NO ART This experimental result shows: arteannuin can significantly reduce CpG ODN, hot colibacillus deactivating is attacked the mice serum cytokine-expressing. The pyemic clinical research that experimental example 10. arteannuin cause because of antibacterial in treatment Selecting bacteria sepsis patient 50 examples, wherein 30 people organize as treatment, wherein male 19 examples, woman's 11 examples, age, average 38.6 ± 13.1 years old, treatment group all oral arteannuin on the basis of conventional therapy was treated in 19-70 year, the bacteria clearance of observing treatment group patient obviously improves, and sepsis obtains obvious control.Other 20 people only give conventional therapy, do not adopt arteannuin to treat.Effect criterion is according to effective, invalid 2 grades of evaluations, effectively: (1) sepsis symptom is controlled, and the state of an illness is clearly better; (2) serum TNF-α concentration significantly reduces.Invalid: (1) medication after 3 days the sepsis state of an illness do not have and take a turn for the better or increase the weight of; (2) serum TNF-α concentration concentration does not have remarkable reduction.Untoward reaction evaluation with patient in the medication process and the untoward reaction that occurs in the 5d after the medication and unusual result of laboratory test according to relevant with medicine, may be relevant, irrelevant, may have nothing to do, can't determine 5 grades and evaluate, relevant and may relevantly be listed as people's untoward reaction. The arteannuin tablet of administrated method: 200mg is oral, 12 hours 1 time, the course of treatment 5-7d. The pyemic effect of treatment after the medication is as shown in the table: Table 1. prevention and treatment sepsis clinical observation situation Group n Effectively Invalid Effective percentage Arteannuin treatment group 30 28 2 93 The conventional therapy group 20 15 5 75 Add up to 50 43 7 86 Table 2. treatment group and matched group serum TNF-α concentration Group n Significantly reduce Do not have significantly and reduce Effective percentage Arteannuin treatment group 30 29 1 97 The conventional therapy group 20 13 7 65 Add up to 50 42 8 84 Untoward reaction: there are 2 routine patients mild nausea, dizziness etc. to occur, feed back transference cure, all the other do not have, and other is bad. Can obtain conclusion from above experiment: arteannuin has reasonable curative effect in treatment aspect bacterial sepsis. In like manner, the arteannuin tablet of oral 200mg is oral, and 12 hours 1 time, 5-7d can prevent or treat the sepsis that causes because of CpG ODN the course of treatment. Same, dihydroartemisinine, Artemether, arteether, artesunate all can reach same pharmacological effect. Embodiment 1 Get arteannuin 200 grams (purity 98%) of natural extract, lactose 50 grams, gelatinized corn starch is an amount of, magnesium stearate is an amount of, behind the mix homogeneously, is prepared into 1000 with direct compression process, packing can obtain the tablet that specification is 200mg then, and device therefor is the conventional equipment of this area. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the tablet of 200mg specification with reference to embodiment 1. Embodiment 2 Get arteannuin 100 grams (purity 98%) of natural extract, lactose 50 grams, gelatinized corn starch is an amount of, magnesium stearate is an amount of, behind the mix homogeneously, is prepared into 1000 with direct compression process, packing can obtain the tablet that specification is 100mg then, and device therefor is the conventional equipment of present production. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the tablet of 100mg specification with reference to embodiment 2. Embodiment 3 Get arteannuin 50 grams (purity 98%) of natural extract, lactose 50 grams, gelatinized corn starch is an amount of, magnesium stearate is an amount of, behind the mix homogeneously, is prepared into 1000 with direct compression process, packing can obtain the tablet that specification is 50mg then, and device therefor is the conventional equipment of present production. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the tablet of 50mg specification with reference to embodiment 3. Embodiment 4 Get arteannuin 200 grams (purity 98%) of natural extract, starch 30 grams, dextrin 5 grams, an amount of mix homogeneously of magnesium stearate, 1000 No. 1 capsules of packing into divide then and pack bottle into or be processed into box promptly. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the capsule of 200mg with reference to embodiment 4. Embodiment 5 Get arteannuin 200 grams 100 grams (purity 98%) of natural extract, starch 30 grams, dextrin 5 grams, an amount of mix homogeneously of magnesium stearate, 1000 No. 1 capsules of packing into divide then and pack bottle into or be processed into box promptly. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the capsule of 100mg specification with reference to embodiment 5. Embodiment 6 Get arteannuin 50 grams (purity 98%) of natural extract, starch 30 grams, dextrin 5 grams, an amount of mix homogeneously of magnesium stearate, 1000 No. 1 capsules of packing into divide then and pack bottle into or be processed into box promptly. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the capsule of 50mg specification with reference to embodiment 6. Embodiment 7 Get arteannuin 200 grams of natural extract, add water for injection and this area wetting agent commonly used such as tween 80, this area suspending agent such as methylcellulose commonly used, the content that makes wetting agent is every liter of 0.1-0.2% gram, the content that makes suspending agent is every liter of 0.5-1% gram, make with ultrasonic Treatment then and be uniformly dispersed, filter, transfer pH value, embedding, sterilization to obtain 1000 muddy outstanding agent.Device therefor is this area common apparatus. In like manner, according to embodiment 7, can obtain the muddy outstanding agent of arteannuin of 100mg and 50mg specification. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the muddy outstanding agent of 50mg, 100mg, 200mg specification with reference to embodiment 7. 1. dihydroartemisinine, the application of Artemether in the pyemic medicine of preparation prevention or treatment CpG ODN initiation. 2. dihydroartemisinine, the application of Artemether in the medication for treating pyemia of preparation prevention or treatment antibacterial and CpG ODN initiation. 3. according to claim 1 or 2 each described purposes, it is characterized in that dihydroartemisinine, Artemether are prepared into any preparation on the pharmaceutics in pharmacy procedure.

CN1833644A青蒿素及其衍生物二氢苦参碱、蒿甲醚、蒿甲醚、青蒿琥酯在药学中的应用---在制备防治CpG-ODN和细菌引起的败血症药物中的应用 CN1833644A Application of artemisinin and its derivatives dihydroartemisinin, artemether, arteether, and artemether in pharmacy---The application in the preparation of drugs for preventing and treating sepsis caused by CpG-ODN and bacteria. 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药中的应用 本发明涉及青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的新用途。该物质具有显著的体内和体外抗炎作用，可以显著抑制灭活大肠杆菌诱导的人THP－1细胞系及小鼠RAW264.7细胞系释放细胞因子TNF－α与IL－6。该物质原料来源广泛，价格低廉。可用于治疗或预防CpG－ODN和细菌引起的脓毒症。 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药中的应用 技术领域 本发明涉及青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的用途，尤其涉及在制药领域中的用途。 背景技术 细菌感染是现在临床病人死亡的主要原因。机体感染时，细菌菌体成分如基因组DNA及细菌内毒素(LPS)通过激活哺乳动物单核/巨噬细胞、树突状细胞等多种免疫细胞，诱导TNF-α、IL-1、IL-6、NO等致炎细胞因子的释放，导致组织器官的损伤，引起脓毒症的发生。 青蒿属菊科植物，1972年我国科研人员最早从中药青蒿中分离得到抗疟有效单体，命名为青蒿素。青蒿素分子式为C15H22O5，根据化学反应，光谱数据和x-射线单品衍射方法，证明青蒿素是一种具有过氧基的新型倍半萜内酯。其衍生物主要有二氢青蒿素、蒿甲醚、蒿乙醚及青蒿琥酯的化学结构式为：（图片见专利文件） 青蒿素及其衍生物用来治疗疟疾相关的发热已经有一千多年的历史，现在临床上主要用于耐药恶性疟疾。Efferth TM，Wang X，Huong SM，Hauber I等在其文章《Antiviral activity of artesunate towards wild-type，recombinantandganciclovir-resistant human cytomegalovimses》(J Mol Med.2002；80(4)：p223-224)中描述了青蒿类物质还具有其它方面的作用，如平喘、抗癌、抗血吸虫及对免疫系统的调节等。国内外有关青蒿素及其衍生物的研究主要集中在抗疟、抗癌、抗血吸虫的作用及其机制上。 对青蒿素及其衍生物的抗内毒素的作用已有研究，Aldieri E，Bergandi L，RigantiC，Costamagna C，Bosia A，Ghigo D等在其文章《Artemisinin inhibits inducible nitricoxide synthase and nuclear factor NF-kB activation》(FEBS Lett.2003；552(2-3)：p141-144)中描述了青蒿素可抑制LPS/TNF-α诱导性NO合酶的合成及NF-κB的激活；梁爱华，薛宝云，李春英等在其文章《青蒿琥酯对内毒素诱导的一氧化氮合成的抑制作用》(中国中药杂志.2001；26(11)：p770-773.)中描述了青蒿素衍生物青蒿琥酯对LPS及合并干扰素刺激小鼠腹腔巨噬细胞NO的合成有明显的抑制作用，对LPS刺激的小鼠腹腔巨噬细胞RAW264.7也具有相似的保护作用，而且随着青蒿琥酯浓度的增加青蒿琥酯对NO合成的抑制作用也增强，梁爱华、薛宝云、王金华等在其文章《青蒿琥酯对内毒素诱导的炎症因子合成抑制作用的研究》(中国中西医结合急救杂志.2001；8(5)：p262.-265)中描述了青蒿琥酯在25～100mg/L对LPS诱导的TNF-α产生具有明显的抑制作用，与LPS单独应用比较抑制率为43％～58％；谭余庆等在其文章《青蒿素提取物抗内毒素作用的实研究》(中国中药杂志.1999；24(3)：p166-171)还发现青蒿提取物、青蒿素可降低内毒素休克小鼠LPO、ACP、内毒素、TNF-α、P450浓度，升高SOD活性，降低小鼠死亡率，延长小鼠的平均生存时间，对小鼠肝、肺组织形态也有一定的保护作用。但是青蒿素及其衍生物对细菌DNA以及细菌(革兰阳性菌和革兰阴性菌)导致的脓毒症是否有效，未见报道。 发明内容 本发明的目的是提供一种青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的新用途，即在制药中的新应用。 实际上，本发明涉青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯作为制备预防或治疗细菌引发的脓毒症药物中的应用。 涉及青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯作为制备预防或治疗CpG ODN引发的脓毒症药物中的应用。 本发明涉青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯作为制备预防或治疗细菌和CpG ODN引发的脓毒症药物中的应用。 所述CpG ODN是指包含有CpG基序的寡核苷酸，是细菌DNA活性的最小单位。 申请人对青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯的体外抗炎作用进行了药理学分析，发现青蒿素、二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均具有显著的体外抗炎作用。青蒿素、二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种都可以显著抑制灭活大肠杆菌诱导的人THP-1细胞系及小鼠RAW264.7细胞系释放细胞因子TNF-α与IL-6，而且在治疗剂量内，随着青蒿素、二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种物质浓度的增加，抑制作用也随之增强，提前给予青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种都可以具有预防作用。 申请人对青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯体内抗炎作用进行了药理学分析，发现青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯中的任何一种都能降低灭活大肠杆菌、细菌(包括革兰阴性、阳性菌)攻击小鼠的死亡率，都可以显著抑制小鼠血清细胞因子TNF-α与IL-6释放，并对灭活大肠杆菌、细菌攻击小鼠的主要脏器(心、肝、肠、肺、肾)具有显著保护作用；青蒿素联合抗生素治疗细菌感染效果更佳。 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯使用常规制剂的方法加上医学上可以接受的载体后可以制备成药剂学上的各种剂型。 本发明的优点在于： (1)本发明对已知的青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯发掘了新的医疗用途，开拓了一个新的应用领域。 (2)本发明的青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯安全无毒，药理作用强，有着良好的药用前景。 (3)我国青蒿素及其衍生物的生产大国，本发明拓宽了青蒿素及其衍生物的适应范围，具有良好的社会与经济效益。 (4)由于目前脓毒症的治疗缺乏有效的药物，因此青蒿素及其衍生物的应用对提高脓毒症的救治率具有重要意义。 (5)本发明的物质制备的药物具有显著的体内和体外抗炎作用，能够有效的预防或治疗脓毒症。 具体实施方式 下面例子为进一步描述本发明而不是限制本发明。 实验例1.青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制CpG-ODN诱导细胞因子释放的量-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃ CO2孵箱培养4h后使细胞贴壁，加入不同浓度的青蒿素(5、10、20、40、80μg/ml)或双氢青蒿素、蒿甲醚、青蒿琥酯，2小时后再加入10μg/ml的刺激性CpG ODN(5′-TCC ATG ACG TTC CTG ACG TT-3′)，置37℃、CO2孵箱培养4h后取细胞培养上清待测细胞因子TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。采用双抗体夹心ELISA法测定细胞培养上清中TNF-α和IL-6的浓度，明确青蒿素或衍生物抑制CpG ODN诱导RAW264.7释放细胞因子的作用。 表1青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制CpG ODN诱导RAW264.7细胞释放细胞因子的量效关系(n＝3， x±SD) 组别 细胞因子 TNF-α(pg/ml) IL-6(pg/ml) 青蒿素(μg/ml)CpG ODN双氢青蒿素蒿甲醚青蒿琥酯Medium 51020408010404040 4321±24**4340±70**4293±78**4068±18**4077±131**4917±313596±10**3708±54**4088±10**377±29 104±7**95±2**71±6**81±11**89±10**163±1580±11**85±25**89±13**74±10 **p＜0.01 vs CpG ODN 此次实验结果表明青蒿素显著抑制CpG ODN诱导RAW264.7释放细胞因子，随青蒿素浓度增加，其抑制作用增强(p＜0.01，见表1)；双氢青蒿素、蒿甲醚及青蒿琥酯也对CpG ODN诱导RAW264.7释放细胞因子也有显著抑制作用。 实验例2.青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制热灭活大肠杆菌诱导细胞因子释放的量-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃ CO2孵箱培养4h后使细胞贴壁，加入不同浓度的青蒿素(5、10、20、40、80μg/ml)或40μg/ml的双氢青蒿素、蒿甲醚或青蒿琥酯，2小时后再加入1×106/ml热灭活大肠杆菌，置37℃、CO2孵箱培养4h后取细胞培养上清待测细胞因子TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。采用双抗体夹心ELISA法测定细胞培养上清中TNF-α和IL-6的浓度，明确青蒿素或衍生物抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子的作用。 表2青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯抑制热灭活大肠杆菌诱导RAW264.7细胞释放TNF-α的量效关系(n＝3， x±SD) 组别 细胞因子 TNF-α(pg/ml) IL-6(pg/ml) 青蒿素(μg/ml)热灭活大肠杆菌双氢青蒿素蒿甲醚青蒿琥酯Medium 510204080404040 4302±268*4145±183**4204±45**3837±48**3926±122**4951±603696±10**3788±51**4098±11**377±29 488±25**295±33**293±67**230±54**184±13**1054±30420±19**365±25**285±13**24±3 **p＜0.01 vs E.coli 此次实验结果表明青蒿素显著抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子，随青蒿素浓度增加，其抑制作用增强(p＜0.01，见表2)；双氢青蒿素、蒿甲醚及青蒿琥酯也对热灭活大肠杆菌诱导RAW264.7释放细胞因子有抑制作用。。 实验例3.青蒿素抑制CpG ODN诱导细胞因子释放的时-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃、CO2孵箱培养4h后使细胞贴壁，以加入CpG ODN时间为0时相点，分别在-4、-2、-1、0、1、2小时加入20μg/ml青蒿素，置37℃、CO2孵箱培养4h后取细胞培养上清待测定TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。明确青蒿素抑制CpG ODN诱导RAW264.7释放细胞因子的能力。 表3青蒿素抑制CpG ODN诱导RAW264.7释放TNF-的时-效关系( x±SD) 时间点 细胞因子 TNF-α(pg/ml) IL-6(pg/ml) -4h-2h-1h0h1h2hCpG 1231±272**1648±17**1450±61**1802±212**1848±222**2491±1412679±158 233±29**349±39**429±11**584±49**873±92**861±90**1638±147 Medium 77±31 241±29 **p＜0.01 vs CpG 此次实验结果表明青蒿素显著抑制CpG ODN诱导RAW264.7释放细胞因子，提前加入青蒿素及在加入CpG ODN后加入青蒿素，均能抑制细胞因子释放，但提前加入抑制作用更强(p＜0.01，见表3)。 实验例4.青蒿素抑制热灭活大肠杆菌诱导细胞因子释放的时-效关系。 培养小鼠巨噬细胞RAW264.7，调整细胞悬液浓度为2×106/ml，加入48孔板中，每孔0.4ml。置37℃ CO2孵箱培养4h后使细胞贴壁，以加入热灭活大肠杆菌时间为0时相点，分别在-4、-2、-1、0、1、2小时加入20μg/ml青蒿素，置37℃、CO2孵箱培养4h后取细胞培养上清待测定TNF-α，再过4小时后取细胞培养上清待测细胞因子IL-6。明确青蒿素抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子的能力。 表4青蒿素抑制热灭活大肠杆菌诱导RAW264.7释放TNF-α的时-效关系(n＝3， x±SD) 时间点 细胞因子 TNF-α(pg/ml) IL-6(pg/ml) -4h-2h-1h0h1h2hE.coliMedium 1377±24**1847±134**2020±57**2004±76**2734±41*2562±155*3171±6349±11 256±27**392±74**893±75**877±86**946±32**942±11**1056±30241±28 **p＜0.01 vs E.coli 此次实验结果表明青蒿素显著抑制热灭活大肠杆菌诱导RAW264.7释放细胞因子，提前加入青蒿素或加入热灭活大肠杆菌后给予青蒿素，均能抑制细胞因子释放，但提前加入青蒿素抑制作用更强(p＜0.01，见表4)。 实验例5.青蒿素及其衍生物对CpG-ODN攻击小鼠的保护作用。 清洁级昆明种小白鼠60只(重庆医科大学实验动物中心提供)，体重18.6±0.5g/只，雌雄各半，随机分为对照组、青蒿素组(100mg/kg)、CpG ODN组(4mg/kg)，青蒿素(50、100、200mg/kg)或青蒿素衍生物+CpG-ODN。每组10只动物。含CpG ODN组动物提前1小时给予D氨基半乳糖。对照不给予任何试剂；青蒿素组给予200mg/kg的青蒿素，给药方式为灌胃给药；CpG ODN组，给予4mg/kg体重的CpG ODN，给药方式为尾静脉注射；青蒿素或其衍生物+CpG ODN组，在灌胃给予不同剂量青蒿素后，立即给予4mg/kg体重的CpG ODN。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表5)。 表5青蒿素、双氢青蒿素、蒿甲醚及青蒿琥酯对CpG ODN攻击小鼠的保护作用 Treatment TotalNumber DeathNumber Mortality(％) P 对照组ART(100mg/kg)ART(50mg/kg)+CpGART(100mg/kg)+CpGART(200mg/kg)+CpGCpGODN双氢青蒿素+CpG蒿甲醚+CpG青蒿琥酯+CpG 101010101010101010 003218124 0030.020.010.080.010.020.040.0 --***-**** *p＜0.05，**p＜0.01 vs CpG 本实验表明，青蒿素、双氢青蒿素和蒿甲醚均可以可降低CpG ODN攻击小鼠的死亡率，表明对致炎因子攻击的小鼠具有保护作用。 实验例6.青蒿素及其衍生物对热灭活大肠杆菌攻击小鼠的保护作用。 清洁级昆明种小白鼠60只(重庆医科大学实验动物中心提供)，体重19.9±0.4g/只，雌雄各半，随机分为对照组、青蒿素组、热灭活大肠杆菌组，青蒿素(50、100、200mg/kg)或衍生物(40mg/kg)+热灭活大肠杆菌组。每组10只动物。对照不给予任何试剂；青蒿素或衍生物组灌胃给予青蒿素或衍生物；热灭活大肠杆菌组，给予1.1×1011/kg的热灭活大肠杆菌35218；青蒿素或衍生物+热灭活大肠杆菌组，在灌胃给予青蒿素后，立即给予热灭活大肠杆菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表6)。 表6青蒿素对热灭活大肠杆菌攻击小鼠的保护作用 Treatment TotalNumber DeathNumber Mortality(％) P 对照组ART(100mg/kg)ART(50mg/kg)+E.coliART(100mg/kg)+E.coliART(200mg/kg)+E.coli热灭活E.coli 35218双氢青蒿素+E.coli蒿甲醚+E.coli青蒿琥酯+E.coli 101010101010151515 003217234 0030.020.010.070.013.320.026.6 --***-**** *p＜0.05；**p＜0.01 vs E.coli 本实验结果显示：青蒿素及衍生物均可以可降低小鼠的死亡率，对致炎因子攻击的小鼠具有保护作用。 实验例7.青蒿素及其衍生物对大肠杆菌35218攻击小鼠的保护作用。 清洁级昆明种小白鼠(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿素组、大肠杆菌组，青蒿素(50、100、200mg/ml)或衍生物+大肠杆菌组。对照不给予任何试剂；青蒿素或衍生物组灌胃给予200mg/kg的青蒿素或衍生物；大肠杆菌组，给予1.1×105/kg活的大肠杆菌；青蒿素或衍生物+大肠杆菌组，在灌胃给予青蒿素或衍生物后，立即给予大肠杆菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表7)。 表7青蒿素对大肠杆菌35218攻击小鼠的保护作用 Treatment TotalNumber DeathNumber Mortality(％) P 对照组ART(100mg/kg)ART(50mg/kg)+E.coliART(100mg/kg)+E.coliART(200mg/kg)+E.coliE.coli双氢青蒿素+E.coli蒿甲醚+E.coli青蒿琥酯+E.coli 202020202020151515 0063214234 0030.015.010.070.013.320.026.6 --***-**** *p＜0.5；**p＜0.01 vs E.coli 本实验结果显示：青蒿素及其衍生物均可以可降低小鼠的死亡率，对致炎因子攻击的小鼠具有保护作用。 实验例8.青蒿素及其衍生物对热灭活金黄色葡萄球菌攻击小鼠的保护作用。 清洁级昆明种小白鼠(重庆医科大学实验动物中心提供)，体重20.1±0.4g/只，雌雄各半，随机分为对照组、青蒿素组、大肠杆菌组，青蒿素(50、100、200mg/kg)或衍生物(40mg/kg)+热灭活金黄色葡萄球菌组。对照不给予任何试剂；青蒿素或衍生物组灌胃给予200mg/kg的青蒿素；热灭活大肠杆菌组，给予1.1×104/kg热灭活金黄色葡萄球菌；青蒿素或衍生物+热灭活金黄色葡萄球菌组，在灌胃给予青蒿素或衍生物后，立即给予热灭活金黄色葡萄球菌。给药完毕后给予正常饮食和饮水，观察7天内小鼠一般情况及死亡率(表8)。 表8青蒿素及其衍生物对金黄色葡萄球菌攻击小鼠的保护作用 Treatment TotalNumber DeathNumber Mortality(％) P 对照组ART(100mg/kg)ART(50mg/kg)+E.coliART(100mg/kg)+E.coliART(200mg/kg)+E.coli热灭活金黄色葡萄球菌双氢青蒿素+Ecoil蒿甲醚+E.coli青蒿琥酯+E.coli 202020202020202020 0096419456 0045.030.020.095.020.025.030.0 --***-****** *p＜0.5；**p＜0.01 vs E.coli 本实验结果显示：青蒿素及其衍生物均可以降低小鼠的死亡率，对致炎因子攻击的小鼠具有保护作用。 实验例9.青蒿素对CpG ODN、热灭活大肠杆菌攻击小鼠血清细胞因子表达影响 清洁级昆明种小白鼠48只(重庆医科大学实验动物中心提供)，体重19.9±0.5g/只，雌雄各半，随机分为对照组、青蒿素组、CpG ODN组，青蒿素+CpG-ODN组、热灭活大肠杆菌组、青蒿素+热灭活大肠杆菌组，每组动物10只。对照不给予任何试剂。青蒿素组给予200mg/kg的青蒿素，给药方式为灌胃给药；CpG ODN组、热灭活大肠杆菌组，分别给予4mg/kg体重的CpG ODN、1.1×1011/kg体重的热灭活大肠杆菌组，给药方式均为尾静脉注射；青蒿素+CpG ODN组，在灌胃给予青蒿素后，立即给予CpG ODN、热灭活大肠杆菌组。给药完毕后摘眼球取血立即离心留置上清保存于-20℃，待测定细胞因子TNF-α(表9)。 表9青蒿素降低CpG ODN、热灭活大肠杆菌攻击小鼠血清细胞因子TNF-α(pg/ml)表达 组别 ART No ART CpG ODNE.coli对照组 88.6±6.8*204.0±34.2*70.9±25.8 113.9±11.8425.7±24.772.5±22.7* *p＜0.5 vs NO ART 本实验结果显示：青蒿素可以可显著降低CpG ODN、热灭活大肠杆菌攻击小鼠血清细胞因子表达。 实验例10.青蒿素在治疗因细菌导致的脓毒症的临床研究 选择细菌脓毒症病人50例，其中30人作为治疗组，其中男19例，女11例，年龄在19-70岁，平均38.6±13.1岁，治疗组在常规治疗的基础上均口服青蒿素进行治疗，观察到治疗组病人的细菌清除率明显提高，脓毒症得到明显的控制。另外20人仅给予常规治疗，不采用青蒿素进行治疗。效果判定标准按照有效、无效2级评定，有效：(1)脓毒症症状得到控制，病情明显好转；(2)血清TNF-α浓度显著降低。无效：(1)用药3天后脓毒症病情无好转或加重；(2)血清TNF-α浓度浓度无显著降低。不良反应评定将病人在用药过程中及用药后5d内出现的不良反应及异常化验结果按照与药物有关、可能有关、无关、可能无关、无法确定5级进行评定，有关及可能有关列人不良反应。 用药方法：200mg的青蒿素片剂口服，12小时1次，疗程5-7d。 用药后的治疗脓毒症的效果如下表所示： 表1.预防和治疗脓毒症临床观察情况 组别 n 有效 无效 有效率 青蒿素治疗组 30 28 2 93 常规治疗组 20 15 5 75 合计 50 43 7 86 表2.治疗组和对照组血清TNF-α浓度 组别 n 显著降低 无显著降低 有效率 青蒿素治疗组 30 29 1 97 常规治疗组 20 13 7 65 合计 50 42 8 84 不良反应：有2例病人出现轻度恶心、头晕等，进食后症状消失，其余无其它不良。 从以上实验可以得到结论：青蒿素在治疗因细菌引起的脓毒症方面具有比较好的疗效。 同理，口服200mg的青蒿素片剂口服，12小时1次，疗程5-7d可以预防或治疗因CpG ODN导致的脓毒症。 同样的，二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以达到同样的药理效果。 实施例1 取已经天然提取的青蒿素200克(纯度98％)，乳糖50克，淀粉糊适量，硬脂酸镁适量，混合均匀后，用直接压片法制备成1000片，然后包装即可得到规格为200mg的片剂，所用设备均为本领域的常规设备。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例1制备成200mg规格的片剂。 实施例2 取已经天然提取的青蒿素100克(纯度98％)，乳糖50克，淀粉糊适量，硬脂酸镁适量，混合均匀后，用直接压片法制备成1000片，然后包装即可得到规格为100mg的片剂，所用设备均为目前生产的常规设备。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例2制备成100mg规格的片剂。 实施例3 取已经天然提取的青蒿素50克(纯度98％)，乳糖50克，淀粉糊适量，硬脂酸镁适量，混合均匀后，用直接压片法制备成1000片，然后包装即可得到规格为50mg的片剂，所用设备均为目前生产的常规设备。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例3制备成50mg规格的片剂。 实施例4 取已经天然提取的青蒿素200克(纯度98％)，淀粉30克，糊精5克，硬脂酸镁适量混合均匀，装入1000粒1号胶囊，然后分装入瓶或加工成盒即得。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例4制备成200mg的胶囊剂。 实施例5 取已经天然提取的青蒿素200克100克(纯度98％)，淀粉30克，糊精5克，硬脂酸镁适量混合均匀，装入1000粒1号胶囊，然后分装入瓶或加工成盒即得。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例5制备成100mg规格的胶囊剂。 实施例6 取已经天然提取的青蒿素50克(纯度98％)，淀粉30克，糊精5克，硬脂酸镁适量混合均匀，装入1000粒1号胶囊，然后分装入瓶或加工成盒即得。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例6制备成50mg规格的胶囊剂。 实施例7 取已经天然提取的青蒿素200克，加入注射用水和本领域常用的润湿剂如吐温-80、本领域常用的助悬剂如甲基纤维素，使润湿剂的含量为0.1-0.2％克每升，使助悬剂的含量为0.5-1％克每升，然后用超声波处理使分散均匀，滤过，调PH值、灌封、灭菌得到1000支浑悬剂。所用设备均为本领域通用设备。 同理，根据实施例7，可以得到100mg和50mg规格的青蒿素浑悬剂。 二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯均可以参照实施例7制备成50mg、100mg、200mg规格的浑悬剂。 1.青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制备预防或治疗细菌引发的脓毒症药物中的应用。 2.根据权利要求1所述的用途，其特征在于，所述细菌为革兰阳性菌或革兰阴性菌。 3.青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制备预防或治治CpG ODN引发的脓毒症的药物中的应用。 4.青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制备预防或治治细菌和CpG ODN引发的脓毒症药物中的应用。 5.根据权利要求1、2、3或4任一项所述的用途，其特征在于，青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药过程中制备成药剂学上的任何一种制剂。 Abrotine, its derivative dihydro-abrotine, artemether, arteether and arte sunate in use of pharmacy An application of arteannuin and its derivatives (dihydroarteannuin, artemether, arteether and artesunate) in preparing the medicines for preventing and treating the sepsis caused by CpG-ODN and bacteria is disclosed. The application in pharmacy of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate Technical field The present invention relates to the purposes of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, relate in particular to the purposes in pharmaceutical field. Background technology Bacterial infection is present clinical patient main causes of death.During organism infection, antibacterial thalline composition such as genomic DNA and bacterial endotoxin (LPS) are by activating panimmunity cells such as mammal Monocytes, dendritic cell, induce the release of proinflammatory cytokines such as TNF-α, IL-1, IL-6, NO, cause the damage of histoorgan, cause pyemic generation. Herba Artemisiae Annuae belongs to feverfew, and China scientific research personnel in 1972 separates from the Chinese medicine Herba Artemisiae Annuae the earliest and obtains malaria effective monomer, called after arteannuin.The arteannuin molecular formula is C15H22O5, and according to chemical reaction, spectroscopic data and x-ray list product diffraction method prove that arteannuin is a kind of sesquiterpene lactone with peroxy.The chemical structural formula that its derivant mainly contains dihydroartemisinine, Artemether, arteether and artesunate is: Arteannuin and derivant thereof are used for treating the relevant heating of malaria the history in more than 1,000 year, is mainly used in the drug resistance pernicious malaria now clinically.Efferth TM, Wang X, Huong SM, Hauber I etc. are at its article " Antiviral activity of artesunate towards wild-type, recombinantandganciclovir-resistant human cytomegalovimses " (J Mol Med.2002; 80 (4): described Herba Artemisiae Annuae class material p223-224) and also had the effect of others, as relieving asthma, anticancer, schistosomicide and to immune adjusting etc.The research of relevant arteannuin and derivant thereof both at home and abroad mainly concentrates on malaria, anticancer, antischistosomal effect and the mechanism thereof. To the existing research of the antiendotoxic effect of arteannuin and derivant thereof, Aldieri E, Bergandi L, RigantiC, Costamagna C, Bosia A, Ghigo D etc. are at its article " Artemisinin inhibits inducible nitricoxide synthase and nuclear factor NF-kB activation " (FEBS Lett.2003; 552 (2-3): described the activation that arteannuin can suppress the synthetic and NF-κ B of LPS/TNF-α inductivity NO synthase p141-144); The beam Aiwa, Xue Baoyun, Li Chunying etc. are at its article " artesunate is to the synthetic inhibitory action of the nitric oxide of endotaxin induction " (CHINA JOURNAL OF CHINESE MATERIA MEDICA .2001; 26 (11): described p770-773.) the artemisinin derivative artesunate to LPS and merge that interferon stimulates Turnover of Mouse Peritoneal Macrophages NO synthetic the obvious suppression effect arranged, the Turnover of Mouse Peritoneal Macrophages RAW264.7 that LPS is stimulated also has similar protective effect, and along with the increase artesunate of artesunate concentration also strengthens the synthetic inhibitory action of NO, beam Aiwa, Xue Baoyun, Wang Jinhua etc. are at its article " artesunate is to the synthetic inhibiting research of the inflammatory factor of endotaxin induction " (Chinese combination of Chinese and Western medicine first aid magazine .2001; 8 (5): inductive TNF-α generation has the obvious suppression effect to LPS at 25～100mg/L to have described artesunate p262.-265), and using the comparison suppression ratio separately with LPS is 43%～58%; Tan Yuqing etc. are at its article " the real research of arteannuin extract anti-endotoxin effect " (CHINA JOURNAL OF CHINESE MATERIA MEDICA .1999; 24 (3): p166-171) find that also Herba Artemisiae Annuae extract, arteannuin can reduce endotoxin shock mice LPO, ACP, endotoxin, TNF-α, P450 concentration; the increased SOD activity; reduce mouse death rate; prolong the mean survival time of mice, Mouse Liver, lung tissue form are also had the certain protection effect.But whether arteannuin and derivant thereof be effective to the sepsis that DNA of bacteria and antibacterial (gram positive bacteria and gram-negative bacteria) cause, and do not appear in the newspapers. Summary of the invention The new purposes that the purpose of this invention is to provide a kind of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, i.e. new application in pharmacy. In fact, the present invention relates to the application in the medication for treating pyemia that arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate cause as preparation prevention or treatment antibacterial. Relate to arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate as the application in the medication for treating pyemia of preparation prevention or treatment CpG ODN initiation. The present invention relates to the application in the medication for treating pyemia that arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate cause as preparation prevention or treatment antibacterial and CpG ODN. Described CpG ODN is meant the oligonucleotide that includes the CpG motif, is the active least unit of DNA of bacteria. The applicant has carried out pharmacology's analysis to the extracorporeal anti-inflammatory effect of arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, finds that arteannuin, dihydroartemisinine, Artemether, arteether, artesunate all have the remarkable vitro antiinflammatory action.Arteannuin, dihydroartemisinine, Artemether, arteether, any in the artesunate can significantly suppress colibacillus deactivating inductive people THP-1 cell line and mice RAW264.7 cell line discharges cytokine TNF-α and IL-6, and in therapeutic dose, along with arteannuin, dihydroartemisinine, Artemether, arteether, the increase of any material concentration in the artesunate, inhibitory action also strengthens thereupon, gives arteannuin and derivative dihydro-abrotine thereof in advance, Artemether, arteether, any in the artesunate can have preventive effect. The applicant is to arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, antiinflammatory action has carried out pharmacology's analysis in the artesunate body, find arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, any in the artesunate can both reduce colibacillus deactivating, antibacterial (comprises Grain-negative, positive bacteria) attacks mortality of mice, can significantly suppress mice serum cytokine TNF-α and IL-6 and discharge, and to colibacillus deactivating, main organs (the heart of germ attack mice, liver, intestinal, lung, kidney) has remarkable protective effect; Arteannuin combined with antibiotic treatment bacterial infection effect is better. Arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate use the method for conventional formulation to add the various dosage forms that can be prepared into behind the acceptable carrier medically on the pharmaceutics. The invention has the advantages that: (1) the present invention has excavated new medical application to known arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate, has opened up a new application. (2) arteannuin of the present invention and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate safety non-toxic, pharmacological action is strong, and good prospect in medicine is arranged. (3) big producing country of China's arteannuin and derivant thereof, the present invention has widened the subject range of arteannuin and derivant thereof, has good society and economy benefit. (4) because present pyemic treatment lacks effective medicine, so the application of arteannuin and derivant thereof is significant to improving pyemic treatment rate. (5) medicine of material preparation of the present invention has in the significant body and the extracorporeal anti-inflammatory effect, can effectively prevent or treat sepsis. The specific embodiment Following example is for further describing the present invention rather than restriction the present invention. Experimental example 1. arteannuin, dihydroarteannuin, Artemether and artesunate suppress the amount-result relation that the CpG-ODN inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃ of CO 2Incubator makes cell attachment after cultivating 4h, the arteannuin (5,10,20,40,80 μ g/ml) of adding variable concentrations or dihydroarteannuin, Artemether, artesunate, the zest CpG ODN (5 '-TCC ATG ACG TTC CTG ACG TT-3 ') that adds 10 μ g/ml after 2 hours again, put and get cells and supernatant cytokine TNF-α to be measured after 37 ℃, CO2 incubator are cultivated 4h, after 4 hours, get cells and supernatant cytokine IL-6 to be measured.The concentration of TNF-α and IL-6 in the employing double-antibody sandwich elisa method mensuration cells and supernatant, clear and definite arteannuin or derivant suppress CpG ODN and induce RAW264.7 to discharge effect of cytokines. Table 1 arteannuin, dihydroarteannuin, Artemether and artesunate suppress CpG ODN and induce the RAW264.7 cell to discharge dose-effect relationship (n=3, the x ± SD) of cytokine Group Cytokine TNF-α (pg/ml) IL-6 (pg/ml) Qinghaosu (μ g/ml) CpG ODN dihydroartemisinine Artemether Artesunate Medium 5 10 20 40 80 10 40 40 40 4321±24 ** 4340±70 ** 4293±78 ** 4068±18 ** 4077±131 ** 4917±31 3596±10 ** 3708±54 ** 4088±10 ** 377±29 104±7 ** 95±2 ** 71±6 ** 81±11 ** 89±10 ** 163±15 80±11 ** 85±25 ** 89±13 ** 74±10 **p＜0.01 vs CpG ODN This time experimental result shows that arteannuin significantly suppresses CpG ODN and induces RAW264.7 to discharge cytokine, increases with arteannuin concentration, and its inhibitory action strengthens (p＜0.01 sees Table 1); Dihydroarteannuin, Artemether and artesunate also induce RAW264.7 to discharge cytokine to CpG ODN also remarkable inhibitory action. Experimental example 2. arteannuin, dihydroarteannuin, Artemether and artesunate suppress the amount-result relation that the hot colibacillus deactivating inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃ of CO 2Incubator makes cell attachment after cultivating 4h, adds the arteannuin (5,10,20,40,80 μ g/ml) of variable concentrations or dihydroarteannuin, Artemether or the artesunate of 40 μ g/ml, adds 1 * 10 again after 2 hours 6The hot colibacillus deactivating of/ml is put and is got cells and supernatant cytokine TNF-α to be measured after 37 ℃, CO2 incubator are cultivated 4h, gets cells and supernatant cytokine IL-6 to be measured after 4 hours.The concentration of TNF-α and IL-6 in the employing double-antibody sandwich elisa method mensuration cells and supernatant, clear and definite arteannuin or derivant suppress hot colibacillus deactivating and induce RAW264.7 to discharge effect of cytokines. Table 2 arteannuin, dihydroarteannuin, Artemether and artesunate suppress hot colibacillus deactivating and induce the RAW264.7 cell to discharge dose-effect relationship (n=3, the x ± SD) of TNF-α Group Cytokine TNF-α (pg/ml) IL-6 (pg/ml) Qinghaosu (μ g/ml) heat-killed escherichia coli dihydroartemisinine Artemether Artesunate Medium 5 10 20 40 80 40 40 40 4302±268 * 4145±183 ** 4204±45 ** 3837±48 ** 3926±122 ** 4951±60 3696±10 ** 3788±51 ** 4098±11 ** 377±29 488±25 ** 295±33 ** 293±67 ** 230±54 ** 184±13 ** 1054±30 420±19 ** 365±25 ** 285±13 ** 24±3 **p＜0.01 vs E.coli This time experimental result shows that arteannuin significantly suppresses hot colibacillus deactivating and induces RAW264.7 to discharge cytokine, increases with arteannuin concentration, and its inhibitory action strengthens (p＜0.01 sees Table 2); Dihydroarteannuin, Artemether and artesunate also induce RAW264.7 to discharge cytokine to hot colibacillus deactivating inhibitory action.。 Experimental example 3. arteannuin suppress the time-effect relationship that the CpG ODN inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃, CO 2Incubator makes cell attachment after cultivating 4h, to add the CpG ODN time is 0 o'clock point mutually, added 20 μ g/ml arteannuin respectively at-4 ,-2 ,-1,0,1,2 hours, put and get cells and supernatant TNF-α to be determined after 37 ℃, CO2 incubator are cultivated 4h, after 4 hours, get cells and supernatant cytokine IL-6 to be measured.Clear and definite arteannuin suppresses CpG ODN and induces RAW264.7 to discharge the ability of cytokine. Table 3 arteannuin suppresses CpG ODN and induces RAW264.7 to discharge the time-effect relationship (x ± SD) of TNF- Time point Cytokine TNF-α (pg/ml) IL-6 (pg/ml) -4h -2h -1h 0h 1h 2h CpG 1231±272 ** 1648±17 ** 1450±61 ** 1802±212 ** 1848±222 ** 2491±141 2679±158 233±29 ** 349±39 ** 429±11 ** 584±49 ** 873±92 ** 861±90 ** 1638±147 Medium 77±31 241±29 **p＜0.01 vs CpG This time experimental result shows that arteannuin significantly suppresses CpG ODN and induces RAW264.7 to discharge cytokine, add arteannuin in advance and after adding CpG ODN, add arteannuin, all can suppress release of cytokines, but add inhibitory action stronger (p＜0.01 sees Table 3) in advance. Experimental example 4. arteannuin suppress the time-effect relationship that the hot colibacillus deactivating inducing cell factor discharges. Cultivate mouse macrophage RAW264.7, adjusting concentration of cell suspension is 2 * 10 6/ ml adds in 48 orifice plates, every hole 0.4ml.Put 37 ℃ of CO 2Incubator makes cell attachment after cultivating 4h, to add the hot colibacillus deactivating time is 0 o'clock point mutually, added 20 μ g/ml arteannuin respectively at-4 ,-2 ,-1,0,1,2 hours, put and get cells and supernatant TNF-α to be determined after 37 ℃, CO2 incubator are cultivated 4h, after 4 hours, get cells and supernatant cytokine IL-6 to be measured.Clear and definite arteannuin suppresses hot colibacillus deactivating and induces RAW264.7 to discharge the ability of cytokine. Table 4 arteannuin suppresses hot colibacillus deactivating and induces RAW264.7 to discharge time-effect relationship (n=3, the x ± SD) of TNF-α Time point Cytokine TNF-α (pg/ml) IL-6 (pg/ml) -4h -2h -1h 0h 1h 2h E.coli Medium 1377±24 ** 1847±134 ** 2020±57 ** 2004±76 ** 2734±41 * 2562±155 * 3171±63 49±11 256±27 ** 392±74 ** 893±75 ** 877±86 ** 946±32 ** 942±11 ** 1056±30 241±28 **p＜0.01 vs E.coli This time experimental result shows that arteannuin significantly suppresses hot colibacillus deactivating and induces RAW264.7 to discharge cytokine, give arteannuin after adding arteannuin in advance or adding hot colibacillus deactivating, all can suppress release of cytokines, but add arteannuin inhibitory action stronger (p＜0.01 sees Table 4) in advance. Experimental example 5. arteannuin and derivant thereof are attacked the protective effect of mice to CpG-ODN. Cleaning level 60 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 18.6 ± 0.5g/ only, male and female half and half, be divided into matched group, arteannuin group (100mg/kg), CpG ODN at random and organize (4mg/kg), arteannuin (50,100,200mg/kg) or artemisinin derivative+CpG-ODN.Every group of 10 animals.Contain CpG ODN treated animal and gave D aminogalactose in 1 hour in advance.Contrast does not give any reagent; The arteannuin group gives the arteannuin of 200mg/kg, and administering mode is a gastric infusion; CpG ODN organizes, and gives the CpG ODN of 4mg/kg body weight, and administering mode is a tail vein injection; Arteannuin or derivatives thereof+CpG ODN group after the filling stomach gives the various dose arteannuin, gives the CpG ODN of 4mg/kg body weight immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 5) in 7 days. Table 5 arteannuin, dihydroarteannuin, Artemether and artesunate are attacked the protective effect of mice to CpG ODN Treatment Total Number Death Number Mortality (％) P Control group A RT (100mg/kg) ART (50mg/kg)+CpG ART (100mg/kg)+CpG ART (200mg/kg)+CpG CpGODN dihydroartemisinine+CpG Artemether+CpG Artesunate+CpG 10 10 10 10 10 10 10 10 10 0 0 3 2 1 8 1 2 4 0 0 30.0 20.0 10.0 80.0 10.0 20.0 40.0 - - * ** - ** ** *p＜0.05， **p＜0.01 vs CpG This experiment shows that arteannuin, dihydroarteannuin and Artemether all can reduce CpG ODN and attack mortality of mice, shows that the mice that pro-inflammatory cytokine is attacked has protective effect. Experimental example 6. arteannuin and derivant thereof are attacked the protective effect of mice to hot colibacillus deactivating. Cleaning level 60 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.4g/ only, male and female half and half, be divided into matched group, arteannuin group, hot colibacillus deactivating group at random, arteannuin (50,100,200mg/kg) or derivant (40mg/kg)+hot colibacillus deactivating group.Every group of 10 animals.Contrast does not give any reagent; Arteannuin or derivant group are irritated stomach and are given arteannuin or derivant; Hot colibacillus deactivating group gives 1.1 * 10 11The hot colibacillus deactivating 35218 of/kg; Arteannuin or derivant+hot colibacillus deactivating group after the filling stomach gives arteannuin, gives hot colibacillus deactivating immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 6) in 7 days. Table 6 arteannuin is attacked the protective effect of mice to hot colibacillus deactivating Treatment Total Number Death Number Mortality (％) P Control group A RT (100mg/kg) ART (50mg/kg)+E.coli ART (100mg/kg)+E.coli ART (the 200mg/kg)+hot deactivation E.coli of E.coli 35218 dihydroartemisinines+E.coli Artemether+E.coli Artesunate+E.coli 10 10 10 10 10 10 15 15 15 0 0 3 2 1 7 2 3 4 0 0 30.0 20.0 10.0 70.0 13.3 20.0 26.6 - - * ** - ** ** *p＜0.05； **p＜0.01 vs E.coli This experimental result shows: arteannuin and derivant all can reduce mortality of mice, and the mice that pro-inflammatory cytokine is attacked has protective effect. The protective effect that experimental example 7. arteannuin and derivant thereof are attacked mice to escherichia coli 35218. Cleaning level Kunming kind white mice (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half are divided into matched group, arteannuin group, escherichia coli group at random, arteannuin (50,100,200mg/ml) or derivant+escherichia coli group.Contrast does not give any reagent; Arteannuin or derivant group are irritated arteannuin or the derivant that stomach gives 200mg/kg; The escherichia coli group gives 1.1 * 10 5The escherichia coli that/kg lives; Arteannuin or derivant+escherichia coli group after the filling stomach gives arteannuin or derivant, gives escherichia coli immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table 7) in 7 days. The protective effect that table 7 arteannuin is attacked mice to escherichia coli 35218 Treatment Total Number Death Number Mortality (％) P Control group A RT (100mg/kg) ART (50mg/kg)+E.coli ART (100mg/kg)+E.coli ART (200mg/kg)+E.coli E.coli dihydroartemisinine+E.coli Artemether+E.coli Artesunate+E.coli 20 20 20 20 20 20 15 15 15 0 0 6 3 2 14 2 3 4 0 0 30.0 15.0 10.0 70.0 13.3 20.0 26.6 - - * ** - ** ** *p＜0.5； **p＜0.01 vs E.coli This experimental result shows: arteannuin and derivant thereof all can reduce mortality of mice, and the mice that pro-inflammatory cytokine is attacked has protective effect. Experimental example 8. arteannuin and derivant thereof are attacked the protective effect of mice to hot deactivation staphylococcus aureus. Cleaning level Kunming kind white mice (Medical University Of Chongqing's Experimental Animal Center provides), body weight 20.1 ± 0.4g/ only, male and female half and half, be divided into matched group, arteannuin group, escherichia coli group at random, arteannuin (50,100,200mg/kg) or derivant (40mg/kg)+hot deactivation staphylococcus aureus group.Contrast does not give any reagent; Arteannuin or derivant group are irritated the arteannuin that stomach gives 200mg/kg; Hot colibacillus deactivating group gives 1.1 * 10 4The hot deactivation staphylococcus aureus of/kg; Arteannuin or derivant+hot deactivation staphylococcus aureus group after the filling stomach gives arteannuin or derivant, gives hot deactivation staphylococcus aureus immediately.Give normal diet and drinking-water after administration finishes, observe mice ordinary circumstance and mortality rate (table in 7 days. Table 8 arteannuin and derivant thereof are attacked the protective effect of mice to staphylococcus aureus Treatment Total Number Death Number Mortality (％) P The hot deactivation staphylococcus aureus dihydroartemisinine of control group A RT (100mg/kg) ART (50mg/kg)+E.coli ART (100mg/kg)+E.coli ART (200mg/kg)+E.coli+Ecoil Artemether+E.coli Artesunate+E.coli 20 20 20 20 20 20 20 20 20 0 0 9 6 4 19 4 5 6 0 0 45.0 30.0 20.0 95.0 20.0 25.0 30.0 - - * ** - ** ** ** *p＜0.5； **p＜0.01 vs E.coli This experimental result shows: arteannuin and derivant thereof all can reduce mortality of mice, and the mice that pro-inflammatory cytokine is attacked has protective effect. Experimental example 9. arteannuin are attacked the influence of mice serum cytokine-expressing to CpG ODN, hot colibacillus deactivating Cleaning level 48 of the kind white mice in Kunming (Medical University Of Chongqing's Experimental Animal Center provides), body weight 19.9 ± 0.5g/ only, male and female half and half, be divided into matched group, arteannuin group, CpG ODN group at random, arteannuin+CpG-ODN group, hot colibacillus deactivating group, arteannuin+hot colibacillus deactivating group, 10 of every treated animals.Contrast does not give any reagent.The arteannuin group gives the arteannuin of 200mg/kg, and administering mode is a gastric infusion; CpG ODN organizes, hot colibacillus deactivating group, gives the CpG ODN, 1.1 * 10 of 4mg/kg body weight respectively 11The hot colibacillus deactivating group of/kg body weight, administering mode is tail vein injection; Arteannuin+CpG ODN group after the filling stomach gives arteannuin, gives CpG ODN, hot colibacillus deactivating group immediately.Plucking eyeball after administration finishes gets the centrifugal immediately indwelling supernatant of blood and is stored in-20 ℃, cytokine TNF-α to be determined (table 9). Table 9 arteannuin reduces CpG ODN, hot colibacillus deactivating is attacked mice serum cytokine TNF-α (pg/ml) and expressed Group ART No ART CpG ODN E.coli matched group 88.6±6.8 * 204.0±34.2 * 70.9±25.8 113.9±11.8 425.7±24.7 72.5±22.7 * *p＜0.5 vs NO ART This experimental result shows: arteannuin can significantly reduce CpG ODN, hot colibacillus deactivating is attacked the mice serum cytokine-expressing. The pyemic clinical research that experimental example 10. arteannuin cause because of antibacterial in treatment Selecting bacteria sepsis patient 50 examples, wherein 30 people organize as treatment, wherein male 19 examples, woman's 11 examples, age, average 38.6 ± 13.1 years old, treatment group all oral arteannuin on the basis of conventional therapy was treated in 19-70 year, the bacteria clearance of observing treatment group patient obviously improves, and sepsis obtains obvious control.Other 20 people only give conventional therapy, do not adopt arteannuin to treat.Effect criterion is according to effective, invalid 2 grades of evaluations, effectively: (1) sepsis symptom is controlled, and the state of an illness is clearly better; (2) serum TNF-α concentration significantly reduces.Invalid: (1) medication after 3 days the sepsis state of an illness do not have and take a turn for the better or increase the weight of; (2) serum TNF-α concentration concentration does not have remarkable reduction.Untoward reaction evaluation with patient in the medication process and the untoward reaction that occurs in the 5d after the medication and unusual result of laboratory test according to relevant with medicine, may be relevant, irrelevant, may have nothing to do, can't determine 5 grades and evaluate, relevant and may relevantly be listed as people's untoward reaction. The arteannuin tablet of administrated method: 200mg is oral, 12 hours 1 time, the course of treatment 5-7d. The pyemic effect of treatment after the medication is as shown in the table: Table 1. prevention and treatment sepsis clinical observation situation Group n Effectively Invalid Effective percentage Arteannuin treatment group 30 28 2 93 The conventional therapy group 20 15 5 75 Add up to 50 43 7 86 Table 2. treatment group and matched group serum TNF-α concentration Group n Significantly reduce Do not have significantly and reduce Effective percentage Arteannuin treatment group 30 29 1 97 The conventional therapy group 20 13 7 65 Add up to 50 42 8 84 Untoward reaction: there are 2 routine patients mild nausea, dizziness etc. to occur, feed back transference cure, all the other do not have, and other is bad. Can obtain conclusion from above experiment: arteannuin has reasonable curative effect in treatment aspect bacterial sepsis. In like manner, the arteannuin tablet of oral 200mg is oral, and 12 hours 1 time, 5-7d can prevent or treat the sepsis that causes because of CpG ODN the course of treatment. Same, dihydroartemisinine, Artemether, arteether, artesunate all can reach same pharmacological effect. Embodiment 1 Get arteannuin 200 grams (purity 98%) of natural extract, lactose 50 grams, gelatinized corn starch is an amount of, magnesium stearate is an amount of, behind the mix homogeneously, is prepared into 1000 with direct compression process, packing can obtain the tablet that specification is 200mg then, and device therefor is the conventional equipment of this area. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the tablet of 200mg specification with reference to embodiment 1. Embodiment 2 Get arteannuin 100 grams (purity 98%) of natural extract, lactose 50 grams, gelatinized corn starch is an amount of, magnesium stearate is an amount of, behind the mix homogeneously, is prepared into 1000 with direct compression process, packing can obtain the tablet that specification is 100mg then, and device therefor is the conventional equipment of present production. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the tablet of 100mg specification with reference to embodiment 2. Embodiment 3 Get arteannuin 50 grams (purity 98%) of natural extract, lactose 50 grams, gelatinized corn starch is an amount of, magnesium stearate is an amount of, behind the mix homogeneously, is prepared into 1000 with direct compression process, packing can obtain the tablet that specification is 50mg then, and device therefor is the conventional equipment of present production. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the tablet of 50mg specification with reference to embodiment 3. Embodiment 4 Get arteannuin 200 grams (purity 98%) of natural extract, starch 30 grams, dextrin 5 grams, an amount of mix homogeneously of magnesium stearate, 1000 No. 1 capsules of packing into divide then and pack bottle into or be processed into box promptly. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the capsule of 200mg with reference to embodiment 4. Embodiment 5 Get arteannuin 200 grams 100 grams (purity 98%) of natural extract, starch 30 grams, dextrin 5 grams, an amount of mix homogeneously of magnesium stearate, 1000 No. 1 capsules of packing into divide then and pack bottle into or be processed into box promptly. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the capsule of 100mg specification with reference to embodiment 5. Embodiment 6 Get arteannuin 50 grams (purity 98%) of natural extract, starch 30 grams, dextrin 5 grams, an amount of mix homogeneously of magnesium stearate, 1000 No. 1 capsules of packing into divide then and pack bottle into or be processed into box promptly. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the capsule of 50mg specification with reference to embodiment 6. Embodiment 7 Get arteannuin 200 grams of natural extract, add water for injection and this area wetting agent commonly used such as tween 80, this area suspending agent such as methylcellulose commonly used, the content that makes wetting agent is every liter of 0.1-0.2% gram, the content that makes suspending agent is every liter of 0.5-1% gram, make with ultrasonic Treatment then and be uniformly dispersed, filter, transfer pH value, embedding, sterilization to obtain 1000 muddy outstanding agent.Device therefor is this area common apparatus. In like manner, according to embodiment 7, can obtain the muddy outstanding agent of arteannuin of 100mg and 50mg specification. Dihydroartemisinine, Artemether, arteether, artesunate all can be prepared into the muddy outstanding agent of 50mg, 100mg, 200mg specification with reference to embodiment 7. 1. arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, the application of artesunate in the medication for treating pyemia of preparation prevention or the initiation of treatment antibacterial. 2. purposes according to claim 1 is characterized in that, described antibacterial is gram positive bacteria or gram-negative bacteria. 3. arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate are in the preparation prevention or control application in the pyemic medicine that CpG ODN causes. 4. arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, the application of artesunate in preparing the medication for treating pyemia that prevents or control antibacterial and CpG ODN initiation. 5. according to claim 1,2,3 or 4 each described purposes, it is characterized in that arteannuin and derivative dihydro-abrotine thereof, Artemether, arteether, artesunate are prepared into any preparation on the pharmaceutics in pharmacy procedure.

CN1823760A艾蒿类药物治疗胶质增生的用途---公开了一种青蒿素类药物在口服或注射治疗神经胶质瘤中的应用 CN1823760A Artemisinin class drugs for the treatment of glioma---discloses the use of artemisinin class drugs for oral or injection treatment of gliomas. 青蒿素类药物治疗神经胶质瘤的用途 本发明公开了青蒿素类药物的一种新的医药用途，即可以作为一种高效、低毒、价廉的新型化疗药治疗神经胶质瘤。对神经胶质瘤患者和神经胶质瘤手术后复发的患者口服或者注射给药，每天使用10－2000mg(优选50－500mg)的剂量治疗，能够使肿瘤消失或者控制其增殖，使患者能够长期正常生活和工作。 青蒿素类药物治疗神经胶质瘤的用途 技术领域 本发明涉及生物医药领域，特别是涉及青蒿素类药物治疗神经胶质瘤的用途。 背景技术 神经胶质瘤是脑部肿瘤的主要类型之一，神经胶质细胞的非正常分化及恶变是神经胶质瘤的重要成因。虽然已有许多肿瘤化疗药，但由于脑组织毛细血管特有的结构，这些抗肿瘤药往往不能透过血脑屏障儿发挥作用。事实上，目前尚无有效治疗神经胶质瘤的药物。 青蒿素(artemisinin，或qinghaosu或arteannuin)是从药用植物黄花蒿(Artemisia annua L.)中提取的一种化合物。青蒿素类药物是从青蒿素衍生的分子结构中具有含有过氧键和青蒿素母核结构的倍半萜类化合物，包括青蒿素、双氢青蒿素(二氢青蒿素，dihydroartemisinin)、青蒿琥酯(artesunate)、蒿甲醚(artemether)、蒿乙醚(arteether)、蒿立酸盐(artelinate)等，目前作为抗疟药使用，对各种类型的疟疾具有治疗作用，尤其对恶性疟和脑型疟具有特效。这些药物经过长期大例数的疟疾临床运用，还证明在使用剂量下十分安全，几乎无任何毒副作用。 鉴于——青蒿素类药物能有效穿透血脑屏障；青蒿素类药物具有抗肿瘤(如白血病、乳腺癌等)作用；青蒿素类药物毒副作用小，而已有化疗药毒性都很强；青蒿素类药物治疗疟疾无抗药性报道，而一般抗肿瘤化学药易产生抗药性等理由，我们近几年开展了用青蒿素类药物对神经胶质瘤患者包括神经胶质瘤术后复发患者的临床治疗研究。 发明内容 我们在临床试验中令人惊喜地发现：对神经胶质瘤患者和神经胶质瘤手术后复发的患者，采用上述青蒿素类药物的一种(优选青蒿琥酯或双氢青蒿素)进行治疗，能够控制肿瘤的增殖，也能够使患者肿瘤不复发，患者长期存活。取得了满意的疗效。 本发明的目的志在克服现有技术的不足而提供一种针对神经胶质瘤的全新、高效的新治疗药物，具体的说，是青蒿素类药物在制备治疗神经胶质瘤的药物中的用途。 ——所述的青蒿素类药物是含有过氧键、具有青蒿素母核结构的倍半萜类化合物及其衍生物，包括青蒿素、双氢青蒿素、青蒿琥酯、蒿甲醚、蒿乙醚、蒿立酸盐。 ——所述的青蒿素类药物选自青蒿素、双氢青蒿素、青蒿琥酯、蒿甲醚。 ——所述的青蒿素类药物的质量标准和/或药品说明书中包含对人体神经胶质瘤的用途； ——所述的青蒿素药物的临床适应中包含神经胶质瘤。 ——所述的青蒿素类药物治疗神经胶质瘤患者每天的剂量是25-500mg(每天的剂量优选50-500mg)，可1次或多次服用或注射。 本发明的意义在于发现了青蒿素类药物的治疗疟疾作用以外的一种新的医学用途，即可以作为一种高效、低毒、价廉的新型化疗药治疗神经胶质瘤。 具体实施方式 青蒿素类药物口服或者注射，能够有效治疗神经胶质瘤。用青蒿素类药物(优选青蒿琥酯或者双氢青蒿素)治疗神经胶质瘤患者18例，其中14例取得显著疗效，显效率达77.8％。 实施例1 某甲，男，成年，1998年经CT诊断，确诊为神经胶质瘤，同年9月对所患神经胶质瘤实施手术治疗。但2001年8月CT检查发现肿瘤复发，2003年3月起停服原先服用的药物，改为服用青蒿琥酯100mg/日，连服2年，2004年11月CT检查，神经胶质瘤消失，且未见任何不良反应，至今患者生活如常。 实施例2 某乙，男，成年，1994年发现患神经胶质瘤并实施手术治疗，2005年1月复发，使用伽玛射线进行姑息治疗，但无效果。2005年3月起口服青蒿琥酯300mg/日，连服4个月，MRI诊断发现肿瘤消失，维持100mg/日剂量治疗，患者能够正常生活工作。治疗期间未见任何不良反应。 1、青蒿素类药物在制备治疗神经胶质瘤的药物中的用途。 2、根据权利要求1所述的用途，其特征在于所述的青蒿素类药物是含有过氧键、具有青蒿素母核结构的倍半萜类化合物及其衍生物，包括青蒿素、双氢青蒿素、青蒿琥酯、蒿甲醚、蒿乙醚、蒿立酸盐。 3根据权利要求1所述的用途，其特征在于所述的青蒿素类药物选自青蒿素、双氢青蒿素、青蒿琥酯、蒿甲醚。 4、根据权利要求1所述的用途，其特征在于所述的青蒿素类药物的质量标准和/或药品说明书中包含对人体神经胶质瘤的用途。 5、根据权利要求1所述的用途，其特征在于所述的青蒿素类药物的临床适应症中包含神经胶质瘤。 6、根据权利要求1所述的用途，其特征在于所述的青蒿素类药物治疗神经胶质瘤患者时，每天的剂量是10-2000mg(每天的剂量优选50-500mg)，可1次或多次服用或注射。 Use of artemisia apiacea kind medicine for treating gliosis An application of arteannuin-kind medicines in treating neuroglioma by oral taking or injection is disclosed. The purposes of artemisia apiacea kind medicine for treating gliosis Technical field The present invention relates to biomedicine field, particularly relate to the purposes of artemisia apiacea kind medicine for treating gliosis. Background technology Glioma is one of main type of brain tumor, the improper differentiation of neurogliocyte and to cancerate be the gliomatous important origin cause of formation.Though existing many chemotherapy of tumors medicines, because cerebral tissue blood capillary its specific structure, these antineoplastic agents often can not see through blood brain barrier and play a role.In fact, still there is not the effectively gliomatous medicine of treatment at present. Arteannuin (artemisinin, or qinghaosu or arteannuin) is a kind of chemical compound that extracts from medicinal plants Herba Artemisiae annuae (Artemisia annua L.).Artemisinin-based drug is to have the sesquiterpenoids that contains peroxide bridge and arteannuin mother nucleus structure from the deutero-molecular structure of arteannuin, comprise arteannuin, dihydroarteannuin (dihydroartemisinine, dihydroartemisinin), artesunate (artesunate), Artemether (artemether), arteether (arteether), the upright hydrochlorate (artelinate) of Artemisia etc., use as antimalarial at present, various types of malaria are had therapeutical effect, especially subtertian malaria and cerebral malaria are had specially good effect.These medicines also prove under using dosage fool proof, almost without any side effects through the malaria clinical application of long-term big routine number. In view of---artemisinin-based drug can effectively penetrate blood brain barrier; Artemisinin-based drug has antitumor (as leukemia, breast carcinoma etc.) effect; The artemisinin-based drug toxic and side effects is little, and existing chemotherapeutic toxicity is all very strong; Artemisinin-based drug treatment malaria does not have the Drug resistance report, and general antitumor chemistry medicine reason such as easily develop immunity to drugs, we had carried out the clinical treatment research that the glioma patient is comprised glioma postoperative recurrence patient with artemisinin-based drug in recent years. Summary of the invention We surprisedly find in clinical trial: to the patient of glioma patient and glioma recurrence after operation, adopt a kind of (the preferred artesunate or the dihydroarteannuin) of above-mentioned artemisinin-based drug to treat, can control the propagation of tumor, also can make patient tumors not recur patient's long-term surviving.Obtained satisfied curative effect. Purpose of the present invention aim at overcoming the deficiencies in the prior art and provide a kind of at gliomatous completely newly, new medicine efficiently, specifically, be the purposes of artemisinin-based drug in the gliomatous medicine of preparation treatment. ---described artemisinin-based drug is sesquiterpenoids and the derivant thereof that contains peroxide bridge, has the arteannuin mother nucleus structure, comprises arteannuin, dihydroarteannuin, artesunate, Artemether, arteether, the upright hydrochlorate of Artemisia. ---described artemisinin-based drug is selected from arteannuin, dihydroarteannuin, artesunate, Artemether. ---comprise purposes in the quality standard of described artemisinin-based drug and/or the package insert to the human nerve glioma; ---comprise glioma in the clinical adaptation of described arteannuin medicine. ---the dosage of described artemisia apiacea kind medicine for treating gliosis patient every day is 25-500mg (the preferred 50-500mg of the dosage of every day), can 1 time or repeatedly take or inject. Meaning of the present invention has been to find a kind of new medical usage beyond the treatment malaria effect of artemisinin-based drug, promptly can be as a kind of efficient, low toxicity, inexpensive novel chemotherapeutic treatment glioma. The specific embodiment Glioma can be effectively treated in the oral or injection of artemisinin-based drug.With artemisinin-based drug (preferred artesunate or dihydroarteannuin) treatment glioma patient 18 examples, wherein 14 examples obtain significant curative effect, and obvious effective rate reaches 77.8%. Embodiment 1 Certain person, the man grows up, and is diagnosed as glioma through the CT diagnosis in 1998, and the same year, JIUYUE was to suffering from glioma enforcement operative treatment.But August calendar year 2001, CT examination was found tumor recurrence, and rise and withdraw the medicine of originally taking in March, 2003, changes into and taking artesunate 100mg/ day, serve on 2 years, in November, 2004 CT examination, glioma disappears, and do not see any untoward reaction, the patient lives as usual so far. Embodiment 2 Certain second, the man grows up, and finds to suffer from glioma and implement operative treatment in 1994, and in January, 2005 recurrence uses gamma ray to carry out palliative treatment, but to no effect.Rise oral artesunate 300mg/ day in March, 2005, serve on 4 months, and the MRI diagnosis finds that tumor disappears, and keeps the treatment of 100mg/ daily dose, and the patient can work orthobiosis.Do not see any untoward reaction during the treatment. 1, the purposes of artemisinin-based drug in the gliomatous medicine of preparation treatment. 2, purposes according to claim 1, it is characterized in that described artemisinin-based drug is sesquiterpenoids and the derivant thereof that contains peroxide bridge, has the arteannuin mother nucleus structure, comprise arteannuin, dihydroarteannuin, artesunate, Artemether, arteether, the upright hydrochlorate of Artemisia. 3 purposes according to claim 1 is characterized in that described artemisinin-based drug is selected from arteannuin, dihydroarteannuin, artesunate, Artemether. 4, purposes according to claim 1 is characterized in that comprising in the quality standard of described artemisinin-based drug and/or the package insert purposes to the human nerve glioma. 5, purposes according to claim 1 is characterized in that comprising glioma in the clinical indication of described artemisinin-based drug. 6, purposes according to claim 1, when it is characterized in that described artemisia apiacea kind medicine for treating gliosis patient, the dosage of every day is 10-2000mg (the preferred 50-500mg of the dosage of every day), can 1 time or repeatedly take or inject.

Ava on X_ _Every American should watch this powerful sermon. The bishop was stabbed during the sermon. Wake up! This is humanity's last chance! #PrayForAmerica #battleoffaith #standwithAmericanpeople #TakeDownTheCCP @LFATVUS @WayneDupreeSho.mp4 视频来源：https://x.com/S7gril/status/1779925997673984208 【翻译】针对最近针对澳大利亚悉尼韦克利基督善牧堂教区主教玛尔玛利·埃玛努埃尔（Mar Mari Emmanuel）的刺杀事件的官方新闻稿 2024年4月16日星期二 亲爱的信徒、朋友和我们圣教堂的追随者，愿主和救主耶稣基督的慈悲和怜悯与您和您的家人同在。 在澳大利亚东部标准时间4月15日星期一晚上7:05分，当我们用亚述语直播圣经讲道时，对主教玛尔玛利·埃玛努埃尔的生命发生了一次袭击。主教目前正在医院接受治疗，他的情况在上帝的神圣恩典和您的祈祷下，稳定并且正在改善。 根据我们的直播（Facebook和YouTube）显示，袭击者带着一把隐蔽的刀靠近讲台，然后突然冲上前去，连续向主教的头部和身体刺出多刀。这名男子还试图袭击我们的一名教区神父艾萨克·罗伊尔（Isaac Royel），他也因受伤接受治疗。教堂内其他人没有受伤，但袭击者被就坐在附近的信徒迅速制服，并被警方拘留，目前已由警方扣押。 与此同时，随着袭击的视频在社交媒体上传播，我们的教堂被大量信息淹没，成千上万的当地人前来支持主教。然而，遗憾的是，许多人违抗了要求离开的指示，当警方开始调查事件时，警方不得不采取必要的步骤来驱散人群。 亲爱的信徒们，请不要让今天对玛尔玛利·埃玛努埃尔主教生命的可怕袭击减损我们的主耶稣基督的圣洁、完美和神圣的名字。自早期以来，圣徒和教会祖先们都证明了这种迫害的形式，因为为了基督的名义，我们被教导要以彼此团结、和平和团结的生活。基督事实上呼吁他的臣民成为“世界的光”，意味着那些带有他印记的人必须热切地履行这一角色。 最后，基督善牧堂恳求所有基督信徒、追随者和玛尔玛利·埃玛努埃尔主教的崇拜者，与邻里和平相处，正如主耶稣基督所吩咐的一样；教会谴责任何形式的报复，教会将此次袭击视为孤立事件，并等待警方对袭击者动机的调查结果；我们的教会还谴责了不服从指示的行为，并要求公众尊重文明秩序，同时保持获得全能上帝认可的和平。 最后，我们要求所有教会成员、信徒和追随者，无论是当地的还是国际的，都要小心观看在网上分享的与此事件有关的材料，包括社交媒体上的帖子，并鼓励人们向教会寻求事件的澄清；并且将玛尔玛利·埃玛努埃尔主教、艾萨克·罗伊尔神父、教会以及袭击者本人的名字交托给祈祷。 愿我们所有人都享受我们主耶稣基督的恩典，阿门。 丹尼尔·科克乌神父 教区神父，玛尔玛利·埃玛努埃尔主教秘书

Eglise医生问答： 请教：D3是如何制造出来的？从哪里提炼的？ 答：维生素 D3是从羊毛脂中提取的粗胆固醇（7-脱氢胆固醇）化合物，在紫外线照射下形成维生素 D3。因其过程模仿了人类皮肤中发生的反应，故生物利用度高于来源于植物的维生素 D2。 后者是通过对“麦角甾醇”（一种从酵母中获得的化合物）施加紫外线辐射而制成。 https://gettr.com/post/p33b4ro09d7 问：请教D3正常值是什么？ 七哥昨日注射D， 我验血值是79，过高吗？我每天用5000IU一粒，太阳下骑自行车30分钟。 答：成人维生素D3正常值：50–100 nmol/L（20–40 ng/mL），请明确剂量单位。疫情期间，我们新中国联邦推荐的成人CCP病毒预防方案建议维生素D3每日摄入量5000IU，伴维生素K2 100mcg; 平均每月150,000IU。文贵先生采用的是每月肌肉注射一次100,000IU。所以，只要日常按照病毒预防方案用药者，无需担心体内缺少维生素D。 但请注意，血清维生素D3的补充可增加小肠壁对钙的吸收，易发生高钙血症。如同时补充维生素K2，可避免钙质在血管壁上的沉积，从而避免因血管壁硬化所致的恶性高血压。 最近研究发现，血液中有足够维生素D时，可帮助阻止新冠病毒进入细胞，增强免疫功能，降低炎症反应，同时促进依赖维生素K2的蛋白质合成。这些蛋白质可减少血栓形成，减少炎性细胞因子释放，降低软组织钙化，保护心血管，增加骨密度。https://gettr.com/post/p1w67ap2768

Ryan Cole博士:维生素D是抵御癌症调节新陈代谢的基础 　　 本文视频引用来源：Covid Through a Pathologists Eye: Ryan Cole on DarkHorse【《通过病理学家之眼看Covid: Ryan Cole在DarkHorse节目中的访谈》】，视频发布日期为2024年3月31日，本段为节选六。 Your browser does not support the video tag. 以下为引用视频的中文大意： 　　Bret Weinstein: 基本免疫学，你知道的，有充分的理由去研究。 　　Dr Ryan Cole: 那你是怎样增强你的免疫系统的？嗯，显然，你一直在谈论维生素D，就是它。 　　Bret Weinstein: 维生素D，我是从你那里学到的。 　　Dr Ryan Cole: 我要给迈克尔·霍利克博士点个赞，我想，因为在流感和感冒季节，我有点借鉴了他的措辞，但我多年来一直在研究他的工作，再说一次，就像在风中吐痰一样，他几年前就试图传达这个观点。他是一个杰出的维生素D研究者，再次强调，我想他也在波士顿，有很多优秀的维生素D研究者，安德森博士在英国。如果我们花200亿美元来补充世界各地缺乏的维生素D水平，我们就能为系统节省大约3000亿美元的费用。 　　Bret Weinstein: 关于维生素D业务最令人烦恼的是，我不在乎你对它对COVID是否有积极影响感到多么不确定。我的意思是，从早期开始，证据在这方面是绝对清楚的。但即使不是这样，假设你一无所知，那么如果你是一个合乎逻辑的人，答案很可能是它有效，因为它在免疫方面是全面有效的。假设它不是。首先，它并不危险，因为身体能够分解过量的维生素D，副作用是什么？它们全都是积极的。 　　Dr Ryan Cole: 是的。每当我谈到维生素D时，我总是说：“确保你摄入了一些镁，因为镁有助于将钙推回骨骼，还有维生素K2，因为人们认为，‘哦，如果这么多好，那么更多就更好了。’”生活中有一个金发姑娘效应。再次强调，复杂的生物系统具有反馈环路，过多可能会造成伤害，过少可能不会有益，所以你必须找到那个幸福的区域。 　　甚至回到COVID，梅奥诊所做了一项研究，如果你的维生素D水平超过30，你就不会进入ICU。就是这么简单。一旦你早早地发表了那篇论文，那么问题就该结束了。我有医院管理人员对当地新闻大声疾呼，“哦，维生素D，无所谓。”它不是一种维生素，它是一种前激素，它是你免疫系统的主要指挥官等等。 　　而且你也提到了，你知道，你可以激活它，使它失活。事实上，在小鼠模型中，实验室模型，如果我想失活维生素D，我该怎么做？我喂它们高果糖玉米糖浆。它脱羟基并失活维生素D。你的杂货店货架上的80％食品中都含有什么？高果糖玉米糖浆。它是维生素D的失活剂。而且我们已经是一个维生素D不足，甚至是缺乏的社会。 　　Bret Weinstein: 对。这是一个新颖的问题。所以，事实上，这是一个非常好的基准，因为希瑟和我在我们的书中写了一篇对补充的怀疑。对吧？基本逻辑是正确的，也就是说，如果你的饮食正确，那么你可能不缺乏大多数东西。 　　然而，首先，我们的饮食并不正确，因为许多这些食物已经被改变，以适应长期的供应链等问题。但更重要的是，维生素D不是你主要从食物中摄入的东西。你主要是在太阳下制造它，而我们却生活在室内。在我们有阳光照射的程度，它通过玻璃来，这减少了大部分的紫外线。 　　所以关键是当我们写书时我们忽略了的一部分是，如果你生活在温带地区，你几乎肯定缺乏维生素D，而这几乎肯定会对你的病原体易感性产生巨大的负面影响。因此，补充是在纠正一个新颖的情况，对吧？然后一旦你有了它比任何其他方法都更好的证据，以应对COVID，对吧？你的单一最低成本，最高效的干预措施就是维生素D。 　　那么答案就是，如果你如此迷恋我们的健康，以至于你愿意剥夺我们的公民自由来保护我们免受这种事物的侵害，那么你也不会推荐这种东西，即使它最终证明没有积极影响，也会让你不那么容易受到其他你可能会遇到的十几件事情影响，我的意思是你可能会得的病，包括癌症在内。 　　Dr Ryan Cole: 包括癌症在内。 　　Bret Weinstein: 包括癌症，是的。你越往北走，结肠癌、前列腺癌、甲状腺癌、乳腺癌的发病率就越高。再次强调，相关性不等于因果关系，但观察到北半球和南半球冬季疾病的模式以及在冬季季节我们远离太阳的角度是非常引人入胜的。这些紫外射线在大气层中反射，直到我们的位置高于37.5度，才能穿透并开始合成。而且正如你所说的。 　　这是一个社会性问题。肥胖会使你的维生素D被囤积起来。这就是为什么我也谈论镁，因为它可以从你的脂肪储存中释放出你的D。你的皮肤越黑，你生活的地方越北。 　　Bret Weinstein: 是的，挑战越大。 　　Dr Ryan Cole: 黑色素是一种天然的防晒霜。你必须花六到十倍的时间在外面，才能像一个皮肤较白的人一样，因为在赤道，那里黑皮肤是保护性的。 　　Bret Weinstein: 太阳总是以更陡的角度照射下来。 　　Dr Ryan Cole: 绝对是，一直都是。 　　Bret Weinstein: 因此，你的挑战就少一些了。一旦你了解了这些事情，就不难了。 　　Dr Ryan Cole: 这一切又回到了什么？免疫系统，因为它是免疫系统的指挥官，它做什么？抵御癌症，调节新陈代谢，管理不同免疫细胞的活动来抵御病毒等等。因此，作为免疫学原理之一，这是基本和基础的。 　　Bret Weinstein: 是的，绝对是。再次强调，所以……… 　　Dr Ryan Cole:而且，像你说的，对于书中的观点，我们在书中说到这一点时，我明白了，我知道他们的出发点是什么，但是我们已经不再过那种理想的适应进化的生活方式了。 　　Bret Weinstein: 确实。如果我们有机会重新写这一部分，我们会完全不同，因为事实是你正在纠正一种由新奇引起的缺陷。这本书就是关于新奇引起的缺陷，而在我们写书时，我们还没有发现这一点。还有其他一些，哦，我想提一下，关于太阳的角度和季节性以及我们倾斜的情况等等，强烈推荐一个叫做 D-Minder 的应用程序。 　　Dr Ryan Cole: 是的，我第一次演讲就提到过那个。 　　Bret Weinstein: 我忘了那个，所以我可能是从那里得到的。但 D-Minder 可以让你知道，根据我所处的位置，在一年中的许多月份你根本无法制造任何维生素D。你可能会出去晒太阳，认为你正在制造维生素D，但事实并非如此，对吧？ 　　那么补充又在哪里呢？嗯，每当你无法在太阳下制造维生素D时，你就应该考虑补充，因为太阳穿透的大气层太厚。同样，了解一天中你可以制造多少维生素D。你取得的维生素D的量取决于你穿了多少衣服，所有这些信息都是非常重要的。能够让一个设备告诉你，这真是太好了。实际上，在这个小时你可以制造一些。 　　Dr Ryan Cole: 这里是一个提醒。我设置了通知，嘿，这是你的维生素D合成高峰，当你在那些健康的维生素D月份合成维生素D时，出去20、30分钟，直到你开始微红，但不要晒伤。然后就遮盖起来。而且自然的维生素D比服用合成的更持久，因为如果你服用维生素D3，你仍然必须经过肝脏旁路和羟化等等，你必须经历多个步骤才能使其活化。 　　阳光是你的朋友，而且有趣的是，阳光不仅仅是为了维生素D。因此，即使在冬天，出去晒太阳也至关重要，因为近红外光刺激了我们在癌症途径中谈论过的那些至关重要的线粒体，线粒体有自己的褪黑素产生，它是人体中最强大的抗氧化剂，但这是细胞内褪黑素，所以它清除细胞内的任何损伤和杂质。因此，每天不管是下雨还是晴天，出去并且接受光照对整体健康至关重要。 　　Bret Weinstein: 是的。而且恰好的是，它也对你的心理产生了极其积极的影响，是的，想象一下，所有这些都指向同一个方向。 　　以下为内嵌中英文字幕的对应视频，视频连接：撕皮儿剥壳——银河系@Spielberg 4月 10日, 2024 　　 　　关联阅读： 　　Ryan Cole博士:以疫苗作为生化武器针对特定人群的问题 　　Ryan Cole博士:mRNA疫苗造成免疫系统窄化及异常IgG4 　　Ryan Cole博士:大多数医生的恐惧和怯懦使疫苗灾难泛滥 　　Ryan Cole博士:mRNA疫苗推出后出现的异乎寻常的血栓 　　Ryan Cole博士:mRNA疫苗推出后癌症激增并且机理改变 　　Ryan博士:新冠疫苗后的超水平死亡和意外猝死还在继续 　　Ryan博士:疫苗污染为苗后癌症等疾病的暴发提供了解释 　　Ryan博士:新冠疫苗强制接种后的癌症暴增以及疫苗污染 　　Ryan博士:疫苗群体的全因死亡率上升以及刺突蛋白毒性 　　Ryan博士:新冠疫苗后人类先天免疫系统被不正常地改变 　　Ryan博士疫苗灾难亲历:老年人患罕见皮肤病&癌症蔓延 　　Ryan博士:维生素D在减轻病毒感染和防癌方面的神奇表现 　　Ryan博士早期用青蒿素及羟氯喹治愈的三四百人无一死亡 　　Ryan Cole博士所看到的接种者体内的长血栓及清除建议 　　Ryan Cole博士:纳豆激酶分解清除刺突蛋白导致的血栓 　　医院拒用伊维菌素而用瑞德西韦致Tamara死亡引发的诉讼 　　重温21年7月白大褂峰会:政府与疫苗公司合谋毒害人类 　　参考连接：https://youtu.be/sEEKW05aHFU .responsive-video { max-width: 100%; height: auto; overflow: hidden; /* 防止视频溢出容器 */ } .responsive-video video { width: 100%; height: auto; }

Cov19期间-注射维他命D 针剂的重要性(中文) The importance of vitamin D injections during Cov19(EN) Cov19 sırasında - D vitamini enjeksiyonlarının önemi（Türkçe ） 维持高维他命D血中浓度有益于COV19病毒感染后的复原和缓解疫苗副作用 Turkish, Chinese, English: The importance of vitamin D injections during Cov19 00:00-01:30：展示了给予维生素D注射的过程； 01:31-03:29：青蒿素、伊维菌素和维生素D（注射）是正在开发的疫苗解毒剂的三个主要成分（意大利语配音）。 资料来源 : https://gettr.com/post/p1y036z06b0 À propos de la vitamine D3 en injection 郭先生介绍科学家推荐的维生素D3针剂:可以预防新冠，也是感染新冠病毒和接种了毒疫苗的解药主要成分之一。 .responsive-iframe { position: relative; width: 100%; height: 0; padding-bottom: 56.25%; /* 16:9 这里根据实际情况调整 */ } .responsive-iframe iframe { position: absolute; top: 0; left: 0; width: 100%; height: 100%; }

CN1758905A青蒿素在治疗致癌病毒 诱导的肿瘤和治疗 CN1758905A Artemisinin in the treatment of tumors induced by oncogenic viruses and treatment. 本文短链接：https://gettr.ink/TZ8jEe 青蒿素在治疗致癌病毒诱导的肿瘤和治疗病毒感染中的应用 在某些方面，本发明涉及通过施用青蒿素－相关化合物治疗增生性子宫颈紊乱(诸如子宫颈癌和子宫颈非典型增生)以及治疗病毒感染的方法。在某些方面，本发明涉及通过施用青蒿素－相关化合物治疗由致癌病毒诱导的肿瘤的方法，杀死或抑制鳞状细胞性癌的方法，以及抑制病毒复制的方法。 青蒿素在治疗致癌病毒 诱导的肿瘤和治疗病毒感染中的应用 背景技术 尽管出现了Papanicolaou(Pap)涂片，但子宫颈癌和前-癌对于女性而言仍然是重要的健康问题，尤其是对美国和发展中国家的未充分监控的女性而言。在世界范围内，每年有250,000女性死于此种癌症。子宫颈非典型增生子宫颈细胞一种恶变前或癌前期的转变，如不进行治疗则可能发展为子宫颈癌。 子宫颈癌的主要危险因素是人乳头瘤病毒(HPV)感染。乳头状瘤病毒感染导致99％的女性子宫颈癌，以及大部分的肛门直肠鳞状细胞癌。此外，乳头状瘤病毒被发现存在于皮肤的鳞状和基底细胞癌以及口腔、咽和喉的鳞状细胞癌细胞中。乳头状瘤病毒也诱导许多的良性肿瘤包括生殖器官疣和常见的手足疣。它们也诱导儿童和成人的咽喉乳头状瘤。目前，没有有效的药物疗法用于治疗人乳头瘤病毒(HPV)感染及其诱导的并发肿瘤。 临床试验评价了注射干扰素到乳头状瘤病毒病灶中并且显示具有一定的效果。然而，在停止服药干扰素之后病毒感染立即复发。局部施用其它的化合物诸如5-氟尿嘧啶(5FU)和鬼臼霉素是有毒的并且同时杀死了感染的和正常的细胞。这些疗法不是高度有效的并且并不特异性地靶向肿瘤细胞。最近的疗法是尝试性的使用离子抗病毒疗法(ICVT)，其是Henderson Marley开发的(参见，例如，WO01/49300，WO01/49242，WO01/66100，WO 02/24207)。由于抗病毒疗法对乳头状瘤病毒感染没有效果，目前的临床方法是开发预防感染的疫苗。疫苗提供了非常大的希望，并且动物研究发现它们是高度安全的。然而，在感染人的100种乳头状瘤病毒中，至少有5种类型诱导子宫颈癌。因此为预防这种女性癌开发多价疫苗是必需的。目前试验仅仅评价抗HPV16型的单价疫苗并且这些试验不会在几年内完成。然后必须发展表达其它HPV型的衣壳蛋白的技术，其不一定是常规的方法。 多年来，病毒病已被认为对选择性的抗病毒化学疗法是顽固的，因为病毒的复制周期也被认为与正常的细胞代谢非常的接近并且任何抑制病毒繁殖的试图也将杀死(或严重地损伤)未感染的细胞。显然，需要其它治疗由病毒感染引起的病症诸如病毒感染和癌症(例如，子宫颈癌)的方法，其是重要的公共卫生问题。 发明概述 本发明涉及通过施用青蒿素和/或青蒿素衍生物治疗由病毒包括人乳头瘤病毒(HPV)，I型人嗜T淋巴细胞病毒(HTLV-1)、疱疹病毒(例如，埃-巴二氏病毒(EBV)，巨细胞病毒(CMV))、类SV40病毒、肝炎病毒、人类免疫缺陷性病毒(HIV)、腺病毒和流感病毒所引起的感染的方法，以及治疗与病毒感染相关的子宫颈紊乱(例如，子宫颈癌和子宫颈非典型增生)。本发明尤其涉及通过施用青蒿素和/或青蒿素衍生物(一或多种衍生物)选择性杀死或抑制细胞诸如恶变前的(癌变前的)以及恶性的(癌性)细胞生长的方法。 在一个实施方案中，本发明提供一种治疗患病毒感染的个体的方法。患病毒感染的个体(患者或受试者)通过施用治疗有效量的青蒿素-相关化合物进行治疗。本申请全文中使用的，术语“青蒿素-相关化合物”包括青蒿素以及青蒿素衍生物(类似物)二者。病毒感染可能是由病毒诸如人乳头瘤病毒(HPV)、I型人嗜T淋巴细胞病毒、疱疹病毒(例如埃-巴二氏病毒(EBV)、巨细胞病毒(CMV))、类SV40病毒、肝炎病毒、人类免疫缺陷性病毒(HIV)、腺病毒以及流感病毒所引起的。 本发明的方法可用于治疗乳头瘤病毒的恶变前和恶性子宫颈病灶。在另一个实施方案中，本发明提供了治疗患增生性子宫颈紊乱的个体的方法。在这些实施方案中，患增生性子宫颈紊乱的个体通过施用治疗有效量的青蒿素-相关化合物进行治疗。此处所述的术语“增生性子宫颈紊乱”包括子宫颈癌和子宫颈前癌(例如，子宫颈非典型增生)。增生性的子宫颈紊乱可能与乳头瘤病毒感染有关。 青蒿素衍生物包括，但不限于，二氢青蒿素，蒿甲醚，蒿乙醚，青蒿琥酯，artelinic acid，和二氢青蒿素丙基碳酸盐。青蒿素-相关化合物可通过各种途径施用于个体，例如，口服，局部地，非肠道，叶鞘内的，全身地，肌内，直肠施用或静脉内。在某些实施方案中，青蒿素-相关化合物与药物载体一起配制。 在某些实施方案中，青蒿素或青蒿素衍生物与其它的抗-病毒或抗-癌治疗，诸如施用抗-病毒或抗-癌药物，放射治疗，光照治疗或免疫治疗相结合。抗-病毒或抗-癌剂可与青蒿素-相关的化合物在相同的制剂中或以分离的制剂形式一起施用来增强治疗。在这些实施方案中，青蒿素-相关的化合物和其它的治疗可同时施用(同时地)或在不同的时间(顺序地)施用，只要以能够产生预期的效果的以及在时间上充分地接近即可。 在另一个实施方案中，本发明提供了杀死或抑制被人乳头瘤病毒感染的细胞的方法，诸如子宫颈癌细胞，肛门直肠鳞状癌细胞，皮肤鳞状细胞癌细胞，皮肤基底癌细胞，以及口腔、咽和喉的鳞状细胞癌细胞。头和颈、食管、气管以及支气管(其中有一些含有HPV)的鳞状细胞性癌也是潜在的靶。受感染细胞和充分量的杀死或抑制受感染细胞生长的青蒿素-相关的化合物相接触。在这些实施方案中，治疗有效量的青蒿素-相关的化合物被施用于需治疗的个体，例如，用于子宫颈癌、肛门直肠癌、鳞状的或基底细胞皮肤癌以及口腔、咽以及喉的鳞状癌的治疗。青蒿素-相关的化合物以充分杀死或抑制人乳头瘤病毒感染细胞的生长的量被通过适于其递送到需治疗位点的途径进行施用(例如，局部地，叶鞘内，直肠，口服，全身地，肌内或静脉内)。 在另一个实施方案中，本发明提供了一种杀死或抑制由致癌病毒诸如HPV，HTLV-1、疱疹病毒(例如，EBV或CMV)，类SV40病毒、肝炎病毒或腺病毒感染的细胞的方法。此外，HIV和流感病毒是潜在的靶。受感染细胞和足以杀死或抑制受感染细胞生长的量的青蒿素-相关化合物接触。在这些实施方案中，通过产生(适于)递送足以杀死或抑制受感染细胞的生长的量到需治疗的位点的途径，将治疗有效量的青蒿素-相关化合物施用于需治疗由HPV、HTLV-1、疱疹病毒(例如，EBV或CMV)，类SV40病毒、肝炎病毒、HIV，腺病毒或流感病毒感染的个体。 在另一个实施方案中，本发明提供了一种治疗人乳头瘤病毒(HPV)感染个体的方法。在这些实施方案中，治疗有效量的青蒿素-相关化合物被通过适于递送足以杀死或抑制受感染细胞生长的量到需治疗的位点的途径施用于个体。这些实施方案对治疗各种其中个体被HPV感染的病症是有用的，诸如其中被杀死或抑制的细胞是子宫颈癌细胞，肛门直肠鳞状癌细胞，皮肤鳞状细胞癌细胞，皮肤基底癌细胞和口腔，咽和喉的鳞状细胞癌细胞的病症。头和颈、食管、气管和支气管的鳞状细胞性癌也是潜在的靶。 在另一个实施方案中，本发明提供了一种治疗由病毒诸如HPV，HTLV-1、疱疹病毒(例如，EBV或CMV)，类SV40病毒、肝炎病毒，HIV，腺病毒或流感病毒感染的个体的方法。在这些实施方案中，通过产生(适于)递送足以杀死或抑制受感染细胞的生长的量到需治疗的位点的途径，将治疗有效量的青蒿素-相关化合物施用于需治疗的由HPV、HTLV-1、疱疹病毒(例如，EBV或CMV)，类SV40病毒、肝炎病毒、HIV，腺病毒或流感病毒感染的个体。 在另一个实施方案中，本发明提供了一种治疗个体中由人乳头瘤病毒所引起的病症的方法。在此实施方案中，治疗有效量的青蒿素-相关化合物被通过适于递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径施用于个体。可通过本发明方法治疗由HPV引起的病症包括，但不限于，子宫颈癌，肛门直肠鳞状癌，皮肤的鳞状细胞癌或基底癌，以及口腔、咽、喉、头和颈、食管、气管和支气管的鳞状细胞癌。 在另一个实施方案中，本发明提供了一种治疗个体中由病毒引起的病症的方法。由病毒诸如HPV、HTLV-1、疱疹病毒(例如，EBV或CMV)、类SV40病毒、肝炎病毒、HIV、腺病毒或流感病毒引起病症，可通过本发明的方法进行治疗。在此实施方案中，治疗有效量的青蒿素-相关化合物被通过适于递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径施用于个体。由这种病毒引起的可通过本发明方法治疗的病症包括，但不限于，癌症，诸如子宫颈癌，肛门直肠鳞状癌，皮肤的鳞状细胞癌或基底癌，以及口腔、咽、喉的鳞状细胞癌。具有诱导人或动物的肿瘤的能力的病毒称为“致癌”病毒。也就是说，它们靶向致癌病毒。它们包括，但不限于，HPV，HTLV-1，疱疹病毒(例如，EBV或CMV)，类SV40病毒，肝炎病毒以及腺病毒。青蒿素-相关化合物还可以用于抑制非-致癌病毒，诸如HIV以及流感病毒。 在另一个实施方案中，本发明提供了一种治疗个体非-恶性乳头状瘤病毒感染的方法，诸如良性肿瘤例如喉的乳头状瘤、生殖器的乳头状瘤(疣)以及常见的手足疣。受感染细胞和足以杀死或抑制受感染细胞生长的量的青蒿素-相关化合物接触。例如，治疗有效量的青蒿素-相关化合物被通过将化合物递送到将杀死或抑制受感染细胞的靶位(例如，喉组织，生殖器官疣或常见的手足疣)的途径施用于个体。 在另一个实施方案中，本发明提供了一种治疗患致癌病毒诱导的肿瘤的个体的方法。在此实施方案中，患致癌病毒诱导的肿瘤的个体被施用治疗有效量的青蒿素-相关化合物。致癌病毒是病毒的集和其包括，但不限于，HPV，HTLV-1，疱疹病毒(例如，EBV或CMV)，类SV40病毒，肝炎病毒以及腺病毒。致癌病毒-诱导的肿瘤可产生在人或非人类动物体中。为了进行说明，乳头状瘤病毒诱导的肿瘤包括在下列位点处的病变：颈，其它的生殖器官位点(例如，阴道，阴茎等等)，直肠，口腔，上呼吸道以及表皮。类SV40病毒诱导的肿瘤包括人间皮细胞瘤，骨肉瘤以及腮腺瘤。疱疹病毒诸如EBV诱导的肿瘤，包括鼻咽癌和何杰金氏病。HTLV-1诱导的肿瘤包括淋巴瘤。肝炎病毒诱导的肿瘤包括肝细胞癌。 在另一个实施方案中，本发明提供了一种杀死或抑制个体的鳞状细胞性癌的方法，包括将治疗有效量青蒿素-相关化合物施用于个体。鳞状细胞性癌选自头和颈，口腔，咽，喉，气管和支气管的鳞状细胞性癌。任选地，鳞状细胞性癌包括HPV感染。 在另一个实施方案中，本发明提供了一种杀死或抑制鳞状细胞性癌的方法，包括将癌瘤与足以杀死或抑制癌细胞生长的量的青蒿素-相关化合物接触。 在另一个实施方案中，本发明提供了抑制病毒在个体中复制的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。病毒选自：人乳头瘤病毒(HPV)，I型人嗜T淋巴细胞病毒(HTLV-1)，疱疹病毒，类SV40病毒，肝炎病毒，人类免疫缺陷性病毒(HIV)，腺病毒和流感病毒。在某些方面，病毒是致癌病毒(例如，HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒或腺病毒)。在其它的方面，病毒是非-致癌病毒(例如，HIV或流感病毒)。 在另一个实施方案中，本发明提供了抑制病毒复制的方法，包括将病毒与足以抑制病毒复制的量的青蒿素-相关化合物接触。 在又一个实施方案中，本发明提供了含有青蒿素-相关化合物和不是青蒿素-相关化合物的第二治疗药物的药物组合物。优选地，第二药物是化疗剂。 在治疗个体方法的所有实施方案中，一或多种青蒿素-相关化合物可共同施用(同时地)或在不同的时间(顺序地)施用。此外，青蒿素-相关化合物可与另一个类型或另一些类型的化合物(非-青蒿素化合物)一起施用。两种类型的化合物可同时或顺序施用。 附图说明 图1显示了青蒿素及其生物活性新陈代谢衍生物，二氢青蒿素(DHA)的结构。 图2显示了青蒿素对于子宫颈癌细胞是致死的。 图3显示了宫颈癌细胞，而不是正常子宫颈细胞，被青蒿素有效地杀死。 图4显示了二氢青蒿素(DHA)对EBV阳性的细胞系，Namalwa细胞，的作用。 图5显示了二氢青蒿素(DHA)对HTLV-I阳性细胞系，MJ细胞，的作用。 发明详述 本发明在某种程度上基于，申请人发现了青蒿素和/或青蒿素衍生物(类似物)在杀死或抑制人乳头瘤病毒转化细胞(例如，子宫颈癌细胞)以及由其它类型病毒诸如HTLV-1、疱疹病毒、类SV40病毒、肝炎病毒、HIV、腺病毒或流感病毒转化的细胞的生长中是有效的。如在这里描述的，申请人表明了青蒿素杀死子宫颈癌细胞、而不是正常的子宫颈细胞。因此，青蒿素及其衍生物可用于治疗病毒感染，和由这种病毒感染引起的病症诸如子宫颈癌症和子宫颈前癌。青蒿素目前应用于人作为抗疟疾药物且可局部和全身施用。 在某些实施方案中，本发明提供了治疗患病毒感染或增生性子宫颈紊乱的个体的方法。如在这里所应用的，由本发明方法治疗的个体(患者或受试者)可以是人或非-人动物。此种个体被通过施用治疗有效量的青蒿素-相关化合物进行治疗。此处所述的术语“青蒿素-相关化合物”包括青蒿素和青蒿素衍生物二者或类似物。青蒿素衍生物或类似物可以是合成的，半合成的或天然的。 在一个方面，本发明的方法可用于治疗由人乳头瘤病毒(HPV)、I型人嗜T淋巴细胞病毒(HTLV-1)、疱疹病毒(例如，EBV或CMV)、类SV40病毒、肝炎病毒、人类免疫缺陷性病毒(HIV)、腺病毒或流感病毒引起的个体感染的方法。本方法还可以用于治疗由对青蒿素或青蒿素衍生物敏感的其它病毒诸如DNA病毒和RNA病毒引起的感染。这种病毒可能会或可能不会引起癌症。 在另一个方面，本方法是治疗个体的增生性子宫颈紊乱诸如子宫颈癌症和子宫颈初癌(例如，子宫颈非典型增生)的方法。此处所述的术语“增生性子宫颈紊乱”是指具有有害或异常的宫颈组织增殖特征的任何子宫颈疾病/紊乱。本领域技术人员能够理解，增生性子宫颈紊乱可能与病毒感染诸如乳头状瘤病毒感染有关。 在一个实施方案中，本发明提供了方法杀死或抑制人乳头瘤病毒细胞诸如子宫颈癌细胞、肛门直肠鳞状癌细胞、皮肤鳞状细胞癌细胞、皮肤基底癌细胞以及口腔、咽、喉、头和颈、食管、气管和支气管的鳞状细胞癌细胞感染的细胞生长的方法。受感染细胞和足以杀死或抑制受感染细胞生长的量的青蒿素-相关化合物接触。在这些实施方案中，治疗有效量的青蒿素-相关化合物被施用于需要治疗的个体，例如，用于治疗子宫颈癌、肛门直肠鳞状癌、皮肤的鳞状细胞癌或基底癌，以及口腔、咽、喉、头和颈、食管、气管和支气管的鳞状细胞癌。青蒿素-相关化合物被以足以杀死或抑制人乳头瘤病毒感染细胞生长的量通过适于其递送到需治疗位点的途径(例如，局部地，叶鞘内，直肠施用，口服，全身地，肌内或静脉内)进行施用。 在另一个实施方案中，本发明提供了杀死或抑制由病毒诸如HPV，HTLV-1，疱疹病毒(例如，EBV或CMV)，类SV40病毒，肝炎病毒，HIV，腺病毒或流感病毒感染的细胞生长的方法。受感染细胞和足以杀死或抑制受感染细胞生长的量的青蒿素-相关化合物接触。在这些实施方案中，通过产生(适于)递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径，将治疗有效量的青蒿素-相关化合物施用于需治疗的由HPV、HTLV-1、疱疹病毒(例如，EBV或CMV)、类SV40病毒、肝炎病毒、HIV、腺病毒或流感病毒感染的个体。 在一个实施方案中，本发明提供了一种治疗人乳头瘤病毒(HPV)感染个体的方法。在此实施方案中，治疗有效量的青蒿素-相关化合物被通过适于递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径施用于个体。这些实施方案对治疗各种个体被HPV感染的病症是有用的，诸如其中被杀死或抑制的细胞是子宫颈癌细胞，肛门直肠鳞状癌细胞，皮肤鳞状细胞癌细胞和基底癌细胞，和口腔，咽和喉的鳞状细胞癌细胞，或头和颈，食管，气管，以及支气管的鳞状细胞癌细胞的病症。 在另一个实施方案中，本发明提供了治疗由病毒诸如HPV，HTLV-1，疱疹病毒(例如，EBV或CMV)，类SV40病毒，肝炎病毒，HIV，腺病毒或流感病毒感染的个体的方法。在这些实施方案中，通过产生(适于)递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径，将治疗有效量的青蒿素-相关化合物施用于需治疗的由HPV，HTLV-1，疱疹病毒(例如，EBV或CMV)，类SV40病毒，肝炎病毒，HIV，腺病毒或流感病毒感染的个体。 在一个实施方案中，本发明提供了一种治疗个体由人乳头瘤病毒引起的病症的方法。在此实施方案中，治疗有效量的青蒿素-相关化合物通过适于递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径施用于个体。可通过本发明方法治疗由HPV引起的病症包括，但不限于，子宫颈癌，肛门直肠鳞状癌，皮肤的鳞状细胞癌或基底癌，以及口腔、咽、喉、头和颈、食管、气管和支气管的鳞状细胞癌。 在另一个实施方案中，本发明提供了治疗个体中由病毒引起的病症的方法。所述病毒包括HPV，HTLV-1，疱疹病毒(例如，EBV或CMV)，类SV40病毒，肝炎病毒，HIV，腺病毒以及流感病毒。在此实施方案中，治疗有效量的青蒿素-相关化合物通过适于递送足以杀死或抑制受感染细胞生长的量到需治疗位点的途径施用于个体。可通过本发明方法治疗由这种病毒引起的病症包括，但不限于子宫颈癌，肛门直肠鳞状癌，皮肤的鳞状细胞癌或基底癌，以及口腔、咽、喉的鳞状细胞癌。头和颈、食管、气管和支气管的鳞状细胞性癌也可以通过此种方式进行治疗。 在另一个实施方案中，本发明提供了治疗个体的非-恶性乳头状瘤病毒感染，诸如良性肿瘤，例如喉的乳头状瘤、生殖器的乳头状瘤(疣)以及常见的手足疣的方法。受感染细胞和足以杀死或抑制细胞生长的量的青蒿素-相关的化合物接触。例如，治疗有效量的青蒿素-相关化合物通过将化合物递送到将杀死或抑制受感染细胞的靶位(例如，喉组织，生殖器官疣或常见的手足疣)的途径施用于个体。 在另一个实施方案中，本发明提供了治疗患由致癌病毒诱导的肿瘤的个体的方法。在此实施方案中，患致癌病毒诱导的肿瘤的个体被施用治疗有效量的青蒿素-相关化合物。致癌病毒是病毒的特异性集合，其包括，但不限于，HPV，HTLV-1，疱疹病毒(例如，EBV，CMV，HHV6，或HHV8)，类SV40病毒，肝炎病毒以及腺病毒。致癌病毒-诱导的肿瘤可产生在人或动物中。为了进行说明，乳头状瘤病毒诱导的肿瘤包括在下列位点处的病变：子宫颈，其它的生殖器官位点(例如，阴道，阴茎等等)，直肠，口腔，上呼吸道，和表皮。类SV40病毒诱导的肿瘤包括人间皮细胞瘤，骨肉瘤和及腮腺瘤。疱疹病毒诸如EBV诱导的瘤，包括鼻咽癌和何杰金氏病。另一种疱疹病毒诸如疱疹病毒8型(HHV8)，也称为KSV，诱导的肿瘤包括卡波西肉瘤(Kaposi's sarcoma)。卡波西肉瘤是一种恶性疾病且通常在HIV感染的免疫抑制患者中发现。这些肿瘤通常表现为皮肤病变。HTLV-1诱导的肿瘤包括淋巴瘤。肝炎病毒诱导的肿瘤包括肝细胞癌。 在另一个实施方案中，本发明提供了一种杀死或抑制个体的鳞状细胞性癌的方法，包括将治疗有效量青蒿素-相关化合物施用于个体。鳞状细胞性癌选自头和颈，口腔，咽的，喉，气管和支气管的鳞状细胞性癌。任选地，鳞状细胞性癌包括HPV感染。 在另一个实施方案中，本发明提供了一种杀死或抑制个体的鳞状细胞性癌的方法，包括将癌瘤与足以杀死或抑制癌细胞生长量的青蒿素-相关化合物接触。 在另一个实施方案中，本发明提供了一种抑制个体体内病毒复制的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。病毒选自：人乳头瘤病毒(HPV)，I型人嗜T淋巴细胞病毒(HTLV-1)，疱疹病毒，类SV40病毒，肝炎病毒，人类免疫缺陷性病毒(HIV)，腺病毒和流感病毒。在某些方面，病毒是致癌病毒(例如，HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒或腺病毒)。在其它的方面，病毒是非-致癌病毒(例如，HIV或流感病毒)。 在另一个实施方案中，本发明提供了一种抑制病毒复制的方法，包括将病毒与足以抑制病毒复制量的青蒿素-相关化合物接触。 在又一个实施方案中，本发明提供了一种含有一种青蒿素-相关化合物和不是青蒿素-相关化合物的第二药物的药物组合物。优选地，第二药物是化疗剂。 青蒿素-相关化合物。 术语“青蒿素-相关化合物”，如在这里应用的，是指青蒿素和青蒿素衍生物二者或类似物。青蒿素是一种天然存在的物质，通过纯化青蒿，黄花蒿(Artemisia annua)获得。青蒿素及其类似物是具有过氧桥的倍半萜烯内酯。 本发明方法集中于青蒿素衍生物或类似物的应用。具有高度水溶性的青蒿素类似物为二氢青蒿素，蒿甲醚，青蒿琥酯，蒿乙醚，二氢青蒿素丙基碳酸盐，和artelinic acid。 这些化合物对人类具有的极低毒性是一个主要的益处。青蒿琥酯，例如，安全性是蒿甲醚的两倍且毒性仅仅是最常见的抗疟疾药物-氯喹啉的五十分之一。 治疗有效量的青蒿素-相关化合物 本发明的方法包括施用治疗有效量的青蒿素-相关化合物(一或多种青蒿素-相关化合物)。术语“治疗有效量”，在这里是指导致受病毒诸如HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒，HIV，腺病毒或流感病毒感染的细胞死亡的量。例如，治疗有效量的青蒿素-相关化合物杀死或抑制子宫颈癌细胞；皮肤的鳞状和基底细胞癌；肛门直肠鳞状上皮细胞癌；卡波西肉瘤，喉乳头状瘤和良性肿瘤诸如生殖器官疣和手足疣的细胞的生长。 青蒿素是一种相对安全的药物且即使在高剂量时也只产生很小的副作用。持续6天口服70mg/kg/天剂量已经应用于人的疟疾治疗。此外，更多有效的类似物和类似化合物也被利用。青蒿素作用的较高效果可通过其它方式来实现。例如，青蒿素与血红素比与游离铁更具活性(Hong等，1974，Mol.Biochem.Parasit.，63：121-128)。可利用转铁蛋白铁(参见，例如，Stout等，1992，Biochim.Biophy.Res.Comm.，189：765-770)或携带血红素的化合物hemoplexin(参见，例如，Smith等，1988，Biochem.J.，256：941-950；Smith等，1990，Europ.J.CellBiol.，53：234-245)将铁导入靶细胞中。本发明中增强胞内铁浓度的药物浓度通常在对特定受试者和药物的最大耐药量范围内，其根据药物、受试者、疾病状况及其它因素进行变化。从约1到约100mg的铁/千克受试者体重/天的剂量范围通常对这些目的是有用的。 青蒿素或青蒿素衍生物化合物施用于需治疗个体的剂量将根据每一个体的例如所用化合物、施用途径以及个体的身体状况和体形而不同。为进行说明，每天每公斤体重可施用约0.1到约100mg。在进一步的实施方案中，每公斤体重每天施用约1到约90mg。或者，每公斤体重每天施用约1到约75mg。日剂量可以为一个单一剂量或可以是分成多剂量进行施用。 青蒿素-相关化合物的实际剂量水平可以变化以便获得在靶细胞(例如，病毒感染细胞或异常的子宫颈细胞)位点有效获得目的治疗或预防应答的量。因此，所选的剂量水平将取决于靶细胞的特性和位点，抑制或杀死靶细胞需要的青蒿素-相关化合物的目的量，所用青蒿素-相关化合物的特性，施用途径及其它因素。局部施用或口服，例如，可典型地每天一次或多次，诸如每天一到三次。 药物组合物 在本发明方法的某些实施方案中，青蒿素-相关化合物与药用载体一起配制。 青蒿素或青蒿素衍生物可单独施用或作为药物制剂(组合物)的一种组分。化合物可被配制以任何用于人或兽医学的适当方式进行施用。在某些实施方案中，包含在药物制剂中的化合物可以本身是活性的，或可以是一种前体药物。术语“前体药物”是指化合物其，在生理条件下，被转化为治疗活性的药物。 润湿剂，乳化剂和润滑剂，诸如十二烷基硫酸钠和硬脂酸镁，以及染色剂，隔离剂，包被剂，甜料，香料和芳香剂，防腐剂和抗氧化剂也可存在于组合物中。 青蒿素-相关化合物的制剂包含那些适于口服/鼻，局部，非肠道，叶鞘内和/或直肠施用的制剂。制剂可以为方便的单位剂型且可以通过药学领域公知的方法进行制备。可与载体结合产生单一剂型的活性成分的量将取决于治疗的宿主，施用的特定方式进行变化。可与载体结合产生单一剂型的活性成分的量通常是产生治疗效果的化合物的量。 制备这制剂或组合物的方法包括结合青蒿素-相关化合物和载体以及，任选地一或多种助剂。通常，通过结合青蒿素-相关化合物与液体载体或磨碎的固体载体或二者，然后如有必要将产品成形来制备制剂。 适于口服的青蒿素-相关化合物制剂可以为胶囊，扁囊剂，丸剂，片剂，锭剂(利用调味基，通常为蔗糖和阿拉伯胶或黄蓍胶)，粉剂，粒剂的形式，或作为水溶液或者非水溶液中的溶液或者悬浮液，或者水包油或油包水的液体乳剂，或作为酏剂或糖浆，或作为锭剂(利用惰性碱，诸如凝胶和甘油，或蔗糖和阿拉伯胶)和/或作为漱口剂等，各自包含预先确定量的作为活性成分的青蒿素-相关化合物。青蒿素-相关化合物也可作为丸剂，干药糖剂或糊剂施用。 在用于口服的固体剂型(胶囊，片剂，丸剂，糖衣丸，粉剂，粒剂等)，青蒿素-相关化合物与一或多种药用载体混合，诸如柠檬酸钠或磷酸二钙，和/或任意的下述物质：(1)填料或增充剂，诸如淀粉，乳糖，蔗糖，葡萄糖，甘露糖醇，和/或硅酸；(2)粘合剂，诸如，例如，羧甲基纤维素，藻酸盐，凝胶，聚乙烯基吡咯烷酮，蔗糖，和/或阿拉伯胶；(3)湿润剂，诸如甘油；(4)崩解剂，诸如琼脂，碳酸钙，马铃薯或木薯淀粉，藻酸，特定的硅酸盐，和碳酸钠；(5)溶液阻滞剂，诸如石蜡；(6)吸收促进剂，诸如季铵化合物；(7)润湿剂，诸如，例如，鲸蜡醇和单硬脂酸甘油酯；(8)吸附剂，诸如高岭土和皂土；(9)润滑剂，诸如滑石粉，硬脂酸钙，硬脂酸镁，固体聚乙二醇，十二烷基硫酸钠，及其混合物；和(10)染色剂。在为胶囊，片剂和丸剂时，药物组合物也可包括缓冲剂。相似类型的固体组合物也可用作利用乳糖或乳糖以及高分子量聚乙二醇等作为赋形剂的软的和硬的-填充胶囊中的填料。 青蒿素-相关化合物的口服液体剂型包括药用的乳剂，微乳剂，溶液，悬浮液，糖浆和酏剂。除了活性成分之外，液体剂型可包含本领域通常应用的惰性稀释剂，诸如水或其它的溶剂，增溶剂和乳化剂，诸如乙醇，异丙醇，碳酸乙酯，乙酸乙酯，苯甲醇，苯甲酸苄酯，丙二醇，1，3-丁二醇，油类(尤其是，棉籽，花生，玉米，胚，橄榄，蓖麻和芝麻的油)，甘油，四氢呋喃甲醇，聚乙二醇和山梨聚糖的脂肪酸酯，及其混合物。除惰性稀释剂之外，口服组合物还可以包括助剂诸如润湿剂，乳化和悬浮剂，甜料，调味剂，颜料，香料和防腐剂。 悬浮液，除活性化合物之外，可包含悬浮剂诸如乙氧基异十八烷醇，聚氧乙烯山梨糖醇，和山梨聚糖酯，微晶纤维素，偏氢氧化铝，皂土，琼脂和黄蓍胶，及其混合物。 尤其是，本发明的方法可局部施用于诸如子宫颈和阴道上的皮肤或粘膜。这样提供了直接递送到肿瘤的最大时机以及诱导副作用的最低机会。局部制剂可进一步包括一或多种已知有效作为皮肤或角质层渗透增强剂的药物。这些实例为2-吡咯烷酮，N-甲基-2-吡咯烷酮，二甲基乙酰胺，二甲基甲酰胺，丙二醇，甲基或异丙醇，二甲亚砜，和氮酮。可进一步包括其它的试剂来制备化妆品用制剂。实例为脂肪，蜡，油类，染料，香料，防腐剂，稳定剂和表面活性剂。角质层分离药物诸如本领域已知的也可被包含在内。实例为水杨酸和硫。 局部或透皮施用青蒿素-相关化合物的剂型包括粉剂，喷雾剂，膏剂，糊剂，乳剂，洗涤剂，凝胶，溶液，药膏和吸入剂。活性化合物可以在无菌条件下与药用载体，任意需要的防腐剂，缓冲液，或可能需要的推进剂混合。膏剂，糊剂，乳剂和凝胶除青蒿素-相关化合物之外可包含赋形剂，诸如动物和植物脂肪，油类，蜡，石蜡，淀粉，黄蓍胶，纤维素衍生物，聚乙二醇，硅树脂，皂土，硅酸，滑石粉和氧化锌或其混合物。 粉剂和喷雾剂除青蒿素-相关化合物外可包含，赋形剂诸如乳糖，滑石粉，硅酸，氢氧化铝，硅酸钙和聚酰胺粉剂，或这些物质的混合物。喷雾剂可另外包含常规的推进剂，诸如含氯氟烃和挥发性的未取代的碳氢化合物，诸如丁烷和丙烷。 适于非肠道施用的药物组合物可包括一或多种青蒿素-相关化合物与一或多种药用无菌等渗水性或非水的溶液，分散体，悬浮液，悬浮液或乳剂，或可仅仅在应用之前被重组到无菌的可注射溶液或分散体中的无菌粉剂，其可包含抗氧化剂，缓冲液，抑菌剂，赋予制剂与受体血液等渗的溶质或悬浮或增稠剂。可用于本发明药物组合物的合适的水性和非水性载体的实例包括水，乙醇，多元醇(诸如甘油，丙二醇，聚乙二醇等)，及其合适的混合物，植物油，诸如橄榄油，和可注射的有机酯，诸如油酸乙酯。可保持适当的流动性，例如通过利用涂敷材料，诸如卵磷脂，通过在为分散体情况下维持所需的颗粒大小，以及通过利用表面活性剂。 这些组合物也可以包含助剂，诸如防腐剂，润湿剂，乳化剂和分散剂。通过包含各种的抗菌的和抗真菌药物，例如，对羟苯甲酸，氯代丁醇，石炭酸山梨酸等来确保防止微生物的作用。其也可以包括将等渗的试剂，诸如糖，氯化钠等加入到组合物中。此外，可通过包含延缓吸收的试剂诸如单硬脂酸铝和凝胶来延长可注射药物剂型的吸收。 通过在可生物降解的聚合物诸如聚交酯-聚醣脂中形成青蒿素-相关化合物的微胶囊基体来产生可注射的存储形式。可取决于药物与聚合物的比率，所用的特定聚合物的特性，来控制药物释放的速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酐)。也通过在与身体组织相容的脂质体或微乳剂中捕获药物来制备储存可注射的制剂。 叶鞘内施用的青蒿素-相关化合物制剂可以是栓剂，其可通过混合本发明的一或多种化合物与一或多种合适的无刺激性的赋形剂或载体来制备，所述赋形剂或载体包括，例如，可可脂，聚乙二醇，栓剂蜡或水杨酸盐，且其在室温下为固态的，但是在体温时是液态的且，因此，将在直肠或阴道腔中熔化并释放活性化合物。任选地，这种适于阴道施用的制剂也包括含有本领域己知的合适载体的阴道栓剂，止血栓，乳剂，凝胶，糊剂，泡沫或喷雾剂。 在另一实施方案中，青蒿素或青蒿素衍生物化合物可在动物饲料中施用于动物。例如，这些化合物可添加至合适的饲料预混料中，然后以足以提供给动物治疗有效的量掺入到完全日料中。或者，包含青蒿素-相关化合物的中间体浓缩物或饲料添加剂可混合到饲料中。制备和施用这种饲料预混料和完全日料的方式描述在参考书(参见，例如，″Applied Animal Nutrition，″W.H.Freedman和CO.，San Francisco，U.S.A，1969或″Livestock Feeds and Feeding，″O和B books，Corvallis，Ore.，U.S.A，1977)中。 施用方法 在某些实施方案中，本发明的方法可单独应用。或者，本发明方法可以与其它的抗-病毒或抗-癌治疗方法(例如，施用抗-病毒或抗-癌药物，放射治疗，光照疗法或免疫治疗)结合应用来治疗或预防增生性子宫颈紊乱或病毒感染。例如，这种方法可用于预防癌，预防癌复发和外科手术后的癌转移，以及作为其它传统癌疗法的辅助手段。类似地，本发明的方法可以与其它的抗病毒疗法相结合。 因此，本发明的方法可以进一步包括已经在子宫颈癌或前癌细胞抑制中应用的任选的一或多种药物成分，用于增加临床的效果。这些药物包括，但不限于，白介素-2，5′-氟尿嘧啶，nedaplatin，氨甲喋呤，长春花碱，阿霉素，paclitaxel(紫杉酚)，顺氯氨铂，13-顺式视黄酸，pyrazoloacridine，以及vinorelbine。在各情况中合适的量将根据特定的药物进行变化，且容易为本领域技术人员所知或者容易地通过常规试验测定。氨甲喋呤，长春花碱，阿霉素，和顺氯氨铂。 在其它情况下，本发明的方法可以进一步包括已知其抗-病毒作用的任选的一或多种药物成分，用于增加临床的效果。这些药物包括，但不限于，5′-氟尿嘧啶，干扰素α，imiquimod，lamivudine，三氧化二砷，辣椒素，核苷类似物(例如，无环鸟苷)，和抗病毒疫苗。 青蒿素-相关化合物可体外，体内或离体应用来杀死或抑制感染细胞。对于体内应用而言，可将青蒿素-相关化合物与药用载体一起施用于人或其它的动物受试者，在靶组织位点集中充分的量来促进杀死或抑制靶细胞。 实施方式 本发明现在为一般地描述，通过参考下列的实施例可更容易被理解，其仅仅是用于说明本发明的某些方面和实施方案，而不意欲对本发明进行限制。 实施例1.青蒿素及其类似物对子宫颈癌细胞的作用 图2显示青蒿素对于子宫颈癌细胞是致死的。所示的子宫颈癌细胞系用25μM青蒿素(或对照溶剂)处理三天，然后用相差显微镜照相。正常的子宫颈细胞(HCX)在对青蒿素应答中显示出较小的形态变化，而子宫颈癌细胞成圆形并从组织培养平皿脱离。 图3表明子宫颈癌细胞，而不是正常子宫颈细胞，被青蒿素有效地杀死。剂量反应曲线显示了二氢青蒿素(DHA)对正常子宫颈细胞(HCX)和3种子宫颈癌细胞系(HeLa，SiHa，Caski)的活力的作用。在用25μM DHA处理3天内，宫颈癌细胞系显示出80％的活力损失。HeLa细胞是最敏感的，在25μM DHA时显示出95％的细胞死亡。 实施例2.二氢青蒿素(DHA)对病毒转化的淋巴样细胞系的作用。 申请人进行了评价青蒿素(DHA)对两种病毒转化的淋巴样细胞系的体外作用的研究。一种细胞系，称为MJ，是HTLV-I阳性的cutneousT细胞白血病系且另一个细胞系，称为Namalwa，是EBV阳性的伯基特氏肿瘤B细胞系。 细胞系培养在RPMI 1640培养基中，补充以10％胎儿牛血清和抗生素。为进行分析，在100μl体积的培养基中的100,000个细胞，被置入微-滴定孔中；添加另外100μl含有0μM，6.25μM，12.5μM，25μM，50μM，100μM和200μM浓度的DHA的培养基。阴性对照仅仅含有培养基。DHA原液(20mM)用于将药物稀释为0到200μM的浓度范围。所有的实验一式三份。37℃和5％CO2中温育不同的时间段后，在台盼蓝存在下通过血细胞计数器计算细胞数。活力表示为对照(无药物)的％。 如图4和图5所示，DHA在6.25μM浓度时杀死大约60％的两种细胞类型(MJ和Namalwa)。DHA可通过干扰病毒机制杀死转化的细胞。因此，青蒿素及其类似物(衍生物)可能具有抗病毒活性(包括抗HTLV和HIV的抗-逆转录病毒活性)。 引入作为参考 在这里提及的所有出版物和专利通过整体引入作为参考如同各单独的出版物或专利被具体和分别地引入作为参考。 虽然发明的具体实施方案已被论述，上述说明书是说明性的而并非限制。对于本领域技术人员来说，参考此说明书和下面的权利要求对本发明进行很多变化是显而易见的。本发明的全部范围应该通过权利要求与它们的同等物，和说明书，与这种变化一起来限定。 1.一种治疗患病毒感染的个体的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 2.根据权利要求1的方法，其中青蒿素-相关化合物是青蒿素。 3.根据权利要求1的方法，其中青蒿素-相关化合物是选自二氢青蒿素，蒿甲醚，蒿乙醚，青蒿琥酯，artelinic acid，以及二氢青蒿素丙基碳酸盐的青蒿素衍生物。 4.根据权利要求1的方法，其中病毒选自：人乳头瘤病毒(HPV)，I型人嗜T淋巴细胞病毒(HTLV-1)，疱疹病毒，类SV40病毒，肝炎病毒，人类免疫缺陷性病毒(HIV)，腺病毒和流感病毒。 5.根据权利要求4的方法，其中的疱疹病毒为埃-巴二氏病毒(EBV)，巨细胞病毒(CMV)或疱疹病毒8(HHV8)。 6.根据权利要求1的方法，其中青蒿素-相关化合物通过选自如下的途径进行施用：口服，局部施用，非肠道施用，叶鞘内施用，直肠施用，全身性施用，肌内施用以及静脉内施用。 7.根据权利要求1的方法，其中青蒿素-相关化合物与药用载体一起配制。 8.根据权利要求1的方法，其中青蒿素-相关化合物与抗-病毒药物一起施用。 9.根据权利要求8的方法，其中青蒿素-相关化合物和抗-病毒药物在同一制剂中。 10.治疗患增生性子宫颈紊乱个体的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 11.根据权利要求10的方法，其中青蒿素-相关化合物是青蒿素。 12.根据权利要求10的方法，其中青蒿素-相关化合物是选自二氢青蒿素，蒿甲醚，蒿乙醚，青蒿琥酯，artelinic acid，以及二氢青蒿素丙基碳酸盐的青蒿素衍生物。 13.根据权利要求10的方法，其中增生性子宫颈紊乱为子宫颈癌。 14.根据权利要求10的方法，其中增生性子宫颈紊乱为子宫颈非典型增生。 15.根据权利要求10的方法，其中青蒿素-相关化合物通过选自如下的途径进行施用：口服，局部施用，非肠道施用，叶鞘内施用，直肠施用，全身性施用，肌内施用以及静脉内施用。 16.根据权利要求10的方法，其中青蒿素-相关化合物与药用载体一起配制。 17.根据权利要求10的方法，其中青蒿素-相关化合物与选自如下的抗癌治疗相结合：施用抗-癌症药物，放射治疗，光照疗法和免疫治疗。 18.根据权利要求17的方法，其中青蒿素-相关化合物和抗-癌药物在同一制剂中。 19.根据权利要求10的方法，其中增生性子宫颈紊乱与乳头状瘤病毒感染有关。 20.一种杀死或抑制人乳头瘤病毒感染的细胞生长的方法，包括将细胞与足以杀死或抑制受感染细胞生长量的青蒿素-相关化合物接触。 21.根据权利要求20的方法，其中的细胞为人细胞。 22.根据权利要求21的方法，其中的人细胞选自：子宫颈癌细胞，肛门直肠鳞状癌细胞，皮肤鳞状细胞癌细胞，皮肤基底癌细胞，和口腔、咽、喉、头和颈、食管、气管和支气管的鳞状细胞癌细胞。 23.一种杀死或抑制被病毒感染的细胞生长的方法，包括将细胞与足以杀死或抑制受感染细胞生长的量的青蒿素-相关化合物接触。 24.根据权利要求的23方法，其中的病毒选自：HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒，HIV，腺病毒和流感病毒。 25.根据权利要求23的方法，其中的细胞为人细胞。 26.一种治疗人乳头瘤病毒感染的个体的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体，其中青蒿素-相关化合物选择性地杀死或抑制乳头状瘤病毒感染细胞的生长。 27.根据权利要求26的方法，其中的细胞为人细胞。 28.根据权利要求27的方法，其中的人细胞选自：子宫颈癌细胞，肛门直肠鳞状癌细胞，皮肤鳞状细胞癌细胞，皮肤基底癌细胞，和口腔、咽、喉、头和颈、食管、气管和支气管的鳞状细胞癌细胞。 29.一种治疗病毒感染个体的方法，包括将病毒感染细胞与治疗有效量的青蒿素-相关化合物接触，其中青蒿素-相关化合物选择性地杀死或抑制病毒感染细胞的生长。 30.根据权利要求的29方法，其中的病毒选自：HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒，HIV，腺病毒和流感病毒。 31.根据权利要求29的方法，其中的细胞为人细胞。 32.一种治疗个体由人乳头瘤病毒引起的病症的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 33.一种治疗个体由病毒引起的病症的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 34.根据权利要求的33方法，其中的病毒选自：HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒，HIV，腺病毒和流感病毒。 35.一种杀死或抑制个体的非-恶性HPV感染细胞的生长的方法，包括将细胞与足以杀死或抑制细胞生长的量的青蒿素-相关化合物接触。 36.根据权利要求35的方法，其中的细胞选自：喉乳头状瘤细胞，生殖器官乳头状瘤(疣)细胞，和常见的手足疣的细胞。 37.一种治疗患致癌病毒诱导肿瘤的个体的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 38.根据权利要求的37方法，其中的致癌病毒选自：HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒和腺病毒。 39.根据权利要求37的方法，其中的肿瘤在人或动物体中。 40.根据权利要求37的方法，其中的肿瘤是良性的或恶性的。 41.根据权利要求37的方法，其中的肿瘤选自：子宫颈瘤，在其它生殖器官部位的肿瘤，直肠瘤，口腔瘤，上呼吸道肿瘤，表皮肿瘤，喉的乳头状瘤，生殖器、手和足的疣，恶变前病变，间皮细胞瘤，骨肉瘤，腮腺瘤，鼻咽癌，何杰金氏病，淋巴瘤和肝细胞癌。 42.一种杀死或抑制个体的鳞状细胞性癌的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 43.根据权利要求42的方法，其中鳞状细胞性癌选自头和颈，口腔，咽，喉，气管和支气管的鳞状细胞性癌。 44.根据权利要求42的方法，其中的鳞状细胞性癌包括HPV感染。 45.一种杀死或抑制鳞状细胞性癌的方法，包括将癌瘤与足以杀死或抑制癌细胞生长量的青蒿素-相关化合物接触。 46.一种抑制个体病毒复制的方法，包括将治疗有效量的青蒿素-相关化合物施用于个体。 47.根据权利要求46的方法，其中的病毒选自：人乳头瘤病毒(HPV)，I型人嗜T淋巴细胞病毒(HTLV-46)，疱疹病毒，类SV40病毒，肝炎病毒，人类免疫缺陷性病毒(HIV)，腺病毒和流感病毒。 48.根据权利要求46的方法，其中的病毒为致癌病毒。 49.根据权利要求48的方法，其中的致癌病毒选自：HPV，HTLV-1，疱疹病毒，类SV40病毒，肝炎病毒和腺病毒。 50.根据权利要求46的方法，其中的病毒为非-致癌病毒。 51.根据权利要求50的方法，其中的非-致癌病毒选自：HIV和流感病毒。 52.一种抑制病毒复制的方法，包括将病毒与足以抑制病毒复制量的青蒿素-相关化合物接触。 53.一种含有一种青蒿素-相关化合物和一种不是青蒿素-相关化合物的第二治疗药物的药物组合物。 54.根据权利要求53的药物组合物，其中的第二治疗药物为一种化疗药物。 https://patents.google.com/patent/CN1758905A/zh?oq=CN1758905A青蒿素在治疗致癌病毒+诱导的肿瘤和治疗 Use of artemisinin for treating tumors induced by oncogenic viruses and for treating viral infections In certain aspects, the invention relates to methods of treating proliferative cervical disorders (such as cervical cancer and cervical dysplasia) and treating virus infections by administering artemisinin-related compounds. In certain aspects, the invention relates to methods of treating a tumor induced by an oncogenic virus, methods of killing or inhibiting a squamous cell carcinoma, and methods of inhibiting the replication of a virus, by administering artemisinin-related compounds. The application of arteannuin in inductive tumor of treatment oncogenic virus and treatment viral infection Background technology Although Papanicolaou (Pap) smear occurred, cervical cancer and preceding-cancer remain important health problem for the women, especially for the abundant women of monitoring of the U.S. and developing country.Worldwide, there are every year 250,000 women to die from this kind cancer.A kind of preceding or precancerous transformation of cancerating of cervical dysplasia may develop into cervical cancer as not treating then. The main hazard factor of cervical cancer is that human papillomavirus (HPV) infects.Papilloma virus infection causes 99% cervical cancers in women, and most anorectal squamous cell carcinomas.In addition, papillomavirus is found in the squamous cell cancerous cell of the squamous that is present in skin and basal cell carcinoma and oral cavity, pharynx and larynx.Papillomavirus also induces many benign tumors to comprise genitals's wart and common brothers' wart.They also induce child and adult's laryngeal papillomas.At present, not having effective pharmacotherapy to be used for the treatment of human papillomavirus (HPV) infects and inductive concurrent tumor. Clinical trial has been estimated injection of interferon in the papillomavirus focus and show to have certain effect.Yet viral infection recurs immediately after the withdrawal interferon.Other chemical compound such as 5-fluorouracil (5FU) and podophyllotoxin of local application is deleterious and killed cell that infect and normal simultaneously.These therapies are not target tumor cells specifically highly effectively and not.Nearest therapy is the use ion antiviral therapy (ICVT) of trial property, its be Henderson Marley exploitation (referring to, for example, WO01/49300, WO01/49242, WO01/66100, WO 02/24207).Because antiviral therapy does not have effect to papilloma virus infection, present clinical method is the vaccine of exploitation prevention infection.Vaccine provides very large hope, and zooscopy finds that they are high safeties.Yet, in 100 kinds of papillomaviruss of infected person, have 5 types of elicitor cervical cancers at least.Therefore be essential for this women's cancer exploitation of prevention polyvalent vaccine.Test is at present only estimated univalent vaccine and these tests of anti-HPV16 type and can not finished in several years.Must development express the technology of the capsid protein of other HPV type then, the method that it is not necessarily conventional. For many years, it is obstinate that virosis has been considered to antiviral chemotherapy optionally because the replicative cycle of virus also be considered to normal cellular metabolism very near and any inhibition virus breeding attempt also will kill cell that (or damage seriously) do not infected.Obviously, () method for example, cervical cancer, it is important public health problem to need disease such as viral infection that other treatment causes by viral infection and cancer. Summary of the invention The present invention relates to comprise human papillomavirus (HPV) by virus by using the treatment of arteannuin and/or artemisinin derivative, I type human T lymphotrophic virus (HTLV-1), herpesvirus are (for example, Epstein-Barr virus (EBV), cytomegalovirus (CMV)), the method for class SV40 virus, hepatitis virus, Human Immunodeficiency Viruses (HIV), adenovirus and the caused infection of influenza virus, and the treatment cervical disorder (for example, cervical cancer and cervical atypism hypertrophy) relevant with viral infection.The invention particularly relates to by using the method that arteannuin and/or artemisinin derivative (one or more derivant) selectivity killed or suppressed cell such as premalignant (precancerous) and the growth of virulent (carcinous) cell. In one embodiment, the invention provides a kind of method for the treatment of the individuality of ill poison infection.The individuality (patient or experimenter) that ill poison infects is treated by the arteannuin-related compound of administering therapeutic effective dose.The application uses in full, term " arteannuin-related compound " comprise arteannuin and artemisinin derivative (analog) the two.Viral infection may be caused by virus such as human papillomavirus (HPV), I type human T lymphotrophic virus, herpesvirus (for example Epstein-Barr virus (EBV), cytomegalovirus (CMV)), class SV40 virus, hepatitis virus, Human Immunodeficiency Viruses (HIV), adenovirus and influenza virus. Method of the present invention can be used for treating preceding and the malignant cervical focus of cancerating of human papillomavirus.In another embodiment, the invention provides the method that the individuality of proliferative cervical disorder is suffered from treatment.In these embodiments, the individuality of suffering from proliferative cervical disorder is treated by the arteannuin-related compound of administering therapeutic effective dose.Term described herein " proliferative cervical disorder " comprises cervical cancer and the preceding cancer (for example, cervical atypism hypertrophy) of cervix uteri.Proliferative cervical disorder may be relevant with parillomarvirus infections. Artemisinin derivative includes, but not limited to dihydroartemisinine, Artemether, arteether, artesunate, artelinic acid, and dihydroartemisinin propyl carbonate.Arteannuin-related compound can be applied to individuality by all means, and is for example oral, partly, non-intestinal, intravaginal, capapie, intramuscular, rectal administration or intravenous.In certain embodiments, arteannuin-related compound is prepared with pharmaceutical carrier. In certain embodiments, arteannuin or artemisinin derivative and other anti--virus or anti--cancer treatment ,-virus anti-or anti--cancer drug such as using, radiotherapy, light exposure treatment or immunization therapy combine.Anti--virus or anti--cancer agent can be used together in identical preparation or with isolating dosage form with the chemical compound of arteannuin-relevant and be strengthened treatment.In these embodiments, the chemical compound of arteannuin-relevant and other treatment can be used (side by side) simultaneously or be used in the different time (sequentially), if with can bring about the desired effect and in time fully near. In another embodiment, the invention provides and kill or suppress by the method for the cell of human papilloma virus infection, such as cervical cancer cell, anorectal squamous cancer cells, the cutaneous squamous cell carcinoma cell, skin substrate cancerous cell, and the squamous cell cancerous cell of oral cavity, pharynx and larynx.The squamous cell carcinoma of head and neck, esophagus, trachea and bronchus (wherein having some to contain HPV) also is potential target.Infected cell contacts with the arteannuin that kills or suppress growth of infected cells-relevant chemical compound of fully measuring.In these embodiments, the arteannuin-relevant chemical compound of treatment effective dose is applied to the individuality that needs treatment, for example, is used for the treatment of the squamous cell carcinoma of cervical cancer, anal orifice and rectal intestine cancer, flaky or basal cell skin cancer and oral cavity, pharynx and larynx.The chemical compound of arteannuin-relevant with fully kill or suppress the human papilloma virus infection cell growth amount by by be suitable for its be delivered to the approach that needs the treatment site used (for example, partly, in the sheath, rectum, oral, capapie, intramuscular or intravenous). In another embodiment, the invention provides and a kind ofly kill or suppress by oncogenic virus such as HPV HTLV-1, herpesvirus (for example, EBV or CMV), the method for the cell of class SV40 virus, hepatitis virus or adenovirus infection.In addition, HIV and influenza virus are potential targets.Infected cell contacts with the arteannuin-related compound that is enough to kill or suppress the amount of growth of infected cells.In these embodiments, send the amount of growth that is enough to kill or suppresses infected cell to the approach in the site that needs treatment by producing (being suitable for), arteannuin-the related compound of treatment effective dose is applied to and need by HPV, HTLV-1, herpesvirus (for example treats, EBV or CMV), class SV40 virus, hepatitis virus, HIV, the individuality of adenovirus or influenza infection. In another embodiment, the invention provides a kind of method of treatment human papillomavirus (HPV) infected individuals.In these embodiments, the arteannuin-related compound of treatment effective dose is applied to individuality by being suitable for sending the amount that is enough to kill or suppresses growth of infected cells to the approach in the site that needs to treat.These embodiments are useful to treating the various wherein individual diseases that infected by HPV, such as the cell of wherein being killed or suppress is cervical cancer cell, anorectal squamous cancer cells, the cutaneous squamous cell carcinoma cell, skin substrate cancerous cell and oral cavity, the disease of the squamous cell cancerous cell of pharynx and larynx.The squamous cell carcinoma of head and neck, esophagus, trachea and bronchus also is potential target. In another embodiment, the invention provides a kind of treatment by virus such as HPV, HTLV-1, herpesvirus (for example, EBV or CMV), class SV40 virus, hepatitis virus, HIV, the method for the individuality of adenovirus or influenza infection.In these embodiments, send the amount of growth that is enough to kill or suppresses infected cell to the approach in the site that needs treatment by producing (being suitable for), with the arteannuin-related compound of treatment effective dose be applied to need treatment by HPV, HTLV-1, herpesvirus (for example, EBV or CMV), class SV40 virus, hepatitis virus, HIV, the individuality of adenovirus or influenza infection. In another embodiment, the invention provides a kind of method for the treatment of in the individuality by the caused disease of human papillomavirus.In this embodiment, the arteannuin-related compound of treatment effective dose is applied to individuality by being suitable for sending the amount that is enough to kill or suppresses growth of infected cells to the approach that needs to treat the site.Can include, but not limited to cervical cancer by the disease that the inventive method treatment is caused by HPV, anorectal squamous cancer, the squamous cell carcinoma of skin or substrate cancer, and the squamous cell carcinoma of oral cavity, pharynx, larynx, head and neck, esophagus, trachea and bronchus. In another embodiment, the invention provides a kind of method for the treatment of the disease that causes by virus in the individuality.Cause disease by virus such as HPV, HTLV-1, herpesvirus (for example, EBV or CMV), class SV40 virus, hepatitis virus, HIV, adenovirus or influenza virus, can treat by method of the present invention.In this embodiment, the arteannuin-related compound of treatment effective dose is applied to individuality by being suitable for sending the amount that is enough to kill or suppresses growth of infected cells to the approach that needs to treat the site.Can include, but not limited to cancer by the disease of the inventive method treatment by what this virus caused, such as cervical cancer, anorectal squamous cancer, the squamous cell carcinoma of skin or substrate cancer, and the squamous cell carcinoma of oral cavity, pharynx, larynx.Virus with ability of the tumor of inducing the human or animal is called " carcinogenic " virus.That is to say their targeting oncogenic viruss.They include, but not limited to HPV, HTLV-1, herpesvirus (for example, EBV or CMV), class SV40 virus, hepatitis virus and adenovirus.Arteannuin-related compound can also be used to suppress non--oncogenic virus, such as HIV and influenza virus. In another embodiment, the invention provides a kind of treat individual non--method of malignant papilloma viral infection, such as benign tumor for example papilloma, phallic papilloma (wart) and common brothers' wart of larynx.Infected cell contacts with the arteannuin-related compound that is enough to kill or suppress the amount of growth of infected cells.For example, the arteannuin-related compound of treatment effective dose is applied to individuality by the approach that chemical compound is delivered to the target position (for example, larynx tissue, genitals's wart or common brothers' wart) that will kill or suppress infected cell. In another embodiment, the invention provides a kind of method for the treatment of the individuality of suffering from the inductive tumor of oncogenic virus.In this embodiment, the individuality of the inductive tumor of trouble oncogenic virus is applied the arteannuin-related compound of treatment effective dose.Oncogenic virus is that the collection of virus includes, but not limited to HPV, HTLV-1, herpesvirus (for example, EBV or CMV), class SV40 virus, hepatitis virus and adenovirus with it.Oncogenic virus-inductive tumor can be created in people or the non-human animal's body.In order to describe, the inductive tumor of papillomavirus is included in the pathological changes of following site: neck, other genital sites (for example, vagina, penis or the like), rectum, oral cavity, upper respiratory tract and epidermis.The tumor of class SV40 virus induction comprises people mesothelial cell's tumor, osteosarcoma and carcinoma of parotid gland.The inductive tumor of herpesvirus such as EBV comprises nasopharyngeal carcinoma and Hokdkin disease.The inductive tumor of HTLV-1 comprises lymphoma.The tumor of induced by hepatitis virus comprises hepatocarcinoma. In another embodiment, the invention provides a kind of method of killing or suppressing the squamous cell carcinoma of individuality, comprise treatment effective dose arteannuin-related compound is applied to individuality.Squamous cell carcinoma is selected from head and neck, oral cavity, pharynx, larynx, the squamous cell carcinoma of trachea and bronchus.Randomly, squamous cell carcinoma comprises that HPV infects. In another embodiment, the invention provides a kind of method of killing or suppressing squamous cell carcinoma, comprise with carcinoma be enough to kill or the arteannuin-related compound of the amount of anticancer growth contacts. In another embodiment, the invention provides and suppress the method that virus is duplicated in individuality, comprise that the arteannuin-related compound with the treatment effective dose is applied to individuality.Virus is selected from: human papillomavirus (HPV), I type human T lymphotrophic virus (HTLV-1), herpesvirus, class SV40 virus, hepatitis virus, Human Immunodeficiency Viruses (HIV), adenovirus and influenza virus.In some aspects, virus is oncogenic virus (for example, HPV, HTLV-1, herpesvirus, class SV40 virus, hepatitis virus or adenovirus).Aspect other, viral right and wrong-oncogenic virus (for example, HIV or influenza virus). In another embodiment, the invention provides the method that suppresses virus replication, comprise the arteannuin-related compound of virus with the amount that is enough to suppress virus replication contacted. In another embodiment, the invention provides and contain arteannuin-related compound and be not the pharmaceutical composition of second medicine of arteannuin-related compound.Preferably, second medicine is a chemotherapeutics. In all embodiments of treatment individual process, one or more arteannuin-related compound can be used (side by side) jointly or use in the different time (sequentially).In addition, arteannuin-related compound can be used with the chemical compound (non--artemisinin compounds) of another type or other types.Two types chemical compound can be used simultaneously or sequentially. Description of drawings Fig. 1 has shown arteannuin and biological activity metabolic derivative thereof, the structure of dihydroartemisinine (DHA). Fig. 2 has shown that arteannuin is lethal for cervical cancer cell. Fig. 3 has shown cervical cancer cell, rather than the normal uterus neck cell, is killed effectively by arteannuin. Fig. 4 has shown dihydroartemisinine (DHA) to EBV positive cells system, the Namalwa cell, effect. Fig. 5 has shown dihydroartemisinine (DHA) to the HTLV-I positive cell line, the MJ cell, effect. Detailed Description Of The Invention The present invention to a certain extent based on, the applicant has found that qinghaosu and/or qinghaosu spread out Biological (analog) killing or suppressing the HPV transformant (for example, cervix cancer is thin Born of the same parents) and by other type virus such as HTLV-1, herpesviral, class SV40 virus, liver Effective in the growth of the cell that scorching virus, HIV, adenovirus or influenza virus transform. As Here describe, the applicant has shown artemisinin kills cervical cancer cell rather than normal Cervical cell. Therefore, qinghaosu and derivative thereof can be used for treating virus infections and by The illness that this virus infections causes such as cervical cancer and cervix before cancer. Qinghaosu is present Be applied to the people as anti-malaria medicaments and can part and systemic administration. In certain embodiments, the invention provides the ill poison for the treatment of infects or the proliferative palace The method of the individuality of neck disorder. As applied here, (suffered from by the individuality of the inventive method treatment Person or experimenter) can be people or non--people animal. This kind is individual to be passed through the administering therapeutic effective dose Qinghaosu-related compound treat. Term described herein " qinghaosu-relevant chemical combination Thing " comprise qinghaosu and artemisinin derivative the two or analog. Artemisinin derivative or similar Thing can synthesize, and is semisynthetic or natural. In one aspect, method of the present invention can be used for treatment by HPV (HPV), I Type human T-cell lymphotropic virus (HTLV-1), herpesviral (for example, EBV or CMV), Class SV40 virus, hepatitis viruse, human immunodeficiency virus (HIV), adenovirus or influenza The method that the individuality that virus causes infects. This method can also be used for the treatment of by to qinghaosu or green grass or young crops The infection that other virus of artemisin derivative sensitivity such as dna virus and RNA virus cause. This virus may or may not can cause cancer. In yet another aspect, this method is that the individual proliferative cervical disorder for the treatment of is such as the uterus The method of neck cancer and cervix precancer (for example, cervical atypism hyperplasia). Described herein Term " proliferative cervical disorder " refers to have harmful or unusual cervical tissue Proliferation Characteristics Any cervix diseases/disorder. It will be appreciated by those skilled in the art that proliferative cervical is disorderly Disorderly may be relevant such as papilloma virus infection with virus infections. In one embodiment, the invention provides method kills or suppresses HPV Cell such as cervical cancer cell, anorectal squamous cancer cells, cutaneous squamous cell carcinoma cell, Skin substrate cancer cell and oral cavity, pharynx, larynx, head and neck, oesophagus, trachea and bronchus The method of the Growth of Cells of squamous cell carcinoma cell infection. Infected cell and be enough to kill or press down The qinghaosu of the amount of growth of infected cells processed-related compound contact. In these embodiments In, the qinghaosu-related compound for the treatment of effective dose is applied to the individuality that needs treatment, for example, The squamous cell carcinoma or the substrate cancer that are used for the treatment of cervix cancer, anorectal squamous cancer, skin, And the squamous cell carcinoma of oral cavity, pharynx, larynx, head and neck, oesophagus, trachea and bronchus. Blue or green Artemisin-related compound is by to be enough to kill or suppress the amount of human papilloma virus infection Growth of Cells (for example, partly, in the leaf sheath, rectum is executed by being suitable for its approach that is delivered to need treatment site With, oral, capapie, intramuscular or intravenous) use. In another embodiment, the invention provides kill or suppress by virus such as HPV, HTLV-1, herpesviral (for example, EBV or CMV), class SV40 virus, liver Scorching virus, HIV, the method for the Growth of Cells of adenovirus or influenza infection. Infected thin Born of the same parents contact with the qinghaosu-related compound that is enough to kill or suppress the amount of growth of infected cells. In these embodiments, send and be enough to kill or suppress infected cell by producing (being suitable for) The amount of growth is executed the qinghaosu-related compound for the treatment of effective dose to the approach that needs the treatment site Be used for to need treatment by HPV, HTLV-1, herpesviral (for example, EBV or CMV), class The individuality of SV40 virus, hepatitis viruse, HIV, adenovirus or influenza infection. In one embodiment, the invention provides a kind of HPV (HPV) for the treatment of The method of infected individuals. In this embodiment, the qinghaosu-related compound for the treatment of effective dose By by being suitable for sending the amount that is enough to kill or suppresses growth of infected cells to needing the treatment site Approach is applied to individuality. The illness that these embodiments are infected by HPV treating various individualities Being useful, is cervical cancer cell such as the cell of wherein being killed or suppress, anal orifice and rectal intestine Squamous cancer cell, cutaneous squamous cell carcinoma cell and substrate cancer cell, and oral cavity, pharynx and larynx Squamous cell cancer cell, or head and neck, oesophagus, tracheae, and bronchial squamous cell carcinoma The illness of cell. In another embodiment, the invention provides the treatment by virus such as HPV, HTLV-1, herpesviral (for example, EBV or CMV), class SV40 virus, hepatitis viruse, HIV, the method for the individuality of adenovirus or influenza infection. In these embodiments, logical Cross generation (being suitable for) and send the amount that is enough to kill or suppresses growth of infected cells to needing the treatment site Approach, with the qinghaosu-related compound for the treatment of effective dose be applied to need treatment by HPV, HTLV-1, herpesviral (for example, EBV or CMV), class SV40 virus, hepatitis viruse, HIV, the individuality of adenovirus or influenza infection. In one embodiment, the invention provides a kind of individuality for the treatment of by HPV The method of the illness that causes. In this embodiment, the qinghaosu for the treatment of effective dose-relevant chemical combination Thing is by being suitable for sending the amount that is enough to kill or suppresses growth of infected cells to needing the treatment site Approach is applied to individuality. Can comprise by the illness that the inventive method treatment is caused by HPV, But be not limited to, cervix cancer, anorectal squamous cancer, the squamous cell carcinoma of skin or substrate cancer, And the squamous cell carcinoma of oral cavity, pharynx, larynx, head and neck, oesophagus, trachea and bronchus. In another embodiment, the invention provides the disease that is caused by virus in the treatment individuality The method of disease. Described virus comprises HPV, HTLV-1, herpesviral (for example, EBV or CMV), class SV40 virus, hepatitis viruse, HIV, adenovirus and influenza virus. At this In the embodiment, the qinghaosu-related compound for the treatment of effective dose is enough to kill by being suitable for sending Or the amount that suppresses growth of infected cells is applied to individuality to the approach that needs the treatment site. Can pass through The illness that the inventive method treatment is caused by this virus includes, but are not limited to cervix cancer, anus Door rectum carcinoma squamosum, the squamous cell carcinoma of skin or substrate cancer, and the squama of oral cavity, pharynx, larynx The shape cell cancer. The squamous cell carcinoma of head and neck, oesophagus, trachea and bronchus also can be passed through This kind mode is treated. In another embodiment, the invention provides treatment individual non--pernicious mamillary Tumor virus infects, such as benign tumour, and for example papilloma of larynx, phallic papilloma (wart) And the method for common brothers' wart. Infected cell and be enough to kill or cytostatic The qinghaosu of amount-relevant compound contact. For example, the qinghaosu for the treatment of effective dose-relevantization Compound is by being delivered to compound target position (for example, the larynx group that will kill or suppress infected cell Knit reproductive organs wart or common brothers' wart) approach be applied to individuality. In another embodiment, the invention provides treatment suffers from by swelling that oncogenic virus is induced The method of the individuality of knurl. The individuality quilt of suffering from this embodiment, the tumour that oncogenic virus induces Qinghaosu-the related compound of administering therapeutic effective dose. Oncogenic virus is the specificity collection of virus Close, it includes, but not limited to HPV, HTLV-1, herpesviral (for example, EBV, CMV, HHV6, or HHV8), class SV40 virus, hepatitis viruse and adenovirus. Carcinogenic Virus-the tumour of inducing can be created among the human or animal. In order to describe papillomavirus The tumour of inducing is included in the pathology of following site: cervix, other genital sites (for example, vagina, penis etc.), rectum, oral cavity, the upper respiratory tract, and epidermis. Class SV40 The tumour of virus induction comprises people mesothelial cell's knurl, osteosarcoma and and carcinoma of parotid gland. Herpesviral is all Such as the knurl that EBV induces, comprise nasopharyngeal carcinoma and Hodgkin's disease. Another kind of herpesviral such as Human herpevirus 8 (HHV8) is also referred to as KSV, and the tumour of inducing comprises Kaposi sarcoma (Kaposi's sarcoma). Kaposi sarcoma is a kind of malignant disease and usually infects at HIV Find in the immunosuppressed patient. These tumours are usually expressed as cutaneous lesions. HTLV-1 induces Tumour comprise lymthoma. The tumour of induced by hepatitis virus comprises hepatocellular carcinoma. In another embodiment, the invention provides a kind of squamous of killing or suppressing individuality The method of cellular cancer comprises treatment effective dose qinghaosu-related compound is applied to individuality. Squamous cell carcinoma is selected from head and neck, the oral cavity, pharynx, larynx, the squamous of trachea and bronchus is thin Born of the same parents' property cancer. Randomly, squamous cell carcinoma comprises that HPV infects. In another embodiment, the invention provides a kind of squamous of killing or suppressing individuality The method of cellular cancer, comprise with the cancer knurl be enough to kill or the sweet wormwood of inhibition cancer cell increment Element-related compound contact. In another embodiment, the invention provides the individual body viral replication in of a kind of inhibition Method, comprise will the treatment effective dose qinghaosu-related compound be applied to individuality. The virus choosing From: HPV (HPV), I type human T-cell lymphotropic virus (HTLV-1), bleb Virus, class SV40 virus, hepatitis viruse, human immunodeficiency virus (HIV), adenovirus And influenza virus. In some aspects, virus be oncogenic virus (for example, HPV, HTLV-1, Herpesviral, class SV40 virus, hepatitis viruse or adenovirus). Aspect other, virus Right and wrong-oncogenic virus (for example, HIV or influenza virus). In another embodiment, the invention provides a kind of method that suppresses virus replication, Comprise virus is contacted with the qinghaosu-related compound that is enough to suppress the virus replication amount. In another embodiment, the invention provides a kind of a kind of qinghaosu-relevant of containing Compound and be not the pharmaceutical composition of second medicine of qinghaosu-related compound. Preferably, Second medicine is chemotherapeutics. Qinghaosu-related compound. Term " qinghaosu-related compound ", as here using, refer to qinghaosu and Artemisinin derivative the two or analog. Qinghaosu is a kind of naturally occurring material, by pure Change sweet wormwood, artemisia annua (Artemisia annua) obtains. Qinghaosu and analog thereof are to have The Sesquiterpene of peroxide bridge. The inventive method concentrates on the application of artemisinin derivative or analog.Analog of artemisinin with high water soluble is a dihydroartemisinine, Artemether, artesunate, arteether, dihydroartemisinin propyl carbonate and artelinic acid. The utmost point hypotoxicity that these chemical compounds have the mankind is a main benefit.Artesunate, for example, safety is that the twice and the toxicity of Artemether only is 1/50th of modal anti-malaria medicaments-chloroquinoline. Arteannuin-the related compound of treatment effective dose Method of the present invention comprises the arteannuin-related compound (one or more arteannuin-related compound) of administering therapeutic effective dose.Term " treatment effective dose " is meant to cause being subjected to virus such as HPV HTLV-1, herpesvirus, class SV40 virus, hepatitis virus, HIV, the amount of the cell death of adenovirus or influenza infection here.For example, the arteannuin-related compound of treatment effective dose kills or the cervical cancer inhibiting cell; The squamous of skin and basal cell carcinoma; The anal orifice and rectal intestine squamous cell cancer; Kaposi sarcoma, the growth of the cell of laryngeal papillomatosis and benign tumor such as genitals's wart and brothers' wart. Even arteannuin is a kind of comparatively safe medicine and also only produces very little side effect when high dose.Lasting 6 days oral 70mg/kg/ days dosage have been applied to people's malaria treatment.In addition, how effective analog and similar compound also are utilized.The higher efficacy of artemisinin action can realize by alternate manner.For example, arteannuin and haemachrome than and free iron have more activity (Hong etc., 1974, Mol.Biochem.Parasit., 63:121-128).Can utilize transferrins ferrum (referring to, for example, Stout etc., 1992, Biochim.Biophy.Res.Comm., 189:765-770) or carry haemachrome chemical compound hemoplexin (referring to, for example, Smith etc., 1988, Biochem.J., 256:941-950; Smith etc., 1990, Europ.J.CellBiol. 53:234-245) imports ferrum in the target cell.In the maximum tolerance scope to particular subject and medicine, it changes according to medicine, experimenter, disease condition and other factor the drug level of the interior concentration of iron of enhancing born of the same parents usually among the present invention.The dosage range in the ferrum from about 1 to about 100mg/kilogram experimenter body weight/sky is useful to these purposes usually. Arteannuin or artemisinin derivative compounds are applied to needs the individual dosage of treatment will be according to for example compound used therefor of each individuality, route of administration and individual health with the bodily form and different.For describing, every day, per kilogram of body weight can use about 0.1 to about 100mg.In further embodiment, per kilogram of body weight uses about 1 to about 90mg every day.Perhaps, per kilogram of body weight uses about 1 to about 75mg every day.Daily dose can maybe can be to be divided into multiple dose to use for a single dose. The artemisinin-related compound level can change so that obtain effectively to obtain in target cell (for example, virus infected cell or unusual cervical cell) site the amount that therapeutic interest or prevention are replied.Therefore, selected dosage level will depend on characteristic and the site of target cell, suppress or kill the purpose amount of the arteannuin-related compound of target cell needs, the characteristic of used arteannuin-related compound, route of administration and other factor.Local application or oral, for example, can be typically once a day or repeatedly, such as every day one to three time. Pharmaceutical composition In some embodiment of the inventive method, arteannuin-related compound is prepared with pharmaceutical carrier. Arteannuin or artemisinin derivative can be used separately or as a kind of component of pharmaceutical preparation (compositions).Chemical compound can be used with any people of being used for or veterinary suitable mode by preparation.In certain embodiments, the chemical compound that is included in the pharmaceutical preparation can itself be active, maybe can be a kind of prodrug.Term " prodrug " be meant chemical compound its, under physiological condition, be converted into the medicine of therapeutic activity. Wetting agent, emulsifying agent and lubricant, such as sodium lauryl sulphate and magnesium stearate, and stain, interleaving agent, coating agent, sweetener, spice and aromatic, antiseptic and antioxidant also can be present in the compositions. The preparation of arteannuin-related compound comprises those and is suitable for oral/nasal, the part, and non-intestinal is in the sheath and/or the preparation of rectal administration.Preparation can and can be prepared by the pharmaceutical field known method for unit dosage forms easily.The amount that can combine the active component that produces single dosage form with carrier will depend on the host of treatment, and the ad hoc fashion of using changes.The amount that can combine the active component that produces single dosage form with carrier normally produces the amount of the chemical compound of therapeutic effect. Prepare this preparation or method for compositions comprise in conjunction with arteannuin-related compound and carrier and, one or more auxiliary agent randomly.Usually, by in conjunction with arteannuin-related compound and liquid-carrier or ground solid carrier or the two, if necessary product shaping is prepared preparation then. Be suitable for oral arteannuin-related compound preparation and can be capsule, cachet, pill, tablet, lozenge (utilizes the seasoning base, be generally sucrose and arabic gum or Tragacanth), powder, the form of granule, or as solution in aqueous solution or the non-aqueous solution or suspension, perhaps oil-in-water or water in oil liquid emulsion, or as elixir or syrup, or (utilize inactive alkali, such as gel and glycerol as lozenge, or sucrose and arabic gum) and/or as collutory etc., the arteannuin-related compound as active component of each self-contained amount of pre-determining.Arteannuin-related compound also can be used as pill, and electuary or paste are used. Be used for oral solid dosage forms (capsule, tablet, pill, dragee, powder, granule etc.), arteannuin-related compound mixes with one or more pharmaceutical carrier, such as sodium citrate or dicalcium phosphate, and/or following substances arbitrarily: (1) filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binding agent, such as, for example, carboxymethyl cellulose, alginate, gel, polyvinyl pyrrolidone, sucrose, and/or arabic gum; (3) wetting agent is such as glycerol; (4) disintegrating agent, such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, specific silicate, and sodium carbonate; (5) solution blocker is such as paraffin; (6) absorption enhancer is such as quaternary ammonium compound; (7) wetting agent, such as, for example, spermol and glyceryl monostearate; (8) adsorbent is such as Kaolin and Bentonite; (9) lubricant, such as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, and composition thereof; (10) stain.Be capsule, when tablet and pill, pharmaceutical composition also can comprise buffer agent.The solid composite of similar type also can be used as and utilizes lactose or lactose and high molecular weight polyethylene glycol etc. as the filler in the soft and hard-filled capsules of excipient. The liquid oral dosage form of arteannuin-related compound comprises medicinal Emulsion, microemulsion, solution, suspension, syrup and elixir.Except active component, liquid dosage form can comprise the inert diluent that use usually this area, such as water or other solvent, solubilizing agent and emulsifying agent, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, the 3-butanediol, oils (especially, Semen Gossypii, Semen arachidis hypogaeae, corn, embryo, Fructus Canarii albi, the oil of Semen Ricini and Semen Sesami), glycerol, tetrahydrofurfuryl carbinol, the fatty acid ester of Polyethylene Glycol and sorbitan, and composition thereof.Except that inert diluent, Orally administered composition can also comprise auxiliary agent such as wetting agent, emulsifying and suspending agent, sweetener, flavoring agent, pigment, spice and antiseptic. Suspension except that reactive compound, can comprise suspending agent such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan ester, and microcrystalline Cellulose, inclined to one side aluminium hydroxide, Bentonite, agar and Tragacanth, and composition thereof. Especially, method of the present invention can be locally applied to such as cervix uteri and supravaginal skin or mucosa.Maximum opportunity that directly is delivered to tumor and the minimum chance of inducing side effect are provided like this.Topical formulations can further comprise one or more known effective medicine as skin or horny layer penetration enhancers.These examples are 2-Pyrrolidone, N-N-methyl-2-2-pyrrolidone N-, dimethyl acetylamide, dimethyl formamide, propylene glycol, methyl or isopropyl alcohol, dimethyl sulfoxine, and azone.The reagent that can further comprise other prepares the used for cosmetic preparation.Example is a fat, wax, oils, dyestuff, spice, antiseptic, stabilizing agent and surfactant.The keratolysis medicine such as known in the art also can be comprised in.Example is salicylic acid and sulfur. The dosage form of part or transdermal administration arteannuin-related compound comprises powder, spray, unguentum, paste, Emulsion, detergent, gel, solution, ointment and inhalant.Reactive compound can be under aseptic condition and pharmaceutical carrier, the antiseptic that needs arbitrarily, buffer, the maybe propellants that may need.Unguentum, paste, Emulsion and gel can comprise excipient except that arteannuin-related compound, such as animal and plant fat, oils, wax, paraffin, starch, Tragacanth, cellulose derivative, Polyethylene Glycol, silicones, Bentonite, silicic acid, Pulvis Talci and zinc oxide or its mixture. Powder and spray can comprise except that arteannuin-related compound, and excipient is such as lactose, Pulvis Talci, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or the mixture of these materials.Spray can comprise conventional propellant in addition, such as chlorofluorocarbon and volatile unsubstituted Hydrocarbon, such as butane and propane. Be suitable for the solution that pharmaceutical composition that non-intestinal uses can comprise one or more arteannuin-related compound and one or more medicinal sterile isotonic water or non-water, dispersion, suspension, suspension or Emulsion, or can only before using, be recombined to aseptic Injectable solution or the sterile powder in the dispersion, it can comprise antioxidant, buffer, antibacterial is given preparation and the isoosmotic solute of receptor blood or suspension or thickening agent.Can be used for the suitable aqueous of pharmaceutical composition of the present invention and the example of non-aqueous carrier and comprise water, ethanol, polyhydric alcohol (such as glycerol, propylene glycol, Polyethylene Glycol etc.), and suitable mixture, vegetable oil, such as olive oil and injectable organic ester, such as ethyl oleate.Can keep suitable flowability, for example by utilizing coating material, such as lecithin, by for keeping required granular size under the dispersion situation, and by utilizing surfactant. These compositionss also can comprise auxiliary agent, such as antiseptic, and wetting agent, emulsifying agent and dispersant.By comprising various antimicrobial and antifungal drugs, for example, p-hydroxybenzoic acid, chlorobutanol, carbolic acid sorbic acid wait guarantees to prevent action of microorganisms.It can comprise that also such as sugar, sodium chloride etc. join in the compositions with isoosmotic reagent.In addition, the absorption that reagent such as aluminum monostearate that can be by comprising delayed absorption and gel prolong the injectable drug dosage form. Produce injectable file layout by the microcapsule matrix that in biodegradable polymer such as polyactide-poly-candy fat, forms arteannuin-related compound.Can be depending on medicine and polymer ratio, the characteristic of used particular polymers is come the speed of control drug release.The example of other biodegradable polymer comprises poly-(ortho esters) and poly-(acid anhydride).Also prepare the injectable preparation of storage by in liposome compatible or microemulsion, catching medicine with bodily tissue. The arteannuin of using in the sheath-related compound preparation can be a suppository, it can be by mixing one or more chemical compound of the present invention and one or more suitable non-irritating excipient or carrier prepares, described excipient or carrier comprise, for example, and cocoa butter, Polyethylene Glycol, suppository wax or Salicylate, and it at room temperature is solid-state, but when body temperature be liquid and, therefore, will in rectum or vaginal canal, melt also release of active compounds.Randomly, this preparation that is suitable for vaginal application also comprises vaginal suppository, tampon, Emulsion, gel, paste, foam or the spray that contains oneself suitable carrier known of this area. In another embodiment, arteannuin or artemisinin derivative compounds can be applied to animal in animal feed.For example, these chemical compounds can be added in the suitable feed pre-mixing material, are incorporated in the complete ration to be enough to the offering effective amount of treatment of animals then.Perhaps, intermediate concentrate or the feed additive that comprises arteannuin-related compound can be mixed in the feedstuff.Preparation and use this feed pre-mixing material and fully the mode of ration be described in handbook (referring to, for example, " Applied Animal Nutrition, " W.H.Freedman and CO., San Francisco, U.S.A, 1969 or " Livestock Feeds and Feeding, " O and B books, Corvallis, Ore., U.S.A, 1977) in. Application process In certain embodiments, method of the present invention can be used separately.Perhaps, the inventive method can with other anti--virus or anti--method of therapy for cancer (for example, using anti--virus or anti--cancer drug, radiotherapy, Light therapy or immunization therapy) in conjunction with being used for treatment or prevention proliferative cervical disorder or viral infection.For example, this method can be used for pre-anti-cancer, the cancerometastasis behind prevention cancer recurrence and the surgical operation, and as the supplementary means of other traditional cancer therapy.Similarly, method of the present invention can combine with other antiviral therapy. Therefore, method of the present invention may further include one or more optional ingredient of having used in cervical cancer or the inhibition of preceding cancerous cell, be used to increase clinical effect.These medicines include, but are not limited to, interleukin-2,5 '-fluorouracil, nedaplatin, methotrexate, vincaleucoblastine, amycin, paclitaxel (taxol), cisplatin, 13-cis-retinoic acid, pyrazoloacridine, and vinorelbine.Amount suitable in each situation will change according to specific medicine, and easily known to those skilled in the art or easily measure by routine test.Methotrexate, vincaleucoblastine, amycin, and cisplatin. In other cases, method of the present invention may further include one or more optional ingredient of known its anti--virus function, is used to increase clinical effect.These medicines include, but are not limited to, 5 '-fluorouracil, interferon-ALPHA, imiquimod, lamivudine, arsenic trioxide, capsaicin, nucleoside analog (for example, acycloguanosine), and antiviral vaccine. Arteannuin-related compound can be external, in the body or exsomatize and should be used for killing or suppressing infection cell.For using in the body, arteannuin-related compound can be applied to people or other animal subjects with pharmaceutical carrier, concentrating fully in target tissue site, amount promotes to kill or suppress target cell. Embodiment For usually describing, by can understanding by easier quilt with reference to following embodiment, it is only used for illustrating some aspect of the present invention and embodiment, and is not intended to limit the invention now in the present invention. Embodiment 1. arteannuin and analog thereof are to the effect of cervical cancer cell Fig. 2 shows that arteannuin is lethal for cervical cancer cell.Shown cervical cancer cell system handled three days with 25 μ M arteannuin (or control solvent), took a picture with phase contrast microscope then.Normal cervical cell (HCX) demonstrates less metamorphosis in arteannuin is replied, and cervical cancer cell is circular and break away from from tissue culture's plate. Fig. 3 shows cervical cancer cell, rather than the normal uterus neck cell, is killed effectively by arteannuin.Dose-effect curve has shown that dihydroartemisinine (DHA) is to normal cervical cell (HCX) and 3 seed cervical cancer tumer lines (HeLa, SiHa, the effect of vigor Caski).Handling in 3 days with 25 μ M DHA, cervical cancer tumer line demonstrates 80% vigor loss.The HeLa cell is the most responsive, demonstrates 95% cell death when 25 μ M DHA. Embodiment 2. dihydroartemisinines (DHA) are to the effect of the lymphoid cell line of virus conversion. The applicant has carried out the research of evaluation arteannuin (DHA) to the interaction in vitro of the lymphoid cell line of two kinds of virus conversions.A kind of cell line is called MJ, is HTLV-I male cutneousT chronic myeloid leukemia system and another cell line, is called Namalwa, is the male Burkitt's tumor B cell line of EBV. Cell line is cultivated in RPMI 1640 culture medium, replenishes with 10% fetal bovine serum and antibiotic.For analyzing, 100,000 cells in the culture medium of 100 μ l volumes are placed in little-titration hole; Add other 100 μ l and contain 0 μ M, 6.25 μ M, 12.5 μ M, 25 μ M, 50 μ M, the culture medium of the DHA of 100 μ M and 200 μ M concentration.Negative control only contains culture medium.It is the concentration range of 0 to 200 μ M that DHA stock solution (20mM) is used for drug dilution.All experiments are triplicate.37 ℃ and 5%CO 2In incubation after different time period, in the presence of trypan blue by hematimeter calculating cell number.Vigor is expressed as the % of contrast (no medicine). As shown in Figure 4 and Figure 5, DHA kills two kinds of cell types (MJ and Namalwa) of about 60% when 6.25 μ M concentration.DHA can kill cell transformed by viral interference mechanism.Therefore, arteannuin and analog thereof (derivant) may have antiviral activity (the anti-retroviral virus activity that comprises anti-HTLV and HIV). Be incorporated herein by reference All publications here mentioned and patent are incorporated herein by reference as each independent publication or patent by integral body and specifically and respectively are incorporated herein by reference. Though the specific embodiments of invention is discussed, above-mentioned description is illustrative and also unrestricted.To those skilled in the art, it is conspicuous with reference to this description and following claim the present invention much being changed.Four corner of the present invention should be by claim and their coordinate, and description, comes together to limit with this variation. 1. the method for the individuality of the ill poison infection of treatment comprises that the arteannuin-related compound that will treat effective dose is applied to individuality. 2. according to the process of claim 1 wherein that arteannuin-related compound is an arteannuin. 3. according to the process of claim 1 wherein that arteannuin-related compound is to be selected from dihydroartemisinine, Artemether, arteether, artesunate, artelinic acid, and the artemisinin derivative of dihydroartemisinin propyl carbonate. 4. according to the process of claim 1 wherein that virus is selected from: human papillomavirus (HPV), I type human T lymphotrophic virus (HTLV-1), herpesvirus, class SV40 virus, hepatitis virus, Human Immunodeficiency Viruses (HIV), adenovirus and influenza virus. 5. according to the method for claim 4, herpesvirus wherein is Epstein-Barr virus (EBV), cytomegalovirus (CMV) or herpesvirus 8 (HHV8). 6. according to the process of claim 1 wherein that arteannuin-related compound uses by being selected from following approach: oral, local application, non-intestinal is used, uses in the sheath, rectal administration, general is used, and intramuscular administration and intravenous are used. 7. according to the process of claim 1 wherein that arteannuin-related compound prepares with pharmaceutical carrier. 8. according to the process of claim 1 wherein that arteannuin-related compound uses with anti--virus drugs. 9. method according to Claim 8, wherein arteannuin-related compound and anti--virus drugs are in same preparation. 10. the method for proliferative cervical disorder individuality is suffered from treatment, comprises that the arteannuin-related compound with the treatment effective dose is applied to individuality. 11. according to the method for claim 10, wherein arteannuin-related compound is an arteannuin. 12. according to the method for claim 10, wherein arteannuin-related compound is to be selected from dihydroartemisinine, Artemether, arteether, artesunate, artelinic acid, and the artemisinin derivative of dihydroartemisinin propyl carbonate. 13. according to the method for claim 10, wherein proliferative cervical disorder is a cervical cancer. 14. according to the method for claim 10, wherein proliferative cervical disorder is the cervical atypism hypertrophy. 15. according to the method for claim 10, wherein arteannuin-related compound is used by being selected from following approach: oral, local application, non-intestinal is used, uses in the sheath, rectal administration, general is used, and intramuscular administration and intravenous are used. 16. according to the method for claim 10, wherein arteannuin-related compound is prepared with pharmaceutical carrier. 17. according to the method for claim 10, wherein arteannuin-related compound be selected from following anticancer therapy and combine: use anti--cancer drug, radiotherapy, Light therapy and immunization therapy. 18. according to the method for claim 17, wherein arteannuin-related compound and anti--cancer drug are in same preparation. 19. according to the method for claim 10, wherein proliferative cervical disorder is relevant with papilloma virus infection. 20. the method for a cell growth of killing or suppressing human papilloma virus infection comprises cell is contacted with the arteannuin-related compound that is enough to kill or suppress the growth of infected cells amount. 21. according to the method for claim 20, cell behaviour cell wherein. 22. method according to claim 21, people's cell wherein is selected from: cervical cancer cell, anorectal squamous cancer cells, cutaneous squamous cell carcinoma cell, the squamous cell cancerous cell of skin substrate cancerous cell and oral cavity, pharynx, larynx, head and neck, esophagus, trachea and bronchus. 23. one kind is killed or suppresses by the method for the cell of viral infection growth, comprises cell is contacted with the arteannuin-related compound that is enough to kill or suppress the amount of growth of infected cells. 24. according to 23 methods of claim, virus wherein is selected from: HPV, HTLV-1, herpesvirus, class SV40 virus, hepatitis virus, HIV, adenovirus and influenza virus. 25. according to the method for claim 23, cell behaviour cell wherein. 26. a method for the treatment of the individuality of human papilloma virus infection comprises that the arteannuin-related compound with the treatment effective dose is applied to individuality, wherein arteannuin-related compound optionally kills or suppresses the growth of papilloma virus infection cell. 27. according to the method for claim 26, cell behaviour cell wherein. 28. method according to claim 27, people's cell wherein is selected from: cervical cancer cell, anorectal squamous cancer cells, cutaneous squamous cell carcinoma cell, the squamous cell cancerous cell of skin substrate cancerous cell and oral cavity, pharynx, larynx, head and neck, esophagus, trachea and bronchus. 29. a method for the treatment of the viral infection individuality comprises the arteannuin-related compound of virus infected cell with the treatment effective dose contacted that wherein arteannuin-related compound optionally kills or suppress the growth of virus infected cell. 30. according to 29 methods of claim, virus wherein is selected from: HPV, HTLV-1, herpesvirus, class SV40 virus, hepatitis virus, HIV, adenovirus and influenza virus. 31. according to the method for claim 29, cell behaviour cell wherein. 32. a method for the treatment of the individual disease that causes by the human papillomavirus, comprise will the treatment effective dose arteannuin-related compound be applied to individuality. 33. a method for the treatment of the individual disease that causes by virus, comprise will the treatment effective dose arteannuin-related compound be applied to individuality. 34. according to 33 methods of claim, virus wherein is selected from: HPV, HTLV-1, herpesvirus, class SV40 virus, hepatitis virus, HIV, adenovirus and influenza virus. 35. a method of killing or suppressing the growth of individual non--pernicious HPV infection cell, comprise with cell be enough to kill or the arteannuin-related compound of cytostatic amount contacts. 36. according to the method for claim 35, cell wherein is selected from: laryngeal papillomatosis cell, the cell of genitals papilloma (wart) cell and common brothers' wart. 37. a method for the treatment of the individuality of suffering from the oncogenic virus induced tumor comprises that the arteannuin-related compound with the treatment effective dose is applied to individuality. 38. according to 37 methods of claim, oncogenic virus wherein is selected from: HPV, HTLV-1, herpesvirus, class SV40 virus, hepatitis virus and adenovirus. 39. according to the method for claim 37, tumor wherein is in human or animal body. 40. according to the method for claim 37, tumor wherein is benign or virulent. 41. according to the method for claim 37, tumor wherein is selected from: tumor of cervix, tumor at other genitals position, the rectum tumor, oral cancer, upper respiratory tract tumor, the epidermis tumor, the papilloma of larynx, the wart of genitals, hands and foot, the preceding pathological changes that cancerates, mesothelial cell's tumor, osteosarcoma, carcinoma of parotid gland, nasopharyngeal carcinoma, Hokdkin disease, lymphoma and hepatocarcinoma. 42. a method of killing or suppressing individual squamous cell carcinoma comprises that the arteannuin-related compound with the treatment effective dose is applied to individuality. 43. according to the method for claim 42, wherein squamous cell carcinoma is selected from head and neck, oral cavity, pharynx, larynx, the squamous cell carcinoma of trachea and bronchus. 44. according to the method for claim 42, squamous cell carcinoma wherein comprises that HPV infects. 45. the method for killing or suppressing squamous cell carcinoma, comprise with carcinoma be enough to kill or the arteannuin-related compound of anticancer increment contacts. 46. a method that suppresses individual virus replication comprises that the arteannuin-related compound with the treatment effective dose is applied to individuality. 47. according to the method for claim 46, virus wherein is selected from: human papillomavirus (HPV), I type human T lymphotrophic virus (HTLV-46), herpesvirus, class SV40 virus, hepatitis virus, Human Immunodeficiency Viruses (HIV), adenovirus and influenza virus. 48. according to the method for claim 46, virus wherein is oncogenic virus. 49. according to the method for claim 48, oncogenic virus wherein is selected from: HPV, HTLV-1, herpesvirus, class SV40 virus, hepatitis virus and adenovirus. 50. according to the method for claim 46, virus wherein is non--oncogenic virus. 51. according to the method for claim 50, non--oncogenic virus wherein is selected from: HIV and influenza virus. 52. a method that suppresses virus replication comprises virus is contacted with the arteannuin-related compound that is enough to suppress the virus replication amount. 53. one kind contain a kind of arteannuin-related compound and a kind of be not the pharmaceutical composition of second medicine of arteannuin-related compound. 54. according to the pharmaceutical composition of claim 53, second medicine wherein is a kind of chemotherapeutics. https://patents.google.com/patent/CN1758905A/en?oq=CN1758905A青蒿素在治疗致癌病毒+诱导的肿瘤和治疗

CN1561994A治疗类风湿性关节炎和免疫性疾病的含青蒿提取物药物组合物---双氢青蒿素，青蒿琥酯，蒿甲醚，蒿甲醚等)的药物组合物 CN1561994A Medicinal composition containing Artemisia extract for treating rheumatoid arthritis and immune-related diseases---a medicinal composition comprising dihydroartemisinin, artemether, arteether, etc 治疗类风湿性关节炎和免疫性疾病的含青蒿提取物药物组合物 本发明涉及一种用于治疗类风湿性关节类和自身免疫性疾病伴关节炎症状的药物，治疗类风湿性关节类和免疫性疾病的含青蒿提取物(双氢青蒿素，青蒿琥酯，蒿甲醚，蒿甲醚等)的药物组合物。该组合物中青蒿素或青蒿素衍生物的含量为1~99％。该药物组合物含有青蒿素或青蒿素衍生物的有效剂量为20~200mg/日。可以为任何常用的药物形式，如：固体制剂，流体，或膏状等。 治疗类风湿性关节类和免疫性疾病的含青蒿提取物药物组合物 技术领域： 本发明涉及一种用于治疗类风湿性关节类和自身免疫性疾病伴关节炎症状的药物，特别是用于治疗类风湿性关节炎和自身免疫性疾病伴关节炎症状的含有青蒿素或青蒿素衍生物(双氢青蒿素，青蒿琥酯，蒿甲醚，蒿甲醚等)的药物组合物。 背景技术： 类风湿性关节炎(以下简称RA)是自身免疫性疾病的一种，是一种世界范围内的原因不明的全身性自身免疫性疾病，其发病率0.4～1％，其主要特征是以慢性，对称性及末梢关节弥漫性滑膜炎、末期出现各种程度的进行性关节破坏，变性及关节功能丧失，严重地影响着患者的劳动及生活能力，给社会造成巨大的负担。而其他的自身免疫性疾病也通常伴有相类似的关节症状，对该类疾病的治疗尚没有特效药物，多采用非甾类消炎镇痛剂及免疫抑制剂治疗，不但不能完全控制病情，且有较大的毒付作用。 近年来中医药对类风湿性关节炎及自身免疫性疾病研究受到国内外专家及患者的重视，开发了一些治疗RA的药物，例如：中国专利申请02137816公开了一种RA的治疗药物组合物，其中含有中药成份：赤茯苓12％，当归12％，地肤子12％，五加皮10％，枇杷叶10％，海桐皮9％，白薇9％，黄芩8％，川黄连7％，广藿香6％，木通5％。再如中国专利申请01117709公开了一种治疗类风湿性关节炎的药物，它是以何首乌、党参、当归、黄芪、黄精、白术、狗脊、全蝎、乌梢蛇、地龙、蚂蚁、丹参、桑枝、桂枝、苍术、羌活、独活、防风、秦艽、桑寄生、杜仲、川牛膝、黄柏、千年健、钻地枫、乳香、没药、青风藤、天南星、鸡血藤、桑葚子、元胡、川芎、枣仁、知母、茯苓、草乌、川乌、仙灵脾、红花、续断、丹皮、忍冬藤、赤芍、薏苡仁、海桐皮、络石藤、甘草为原料，根据每味中药的不同特性，针对类风湿性关节炎的不同症状，按比例配制成基本药剂、寒甚或热甚者相适应的药剂。 上述这些中药组合物一般都是中药的常规用药，使用时医生还必须根据中医辨证论治的原则按照患者的情况进行组方；也有一些中成药成分较多，制备复杂，实际应用还不能完全满足临床医生及患者的需要。 青蒿素是我国学者自主开发且被国际公认的中药提取物，青蒿素及其衍生物是一类有效的抗疟药和抗疟药物组合物。系从我国中药黄花蒿中提取的有效单体成分，已被世界卫生组织推荐为抗疟疾新药。近年来随着国家及各研究单位对青蒿素研究的继续深入，开发了一些以青蒿素为主要成分的新的复方制剂的抗疟剂，如：中国专利申请00113134公开了一种治疗疟疾的复方制剂；同时还不断发现了在其他新领域中的应用，如：中国专利申请99103346公开了一种治疗红斑狼疮和光敏性疾病的含双氢青蒿素的药物组合物等。现有文献报道可以将青蒿油搽剂应用于癣病的治疗，通过对青蒿素的体外抗真菌作用的研究，证实青蒿素的抗菌普及作用与目前常用的广谱抗真菌药酮康唑相似，且对某些真菌的作用强于酮康唑，即其抗真菌作用效果良好。 发明内容： 本发明的目的，是提供一种安全有效的治疗类风湿性关节类和免疫性疾病的含青蒿提取物药物组合物。 本发明的技术方案如下。 一种治疗类风湿性关节炎和免疫性疾病的含青蒿提取物药物组合物，为含有有效剂量的青蒿素或青蒿素衍生物的药物组合物。 所述的蒿素衍生物包括双氢青蒿素，青蒿琥酯，蒿甲醚和蒿甲醚。 该组合物中青蒿素或青蒿素衍生物的含量为1～99％。 所述的药物组合物含有青蒿素或青蒿素衍生物的有效剂量为20～200mg/日。 该药物组合物可以单独使用，也可以与现有治疗RA和自身免疫性疾病的其他药物联合使用。 所述的药物组合物为可以是任何常用的药物形式，如：固体制剂，流体，或膏状等。 本发明是基于这样的事实完成的。本案发明人在长期的临床治疗RA和自身免疫性疾病及各种关节炎的过程中发现中药青蒿具有较好的清热解毒，消肿，止痛功效。而青蒿素又是我国自70年代开始研究的中药一类新药，为此我们在免疫和自身免疫性疾病方面对青蒿素或其衍生物以及含青蒿素的药物组合物进行了研究，表明青蒿素在具有免疫调节的基础上，从药效学及临床研究均证明青蒿素或青蒿素衍生物对RA和自身免疫性疾病伴关节症状的具有较好的疗效，具有消炎、镇痛、免疫调节的疗效。且具有见效快，无明显的毒副作用的优势。 本发明的药物组合物适用于风湿性关节炎和自身免疫性疾病伴关节表现的病症。 本发明的药物组合物可以是任何常用的药物形式，可以为固体制剂，如：片剂、胶剂、栓剂、粉剂、颗粒剂、霜剂等；也可以为流体制剂，如：口服液、注射液；或膏状等。 本发明的制备方法，为本领域普通技术人员所公知的常用制备方法。 按照本发明的药物组合物，优先是将其制成片剂或胶囊，每一片剂或胶囊含有10-100mg的青蒿素或青蒿素衍生物。 附图说明： 图1为药物组合物对大鼠佐剂性关节炎的影响(右后足) 图2药物组合物对大鼠(左后足)佐剂性关节炎的影响 具体实施方式： 本发明的药物组合物一般为口服给药，也可以其他途径给药，如治疗RA和自身免疫性疾病伴关节症状的可以使用外用制剂。用量一般为1-10mg/Kg体重/天，成年患者的用量优选为每人每天20-200mg。 本发明使用的青蒿素或青蒿素衍生物(双氢青蒿素，青蒿琥酯，蒿甲醚，蒿乙醚)的制备工艺是已知的，有关其制备方法可见于诸文献报道。 通过以下试验可以对本发明进行更进一步的说明。但应该说明的是本发明的实验内容只用于说明本发明，而不是限制本发明。 本发明的药物组合物对试验性一般关节炎及免疫性关节炎的影响 实验材料 动物：①健康Wistar大白鼠，体重130±20g、180±20g和150±20g，雌雄均有。合格证编号依次为：SCXK(京)2002-0003、SCXK(京)2002-0003和SCK(京)2002-0006；②健康昆明种小白鼠，体重20±20g和13g±2g，雌雄均有。合格证编号均为SCXK(京)2002-001。均由我所动物室供给。 主要药物： ①含有青蒿提取物包括青蒿素及青蒿素衍生物(双氢青蒿素，青蒿琥酯，蒿甲醚，蒿甲醚等)的药物组合物。以下简称[药物组合物]。 ②强的松(5mg/片)，东北制药总厂生产，批号20031113； ③角叉菜胶，美国Sigma公司产品，批号87F-0463； ④Freund’s完全佐剂，用卫生部北京生物制品研究所提供的卡介苗(批号20030115)制备，内含结核杆菌0.7mg/0.07ml。 仪器：鼠足容积测定仪，自制。 方法与结果 一、对大鼠角叉菜胶性足肿胀的影响 参照大鼠足趾浮肿毛细血管放大测量法，取大鼠72只，体重130±20g，雌雄各半，随机均分为五组，即空白对照组和模型组(给与给药大剂量组相当量的蒸馏水)，药物组合物大剂量组(54.0mg/Kg)、中剂量组(27.0mg/Kg)和小剂量组(5.4mg/Kg)及阳性对照组(强的松5.0mg/Kg)。均为口服灌胃给药，每日一次，连续14天。于末次给药后1小时测定鼠足容积(ml)，即将1％角叉菜胶生理盐水0.1ml注入大鼠左后肢足跖皮下致炎，分别于注入后1小时、2小时、4小时、及6及小时，用鼠足容积测定仪测定鼠足容积，计算出肿胀值，用T检验比较各时间给药组与对照组的差异情况。结果见表1。 表1.药物组合物对大鼠角叉菜胶性足肿胀的影响(X±SD) 剂量 动物数 肿胀值(ml) 组别 (mg/Kg) (只) 正常 1小时 2小时 4小时 6小时 对照组 12 29.00±1.88 30.00±1.90** 30.17±2.16** 30.17±2.17** 30.17±2.17** 模型组 12 28.33±2.49 34.25±2.86 38.67±3.63 38.67±3.63 38.67±3.63 强的松组 5 12 29.08±2.47 33.75±2.86 36.08±4.10 36.08±4.10 36.08±4.10 大剂量组 54 12 28.33±3.22 33.91±3.62 34.64±2.87** 34.64±2.87** 34.64±2.87** 中剂量组 27 12 28.00±2.34 33.42±2.47 36.58±3.06 36.58±3.06 36.58±3.06 小剂量组 5.4 12 28.67±2.54 34.58±2.35 36.33±3.53 36.33±3.53 36.33±3.53 与模型组比较：**P＜0.01 由表1可见，药物组合物给药各组足肿胀值均低于模型组，其中大剂量组作用明显，以致炎后2、4、6小时足肿胀值与模型组比较P值均小于0.01，中、小剂量组足肿胀值虽无显著差异，但与强的松作用一致。说明药物组合物能抑制致炎剂角叉菜胶所致的足肿胀，即对致炎剂角叉菜胶引起的实验性关节炎肿胀具有抑制作用，且药物作用与药物剂量有关。 二、药物组合物对大鼠肉芽肿形成的影响 取大鼠72只，体重180±20克，雌雄各半。实验前所有动物腹腔注射戊巴比妥钠30mg/kg麻醉，采用手术方法分别于每只动物背部皮下植入已消毒和称重的纽扣，缝合皮肤后，外部消毒。术后第二天，将成活动物均匀分为五组，即空白对照组(给与给药大剂量组相当量的蒸馏水)，药物组合物大剂量组(54.0mg/kg)、中剂量组(27.0mg/kg)和小剂量组(5.4mg/kg)以及阳性对照组(强的松5.0mg/kg)。各组动物均采用灌胃给药，每天给药一次，连续给药14天。于末次给药后第二天处死动物，取出植入的纽扣，仔细剥离附着组织，称重，减去纽扣重，即为肉芽肿组织重量，用T检验进行统计学处理。结果见表2。 表2药物组合物对大鼠肉芽肿形成的影响 与空白对照组比较：**P＜0.01 由表2可见，药物组合物给药各组肉芽肿重量均明显低于空白对照组 剂量 动物数 肉芽肿重量 组别 (mg/Kg) (只) (mg) 对照组 11 259.73±44.58 强的松组 5 12 173.75±43.10** 大剂量组 54 12 176.42±37.98** 中剂量组 27 12 177.17±32.25** 小剂量组 5.4 12 180.50±34.63** (P＜0.01)。说明该药物组合物对肉芽肿的形成有明显的抑制作用，提示该药具有很好的抗结缔组织增生炎症的作用。 三、对小鼠热板法疼痛反应的影响 参照小鼠热板法加以改良，取小鼠80，体重20g±2g，雌雄各半，均分为五组，即空白对照组(给与给药大剂量组相当量的蒸馏水)，给药大剂量组(78.0mg/Kg)、中剂量组(39.0mg/Kg)和小剂量组(7.8mg/Kg)以及阳性对照组(阿斯匹林100.0mg/Kg)。均为口服灌胃给药，每天一次，连续14天。于末次给药后1小时，将各组小鼠分放在预先加热到55℃的铝盒内，以添后足作为疼痛反应的指标，记录小鼠自投入热板至出现舔后足反应的时间，用T检验进行统计学处理。结果见表3。 表3.药物组合物对小鼠热板法疼痛反映的影响( X±SD) 剂量 动物数 出现疼痛反应时间 组别 (mg/kg) (n) (s) 对照组 21 23.05±6.39 阿司匹林组 100 19 36.74±11.79** 大计量组 78 20 38.15±8.82** 中剂量组 39 19 31.68±8.39** 小计量组 7.8 21 29.29±6.63* 与对空白对照组比较：*P＜0.05，**P＜0.01 由表3可见，与空白对照组比较，药物组合物给药各组疼痛反应出现时间均延长，具有显著性差异(P＜0.05-0.01)，与阿斯匹林作用一致，其中大剂量组作用最明显，中剂量组次之，小剂量组再次之。说明药物组合物对热刺激法引起的小鼠疼痛反应有明显的抑制作用，且药物作用与药物剂量有一定的关系。 四、对小鼠化学刺激法疼痛反应的影响 按常规方法，取小鼠70只，体重13g±2g，雌雄各半，随机分为五组，即空白对照组(给与给药大剂量组相当量的蒸馏水)、给药大剂量组(78.0mg/Kg)、中剂量组(39.0mg/Kg)和小剂量组(7.8mg/Kg)以及阳性对照组(阿斯匹林100.0mg/Kg)。均为口服灌胃给药，每天一次，连续14 。于末次给药后1小时将0.6％的醋酸溶液注射于小鼠腹腔内，以引起深部的、大面积而持久的疼痛刺激，致使小鼠产生扭体反应，观察并记录各组小鼠出现扭体反应的时间(潜伏期)及20分钟内产生扭体反应的次数，用T检验进行统计学处理。结果见表4。 表4.药物组合物对小鼠化学刺激法疼痛反应的影响( X±SD) 动物数 剂量 扭体次数 组别 (n) (mg/Kg) (次数/20min) 对照组 15 38.87±8.48 阿司匹林组 12 100 23.67±10.77** 大剂量组 13 78 28.85±14.09* 中剂量组 9 39 26.89±16.68* 小剂量组 11 7.8 37.82±10.88 与空白对照组比较：*P＜0.05，**P＜0.01 注：因小鼠体重过小，在实验过程中可能由于灌胃不当而死了部分，致每组数量参差不齐。 由表4可见，与空白对照组比较，药物组合物大、中剂量组疼痛反应出现时间稍延长；20分钟内扭体次数则明显减少(P＜0.05)，与阿斯匹林作用相似。说明该药物组合物对热刺激法引起的小鼠疼痛反应有明显的抑制作用，且与药物剂量有一定的关系。 五、对大鼠佐剂性关节炎的影响 参照藤村一及WAX等法，取大鼠72只，体重150±20g，雌雄各半，随机均分为5组，其中一组为模型组(给与给药大剂量组相当量的蒸馏水)；三组为阳性对照组(强的松5.0mg/Kg)；三组为肿立消给药组，剂量分别为54.0mg/Kg、27.0mg/Kg和5.4mg/Kg。均为口服灌胃，每天一次，于注射Frdund’s完全佐剂当天开始给药，直至实验结束。将Freund’s完全佐剂0.05ml(内含死结核杆菌0.5mg)皮内注射于大鼠右后足垫内。注射佐剂前及后26天内隔日用鼠足容积测量仪测定大鼠右、左后足容积(ml)，用T检验进行统计学处理。结果见表5、表6和图1药物组合物对大鼠佐剂性关节炎的影响(右后足)和图2药物组合物对大鼠(左后足)佐剂性关节炎的影响。 表5.药物组合物对大鼠佐剂性关节炎的影响(右后足)( X±SD) 剂量 动物数 肿胀值(ml) 组别 (mg/Kg) (只) 注射前 注射后第2天 第4天 第6天 第8天 第10天 模型组 12 29.17±1.27 39.92±2.64 43.00±3.69 41.00±5.34 38.17±3.81 39.33±2.49 强的松组 5 12 28.75±1.66 39.00±3.13 39.42±2.54* 36.92±2.91* 35.66±2.94 36.25±3.59* 大剂量组 54 12 29.08±1.31 40.58±3.15 39.92±2.99* 37.83±3.61 35.67±3.82 34.42±3.78** 中剂量组 27 11 29.00±1.79 40.09±3.83 39.82±3.95 37.64±4.21 35.55±2.84 34.55±2.84** 小剂量组 5.4 12 28.67±1.56 39.25±3.08 40.00±2.34* 37.75±2.45 34.42±2.23** 34.92±2.50** 表6药物组合物对大鼠佐剂性关节炎的影响(左后足)( X±SD) 组别 剂量 动物数 肿胀值(ml) (mg/Kg) (只) 注射前 注射后第2天 第4天 第6天 第8天 第10天 模型组 12 26.17±1.75 29.08±0.99 29.17±1.12 28.83±0.94 28.58±1.08 30.50±1.93 阳性药组 5 12 26.25±2.05 28.58±1.73 29.25±1.87 28.42±1.73 28.50±1.51 30.08±1.73 大剂量组 54 12 26.00±1.65 28.75±1.66 28.83±2.21 28.75±1.55 28.42±1.88 29.33±2.06 中剂量组 27 11 25.91±1.45 29.45±1.92 28.18±1.47 28.18±1.40 28.46±1.75 29.18±1.60 小剂量组 5.4 12 26.50±2.07 29.17±1.47 29.25±1.77 28.58±1.83 28.08.±1.97 29.50±2.78 肿胀值(ml) 第12天 第14天 第16天 第18天 第20天 第22天 第24天 第26天 29.92？.02 31.83？.99 31.42？.11 31.00？.95 30.58？.35 31.25？.18 31.42？.73 31.00？.86 29.17？.17 30.83？.21 29.58？.11* 29.83？.82 29.25？.60 29.92？.88 30.33？.78 30.33？.15 28.25？.18 29.58？.64* 28.83？.33**29.08？.64* 29.00？.45* 28.92？.35* 29.17？.25* 29.00？.49* 29.09？.43 29.82？.23* 28.82？.94**29.36？.91* 28.55？.21* 29.17？.25* 29.27？.00* 29.09？.17* 29.17？.76 30.58？.08 29.17？.43 29.58？.03 28.92？.68* 29.17？.44* 29.08？.19**29.33？.15 与模型组比较：*P＜0.05，**P＜0.01 由表可见，大鼠右后足注射Freund’s佐剂后即早期炎症反应，于注射后次日即呈明显肿胀，逐渐加重，至第4天，足肿胀达高峰，然后逐渐减轻；于注射后第10天再度肿胀，至第18天发展成十分严重的肿胀状态，持续到观察期结束；因迟发性超敏反应，未注射佐剂的左后足于第10天开始肿大，且红肿明显，持续到观察期结束。 药物组合物给药各组注射佐剂的右后足肿胀趋势与强的松组基本一致，与模型组比较P＜0.05-0.01；未注射佐剂的左后足肿胀趋势也与强的松组基本一致，与模型组比较，P值也＜0.05-0.01，且其作用的显著性还优于强的松，但药物组合物给药各组作用差异不明显。以上说明药物组合物对Freund’s佐剂所致的原发性非特异性炎症和续发性炎症损害均有明显的抑制作用，即对Frdund’s佐剂所致对大鼠佐剂性关节炎有明显的抑制作用。 上述试验结果表明：药物组合物对对致炎剂角叉菜胶所致大鼠足肿胀即实验性关节肿胀具有明显的抑制作用；对大鼠实验性肉芽肿形成即对结缔组织增生性炎症有明显的抑制作用。 同时，该药物组合物对热刺激及化学刺激所引起的小鼠疼痛反应均有明显的抑制作用。 在上述实验的基础上，我们进一步进行并完成了佐剂性关节炎实验，结果说明，药物组合物对Freund’s完全佐剂所致大鼠佐剂性关节炎(系免疫性炎症模型)有明显抑制作用。且作用与强的松一致，甚至在还某些阶段还优于强的松。 大鼠佐剂性关节炎常作为类风湿性关节炎及免疫性关节炎的一种实验模型，上述实验结果说明并肯定该药物组合物对大鼠佐剂性关节炎的防治作用，为该药物组合物防治类风湿性关节及自身免疫性疾病伴关节炎提供了一定的基础和依据。 以上部分实验资料只在于对本发明进行了说明。但应该理解的事，对于本发明的实验技术人员来说，可以在不偏离本发明的精神实质的前提下，对本发明进行的修正和改进，都属于本发明的保护范围。 下面举数个配方例对本发明作进一步详细说明。 配方例一： 用20％的青蒿素或青蒿素衍生物的药物组合物，80％中药提取物组成配方。 配方例二： 用60％的青蒿素或青蒿素衍生物的药物组合物，40％中药或天然药提取物组成配方。 配方例三： 用90％的青蒿素或青蒿素衍生物的药物组合物，10％其他合成制剂组成配方。 需要说明的是中药提取物的原材料是一般技术人员或临床上可以使用的中药或天然药。该中药或天然药的提取物可以是单品种，也可以是多品种。其他合成制剂可以是化学合成药物，也可以是药物的载体。 本发明所述的制剂是将上述药物与多种药学上可以接受的赋形剂结合，采用混合，溶解，粒化，成片，糖包衣或膜包衣等已知方法制备成固态或液态形式的制剂，如片剂，胶囊，栓剂，颗粒剂及注射剂等。 1、一种治疗类风湿性关节炎和免疫性疾病的含青蒿提取物的药物组合物，其特征在于：为含有有效剂量的青蒿提取物如青蒿素或青蒿素衍生物的药物组合物。 2、如权利要求1所述的治疗类风湿性关节炎和免疫性疾病的含青蒿提取物的药物组合物，其特征在于：所述的蒿素衍生物包括双氢青蒿素，青蒿琥酯，蒿甲醚和蒿甲醚。 3、如权利要求1所述的治疗类风湿性关节炎和免疫性疾病的含青蒿提取物的药物组合物，其特征在于：该组合物中青蒿素或青蒿素衍生物的含量为1~99％。 4、如权利要求1所述的治疗类风湿性关节炎和免疫性疾病的含青蒿提取物的药物组合物，其特征在于：所述的药物组合物含有青蒿素或青蒿素衍生物的有效剂量为20~200mg/日。 5、如权利要求1所述的治疗类风湿性关节炎和免疫性疾病的含青蒿提取物的药物组合物，其特征在于：该药物组合物可以单独使用，也可以与现有治疗RA和自身免疫性疾病的其他药物联合使用。 https://patents.google.com/patent/CN1561994A/zh?oq=CN1561994A治疗类风湿性关节炎和免疫性疾病的含青蒿提取物药物组合物---双氢青蒿素，青蒿琥酯，蒿甲醚，蒿甲醚等)的药物组合物 Medicinal compositon containing artemisine extract for treating rheumatoid arthritis and immunologic disease A composite medicine for treating the umatoid arthritis and autoimmune disease contains the sweet worm wood herb's extract (dihydroarteannuin, artesumate, artemether, etc). Treatment rheumatoid joint class and immune disease contain the Herba Artemisiae Annuae extract pharmaceutical composition Technical field: The present invention relates to a kind of medicine that is used for the treatment of rheumatoid joint class and autoimmune disease companion arthritic symptom, contain arteannuin or artemisinin derivative (dihydroarteannuin especially for treatment rheumatoid arthritis and autoimmune disease companion arthritic symptom, artesunate, Artemether, Artemether etc.) pharmaceutical composition. Background technology: Rheumatoid arthritis (hereinafter to be referred as RA) is a kind of of autoimmune disease, it is a kind of worldwide agnogenic systemic autoimmune disease, its sickness rate 0.4～1%, its principal character is with chronic, symmetry and tip joint diffusivity synovitis, the carrying out property destruction of joint of various degree appears latter stage, degeneration and function of joint are lost, and seriously affect patient's work and viability, cause huge burden to society.And other autoimmune disease is also usually with similar joint symptom, such treatment of diseases still there is not specific medicament, non-steroid class analgesic agents and the immunosuppressant treatments of adopting more, disease controlling fully not only, and have bigger poison to pay effect. Research is subjected to domestic and international expert and patient's attention to Chinese medicine to rheumatoid arthritis and autoimmune disease in recent years, has developed the medicine of some treatment RA, and for example: Chinese patent application 02137816 discloses the medicine compositions of a kind of RA, wherein contain Chinese medicinal ingredients: Poria 12%, Radix Angelicae Sinensis 12%, the Fructus Kochiae 12%, Cortex Acanthopancis 10%, Folium Eriobotryae 10%, Cortex erythrinae 9%, Radix Cynanchi Atrati 9%, Radix Scutellariae 8%, Rhizoma Coptidis 7%, Herba Pogostemonis 6%, Caulis Akebiae 5%.Chinese patent application 01117709 discloses a kind of medicine for the treatment of rheumatoid arthritis for another example, it is with Radix Polygoni Multiflori, Radix Codonopsis, Radix Angelicae Sinensis, the Radix Astragali, Rhizoma Polygonati, the Rhizoma Atractylodis Macrocephalae, Rhizoma Cibotii, Scorpio, Zaocys, Pheretima, Formica fusca, Radix Salviae Miltiorrhizae, Ramulus Mori, Ramulus Cinnamomi, Rhizoma Atractylodis, Rhizoma Et Radix Notopterygii, Radix Angelicae Pubescentis, Radix Saposhnikoviae, Radix Gentianae Macrophyllae, Herba Taxilli, the Cortex Eucommiae, Radix Cyathulae, Cortex Phellodendri, Rhizoma Homalomenae, bore Cortex Illici difengpi, Olibanum, Myrrha, Caulis Sinomenii, Rhizoma Arisaematis, Caulis Spatholobi, Fructus Mori, Rhizoma Corydalis, Rhizoma Chuanxiong, Semen Ziziphi Spinosae, the Rhizoma Anemarrhenae, Poria, Radix Aconiti Kusnezoffii, Radix Aconiti, Herba Epimedii, Flos Carthami, Radix Dipsaci, Cortex Moutan, Caulis Lonicerae, Radix Paeoniae Rubra, Semen Coicis, Cortex erythrinae, Caulis Trachelospermi, Radix Glycyrrhizae is a raw material, different qualities according to every flavor Chinese medicine, at the different symptoms of rheumatoid arthritis, be mixed with basic medicament in proportion, even the medicament that cold hot very person adapts. Above-mentioned these Chinese medicine compositions generally all are the routine administrations of Chinese medicine, use Shi doctor also must carry out prescription according to patient's situation according to the principle of differentiation of tcm; Also have some Chinese patent medicine compositions more, preparation is complicated, and practical application can't be satisfied clinician and patient's needs fully. Arteannuin is Chinese scholar independent development and by internationally recognized Chinese medicine extract, arteannuin and derivant thereof are effective antimalarial of a class and antimalarial agent compositions.The effective monomer component that system extracts from China Chinese medicine Herba Artemisiae annuae has been the malaria new drug by world health organisation recommendations.Along with country and each research unit are goed deep into the continuation of arteannuin research, having developed some is the anti-malarial agents of the new compound preparation of main component with the arteannuin in recent years, as: Chinese patent application 00113134 discloses a kind of compound preparation for the treatment of malaria; Also constantly found the application in other frontiers simultaneously, as: Chinese patent application 99103346 discloses a kind of pharmaceutical composition that contains dihydroarteannuin for the treatment of lupus erythematosus and photosensitive diseases etc.Existing bibliographical information can be applied to the Herba Artemisiae Annuae oil liniment treatment of tinea, by research to the external antifungic action of arteannuin, the antibiotic universal effect that confirms arteannuin is similar to broad-spectrum antifungal medicine ketoconazole commonly used at present, and the effect to some fungus is better than ketoconazole, and promptly its antifungic action is respond well. Summary of the invention: Purpose of the present invention, provide a kind of treat rheumatoid joint class and immune disease safely and effectively contain the Herba Artemisiae Annuae extract pharmaceutical composition. Technical scheme of the present invention is as follows. A kind of treat rheumatoid arthritis and immune disease contain the Herba Artemisiae Annuae extract pharmaceutical composition, be the arteannuin that contains effective dose or the pharmaceutical composition of artemisinin derivative. Described artemisin derivant comprises dihydroarteannuin, artesunate, Artemether and Artemether. The content of arteannuin or artemisinin derivative is 1～99% in the said composition. The effective dose that described pharmaceutical composition contains arteannuin or artemisinin derivative is 20～200mg/ day. This pharmaceutical composition can use separately, also can unite use with the other drug of existing treatment RA and autoimmune disease. Described pharmaceutical composition is can be any medicament forms commonly used, as: solid preparation, fluid, or paste etc. The present invention is based on that such fact finishes.This case inventor finds that in secular clinical treatment RA and autoimmune disease and various arthritic process the Chinese medicine Herba Artemisiae Annuae has heat-clearing and toxic substances removing preferably, detumescence, pain relieving effect.And arteannuin is Chinese medicine one kind new medicine that China began one's study from the seventies, we are studying arteannuin or derivatives thereof and the pharmaceutical composition that contains arteannuin aspect immunity and the autoimmune disease for this reason, show that arteannuin has on the immunoregulatory basis, prove all that from pharmacodynamics and clinical research arteannuin or artemisinin derivative to the curative effect preferably that has of RA and autoimmune disease companion joint symptom, have antiinflammatory, analgesia, immunoregulatory curative effect.And has instant effect, the advantage of no obvious toxic and side effects. Pharmaceutical composition of the present invention is applicable to the disease of rheumatic arthritis and autoimmune disease companion joint performance. Pharmaceutical composition of the present invention can be any medicament forms commonly used, can be solid preparation, as: tablet, colloid, suppository, powder, granule, cream etc.; Also can be fluid preparation, as: oral liquid, injection; Or paste etc. Preparation method of the present invention is the known preparation method commonly used of those of ordinary skills. According to pharmaceutical composition of the present invention, preferentially be to be made into tablet or capsule, each tablet or capsule contain arteannuin or the artemisinin derivative of 10-100mg. Description of drawings: Fig. 1 is the influence (right back foot) of pharmaceutical composition to rat assist agent arthritis Fig. 2 pharmaceutical composition is to the influence of rat (left back foot) adjuvant-induced arthritis The specific embodiment: Pharmaceutical composition of the present invention is generally oral administration, also can other administration, can use external preparation as treatment RA and autoimmune disease companion joint symptom.Consumption is generally the 1-10mg/Kg body weight/day, and the consumption of adult patients is preferably 20-200mg for each person every day. The arteannuin that the present invention uses or the preparation technology of artemisinin derivative (dihydroarteannuin, artesunate, Artemether, arteether) are known, and relevant its preparation method is found in all bibliographical informations. Can further illustrate the present invention by following test.But should be noted that experiment content of the present invention only is used to illustrate the present invention, rather than restriction the present invention. Pharmaceutical composition of the present invention is to the influence of tentative general arthritis and autoimmune arthritis Experiment material Animal: 1. healthy Wistar rat, body weight 130 ± 20g, 180 ± 20g and 150 ± 20g, male and female all have.Quality certification numbering is followed successively by: SCXK (capital) 2002-0003, SCXK (capital) 2002-0003 and SCK (capital) 2002-0006; 2. healthy Kunming kind white mice, body weight 20 ± 20g and 13g ± 2g, male and female all have.Quality certification numbering is SCXK (capital) 2002-001.Supply with by my animal housing of institute. Main medicine: 1. contain the pharmaceutical composition that Herba Artemisiae Annuae extract comprises arteannuin and artemisinin derivative (dihydroarteannuin, artesunate, Artemether, Artemether etc.).Hereinafter to be referred as [pharmaceutical composition]. 2. prednisone (5mg/ sheet), Dongbei Pharmaceutical General Factory production, lot number 20031113; 3. carrageenin, U.S. Sigma company product, lot number 87F-0463; 4. Freund ' s Freund's complete adjuvant, bacillus calmette-guerin vaccine (lot number 20030115) preparation with the Beijing Biological Product Inst., Ministry of Public Health provides includes tubercule bacillus 0.7mg/0.07ml. Instrument: Mus foot volume determination instrument, self-control. Method and result One, to the influence of rat carrageenan foot swelling With reference to rat toes edema blood capillary measurement by magnification method, get 72 of rats, body weight 130 ± 20g, male and female half and half, be divided into five groups at random, be blank group and model group (giving distilled water) with the heavy dose of group of administration a great deal of, the heavy dose of group of pharmaceutical composition (54.0mg/Kg), middle dosage group (27.0mg/Kg) and small dose group (5.4mg/Kg) and positive controls (prednisone 5.0mg/Kg).Be the oral administration gavage administration, once a day, continuous 14 days.1 hour mensuration Mus foot volume (ml) after the last administration, be about to 1% carrageenin normal saline 0.1ml and inject the subcutaneous inflammation that causes of the rat left hind foot sole of the foot, respectively at inject back 1 hour, 2 hours, 4 hours, and 6 and hour, measure Mus foot volume with Mus foot volume determination instrument, calculate the swelling value, compare the difference condition of each time administration group and matched group with the T check.The results are shown in Table 1. Table 1. pharmaceutical composition is to the influence of rat carrageenan foot swelling (X ± SD) Dosage number of animals swelling value (ml) Group (mg/Kg) (only) Normal 1 hour 2 hours 4 hours 6 hours Matched group 12 29.00 ± 1.88 30.00 ± 1.90 *30.17 ± 2.16 *30.17 ± 2.17 *30.17 ± 2.17 * Model group 12 28.33 ± 2.49 34.25 ± 2.86 38.67 ± 3.63 38.67 ± 3.63 38.67 ± 3.63 Prednisone group 5 12 29.08 ± 2.47 33.75 ± 2.86 36.08 ± 4.10 36.08 ± 4.10 36.08 ± 4.10 Heavy dose of group 54 12 28.33 ± 3.22 33.91 ± 3.62 34.64 ± 2.87 *34.64 ± 2.87 *34.64 ± 2.87 * Middle dosage group 27 12 28.00 ± 2.34 33.42 ± 2.47 36.58 ± 3.06 36.58 ± 3.06 36.58 ± 3.06 Small dose group 5.4 12 28.67 ± 2.54 34.58 ± 2.35 36.33 ± 3.53 36.33 ± 3.53 36.33 ± 3.53 Compare with model group: *P＜0.01 By table 1 as seen, the pharmaceutical composition administration is respectively organized the foot swelling value and all is lower than model group, and wherein heavy dose of group of effect is obvious, thus 2,4, the 6 hours foot swelling values in scorching back and model group relatively the P value all less than 0.01, in, though small dose group foot swelling value do not have significant difference, and is consistent with the prednisone effect.Illustrate that pharmaceutical composition can suppress the foot swelling due to the proinflammatory agent carrageenin, promptly inhibited to the experimental arthritis swelling that the proinflammatory agent carrageenin causes, and drug effect is relevant with drug dose. Two, pharmaceutical composition is to the influence of rat granuloma formation Get 72 of rats, body weight 180 ± 20 grams, male and female half and half.All animal lumbar injection pentobarbital sodium 30mg/kg anesthesia before the experiment, the button that adopts operation method to sterilize and weighed respectively at every subcutaneous implantation of back part of animal, behind the skin suture, outside sterilization.Second day after operation, to become live animal evenly to be divided into five groups, be blank group (giving distilled water) with the heavy dose of group of administration a great deal of, the heavy dose of group of pharmaceutical composition (54.0mg/kg), middle dosage group (27.0mg/kg) and small dose group (5.4mg/kg) and positive controls (prednisone 5.0mg/kg).Each treated animal all adopts gastric infusion, and be administered once every day, successive administration 14 days.Put to death animal in second day after the last administration, take out the button of implanting, carefully peel off adhering tissue, weigh, it is heavy to deduct button, is granuloma tissue weight, carries out statistical procedures with the T check.The results are shown in Table 2. The influence that table 2 pharmaceutical composition forms the rat granuloma Compare with the blank group: *P＜0.01 By table 2 as seen, the pharmaceutical composition administration is respectively organized granuloma weight and all is starkly lower than the blank group Dosage number of animals granuloma weight Group (mg/Kg) (only) (mg) Matched group 11 259.73 ± 44.58 Prednisone group 5 12 173.75 ± 43.10** Heavy dose of group 54 12 176.42 ± 37.98** Middle dosage group 27 12 177.17 ± 32.25** Small dose group 5.4 12 180.50 ± 34.63** (P＜0.01)。Illustrate that this pharmaceutical composition is formed with the obvious suppression effect to granulomatous, points out this medical instrument to have good resistive connection to form the effect of hamartoplasia inflammation. Three, to the influence of mice hot plate method pain reaction Improved with reference to the mice hot plate method, get mice 80, body weight 20g ± 2g, male and female half and half, be divided into five groups, be blank group (giving distilled water) with the heavy dose of group of administration a great deal of, the heavy dose of group of administration (78.0mg/Kg), middle dosage group (39.0mg/Kg) and small dose group (7.8mg/Kg) and positive controls (aspirin 100.0mg/Kg).Be the oral administration gavage administration, once a day, continuous 14 days.After the last administration 1 hour, each group mice divided be placed in the aluminum box that is heated to 55 ℃ in advance, to add the index of metapedes as pain reaction, the record mice carries out statistical procedures from dropping into hot plate to the time that the metapedes reaction occurs licking with the T check.The results are shown in Table 3. The influence that table 3. pharmaceutical composition reflects mice hot plate method pain (X ± SD) The pain reaction time appears in the dosage number of animals Group (mg/kg) is (s) (n) Matched group 21 23.05 ± 6.39 Aspirin group 100 19 36.74 ± 11.79 * Big metering organizes 78 20 38.15 ± 8.82 * Middle dosage group 39 19 31.68 ± 8.39 * Subtotal amount group 7.8 21 29.29 ± 6.63 * With to the blank group relatively: *P＜0.05, *P＜0.01 By table 3 as seen, compare with the blank group, the pharmaceutical composition administration is respectively organized the pain reaction time of occurrence and is all prolonged, (P＜0.05-0.01), consistent with the aspirin effect, wherein heavy dose of group of effect is the most obvious to have significant difference, middle dosage group is taken second place, and small dose group is taken second place again.Illustrate that pharmaceutical composition has the obvious suppression effect to the mice pain reaction that the thermostimulation method causes, and drug effect and drug dose there is certain relation. Four, to the influence of mice chemical stimulation method pain reaction According to a conventional method, get 70 of mices, body weight 13g ± 2g, male and female half and half, be divided into five groups at random, i.e. blank group (giving distilled water), the heavy dose of group of administration (78.0mg/Kg), middle dosage group (39.0mg/Kg) and small dose group (7.8mg/Kg) and positive controls (aspirin 100.0mg/Kg) with the heavy dose of group of administration a great deal of.Be the oral administration gavage administration, once a day, continuous 14.After the last administration, 0.6% acetum was injected in the mouse peritoneal in 1 hour, with cause the deep, large tracts of land and persistent pain stimulation, cause mice to produce writhing response, observe and the number of times that produces writhing response in the time (incubation period) and 20 minutes that writhing response appears in mice respectively organized in record, carry out statistical procedures with the T check.The results are shown in Table 4. Table 4. pharmaceutical composition is to the influence of mice chemical stimulation method pain reaction (X ± SD) Number of animals dosage is turned round the body number of times Group (n) is (number of times/20min) (mg/Kg) Matched group 15 38.87 ± 8.48 Aspirin group 12 100 23.67 ± 10.77 * Heavy dose of group 13 78 28.85 ± 14.09 * Middle dosage group 9 39 26.89 ± 16.68 * Small dose group 11 7.8 37.82 ± 10.88 Compare with the blank group: *P＜0.05, *P＜0.01 Annotate: because of the mice body weight too small, may be in experimentation owing to irritate the improper and part in the dust of stomach, it is uneven to cause every group of quantity. By table 4 as seen, compare with the blank group, the big or middle dosage group of pharmaceutical composition pain reaction time of occurrence prolongs slightly; Turn round the body number of times in 20 minutes and then obviously reduce (P＜0.05), similar to the aspirin effect.Illustrate that this pharmaceutical composition has the obvious suppression effect to the mice pain reaction that the thermostimulation method causes, and certain relation is arranged with drug dose. Five, to the influence of rat assist agent arthritis With reference to methods such as rattan village one and WAX, get 72 of rats, body weight 150 ± 20g, male and female half and half are divided into 5 groups at random, and wherein one group is model group (giving the distilled water with the heavy dose of group of administration a great deal of); Three groups of positive matched groups (prednisone 5.0mg/Kg); Three groups are the swollen upright administration group that disappears, and dosage is respectively 54.0mg/Kg, 27.0mg/Kg and 5.4mg/Kg.Be oral administration gavage, once a day, began administration the same day, finish until experiment in injection Frdund ' s Freund's complete adjuvant.With Freund ' s Freund's complete adjuvant 0.05ml (include fast knot nuclear bacillus 0.5mg) intradermal injection in the right back foot pad of rat.Injection adjuvant is measured the rat right side, left back sufficient volume (ml) with Mus foot volumetric measurement instrument before and after in 26 days the next day, carries out statistical procedures with the T check.The results are shown in Table 5, table 6 and Fig. 1 pharmaceutical composition be to the influence to rat (left back foot) adjuvant-induced arthritis of the influence (right back foot) of rat assist agent arthritis and Fig. 2 pharmaceutical composition. Table 5. pharmaceutical composition is to the influence (right back foot) of rat assist agent arthritis (X ± SD) Dosage number of animals swelling value (ml) Group (mg/Kg) (only) The injection back is the 2nd day the 4th day the 6th day the 8th day the 10th day before the injection Model group 12 29.17 ± 1.27 39.92 ± 2.64 43.00 ± 3.69 41.00 ± 5.34 38.17 ± 3.81 39.33 ± 2.49 Prednisone group 5 12 28.75 ± 1.66 39.00 ± 3.13 39.42 ± 2.54 *36.92 ± 2.91 *35.66 ± 2.94 36.25 ± 3.59 * Heavy dose of group 54 12 29.08 ± 1.31 40.58 ± 3.15 39.92 ± 2.99 *37.83 ± 3.61 35.67 ± 3.82 34.42 ± 3.78 * Middle dosage group 27 11 29.00 ± 1.79 40.09 ± 3.83 39.82 ± 3.95 37.64 ± 4.21 35.55 ± 2.84 34.55 ± 2.84 * Small dose group 5.4 12 28.67 ± 1.56 39.25 ± 3.08 40.00 ± 2.34 *37.75 ± 2.45 34.42 ± 2.23 *34.92 ± 2.50 * Table 6 pharmaceutical composition is to the influence (left back foot) of rat assist agent arthritis (X ± SD) Group dosage number of animals swelling value (ml) (mg/Kg) injected the back the 2nd day the 4th day the 6th day the 8th day the 10th day before (only) injection Model group 12 26.17 ± 1.75 29.08 ± 0.99 29.17 ± 1.12 28.83 ± 0.94 28.58 ± 1.08 30.50 ± 1.93 Positive drug group 5 12 26.25 ± 2.05 28.58 ± 1.73 29.25 ± 1.87 28.42 ± 1.73 28.50 ± 1.51 30.08 ± 1.73 Heavy dose of group 54 12 26.00 ± 1.65 28.75 ± 1.66 28.83 ± 2.21 28.75 ± 1.55 28.42 ± 1.88 29.33 ± 2.06 Middle dosage group 27 11 25.91 ± 1.45 29.45 ± 1.92 28.18 ± 1.47 28.18 ± 1.40 28.46 ± 1.75 29.18 ± 1.60 Small dose group 5.4 12 26.50 ± 2.07 29.17 ± 1.47 29.25 ± 1.77 28.58 ± 1.83 28.08. ± 1.97 29.50 ± 2.78 Swelling value (ml) The 12nd day the 14th day the 16th day the 18th day the 20th day the 22nd day the 24th day the 26th day 29.92？.02 31.83？.99 31.42？.11 31.00？.95 30.58？.35 31.25？.18 31.42？.73 31.00？.86 29.17？.17 30.83？.21 29.58？.11 *?29.83？.82 29.25？.60 29.92？.88 30.33？.78 30.33？.15 28.25？.18 29.58？.64 *?28.83？.33 **29.08？.64 *?29.00？.45 *?28.92？.35 *?29.17？.25 *?29.00？.49 * 29.09？.43 29.82？.23 *?28.82？.94 **29.36？.91 *?28.55？.21 *?29.17？.25 *?29.27？.00 *?29.09？.17 * 29.17？.76 30.58？.08 29.17？.43 29.58？.03 28.92？.68 *?29.17？.44 *?29.08？.19 **29.33？.15 Compare with model group: *P＜0.05, *P＜0.01 By table as seen, be early stage inflammatory reaction behind the right back foot injection of rat Freund ' the s adjuvant, promptly be obvious swelling next day in the injection back, increase the weight of gradually, to the 4th day, foot swelling reached the peak, alleviates gradually then; In injection back swelling once again in the 10th day, developed into very serious swelling state to the 18th day, last till that the observation period finishes; Because of delayed hypersensitivity, the left back foot of injection adjuvant did not begin enlargement in the 10th day, and obviously red and swollen, lasted till that the observation period finishes. The right back foot swelling trend and the prednisone group basically identical of injection adjuvant respectively organized in the pharmaceutical composition administration, compares P＜0.05-0.01 with model group; Not the left back foot swelling trend of injection adjuvant also with prednisone group basically identical, with model group relatively, the P value also＜0.05-0.01, and the significance of its effect also is better than prednisone, but that difference between the effects is respectively organized in the pharmaceutical composition administration is not obvious.More than the explanation pharmaceutical composition all has the obvious suppression effect to constitutional nonspecific inflammation and the infringement of supervention inflammation due to Freund ' the s adjuvant, promptly due to Frdund ' s adjuvant rat assist agent arthritis is had the obvious suppression effect. Above-mentioned result of the test shows: pharmaceutical composition is that experimental arthroncus has the obvious suppression effect to rat paw edema due to the proinflammatory agent carrageenin; Formation promptly has the obvious suppression effect to the connective tissue proliferation inflammation to the rat experiment granuloma. Simultaneously, this pharmaceutical composition all has the obvious suppression effect to thermostimulation and the caused mice pain reaction of chemical stimulation. On the basis of above-mentioned experiment, we further carry out and have finished the adjuvant-induced arthritis experiment, presentation of results, and pharmaceutical composition has obvious inhibitory action to rat assist agent arthritis (being the immune inflammation model) due to Freund ' the s Freund's complete adjuvant.And effect is consistent with prednisone, even also is better than prednisone in some stage of going back. A kind of experimental model of rat assist agent arthritis Chang Zuowei rheumatoid arthritis and autoimmune arthritis, the explanation of above-mentioned experimental result also certainly this pharmaceutical composition to the preventive and therapeutic effect of rat assist agent arthritis, for this pharmaceutical composition control rheumatoid joint and autoimmune disease companion arthritis provide certain basis and foundation. Only be to describe the present invention with the top experimental data.But the thing that should be appreciated that, for experimental technique personnel of the present invention, can be under the prerequisite that does not depart from spirit of the present invention, correction and improvement to the present invention carries out all belong to protection scope of the present invention. Lifting several Formulation Examples below is described in further detail the present invention. Formulation Example one: The arteannuin with 20% or the pharmaceutical composition of artemisinin derivative, 80% Chinese medicine extract compositing formula. Formulation Example two: The arteannuin with 60% or the pharmaceutical composition of artemisinin derivative, 40% Chinese medicine or crude drug extract compositing formula. Formulation Example three: The arteannuin with 90% or the pharmaceutical composition of artemisinin derivative, 10% other synthesising preparation compositing formulas. The raw material that need to prove Chinese medicine extract is those skilled in the art or operable clinically Chinese medicine or crude drug.The extract of this Chinese medicine or crude drug can be a single variety, also can be many kinds.Other synthesising preparations can be chemical synthetic drugs, also can be the carriers of medicine. Preparation of the present invention is that said medicine is combined with multiple pharmaceutically acceptable excipient, adopts and mixes, dissolving, granulation; in flakes, known methods such as sweet tablet or film coating are prepared into the preparation of solid-state or liquid form, as tablet; capsule, suppository, granule and injection etc. 1, a kind of pharmaceutical composition that contains Herba Artemisiae Annuae extract for the treatment of rheumatoid arthritis and immune disease is characterized in that: be the Herba Artemisiae Annuae extract that contains effective dose such as the pharmaceutical composition of arteannuin or artemisinin derivative. 2, the pharmaceutical composition that contains Herba Artemisiae Annuae extract of treatment rheumatoid arthritis as claimed in claim 1 and immune disease is characterized in that: described artemisin derivant comprises dihydroarteannuin, artesunate, Artemether and Artemether. 3, the pharmaceutical composition that contains Herba Artemisiae Annuae extract of treatment rheumatoid arthritis as claimed in claim 1 and immune disease is characterized in that: the content of arteannuin or artemisinin derivative is 1 ~ 99% in the said composition. 4, the pharmaceutical composition that contains Herba Artemisiae Annuae extract of treatment rheumatoid arthritis as claimed in claim 1 and immune disease is characterized in that: the effective dose that described pharmaceutical composition contains arteannuin or artemisinin derivative is 20 ~ 200mg/ day. 5, the pharmaceutical composition that contains Herba Artemisiae Annuae extract of treatment rheumatoid arthritis as claimed in claim 1 and immune disease, it is characterized in that: this pharmaceutical composition can use separately, also can unite use with the other drug of existing treatment RA and autoimmune disease. https://patents.google.com/patent/CN1561994A/en?oq=CN1561994A治疗类风湿性关节炎和免疫性疾病的含青蒿提取物药物组合物---双氢青蒿素，青蒿琥酯，蒿甲醚，蒿甲醚等)的药物组合物

CN1313145C青蒿素相关性内过氧化物与携带铁的 蛋白质之间的共价缀合物及其使用方法 CN1313145C Covalent conjugates between artemisinin-related peroxides and iron-carrying proteins and their methods of use. 青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物及其使用方法 本发明在一个方面中提供了青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物。在某些实施方案中，该共价缀合物包括阿替林酯和全运铁蛋白。本发明在另一个方面中提供了给予本发明的共价缀合物以治疗癌症和由可结合携带铁的蛋白质的病原体所导致的感染的方法。 青蒿素相关性内过氧化物与携带铁的 蛋白质之间的共价缀合物及其使用方法 相关申请的交叉引用 本申请要求按照35U.S.C.119于2002年6月6日提交的美国临时申请号60/386,928的利益。 发明领域 本发明涉及青蒿素(artemisinin)相关性内过氧化物(endoperoxide)与携带铁的蛋白质之间的共价缀合物和这些缀合物在治疗癌症和由可结合携带铁的蛋白质的病原体导致的感染中的应用。 发明背景 青蒿素是从植物黄花蒿(Artemisia annua L)中分离的倍半萜内酯类，该植物的提取物已经用于治疗疟疾至少1600年。青蒿素分子含有内过氧化桥，它与铁原子反应形成自由基。青蒿素的抗疟作用是因其与寄生虫内的血红素发生反应形成自由基而使细胞死亡所导致的。癌细胞具有显著高于正常细胞的铁流入。因此，已经证实青蒿素和青蒿素类似物对建立的肿瘤和肿瘤细胞系具有细胞毒性(例如，参见Woerdenbag等(1993)《天然产物杂志》(J.Nat.Prod.)56(6)：849-56；Lai &Singh(1995)《癌症通讯》(Cancer Lett.)91：41-6；Efferth等(2001)《国际肿瘤学杂志》(Int.J.Oncol.)18：767-73；Li等(2001)《生物有机药物化学通讯》(Bioorg.Med.Chem.Lett.)11：5-8；Singh& Lai(2001)《生命科学》(Life Sci.)70：49-56；Efferth等(2002)《生物化学与药理学》(Biochem.Pharmacol.)64：617-23；Efferth等(2002)《血细胞、分子和疾病》(Blood Cells，Molecules & Diseases)28(2)：160-8；Sadava等(2002)《癌症通讯》(Cancer Lett.)179：151-6)。 已经描述了青蒿素的许多类似物和其它具有生物活性的含有内过氧化桥(endoperoxide bridge)的化合物(例如，参见美国专利US5,180,840；美国专利US5,216,175；美国专利US5,225,427；Cumming等(1998)《药物化学杂志》(J Med.Chem.)41(6)：952-64；Posner等(1999)《药物化学杂志》(J Med.Chem.)42：300-4；Li等(2001)《生物有机药物化学通讯》(Bioorg.Med.Chem.Lett.)11：5-8；Wu等(2001)《欧洲药物化学杂志》(Eur.J.Med.Chem.)36：469-79；Posner等(2003)《药物化学杂志》(J Med.Chem.)46：1060-5)。已经用于治疗疟疾的青蒿素类似物包括二氢青蒿素、蒿甲醚、青蒿琥酯、蒿乙醚、二氢青蒿素丙基碳酸酯和artelinic acid。 青蒿素是相对安全的药物，甚至在高剂量下也只有极少且低微的副作用。已经将6天70mg/kg/天的口服剂量用于治疗人疟疾。在用青蒿琥酯治疗癌症患者后，没有观察到明显的不良副作用(口服剂量50mg/天；肌内剂量60mg/天；为期9个月)(Singh &Verma(2002)《肿瘤学学报》(Arch.Oncol.)10(4)：279-80)。还已将青蒿素和青蒿素类似物用于治疗皮肤病，诸如银屑病、起泡性皮肤病、病毒疣、上皮软疣(mulluscum contagiosum)和痔(例如，参见美国专利US4,978,676；美国专利US5,219,880)。还将青蒿素和青蒿素类似物用于预防疟疾。 已经证实给予铁盐或携带铁的蛋白质全运铁蛋白(holotransferrin)增加了癌细胞和植入的肿瘤对青蒿素及其类似物的敏感性(Lai & Singh(1995)《癌症通讯》(Cancer Lett.)91：41-46；Moore等(1995)《癌症通讯》(Cancer Lett.)98：83-7；Singh & Lai(2001)《生命科学》(Life Sci.)70：49-56；Sadava等(2002)《癌症通讯》(Cancer Lett.)1179：151-6)。 还证实某些病原体通过结合携带铁的宿主蛋白质而获得铁。例如，细菌性脑膜炎的病原体脑膜炎奈瑟氏球菌表达携带铁的化合物的细胞表面受体，诸如运铁蛋白(transferrin)和乳铁蛋白(lactoferrin)(Evans & Oakhill(2002)《生物化学协会学报》(Biochem.Soc.Trans.)30(4)：705-7)。目前，尚无疫苗可用于脑膜炎奈瑟氏球菌B型菌株即西方世界中最流行的菌株。此外，已经证实人胃炎、胃和十二指肠溃疡和腺癌的病原体幽门螺杆菌(Helicobacter pylori)可通过结合人乳铁蛋白而获得铁(Husson等(1993)《感染性免疫》(Infect.Immun.)61(6)：2694-7)。 本领域中仍需要有效力增加的青蒿素组合物，以用于治疗癌症和由可结合携带铁的宿主蛋白的病原体导致的疾病。还需要用于治疗癌症和由可通过摄入携带铁的宿主蛋白而获得铁的病原体所导致的感染的方法。本发明满足了这些需求。 发明概述 本发明在一个方面中提供了新化合物和包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物的组合物。青蒿素相关性内过氧化物可以通过酰肼部分、肼部分或氨氧基部分与携带铁的化合物连接。在某些实施方案中，所述的青蒿素相关性内过氧化物具有如下结构： 其中n＝1-3，m＝0-3，Ar＝芳基，且Y＝-(C＝O)NH-、-NH-或-O-。有代表性的存在于本发明共价缀合物中的青蒿素相关性内过氧化物包括阿替林酯(artelinate)和二氢青蒿素。 有代表性的存在于本发明共价缀合物中的携带铁的蛋白质包括蛋白质中的运铁蛋白家族、与中性明胶酶相关的脂质运载蛋白(neutralgelatinaseassociated lipocalin，NGAL)、血红素蛋白和其它携带铁的蛋白质。因此，所述的共价缀合物可以包括：例如阿替林酯与全运铁蛋白、阿替林酯与全乳铁蛋白(hololactoferrin)或阿替林酯与血红蛋白的缀合物。本发明还提供了包含本发明共价缀合物和药物上可接受的载体的组合物。本发明的共价缀合物可用于治疗癌症和由可结合携带铁的蛋白质的病原体所导致的感染。 本发明在另一个方面中提供了对需要的受试者给予本发明的共价缀合物的方法。在本发明该方面中适合于给药的典型共价缀合物包括：例如阿替林酯与全运铁蛋白之间、阿替林酯与全乳铁蛋白之间和阿替林酯与血红蛋白之间的共价缀合物。 在某些实施方案中，本发明提供了治疗癌症的方法，通过对有此需要的人或动物受试者给予有效量的组合物来进行，该组合物包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物。可以通过局部或全身性给予所述的共价缀合物，或可以将它们直接注入肿瘤。可以单独或与一种或多种其它治疗剂一起给予所述的共价缀合物。例如，可以与例如可通过增加缀合物中携带铁的蛋白质的细胞表面受体数来增加向细胞内的铁转运的活性剂一起给予所述的共价缀合物。 本发明还提供了治疗由可结合携带铁的蛋白质的病原体所导致的感染的方法，通过对有此需要的人或动物受试者给予有效量的组合物来进行，该组合物包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物。在一个实施方案中，所述的病原体包括幽门螺杆菌，其中携带铁的蛋白质包括人乳铁蛋白，且其中所述青蒿素相关性内过氧化物选自阿替林酯和二氢青蒿素组成的组。在其它典型的实施方案中，所述的病原体包括脑膜炎奈瑟氏球菌，其中所述携带铁的蛋白质包括人运铁蛋白，且其中所述青蒿素相关性内过氧化物选自阿替林酯和二氢青蒿素组成的组。 在另外的实施方案中提供了治疗幽门螺杆菌感染的方法，通过对有此需要的人或动物受试者给予有效量的组合物来进行，该组合物包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物。 优选实施方案的详细描述 本发明在一个方面中提供了包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物的组合物。本文所用的术语″共价缀合物″指的是其中青蒿素相关性内过氧化物与携带铁的蛋白质共价连接在一起的化合物。术语″青蒿素相关性内过氧化物″指的是含有内过氧桥(endoperoxide bridge)的化合物，它可与铁原子反应而形成自由基，导致细胞死亡。青蒿素相关性内过氧化物化合物还可以在有铜和锰存在的情况下形成自由基。有代表性的青蒿素相关性内过氧化物如本文所述，不过，显然其它内过氧化物也可用于该目的。 一般来说，青蒿素相关性内过氧化物选自由倍半萜内酯类及其醇类、碳酸酯类、酯类、醚类和磺酸酯类、阿替夫林、1，2，4-三烷类和1，2，4，5-四烷类组成的组。青蒿素相关性内过氧化物可具有如下结构： 其中R为 或 ，R1为氢、羟基、烷基或具有下列通式： -O-R2， 或 其中R2为烷基或芳基且n为1-6；或者其药学上可接受的盐。本文所用的术语″烷基″指的是含有1-6个碳原子、优选1-4个碳原子的低级烷基。本发明的烷基可以是直链或支链基团。术语″芳基″指的是含有4-14个主链碳或杂原子的单环和多环芳族基团，包括碳环芳基和杂环芳基。碳环芳基是其中所有的环原子均为碳的芳基。杂环芳基含有1-4个杂原子作为环原子，剩余的环原子为碳。有代表性的芳基包括例如苯基和苄基。药物上可接受的盐包括碱金属或碱土金属盐，优选钠或钾盐。 例如，本发明的青蒿素相关性内过氧化物包括：青蒿素，其中R为 二氢青蒿素(R1＝-OH)；artesunicacid(R1＝-OCO(CH2)2CO2H)；以及青蒿琥酯；蒿甲醚(R1＝-OCH3)；和蒿乙醚(R1＝-OC2H5)。本发明其它有代表性的内过氧化物化合物包括artelinicacid、二氢青蒿素丙基碳酸酯、阿替夫林(Ro.42-1611)及其类似物(Biirgen等(1994)Sixth Int.Cong.Infect.Dis.Abst.427，p.152，Prague)、1，2，4-三烷类(Peters等(1993)Ann.Trop.Med.Parasit.87(1)：9-16)和1，2，4，5-四烷类(Vennerstrom等(1992)《药物化学杂志》(J Med Chem.)35(16)：3023-3027)。青蒿素的其它合适的结构类似物描述在例如美国专利US5,216,175和US5,180,840、Cumming等(1998)《药物化学杂志》(J Med Chem.)41(6)：952-64和PCT专利申请WO 97/01548、WO 99/33461和WO 00/42046中。 青蒿素相关性内过氧化物的来源可以为天然(例如分离自植物)、合成或半合成的。例如，可以通过在微生物宿主中表达相关合成途径中的酶来产生自由基发生剂(例如，参见Martin等(2003)《天然生物技术》(Nature Biotechnol.)，在线公开：2003年6月1日，doi：10.1038/nbt833)。 本文所用的术语″携带铁的蛋白质″指的是适合于将铁转运至细胞的蛋白质。本发明共价缀合物中携带铁的蛋白质可以为哺乳动物蛋白，例如人蛋白质。典型的携带铁的蛋白质包括蛋白质中的运铁蛋白家族、与中性明胶酶相关的脂质运载蛋白(neutral gelatinase-associatedlipocalin，NGAL)、血红素蛋白和其它结合铁的蛋白质。铁在细胞生长中起着关键的作用。蛋白质中的运铁蛋白家族包括运铁蛋白、乳铁蛋白、卵运铁蛋白(ovotransferrin)和黑运铁蛋白(melanotransferrin)(Aisen & Harris(1989)在《铁载体和铁蛋白》(Iron Carriers and IronProteins)中所述(ed.Loehr，VCH，New York)273-320页；Baker(1994)《高级无机化学》(Adv.Inorg.Chem.)41：389-463)。所有这些蛋白质均为结构相关性的单链糖蛋白，含有670-690个氨基酸。运铁蛋白将铁和血红素从循环中转运入细胞。运铁蛋白的载铁形式(全运铁蛋白)结合细胞表面上的运铁蛋白受体，并通过受体介导的胞吞作用被摄入细胞内，在此释放铁。乳铁蛋白在从人乳中吸收铁的过程中具有关键作用。乳铁蛋白的另一种功能是阻止铁接触传染原。不同于运铁蛋白，乳铁蛋白可以在低pH下稳定地结合铁并吸收入肠中。 NGAL是与运铁蛋白家族无关的携带铁的蛋白质，推测它可以将铁递送至分化着的上皮细胞处(Kaplan(2002)《细胞》(Cell)111：603-6)。血红素蛋白为诸如血红蛋白、肌红蛋白、血红素结合蛋白、细胞色素、过氧化氢酶和过氧化物酶这类携带血红素作为辅基的蛋白质。例如，血红素结合蛋白是60kDa的血清糖蛋白，它以极高的亲合力从血流中螯合血红素，并将其转运至肝(Baker等(2003)《美国国家科学院学报》(Proc.Natl.Acad Sci.US.A.)100(7)：3579-83)。 在本发明的共价缀合物中，青蒿素相关性内过氧化物与携带铁的蛋白质连接，连接的方式可以是能保留携带铁的蛋白质的活性和青蒿素相关性内过氧化物的活性二者的任何方式。例如，如实施例1中所述，可以通过下列步骤将青蒿素相关性内过氧化物与糖基化的携带铁的蛋白质连接：首先制备青蒿素相关性内过氧化物的酰肼衍生物，然后使其与携带铁的蛋白质上的一个或多个氧化多糖基团连接。为了制备青蒿素相关性内过氧化物的酰肼衍生物，可以首先通过下列步骤形成青蒿素相关性内过氧化物的酯：将1-羟基苯并三唑(HOBt)加入到青蒿素相关性内过氧化物中，随后添加乙基二甲基乙基碳二亚胺。然后使HOBt酯与肼反应生成酰肼衍生物。随后使该酰肼衍生物与携带铁的蛋白质共价连接，其中已用氧化剂(诸如高碘酸钠)氧化了多糖基团。任何含有-(C＝O)NH-基团的青蒿素相关性内过氧化物均可以用于制备可与运铁蛋白或其它携带铁的糖蛋白连接的酰肼衍生物(例如，参见Gumming等(1998)《药物化学杂志》(J Med.Chem.)41(6)：952-64)。 还可以通过首先制备青蒿素相关性内过氧化物的肼或氨氧基衍生物而将青蒿素相关性内过氧化物与糖基化的携带铁的蛋白质连接起来。为了制备青蒿素相关性内过氧化物的肼或氨氧基衍生物，首先通过下列步骤形成青蒿素相关性内过氧化物的卤化物：将卤代醇加入到青蒿素相关性内过氧化物中，随后添加三氟化硼合乙醚。然后可以使所述的卤化物或青蒿素相关性内过氧化物与肼或羟基胺反应而分别生成肼或氨氧基衍生物。卤代基团可以被对甲苯磺酰基或甲磺酰基取代而用于反应。然后可以使肼或氨氧基衍生物与携带铁的蛋白质共价连接，其中已用氧化剂(诸如高碘酸钠)氧化了多糖基团。任何含有-(C＝O)NH-、-NH-或-O-基团的青蒿素相关性内过氧化物均可以用于制备可与运铁蛋白或其它携带铁的糖蛋白连接的肼衍生物或氨氧基衍生物。 适合于按照这种方式连接的青蒿素相关性内过氧化物包括可以从中制备酰肼、肼或氨氧基衍生物而不破坏内过氧桥活性的化合物。一般来说，通过间隔基(诸如烃链)将内过氧桥与酰肼、肼或氨氧基隔开。还可以将醚类、酯类、酰胺类、硫化物和二硫化物用作间隔基。例如，可以用苯环将内过氧化桥与如阿替林酯上的酰肼、肼或氨氧基隔离开。因此，适用于本发明的青蒿素相关性内过氧化物包括、但不限于如下结构的内过氧化物： 其中n＝1-3，m＝0-3，Ar＝芳基，例如苯基、萘基、芘基、吡啶基或嘧啶基，且Y＝-(C＝O)NH-、-NH-或-O-。有代表性的存在于本发明共价缀合物中的青蒿素相关性内过氧化物包括阿替林酯和二氢青蒿素。 用于将青蒿素相关性内过氧化物与携带铁的糖蛋白相连接的方法包括硼酸酯介导的与携带铁的糖蛋白上的糖残基的连键(例如，参见美国专利US5,919,708)。因此，含有硼酸酯基的青蒿素相关性内过氧化物将与蛋白质表面上的糖残基的1，2-二醇部分反应。 就非糖基化的携带铁的蛋白质而言，可以如实施例2中所述通过使用氨基酸侧链使青蒿素相关性内过氧化物与该蛋白质连接。例如，青蒿琥酯和阿替林酯带有可以用N-羟基琥珀酰亚胺(例如，参见Lewis等(1994)《生物缀合物化学》(Bioconj.Chem.)5(6)：655-76)和水溶性碳化二亚胺试剂、诸如N-乙基(etheyl)-N′-二甲氨基乙基碳化二亚胺活化成活性酯的游离羧酸基。可以将这种酯与非糖基化的携带铁的蛋白质的水溶液混合而将青蒿素相关性内过氧化物与该蛋白质表面上的Lys残基连接。 可以通过本领域中的标准方法，例如通过使用凝胶过滤色谱法、离子交换和反相或疏水相互作用高压液相色谱法(HPLC)纯化所述的共价缀合物。可以通过使用本领域中的标准方法，例如离子喷雾质谱法，测定与一个分子的携带铁的蛋白质相结合的青蒿素相关性内过氧化物分子的数量。共价缀合物中青蒿素相关性内过氧化物与携带铁的蛋白质的比例取决于所用的携带铁的蛋白质和形成缀合物的方法。例如，使用实施例1中所述的方法获得每分子的全运铁蛋白含有1-10个分子的青蒿素相关性内过氧化物的共价缀合物。 本发明还提供了包括本发明共价缀合物的组合物。在某些实施方案中，如实施例1中所述，本发明的组合物包括阿替林酯与人全运铁蛋白之间的共价缀合物。在其它实施方案中，所述的组合物包括阿替林酯与人全乳铁蛋白之间的共价缀合物。 本发明的共价缀合物可用于治疗癌症。由于大部分癌细胞快速分裂，所以它们具有比正常细胞更高的铁摄取速率，且表达的细胞表面运铁蛋白受体的浓度也高于正常细胞。已经证实给予铁盐或全运铁蛋白增加了癌细胞对青蒿素及其类似物的敏感性(Moore等(1995)《癌症通讯》(Cancer Lett.)98：83-7；Singh & Lai(2001)《生命科学》(LifeSci.)70：49-56；Sadava等(2002)《癌症通讯》(Cancer Lett.)1179：151-6)。因此，通过将青蒿素相关性内过氧化物与携带铁的蛋白质、诸如全运铁蛋白共价连接，可增加青蒿素相关性内过氧化物对癌症的功效和选择性，因为内过氧化物和铁同时被转运至或转运入同一细胞。 本发明的共价缀合物还可用于治疗具有共价缀合物中所述携带铁的蛋白质的受体的致病生物体所导致的感染。为了建立成功的感染，病原体必须克服宿主施加的严格铁限制。为了克服这种限制，许多病原体从携带铁的宿主蛋白中获得铁(例如，参见Cornelissen，(2003)Front.Biosci.8：D836-47)。例如，细菌性脑膜炎的病原体脑膜炎奈瑟氏球菌表达携带铁的蛋白质-运铁蛋白和乳铁蛋白的细胞表面受体(Evans&Oakhill(2002)《生物化学协会学报》(Biochem.Soc.Trans.)30(4)：705-7)，人胃炎和消化性溃疡的病原体幽门螺杆菌表达人乳铁蛋白的受体(Husson等(1993)《感染性免疫》(Infect.Immun.)61(6)：2694-7)，而金黄色葡萄球菌表达血红蛋白受体(Mazmanian等(2003)《科学》(Science)299：906-9)。因此，本发明的共价缀合物可用于杀死其中具有共价缀合物中所述携带铁的蛋白质的受体的致病生物体。例如，青蒿素相关性内过氧化物与人运铁蛋白或人全乳铁蛋白之间的共价缀合物可以用于治疗脑膜炎奈瑟氏球菌导致的细菌性脑膜炎或幽门螺杆菌导致的胃炎和消化性溃疡病。 按照本发明的方法，当对癌细胞给药时，青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物具有优于分别给予青蒿素相关性内过氧化物和携带铁的蛋白质所达到的细胞毒性活性。此外，本发明的共价缀合物可有效杀伤带有携带铁的蛋白质的受体的病原体。 本发明在第二个方面中提供了对有此需要的受试者给予组合物的方法，该组合物包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物。青蒿素相关性内过氧化物与携带铁的蛋白质的共价缀合物如上所述。例如，如实施例1中所述，某些实施方案提供了阿替林酯与全运铁蛋白的共价缀合物。 这些方法适合于任意动物受试者，诸如人体受试者。例如，需要有包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物的组合物的受试者可以是癌症患者。如上所述，快速增殖的细胞、诸如癌细胞一般具有较高的细胞表面运铁蛋白受体浓度。该方法提供了选择性递送内过氧化物部分和铁的机制，它可以对快速增殖的细胞、诸如癌细胞产生反应。因此，本发明提供了治疗癌症的方法，通过对有此需要的人或动物受试者给予有效量的化合物来进行，该化合物包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物。其它存在细胞过度增殖且可以用本发明的共价缀合物治疗的疾病包括、但不限于再狭窄、自身免疫病、关节炎、移植物排斥、炎症性肠病或医疗操作后诱发的增殖。在某些实施方案中，所述的方法包括给予化合物的步骤，该化合物包括阿替林酯与人全运铁蛋白之间的共价缀合物。 还可以给予包括青蒿素相关性内过氧化物与携带铁的蛋白质之间的共价缀合物的化合物和组合物，以便治疗由表达共价缀合物中所述携带铁的蛋白质的细胞表面受体的病原体所导致的感染。本文所用的术语″治疗病原体导致的感染″指的是抑制病原体生长和/或预防或改善与该感染相关的疾病症状。 具有携带铁的宿主蛋白的受体的典型病原体如上所述，包括表达人运铁蛋白的受体的脑膜炎奈瑟氏球菌和表达人乳铁蛋白的受体的幽门螺旋菌。目前已经证实金黄色葡萄球菌表达血红蛋白受体(Mazmanian等(2003)《科学》(Science)299：906-9)，单核细胞增生利斯特氏菌(Listeria monocytogenes)和炭疽芽孢杆菌(Bacillus anthracis)也表达类似的蛋白质(Cabanes等(2002)《微生物学趋势》(Trends.Microbiol.)10(5)：238-45)。表达携带铁的宿主蛋白的受体的典型病原体实例如表1中所示。一旦该携带铁的蛋白质与病原体表达的受体相结合，则铁或血红素一般从携带铁的蛋白质中释放出来，并被转运入细胞(例如，参见Gray-Owens &Schryyers(1996)《微生物学趋势》(Trends.Microbiol.)4(5)：185-91；Wandersman &Stojiljkovic(2000)《最新微生物学观点》(Curer.Op.Microbiol.)3：215-20)。 表1.人和动物病原体中携带铁的蛋白质的受体 病原体 宿主 疾病 受体 牛莫拉氏菌粘膜炎莫拉氏菌腔隙莫拉氏菌脑膜炎奈瑟氏球菌淋病奈瑟氏球菌放线共生放线杆菌(Actinobacillusactinomycetecomitans)马驹放线杆菌胸膜肺炎放线杆菌(Actinobacilluspleuropneumoniae)羔羊嗜血菌鸟巴斯德氏菌流感嗜血杆菌副鸡嗜血杆菌(Haemophilusparagallinarum)睡眠嗜血杆菌(Haemophilus somnus)副猪嗜血杆菌杜克氏嗜血杆菌 牛人人人人人马猪绵羊家禽人家禽牛猪人 角膜结膜炎中耳炎角膜结膜炎脑膜炎淋病青少年牙周炎败血症肺炎败血症窦炎脑膜炎，中耳炎传染性鼻炎血栓栓塞性脑膜脑炎格拉瑟病生殖器溃疡病 运铁蛋白，乳铁蛋白1运铁蛋白，乳铁蛋白1运铁蛋白，乳铁蛋白1运铁蛋白，乳铁蛋白1血红蛋白1，19运铁蛋白，乳铁蛋白，血红蛋白1，18运铁蛋白1运铁蛋白1运铁蛋白1运铁蛋白1运铁蛋白1运铁蛋白，血红蛋白1，20运铁蛋白1运铁蛋白1运铁蛋白1血红蛋白15 病原体 宿主 疾病 受体 溶血巴斯德氏菌多杀巴斯德氏菌金黄色葡萄球菌表皮葡萄球菌(Staphyloccusepidermidis)肺炎链球菌Leishmaniachagasi大肠埃希氏杆菌K88Tritrichonomasfoetus苍白密螺旋体肺炎枝原体百日咳博德特氏菌Trichonomasvaginalis杀鲑气单胞菌幽门螺杆菌小肠结肠炎耶尔森氏菌创伤弧菌牙龈卟啉单胞菌(Porphyromonasgingivalis) 牛，绵羊，山羊牛人人人人猪牛人人人人鱼人人鳗鱼(eel)人 航运热，巴斯德菌病肺炎，败血症菌血症，肺炎，心内膜炎，脓毒性关节炎，骨髓炎，深脓肿，食物中毒心内膜炎，眼内炎，败血症，膀胱炎肺炎，脑膜炎，菌血症，中耳炎利什曼病肠病发生毛滴虫病梅毒肺炎百日咳阴道病疖病胃炎，胃和十二指肠溃疡，胃腺癌，淋巴瘤肠炎食物中毒，败血症，创伤感染牙周病 运铁蛋白1运铁蛋白1运铁蛋白血红蛋白2，13运铁蛋白2乳铁蛋白3运铁蛋白，乳铁蛋白4运铁蛋白5乳铁蛋白血红蛋白6乳铁蛋白7乳铁蛋白8乳铁蛋白9乳铁蛋白10运铁蛋白，乳铁蛋白11乳铁蛋白12血红蛋白，肌红蛋白，血红素结合蛋白，过氧化氢酶，清蛋白-血红素14血红蛋白16血红蛋白17 1 Gray-Owen & Schryvers(1996)Trends 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本发明该方面的方法提供了选择性递送内过氧化物部分和铁的机制，它可以通过使共价缀合物与携带铁的蛋白质的受体结合而对致病生物体的细胞膜产生直接的反应。按照本发明的方法，结合的共价缀合物中的内过氧化物部分与从携带铁的蛋白质中释放的铁或血红素反应，从而在病原体附近产生有害自由基。因此，本发明提供了治疗幽门螺杆菌导致的疾病的方法，通过对有此需要的人体受试者给予有效量的包括青蒿素相关性内过氧化物与人全乳铁蛋白之间的共价缀合物的组合物来进行。本发明还提供了治疗脑膜炎奈瑟氏球菌导致的疾病的方法，通过对有此需要的人体受试者给予有效量的包含青蒿素相关性内过氧化物与人全运铁蛋白之间的共价缀合物的组合物来进行。 可以通过给予有效量的包括本发明共价缀合物的组合物治疗的其它典型的感染包括局部细菌感染，诸如龈炎、皮肤和眼部感染。 所述共价缀合物的有效量一般可达最大耐受剂量，但浓度并非关键且可以广泛改变。当然，临床医师使用的精确量随化合物、给药途径、患者的身体情况和其它因素而改变。可以将每日剂量作为单剂量给药或可以将其分成多次剂量给药。 实际给予的本发明缀合物的用量应是治疗有效量，本文所用的该术语表示产生实质性的有益作用所需的用量。可以根据由体外或动物模型试验系统得到的剂量-反应曲线外推出有效剂量。一般还将动物模型用于确定理想的剂量范围和给药途径。然后将这类信息用于确定用于人或其它哺乳动物的有用剂量和给药途径。有效剂量的测定也属于本领域技术人员的能力范围。因此，实际给予的用量取决于治疗所施用的个体，并优选是优化用量，以便获得所需作用而没有显著副作用。 可以通过标准制药步骤在细胞培养物或实验动物中测定本发明共价缀合物的治疗功效和可能的毒性(例如ED50，即有效治疗50％群体的剂量；和LD50，即使50％群体致死的剂量)。治疗与毒性作用之间的剂量比为治疗指数，可以将其表示为LD50与ED50之比。表现出高治疗指数的共价缀合物特别适合于实施本发明的方法。可以将从细胞培养试验和动物研究中获得的数据用于配制人或其它哺乳动物所使用的剂量范围。这类缀合物的剂量优选属于包括几乎没有或无毒性的ED50的循环浓度范围内。剂量一般在该范围内改变，这取决于所用的剂型、受试者的敏感性和给药途径。因此，最佳用量可以根据给药方法的不同而改变，并且一般为以相同或相似形式给药的常用药剂的用量。 可以将本发明的共价缀合物单独或与一种或多种其它治疗活性剂一起给药。例如，在治疗癌症的过程中，可以将该缀合物与治疗剂联用，所述的治疗剂包括、但不限于：雄激素抑制剂，诸如氟他胺和luprolide；抗雌激素药，诸如他莫昔芬；抗代谢药和细胞毒性剂，诸如柔红霉素、氟尿嘧啶、氟尿苷、干扰素α、氨甲蝶呤、普卡霉素、巯基嘌呤、硫鸟嘌呤、多柔比星、卡莫司汀、洛莫司汀、阿糖胞苷、环磷酰胺、多柔比星、雌莫司汀、六甲蜜胺、羟基脲、异环磷酰胺、丙卡巴肼、丝裂菌素制剂、白消安、米托蒽醌、卡铂、顺铂、链佐星、博来霉素、放线菌素和伊达比星；激素，诸如甲羟孕酮、雌莫司汀、炔雌醇、雌二醇、亮丙立德、甲地孕酮、奥曲肽、己烯雌酚、氯烯雌醚、依托泊苷、鬼臼毒素和戈舍瑞林；氮芥衍生物，诸如美法仑、苯丁酸氮芥、methlorethamine和塞替派；类固醇，诸如倍他米松；和其它抗肿瘤药，诸如活牛分枝杆菌(Mycobacterium bovis)、dicarbazine、天冬酰胺酶、亚叶酸、米托坦、长春新碱、长春碱和泰索帝。在每种情况中的适宜用量随特定活性剂的不同而改变，本领域技术人员易于得知或易于通过常规实验测定。 还可以将本发明的共价缀合物与例如可增加缀合物中携带铁的蛋白质的细胞表面受体数量而增加铁向细胞内的转运的活性剂联合给药。例如，已经证实胰岛素、胰岛素样生长因子I和表皮生长因子会引起细胞表面上的运铁蛋白受体数量增加(例如，参见Davis等(1987)《生物化学杂志》(J Biol.Chem.)261(19)：8708-11；Davis等(1986)《生物化学杂志》(J Biol.Chem.)262(17)：13126-34)。因此，在某些实施方案中，将本发明含有运铁蛋白的共价缀合物与胰岛素、胰岛素样生长因子I或表皮生长因子联合给药。 可以通过任意有效途经、例如通过非肠道或口服来给予本发明的共价缀合物。给药方法包括局部(例如皮肤贴剂)、吸入、口含、动脉内、皮下、髓内、静脉内、鼻内、直肠内、眼内给药和其它常用方式。例如，可以将所述的共价缀合物直接注入肿瘤、注入肿瘤附近或注入对肿瘤供血的血管。 可以将本发明的共价缀合物配制成组合物，该组合物中另外含有合适的药物上可接受的载体，包括赋形剂和其它有利于对哺乳动物受试者给予该共价缀合物的其它化合物。有关配制和给药的更具体的技术可以在最新版《Remington氏药物科学》(″Remington′s PharmaceuticalSciences″)(Maack Publishing Co，Easton PA)中找到。 可以使用本领域中众所周知的药物上可接受的载体配制用于口服给药的组合物，其剂量适合于口服给药。这类载体能够将含有本发明的共价缀合物的组合物配制成适合于受试者摄取的片剂、丸剂、锭剂、胶囊、液体、凝胶、糖浆剂、浆液、混悬液等。可以将口服应用的组合物与固体赋形剂一起配制，任选研磨所得混合物，并且如果需要，在加入合适的其它化合物后将该颗粒混合物进行加工，以制成片剂或锭剂药芯。合适的赋形剂包括碳水化合物或蛋白质填料。它们包括、但不限于：糖类，包括乳糖、蔗糖、甘露糖醇或山梨醇；来自玉米、小麦、稻、马铃薯或其它植物的淀粉；纤维素，诸如甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素钠；和树胶，诸如阿拉伯胶和黄耆胶；以及蛋白质，诸如明胶和胶原蛋白。如果需要，可以加入崩解剂或加溶剂，诸如交联聚乙烯吡咯烷酮、琼脂、藻酸或其盐，诸如藻酸钠。 给锭芯包合适的包衣层，诸如浓糖溶液，其还可以含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆用溶液和合适的有机溶剂或溶剂混合物。可以向片剂或锭剂包衣层中加入染料或色素以用于产品识别或表征活性化合物用量(即剂量)。 例如，可以将用于口服给药的共价缀合物配制成由明胶制成的推入配合式胶囊以及由明胶和诸如甘油或山梨醇这类包衣材料组成的密封软胶囊。推入配合式胶囊可以含有共价缀合物，其中混有：填充剂或粘合剂，诸如乳糖或淀粉；润滑剂，诸如滑石或硬脂酸镁；和任选的稳定剂。在软胶囊中，可以将共价缀合物溶于或悬浮于合适的含有或不含稳定剂的液体中，诸如脂肪油、液体石蜡或液体聚乙二醇。 非肠道给药用组合物包括一种或本发明共价缀合物的水溶液。为了进行注射，可以用生理上相容的缓冲液、诸如Hank′s溶液、林格液或生理缓冲盐水将本发明的共价缀合物配制成水溶液。含水的注射混悬液可以含有增加该混悬液粘度的物质，诸如羧甲基纤维素钠、山梨醇或葡聚糖。另外，可以将共价缀合物的混悬液制备成适宜的油性注射混悬液。合适的亲脂性溶剂或载体包括：脂肪油，诸如芝麻油；或合成的脂肪酸酯类，诸如油酸乙酯或甘油三酯类；或脂质体。该混悬液还可以任选含有合适的稳定剂或增加共价缀合物溶解度的试剂以便制备高浓度溶液。 为了进行局部或鼻部给药，一般将适合于透入特定屏障的渗透剂用于制剂中。它们的实例为2-吡咯烷酮、N-甲基-2-吡咯烷酮、二甲基乙酰胺、二甲基甲酰胺、丙二醇、甲醇或异丙醇、二甲亚砜和月桂氮酮。还可以包括其它试剂以使制剂在美容上可接受。它们的实例为脂肪、蜡、油、染料、香料、防腐剂、稳定剂和表面活性剂。还可以包括诸如本领域中公知的那些角质分解剂。实例为水杨酸和硫。为了进行局部给药，组合物可以为用于全身递送所述化合物的经皮软膏或贴剂的形式，可以按照常规方式制备(例如，参见Barry，《皮肤病用制剂》(Dermatological Formulations)(Drugs and the PharmaceuticalSciences--Dekker)；Harrys Cosmeticology(Leonard Hill Books)。 为了进行直肠给药，可以以栓剂或滞留型灌肠剂的形式给予组合物。可以通过将共价缀合物与合适的无刺激性赋形剂混合来制备这类组合物，所述的无刺激性赋形剂在常温下为固体，而在直肠温度下为液体，由此在直肠中熔化而释放药物。合适的赋形剂包括、但不限于可可脂和聚乙二醇类。 这些不同类型的添加剂各自的用量对本领域技术人员而言是显而易见的，最佳用量与设计用于相同类型给药的其它已知制剂相同。例如，角质层渗透促进剂一般是约0.1％-约15％浓度。 可以按照与本领域中已知类似的方式制备含有本发明共价缀合物的组合物(例如，通过常规的混合、溶解、成粒、制锭、研磨、乳化、包囊、包埋或冻干法)。还可以通过常规方式(例如包衣)改变组合物成以提供适当释放特性，例如缓释或靶向释放。 可以盐的形式提供包含共价缀合物的组合物，并且可以与许多酸成盐，包括、但不限于盐酸、硫酸、乙酸、乳酸、酒石酸、苹果酸、琥珀酸等。盐倾向于比相应的游离碱形式更易溶于水性或其它质子溶剂。 在制备了制成含有共价缀合物和可接受的载体的这类组合物后，可以将它们放入合适的容器并标记使用。 下列实施例仅解释了目前已知用于实施本发明的最佳方式，但不应用于限制本发明。 实施例1 本实施例描述了本发明有代表性的组合物的制备方法，该组合物含有一种或多种与全运铁蛋白分子共价连接的青蒿素相关性内过氧化物分子。 Artelinic acid hydrazide的合成(ART-NH-NH2)：制备青蒿琥酯的酰肼衍生物的尝试并不成功，因环化反应而导致形成二氢青蒿素。如上所述由二氢青蒿素合成阿替林酯(Shrimali等(1998)《印度化学杂志》(Indian J Chem.)37B：1161-1163)。将artelinic acid(0.1g，0.24mmol)溶于无水乙腈(0.48mL)。向该溶液中加入1-羟基苯并三唑(HOBt)(0.038g，0.29mmol)，随后添加乙基二甲基乙基碳化二亚胺(0.055g，0.29mmol)。在室温下搅拌该反应混合物并通过薄层色谱法(TLC)监测，直到所有的酸均转化成HOBt酯。 将肼(0.46mL，0.48mmol)在乙腈(0.48mL)中的溶液冷却至0℃，并将上述反应混合物加入到该体系中，同时将温度维持在0-10℃。正如通过TLC测定的，在10分钟后反应完全。将该反应混合物倾入水(5mL)中、用乙酸乙酯(3×10mL)萃取并用盐水洗涤。分离有机相、用无水硫酸钠干燥并蒸发至干。通过使用甲醇/氯仿梯度的硅胶色谱法纯化粗产物而得到纯的产物(0.078g)，产率为76％。 阿替林酯-全运铁蛋白缀合物的合成：在室温下使用10mmol/L高碘酸钠将溶于1ml 0.1mol/L pH 5.5的乙酸钠的全运铁蛋白(2mg)在其聚糖水平氧化30分钟。将该溶液上样到安装了UV监测器的短Sephadex G-25柱。用0.1mol/L pH 5.5的乙酸钠洗脱该柱并收集蛋白质级分。向氧化的全运铁蛋白中加入过量的ART-NH-NH2溶液并将该反应体系在室温下保持过夜，同时轻轻振摇。然后将阿替林酯-全运铁蛋白缀合物溶液上样到Sephadex G-25柱上，以除去过量的ART-NH-NH2。用pH 7.5的0.1mol/L Tris-HCl缓冲液洗脱该柱，并收集蛋白质级分。将缀合物储存在4℃下。 通过疏水相互作用HPLC纯化阿替林酯-全运铁蛋白缀合物，得到均一的蛋白质缀合物。通过离子喷雾质谱法测定每个全运铁蛋白分子的青蒿琥酯分子数。 尽管已经解释和描述了本发明的优选实施方案，但是可以理解可以对其中进行各种改变而不会脱离本发明的实质和范围。 实施例2 本实施例描述了本发明有代表性的组合物的制备方法，该组合物含有与血红蛋白分子共价连接的一个或多个青蒿素相关性内过氧化物分子。 为了用青蒿素衍生物共价修饰非糖基化的蛋白质，诸如血红蛋白，首先将青蒿素的羧酸衍生物、诸如artelinic acid活化为N-羟基琥珀酰亚胺(HOSu)酯，以便与蛋白质表面上的赖氨酸残基反应。将artelinicacid(4.2mg，0.01mmol)溶于二甲基甲酰胺(DMF)(0.5mL)中，并将该溶液在冰浴中冷却。向该溶液中加入N-乙基-N′-二甲氨基乙基碳二亚胺(EDC)(1.5mg，0.01mmol)和HOSu(1.1mg，0.01mmol)。将该反应混合物在0℃下保持搅拌2小时以完全形成artelinic acid的HOSu酯。 将血红蛋白(10mg)溶于7.0的0.1M磷酸盐缓冲液(5mL)。在0℃下将artelinicacid HOSu酯的DMF溶液缓慢加入到血红蛋白溶液中。将该反应混合物在0℃下保持搅拌2小时并在室温下再保持搅拌2小时。然后使该反应混合物上样到用pH 7的0.1M磷酸盐缓冲液平衡的Sephadex G-25柱上，并用相同的缓冲液洗脱该柱。经修饰的血红蛋白以外水体积洗脱下来。合并含有血红蛋白的级分，然后通过疏水相互作用HPLC纯化。通过离子喷雾质谱法测定与蛋白质连接的青蒿素衍生物数目。 1.包含与携带铁的蛋白质共价连接的青蒿素相关性内过氧化物的共价缀合物。 2.权利要求1所述的共价缀合物，其中所述青蒿素相关性内过氧化物包括阿替林酯。 3.权利要求1所述的共价缀合物，其中所述青蒿素相关性内过氧化物是酰肼衍生物。 4.权利要求2所述的共价缀合物，其中所述青蒿素相关性内过氧化物具有如下结构： 其中n＝1-3，m＝0-3，Ar＝芳基，且Y＝-(C＝O)NH-、-NH-或-O-。 5.权利要求1所述的共价缀合物，其中所述携带铁的蛋白质选自全运铁蛋白、全乳铁蛋白、血红蛋白、血红素结合蛋白和与中性明胶酶相关的脂质运载蛋白组成的组。 6.权利要求5所述的共价缀合物，其中所述携带铁的蛋白质为全运铁蛋白。 7.权利要求5所述的共价缀合物，其中所述携带铁的蛋白质为全乳铁蛋白。 8.权利要求5所述的共价缀合物，其中所述携带铁的蛋白质为哺乳动物蛋白。 9.权利要求5所述的共价缀合物，其中所述携带铁的蛋白质为人蛋白。 10.权利要求1所述的共价缀合物，其中包括阿替林酯和全运铁蛋白。 11.权利要求1所述的共价缀合物，其中包括阿替林酯和全乳铁蛋白。 12.权利要求1所述的共价缀合物，其中包括阿替林酯和血红蛋白。 13.一种组合物，其中包括与携带铁的蛋白质共价连接的青蒿素相关性内过氧化物的共价缀合物，以及药物上可接受的载体。 14.包含与携带铁的蛋白质共价连接的青蒿素相关性内过氧化物的共价缀合物在制备用于治疗癌症的药物中的用途。 15.权利要求14所述的用途，其中所述青蒿素相关性内过氧化物选自阿替林酯和二氢青蒿素组成的组。 16.权利要求14所述的用途，其中所述携带铁的化合物为全运铁蛋白。 17.权利要求14所述的用途，其中所述药物被制成经非胃肠道给药。 18.含有青蒿素相关性内过氧化物与携带铁的蛋白质的共价缀合物在制备用于治疗被病原体感染的受试者的药物中的用途，其中所述的病原体表达该携带铁的蛋白质的受体。 19.权利要求18所述的用途，其中所述的青蒿素相关性内过氧化物选自阿替林酯和二氢青蒿素组成的组。 20.权利要求18所述的用途，其中所述的携带铁的蛋白质选自全运铁蛋白、全乳铁蛋白、血红蛋白、血红素结合蛋白和与中性明胶酶相关的脂质运载蛋白组成的组。 21.权利要求18所述的用途，其中所述的病原体包括幽门螺杆菌(Helicobacter pylori)，其中所述的携带铁的蛋白质包括人乳铁蛋白，且其中所述的青蒿素相关性内过氧化物选自阿替林酯和二氢青蒿素组成的组。 22.权利要求18所述的用途，其中所述的病原体包括脑膜炎奈瑟氏球菌(Neisseria meningitidis)，其中所述的携带铁的蛋白质包括人运铁蛋白，且其中所述的青蒿素相关性内过氧化物选自阿替林酯和二氢青蒿素组成的组。 https://patents.google.com/patent/CN1313145C/zh?oq=CN1313145C青蒿素相关性内过氧化物与携带铁的+蛋白质之间的共价缀合物及其使用方法 Covalent conjugates between artemisinin-related endoperoxides and iron-carrying proteins and methods of use In one aspect, the invention provides covalent conjugates between artemisinin related endoperoxides and iron-carrying proteins. In some embodiments, the covalent conjugates comprise artelinate and holotransferrin. In another aspect, the invention provides methods for administering the covalent conjugates of the invention to treat cancer and infections by pathogens that bind iron-carrying proteins. Arteannuin dependency endoperoxide and carry covalent conjugates and using method thereof between the protein of ferrum The cross reference of related application The application requires the interests of the U.S. Provisional Application submitted on June 6th, 2002 according to 35U.S.C.119 number 60/386,928. Invention field The present invention relates to covalent conjugates between arteannuin (artemisinin) dependency endoperoxide (endoperoxide) and the protein that carries ferrum and these conjugates in the treatment cancer with by can be in conjunction with the application in the infection that the proteinic pathogen of carrying ferrum causes. Background of invention Arteannuin is an isolating sesquiterpene lactones class from plant Artemisia annua (Artemisia annua L), and the extract of this plant has been used for the treatment of malaria at least 1600 years.The arteannuin molecule contains the endoperoxides bridge, and it and iron atom reaction form free radical.The malaria effect of arteannuin is to form free radical cell death is caused because of the haemachrome in itself and the parasite reacts.Cancerous cell has and is significantly higher than Normocellular flowing molten iron and goes into.Therefore, confirmed that arteannuin and analog of artemisinin have cytotoxicity (for example, referring to (1993) such as Woerdenbag " natural product magazine " (J.Nat.Prod.) 56 (6): 849-56 to the tumor set up and tumor cell line; Lai ﹠amp; Singh (1995) " cancer communication " (Cancer Lett.) 91:41-6; Efferth etc. (2001) " international oncology's magazine " are 18:767-73 (Int.J.Oncol.); Li etc. (2001) " communication of bioorganic pesticide thing chemistry " are 11:5-8 (Bioorg.Med.Chem.Lett.); Singh﹠amp; Lai (2001) " life sciences " (Life Sci.) 70:49-56; Efferth etc. (2002) " biochemistry and pharmacology " are 64:617-23 (Biochem.Pharmacol.); Efferth etc. (2002) " hemocyte, molecule and disease " (Blood Cells, Molecules ﹠amp; Diseases) 28 (2): 160-8; Sadava etc. (2002) " cancer communication " (Cancer Lett.) 179:151-6). The chemical compound that contains endoperoxides bridge (endoperoxide bridge) of having described many analog of arteannuin and other biologically active is (for example, referring to U.S. Pat 5,180,840; U.S. Pat 5,216,175; U.S. Pat 5,225,427; Cumming etc. (1998) " pharmaceutical chemistry magazine " (J Med.Chem.) 41 (6): 952-64; Posner etc. (1999) " pharmaceutical chemistry magazine " (J Med.Chem.) 42:300-4; Li etc. (2001) " communication of bioorganic pesticide thing chemistry " are 11:5-8 (Bioorg.Med.Chem.Lett.); Wu etc. (2001) " European pharmaceutical chemistry magazine " are 36:469-79 (Eur.J.Med.Chem.); Posner etc. (2003) " pharmaceutical chemistry magazine " (J Med.Chem.) 46:1060-5).The analog of artemisinin that has been used for the treatment of malaria comprises dihydroartemisinine, Artemether, artesunate, arteether, dihydroartemisinin propyl carbonic ester and artelinic acid. Arteannuin is comparatively safe medicine, even also has only few and humble side effect under high dose.6 days 70mg/kg/ days oral dose is used for the treatment of people's malaria.After with artesunate treatment cancer patient, do not observe tangible adverse side effect (oral dose 50mg/ days; Intramuscular dosage 60mg/ days; 9 months by a definite date) (Singh ﹠amp; Verma (2002) " oncology's journal " (Arch.Oncol.) 10 (4): 279-80).Also arteannuin and analog of artemisinin are used for the treatment of dermatosis, such as psoriasis, foaming characteristic dermatosis, viral verruca, condyloma subcutaneum (mulluscum contagiosum) and hemorrhoid (for example, referring to U.S. Pat 4,978,676; U.S. Pat 5,219,880).Also arteannuin and analog of artemisinin are used for prevention of malaria. The verified protein ferritin for the national games (holotransferrin) that gives iron salt or carry ferrum has increased the sensitivity (Lai of the tumor of cancerous cell and implantation to arteannuin and analog thereof; Singh (1995) " cancer communication " (Cancer Lett.) 91:41-46; Moore etc. (1995) " cancer communication " (Cancer Lett.) 98:83-7; Singh ﹠amp; Lai (2001) " life sciences " (Life Sci.) 70:49-56; Sadava etc. (2002) " cancer communication " (Cancer Lett.) 1179:151-6). Confirm that also some pathogen is by obtaining ferrum in conjunction with the host protein that carries ferrum.For example, the pathogen Neisseria meningitidis of bacterial meningitis is expressed the cell surface receptor of the chemical compound that carries ferrum, such as transferrin (transferrin) and lactoferrin (lactoferrin) (Evans ﹠amp; Oakhill (2002) " biochemistry association journal " (Biochem.Soc.Trans.) 30 (4): 705-7).At present, still not having vaccine, to can be used for Neisseria meningitidis Type B bacterial strain be most popular bacterial strain in the Western countries.In addition, the pathogen helicobacter pylori of confirmer's gastritis, gastric duodenal ulcer and adenocarcinoma (Helicobacter pylori) can (Husson etc. (1993) " infectious immunity " (Infect.Immun.) 61 (6): 2694-7) by obtain ferrum in conjunction with human lactoferrin. Still need the arteannuin compositions that render a service to increase in this area, to be used for the treatment of cancer and by the disease that can cause in conjunction with the pathogen of the host protein that carries ferrum.Also need to be used for the treatment of cancer and by the method that can obtain the infection that pathogen caused of ferrum by the host protein that ferrum is carried in absorption.The present invention has satisfied these demands. Summary of the invention Noval chemical compound is provided among the present invention in one aspect and comprises arteannuin dependency endoperoxide and carry the compositions of the covalent conjugates between the protein of ferrum.Arteannuin dependency endoperoxide can be connected with the chemical compound that carries ferrum by hydrazides part, hydrazine part or aminooxy group part.In certain embodiments, described arteannuin dependency endoperoxide has following structure: N=1-3 wherein, m=0-3, the Ar=aryl, and Y=-(C=O) NH-,-NH-or-O-.The representational arteannuin dependency endoperoxide that is present in the covalent conjugates of the present invention comprises artelinate (artelinate) and dihydroartemisinine. The representational protein that carries ferrum that is present in the covalent conjugates of the present invention comprise transferrin family in the protein, the lipocalin protein relevant with neutral gelatinase (neutralgelatinaseassociated lipocalin, NGAL), hemoprotein and other carry the protein of ferrum.Therefore, described covalent conjugates can comprise: the conjugate of artelinate and ferritin for the national games, artelinate and full milk ferritin (hololactoferrin) or artelinate and hemoglobin for example.The present invention also provides the compositions that comprises covalent conjugates of the present invention and pharmaceutically acceptable carrier.Covalent conjugates of the present invention can be used for treating cancer and by can be in conjunction with the infection that proteinic pathogen caused of carrying ferrum. The present invention provides the method that the experimenter of needs is given covalent conjugates of the present invention in one aspect of the method.The typical covalent conjugates that is suitable for administration in the present invention is aspect this comprises: for example between artelinate and the ferritin for the national games, between artelinate and the full milk ferritin and the covalent conjugates between artelinate and the hemoglobin. In certain embodiments, the invention provides the treatment method for cancer, by the compositions that has this human or animal experimenter who needs to give effective dose is carried out, said composition comprises arteannuin dependency endoperoxide and carries covalent conjugates between the protein of ferrum.Can give described covalent conjugates by part or general, maybe they directly can be injected tumor.Can give described covalent conjugates separately or with one or more other therapeutic agents.For example, can give described covalent conjugates with the activating agent that for example can increase to intracellular iron transfer by the proteinic cell surface receptor number that carries ferrum in the increase conjugate. The present invention also provides treatment by can be in conjunction with the method for the infection that proteinic pathogen caused of carrying ferrum, by the compositions that has this human or animal experimenter who needs to give effective dose is carried out, said composition comprises arteannuin dependency endoperoxide and carries covalent conjugates between the protein of ferrum.In one embodiment, described pathogen comprises helicobacter pylori, and the protein that wherein carries ferrum comprises human lactoferrin, and wherein said arteannuin dependency endoperoxide is selected from the group of artelinate and dihydroartemisinine composition.In other typical embodiment, described pathogen comprises Neisseria meningitidis, and the wherein said protein that carries ferrum comprises human transferrin, and wherein said arteannuin dependency endoperoxide is selected from the group of artelinate and dihydroartemisinine composition. The method of treatment helicobacter pylori infections is provided in other embodiments, by the compositions that has this human or animal experimenter who needs to give effective dose is carried out, said composition comprises arteannuin dependency endoperoxide and carries covalent conjugates between the protein of ferrum. Detailed description of the preferred embodiments The compositions of the covalent conjugates between the protein that comprises arteannuin dependency endoperoxide and carry ferrum is provided among the present invention in one aspect.Term used herein " covalent conjugates " refers to wherein arteannuin dependency endoperoxide and the covalently bound chemical compound together of protein that carries ferrum.Term " arteannuin dependency endoperoxide " refers to the chemical compound that contains interior peroxide bridge (endoperoxide bridge), and it can form free radical with the iron atom reaction, causes cell death.Arteannuin dependency endoperoxides compounds can also form free radical under the situation that has copper and manganese to exist.Representational arteannuin dependency endoperoxide is as described herein, and but, obviously other endoperoxide also can be used for this purpose. In general, arteannuin dependency endoperoxide is selected from by sesquiterpene lactones class and alcohols, carbonates, esters, ethers and sulfonic acid esters, arteflene, 1,2,4-three  alkanes and 1,2,4, the group that 5-four  alkanes are formed.Arteannuin dependency endoperoxide can have following structure: Wherein R is Or , R 1For hydrogen, hydroxyl, alkyl or have following general formula: -O-R 2, Or R wherein 2For alkyl or aryl and n are 1-6; Perhaps its pharmaceutically acceptable salt.Term used herein " alkyl " refers to the low alkyl group that contains 1-6 carbon atom, preferred 1-4 carbon atom.Alkyl of the present invention can be the straight or branched group.Term " aryl " refers to and contains 4-14 main chain carbon or heteroatomic monocycle and polycyclic aromatic group, comprises isocyclic aryl and heterocyclic aryl.Isocyclic aryl is the aryl that wherein all annular atomses are carbon.Heterocyclic aryl contains 1-4 hetero atom as annular atoms, and remaining annular atoms is a carbon.Representational aryl comprises for example phenyl and benzyl.Pharmaceutically acceptable salt comprises alkali metal or alkali salt, preferred sodium or potassium salt. For example, arteannuin dependency endoperoxide of the present invention comprises: arteannuin, wherein R is Dihydroartemisinine (R 1=-OH); Artesunicacid (R 1=-OCO (CH 2) 2CO 2H); And artesunate; Artemether (R 1=-OCH 3); And arteether (R 1=-OC 2H 5).Other representational endoperoxides compounds of the present invention comprises artelinicacid, dihydroartemisinin propyl carbonic ester, arteflene (Ro.42-1611) and analog thereof (Biirgen etc. (1994) Sixth Int.Cong.Infect.Dis.Abst.427, p.152, Prague), 1,2,4-three  alkanes (Peters etc. (1993) Ann.Trop.Med.Parasit.87 (1): 9-16) with 1,2,4,5-four  alkanes (Vennerstrom etc. (1992) " pharmaceutical chemistry magazine " (J Med Chem.) 35 (16): 3023-3027).The analog that other of arteannuin is suitable is described in for example U.S. Pat 5,216,175 and US5,180,840, (1998) " pharmaceutical chemistry magazine " (J Med Chem.) 41 (6) such as Cumming: among 952-64 and PCT patent application WO 97/01548, WO 99/33461 and the WO 00/42046. The source of arteannuin dependency endoperoxide can be natural (for example separating from plant), synthetic or semisynthetic.For example, can (for example produce free radical generating agent by the enzyme of in microbial hosts, expressing in the relevant route of synthesis, referring to (2003) such as Martin " natural biological technology " (Nature Biotechnol.), online open: on June 1st, 2003, doi:10.1038/nbt833). Term used herein " carries the protein of ferrum " and refers to and is suitable for the protein of iron transfer to cell.The protein that carries ferrum in the covalent conjugates of the present invention can be mammalian proteins, for example human protein.The protein that typically carries ferrum comprise transferrin family in the protein, the lipocalin protein relevant with neutral gelatinase (neutral gelatinase-associatedlipocalin, NGAL), hemoprotein and other protein in conjunction with ferrum.Ferrum plays a part crucial in the cell growth.Transferrin family in the protein comprises transferrin, lactoferrin, ovum transferrin (ovotransferrin) and bad luck ferritin (melanotransferrin) (Aisen ﹠amp; Harris (1989) is at (ed.Loehr, VCH, New York) 273-320 page or leaf described in " siderophore and ferritin " (Iron Carriers and IronProteins); Baker (1994) " senior inorganic chemistry " is 41:389-463 (Adv.Inorg.Chem.)).All these protein are the strand glycoprotein of structural dependence, contain 670-690 aminoacid.Transferrin is transported into cell with ferrum and haemachrome from the circulation transfer.The ferrum form (ferritin for the national games) of carrying of transferrin is in conjunction with the transferrin receptor on the cell surface, and is ingested in the cell by receptor-mediated endocytosis, discharges ferrum at this.Lactoferrin has pivotal role in the process that absorbs ferrum from human milk.The another kind of function of lactoferrin is to stop the ferrum contagium.Be different from transferrin, lactoferrin can be under low pH stably in conjunction with ferrum and be absorbed in the intestinal. NGAL is and the irrelevant protein that carries ferrum of transferrin family, infers that it can be delivered to ferrum the epithelial cell place (Kaplan (2002) " cell " is 111:603-6 (Cell)) that is breaking up.Hemoprotein is for to carry the protein of haemachrome as prothetic group such as this class of hemoglobin, Myoglobin, Hemopexin, cytochrome, catalase and peroxidase.For example, Hemopexin is the seroglycoid of 60kDa, it is with high affinity chelating haemachrome from blood flow, and it is transported to liver (Baker etc. (2003) " NAS's journal " (Proc.Natl.Acad Sci.US.A.) 100 (7): 3579-83). In covalent conjugates of the present invention, arteannuin dependency endoperoxide is connected with the protein that carries ferrum, and ways of connecting can be the two any way of activity that can keep the activity of proteins of carrying ferrum and arteannuin dependency endoperoxide.For example, as described in example 1 above, can through the following steps arteannuin dependency endoperoxide be connected with the glycosylated protein that carries ferrum: at first prepare the hydrazide derivatives of arteannuin dependency endoperoxide, it is connected with one or more oxidation of polysaccharides groups on the protein that carries ferrum.In order to prepare the hydrazide derivatives of arteannuin dependency endoperoxide, can form the ester of arteannuin dependency endoperoxide at first through the following steps: I-hydroxybenzotriazole (HOBt) is joined in the arteannuin dependency endoperoxide, add ethyl dimethyl ethyl carbodiimide subsequently.Make HOBt ester and hydrazine reaction generate hydrazide derivatives then.Make this hydrazide derivatives covalently bound subsequently, wherein used the oxidized polysaccharide group of oxidant (such as sodium metaperiodate) with the protein that carries ferrum.Any containing-(C=O), the arteannuin dependency endoperoxide of NH-group all can be used to prepare the hydrazide derivatives that can be connected with transferrin or other glycoprotein that carries ferrum (for example, referring to (1998) such as Gumming " pharmaceutical chemistry magazine " (J Med.Chem.) 41 (6): 952-64). Hydrazine that can also be by at first preparing arteannuin dependency endoperoxide or aminooxy group derivant and arteannuin dependency endoperoxide and the glycosylated protein that carries ferrum are coupled together.For hydrazine or the aminooxy group derivant for preparing arteannuin dependency endoperoxide, form the halogenide of arteannuin dependency endoperoxide at first through the following steps: halohydrin is joined in the arteannuin dependency endoperoxide, add etherate of trifluoroboron subsequently.The reaction of described halogenide or arteannuin dependency endoperoxide and hydrazine or hydroxylamine be can make then and hydrazine or aminooxy group derivant generated respectively.The halo group can and be used for reaction by p-toluenesulfonyl or mesyl replacement.Can make hydrazine or aminooxy group derivant covalently bound then, wherein use the oxidized polysaccharide group of oxidant (such as sodium metaperiodate) with the protein that carries ferrum.The NH-of any containing-(C=O) ,-NH-or-the arteannuin dependency endoperoxide of O-group all can be used to prepare the hydrazine derivate or the aminooxy group derivant that can be connected with transferrin or other glycoprotein that carries ferrum. The arteannuin dependency endoperoxide that is suitable for connecting in this manner comprise can therefrom prepare hydrazides, hydrazine or aminooxy group derivant and do not destroy in the active chemical compound of peroxide bridge.In general, by at interval basic (such as hydrocarbon chain) interior peroxide bridge and hydrazides, hydrazine or aminooxy group are separated.Can also be with ethers, esters, amide-type, sulfide and disulphide as basic at interval.For example, can with phenyl ring with the endoperoxides bridge with keep apart as the hydrazides on the artelinate, hydrazine or aminooxy group.Therefore, be applicable to the endoperoxide of arteannuin dependency endoperoxide of the present invention including, but not limited to following structure: N=1-3 wherein, m=0-3, the Ar=aryl, for example phenyl, naphthyl, pyrenyl, pyridine radicals or pyrimidine radicals, and Y=-(C=O) NH-,-NH-or-O-.The representational arteannuin dependency endoperoxide that is present in the covalent conjugates of the present invention comprises artelinate and dihydroartemisinine. Be used for the method that arteannuin dependency endoperoxide is connected with the glycoprotein that carries ferrum is comprised borate mediation with the glycoprotein that carries ferrum on company's key (for example, referring to U.S. Pat 5,919,708) of saccharide residue.Therefore, contain the boric acid ester group arteannuin dependency endoperoxide will with 1 of saccharide residue on the protein surface, the reaction of 2-glycol moiety. With regard to the nonglycosylated protein that carries ferrum, can be as described in example 2 above by using amino acid side chain that arteannuin dependency endoperoxide is connected with this protein.For example, artesunate and artelinate have can use N-hydroxy-succinamide (for example, referring to (1994) such as Lewis " bioconjugates chemistry " (Bioconj.Chem.) 5 (6): 655-76) with water-soluble carbodiimide reagent, activate into free carboxy acid's base of active ester such as N-ethyl (etheyl)-N '-dimethylaminoethyl carbodiimides.Can be with this ester with nonglycosylated proteinic aqueous solution of carrying ferrum and arteannuin dependency endoperoxide is connected with Lys residue on this protein surface. Can be by the standard method in this area, for example by using gel filtration chromatography, ion exchange and the anti-phase or described covalent conjugates of hydrophobic interaction high pressure lipuid chromatography (HPLC) (HPLC) purification.Can be by using the standard method in this area, ionspray mass spectrometry is for example measured the quantity of the arteannuin dependency endoperoxide molecule that combines with the protein that carries ferrum of a molecule.Arteannuin dependency endoperoxide depends on used protein that carries ferrum and the method that forms conjugate with the proteinic ratio of carrying ferrum in the covalent conjugates.For example, the ferritin for the national games that uses the method described in the embodiment 1 to obtain per molecule contains the covalent conjugates of the arteannuin dependency endoperoxide of 1-10 molecule. The present invention also provides the compositions that comprises covalent conjugates of the present invention.In certain embodiments, as described in example 1 above, compositions of the present invention comprises the covalent conjugates between artelinate and the people's ferritin for the national games.In other embodiments, described compositions comprises the covalent conjugates between artelinate and the people's full milk ferritin. Covalent conjugates of the present invention can be used for treating cancer.Because most of cancerous cell divides fast, so they have the ferrum uptake rate higher than normal cell, and the concentration of the cell surface transferrin receptor of expressing also is higher than normal cell.Verifiedly give iron salt or ferritin for the national games has increased sensitivity (Moore etc. (1995) " cancer communication " (Cancer Lett.) 98:83-7 of cancerous cell to arteannuin and analog thereof; Singh ﹠amp; Lai (2001) " life sciences " is 70:49-56 (LifeSci.); Sadava etc. (2002) " cancer communication " (Cancer Lett.) 1179:151-6).Therefore, by with arteannuin dependency endoperoxide and the protein, covalently bound that carries ferrum such as ferritin for the national games, can increase effect and the selectivity of arteannuin dependency endoperoxide, because endoperoxide and ferrum are transported to simultaneously or transport into same cell to cancer. Covalent conjugates of the present invention also can be used for treating the infection that pathogenic organisms body with the proteinic receptor that carries ferrum described in the covalent conjugates is caused.In order to set up successful infection, pathogen must overcome the strict ferrum restriction that the host applies.In order to overcome this restriction, many pathogen obtain ferrum (for example, referring to Cornelissen, (2003) Front.Biosci.8:D836-47) from the host protein that carries ferrum.For example, the pathogen Neisseria meningitidis of bacterial meningitis is expressed and carries the protein-transferrin of ferrum and the cell surface receptor (Evans﹠amp of lactoferrin; Oakhill (2002) " biochemistry association journal " (Biochem.Soc.Trans.) 30 (4): 705-7), (Husson etc. (1993) " infectious immunity " (Infect.Immun.) 61 (6): 2694-7), and staphylococcus aureus is expressed hemoglobin receptor (Mazmanian etc. (2003) " science " are 299:906-9 (Science)) to the receptor of the pathogen helicobacter pylori expressing human lactoferrin of people's gastritis and peptic ulcer.Therefore, covalent conjugates of the present invention can be used for killing the pathogenic organisms body that wherein has the proteinic receptor that carries ferrum described in the covalent conjugates.For example, the covalent conjugates between arteannuin dependency endoperoxide and human transferrin or the people's full milk ferritin can be used for the treatment of gastritis and the peptic ulcer disease that bacterial meningitis that Neisseria meningitidis causes or helicobacter pylori cause. According to method of the present invention, when to the cancerous cell administration, arteannuin dependency endoperoxide and the covalent conjugates of carrying between the protein of ferrum have the cellular cytoxicity activity that protein reached that is better than giving arteannuin dependency endoperoxide respectively and carries ferrum.In addition, covalent conjugates of the present invention can effectively be killed and wounded the pathogen that has the proteinic receptor that carries ferrum. The present invention provides in aspect second there being this experimenter who needs to give method for compositions, and said composition comprises arteannuin dependency endoperoxide and carries covalent conjugates between the protein of ferrum.Arteannuin dependency endoperoxide and the proteinic covalent conjugates of carrying ferrum are as mentioned above.For example, as described in example 1 above, some embodiment provides the covalent conjugates of artelinate and ferritin for the national games. These methods are suitable for any animal experimenter, such as the human body experimenter.For example, the experimenter who needs the compositions of the covalent conjugates between the protein that comprises arteannuin dependency endoperoxide and carry ferrum can be the cancer patient.As mentioned above, the cell of fast breeding, generally have higher cell surface transferrin receptor concentration such as cancerous cell.The mechanism that this method provides selectivity to send endoperoxide part and ferrum, it can produce to the cell of fast breeding, such as cancerous cell reacts.Therefore, the invention provides the treatment method for cancer, by the chemical compound that has this human or animal experimenter who needs to give effective dose is carried out, this chemical compound comprises arteannuin dependency endoperoxide and carries covalent conjugates between the protein of ferrum.The propagation that there is cell hyperproliferation in other and can brings out after including, but not limited to restenosis, autoimmune disease, arthritis, transplant rejection, inflammatory bowel or medical care precess with the disease of covalent conjugates of the present invention treatment.In certain embodiments, described method comprises the step that gives chemical compound, and this chemical compound comprises the covalent conjugates between artelinate and the people's ferritin for the national games. Can also comprise arteannuin dependency endoperoxide and carry the chemical compound and the compositions of the covalent conjugates between the protein of ferrum, so that treatment is by expressing the infection that pathogen caused of carrying the proteinic cell surface receptor of ferrum described in the covalent conjugates.Term used herein " infection that the treatment pathogen causes " refers to and suppresses pathogenic growth and/or prevention or improve the disease symptoms relevant with this infection. Have the host protein that carries ferrum receptor typical pathogen as mentioned above, comprise the helicobacter pylori of the receptor of the Neisseria meningitidis of receptor of expressing human transferrin and expressing human lactoferrin.Confirmed that at present staphylococcus aureus expresses hemoglobin receptor (Mazmanian etc. (2003) " science " are 299:906-9 (Science)), Listeria monocytogenes (Listeria monocytogenes) and Bacillus anthracis (Bacillus anthracis) are also expressed similar protein (Cabanes etc. (2002) " microbiology trend " (Trends.Microbiol.) 10 (5): 238-45).It is as shown in table 1 that the typical pathogen example of receptor of host protein of ferrum is carried in expression.In case this protein that carries ferrum combines with the receptor that pathogen is expressed, then ferrum or haemachrome generally discharge from the protein that carries ferrum, and are gone into cell (for example, referring to Gray-Owens ﹠amp by transhipment; Schryyers (1996) " microbiology trend " (Trends.Microbiol.) 4 (5): 185-91; Wandersman ﹠amp; Stojiljkovic (2000) " up-to-date microbiology viewpoint " is 3:215-20 (Curer.Op.Microbiol.)). Carry the proteinic receptor of ferrum in the table 1. humans and animals pathogen Pathogen The host Disease Receptor Ox catarrhalis morazella catarrhalis lacuna catarrhalis Neisseria meningitidis Diplococcus gonorrhoeae actinobacillus actinomycetem comitans (Actinobacillus actinomycetecomitans) actinobacillus equuli Actinobacillus pleuropneumoniae (Actinobacillus pleuropneumoniae) Haemophilus agni bird pasteurella haemophilus influenzae haemophilus paragallinarum (Haemophilus paragallinarum) Haemophilus somnus (Haemophilus somnus) haemophilus parasuis haemophilus ducreyi Ox everybody everybody the pig sheep poultry people of forces poultry ox pig people Keratoconjunctivitis tympanitis keratoconjunctivitis meningitis gonorrhoea juvenile periodontitis septicemia pneumosepticemia sinusitis meningitis, the sick genitals canker of tympanitis infective rhinitis's thromboembolia type meningoencephalitis Karl-Heinz Grasser Transferrin, lactoferrin 1Transferrin, lactoferrin 1Transferrin, lactoferrin 1Transferrin, lactoferrin 1Hemoglobin 1，19Transferrin, lactoferrin, hemoglobin 1，18Transferrin 1Transferrin 1Transferrin 1Transferrin 1Transferrin 1Transferrin, hemoglobin 1，20Transferrin 1Transferrin 1Transferrin 1Hemoglobin 15 Pathogen The host Disease Receptor Haemolysis pasteurella multocida staphylococcus aureus MRSE, (Staphyloccus epidermidis) streptococcus pneumonia Leishmania chagasi bacillus coli K88 Tritrichonomas foetus Spirochaeta pallida Mycoplasma pneumoniae Bordetella pertussis Trichonomas vaginalis aeromonas salmonicida helicobacter pylori yersinia enterocolitica Vibrio vulnificus porphyromonas gingivalis, (Porphyromonas gingivalis) Ox; Sheep, everybody eel (eel) people of everybody people mermaid of goat ox everybody everybody pig ox Shipping fever, the hemorrhagic septicemia pneumonia, the septicemia bacteremia, pneumonia, endocarditis, septic arthritis, osteomyelitis, deep abscess, the alimentary toxicosis endocarditis, endophthalmitis, septicemia, the cystitis pneumonia, meningitis, bacteremia, otitis media leishmaniasis enteropathy generation trichomonacide syphilis pneumonia pertussis vaginosis furunculosis gastritis, gastric duodenal ulcer, adenocarcinoma of stomach, lymphoma enteritis alimentary toxicosis, septicemia, the traumatic infection periodontal disease Transferrin 1Transferrin 1The transferrin hemoglobin 2，13Transferrin 2Lactoferrin 3Transferrin, lactoferrin 4Transferrin 5The lactoferrin hemoglobin 6Lactoferrin 7Lactoferrin 8Lactoferrin 9Lactoferrin 10Transferrin, lactoferrin 11Lactoferrin 12Hemoglobin, Myoglobin, Hemopexin, catalase, albumin-haemachrome 14Hemoglobin 16Hemoglobin 17 1 Gray-Owen & Schryvers(1996)Trends Microbiol.4(5)：185-91 2 Modun et al.(1998)Infect.Immun.66(8)：3591-6 3 Hammerschmidt et al.(1999)Infect.Immun.67(4)：1683-7 4 Britigan et al.(1998)Adv.Exp.Med.Biol.443：135-40 5 Grange et al.(1997)Adv.Exp.Med.Biol.412：357-61 6 Tachezy et al.(1996)Exp.Parasitol.83(2)：216-28 7 Alderete et al.(1988)Genitourin.Med.64(6)：359-63 8 Tryon & Baseman(1987)Microb.Pathog.3(6)：437-43 9 Redhead et al.(1987)J.Gen.Microbiol.133(4)：891-8 10 Peterson & Alderete(1984)J.Exp.Med.160(2)：398-410 11 Chart & Trust(1983)J.Bacteriol.156(2)：758-64 12 Dhaenens et al.(1997)Infect.Immun.65(2)：514-8 13 Mazmanian et al.(2003)Science 299：906-9 14 Bracken et al.(1999)J.Bacteriol.181(19)：6063-72 15 Al-Twafiq et al.(2000)J.Infect.Dis.181(3)：1049-54 16 Fouz et al.(1997)Microbiol.Lett.156(2)：187-91 17 Simpson et al.(2000)J.Bacteriol.182(10)：5737-48 18 Chen et al.(1996)Infect.Immun.64：5008-14 19 Stojiljkovic et al.(1996)J.Bacteriol.179(15)：4670-78 20 Frangipane et al.(1994)FEMS Microbiol.Lett.118：243-8 The mechanism that the method for this aspect of the present invention provides selectivity to send endoperoxide part and ferrum, it can produce directly reaction with the proteinic receptors bind of carrying ferrum to the cell membrane of pathogenic organisms body by making covalent conjugates.According to method of the present invention, the endoperoxide part in the bonded covalent conjugates and ferrum that from the protein that carries ferrum, discharges or haemachrome reaction, thus near pathogen, produce harmful free radical.Therefore, the invention provides the method for the disease that causes of treatment helicobacter pylori, by the compositions that comprises the covalent conjugates between arteannuin dependency endoperoxide and the people's full milk ferritin that has this human body experimenter who needs to give effective dose is carried out.The present invention also provides the method for the treatment disease that Neisseria meningitidis causes, by the compositions that comprises the covalent conjugates between arteannuin dependency endoperoxide and the people's ferritin for the national games that has this human body experimenter who needs to give effective dose is carried out. Other typical infection of the combination treatment that comprises covalent conjugates of the present invention that can be by giving effective dose comprises localized bacterial infection, such as gingivitis, skin and ocular infection. The effective dose of described covalent conjugates generally can reach maximum tolerated dose, but concentration and non-key and can extensively change.Certainly, the accurate amount of clinicist's use changes with chemical compound, route of administration, patient's body situation and other factors.Dosage every day maybe can be able to be divided into the multidose administration as single dose administration. The consumption of the actual conjugate of the present invention that gives should be the treatment effective dose, and the required consumption of substantial beneficial effect represented to produce in this term used herein.Can be according to by the extrapolated effective dose of dose-response curve external or that animal model test system obtains.Generally also animal model is used for determining ideal dosage range and route of administration.Then this category information is used to be identified for people or other mammiferous useful dosage and route of administration.The mensuration of effective dose also belongs to those skilled in the art's limit of power.Therefore, the actual consumption that gives depends on the individuality that treatment is used, and preferably optimizes consumption, does not have remarkable side effect so that obtain required effect. Can in cell culture or laboratory animal, measure the therapeutic efficiency of covalent conjugates of the present invention and possible toxicity (ED for example by standard pharmacy step 50, promptly effectively treat the dosage of 50% colony; And LD 50Even, the lethal dosage of 50% colony).Dosage between treatment and the toxic action can be expressed as LD with it than for therapeutic index 50With ED 50The ratio.The covalent conjugates that shows high therapeutic index is particularly suitable for implementing method of the present invention.The data that obtain can be used to prepare people or the employed dosage range of other mammal from cell culture test and zooscopy.The dosage of this class conjugate preferably belongs to and comprises almost not having or avirulent ED 50The circulation composition scope in.Dosage generally changes in this scope, and this depends on used dosage form, experimenter's sensitivity and route of administration.Therefore, optimum amount can change according to the difference of medication, and is generally the consumption with the medicament commonly used of same or similar form administration. Can be with covalent conjugates of the present invention separately or with one or more other therapeutic activity agent administrations.For example, in the process of treatment cancer, can be with this conjugate and therapeutic agent coupling, described therapeutic agent is including, but not limited to inhibitor for androgen, such as flutamide and luprolide; Antiestrogen is such as tamoxifen; Antimetabolite and cytotoxic agent are such as daunorubicin, fluorouracil, floxuridine, interferon-ALPHA, methotrexate, plicamycin, purinethol, thioguanine, doxorubicin, carmustine, lomustine, cytosine arabinoside, cyclophosphamide, doxorubicin, estramustine, altretamine, hydroxyurea, ifosfamide, procarbazine, Mutamycin, busulfan, mitoxantrone, carboplatin, cisplatin, streptozocin, bleomycin, D actinomycin D and idarubicin; Hormone is such as medroxyprogesterone, estramustine, ethinylestradiol, estradiol, leuproside, megestrol, octreotide, diethylstilbestrol, chlorotrianisene, etoposide, podophyllotoxin and goserelin; Nitrogen mustard derivatives replaces group such as melphalan, chlorambucil, methlorethamine and plug; Steroid is such as betamethasone; With other antineoplastic agent, such as cattle on the hoof mycobacteria (Mycobacterium bovis), dicarbazine, asparaginase, folinic acid, mitotane, vincristine, vinblastine and taxotere.Suitable consumption in each case changes with the difference of particular active agent, and those skilled in the art are easy to learn or are easy to and measure by normal experiment. Covalent conjugates of the present invention can also be increased the activating agent administering drug combinations of ferrum to intracellular transhipment with for example increasing the proteinic cell surface receptor quantity of carrying ferrum in the conjugate.For example, confirmed that insulin, insulin-like growth factor I and epidermal growth factor can cause that the transferrin receptor quantity on the cell surface increases (for example, referring to (1987) " journal of biological chemistry " (J Biol.Chem.) 261 (19): 8708-11 such as Davis; Davis etc. (1986) " journal of biological chemistry " (J Biol.Chem.) 262 (17): 13126-34).Therefore, in certain embodiments, the present invention is contained covalent conjugates and insulin, insulin-like growth factor I or the epidermal growth factor administering drug combinations of transferrin. Can be by any some effective, for example by non-intestinal or orally give covalent conjugates of the present invention.Medication comprises part (for example skin patch), sucks, sucks, in the intra-arterial, subcutaneous, marrow, intravenous, intranasal, internal rectum, eye drops and other usual way.For example, described covalent conjugates directly can be injected tumor, inject near the tumor or inject blood vessel tumor feeding. Covalent conjugates of the present invention can be mixed with compositions, contain suitable pharmaceutically acceptable carrier in the said composition in addition, comprise that excipient and other help mammalian subject is given other chemical compound of this covalent conjugates.About preparation and the technology more specifically of administration can find in latest edition " RemingtonShi pharmaceutical science " (" Remington ' s PharmaceuticalSciences ") (Maack Publishing Co, Easton PA). Can use pharmaceutically acceptable carrier preparation well known in the art to be used for liquid preparations for oral administration, its dosage is suitable for oral administration.This class carrier can be mixed with the compositions that contains covalent conjugates of the present invention the tablet that is suitable for experimenter picked-up, pill, lozenge, capsule, liquid, gel, syrup, serosity, suspension etc.The compositions of oral application can be prepared with solid excipient, optional grinding gained mixture, and if desired, after adding other suitable chemical compound, this granulate mixture is processed, to make tablet or lozenge medicated core.Suitable excipient comprises carbohydrate or protein filler.They including, but not limited to: saccharide comprises lactose, sucrose, mannitol or sorbitol; Starch from corn, Semen Tritici aestivi, rice, Rhizoma Solani tuber osi or other plant; Cellulose is such as methylcellulose, hydroxypropyl emthylcellulose or sodium carboxymethyl cellulose; And natural gum, such as arabic gum and tragacanth gum; And protein, such as gelatin and collagen protein.If desired, can add disintegrating agent or solubilizer, such as crospolyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium alginate. Give ingot core enclose suitable coatings, such as priming, it can also contain Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, carbomer gel, Polyethylene Glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Can in tablet or lozenge coatings, add dyestuff or pigment to be used for product identification or to characterize reactive compound consumption (being dosage). For example, the covalent conjugates that is used for oral administration can be mixed with the sucking fit formula capsule made by gelatin and by gelatin and the sealing soft capsule formed such as glycerol or this class coating material of sorbitol.Sucking fit formula capsule can contain covalent conjugates, wherein is mixed with: filler or binding agent, such as lactose or starch; Lubricant is such as Talcum or magnesium stearate; With optional stabilizing agent.In soft capsule, covalent conjugates can be dissolved in or be suspended in suitable containing or do not contain in the liquid of stabilizing agent, such as fatty oil, liquid paraffin or liquid macrogol. Parenterai administration comprises a kind of aqueous solution of or covalent conjugates of the present invention with compositions.In order to inject, can be with the buffer of physical compatibility, covalent conjugates of the present invention is mixed with aqueous solution such as Hank ' s solution, Ringer's solution or physiological buffer saline.Aqueous injection suspension can contain the material that increases this suspension viscosity, such as sodium carboxymethyl cellulose, sorbitol or glucosan.In addition, the suspension of covalent conjugates can be prepared into suitable oily injection suspension.Suitable lipophilic solvent or carrier comprise: fatty oil, such as Oleum sesami; Or synthetic fatty acid ester, such as ethyl oleate or triglyceride; Or liposome.This suspension can also be chosen the reagent that contains suitable stabilizers or increase the covalent conjugates dissolubility wantonly so that prepare highly concentrated solution. In order to carry out part or nasal administration, the penetrating agent that generally will be suitable for penetrating particular barrier is used for preparation.Their example is 2-Pyrrolidone, N-N-methyl-2-2-pyrrolidone N-, dimethyl acetylamide, dimethyl formamide, propylene glycol, methanol or isopropyl alcohol, dimethyl sulfoxine and Laurel nitrogen  ketone.Preparation can also comprise other reagent so that can be accepted in beauty treatment.Their example is fat, wax, oil, dyestuff, spice, antiseptic, stabilizing agent and surfactant.Can also comprise all those cutin distintegrants as known in the art.Example is salicylic acid and sulfur.In order to carry out topical, compositions can be the percutaneous ointment that is used for the described chemical compound of systemic delivery or the form of patch, (for example can prepare in a conventional manner, referring to Barry, " dermatosis preparation " (Dermatological Formulations) (Drugs and the PharmaceuticalSciences--Dekker); Harrys Cosmeticology (Leonard Hill Books). In order to carry out rectally, can give compositions with the form of suppository or retention enema.Can prepare this based composition by covalent conjugates is mixed with suitable nonirritant excipient, described nonirritant excipient is a solid at normal temperatures, and is liquid under rectal temperature, fusing and discharge medicine in rectum thus.Suitable excipient is including, but not limited to cocoa butter and polyethylene glycols. These dissimilar additives consumption separately will be apparent to those skilled in the art, and optimum amount is identical with other known formulations that is designed for the same type administration.For example, the horny layer penetration enhancer generally is about 15% concentration of about 0.1%-. Can according to this area in like the known class mode prepare the compositions that contains covalent conjugates of the present invention mixing, dissolving, granulating, system ingot, grinding, emulsifying, encapsulation, embedding or the lyophilization of routine (for example, by).(for example coating) changes compositions one-tenth so that suitable release characteristics to be provided by conventional methods, and for example slow release or targeting discharge. Form that can salt provides the compositions that comprises covalent conjugates, and can with many sour salifies, including, but not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.Salt tends to more be soluble in aqueous or other proton solvent than corresponding free alkali form. Prepared make this based composition that contains covalent conjugates and acceptable carrier after, they can be put into suitable containers and labelling and use. The following example has only been explained and has been become known at present implementing best mode of the present invention, but shall not be applied to restriction the present invention. Embodiment 1 Present embodiment has been described the representational preparation of compositions method of the present invention, and said composition contains one or more and the covalently bound arteannuin dependency endoperoxide molecule of ferritin molecule for the national games. Synthetic (the ART-NH-NH of Artelinic acid hydrazide 2 the trial of the hydrazide derivatives of preparation artesunate is also unsuccessful, because of cyclization causes forming dihydroartemisinine.As mentioned above by the synthetic artelinate (Shrimali etc. (1998) " India's The Chemicals " (Indian J Chem.) 37B:1161-1163) of dihydroartemisinine.(0.1g 0.24mmol) is dissolved in anhydrous acetonitrile (0.48mL) with artelinic acid.In this solution, add I-hydroxybenzotriazole (HOBt) (0.038g, 0.29mmol), add subsequently ethyl dimethyl ethyl carbodiimides (0.055g, 0.29mmol).At room temperature stir this reactant mixture and, all change into the HOBt ester up to all acid by thin layer chromatography (TLC) monitoring. With hydrazine (0.46mL, 0.48mmol) solution in acetonitrile (0.48mL) is cooled to 0 ℃, and above-mentioned reactant mixture is joined in this system, simultaneously with temperature maintenance at 0-10 ℃.As what measure, complete at 10 minutes afterreactions by TLC.With in this reactant mixture impouring water (5mL), (the salt water washing is also used in 3 * 10mL) extractions with ethyl acetate.Separate organic facies, with anhydrous sodium sulfate drying and be evaporated to dried.Obtain pure product (0.078g) by the silica gel chromatography purification crude product that uses methanol/chloroform gradient, productive rate is 76%. Artelinate-ferritin conjugate for the national games synthetic: at room temperature use the 10mmol/L sodium metaperiodate will be dissolved in the ferritin for the national games (2mg) of sodium acetate of 1ml 0.1mol/L pH 5.5 the horizontal oxidation of its polysaccharide 30 minutes.With sample on this solution to the short Sephadex G-25 post that the UV monitor has been installed.With this post of sodium acetate eluting of 0.1mol/L pH 5.5 and collect the protein fraction.In the ferritin for the national games of oxidation, add excessive ART-NH-NH 2Solution also at room temperature keeps this reaction system to spend the night, jolting gently simultaneously.Then with sample on artelinate-ferritin conjugate solution for the national games to Sephadex G-25 post, to remove excessive ART-NH-NH 2With this post of 0.1mol/L Tris-HCl buffer solution elution of pH 7.5, and collect the protein fraction.Conjugate is stored under 4 ℃. By hydrophobic interaction HPLC purification artelinate-ferritin conjugate for the national games, obtain the protein conjugate of homogeneous.Measure the artesunate molecular number of each ferritin molecule for the national games by ionspray mass spectrometry. Although explained and described the preferred embodiments of the invention, be appreciated that and can not break away from the spirit and scope of the invention to wherein carrying out various changes. Embodiment 2 Present embodiment has been described the representational preparation of compositions method of the present invention, and said composition contains the one or more arteannuin dependency endoperoxide molecules covalently bound with haemoglobin molecule. In order to use the nonglycosylated protein of artemisinin derivative covalent modification, such as hemoglobin, at first with the carboxylic acid derivates of arteannuin, activation is N-hydroxy-succinamide (HOSu) ester such as artelinic acid, so as with protein surface on the lysine residue reaction.With artelinicacid (4.2mg, 0.01mmol) be dissolved in dimethyl formamide (DMF) (0.5mL) in, and this solution cooled off in ice bath.In this solution, add N-ethyl-N '-dimethylaminoethyl carbodiimide (EDC) (1.5mg, 0.01mmol) and HOSu (1.1mg, 0.01mmol).This reactant mixture is kept down stirring 2 hours to be completed into the HOSu ester of artelinic acid at 0 ℃. Hemoglobin (10mg) is dissolved in 7.0 0.1M phosphate buffer (5mL).DMF solution with artelinicacid HOSu ester under 0 ℃ slowly joins in the hemoglobin solutions.This reactant mixture is kept down stirring 2 hours and at room temperature keeps stirring 2 hours again at 0 ℃.Make on this reactant mixture sample to on the equilibrated Sephadex G-25 of the 0.1M phosphate buffer post of pH 7 then, and with this post of identical buffer solution elution.Modified hemoglobin elutes with void volume.Merge the fraction that contains hemoglobin, then by hydrophobic interaction HPLC purification.Measure the artemisinin derivative number that is connected with protein by ionspray mass spectrometry. 1. the covalent conjugates that comprises the arteannuin dependency endoperoxide covalently bound with carrying the protein of ferrum. 2. the described covalent conjugates of claim 1, wherein said arteannuin dependency endoperoxide comprises artelinate. 3. the described covalent conjugates of claim 1, wherein said arteannuin dependency endoperoxide is a hydrazide derivatives. 4. the described covalent conjugates of claim 2, wherein said arteannuin dependency endoperoxide has following structure: N=1-3 wherein, m=0-3, the Ar=aryl, and Y=-(C=O) NH-,-NH-or-O-. 5. the described covalent conjugates of claim 1, the wherein said protein that carries ferrum are selected from the group that ferritin for the national games, full milk ferritin, hemoglobin, Hemopexin and the lipocalin protein relevant with neutral gelatinase are formed. 6. the described covalent conjugates of claim 5, the wherein said protein that carries ferrum is ferritin for the national games. 7. the described covalent conjugates of claim 5, the wherein said protein that carries ferrum is the full milk ferritin. 8. the described covalent conjugates of claim 5, the wherein said protein that carries ferrum is mammalian proteins. 9. the described covalent conjugates of claim 5, the wherein said protein behaviour albumen that carries ferrum. 10. the described covalent conjugates of claim 1 is comprising artelinate and ferritin for the national games. 11. the described covalent conjugates of claim 1 is comprising artelinate and full milk ferritin. 12. the described covalent conjugates of claim 1 is comprising artelinate and hemoglobin. 13. a compositions, comprising with the covalent conjugates of the covalently bound arteannuin dependency endoperoxide of the protein that carries ferrum, and pharmaceutically acceptable carrier. 14. the covalent conjugates that comprises the arteannuin dependency endoperoxide covalently bound with carrying the protein of ferrum is used for the treatment of purposes in the medicine of cancer in preparation. 15. the described purposes of claim 14, wherein said arteannuin dependency endoperoxide are selected from the group of artelinate and dihydroartemisinine composition. 16. the described purposes of claim 14, the wherein said chemical compound that carries ferrum is a ferritin for the national games. 17. the described purposes of claim 14, wherein said medicine is made into through parenteral administration. Be used for the treatment of by the purposes in the experimenter's of pathogenic infection the medicine in preparation with the proteinic covalent conjugates of carrying ferrum 18. contain arteannuin dependency endoperoxide, wherein said pathogen is expressed this proteinic receptor that carries ferrum. 19. the described purposes of claim 18, wherein said arteannuin dependency endoperoxide are selected from the group of artelinate and dihydroartemisinine composition. 20. the described purposes of claim 18, the wherein said protein that carries ferrum are selected from the group that ferritin for the national games, full milk ferritin, hemoglobin, Hemopexin and the lipocalin protein relevant with neutral gelatinase are formed. 21. the described purposes of claim 18, wherein said pathogen comprises helicobacter pylori (Helicobacter pylori), the wherein said protein that carries ferrum comprises human lactoferrin, and wherein said arteannuin dependency endoperoxide is selected from the group of artelinate and dihydroartemisinine composition. 22. the described purposes of claim 18, wherein said pathogen comprises Neisseria meningitidis (Neisseria meningitidis), the wherein said protein that carries ferrum comprises human transferrin, and wherein said arteannuin dependency endoperoxide is selected from the group of artelinate and dihydroartemisinine composition. https://patents.google.com/patent/CN1313145C/en?oq=CN1313145C青蒿素相关性内过氧化物与携带铁的+蛋白质之间的共价缀合物及其使用方法

CN1295231C溴二氢青蒿素---特别适用于治疗各种癌症的溴代二氢青蒿素 CN1295231C Artemisinin bromide---Artemisinin bromide is particularly suitable for treating various cancers 溴代二氢青蒿素 本发明公开了一种溴代二氢青蒿素，其特别适用于治疗各种癌症；申请人首创将二氢青蒿素上的3-C位甲基溴化，在二氢青蒿素的母核上直接引进杂原子；主要是以二氢青蒿素为母核，制成溴代二氢青蒿素；利用卤族元素有更强的极性，使二氢青蒿素的氧桥更容易断裂成自由基；大大增强药效，本发明溴化工艺简单，易于工业化生产，溴化有很好的专一性，使产品的合成工艺有很好的特异性，易于量化控制，对正常细胞无毒副作用，用溴代二氢青蒿素对人肝癌细胞株-Hepg2细胞毒性研究表明，溴代二氢青蒿素对体外Hepg2细胞的细胞毒IC50＜8nM。 溴代二氢青蒿素 技术领域 本发明涉及化学合成物技术领域，具体的说，是涉及二氢青蒿素的一种衍生物一溴代二氢青蒿素。 背景技术 现有从植物中提取的天然抗癌药物，由于其疗效有限和毒副作用强限制了其临床应用，始终不能成为抗癌的主力药物。 例如：紫杉醇被当今世界上公认为广谱、活性最强的抗癌药物，尤其是对子宫癌、卵巢癌、乳腺癌具有特殊的疗效，它的问世被誉为90年代国际上抗癌药三大成就之一；目前治疗妇女乳腺癌的常见用药有欧洲紫杉醇和太平洋紫杉醇；可以延长恶化时间两个月和增加存活时间3个月。 但两种紫杉醇都有副作用，病人会出现手脚麻痹的现象，太平洋紫杉醇毒性最常见且致命的副作用就是有15-20％的患者发生急性过敏性休克；副作用：抑制造血细胞，过敏，胃肠不适，以及轻度的肝脏损伤；欧洲紫杉醇常见的副作用是骨髓抑制、血球低下、疲倦等。 又如喜树碱：喜树碱是从我国喜树中提取的一种生物碱，应用于临床如消化系统肿瘤，黑色素瘤等之治疗并有部分成效；其作用机理经动力学的研究证明，喜树碱是属于细胞周期特异性药物，能使癌细胞停留于S期(DNA合成期)，阻止其进一步分裂。动物实验证明对Erlich腹水瘤细胞DNA、RNA的合成均有较明显抑制作用，上海地区用喜树碱治疗胃癌435例，有效率61％；但有严重副作用如骨髓抑制，出血性膀胱炎及消化系统之症状。 青蒿素是我国药学工作者1971年从菊科植物黄花蒿叶中提取分离到的一种具有过氧桥的倍半萜内酯类化合物；青蒿素及其衍生物是含过氧桥的倍半萜内酯类新型抗疟药，具有高效、快速、低毒、安全等特点；研究表明，青蒿素对疟原虫配子体有杀灭作用，其强度和剂量与配子体成熟度相关。 早期的研究表明，青蒿素选择性杀灭红内期疟原虫的机理主要是作用于疟原虫的膜系结构，使核膜、质膜破坏，线粒体肿胀皱缩，内外膜剥离，对核内染色物质也有一定影响，青蒿素及其衍生物通过影响线粒体的功能，阻断疟原虫营养的供应，从而达到抗疟目的；青蒿素类药应用十多年来尚未见有关抗药性的报道，在对多重抗药性恶性疟疾的治疗上，青蒿琥酯和蒿甲醚也有良好的疗效。 青蒿素及其衍生物还有以下作用： 抗卡氏肺孢子虫肺炎作用：动物实验证实，青蒿素对大鼠卡氏肺孢子虫肺炎有效；用双氢青蒿素60毫克/千克治疗大鼠卡氏肺孢子虫肺炎，大鼠存活数、存活率均高于感染组；治疗后大鼠平均肺重、平均肺重/体重比和包囊数均低于感染组，肺组织炎症反应明显减轻；进一步的研究表明，双氢青蒿素主要破坏卡氏肺孢子虫膜系结构，引起孢子虫滋养体胞浆及包囊内出现空泡，线粒体肿胀，核膜破裂，内质网肿胀，囊内小体溶解破坏等超微结构的改变。 抗孕作用：青蒿琥酯和双氢青蒿素对小鼠、金黄地鼠、大鼠及兔均有抗孕作用，金黄地鼠和豚鼠表现为流产，小鼠、大鼠和兔表现为胚胎吸收。青蒿琥酯(40毫克/千克)×5天可使妊娠大鼠血清孕酮含量下降并损伤胎膜和胎盘使胚胎坏死而终止妊娠；二氢青蒿素对体外培养的人胎膜细胞亦有直接杀伤作用；二氢青蒿素类药对胚胎有较高的选择性毒性，较低剂量即可使胚胎死亡而导致流产，但对母体子宫、卵巢和一般健康状况无明显影响，此类药有可能被开发为人工流产药物。 对肿瘤的作用：二氢青蒿素及其衍生物对鼠艾氏腹水瘤细胞和人HeLa细胞有细胞毒活性；用青蒿琥酯处理的HeLa细胞可见梯状DNA和凋亡小体。Beekman等对从9种不同组织中培养的60株肿瘤细胞进行检测发现，双氢青蒿素对白血病、黑色素瘤、结肠癌、前列腺癌和乳腺癌细胞株高度敏感，而对非小细胞肺癌、中枢神经系统肿瘤、卵巢癌和肾癌细胞株的活性较低；其抗肿瘤作用可能同二氢青蒿素与Fe2+反应产生大量自由基以及烷基化作用有关。 抗血吸虫作用：青蒿素及其多种衍生物均有抗血吸虫作用，在整个服药阶段对幼虫期的血吸虫都有杀灭作用，因此具有良好的预防效果，二氢青蒿素还能杀灭进入宿主体内的幼虫，对疫水接触者具有保护作用，用于感染日本血吸虫尾蚴后的早期治疗，可降低血吸虫感染率和感染程度，并可预防血吸虫病发生。其抗血吸虫活性基团是过氧桥，作用机理是影响虫体的糖代谢。在大规模应用青蒿琥酯预防性治疗接触疫水的人群时发现，17031人在服药后无急性血吸虫病发生，因此认为二氢青蒿素预防血吸虫病具有高效、安全、方便等特点，是目前比较理想的预防药。 治疗弓形虫感染作用：体外实验证实，青蒿素(蒿甲醚)能抑制弓形虫侵入细胞。青蒿素主要作用于虫体细胞膜、线粒体及细胞核，继而广泛损伤其膜系结构，造成核膜断裂、线粒体肿胀、空泡样变性、内质网扩张甚至出现核碎裂、核溶解现象。 对心血管的作用：青蒿素有减慢心率，抗心律失常，抑制心肌收缩力等作用。二氢青蒿素能明显对抗结扎冠脉引起的心律失常，可使氯化钙、氯仿引起的心律失常发作时间明显推迟，室颤明显减少，其作用与其抑制内向整流钾电流和浦肯野纤维瞬间外向钾电流有关。 对免疫系统的作用：双氢青蒿素、青蒿琥酯均对超适剂量免疫法诱导的供体鼠T细胞的产生有显著抑制作用，且两者都能增强受体鼠反应阶段细胞的活性。 其他：双氢青蒿素对杜氏利什曼原虫有显著抑制作用并呈剂量相关性。其机理系影响杜氏利什曼原虫前鞭毛体DNA合成，使虫体变形，核、动基体不完整，胞质内出现多个空泡，鞭毛脱落。青蒿提取物还可杀灭阴道毛滴虫和溶组织阿米巴滋养体。青蒿琥酯能松弛豚鼠气管平滑肌并非竞争性拮抗乙酰胆碱、组织胺的收缩气管作用，机理与激活腺苷酸环化酶关，且不被β肾上腺素受体噻吗洛尔所阻断。 近年来，各国的药物学家对青蒿素及其衍生物的抗癌作用进行了更广泛的研究，深层次药理、药效、毒副作用和药物动力学研究表明： 药理：用青蒿素及其衍生物对付血癌和乳腺癌细胞，发现青蒿素的选择性是其他化学疗法的100倍，而且，青蒿素可以杀死癌细胞，但不伤害周围健康细胞。“癌症细胞分裂时需要大量铁质才能复制DNA，因此癌细胞的铁质含量比正常细胞高出许多。”这些携带青蒿素衍生物的蛋白进入癌细胞后，青蒿素中的3-C位上的氧原子和12-C位上的氧原子之间形成氧桥，铁离子就被释放并与青蒿素衍生物反应，从而破坏癌细胞，氧桥断裂释放出自由基(氧原子)，自由基攻击癌细胞膜，使膜破裂而癌细胞死亡；这是把青蒿素转为抗癌药物的关键。由于癌细胞对铁的贪婪，使得药物具有很高的选择性；实验表明青蒿素标记的铁传蛋白选择和杀死癌症细胞的效率是杀死正常细胞的效率34000倍(资料出处)。 药效比较：IC50是体外癌细胞半数致死量，IC50能直观地反应药效强弱。 羟基喜树碱IC50为206u mol～305u molng； 紫杉醇IC50为8.6u mol； 二氢青蒿素IC50为24n mol(0.024 u mol)。 毒副作用：对神经系统、呼吸系统、心血管系统均无明显药理作用，仅在剂量大至40mg/kg时显示一定的镇痛、镇静作用。该药安全性较大，LD50为834.5mg/kg，化疗指数为834.0，大鼠20-180(MKD)连续30天给药，对生理、生化指标及主要脏器病理学检查均未见明显变化。特殊毒性方面，致突变实验阴性，生殖毒方面，在小鼠妊娠敏感期给药，增加吸收胎的发生，未见致畸作用。 药代动力学：小鼠灌服3H-二氢青蒿素后，血液内放射性迅速上升，半小时至1小时达到高峰，随后迅速下降，4小时降到峰值的一半，以后缓慢消失。胃肠道残留量的测量表明，半小时残留58％，1小时残留35.3％，半量消失时间约为1.2小时。经口给药后分布广泛，1小时开始达到高峰，同位素法表明各组织中胆、肝、肾最多，心、肺、脾等次之。显色法表明肌肉注射1～8小时达到高峰，肝、脑、骨、血液含量较高。口服后24小时内，80％放射性经粪、尿排出，显色法结果类似。上述结果表明二氢青蒿素进入体内后吸收快、分布广，排泄快。 1997年美国华盛顿大学生物工程系的赖亨利教授和纳伦德拉星开始设想同样的机理一定也能作用于癌症：癌症细胞分裂时需要大量铁质才能复制DNA，因此癌细胞的铁质含量比正常细胞高出许多；经研究发现，癌细胞比正常细胞含铁高5-15倍，高的达50倍，最高的白血病癌细胞居然达1000倍。赖教授称：“青蒿素不但有效，而且选择性非常强；对癌细胞有很高的毒性，但对正常细胞的影响很小。”它有可能成为无毒的高效抗癌药；哈医大的黑龙江省生物医药工程重点实验室杨宝峰、周晋教授研究发现，二氢青蒿素能有效抑制实体肿瘤细胞的增殖。他们发现，白血病细胞膜是二氢青蒿素攻击的一个主要靶点，起抗瘤机制有“凋亡”和“胀亡”两种。白血病细胞膜遭到破坏后，大量的钙离子就会进入细胞内，一方面引起细胞程序化死亡，即“凋亡”，另一方面导致细胞内的渗透压发生改变，吸收大量水分，使细胞膨胀直至死亡，即“胀亡”；这种推测在临床实验中得到了广泛支持：将若干组乳腺癌细胞和正常乳腺细胞与转铁蛋白接触，8小时以后，只剩下25％癌细胞。16小时过去以后，几乎所有癌细胞都死亡了，而正常细胞不受影响。例如一只患有严重骨癌的狗已经不能行走，在接受二氢青蒿素辅之以铁的治疗下，5天就完全恢复，赖教授的理论得到了验证。 现有技术中，上海药物研究所以二氢青蒿素酯、醚衍生物的方式来引进卤素，虞佩琳等二氢青蒿素类似物的研究、药学学报1985；20(5)：357~365，在抗癌实验(A549)中，对比物IC50是1227nM，引进溴元素的IC50是47nM，药效增强约26倍(Ying Li et al.Novel Antitumor Artemisinin DerivativesTargeting G1 Phase of the Cell Cycle.Bioorg.& Med.Chem.Lett.11(2001)5-8)。 专利权人是中国科学院上海药物研究所的中国专利02128494、名称为叔丁氧羰基二氢青蒿素、其制备方法及药物组合物，其发明提供结构式所示的叔丁氧羰基二氢青蒿素：系以二氢青蒿素为起始原料，与双叔丁基二碳酸酯在有机溶剂中进行酰化反应而制得；发明的抗寄生虫病药物组合物包含治疗有效量的叔丁氧羰基二氢青蒿素和药学上可接受的载体，与以前合成的二氢青蒿素衍生物相比，叔丁氧羰基二氢青蒿素有最大的治疗指数(＞1700)，是高效、低毒的抗寄生虫药物，在防治血吸虫病、疟疾等寄生虫病过程中可减少毒副作用的产生，尤其是在恶性疟疾的治疗中，对降低儿童死亡率有重大的意义。 申请人是浙江大学、申请号是03116762.4、发明名称为青蒿琥酯和二氢青蒿素抗血管生成作用的药物制剂及用途的中国专利申请公开了青蒿琥酯和二氢青蒿素在抗血管生成作用方面的药物制剂及其用途；该药物制剂主要含有青蒿琥酯或二氢青蒿素，其制剂形式主要为微球注射液；该发明提供的药物制剂在抗肿瘤血管生成方面有活性，可用于肿瘤血管生成及其他与血管生成有关的疾病治疗，还可用于肿瘤化疗和/或辅助化疗方面的治疗。该制剂在给药部位缓慢释放药物与吸收，延长药物作用时间；该发明以血管生成理论为背景，研究并阐明中药有效单体成分作用和机制，是发展中医药理论新的重要方向，为发现新的理论和药物作用新的靶点提供重要依据，为二氢青蒿素类药物的新用途开发提供依据。 综上所述，现有技术有以下方面的不足： 首先是青蒿素及其衍生物的医药用途虽然得到验证和肯定，但对癌症的适应症范围不够全面； 其次是现有的二氢青蒿素及其衍生物治疗癌症的药效还有待提高。 技术内容 因此，人们期待着具有更为广谱、特效、安全性高、毒副作用小和给药方式更简单的治疗癌症的药物，本发明的目的就是旨在克服上述现有技术缺限，提供一类基于二氢青蒿素的新化合物，它具有极为广谱的治疗癌症的医学效果和特别的疗效，且无任何毒副作用。 为了达到上述发明目的，本发明人研究了很多二氢青蒿素及其衍生物，并结合现有技术的教导，考虑到卤族元素取代基对药物效用有积极的影响，如溴化物具有加强药效的功能，成为许多感冒糖浆中的最佳药剂，通过无数次选择、试验，我们自主合成了溴代二氢青蒿素。 实际上，在二氢青蒿素的母核上引进杂原子是非常困难的，上海药物研究所是以二氢青蒿素酯、醚衍生物的方式来引进卤素。 溴代二氢青蒿素的化学名称为(3R，5aS，6R，8aS，9R，12S，12aR)-八氢-3-溴代亚甲基-6，9-二甲基-3，12-桥氧-12H-吡喃并[4，3-j]-1，2-苯并二塞平-10(3H)醇。 其结构式为： 本发明的主要目的是将二氢青蒿素上的3-C位甲基卤化。 合成溴代二氢青蒿素的步骤为：将二氢青蒿素溶于酯溶性溶剂，在溶液中导入溴源，进行合成反应，并去除残留溴源，后萃取提纯，并脱水结晶，得到标的化合物。 由于二氢青蒿素具有过氧桥的倍半萜内酯类结构，其应选择酯溶性溶剂对其溶解分散，较为优选的酯溶性溶剂是：乙腈、二甲基甲酰胺、乙酸、氯仿、四氯化碳。 上述的合成工艺中，所述的溴源可是单一成份的气体或液体，也可是溴化物。 液溴、溴氢酸、溴化氢气体等都可作为标的化合物的溴源导入。 在合成工艺中，当导入溴源进行溴化反应时，可加入催化剂对溴化反应进行催化。 所述的催化剂是二氧化锰、硅铝酸盐、卤化亚铜； 或是用卤钨灯直接进行照射。 本发明涉及的溴代二氢青蒿素在制备治疗癌症的药物组合物中可得到极积的应用； 本发明涉及的溴代二氢青蒿素可制成各种符合药剂学要求的各种口服剂型； 本发明涉及的溴代二氢青蒿素的可制成各种符合药剂学要求的各种外用剂型； 本发明涉及的溴代二氢青蒿素可制成各种符合药剂学要求的各种注射剂型； 所述的口服剂型包括：滴丸、速释滴丸、胶囊、颗粒、喷雾剂、口服液、片剂、骨架型缓释制剂包括：(1)不溶性(如乙基纤维素EC、聚乙烯、聚丙烯、聚硅氧烷、乙烯-醋酸乙烯共聚物、聚甲基丙烯酸甲酯等)；(2)蜡质骨架(如脂肪、蜡类物质、硬脂酸、硬脂醇、单硬脂酸甘油酯、巴西棕榈蜡、十八烷醇等)；(3)亲水凝胶(如CMC、CMC-Na、MC、PVA、HEC、SCMC、海藻酸钠、果胶、藻酸盐、琼脂、羟丙基甲基纤维素HPMC、脱乙酰壳多糖、壳多糖、半乳糖甘露聚糖等)；(4)胃内滞留片等；缓释包衣制剂包括：(1)膜控释小片、(2)微孔膜包衣片、(3)小丸剂包括：膜控小丸、骨架型小丸； 所述的注射剂型包括：注射液(普通)、冻干粉针、粉针(普通)、大输液、高浓度注射液、注射用片剂； 所述外用剂型包括：膜剂、栓剂、气雾剂、透皮制剂释药 上述剂型中： 滴丸是在中药丸剂基础上发展起来的，具有传统丸剂所没有的多种特点，故发展非常迅速。由于片剂服用量大，崩解度差，对肠胃道有刺激作用，而滴丸用舌下含服，从而大大减少了对肠胃道刺激。与其它剂型(软胶囊、冲剂、颗粒剂、胶囊剂、口服液)比较，具有比表面积大，溶出速度快的特点，这是因为滴丸可提高难溶性药物的生物利用度。由于滴丸是在骤冷条件下形成的固体分散体，药物以极小的晶粒存在，故舌下含服经舌粘膜吸收，直接进入血循环，起效快；临床应用适合于对口腔癌、喉癌的专用药。 缓释控释制剂 近年来缓释、控释制剂为开发研究热点。缓释制剂是指可以减少服药次数，提供比较平稳的血药浓度的制剂，以达到减少副作用，维持持久药效的目的。控释制剂是指通过制剂手段提供释放药物的程序，在预定的时间内药物自动按某一速度从剂型中释放与作用器官或特定的靶部位，使血药浓度长时间恒定维持在有效浓度范围内，释药均匀平衡，控释体系释药速度与时间无关，避免了传统常规制剂给药频繁所出现的“峰谷”现象，提高了临床用药安全性与有效性，可代替静脉滴注，也可根据机体需要自动控制给药速度。其目的在于寻求提供理想血药浓度的途径，提高药物的安全性和有效性。口服缓释控释制剂的研究发展很快，其种类不断增加，设计方法逐渐趋于半定量或定量化；临床应用适合于对全身各种癌症的用药。 膜剂 膜剂是近年来国内外研究和应用进展很快的剂型，临床很受欢迎，可用于口服、口眼耳鼻喉、皮肤及妇科癌症等。随着TTS(即透皮治疗系统)的不断发展，一些膜剂尤其是鼻腔、皮肤用药膜亦可起到全身作用，故在临床应用上有取代部分片剂、软膏剂和栓剂等的趋势。且具有疗程短、副作用小、药膜释放速度快的优点，是治疗各种阴道癌、宫颈癌的首选药物。由于膜剂本身体积小，重量轻，随身携带极为方便；如将生物粘附技术引入食道癌治疗的靶向制剂，所制成的磁性微球可很好地将药物粘附在癌细胞上；临床应用适合于口、咽、鼻、喉、皮肤、妇女阴道、宫颈癌的专用药。 微囊 微囊是利用天然或合成高分子材料或共聚物(囊膜材料)将药物包裹而成的一种新的剂型。药物微型包裹后利于携带，便于服用。它的优点在于可延长或控制药物的释放，制成长效制剂。囊膜有隔离外界与药物接触作用，可防止药物氧化、水解和挥发，掩盖不良气味，减少复方制剂中的配伍禁忌。也可制备特殊性能微囊(磁性微囊、PH敏感微囊)起到靶向释药作用，采用明胶冻凝法将其包成微囊，其包囊率及温室贮存稳定性较好。 微囊系利用天然的或合成的高分子材料将固体或液体药物包裹而成的直径1-500um的微小胶囊，其外型取决于囊心物质的性质和囊材凝聚的方式，微囊外面呈球状实体或呈平滑的球状膜壳形，葡萄患形及表面平滑或折叠的不规则结构等各种形状，它常用于增加药物的稳定性，掩盖药物的不良气味，改良和延缓药物的释放；临床应用适合于全身癌症的用药。 栓剂 栓剂不仅可起到局部治疗作用，而且还可通过直肠吸收到全身治疗作用，直肠给药后，药物不直接通过肝脏，可防止或减少药物在肝脏的代谢，减轻药物对肝脏的毒副作用。栓剂具有吸收快，起效迅速，生物利用度高，能维持较长时间血药浓度的优点。腔肠给药用药的有发展潜力的主渠道之一，这一领域的研究必定会推动栓剂的迅速发展；临床应用适合于肠癌、前列腺癌等。 气雾剂 气雾剂具有剂量小，分布均匀，奏效快，使用方便等特点。吸入时可减少胃肠道副作用，外用则避免对创面的刺激性，并可用定量阀门控制剂量，具有速效和定位作用。临床上主要用于幼儿不能口服或不愿口服者；本剂型临床应用适合于上皮肤癌、上呼吸道癌、肺癌等。 靶向制剂 靶向给药也是近年来国内外一个极为重要的开发热点，尤其在抗癌药物方面已取得重大发展，其原理为抗癌物与铁磁性材料包封与高分子骨架材料中，制成的超微球控释制剂在体外磁场导向下聚集滞留在靶区的癌组织上，缓慢释放药物，对癌细胞，进行有效的攻击，既可避免伤害正常细胞，又可减少用药量和降低毒性，提高疗效。磁性靶位释药系统在靶位给药方面提供了一个新的开发途径，而脂质体仍为靶向制剂中研究的热点；本剂型临床应用适合于全身各种癌症的用药。 微丸 是指直径小于2.5mm的各类丸剂，可根据不同需要将其制成速释或缓释微丸。速释微丸可使药物迅速释放。本研究的重点是缓释微丸，缓释微丸是由药物与阻滞剂混合制成或先制成普通丸芯而后再包控释膜而成。微丸压制成片，或将速释微丸与缓释微丸装于胶囊壳中制成控释胶囊剂。 微丸之有许多其他口服制剂无法相比的优点：①可通过控释微丸包衣制成缓控释制剂；②在胃肠道分布面积大，生物利用度高，刺激性小；③由于粒径小，受消化道输送食物节律影响小(如幽门关闭等)；④控释微丸可使血药浓度迅速达到疗效浓度，并维持平稳、长时间的有效浓度，血药波动小；⑤微丸的流动性好，大小均匀，易于处理(如包衣、分剂量)；⑥改善药物稳定性，掩盖不良味道；⑦适合复方制剂的配伍；本剂型临床应用适合于全身各种癌症的用药。 透皮制剂释药 本透皮制剂主要为凝胶制剂，可持续维持本药的血药浓度24小时，避免口服和静脉给药途径的血药浓度波动；本剂型临床应用适合于全身各种癌症的用药，尤其是皮肤癌。 二氢青蒿素可直接购买，也可直接从植物中提取青蒿素，后还原成二氢青蒿素。 与现有的二氢青蒿素相比，溴代二氢青蒿素有以下几方面突出的优点： 申请人首创在在二氢青蒿素的母核上直接引进杂原子，将二氢青蒿素上的3-C位甲基溴化。 药效更强：卤族元素的极性更强，因此比二氢青蒿素的生理活性更强；按二氢青蒿素抗癌原理，其作用方式是其特有的氧桥断裂产生自由基，引起癌细胞膜破裂而杀死癌细胞；a-甲基的溴化有利于吸引3，12碳位上的氧桥断裂产生自由基，可以大大增强药效，按四川大学华西医学院用溴代二氢青蒿素对人肝癌细胞株-Hepg2细胞毒性研究表明，溴代二氢青蒿素对体外Hepg2细胞的细胞毒IC50＜8nM。 溴化工艺简单、并易于工业控制，有很好的专一性，使产品的合成工艺有很好的特异性，并且易于量化控制。 溴代二氢青蒿素无毒副作用。 附图说明 图1是溴代二氢青蒿素体用于体外癌细胞株癌细胞生存率示意图(％)。 图2是合成溴代二氢青蒿素的工艺流程图。 具体实施方式 实施例1： 本实施例描述用黄花青蒿制备青蒿素、将青蒿素还原成二氢青蒿素、用二氢青蒿素导入溴源合成溴代二氢青蒿素的过程。 黄花青蒿5000Kg用8倍乙醇24h回流浸提，浸提液注入层析硅胶柱，直到流完；用石油醚洗脱，开始为黄绿液体；洗到液体基本为无色透明或用硅胶G板薄层监测有浅蓝色荧光斑点时，换洗脱液为10％乙酸乙酯+90％石油醚洗脱，并收集其洗脱液，用上述薄层监测至无蓝色荧光斑点； 收集的洗脱液浓缩，静置过夜，收集析出的粗结晶；用30倍的50％的乙醇液重结晶，得青蒿素针状结晶； 将青蒿素10Kg溶入300L甲醇中，搅拌下加季铵盐EtNCl 4Kg，充分搅拌混均后加入硼氢化钾4Kg，加磷酸二氢钠1.65Kg，室温下反应至白色结晶析出，质液明显分离；将全部反应物倒入0℃的冰水中，静置析出白色固体；收集白色固体，用蒸馏水反复洗涤3次、干燥，得二氢青蒿素，为白色粉末状结晶。 将反应釜用N2干燥，加入100mol二氢青蒿素和1000L氯仿，溶解；加入14KgMnO2，搅匀。并于40～60℃温度下以大约16L/分钟的速度导入液溴100mol，同时进行搅拌；60分钟后，过滤反应物；向过滤物中加入1000～5000L10％的硫代硫酸钠水溶液洗涤，收集有机层；再加入5000～15000L10％的碳酸氢钠溶液洗涤，收集有机层；有机层用无水硫酸钠脱水后减压浓缩成白色结晶，晶体用正己烷洗涤，滤出结晶，干燥，得到溴代二氢青蒿素，为白色粉末状结晶。 实施例2： 本实施例描述用青蒿素还原成二氢青蒿素、用二氢青蒿素导入溴源合成溴代二氢青蒿素的过程。 市售青蒿素粗粉(与生药比为1∶4)备用加5倍50％乙醇溶解，溶解液注入层析硅胶柱，直到流完；用石油醚洗脱，开始为黄绿液体；洗到液体基本为无色透明或用硅胶G板薄层监测有浅蓝色荧光斑点时，换洗脱液为40％乙酸乙酯+60％石油醚洗脱，并收集其洗脱液，用上述薄层监测至无蓝色荧光斑点；收集的洗脱液浓缩，干燥；用乙酸乙酯精制，得青蒿素针状结晶。 将提纯后的青蒿素10Kg溶入300L50％乙醇中，搅拌下加季铵盐EtNCl 4Kg，充分搅拌混均后加入硼氢化钾4Kg，加磷酸二氢钠1.65Kg，室温下反应至白色结晶析出，质液明显分离；将全部反应物倒入0℃的冰水中，静置析出白色固体；收集白色固体，用蒸馏水反复洗涤3次、干燥，得二氢青蒿素，为白色粉末状结晶。 反应釜用N2干燥，加入100mol二氢青蒿素和1000L四氯化碳，溶解；加入14KgMnO2，搅匀。并于40℃温度下以大约16L/分钟的速度导入液溴，同时进行搅拌；90分钟后，过滤反应物；过滤物用1000～2000L的水搅拌洗涤，收集有机层；有机层用无水硫酸钠脱水后减压浓缩成白色结晶，晶体用正己烷洗涤，滤出结晶，干燥，得到溴代二氢青蒿素，为白色粉末状结晶。 实施例3溴代二氢青蒿素的制备 反应釜用N2干燥，加入100mol二氢青蒿素和1000L氯仿，溶解；加入14KgMnO2，搅匀。并于40～60℃温度下以大约16L/分钟的速度导入液溴100mol，同时进行搅拌；60分钟后，过滤反应物；向过滤物中加入1000～5000L10％的硫代硫酸钠水溶液洗涤，收集有机层；再加入5000～15000L10％的碳酸氢钠溶液洗涤，收集有机层；有机层用无水硫酸钠脱水后减压浓缩成白色结晶，晶体用正己烷洗涤，滤出结晶，干燥，得到溴代二氢青蒿素，为白色粉末状结晶。 实施例4溴代二氢青蒿素的制备 反应釜用N2干燥，加入100mol二氢青蒿素和1000L四氯化碳，溶解；加入14KgMnO2，搅匀。并于40℃温度下以大约16L/分钟的速度导入液溴，同时进行搅拌；90分钟后，过滤反应物；过滤物用1000～2000L的水搅拌洗涤，收集有机层；有机层用无水硫酸钠脱水后减压浓缩成白色结晶，晶体用正己烷洗涤，滤出结晶，干燥，得到溴代二氢青蒿素，为白色粉末状结晶。 实施例5溴代二氢青蒿素的制备 反应釜用N2干燥，加入100mol二氢青蒿素和1000L乙腈，溶解；于室温下以大约10L/分钟的速度导入液溴，同时进行搅拌；在1000W卤素灯光催化下，反应6小时；向反应物中加入1000～5000L10％的硫代硫酸钠水溶液洗涤，收集有机层；再加入5000～15000L10％的碳酸氢钠溶液洗涤，收集有机层；有机层用无水硫酸钠脱水后减压浓缩成白色结晶，晶体用正己烷洗涤，滤出结晶，干燥，得到溴代二氢青蒿素，为类白色粉末状结晶。 实施例6溴代二氢青蒿素的制备 1.5Kg二氢青蒿素和5L氯仿混合，溶解；加入14KgMnO2，搅匀。并于40℃温度下以大约16L/分钟的速度导入液溴，同时进行搅拌；90分钟后，过滤反应物；过滤物再用氯仿精制一次；用无水硫酸钠脱水后减压浓缩成白色结晶，晶体用正己烷洗涤，滤出结晶，干燥，得到溴代二氢青蒿素，为白色粉末状结晶。 实施例7 Br-DHA对人肝癌细胞株-Hepg2细胞毒性的研究报告(四川大学华西医学院2004.12.22) 1.材料： 1.1细胞株：人肝癌细胞株Hepg2购于美国ATCC，10％FBS/DMEM常规培养。 1.2受试品Br-DHA：白色粉末，平均分子量320g/mol，批号20041205。硫酸亚铁：白色粉末，批号：20041205。转铁蛋白，Sigma公司。 2.方法： 2.1细胞毒实验方法： 取对数生长期的Hepg2细胞，常规方法消化，以8×103的密度接种于24孔细胞培养板。接种24h后，接表1分别加入转铁蛋白、硫酸亚铁，培养8小时后，加入Br-DHA。药物作用72小时后，常规方法细胞计数结果见图1。 3.结果：(见下表) 4.小结 在上述实验条件下，发现Br-DHA对体外Hepg2细胞的细胞毒IC50＜8nM。 表1：Br-DHA给药剂量表 组别 转铁蛋白(nM) 硫酸亚铁(mg) Br-DHA(nM) 空白 ------------- ------------- ------------ 转铁蛋白 880nM 0.25 Br-DHA 880nM880nM880nM 0.250.010.002 1000408 注：硫酸亚铁：Br-DHA＝250ng：1nM；每剂量样本数N＝4 实施例8 Br-DHA体外抗肿瘤活性的研究(四川大学华西药学院)。 1.材料 1.1细胞株： 人肝癌细胞株Hepg2购于美国ATCC， 人肺癌细胞株A549，购于中国科学院上海细胞所。 1.2培养基： Dulbecco’s Modified Eagle Medium(DMEM)：GIBCOBRL，Cat.No：12100-038，RPMI1640：GIBCOBRL，Cat.No：430-1800EB， Fetal Bovine Serum：Cat.No：CH30160.03 胰酶：GIBCOBRL，Cat.No：27250-018。 1.3受试品： Br-DHA：白色粉末，平均分子量320，大陆蓉东药业，批号：20041205， 硫酸亚铁：白色粉末，大陆蓉东药业，批号：20041205， 转铁蛋白：白色晶状粉末，平均分子量79000，Sigma。 2.方法 2.1细胞培养： Hepg2与A549细胞分别常规培养于10％FBS/DMEM与10％FBS/RPMI1640中，2-3天换液。 2.2药物配制： 用十万分之一电子天平精密称取转铁蛋白、硫酸亚铁、BrDHA，其中转铁蛋白、硫酸亚铁直接溶于细胞培养基后过滤除菌，转铁蛋白Co＝17.6nM，硫酸业铁Co＝5mg/L；而BrDHA先溶于DMSO后，再用细胞培养基稀释到所需浓度，过滤除菌Co＝6.4mg/L。受试品的不同浓度由低比稀释配制。 转铁蛋白、硫酸亚铁、BrDHA的溶液均于临用前新鲜配制，每孔加50uL。 2.3细胞毒试验方法： 取对数生长期的Hepg2、A549细胞，常规方法消化，以8×103的密度接种于2/4孔细胞培养板。接种24h后，接表1、2分别加入转铁蛋白、相应剂量的硫酸亚铁。孵育8h后，加入各剂量的Br-DHA。药物作用72小时后，常规方法细胞计数结果见表2、3。 3.结果：见表2、表3。 4.结论：本实验表明Br-DHA对人肝癌细胞株Hepg2细胞和人肺癌细胞株A549细胞均有非常明显的体外抗肿瘤作用，对Hepg2和A549细胞的IC50分别＜8nM和31.6nM。(表2、表3见本页) 表2、Br-DHA对人肝癌细胞株--Hepg2体外抗肿瘤活性 组别 样本数 药物剂量 细胞生存率(％) 转铁蛋白nM 硫酸亚铁mg/L BrDHAnM 空白对照 4 ----- ----- ----- 100.0±9.1 转铁蛋白 4 880 0.25 ----- 44.7±5.6 BrDHA 4 880 0.25 1000 23.3±5.3 4 880 0.05 200 32.7±14.1 4 880 0.01 40 31.1±10.6 4 880 0.002 8 41.6±3.6 注.硫酸亚铁：BrDHA＝250ng：1nM 表3、Br-DHA对人肺癌细胞株--A549体外抗肿瘤活性 组别 样本数 药物剂量 细胞生存率(％) 转铁蛋白nM 硫酸亚铁mg/L BrDHAnM 空白对照 4 ----- ----- ----- 100.0±14.9 转铁蛋白 4 880 0.25 ----- 59.0±9.8 BrDHA 4 880 0.25 1000 17.4±7.5 4 880 0.05 100 39.0±5.2 4 880 0.0025 10 58.2±5.2 4 880 0.00025 1 59.0±1 3.0 注.硫酸亚铁∶BrDHA＝250ng∶1nM。 实施例9 中国科学院成都分院分析测试中心 分析、测试结果报告单 溴化率的计算： 1、二氢青蒿素(DHA)分子量为284.34，溴原子(Br)分子量为79.90，氢原子(H)分子量为1； 2、二氢青蒿素的一个氢原子被溴原子取代后， 溴代二氢青蒿素的分子量为：(284.34-1)+79.90＝363.24 3、溴化率的计算： 79.90÷363.24＝21.996％≈22.0％。 检验报告上22.90％属正常值。... https://patents.google.com/patent/CN1295231C/zh?oq=CN1295231C溴二氢青蒿素---特别适用于治疗各种癌症的溴代二氢青蒿素 Bromo-dihydroartemisine The present invention discloses bromo-dihydroarteannuin which is especially suitable for treating various kinds of cancer. In the present invention, firstly, 3-C methyl of dihydroarteannuin is bromized, and hetero atoms are directly introduced into the mother nucleus of the dihydroarteannuin; the dihydroarteannuin is mainly used as the mother nucleus to prepare bromo-dihydroarteannuin; by using the high polarity of halogen elements, the oxygen bridge of the dihydroarteannuin is easily ruptured to form a free radical, and the effect of medicine is largely increased. The present invention has the advantages of simple bromination technology, easy industrialized preparation and good bromination specificity. Thus, the synthesis technology of the product has good specificity, the product is convenient for quantization control, and the product has no toxic or side effect on normal cells. Researches on the cytotoxicity of the liver cancer cell strain-Hepg2 of a human body by using bromo-dihydroarteannuin indicate that the IC50 of the bromo-dihydroarteannuin for the cytotoxin of Hepg2 cells in vitro is less than 8nM. Br-DHA Technical field The present invention relates to the synthetics technical field, specifically, relate to a kind of derivative one bromo Dihydroartemisinin of Dihydroartemisinin. Background technology The existing natural anti-cancer drugs that extracts from plant because its curative effect finite sum toxic side effect has limited its clinical application by force, can not become anticancer main force's medicine all the time. For example: taxol is known as wide spectrum, the strongest active cancer therapy drug in the world today, especially uterus carcinoma, ovarian cancer, mammary cancer are had special curative effect, and its appearance is described as the nineties of one of anticarcinogen three big achievements in the world; The common medication of treatment women breast cancer at present has the pure and mild Paclitaxel of European yew; Can prolong two months deterioration time and increase by 3 months survival time. But two kinds of taxols all have side effect, and the phenomenon of hand and foot numbness can appear in patient, and the common and the most fatal side effect of Paclitaxel toxicity is exactly that acute anaphylactic shock takes place for the patient of 15-20%; Side effect: suppress hematopoietic cell, allergy, gastrointestinal upset, and slight hepar damnification; The common side effect of European yew alcohol is that bone marrow depression, blood cell are low, tired etc. Camptothecine and for example: camptothecine is a kind of alkaloid that extracts from China camplotheca acuminata, is applied to clinically in digestive system tumor, and the treatment of melanoma etc. also has the part effect; Its mechanism of action studies have shown that through dynamic (dynamical) camptothecine is to belong to cell cycle specific agents, can make cancer cells stay in the S phase (DNA synthesis phase), stops its further division.The experimentation on animals proof all has than obvious restraining effect the synthetic of Erlich ascitic tumor cell DNA, RNA, and cancer of the stomach 435 examples, efficient 61% are treated with camptothecine in the area, Shanghai; But serious side effects such as bone marrow depression are arranged, the symptom of hemorrhagic cystitis and Digestive tract. Artemisinin be China pharmacy worker 1971 from feverfew chrysanthemum mugwort extraction separation to a kind of sesquiterpene lactones compounds with peroxide bridge; Artemisinin and derivative thereof are the novel antimalarial drugs of sesquiterpene lactones class that contains peroxide bridge, have efficient, fast, characteristics such as low toxicity, safety; Studies show that Artemisinin has killing action to gametocyte, its intensity is relevant with the gametophyte ripening degree with dosage. Early stage studies show that, the plasmodial mechanism of Artemisinin selectively killing erythrocytic stage mainly is to act on plasmodial film structure, nuclear membrane, plasma membrane are destroyed, the mitochondrial swelling shrinkage, interior adventitia is peeled off, and coloring matter in examining is also had certain influence, and Artemisinin and derivative thereof are by the mitochondrial function of influence, the supply of blocking-up plasmodium nutrition, thus reach the antimalarial purpose; Arteannuin medicine is used and is not seen relevant drug-fast report during the last ten years as yet, and in the treatment to the multiple drug resistance pernicious malaria, Artesunate and Artemether also have good curative effect. Artemisinin and derivative thereof also have following effect: The effect of anti-Pneumocystis carinii pneumonia: experimentation on animals confirms that Artemisinin is effective to rat Pneumocystis carinii pneumonia; With dihydroarteannuin 60 mg/kg treatment rat Pneumocystis carinii pneumonia, survival of rats number, survival rate all are higher than infected group; Heavy, average lung weight/weight ratio of the average lung of treatment back rat and packing number average are lower than infected group, and the lung tissue inflammatory reaction obviously alleviates; Studies show that further dihydroarteannuin mainly destroys the Pneumocystis carinii film structure, cause in sporozoite trophont endochylema and the packing cavity to occur, mitochondrial swelling, nuclear membrane breaks, endoplasmic reticulum swelling, Ultrastructural changes such as the interior corpusculum dissolved destruction of capsule. Anti-pregnant effect: Artesunate and dihydroarteannuin all have anti-pregnant effect to mouse, Golden Hamster, rat and rabbit, and Golden Hamster and cavy show as miscarriage, and mouse, rat and rabbit show as the embryo and absorb.Artesunate (40 mg/kg) * pregnant rat serum progesterone content was descended in 5 days and damage fetal membrane and placenta to make embryo necrosis and termination of pregnancy; Dihydroartemisinin also has direct killing effect to people's fetal membrane cell of vitro culture; Dihydroartemisinin class medicine has higher selective toxicity to the embryo, can make embryonic death and cause miscarriage than low dosage, but parent uterus, ovary and general health situation are not had obvious influence, and this type of medicine might be developed to the artificial abortion medicine. Effect to tumour: Dihydroartemisinin and derivative thereof have cytotoxic activity to mouse ehrlich ascites tumor cell and human Hela cell; Visible scalariform DNA of HeLa cell and apoptotic body with the Artesunate processing.Beekman etc. detect discovery to the 60 strain tumour cells of cultivating from 9 kinds of different tissues, dihydroarteannuin is extremely sensitive to leukemia, melanoma, colorectal carcinoma, prostate cancer and breast carcinoma cell strain, and lower to the activity of nonsmall-cell lung cancer, central nerve neuroma, ovarian cancer and renal cancer cell line; Its antitumor action may be relevant with Fe2+ reaction a large amount of free radicals of generation and alkylating with Dihydroartemisinin. Anti-schistosome function: Artemisinin and multiple derivative thereof all have anti-schistosome function; in the whole stage of taking medicine the schistosomicide of larval stage all there is killing action; therefore has the good preventing effect; Dihydroartemisinin can also be killed and enter the intravital larva of host; the contactee has provide protection to epidemic disease water; be used to infect the early treatment behind the schistosoma japonicum cercariae, can reduce schistosomicide rate and gradient of infection, and can prevent schistosomicide to take place.Its schistosomicide active group is a peroxide bridge, and the mechanism of action is the carbohydrate metabolism that influences polypide.When the crowd of large-scale application Artesunate prophylactic treatment contact epidemic disease water, find, 17031 people are taken place at the no acute schistosomiasis in back of taking medicine, therefore thinking that Dihydroartemisinin prevents characteristics such as schistosomicide has efficiently, safety, convenience, is present more satisfactory prophylactic agent. The effect of treatment arch insect infection: experiment in vitro confirms that Artemisinin (Artemether) can suppress toxoplasma gondii and invade cell.Artemisinin mainly acts on polypide cytolemma, plastosome and nucleus, and its film structure of extensive injuries causes nuclear membrane fracture, mitochondrial swelling, the sex change of cavity sample, reticulum dilatation even nuclear fragmentation, karyolysis phenomenon occur then. To cardiovascular effect: sweet wormwood have reducing heart rate, and anti-arrhythmia suppresses effects such as myocardial contraction.Dihydroartemisinin can obviously resist the irregular pulse that the ligation coronary artery causes, the arrhythmia episode time that calcium chloride, chloroform are caused obviously postpones, quiver and obviously reduce in the chamber, its effect is relevant with Purkinje fiber export-oriented potassium current of moment with its inhibition inward rectification potassium current. To immune effect: dihydroarteannuin, Artesunate all have remarkable restraining effect to the generation of super suitable dosage immunization inductive donor mouse T cell, and both can both strengthen acceptor mouse step of reaction cell activity. Other: dihydroarteannuin has remarkable restraining effect and is dosage correlation Leishmania donovani.It is synthetic that its mechanism system influence Leishmania donovani promastigote DNA, makes the polypide distortion, and nuclear, kinetoplast are imperfect, a plurality of cavitys of appearance in the kytoplasm, and flagellum comes off.Artemisinin also can be killed Trichomonas vaginalis and amoeba histolytica's trophont.Can the relax contraction tracheae effect of guinea pig tracheal smooth muscle and noncompetitive antagonism vagusstoff, histamine of Artesunate, mechanism and activated adenyl cyclase close, and are not blocked by the beta-2 adrenoceptor timolol. In recent years, the medicine scholar of various countries has carried out research widely to the antitumous effect of Artemisinin and derivative thereof, and profound pharmacology, drug effect, toxic side effect and pharmacokinetic study show: Pharmacology: tackle leukemia and breast cancer cell with Artemisinin and derivative thereof, find that the selectivity of Artemisinin is other chemotherapeutic 100 times, and Artemisinin can kill cancer cell, but does not injure healthy cell on every side." need a large amount of ironys ability repetition DNAs during the cancer cell division, so the irony content of cancer cells is more high than normal cell." after these albumen that carry artemisinin derivative enter cancer cells; form oxo bridge between Sauerstoffatom on the 3-C position in the Artemisinin and the Sauerstoffatom on the 12-C position; iron ion just is released and reacts with artemisinin derivative; thus destruction of cancer cells; and the oxo bridge fracture discharges free radical (Sauerstoffatom); free radical is attacked cancer cell membrane, makes film rupture and cancer cell death; This is the key that Artemisinin is transferred to cancer therapy drug.Because cancer cells makes medicine have very high selectivity to the greediness of iron; Experiment shows that the iron biography albumen of Artemisinin mark is selected and the efficient of kill cancer cell is to kill 34000 times of Normocellular efficient (data source). Drug effect compares: IC50 is the cancer cell in vitro medium lethal dose, and IC50 can react a little less than the strong drug action intuitively. Hydroxycamptothecine IC50 is 206u mol～305u molng; Taxol IC50 is 8.6u mol; Dihydroartemisinin IC50 is 24n mol (0.024 u mol). Toxic side effect: neural system, respiratory system, cardiovascular systems are not all had obvious pharmacological action, only show certain analgesia, sedative effect during greatly to 40mg/kg at dosage.This medicine security is bigger, LD 50Be 834.5mg/kg, chemotherapeutic index is 834.0, and rat 20-180 (MKD) administration in continuous 30 days there is no considerable change to physiology, biochemical indicator and main organs pathological examination.The specific toxicity aspect, the mutagenic test feminine gender, reproduction poison aspect in mouse pregnancy critical porion administration, increases the generation that absorbs tire, does not see teratogenesis. Pharmacokinetics: behind the mouse gavaging 3H-Dihydroartemisinin, radioactivity rises rapidly in the blood, hour peaks half an hour to 1, descends rapidly subsequently, drops to half of peak value, and slowly disappears later in 4 hours.The measurement of gi tract residual quantity shows, residual 58%, 1 hour of half an hour is residual 35.3%, partly measures extinction time and is about 1.2 hours.Widely distributed behind the oral administration, 1 hour begins to peak, and isotope method shows that courage, liver, kidney are maximum in each tissue, and the heart, lung, spleen etc. take second place.Development process shows that intramuscular injection peaked in 1～8 hour, and liver, brain, bone, blood content are higher.In oral back 24 hours, 80% radioactivity is discharged through excrement, urine, and the development process result is similar.The above results show Dihydroartemisinin enter in the body post-absorption fast, distribute extensively, drain fast. The Lai Hengli professor of Washington, DC university bioengineering dept in 1997 and Na Lundela star begin to imagine same mechanism and necessarily also can act on cancer: need a large amount of ironys ability repetition DNAs during the cancer cell division, so the irony content of cancer cells is more high than normal cell; Find that after deliberation cancer cells is than the high 5-15 of normal cell iron content times, high reaches 50 times, and the highest leukaemia cancer cell reaches 1000 times unexpectedly.Professor Lai claims: " Artemisinin is not only effective, and selectivity is very strong; Cancer cells there is very high toxicity, but very little to Normocellular influence." it might become nontoxic efficient anticarcinogen; The Yang Baofeng of Heilongjiang Province biological medicine engineering key lab, professor Zhou Jin that breathe out medical university discover that Dihydroartemisinin can effectively suppress the propagation of solid tumor cell.They find that leukemia cell's film is the main target spot that Dihydroartemisinin is attacked, and playing anti-knurl mechanism has " apoptosis " and " expand and die " two kinds.After leukemia cell's film was destroyed, a large amount of calcium ions will enter in the cell, caused programmed cell death on the one hand, i.e. " apoptosis " causes intracellular osmotic pressure to change on the other hand, absorbs large quantity of moisture, make cell expansion until death, promptly " expand and die "; This supposition has obtained extensive support in clinical experiment: some groups of breast cancer cells contacted with Transferrins,iron complexes with the normal breast cell, and after 8 hours, only remaining 25% cancer cells.After past 16 hours, nearly all cancer cells is all dead, and normal cell is unaffected.For example a dog that suffers from serious osteocarcinoma can not walk, and is accepting under the treatment that Dihydroartemisinin is aided with iron, just recovers fully in 5 days, relies professor's theory to obtain checking. In the prior art, so the mode of Shanghai drug research Dihydroartemisinin ester, ether derivant is introduced halogen, the research of Dihydroartemisinin analogues such as Yu Peilin, Acta Pharmaceutica Sinica 1985; 20 (5): 357 ~ 365, in anticancer experiment (A549), comparison IC50 is 1227nM, the IC50 that introduces bromo element is 47nM, and drug effect strengthens about 26 times (Ying Li et al.Novel Antitumor Artemisinin DerivativesTargeting G1 Phase of the Cell Cycle.Bioorg.﹠amp; Med.Chem.Lett.11 (2001) 5-8). The patentee is that Chinese patent 02128494, the name of Shanghai Pharmaceutical Inst., Chinese Academy of Sciences is called tert-butoxy carbonyl dihydro artemisinin, its preparation method and pharmaceutical composition, its invention provides the tert-butoxy carbonyl dihydro artemisinin shown in the structural formula: be to be starting raw material with the Dihydroartemisinin, carry out acylation reaction with dual-tert-butyl two carbonic ethers in organic solvent and make; The medicine for parasitic disease composition of invention comprises the tert-butoxy carbonyl dihydro artemisinin and the pharmaceutically acceptable carrier for the treatment of significant quantity, compared with former synthetic dihydroqinghaosu, tert-butoxy carbonyl dihydro artemisinin has maximum therapeutic index (＞1700), it is anti-parasite medicine efficient, low toxicity, in parasitosis processes such as prevention and cure of schistosomiasis, malaria, can reduce the generation of toxic side effect, especially in the treatment of pernicious malaria, significant meaning is arranged to reducing child mortality. The applicant is that Zhejiang University, application number are 03116762.4, denomination of invention is that the pharmaceutical preparation of Artesunate and Dihydroartemisinin blood vessel formation against function and the Chinese patent application of purposes disclose Artesunate and Dihydroartemisinin pharmaceutical preparation aspect blood vessel formation against function and uses thereof; This pharmaceutical preparation mainly contains Artesunate or Dihydroartemisinin, and its dosage form is mainly microsphere injection liquid; The pharmaceutical preparation that this invention provides is having activity aspect the antineoplastic vascular generation, can be used for the disease treatment of tumor-blood-vessel growth and other and associated angiogenesis, also can be used for the treatment of chemotherapy of tumors and/or adjuvant chemotherapy aspect.Said preparation slowly discharges medicine and absorption at medicine-feeding part, prolong drug action time; This invention is a background with the vasculogenesis theory, research is also illustrated effect of Chinese medicine effective monomer component and mechanism, be the new important directions of developing Chinese medicine pharmacology opinion, provide important evidence, for the new purposes exploitation of Dihydroartemisinin class medicine provides foundation for finding the new target spot of new theory and drug effect. In sum, prior art has the deficiency of following aspect: Though the medicinal use that at first is Artemisinin and derivative thereof is verified and affirms, and is comprehensive inadequately to the indication scope of cancer; Next is that the drug effect of existing Dihydroartemisinin and derivatives for treating cancer thereof is still waiting to improve. Technology contents Therefore, people wait in expectation have more wide spectrum, special efficacy, safe, toxic side effect is little and the medicine of the simpler treatment cancer of administering mode, purpose of the present invention just is intended to overcome above-mentioned prior art and lacks limit, the new compound of one class based on Dihydroartemisinin is provided, it has very the medical science effect and the special curative effect of the treatment cancer of wide spectrum, and without any side effects. In order to reach the foregoing invention purpose, the inventor has studied a lot of Dihydroartemisinins and derivative thereof, and in conjunction with the instruction of prior art, consider that the haloid element substituting group has active influence to medicinal effectiveness, has the function of strengthening drug effect as bromide, become the best medicament in many flu syrup, by selecting many times, test, we have independently synthesized Br-DHA. In fact, it is very difficult introducing heteroatoms on the parent nucleus of Dihydroartemisinin, and the institute of materia medica, Shanghai introduces halogen in the mode of Dihydroartemisinin ester, ether derivant. The chemical name of Br-DHA be (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3-bromo methylene radical-6,9-dimethyl-3,12-bridging oxygen-12H-pyrans is [4,3-j]-1 also, 2-benzo two Sai Ping-10 (3H) alcohol. Its structural formula is: Main purpose of the present invention is with the 3-C position methyl halogenation on the Dihydroartemisinin. The step of synthetic Br-DHA is: Dihydroartemisinin is dissolved in the ester soluble solvent, imports the bromine source in solution, carry out building-up reactions, and remove residual bromine source, back purification by liquid extraction, and dehydration crystallization obtain the target compound. Because Dihydroartemisinin has the sesquiterpene lactones class formation of peroxide bridge, it should select the ester soluble solvent that its dissolving is disperseed, and comparatively preferred ester soluble solvent is: acetonitrile, dimethyl formamide, acetate, chloroform, tetracol phenixin. In the above-mentioned synthesis technique, described bromine source is the gas or the liquid of single composition, also bromide. The bromine source that liquid bromine, bromine hydracid, bromize hydrogen gas etc. all can be used as the target compound imports. In synthesis technique, when bromination reaction is carried out in importing bromine source, can add catalyzer bromination reaction is carried out catalysis. Described catalyzer is Manganse Dioxide, silico-aluminate, cuprous halide; Or directly shine with halogen tungsten lamp. The Br-DHA that the present invention relates to can obtain extremely long-pending application in the pharmaceutical composition of preparation treatment cancer; The Br-DHA that the present invention relates to can be made into the various various oral dosage forms that pharmaceutics requires that meet; The Br-DHA that the present invention relates to can be made into the various various exterior-applied formulations that pharmaceutics requires that meet; The Br-DHA that the present invention relates to can be made into the various various injection types that pharmaceutics requires that meet; Described oral dosage form comprises: dripping pill, quick-release dripping pill, capsule, particle, sprays, oral liquid, tablet, skeleton type sustained release preparation comprise: (1) insoluble (as ethyl cellulose EC, polyethylene, polypropylene, polysiloxane, ethylene-vinyl acetate copolymer, polymethylmethacrylate etc.); (2) wax skeleton (as fat, Wax, stearic acid, stearyl alcohol, glyceryl monostearate, carnauba wax, Stearyl alcohol etc.); (3) hydrophilic gel (as CMC, CMC-Na, MC, PVA, HEC, SCMC, sodium alginate, pectin, alginate, agar, Vltra tears HPMC, chitosan, chitin, galactomannan etc.); (4) Entogastric lingering sheet etc.; The sustained release coating preparation comprises: (1) film controlled release small pieces, (2) microporous membrane coating tablet, (3) pilule comprise: film controlled piller, matrix type piller; Described injection type comprises: injection liquid (common), freeze-dried powder, powder pin (common), infusion solutions, high density injection liquid, injection tablet; Described exterior-applied formulation comprises: film, suppository, aerosol, preparation capable of permeating skin release In the above-mentioned formulation: Dripping pill grows up on the medicine pill basis, has the unexistent multiple characteristics of traditional pill, so development is very fast.Because the tablets amount is big, disintegration is poor, and intestines and stomach is had hormesis, and the dripping pill sublingual administration stimulates intestines and stomach thereby significantly reduced.Compare with other formulation (soft capsule, electuary, granule, capsule, oral liquid), it is big to have specific surface area, the characteristics that dissolution rate is fast, and this is because dripping pill can improve the bioavailability of insoluble drug.Because dripping pill is the solid dispersion that forms under quenching conditions, medicine exists with minimum crystal grain, so sublingual administration absorbs through periglottis, directly enters circulation of blood, and is rapid-action; Clinical application is suitable for the special-purpose medicine to oral carcinoma, laryngocarcinoma. The sustained-release and controlled release preparation Slowly-releasing, controlled release preparation are the development research focus in recent years.Sustained release preparation is meant and can reduces medicining times, and the preparation of comparison stable blood concentration is provided, and to reach the minimizing side effect, keeps the purpose of lasting drug effect.Controlled release preparation is meant by the preparation means provides the program that discharges medicine, medicine is automatically by a certain speed release and effect organ or specific target site from formulation within the predetermined time, make long-time constant the maintaining in the effective concentration scope of Plasma Concentration, the release uniform balance, control delivery drug release rate and time are irrelevant, avoided frequent " peak valley " phenomenon that occurs of traditional conventional formulation administration, clinical drug safety and validity have been improved, can replace intravenous drip, also can control injection speed automatically according to the body needs.Its purpose is to seek to provide the approach of desirable Plasma Concentration, improves the security and the validity of medicine.The researchdevelopment of oral sustained release controlled release preparation is very fast, and its kind constantly increases, and method of design is tending towards sxemiquantitative or quantification gradually; Clinical application is suitable for the medication to the various cancers of whole body. Film Film is research both at home and abroad in recent years and uses the formulation that makes much progress, and clinical being popular can be used for oral, mouthful diseases of eye, ear, nose and throat, skin and gynecological cancer etc.Along with the continuous development of TTS (being transdermal therapeutic system), some films especially nasal cavity, dermatologic film also can play general action, so the trend that replaces part tablet, ointment and suppository etc. is arranged in clinical application.And having short treating period, side effect is little, medicine film release rate is fast advantage, is the choice drug of the various carcinomas of vagina of treatment, cervical cancer.Because the volume of film own is little, in light weight, it is very convenient to carry; As the bioadhesion technology being introduced the targeting preparation of esophagus cancer treatment, made magnetic microsphere can stick to medicine on the cancer cells well; Clinical application is suitable for the special-purpose medicine of mouth, pharynx, nose, larynx, skin, woman vagina, cervical cancer. Micro-capsule Micro-capsule is an a kind of new formulation of utilizing natural or synthesized polymer material or multipolymer (capsule film material) that the medicine parcel is formed.Be beneficial to behind the miniature parcel of medicine and carry, be convenient to take.Its advantage is to prolong or to control the release of medicine, makes prolonged action preparation.Cyst membrane has isolates extraneous and medicine contact action, can prevent oxidation of drug, hydrolysis and volatilization, covers unpleasant odor, reduces the incompatibility in the compound preparation.Also can prepare property micro-capsule (magnetic micro-capsule, the responsive micro-capsule of PH) and play the targeting drug release effect, adopt the gelatin congealing method that it is bundled into micro-capsule, its packing rate and greenhouse package stability are better. Micro-capsule system utilizes tiny capsules natural or that the synthetic macromolecular material wraps up solid or liquid medicine the diameter 1-500um that forms, its external form depends on the character of core material and the mode of capsule material cohesion, the micro-capsule outside is spherical entity or is level and smooth spherical putamina shape, grape is suffered from shape and surface smoothing or folding different shapes such as erratic composition, it is usually used in increasing stability of drug, cover the unpleasant odor of medicine, improve and delay the release of medicine; Clinical application is suitable for the medication of whole body cancer. Suppository Suppository not only can play local therapeutic effects, but also can absorb the whole body therapeutic effect by rectum, and behind the rectal administration, medicine directly by liver, can not prevent or reduce the metabolism of medicine at liver, alleviates the toxic side effect of medicine to liver.Suppository has and absorbs soon, and onset is rapid, and the bioavailability height can be kept the advantage of long period Plasma Concentration.Coelenteron administration medication one of main channel of development potentiality arranged, the research in this field must promote developing rapidly of suppository; Clinical application is suitable for intestinal cancer, prostate cancer etc. Aerosol Characteristics such as it is little that aerosol has dosage, is evenly distributed, and it is fast to prove effective, easy to use.Can reduce gastrointestinal side effect during suction, the pungency to the surface of a wound is then avoided in external application, and available quantitative valve control dosage, has quick-acting and positioning action.Being mainly used in the child clinically can not be oral or be reluctant oral person; The clinical application of this formulation is suitable for skin carcinoma, upper respiratory tract cancer, lung cancer etc. Targeting preparation Target administration also is a domestic and international in recent years very important exploitation focus, especially aspect cancer therapy drug, obtained significant development, its principle be anticarcinogen and ferromagnetic substance seal with the high-molecular bone frame material in, the ultra micro ball controlled release preparation of making is assembled under external magnetic field guiding and is trapped on the cancerous tissue of target area, slowly discharges medicine, to cancer cells, effectively attack, both can avoid injuring normal cell, and can reduce dosage again and reduce toxicity, improve curative effect.Magnetic target position medicine releasing system provides a new development approach aspect targeting of drugs, and liposome still is the focus of studying in the targeting preparation; The clinical application of this formulation is suitable for the medication of the various cancers of whole body. Micropill Be meant all kinds of pills of diameter, can be made into quick-release or sustained release pellet according to different needs less than 2.5mm.Fast release micropill can make medicine discharge rapidly.The emphasis of this research is a sustained release pellet, and sustained release pellet is to be mixed and made into or to make earlier common ball core by medicine and retarding agent then to wrap release-controlled film again and form.Micropill compacting or is loaded on fast release micropill and sustained release pellet and makes Extencap in the capsule shell in flakes. The advantage that has many other oral preparations to compare of micropill: 1. can make sustained-release preparation by the controlled release micro pill dressing; 2. big at the gi tract distribution area, the bioavailability height, pungency is little; 3. because particle diameter is little, be subjected to digestive tube to carry the food rhythm and pace of moving things to influence little (close as pylorus etc.); 4. controlled release micro pill can make Plasma Concentration reach curative effect concentration rapidly, and keeps steady, long effective concentration, and the fluctuation of blood medicine is little; 5. the good fluidity of micropill is evenly big or small, is easy to handle (as dressing, divided dose); 6. improve medicine stability, cover undesirable taste; 7. the compatibility that is fit to compound preparation; The clinical application of this formulation is suitable for the medication of the various cancers of whole body. The preparation capable of permeating skin release This preparation capable of permeating skin is mainly gel preparation, and the sustainable Plasma Concentration of keeping this medicine 24 hours is avoided oral and the blood concentration fluctuation intravenously administrable approach; The clinical application of this formulation is suitable for the medication of the various cancers of whole body, especially skin carcinoma. Dihydroartemisinin can directly be bought, and also can directly extract Artemisinin from plant, after be reduced into Dihydroartemisinin. Compare with existing Dihydroartemisinin, Br-DHA has the outstanding advantage of following several respects: Applicant's initiative is directly introduced heteroatoms on the parent nucleus at Dihydroartemisinin, with the 3-C position methyl bromination on the Dihydroartemisinin. Drug effect is stronger: the polarity of haloid element is stronger, and is therefore stronger than the physiologically active of Dihydroartemisinin; Press the anticancer principle of Dihydroartemisinin, its mode of action is that its distinctive oxo bridge fracture produces free radical, causes that cancer cell membrane breaks and kill cancer cell; The bromination of a-methyl helps attracting 3, oxo bridge fracture on 12 carbon potentials produces free radical, can strengthen drug effect greatly, with Br-DHA human hepatoma cell strain-Hepg2 Study of cytotoxicity is shown that by West China medical college of Sichuan University Br-DHA is to the cell toxicant IC50＜8nM of external Hepg2 cell. Bromination technology is simple and be easy to Industry Control, and good specificity is arranged, and makes the synthesis technique of product that excellent specificity be arranged, and is easy to quantified controlling. Br-DHA has no side effect. Description of drawings Fig. 1 is that the Br-DHA body is used for cancer cell in vitro strain cancer cells survival rate synoptic diagram (%). Fig. 2 is the process flow sheet of synthetic Br-DHA. Embodiment Embodiment 1: Present embodiment is described with the chrysanthemum sweet wormwood and is prepared Artemisinin, Artemisinin is reduced into Dihydroartemisinin, imports the process that Br-DHA is synthesized in the bromine source with Dihydroartemisinin. Chrysanthemum sweet wormwood 5000Kg injects the chromatography silicagel column with 8 times of ethanol 24h backflow lixiviates, vat liquor, up to having flowed; Use the sherwood oil wash-out, begin to be yellowish green liquid; When washing liquid and be substantially water white transparency or with the monitoring of silica gel G plate thin layer light blue fluorescence spot being arranged, changing elutriant is 10% ethyl acetate+90% sherwood oil wash-out, and collects its elutriant, monitors to there not being the blue-fluorescence spot with above-mentioned thin layer; The elutriant of collecting concentrates, and standing over night is collected the coarse crystallization of separating out; With 30 times 50% ethanol liquid recrystallization, Artemisinin needle crystal; Artemisinin 10Kg is dissolved in the 300L methyl alcohol, add quaternary ammonium salt EtNCl 4Kg under stirring, fully stir the back that is mixed and add POTASSIUM BOROHYDRIDE 4Kg, add biphosphate sodium 1.65Kg, react under the room temperature to white crystals and separate out, matter liquid obviously separates; The total overall reaction thing poured in 0 ℃ the frozen water, leave standstill and separate out white solid; Collect white solid,, get Dihydroartemisinin, be the white powder crystallization with distilled water repetitive scrubbing 3 times, drying. With reactor N2 drying, add 100mol Dihydroartemisinin and 1000L chloroform, dissolving; Add 14KgMnO2, stir evenly.And the speed with about 16L/ minute imports liquid bromine 100mol under 40～60 ℃ of temperature, stirs simultaneously; After 60 minutes, the filtering reaction thing; The sodium thiosulfate solution washing that in filtrate, adds 1000～5000L10%, collected organic layer; The sodium hydrogen carbonate solution washing that adds 5000～15000L10% again, collected organic layer; Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Br-DHA, is the white powder crystallization. Embodiment 2: Present embodiment is described with Artemisinin and is reduced into Dihydroartemisinin, imports the process that Br-DHA is synthesized in the bromine source with Dihydroartemisinin. Commercially available Artemisinin meal (with the crude drug ratio be 1: 4) standbyly add 5 times of 50% dissolve with ethanol, lysate injects the chromatography silicagel column, up to having flowed; Use the sherwood oil wash-out, begin to be yellowish green liquid; When washing liquid and be substantially water white transparency or with the monitoring of silica gel G plate thin layer light blue fluorescence spot being arranged, changing elutriant is 40% ethyl acetate+60% sherwood oil wash-out, and collects its elutriant, monitors to there not being the blue-fluorescence spot with above-mentioned thin layer; The elutriant of collecting concentrates, drying; Refining with ethyl acetate, get Artemisinin needle crystal. Artemisinin 10Kg after purifying is dissolved in the 300L50% ethanol, add quaternary ammonium salt EtNCl 4Kg under stirring, fully stir the back that is mixed and add POTASSIUM BOROHYDRIDE 4Kg, add biphosphate sodium 1.65Kg, react under the room temperature to white crystals and separate out, matter liquid obviously separates; The total overall reaction thing poured in 0 ℃ the frozen water, leave standstill and separate out white solid; Collect white solid,, get Dihydroartemisinin, be the white powder crystallization with distilled water repetitive scrubbing 3 times, drying. Reactor N2 drying adds 100mol Dihydroartemisinin and 1000L tetracol phenixin, dissolving; Add 14KgMnO2, stir evenly.And the speed with about 16L/ minute imports the liquid bromine under 40 ℃ of temperature, stirs simultaneously; After 90 minutes, the filtering reaction thing; Filtrate is with the water agitator treating of 1000～2000L, collected organic layer; Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Br-DHA, is the white powder crystallization. The preparation of embodiment 3 Br-DHAs Reactor N2 drying adds 100mol Dihydroartemisinin and 1000L chloroform, dissolving; Add 14KgMnO2, stir evenly.And the speed with about 16L/ minute imports liquid bromine 100mol under 40～60 ℃ of temperature, stirs simultaneously; After 60 minutes, the filtering reaction thing; The sodium thiosulfate solution washing that in filtrate, adds 1000～5000L10%, collected organic layer; The sodium hydrogen carbonate solution washing that adds 5000～15000L10% again, collected organic layer; Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Br-DHA, is the white powder crystallization. The preparation of embodiment 4 Br-DHAs Reactor N2 drying adds 100mol Dihydroartemisinin and 1000L tetracol phenixin, dissolving; Add 14KgMnO2, stir evenly.And the speed with about 16L/ minute imports the liquid bromine under 40 ℃ of temperature, stirs simultaneously; After 90 minutes, the filtering reaction thing; Filtrate is with the water agitator treating of 1000～2000L, collected organic layer; Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Br-DHA, is the white powder crystallization. The preparation of embodiment 5 Br-DHAs Reactor N2 drying adds 100mol Dihydroartemisinin and 1000L acetonitrile, dissolving; Speed with about 10L/ minute under room temperature imports the liquid bromine, stirs simultaneously; Under the photochemical catalysis of 1000W halogen lamp, reacted 6 hours; The sodium thiosulfate solution washing that in reactant, adds 1000～5000L10%, collected organic layer; The sodium hydrogen carbonate solution washing that adds 5000～15000L10% again, collected organic layer; Organic layer with anhydrous sodium sulfate dehydration after concentrating under reduced pressure become white crystals, crystal washs with normal hexane, leaches crystallization, drying obtains Br-DHA, is the crystallization of off-white powder shape. The preparation of embodiment 6 Br-DHAs 1.5Kg Dihydroartemisinin and 5L chloroform mix, dissolving; Add 14KgMnO2, stir evenly.And the speed with about 16L/ minute imports the liquid bromine under 40 ℃ of temperature, stirs simultaneously; After 90 minutes, the filtering reaction thing; Filtrate is refining once with chloroform again; Become white crystals with concentrating under reduced pressure behind the anhydrous sodium sulfate dehydration, crystal washs with normal hexane, leaches crystallization, and drying obtains Br-DHA, is the white powder crystallization. Embodiment 7 Br-DHA is to the Cytotoxic research report of human hepatoma cell strain-Hepg2 (2004.12.22 of West China medical college of Sichuan University) 1. material: 1.1 cell strain: human hepatoma cell strain Hepg2 purchases the ATCC in the U.S., and 10%FBS/DMEM is conventional to be cultivated. 1.2 be subjected to test product Br-DHA: white powder, molecular-weight average 320g/mol, lot number 20041205.Ferrous sulfate: white powder, lot number: 20041205.Transferrins,iron complexes, Sigma company. 2. method: 2.1 cellulotoxic experiment method: The Hepg2 cell of taking the logarithm vegetative period, ordinary method digestion is with 8 * 10 3Density be inoculated in 24 porocyte culture plates.Behind the inoculation 24h, connect table 1 and add Transferrins,iron complexes, ferrous sulfate respectively, cultivate after 8 hours, add Br-DHA.Behind the drug effect 72 hours, the ordinary method cell counting the results are shown in Figure 1. 3. result: (seeing the following form) 4. brief summary Under above-mentioned experiment condition, find the cell toxicant IC50＜8nM of Br-DHA to external Hepg2 cell. Table 1:Br-DHA dosage table Group Transferrins,iron complexes (nM) Ferrous sulfate (mg) Br-DHA(nM) Blank ------------- ------------- ------------ Transferrins,iron complexes 880nM 0.25 Br-DHA 880nM 880nM 880nM 0.25 0.01 0.002 1000 40 8 Annotate: ferrous sulfate: Br-DHA=250ng:1nM; Every dosage sample number N=4 Embodiment 8 The research of Br-DHA anti tumor activity in vitro (HuaXi college of pharmacy, SiChuan University). 1. material 1.1 cell strain: Human hepatoma cell strain Hepg2 purchases the ATCC in the U.S., Human lung carcinoma cell line A549 purchases the Shanghai cell institute in the Chinese Academy of Sciences. 1.2 substratum: Dulbecco’s Modified Eagle Medium(DMEM)：GIBCOBRL，Cat.No：12100-038，RPMI1640：GIBCOBRL，Cat.No：430-1800EB， Fetal Bovine Serum：Cat.No：CH30160.03 Pancreatin: GIBCOBRL, Cat.No:27250-018. 1.3 be subjected to test product: Br-DHA: white powder, molecular-weight average 320, continent Rong east medicine company, lot number: 20041205, Ferrous sulfate: white powder, continent Rong east medicine company, lot number: 20041205, Transferrins,iron complexes: white crystalline powder, molecular-weight average 79000, Sigma. 2. method 2.1 cell cultures: Hepg2 and A549 cell routine respectively are incubated among 10%FBS/DMEM and the 10%FBS/RPMI1640, change liquid in 2-3 days. 2.2 medicine preparation: Take by weighing Transferrins,iron complexes, ferrous sulfate, BrDHA with 100,000/electronic balance precision, wherein Transferrins,iron complexes, ferrous sulfate directly are dissolved in the degerming of cell culture medium after-filtration, Transferrins,iron complexes C o=17.6nM, sulfate industry iron C o=5mg/L; And after BrDHA is dissolved in DMSO earlier, be diluted to desired concn with cell culture medium again, filtration sterilization C o=6.4mg/L.Prepared than dilution by low by the different concns of test product. All in facing with preceding fresh preparation, every hole adds 50uL to the solution of Transferrins,iron complexes, ferrous sulfate, BrDHA. 2.3 cytotoxicity test method: The Hepg2 that takes the logarithm vegetative period, A549 cell, ordinary method digestion is with 8 * 10 3Density be inoculated in 2/4 porocyte culture plate.Behind the inoculation 24h, connect the ferrous sulfate that table 1,2 adds Transferrins,iron complexes, corresponding dosage respectively.After hatching 8h, add the Br-DHA of each dosage.Behind the drug effect 72 hours, the ordinary method cell counting the results are shown in Table 2,3. 3. result: see Table 2, table 3. 4. conclusion: this experiment shows that Br-DHA all has very obvious in-vitro antitumor action to human hepatoma cell strain Hepg2 cell and human lung carcinoma cell line A549 cell, to the IC of Hepg2 and A549 cell 50Difference＜8nM and 31.6nM.(table 2, table 3 are seen this page or leaf) Table 2, Br-DHA are to human hepatoma cell strain--the Hepg2 anti tumor activity in vitro Group Sample number Drug dose Cells survival rate (%) Transferrins,iron complexes nM Ferrous sulfate mg/L BrDHAnM Blank 4 ----- ----- ----- 100.0±9.1 Transferrins,iron complexes 4 880 0.25 ----- 44.7±5.6 BrDHA 4 880 0.25 1000 23.3±5.3 4 880 0.05 200 32.7±14.1 4 880 0.01 40 31.1±10.6 4 880 0.002 8 41.6±3.6 Annotate. ferrous sulfate: BrDHA=250ng:1nM Table 3, Br-DHA are to human lung carcinoma cell line--the A549 anti tumor activity in vitro Group Sample number Drug dose Cells survival rate (%) Transferrins,iron complexes nM Ferrous sulfate mg/L BrDHAnM Blank 4 ----- ----- ----- 100.0±14.9 Transferrins,iron complexes 4 880 0.25 ----- 59.0±9.8 BrDHA 4 880 0.25 1000 17.4±7.5 4 880 0.05 100 39.0±5.2 4 880 0.0025 10 58.2±5.2 4 880 0.00025 1 59.0±1 3.0 Annotate. ferrous sulfate: BrDHA=250ng: 1nM. Embodiment 9 Analytical Test Center, Chengdu Branch, Chinese Academy of Sciences Analysis, test result report The calculating of bromination rate: 1, Dihydroartemisinin (DHA) molecular weight is 284.34, and bromine atoms (Br) molecular weight is 79.90, and hydrogen atom (H) molecular weight is 1; 2, after Dihydroartemisinin hydrogen atom is replaced by bromine atoms, The molecular weight of Br-DHA is: (284.34-1)+and 79.90=363.24 3, the calculating of bromination rate: 79.90÷363.24＝21.996％≈22.0％。 22.90% belongs to normal value on the survey report.... https://patents.google.com/patent/CN1295231C/en?oq=CN1295231C溴二氢青蒿素---特别适用于治疗各种癌症的溴代二氢青蒿素

CN1264508C治疗妇科病的青蒿素制剂---青蒿素制剂对妇科具有良好的抑制或杀灭作用。阴道霉菌病、滴虫和其他病原体 CN1264508C Artemisinin preparation for treating gynecological diseases---Artemisinin preparations exhibit good inhibitory or killing effects on gynecological conditions such as vaginal candidiasis, trichomoniasis, and other pathogens. 治疗妇科疾病的青蒿素制剂 本发明提供一种治疗妇科疾病的青蒿素制剂，它由药用辅料以及药物有效成分制成医药上可接受的制剂，其特征在于药物有效成分为青蒿素或其衍生物，且每个最小制剂单元含有青蒿素或其衍生物0.02g-1.0g。对妇科霉菌性阴道炎、滴虫等病原菌有良好的抑制或杀灭作用。加之使用了柠檬酸等有机酸来调整药物的pH值，使之在病灶所处的酸性环境中也能充分发挥其药效，由于还可配入适宜的芳香剂，使药物更具芳香化浊的效果，同时药物散发出来的宜人清香，适应了人体生理的人性化设计。另本发明还具有内在质量优秀、外在质量宜人等特点，从而可大大提高患者使用的依从性，进而为提高疗效乃至根治疾病打下基础。 治疗妇科疾病的青蒿素制剂 技术领域 本发明涉及一种治疗妇科疾病的青蒿素药物制剂，属医药的技术领域。 背景技术 妇科疾病是严重危害妇女身心健康的疾病，在妇科疾病中最为常见的是滴虫性阴道炎、霉菌性阴道炎等，这主要与女性外生殖道的特殊环境有关。青蒿为一种常用中药，其入药最早见于马王堆三号汉墓出土的《五十二病方》。青蒿(Artemisia annua L)，性寒味苦，常用来清热、解暑。据李时珍的《本草纲目》记载：青蒿主治皮肤病、鼻出血、痔疮便血、疟疾、虚热等。自二十世纪七十年代，中国科学家首次从青蒿中分离提取出抗疟新药—青蒿素以来，青蒿素引起了医药界的广泛关注。目前已上市的青蒿素及其衍生物有：青蒿素、蒿甲醚、青蒿琥酯、双氢青蒿素、蒿乙醚、蒿醚林酸等，并且国内外都还在不断地研究青蒿素的新的衍生物。青蒿素及其衍生物在医药领域中的应用及研究已有过报道，但在妇科疾病如滴虫性阴道炎、霉菌性阴道炎等的研究与应用则未见报道。 发明内容 本发明的目的旨在提供一种质量稳定、安全性好、疗效优越的治疗妇科疾病的青蒿素药物制剂。 本发明根据妇科疾病的特点，结合本发明对青蒿素类药学药效毒理的研究，将药物开发为直接作用在病灶的制剂。 本发明通过下列技术方案实现：它由药用辅料以及药物有效成分制成医药上可接受的制剂，其特征在于药物有效成分为青蒿素或其衍生物，且每个最小制剂单元含有青蒿素或其衍生物0.02g-1.0g。 所述药用辅料是羟丙环糊精、聚异丁烯酸甘油酯、乙醇、丙二醇、乙基纤维素、羟丙甲纤维素、PEG-10000、羟甲基纤维素、可溶性淀粉、明胶、甘油、月见草油、花生油、维生素E、聚乙二醇、羟乙烯聚合物、三乙醇胺中的一种或几种。 上述药用辅料中可加入能调节pH值至4～6的柠檬酸、马来酸、琥珀酸、苹果酸等有机酸中的一种或几种，以便于适应阴道内环境，同时有效发挥药物作用。 上述药用辅料中还可加入肉桂油、青蒿油、艾蒿油、山苍子油等天然芳香植物挥发油或其有效单体中的一种或几种，以便用它们化浊。 本发明提供的青蒿素制剂用常规的制备方法制得。 本发明提供的青蒿素制剂对妇科霉菌性阴道炎、滴虫等病原菌有良好的抑制或杀灭作用。 本发明所述青蒿素制剂中的主要活性成分青蒿素或其衍生物，经研究证实，对滴虫和深部霉菌(如白色念珠菌等)具有抑制或杀灭作用，加之使用了柠檬酸等有机酸来调整药物的pH值，使之在病灶所处的酸性环境中也能充分发挥其药效，由于还可配入适宜的芳香剂，使药物更具芳香化浊的效果，同时药物散发出来的宜人清香，适应了人体生理的人性化设计。另本发明还具有内在质量优秀、外在质量宜人等特点，从而可大大提高患者使用的依从性，进而为提高疗效乃至根治疾病打下基础。 实施例1 青蒿素羟丙环糊精软膏(40支)，处方： 青蒿素 0.8g 丙环糊精 40g 聚异丁烯酸甘油酯 10g 乙醇 40g 丙二醇 60g 柠檬酸 2g 肉桂油 2ml 蒸馏水加至 1000g 制备：先将青蒿素和羟丙环糊精混匀后，进行气流粉碎超细化(粒径＜10μm)，同时完成包结工作。然后与柠檬酸加入500ml蒸馏水中制得水相。余物用乙醇丙二醇溶解得油相，合并，补加蒸馏水至1000g，进行乳化，分装，即得青蒿素软膏每支25g：20mg的成品。 实施例2 蒿甲醚微囊片(1000粒)，处方： 蒿甲醚 80g 乙基纤维素 150g 羟丙甲纤维素 50g PEG-10000 2g 柠檬酸 6g 制备：将上述处方量的各物质溶于2200ml异丙醇溶剂中，选择进口温度60～70℃，出口温度50～55℃，经喷雾干燥即得蒿甲醚的微囊，以片重0.29压片，可得1000片含量为80mg蒿甲醚微囊片 实施例3 青蒿琥酯异型片(1000片)，处方： 青蒿琥酯 160g 羧甲基纤维素 10g 羟丙甲纤维素 20g 可溶性淀粉 200g PEG-10000 2g 苹果酸 4g 肉桂油 2ml 青蒿油 1ml 制备：将处方量的各物质混合、打粉、制粒、干燥，以片重0.399压异型片，可得1000片含量为160mg青蒿琥酯异型片 实施例4 双氢青蒿素栓剂(1000支)，处方： 双氢青蒿素 200g 明胶 600g 甘油 2100g PEG-10000 2g 马来酸 6g 山苍子油 1ml 水 300g 制备：将处方量的双氢青蒿素、马来酸和山苍子油溶于甘油，将明胶和PEG-10000溶于水，于50～55℃水浴中加热溶解，混合两个溶液，加入每栓3.2g栓剂模型中成型，得每个栓剂含双氢青蒿素200mg得阴道用栓剂。 实施例5 蒿乙醚阴道用软胶囊(1000粒)，处方： 蒿乙醚 100g 月见草油 400g 红花油 200g 维生素E 50g 艾蒿油 1ml 制备：将月见草油和红花油混合，依次加入维生素E、艾蒿油、马来酸、蒿乙醚，搅拌溶解，按每粒771mg内容物用阴道用软胶囊模来加工处理，即得蒿乙醚阴道用软胶囊1000粒、规格为100mg。 实施例6 蒿甲醚软膏(100支)，处方： 蒿甲醚 100.0g 丙二醇 150.0g 聚乙二醇 450.0g 羧乙烯聚合物 50.0g 甘油 100.0g 三乙醇胺 10.0g 肉桂油 5.0ml 精制水 285.0g 制备：先将蒿甲醚和肉桂油溶于丙二醇和聚乙二醇的混合物中，加入羧乙烯聚合物的水膨胀液及甘油后，再加入三乙醇胺，搅拌制成软膏，得1150g，分装成每支11.5g的软管包装，可得100支蒿甲醚软膏，规格为1g蒿甲醚/支。 药效学研究： 1、对滴虫病的作用和止痒效果的观察 药物：实施例6蒿甲醚软膏甲硝唑片 病人：医院确诊的门诊病人8人，分两组。 试验：一组病人(试验组)4名用实施例6制备的蒿甲醚软膏；另一组病人(对照组)4名用甲硝唑片。用药方法为早晚各一次，常规清洗外阴后，阴道内给药，7天为一疗程。一个疗程后用[悬滴法]化验检查。并询问病人止痒效果。 结果：试验组4名病人检查均为阴性，病人主观感觉止痒效果明显；对照组3名人为阴性，病人主观感觉有一定的止痒效果。表明蒿甲醚软膏对阴道滴虫病具有治疗作用，且对直接的表现症状——瘙痒效果明显。 2、对真菌的作用 药物：实施例3青蒿琥酯异型片制霉菌素 菌种：白色念球菌，试验用第二代新鲜培养物，由中国科学院微生物研究所提供。 培养基：自制备用。 液体试管法： 取灭菌小试管若干支，用培养基稀释被试药使其浓度为0.5、0.25、0.125、0.06g/ml，每管加入1毫升，再加入200倍稀释的18小时真菌培养物0.1ml，于37℃培养18小时后观察有无真菌生长。真菌不生长的最高药物稀释度为该药的最低抑菌浓度。结果如下： 样品 浓度(g/ml) 0.5 0.25 0.125 0.06 0 空白青蒿制霉 -- -- +- +++ +++ 注：表中“-”表示细菌没有生长，即有抑菌作用；“+”表示细菌已有生长，即表示没有抑菌作用。 结果表明：该制剂对白色念珠菌有较好的抑制或杀灭作用，作用机理有待进一步研究。 3、皮肤黏膜刺激性试验 药物：实施例5制得的蒿乙醚阴道用软胶囊 动物：大白兔雌性4只，体重2.1±0.5kg。 方法：动物分为对照组和给药组，每组两只，将药液0.2ml注入兔子阴道内，观察小时局部及全身反应，随后处死动物，取出阴道黏膜进行病理学检查。 结果：观察结果表明用药后阴道组织无充血、红肿等黏膜受到刺激的现象。 1、一种治疗妇科疾病的青蒿素制剂，其特征在于由下列组分： 青蒿素 0.8g 丙环糊精 40g 聚异丁烯酸甘油酯 10g 乙醇 40g 丙二醇 60g 柠檬酸 2g 肉桂油 2ml 蒸馏水加至 1000g 制成每支含青蒿素20mg的青蒿素软膏40支。 2、一种治疗妇科疾病的青蒿素制剂，其特征在于由下列组分： 蒿甲醚 80g 基纤维素 150g 羟丙甲纤维素 50g PEG-10000 2g 柠檬酸 6g 制成每片含青蒿素80mg的蒿甲醚微囊1000片。 3、一种治疗妇科疾病的青蒿素制剂，其特征在于由下列组分： 青蒿琥酯 160g 羧甲基纤维素 10g 羟丙甲纤维素 20g 可溶性淀粉 200g PEG-10000 2g 苹果酸 4g 肉桂油 2ml 青蒿油 1ml 制成每片含青蒿素160mg的青蒿琥酯异型片1000片。 4、一种治疗妇科疾病的青蒿素制剂，其特征在于由下列组分： 双氢青蒿素 200g 明胶 600g 甘油 2100g PEG-10000 2g 马来酸 6g 山苍子油 1ml 水 300g 制成每支含青蒿素200mg的双氢青蒿素栓1000支。 5、一种治疗妇科疾病的青蒿素制剂，其特征在于由下列组分： 蒿乙醚 100g 月见草油 400g 红花油 200g 维生素E 50g 艾蒿油 1ml 制成1000粒蒿乙醚阴道用软胶囊。 6、一种治疗妇科疾病的青蒿素制剂，其特征在于由下列组分： 蒿甲醚 100.0g 丙二醇 150.0g 聚乙二醇 450.0g 羧乙烯聚合物 50.0g 甘油 100.0g 三乙醇胺 10.0g 肉桂油 5.0ml 精制水 285.0g 制成100支蒿甲醚软膏。 https://patents.google.com/patent/CN1264508C/zh?oq=CN1264508C治疗妇科病的青蒿素制剂---青蒿素制剂对妇科具有良好的抑制或杀灭作用。阴道霉菌病、滴虫和其他病原体 Arteannuin preparation for treating gynecopathy The present invention provides an arteannuin preparation used for curing gynecopathy, which is a medical acceptable preparation prepared from a medical adjuvant and a medical effective component. The present invention is characterized in that the medical effective component is arteannuin or a derivative thereof, and each smallest preparation unit contains 0.02 to 1.0g of arteannuin or derivative thereof, so that the arteannuin preparation has a favorable inhibitory function or a killing function on gynecological colpomycosis, trichomonad and other pathogens; additionally, the medical pH value is adjusted by organic acid, such as citric acid, etc., to make the medical effect fully exerted in the acid environment of focus; a suitable flavoring agent is matched to make the medicine have favorable effect of eliminating turbid pathogen with aromatics, and the hospitable delicate fragrance given forth from the medicine adapts to the humanization design of the human body physiology. In addition, the present invention has the characteristics of excellent inner quality, hospitable external quality, etc., so that the dependence of the patient can be greatly improved to supply the basis for increasing the curative effect or even eradicating the disease. The arteannuin preparation of treatment gynaecopathia Technical field The present invention relates to a kind of arteannuin pharmaceutical preparation for the treatment of gynaecopathia, belong to the technical field of medicine. Background technology Gynaecopathia is the able-bodied disease of serious harm women, and the most commonly trichomonal vaginitis, colpitis mycotica etc. in gynaecopathia, this main and women special environments of reproductive tract outward are relevant.Herba Artemisiae Annuae is a kind of conventional Chinese medicine, and it is used as medicine and sees " 52 Bingfang " that No. three tomb of Han dynasty in Mawangdui are unearthed the earliest.Herba Artemisiae Annuae (Artemisia annua L), bitter in the mouth cold in nature is commonly used to heat clearing away, expelling summer-heat.Compendium of Material Medica record according to Li Shizhen (1518-1593 A.D.): Herba Artemisiae Annuae cures mainly dermatosis, epistaxis, hemorrhoidal hemorrhage, malaria, deficiency-heat etc.From nineteen seventies, the Chinese science man first from Herba Artemisiae Annuae separation and Extraction gone out since new antimalarial agent-arteannuin, arteannuin has caused the extensive concern of the world of medicine.The arteannuin and the derivant thereof of having gone on the market at present have: arteannuin, Artemether, artesunate, dihydroarteannuin, arteether, the acid of Artemisia ether woods etc., and all also constantly studying the new derivant of arteannuin both at home and abroad.Application and the research in field of medicaments of arteannuin and derivant thereof had report, but did not then appear in the newspapers with application in the research of gynaecopathia such as trichomonal vaginitis, colpitis mycotica etc. Summary of the invention Purpose of the present invention aims to provide the arteannuin pharmaceutical preparation of a kind of steady quality, safety is good, curative effect is superior treatment gynaecopathia. The present invention in conjunction with the research of the present invention to artemisine pharmacy drug effect toxicity, is the preparation that act directly on focus with drug development according to the characteristics of gynaecopathia. The present invention realizes by following technical proposal: it makes acceptable preparation by pharmaceutic adjuvant and effective ingredient, it is characterized in that effective ingredient is the arteannuin or derivatives thereof, and each minimum preparation unit contains arteannuin or derivatives thereof 0.02g-1.0g. Described pharmaceutic adjuvant is one or more in hydroxypropyl cyclodextrin, polyisobutylene acid glyceride, ethanol, propylene glycol, ethyl cellulose, hypromellose, PEG-10000, hydroxy methocel, soluble starch, gelatin, glycerol, Radix Oenotherae erythrosepalae oil, Oleum Arachidis hypogaeae semen, vitamin E, Polyethylene Glycol, hydroxyalkyl vinyl polymer, the triethanolamine. Can add in the organic acid such as the citric acid that can regulate pH value to 4～6, maleic acid, succinic acid, malic acid one or more in the above-mentioned pharmaceutic adjuvant, so that adapt to the intravaginal environment, effective performance drug effect simultaneously. Also can add in Oleum Cinnamomi, Herba Artemisiae Annuae oil, mugwort oil, Fructus Litseae wet goods natural aromatic plant volatile oil or its effective monomer one or more in the above-mentioned pharmaceutic adjuvant, so that change turbid with their. Arteannuin preparation provided by the invention makes with conventional preparation method. Arteannuin preparation provided by the invention has good inhibition or killing action to pathogen such as gynecological's colpitis mycotica, infusorian. Main active arteannuin or derivatives thereof in the arteannuin preparation of the present invention, confirm after deliberation, infusorian and deep mycete (as Candida albicans etc.) are had and suppress or killing action, used organic acid such as citric acid to adjust the pH value of medicine in addition, make it in the residing sour environment of focus, also can give full play to its drug effect, owing to also can allocate suitable aromatic into, make medicine have more the effect of eliminating turbid pathogen with aromatics, the pleasant delicate fragrance that the while medicine comes out has adapted to the human oriented design of Human Physiology.The present invention also has characteristics such as inherent quality is outstanding, external quality is pleasant in addition, thereby can improve the compliance that the patient uses greatly, and then lays the first stone for improving curative effect and even radical curing of disease. Embodiment 1 Arteannuin hydroxypropyl cyclodextrin ointment (40), prescription: The arteannuin 0.8g third cyclodextrin 40g Polyisobutylene acid glyceride 10g ethanol 40g Propylene glycol 60g citric acid 2g Oleum Cinnamomi 2ml distilled water adds to 1000g Preparation: earlier with behind arteannuin and the hydroxypropyl cyclodextrin mixing, carry out comminution by gas stream super-refinement (particle diameter＜10 μ m), finish inclusion work simultaneously.Add in the 500ml distilled water with citric acid then and make water.Excess with the ethanol propylene glycol dissolve oil phase, merge, add distilled water to 1000g, carry out emulsifying, packing promptly gets the finished product of every 25g:20mg of arteannuin ointment. Embodiment 2 Artemether microencapsule tablet (1000), prescription: Artemether 80g ethyl cellulose 150g Hypromellose 50g PEG-10000 2g Citric acid 6g Preparation: each material of above-mentioned recipe quantity is dissolved in the 2200ml isopropanol solvent, select 60～70 ℃ of inlet temperatures, 50～55 ℃ of outlet temperatures, the spray-dried microcapsule that promptly gets Artemether, weigh 0.29 tabletting with sheet, can get 1000 content is 80mg Artemether microencapsule tablet Embodiment 3 Artesunate special-shaped tablets (1000), prescription: Artesunate 160g carboxymethyl cellulose 10g Hypromellose 20g soluble starch 200g PEG-10000 2g malic acid 4g Oleum Cinnamomi 2ml Herba Artemisiae Annuae oil 1ml Preparation: each material of recipe quantity is mixed, beats powder, granulation, drying, weigh 0.399 with sheet and press special-shaped tablets, can get 1000 content is 160mg artesunate special-shaped tablets Embodiment 4 bi-hydrogen arteannuin suppositories (1000), prescription: Dihydroarteannuin 200g gelatin 600g Glycerol 2100g PEG-10000 2g Maleic acid 6g litsea cubeba oil 1ml Water 300g Preparation: dihydroarteannuin, maleic acid and the litsea cubeba oil of recipe quantity are dissolved in glycerol, gelatin and PEG-10000 is water-soluble, heating for dissolving in 50～55 ℃ of water-baths, mix two solution, add molding in every bolt 3.2g suppository mould, each suppository contains dihydroarteannuin 200mg and gets vaginal suppository. Embodiment 5 Arteether soft capsule for vagina (1000), prescription: Arteether 100g Radix Oenotherae erythrosepalae oil 400g Safflower oil 200g vitamin E 50g Mugwort oil 1ml Preparation: Radix Oenotherae erythrosepalae oil and Flos Carthami oil is mixed, add vitamin E, mugwort oil, maleic acid, arteether successively, stirring and dissolving is come processed by every 771mg content with the soft capsule for vagina mould, promptly gets 1000 of arteether soft capsule for vagina, specification is 100mg. Embodiment 6 Artemether ointment (100), prescription: Artemether 100.0g propylene glycol 150.0g Polyethylene Glycol 450.0g carboxy vinyl polymer 50.0g Glycerol 100.0g triethanolamine 10.0g Oleum Cinnamomi 5.0ml Purified Water 285.0g Preparation: earlier Artemether and Oleum Cinnamomi are dissolved in the mixture of propylene glycol and Polyethylene Glycol, after adding the water inflation fluid and glycerol of carboxy vinyl polymer, add triethanolamine again, ointment is made in stirring, get 1150g, be distributed into the hose packing of every 11.5g, can get 100 Artemether ointment, specification be the 1g Artemether/. Pharmacodynamic study: 1, to the effect of trichomoniasis and the observation of antipruritic effect Medicine: embodiment 6 Artemether ointment Metronidazole Tablets Patient: outpatient 8 people that hospital makes a definite diagnosis, divide two groups. Test: 4 Artemether ointment of one group of patient (test group) with embodiment 6 preparations; Another group patient (matched group) 4 used Metronidazole Tablet.Administrated method is sooner or later respectively once, behind the conventional cleaning pudendum, and intravaginal administration, 7 days is a course of treatment.Use [sessile drop method] laboratory examination after the course of treatment.And inquiry patient antipruritic effect. The result: 4 patients of test group check all negative, and patient's subjective sensation antipruritic effect is obvious; 3 famous persons are negative for matched group, and patient's subjective sensation has certain antipruritic effect.Show that Artemether ointment has therapeutical effect to trichomonal vaginitis, and to direct reveal any symptoms---the pruritus effect is obvious. 2, to the effect of fungus Medicine: embodiment 3 artesunate special-shaped tablets nystatins Strain: Candida albicans, test is provided by Institute of Microorganism, Academia Sinica with second filial generation fresh cultured thing. Culture medium: make by oneself standby. Liquid tube method: Get some of sterilization small test tubes, made by reagent with culture medium dilution that its concentration is 0.5,0.25,0.125,0.06g/ml, every pipe adds 1 milliliter, adds 18 hours fungal cultures 0.1ml of 200 times of dilutions again, observes after 18 hours in 37 ℃ of cultivations to have or not conk.The highest drug dilution degree that fungus does not grow is the minimum inhibitory concentration of this medicine.The result is as follows: Sample Concentration (g/ml) 0.5 0.25 0.125 0.06 0 Blank Herba Artemisiae Annuae system is mould - - - - + - ++ + +++ Annotate: not growth of "-" expression antibacterial in the table promptly has bacteriostasis; The existing growth of "+" expression antibacterial, i.e. expression does not have bacteriostasis. The result shows: said preparation has inhibition or killing action preferably to Candida albicans, and the mechanism of action remains further to be studied. 3, skin mucosa irritation test The arteether soft capsule for vagina that medicine: embodiment 5 makes Animal: female 4 of White Rabbit, body weight 2.1 ± 0.5kg. Method: animal is divided into matched group and administration group, and two every group, medicinal liquid 0.2ml is injected the rabbit intravaginal, observe hour part and general reaction, put to death animal subsequently, take out vaginal mucosa and carry out pathological examination. The result: vagina tissue did not have the phenomenon that mucosas such as hyperemia, redness are upset after observed result showed medication. 1, a kind of arteannuin preparation for the treatment of gynaecopathia is characterized in that by following component: The arteannuin 0.8g third cyclodextrin 40g Polyisobutylene acid glyceride 10g ethanol 40g Propylene glycol 60g citric acid 2g Oleum Cinnamomi 2ml distilled water adds to 1000g Make 40 of every arteannuin ointment that contains arteannuin 20mg. 2, a kind of arteannuin preparation for the treatment of gynaecopathia is characterized in that by following component: Artemether 80g base cellulose 150g Hypromellose 50g PEG-10000 2g Citric acid 6g Make 1000 of every Artemether microcapsules that contains arteannuin 80mg. 3, a kind of arteannuin preparation for the treatment of gynaecopathia is characterized in that by following component: Artesunate 160g carboxymethyl cellulose 10g Hypromellose 20g soluble starch 200g PEG-10000 2g malic acid 4g Oleum Cinnamomi 2ml Herba Artemisiae Annuae oil 1ml Make 1000 of every artesunate special-shaped tablets that contains arteannuin 160mg. 4, a kind of arteannuin preparation for the treatment of gynaecopathia is characterized in that by following component: Dihydroarteannuin 200g gelatin 600g Glycerol 2100g PEG-10000 2g Maleic acid 6g litsea cubeba oil 1ml Water 300g Make 1000 on every dihydroarteannuin bolt that contains arteannuin 200mg. 5, a kind of arteannuin preparation for the treatment of gynaecopathia is characterized in that by following component: Arteether 100g Radix Oenotherae erythrosepalae oil 400g Safflower oil 200g vitamin E 50g Mugwort oil 1ml Make 1000 arteether soft capsule for vagina. 6, a kind of arteannuin preparation for the treatment of gynaecopathia is characterized in that by following component: Artemether 100.0g propylene glycol 150.0g Polyethylene Glycol 450.0g carboxy vinyl polymer 50.0g Glycerol 100.0g triethanolamine 10.0g Oleum Cinnamomi 5.0ml Purified Water 285.0g Make 100 Artemether ointment. https://patents.google.com/patent/CN1264508C/en?oq=CN1264508C治疗妇科病的青蒿素制剂---青蒿素制剂对妇科具有良好的抑制或杀灭作用。阴道霉菌病、滴虫和其他病原体

CN1208061C青蒿琥酯和二氢青蒿素在抗血管生成药 CN1208061C Artemether and dihydroartemisinin in anti-angiogenesis drugs. 青蒿琥酯和二氢青蒿素在抗血管生成药物中的应用 本发明涉及青蒿琥酯和二氢青蒿素在抗血管生成药物中的应用。该药物制剂主要含有青蒿琥酯或二氢青蒿素，其制剂形式主要为微球注射液。本发明提供的药物制剂在抗肿瘤血管生成方面有活性，可用于肿瘤血管生成及其他与血管生成有关的疾病治疗，还可用于肿瘤化疗和/或辅助化疗方面的治疗。本发明以血管生成理论为背景，研究并阐明中药有效单体成分作用和机制，是发展中医药理论新的重要方向，为发现新的理论和药物作用新的靶点提供重要依据，为青蒿素类药物的新用途开发提供依据。 青蒿琥酯和二氢青蒿素在抗血管生成药物中的应用 技术领域 本发明属药物应用，涉及青蒿素及其衍生物在抗血管生成作用方面的药物用途。 背景技术 血管生成是指已存在的血管(毛细血管和小静脉)通过出芽或分裂的方式产生新的血管。生理与病理条件下，如胚胎发生，女性生殖周期、炎症反应、伤口愈合、肿瘤发生等过程都进行着血管生成。特别是病理条件下，据统计，大约20～40种人类疾病与血管生成的上调或下调有关。1971年，Folkman建立了血管生成与肿瘤生长间联系的学说，提出血管生成不但能为肿瘤细胞提供丰富的营养维持其旺盛的代谢，同时又为肿瘤细胞离开原发病灶通过血液转移创造了有利的条件。许多肿瘤在没有新生血管生成之前只能长到几毫米大小，血管生成被抑制，肿瘤细胞虽仍在高速增殖，但同时进行着快速的细胞凋亡，故能有效地抑制肿瘤的生长和转移。因此，寻找新生血管生长抑制剂已成为国际上近年来抗肿瘤生长和转移治疗的又一重要的方向。抗血管生成药物与其他抗癌药物比较有许多优势，如很少产生耐药性，副作用小，效率高，全球已有40家以上的制药公司在开发研制抗血管生成剂。 自从1988年抗血管生成治疗进入临床试验以来，大约已有20余种血管生成抑制剂进入临床试验，其中有的是针对参与新血管形成的特异分子如干扰素α；有的抑制钙介导的细胞信号转导如钙通道阻滞剂；有的则直接抑制内皮细胞的功能或反应如烟曲霉醇(TNP-470)。综合分析上述作用机制，抑制血管生成的较好靶点是内皮细胞，通过封闭或下调其表面的促血管生长因子受体，抑制内皮细胞的生长，迁移和管腔形成，可高效地破坏新生血管形成。而对于肿瘤血管新生，由于许多恶性瘤细胞本身可分泌促血管生长因子，作用于瘤旁血管内皮细胞的受体，促进肿瘤血管生长。故下调肿瘤细胞内的血管生长因子蛋白表达，抑制其血管生长因子的分泌，也可以达到抗肿瘤血管生长作用。 70年代，我国学者自从中草药黄花蒿中分离出抗疟药青蒿素(artemisinin)后，又陆续合成了蒿甲醚、青蒿琥酯(artesunate)和二氢青蒿素(dihydroartemisinin)等有效衍生物。这类药物的问世，在抗疟药物研究史上树立了新的里程碑。在世界各地上百万起抗疟感染使用中，青蒿素类药物疗效显著，对人体毒副作用小，且迄今尚未见抗药性出现，被世界卫生组织推荐为高效安全的重要抗疟药。各国学者对青蒿素类药物十余年研究中发现，这类药物除了其特殊显著的抗疟疗效外，还具有较强的抗肿瘤作用。 青蒿素(Artemisinin)是我国科学家在1971年首次从菊科植物黄花蒿(Artemisia annua Linn)提出的具有新型结构的倍半萜内酯。它具有十分优良的抗疟作用，包括那些对氯喹有耐药性的恶性疟原虫感染。立即引起世界范围内的重视，由于存在口服活性低，水溶度小，复发率高等缺点，使扩大应用受到限制。因此我国科学家合成了大量的衍生物，根据青蒿素在体内的还原代谢物为二氢青蒿素(Dihydroartemisinin)，将青蒿素C10羰基还原得二氢青蒿素，抗鼠疟(P.berghei)比青蒿素强一倍。将二氢青蒿素进行酯化得青蒿琥酯(Artesunate)，化学名为二氢青蒿素-10-α-丁二酸单酯，其钠盐制成粉针剂，供静注，对疟原虫无性体有较强的杀灭作用。青蒿琥酯在机体内立即转化为还原青蒿素，即二氢青蒿素。由于还原青蒿素不溶于水，对血浆和组织蛋白有较强的结合力，使药物迅速向全身各组织转运并清除。因此，青蒿琥酯具有高效、速效、低毒、不易产生耐受等特点，对间日疟、恶性疟、脑型疟均有效，临床主要适用于脑型疟及各种危重疟疾的治疗。 二氢青蒿素 青蒿琥酯 发明内容 本发明的一个目的是提供青蒿琥酯和/或二氢青蒿素在抗血管生成药物中的应用。 本发明提供的青蒿琥酯或二氢青蒿素，还可在肿瘤化疗和/或辅助化疗方面的应用。 本发明具有以下优点： (1)青蒿琥酯和二氢青蒿素两者是传统的青蒿类抗疟药中最具有代表性的药物，一直以来用于抗疟治疗，本发明的特点是首次提出青蒿琥酯和二氢青蒿素具有抗血管生成作用，并将他们作为用于肿瘤血管生成及其他血管生成有关的疾病治疗的药物。人类许多疾病与血管生成有关，青蒿素类药物作为血管生成抑制剂将会在这些疾病的治疗中得到重要的应用。 (2)本发明为青蒿素类药物开发成为抗肿瘤药物提供药效学及作用机制的研究依据，具有将青蒿素类药物开发成为肿瘤化疗和/或辅助化疗等类药物的价值。 (3)本发明以血管生成理论为背景，研究并阐明中药有效单体成分作用和机制，是发展中医药理论新的重要方向，为发现新的理论和药物作用新的靶点提供重要依据。 附图说明 图1.为青蒿琥酯对鸡胚尿囊膜血管生成的影响。 图2.1a为HE染色(伊红-苏木素染色)。 图2.1b为血管CD31染色。 图2.2.为青蒿琥酯对VEGF表达的影响。 图2.3.为青蒿琥酯对KDR/flk-1受体表达的影响。 图3.为用药期间裸鼠移植瘤体积变化。 图4为青蒿琥酯和二氢青蒿素对血管内皮细胞增殖的影响。 图5为青蒿琥酯和二氢青蒿素对血管内皮细胞迁移的影响。 图6为青蒿琥酯和二氢青蒿素对血管内皮细胞小管成型的影响。 图7.1为二氢青蒿素对血管内皮细胞迁移的影响。 图7.2为二氢青蒿素对血管内皮细胞小管成型的影响。 具体实施方式 本发明结合具体实施例和附图作进一步说明。应理解，这些实施例仅用于说明目的，而不用于限制本发明范围。 实施例1：制备青蒿琥酯微球注射液的一种方法 用缓释聚合物(Polycaprolactone，PCL)研磨青蒿琥酯，制备成的熔融混合液用生物相容性和生物降解性聚合物制成微球注射液。所用的聚合物释药后水解为对人体无害的降解物(水和二氧化碳)。该微球注射液肌注后，在给药部位缓慢释放药物与吸收，使作用时间延长，可用于肿瘤及其他血管生成有关的疾病治疗。 实施例2：青蒿琥酯微球注射液整体抑制血管生成实验 (1)抑制鸡胚尿囊膜血管生成 实验材料：青蒿琥酯(原料药由广西桂林第二制药厂提供)采用本发明的微球注射液；氢化可的松(浙江仙居制药厂产品)；种蛋(购于杭州四季青名鸡养殖场)。 方法：将7-8天的鸡胚开窗，分别加入青蒿琥酯、阳性对照品(氢化可的松)及溶剂对照品(空白微球注射液)，孵化24h后，用甲醇、丙酮1∶1混合液固定鸡胚尿囊膜，制成标本，在解剖显微镜下计数血管数。 结果： 血管生成抑制率 青蒿琥酯在剂量15、30、60、80μg/胚时，对鸡胚尿囊膜血管生成抑制率分别为50％、55.6％、87.5％及100％。阳性对照组氢化可的松30μg/胚的抑制率66％，溶剂对照组等容积空白微球注射液/胚的抑制率0％。每胚给药容积100μl。结果见表1。 表1青蒿琥酯对鸡胚尿囊膜血管生成的抑制作用 剂量 血管膜阳性数 血管膜 血管膜 抑制率 药品 (μg/胚) + ++ 阴性数 存活数 ％ 空白微球液 30 0 0 10 10 0 青蒿琥酯 15 9 0 9 18 50.0 青蒿琥酯 30 8 2 8 18 55.6 青蒿琥酯 60 3 11 2 16 87.5 青蒿琥酯 80 0 10 0 10 100.0 氢化可的松 30 3 5 4 12 66.7 血管计数 溶剂对照组的血管密度、分支明显多于给药组，且管径较粗，参见图1，其中：(a)溶剂对照、(b)青蒿琥酯30μg/胚、(c)氢化可的松30μg/胚。高浓度给药时，只有极少数管径细小的血管、无明显分支状，甚至未见血管，出现溶血现象，个别鸡胚死亡。在青蒿琥酯剂量60、30、15μg/胚时，血管计数分别为3.8、9.7、27.1条，阳性对照组19.5条，溶剂对照组40.5条。与溶剂对照组比较，各组数据呈显著性差异(P＜0.01)。结果见表2。 表2青蒿琥酯对鸡胚尿囊膜血管生成的影响 药品 剂量(μg/胚) n数 血管数( x±s) 空白微球液 30 15 40.6±2.3 青蒿琥酯 15 15 27.1±8.5* 青蒿琥酯 30 15 9.7±2.7* 青蒿琥酯 60 15 3.8±1.6* 氢化可的松 30 15 19.5±5.6* *P＜0.01vs3％空白微球液，t test (2)抑制人卵巢癌裸鼠移植瘤血管生成 实验材料：青蒿琥酯(原料药由广西桂林第二制药厂提供)采用本发明的微球注射液。HO-8910人卵巢癌细胞株(由浙江省肿瘤研究所提供)，BALB/C裸小鼠32只，体重(20±2)g，雄性，6～8周龄(由上海市肿瘤研究所提供)。含10％小牛血清的RPMI-1640细胞培养液。血管内皮生长因子(VEGF)多克隆抗体(兔抗人，美国Santa Cruz公司)，VEGFR-2(KDR/flk-1受体)多克隆抗体(兔抗人，美国Santa Cruz公司)，CD31因子单克隆抗体(大鼠抗小鼠，美国Santa Cruz公司)。 方法： 抑制人卵巢癌裸鼠移植瘤模型建立及给药方案 用RPMI-1640加10％小牛血清培养HO-8910人卵巢癌细胞。细胞按1×107/ml悬浮于无血清培养液中，每只小鼠左腋皮下接种0.2ml。约4天左右可形成肉眼可见的瘤块，成瘤率100％。成瘤后第3天开始给药，随机分成4组：青蒿琥酯高剂量组100mg/(kg·d)，中剂量组50mg/(kg·d)，低剂量组10mg/(kg·d)和空白微球注射液组。每组8只，肌肉注射给药，每天1次，连续给药10天，对照组给予等容量的空白微球注射液。末次给药24小时后，处死动物，取出瘤块。 肿瘤体积变化及药物的毒副作用 给药期间观察裸小鼠的一般情况及移植瘤生长情况，每3天测定一次肿瘤体积。测量方法为：用游标卡尺测量肿瘤长轴(a)，短轴(b)，根据公式V＝0.5ab2计算肿瘤体积，绘制肿瘤体积增长曲线。同时测定裸鼠体重。 HE染色和免疫组化 上述肿瘤组织标本经常规处理后制成5μM厚石蜡切片，HE染色，参见图2.1a，常规指标观察。用SABC免疫组化法，采用鼠抗鼠CD31因子抗体，兔抗人VEGF抗体和兔抗人VEGFR-2抗体检测肿瘤标本中血管生成，VEGF和KDR/flk-1受体表达，用BPS代替一抗作阴性。①血管计数：每张切片高倍镜(×200)下随机选择6个视野观察血管并计数，取平均值为每例的最终值。②VEGF及KDR/flk-1受体表达：每张切片高倍镜(×400)下随机选择6个视野，每个视野中计数200个细胞中VEGF与KDR/flk-1受体阳性的细胞个数，小于10％阳性细胞为阴性(-)，10％-30％为弱阳性(+)，30％-70％为中阳性(++)，70％-100％为强阳性(+++)。VEGF在肿瘤细胞浆中表达，KDR/flk-1受体在肿瘤细胞和血管内皮细胞中均有表达，表达部位免疫组化染色呈棕黄色。 结果： 血管计数高剂量组(100mg kg-1d-1)，中剂量组(50mg kg-1d-1)和低剂量组(10mg kg-1d-1)血管CD31染色，结果参见图2.1b。血管计数分别为11.61±4.32，27.75±8.04，47.92±11.49，空白微球注射液组为48.98±9.40，与空白微球注射液对照组相比较高、中剂量组血管计数均明显减少(P＜0.01)，低剂量组无明显差异(P＞0.05)。参见表3。 表3 青蒿琥酯对裸鼠移植瘤血管密度的影响 组别(mg/kg·d) 动物数(n) 血管密度( x±s) 空白微球(10ml/kg.d) 8 48.98±9.40 低剂量10 8 47.92±11.49 中剂量50 8 27.75±8.04** 高剂量100 8 11.61±4.32** *P＜0.05，**P＜0.01vs空白微球组，t检验 VEGF，KDR/flk-1蛋白表达 治疗组与空白微球注射液组VEGF，KDR/flk-1受体在肿瘤细胞和血管细胞中表达阳性率参见图2.2、图2.3，图2.2中：(a)空白微球注射液组、(b)青蒿琥酯中剂量组、(c)阴性对照组，图2.3中：(a)空白微球注射液组、(b)青蒿琥酯中剂量组、(c)青蒿琥酯高剂量组。高剂量组(100mg/kg·d)，中剂量组(50mg/kg·d)和低剂量组(10mg/kg·d)VEGF，flt-1免疫组化染色阳性率与对照组相比较均有明显差异(P＜0.05)。见表4。 表4青蒿琥酯对肿瘤组织VEGF和 KDR/flt-1表达的影响 组别 动物数 VEGF表达 KDR/flk-1表达 (mg/kg·d) (n) 肿瘤细胞 肿瘤细胞 血管内皮细胞 空白微球 8 +++(8) +++(7)++(1) +++(8) 10 8 +++(4)++(4) +++(3)++(5) +++(2)++(6)* 50 8 ++(1)+(4)-(3)** ++(4)+(3)-(1)** ++(2)+(4)-(2)** 100 8 ++(1)+(2)-(5)** ++(2)+(2)-(4)** ++(1)+(2)-(5)** *P＜0.05，**P＜0.01vs空白微球组，x2检验 肿瘤体积变化及药物的毒副作用 移植瘤生长及体积变化参见图3，成瘤时(接种4天后)，治疗组与空白微球注射液组瘤体大小差异无显著性(P＞0.05)。用药过程中，治疗组肿瘤生长较慢，用药第1，4，7，10天测定肿瘤体积，高，中剂量组肿瘤体积均小于对照组，有显著性差异(P＜0.05)。用药期间，四组荷瘤裸鼠活动良好，未见特殊不良反应，无一例死亡。用药10天后对照组及高，中，低治疗组平均去瘤鼠重(g)分别为22.1±1.86，22.62±2.4，21.83±2.1，22.25±2.36，治疗组与空白微球注射液对照组比较无显著差异(P＞0.05)。 实施例3：青蒿琥酯和二氢青蒿素体外抑制血管生成实验 实验材料：青蒿琥酯、二氢青蒿素(原料药由广西桂林第二制药厂提供) 方法： (1)人脐静脉内皮细胞(HUVEC)培养 取新鲜健康的胎儿脐带，灌入5％的胶原酶，37℃水浴15～20min，用PBS液冲洗脐静脉，离心，弃上清液，用培养液悬浮细胞，置培养瓶中培养，隔天换液一次，培养液为DMEM含15％的小牛血清和10ng/ml的VEGF。用兔抗人VIII因子抗体行免疫组化鉴定后取第2～3代细胞供研究用。 (2)HUVEC增殖抑制 将HUVEC以5×104个/ml密度接种于24孔培养板中，置孵箱5％CO2，37℃孵育24小时待完全贴壁后，加入药物(青蒿琥酯或二氢青蒿素)，并设生理盐水和DMSO对照组。每组设3个复孔，作用48小时后，用MTT法检测细胞存活率。 (3)HUVEC迁移抑制 用刀片损伤生长在35mm塑料培养皿中已融合为单层的HUVEC，用PBS液冲洗3次，加入含15％小牛血清的DMEM培养液，然后加入测试药物(青蒿琥酯或二氢青蒿素)，置5％CO2，37℃培养箱中，24小时后从受伤边缘起连续计数(500×250)μM区段中迁移的HUVEC数，数值表示10个随机视野内的细胞数均值。 (4)HUVEC小管形成抑制 I型胶原(Sigma，Bomem Belgium)，DMEM(×10)，0.05M NaOH+0.2MHEPES+0.26MNaHCO2以体积比8∶1∶1：于冰浴下迅速混合，涂布于24孔培养板底部，置37℃形成胶原凝胶，将HUVEC以5×104个/ml的密度悬浮于10％小牛血清DMEM培养液中，每孔加入0.5ml，所用的药物(青蒿琥酯或二氢青蒿素)也在此时以一定的浓度加入，在5％CO2，37℃培养箱中培育48小时，于倒置显微镜下(×200)用曲尺随机测定10个视野中小管的总长度。 结果： (1)对HUVEC增殖的影响 生理盐水对照组和DMSO对照组OD值为0.71±0.05和0.72±0.05。与相应的溶剂对照组比较，药物浓度为0.5μmol/L时，对HUVEC增殖抑制作用均不明显，青蒿琥酯和二氢青蒿素的OD值为0.70±0.04和0.69±0.07(P＞0.05)；浓度为2.5μmol/L时，二氢青蒿素的OD值为0.66±0.04(P＜0.05)，对HUVEC的增殖有抑制作用；当浓度为12.5和50μmol/L时，二种药物对HUVEC均有明显的增殖抑制作用(P＜0.01)，OD值分别为0.59±0.04，0.42±0.03(青蒿琥酯)和0.50±0.04，0.36±0.03(二氢青蒿素)；OD值下降有剂量依赖性，各用药组间差异有显著性(P＜0.05，n＝3)。药物浓度(μmol/L)与细胞存活率(％)的关系见参图4(n＝3)，其中(▲)青蒿琥酯、(■)二氢青蒿素。 (2)对HUVEC迁移的影响 细胞迁移实验结果表明，在青蒿琥酯和二氢青蒿素的作用下，HUVEC迁移进入受伤裸露区的数量明显减少，参见图5、图7.1，图5中：(▲)青蒿琥酯、(■)二氢青蒿素，图7.1中：(a)溶剂对照、(b)2.5μM二氢青蒿素、(c)50μM二氢青蒿素。 生理盐水和DMSO对照组HUVEC迁移的细胞数为256±28和258±29。当药物浓度为0.5μmol/L时，迁移抑制作用不明显，青蒿琥酯和二氢青蒿素组细胞迁移个数为252±46和241±23(P＞0.05)；当浓度为2.5，12.5，50μmol/L时，用药组与对照组之间有显著性差异(P＜0.01)，青蒿琥酯和二氢青蒿素组迁移细胞数分别为182.6±25，88.7±11，7.6±6和147±18，45±9，1.5±1。药物浓度(μmol/L)与细胞迁移率(％)的关系参见图5(n＝3)。 (3)青蒿琥酯和二氢青蒿素对HUVEC小管成型的影响 HUVEC在胶原凝胶基质中生长2~3天时，细胞由原来的多角形变成长梭形，并向凝胶基质中延伸生长，呈线形排列而形成管状结构，多个管状结构相互连接形成三维网状结构。参见图6、图7.2，图6中：(▲)青蒿琥酯、(■)二氢青蒿素，图7.2中：(a)溶剂对照、(b)12.5μM二氢青蒿素、(c)50μM二氢青蒿素。 48h后，生理盐水和DMSO对照组每个视野中小管总长度为4.90±0.55mm和5.18±0.65mm；当药物浓度为0.5μmol/L时，用药组小管长度与对照组比较均没有显著差异(P＞0.05)；当药物浓度为2.5μmol/L时，二氢青蒿素组小管总长度为3.85±0.35mm，呈现出明显的抑制作用(P＜0.05)；当浓度为12.5，50μmol/L时，二种药物均有显著的小管抑制作用(P＜0.01)。青蒿琥酯和二氢青蒿素组小管总长度分别为3.47±0.32mm，1.30±0.08mm和1.65±0.73mm，0.42±0.02mm。药物浓度(μmol/L)与小管形成率(％)之间的关系参见图6(n＝3)。 本发明涉及的部分参考文献： [1]Folkman J.Angiogenesis in cancer，rheumatoid and disease.Nat Med1995，1：27-31. 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[8]Satake S，Kuzuya M，Ramas MA，et al.Angiogenic stimuli are essential forsurvival of vascular endothelial cells in three-dimensional collagen lattice.Biochem Biophys Res Commun 1998，244：642-646. [9]Weidner N，Sample JP，Folkman J，et al.tumor angiogenesis andmetastasis-correlation in invasive breast carcinoma.N Engl J Med 1991，324，1-8. [10]Klagsbrun M，Moses MA.Molecular angiogenesis.Chem Biol 1999，6：217-224. [11]Ferrara N，Houck I，Jakeman L，et al.Molecular and biological properties of thevascular endothelial growth factor family of proteins.Endocr Rev 1999，13：18-42. [12]Shen BO，Lee DR，Zioncheck TF Vascular endothelial growth factor governsendothelial nitric-oxide synthase expression via KDR/Flk-1 receptor and aprotein kinasa C signaling pathway.J boil Chem 1999，274：33057-33063. [13]Claffey KP，Brow LF，Aguila LF Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth，angiogenesis，and experimental metastasis.Cancer Res 1996，56：172-182. 本发明提及的所有文献都在申请中引用作为参考，就如同每一篇文献都被单独引用作为参考那样。此外应理解，本发明是结合最佳实施例进行描述的，然而在阅读了本发明的上述内容后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 https://patents.google.com/patent/CN1208061C/zh?oq=CN1208061C青蒿琥酯和二氢青蒿素在抗血管生成药 Artesunate and dihydroarteannuin medicine preparation for proofing formation of blood vessel and use thereof The present invention relates to an artesunate and dihydroartemisinin medicine preparation for resisting angiogenesis and an application thereof. The medicine preparation principally contains artesunate or dihydroartemisinin, and the dosage form principally is a microsphere injection. The medicine preparation provided by the present invention has activity in resisting tumor angiogenesis and can be used for treating tumor angiogenesis and other diseases relevant to angiogenesis, and for therapies, such as tumour chemotherapies and/or adjuvant chemotherapies. The preparation slowly releases medicine and absorbs in administration sites and prolongs medicine action time. The present invention uses an angiogenesis theory as a background, researches and states traditional Chinese medicine effective monomer ingredient action and mechanisms, is new and important direction for developing Chinese medicine theories, provides important reference for discovering new theories and medicine action new targets and provides reference for the development of the new applications of artemisinin medicine. The application in anti-angiogenic medicaments of artesunate and dihydroartemisinine Technical field The invention belongs to medicinal application, relate to arteannuin and derivant thereof the medicinal usage aspect blood vessel formation against function. Background technology Angiogenesis is meant that already present blood vessel (blood capillary and venule) is by sprouting or splitted mode produces new blood vessel.Under physiology and the pathological conditions, take place as the embryo, processes such as female reproduction cycle, inflammatory reaction, wound healing, tumor generation are all being carried out angiogenesis.Particularly under the pathological conditions, according to statistics, the rise of about 20～40 kinds of human diseasess and angiogenesis or reduce relevant.1971, Folkman has set up the theory of getting in touch between angiogenesis and tumor growth, propose angiogenesis and not only can keep its vigorous metabolism, created advantageous conditions for tumor cell leaves primary lesion by blood transfer again simultaneously for tumor cell provides abundant nutrition.Many tumors are not having can only to grow several millimeters sizes before the new vessels generation, and angiogenesis is suppressed, though tumor cell is carrying out apoptosis fast, so can suppress growth of tumor and transfer effectively simultaneously still breeding at a high speed.Therefore, seek the new vessels growth inhibitor and become in the world neoplasm growth and the another important direction that shifts treatment in recent years.Anti-angiogenic medicaments and other cancer therapy drugs relatively have many advantages, and as seldom producing drug resistance, side effect is little, the efficient height, and the whole world above drugmaker of existing 40 families is developing anti-angiogenic agent. Since angiogenesis inhibitor treatment in 1988 entered clinical trial, approximately kind of an angiogenesis inhibitor entered clinical trial surplus in the of existing 20, wherein had plenty of at the special molecular such as the interferon-ALPHA that participate in neovascularization; The cell signalling such as the calcium channel blocker of the inhibition calcium mediation that has; Function that then directly suppresses endotheliocyte that has or reaction are as aspergillus fumigatus cedrol (TNP-470).The above-mentioned mechanism of action of analysis-by-synthesis, the better target spot that suppresses angiogenesis is an endotheliocyte, by sealing or reduce its surperficial angiogenic growth factor receptor, suppresses the growth of endotheliocyte, migration and tube chamber form, and can destroy new vessels efficiently and form.And,, act on the receptor of the other vascular endothelial cell of tumor because many malignant tumor cells itself can be secreted angiogenic growth factor for neonate tumour blood vessel, promote tumor vascular growth.So the angiogenesis factor protein expression in the downward modulation tumor cell suppresses the secretion of its angiogenesis factor, also can reach antineoplastic vascular growth effect. The seventies, Chinese scholar is isolated antimalarial arteannuin (artemisinin) in Chinese herbal medicine Hemerocallis citrina Baroni Artemisia after, Artemether, artesunate (artesunate) and dihydroartemisinine effective derivants such as (dihydroartemisinin) have been synthesized again successively.New milestone is set up in the appearance of this class medicine on the antimalarial agent research history.In up to a million malaria infection were used all over the world, artemisinin-based drug is evident in efficacy, and was little to the human body toxic and side effects, and do not see as yet that so far Drug resistance occurs, and is the important antimalarial of highly effective and safe by world health organisation recommendations.The various countries scholar is to finding that this class medicine also has stronger antitumor action except its special significant malaria curative effect in the research in surplus the artemisinin-based drug ten year. Arteannuin (Artemisinin) is the sesquiterpene lactones with new structure that China scientist proposed from feverfew Herba Artemisiae annuae (Artemisia annua Linn) first in 1971.It has very good malaria effect, comprises that those have chemical sproof falciparum infection to chloroquine.Cause worldwide attention immediately, owing to exist Orally active low, water-soluble degree is little, and shortcomings such as relapse rate height make to enlarge to use to be restricted.Therefore China scientist has synthesized a large amount of derivants, is dihydroartemisinine (Dihydroartemisinin) according to arteannuin reductive metabolites in vivo, with arteannuin C 10Carbonyl reduction gets dihydroartemisinine, and anti-Mus malaria (P.berghei) is stronger one times than arteannuin.Dihydroartemisinine is carried out esterification get artesunate (Artesunate), chemistry dihydroartemisinine by name-10-α-succinate monoester, its sodium salt is made injectable powder, for quiet notes, the plasmodium phorozoon is had stronger killing action.Artesunate is converted into dihydroartemisinine, i.e. dihydroartemisinine immediately in body.Because dihydroartemisinine is water insoluble, and blood plasma and histone are had stronger adhesion, make medicine rapidly to whole body each tissue transhipment and removing.Therefore, that artesunate has is efficient, quick-acting, low toxicity, be difficult for producing characteristics such as tolerance, all effective to tertian malaria, subtertian malaria, cerebral malaria, the clinical treatment that mainly is applicable to cerebral malaria and various critical malaria. The dihydroartemisinine artesunate Summary of the invention An object of the present invention is to provide the application in anti-angiogenic medicaments of artesunate and/or dihydroartemisinine. Artesunate provided by the invention or dihydroartemisinine also can be in the application aspect chemotherapy of tumors and/or the adjuvant chemotherapy. The present invention has the following advantages: (1) artesunate and dihydroartemisinine are the most representative medicines in the traditional Herba Artemisiae Annuae class antimalarial, be used for the malaria treatment all the time, characteristics of the present invention are to propose artesunate first and dihydroartemisinine has blood vessel formation against function, and with their medicine as the disease treatment that is used for tumor-blood-vessel growth and other associated angiogenesis.Human numerous disease and associated angiogenesis, artemisinin-based drug will obtain important use as angiogenesis inhibitor in these treatment of diseases. (2) the present invention provides pharmacodynamics and Its Mechanisms foundation for the artemisinin-based drug exploitation becomes antitumor drug, has the value with artemisinin-based drug exploitation becoming class medicines such as chemotherapy of tumors and/or adjuvant chemotherapy. (3) the present invention is a background with the angiogenesis theory, studies and illustrate effect of Chinese medicine effective monomer component and mechanism, is the new important directions of developing Chinese medicine pharmacology opinion, provides important evidence for finding the new target spot of new theory and drug effect. Description of drawings Fig. 1. be the influence of artesunate to the chick chorioallantoic membrane angiogenesis. Fig. 2 .1a is HE dyeing (Yihong-haematoxylin dyeing). Fig. 2 .1b is blood vessel CD 31Dyeing. Fig. 2 .2. is the influence of artesunate to vegf expression. Fig. 2 .3. is the influence of artesunate to the KDR/flk-1 expression of receptor. Fig. 3. be transplanted tumor in nude mice change in volume during the medication. Fig. 4 is the influence to vascular endothelial cell proliferation of artesunate and dihydroartemisinine. Fig. 5 is the influence to migration of vascular endothelial cells of artesunate and dihydroartemisinine. Fig. 6 is the influence to the molding of vascular endothelial cell tubule of artesunate and dihydroartemisinine. Fig. 7 .1 is the influence of dihydroartemisinine to migration of vascular endothelial cells. Fig. 7 .2 is the influence of dihydroartemisinine to the molding of vascular endothelial cell tubule. The specific embodiment The present invention is described further with accompanying drawing in conjunction with specific embodiments.Should be understood that these embodiment only are used for illustration purpose, and be not used in the restriction scope of the invention. Embodiment 1: a kind of method of preparation artesunate microsphere injection liquid (Polycaprolactone PCL) grinds artesunate, and the melting mixing liquid that is prepared into is made microsphere injection liquid with biocompatibility and Biodegradable polymer with release polymer.Used polymer release posthydrolysis is harmless degradation product (water and carbon dioxide).After this microsphere injection liquid intramuscular injection, slowly discharge medicine and absorption, prolonged action time, can be used for the disease treatment of tumor and other associated angiogenesis at medicine-feeding part. Embodiment 2: the whole angiogenesis that suppresses of artesunate microsphere injection liquid is tested (1) suppresses the chick chorioallantoic membrane angiogenesis Experiment material: artesunate (crude drug is provided by Guilin second pharmaceutical factory) adopts microsphere injection liquid of the present invention; Hydrocortisone (Xianju, Zhejiang pharmaceutical factory product); Hatching egg (purchasing) in Hangzhou Ilex purpurea Hassk.[I.chinensis Sims name chicken plant. Method: 7-8 days Embryo Gallus domesticus is windowed, add artesunate, positive reference substance (hydrocortisone) and solvent control product (blank microsphere injection liquid) respectively, behind the hatching 24h, with the fixing chick chorioallantoic membrane of 1: 1 mixed liquor of methanol, acetone, make specimen, counting blood vessel number under anatomic microscope. The result: The angiogenesis suppression ratioArtesunate is respectively 50%, 55.6%, 87.5% and 100% to chick chorioallantoic membrane angiogenesis suppression ratio when dosage 15,30,60,80 μ g/ embryos.The suppression ratio 66% of positive controls hydrocortisone 30 μ g/ embryos, the suppression ratio 0% of the blank microsphere injection liquid/embryo of solvent control group isometric(al).Every embryo administration volume 100 μ l.The results are shown in Table 1. Table 1 artesunate is to the inhibitory action of chick chorioallantoic membrane angiogenesis Dosage The tunica vasculose number positiveTunica vasculose tunica vasculose suppression ratio Medicine (μ g/ embryo)+++ negative number survival number % Blank microsphere liquid 30 00 10 10 0 Artesunate 15 909 18 50.0 Artesunate 30 828 18 55.6 Artesunate 60 3 11 2 16 87.5 Artesunate 80 0 10 0 10 100.0 Hydrocortisone 30 354 12 66.7 Vascular countsThe vessel density of solvent control group, branch are obviously more than the administration group, and caliber is thicker, referring to Fig. 1, wherein: (a) solvent control, (b) artesunate 30 μ g/ embryos, (c) hydrocortisone 30 μ g/ embryos.During the high concentration administration, have only the tiny blood vessel of only a few caliber, do not have obvious branch-like, even do not see and haemolysis occurs by blood vessel, indivedual chicken embryo deaths.When artesunate dosage 60,30,15 μ g/ embryos, vascular counts is respectively 3.8,9.7,27.1,19.5 of positive controls, 40.5 of solvent control groups.Compare with the solvent control group, each is organized data and is significant difference (P＜0.01).The results are shown in Table 2. Table 2 artesunate is to the influence of chick chorioallantoic membrane angiogenesis Drug dose (μ g/ embryo) n counts blood vessel number (x ± s) Blank microsphere liquid 30 15 40.6 ± 2.3 Artesunate 15 15 27.1 ± 8.5 * Artesunate 30 15 9.7 ± 2.7 * Artesunate 60 15 3.8 ± 1.6 * Hydrocortisone 30 15 19.5 ± 5.6 * *The blank microsphere liquid of P＜0.01vs3%, t test (2) suppress human ovarian cancer transplanted tumor in nude mice angiogenesis Experiment material: artesunate (crude drug is provided by Guilin second pharmaceutical factory) adopts microsphere injection liquid of the present invention.HO-8910 human oophoroma cell line (providing) by the institute of oncology, Zhejiang Province, 32 of BALB/C nude mouses, body weight (20 ± 2) g, male, 6～8 ages (providing) in week by the Shanghai Inst. of Tumor.The RPMI-1640 cell culture fluid that contains 10% calf serum.VEGF (VEGF) polyclonal antibody (the anti-people of rabbit, U.S. Santa Cruz company), VEGFR-2 (KDR/flk-1 receptor) polyclonal antibody (the anti-people of rabbit, U.S. Santa Cruz company), CD 31Factor monoclonal antibodies (rat anti-mouse, U.S. Santa Cruz company). Method: Suppress human ovarian cancer transplanted tumor in nude mice modelling and dosage regimen Add 10% calf serum with RPMI-1640 and cultivate the HO-8910 Proliferation of Human Ovarian Cell.Cell is by 1 * 10 7/ ml is suspended in the serum-free medium, every mice left side axil subcutaneous vaccination 0.2ml.Can form macroscopic tumor piece, tumor formation rate 100% in about about 4 days.Beginning administration in the 3rd day is divided into 4 groups: artesunate high dose group 100mg/ (kgd), middle dosage group 50mg/ (kgd), low dose group 10mg/ (kgd) and blank microsphere injection liquid group at random after the one-tenth tumor.Every group 8, administered intramuscular, every day 1 time, successive administration 10 days, matched group wait the blank microsphere injection liquid of capacity.After the last administration 24 hours, put to death animal, take out the tumor piece. The toxic and side effects of gross tumor volume variation and medicineObserve ordinary circumstance and the growth of xenografted situation of nude mouse during the administration, gross tumor volume of per 3 days mensuration.Measuring method is: with vernier caliper measurement tumor major axis (a), minor axis (b) is according to formula V=0.5ab 2Calculate gross tumor volume, draw the gross tumor volume growth curve.Measure the nude mice body weight simultaneously. HE dyeing and SABCAbove-mentioned tumor tissues specimen is made the thick paraffin section of 5 μ M after routine is handled, HE dyeing, and referring to Fig. 2 .1a, conventional index is observed.With SABC SABC method, adopt mouse-anti Mus CD 31Factor antibody, rabbit anti-people VEGF antibody and rabbit human VEGFR-3 resistant-2 antibody test tumor specimen medium vessels generate, and VEGF and KDR/flk-1 expression of receptor replace an anti-feminine gender of doing with BPS.1. vascular counts: select 6 visuals field to observe blood vessels and counting under every section high power lens (* 200) at random, averaging is the end value of every example.2. VEGF and KDR/flk-1 expression of receptor: select 6 visuals field at random under every section high power lens (* 400), the number of cells of VEGF and KDR/flk-1 receptor positive in 200 cells of counting in each visual field, less than 10% positive cell negative (-), 10%-30% is the weak positive (+), 30%-70% is the middle positive (++), and 70%-100% is strong positive (+++).VEGF expresses in the tumor cell slurry, and the KDR/flk-1 receptor all has expression in tumor cell and vascular endothelial cell, and the expressive site immunohistochemical staining is pale brown color. The result: Vascular countsHigh dose group (100mg kg -1d -1), middle dosage group (50mg kg -1d -1) and low dose group (10mg kg -1d -1) blood vessel CD 31Dyeing, the result is referring to Fig. 2 .1b.Vascular counts is respectively 11.61 ± 4.32,27.75 ± 8.04,47.92 ± 11.49, blank microsphere injection liquid group is 48.98 ± 9.40, compare higher, middle dosage group vascular counts with blank microsphere injection liquid matched group and all obviously reduce (P＜0.01), low dose group no significant difference (P＞0.05).Referring to table 3. Table 3 artesunate is to the influence of transplanted tumor in nude mice vessel density Group (mg/kgd) number of animals (n) vessel density (x ± s) Blank microsphere (10ml/kg.d) 8 48.98 ± 9.40 Low dosage 10 8 47.92 ± 11.49 Middle dosage 50 8 27.75 ± 8.04 * High dose 100 8 11.61 ± 4.32 * *P＜0.05, *The blank microsphere group of P＜0.01vs, the t check VEGF, the KDR/flk-1 protein expressionTreatment group and blank microsphere injection liquid group VEGF, the KDR/flk-1 receptor in tumor cell and vascular cell The positive expression rate referring to Fig. 2 .2, Fig. 2 .3, among Fig. 2 .2: (a) dosage group, (c) negative control group in blank microsphere injection liquid group, (b) artesunate, among Fig. 2 .3: (a) dosage group, (c) artesunate high dose group in blank microsphere injection liquid group, (b) artesunate.High dose group (100mg/kgd), middle dosage group (50mg/kgd) and low dose group (10mg/kgd) VEGF, flt-1 immunohistochemical staining positive rate compare with matched group all notable difference (P＜0.05).See Table 4. Table 4 artesunate to tumor tissues VEGF and KDR/The influence that flt-1 expresses Group number of animals vegf expression KDR/Flk-1 expresses (mg/kgd) (n) tumor cell tumor cell vascular endothelial cell Blank microsphere 8 +++(8) +++(7) ++ (1) +++(8) 10 8 +++(4)++(4) +++(3)++(5) +++(2)++(6) * 50 8 ++(1)+(4)-(3) ** ++(4)+(3)-(1) ** ++(2)+(4)-(2) ** 100 8 ++(1)+(2)-(5) ** ++(2)+(2)-(4) ** ++(1)+(2)-(5) ** *P＜0.05, *The blank microsphere group of P＜0.01vs, x 2Check The toxic and side effects of gross tumor volume variation and medicineGrowth of xenografted and change in volume are referring to Fig. 3, and when becoming tumor (inoculating after 4 days), treatment group and blank microsphere injection liquid group tumor body difference in size do not have significance (P＞0.05).In the medication process, treatment group tumor growth is slower, and medication the 1st, 4 was measured gross tumor volume in 7,10 days, and height, middle dosage group gross tumor volume have significant difference (P＜0.05) all less than matched group.During the medication, four groups of tumor bearing nude mices are movable good, do not see special untoward reaction, and none example is dead.Medication is matched group and height after 10 days, in, low treatment group on average goes tumor Mus heavy (g) to be respectively 22.1 ± 1.86,22.62 ± 2.4, and 21.83 ± 2.1,22.25 ± 2.36, treatment group and blank microsphere injection liquid matched group relatively do not have significant difference (P＞0.05). Embodiment 3: artesunate and the experiment of dihydroartemisinine vitro inhibition angiogenesis Experiment material: artesunate, dihydroartemisinine (crude drug is provided by Guilin second pharmaceutical factory) Method: (1) Human umbilical vein endothelial cells (HUVEC) is cultivated Get the fetal cord of fresh and healthy, pour into 5% collagenase, 37 ℃ of water-bath 15～20min are with PBS liquid flushing umbilical vein, centrifugal, abandon supernatant, use the culture fluid suspension cell, put in the culture bottle and cultivate, change liquid every other day once, culture fluid is that DMEM contains 15% calf serum and the VEGF of 10ng/ml.Use with getting the cell confession research of the 2nd～3 generation after the evaluation of the anti-people VIII of rabbit factor antibody row SABC. (2) HUVEC propagation suppresses With HUVEC with 5 * 10 4Individual/ml density is inoculated in 24 well culture plates, puts incubator 5%CO 2, 37 ℃ hatch treated in 24 hours fully adherent after, add medicine (artesunate or dihydroartemisinine), and establish normal saline and DMSO matched group.Establish 3 multiple holes for every group, act on after 48 hours, detect cell survival rate with mtt assay. (3) the HUVEC migration suppresses Be grown in the HUVEC that has been fused to monolayer in the 35mm plastic culture dish with the blade damage,, add the DMEM culture fluid that contains 15% calf serum, add testing drug (artesunate or dihydroartemisinine) then, put 5%CO with PBS liquid flushing 3 times 2, in 37 ℃ of incubators, the HUVEC number that from injured edge continuous counter (500 * 250) μ M section, moves after 24 hours, 10 of numeric representations are the cell number average in the visual field at random. (4) the HUVEC tubule forms and suppresses Type i collagen (Sigma, Bomem Belgium), DMEM (* 10), 0.05M NaOH+0.2MHEPES+0.26MNaHCO 2With volume ratio 8: 1: 1: mix rapidly down in ice bath, coat 24 well culture plates bottom, put 37 ℃ and form collagen gels, with HUVEC with 5 * 10 4The density of individual/ml is suspended in the 10% calf serum DMEM culture fluid, and every hole adds 0.5ml, and used medicine (artesunate or dihydroartemisinine) also adds with certain concentration at this moment, at 5%CO 2, cultivated 48 hours in 37 ℃ of incubators, (* 200) measure the total length of tubule in 10 visuals field at random with trisquare under inverted microscope. The result: (1) influence that HUVEC is bred Normal saline matched group and DMSO matched group OD value are 0.71 ± 0.05 and 0.72 ± 0.05.Compare with the corresponding solvent matched group, all not obvious to the HUVEC inhibited proliferation when drug level is 0.5 μ mol/L, the OD value of artesunate and dihydroartemisinine is 0.70 ± 0.04 and 0.69 ± 0.07 (P＞0.05); When concentration was 2.5 μ mol/L, the OD value of dihydroartemisinine was 0.66 ± 0.04 (P＜0.05), and the propagation of HUVEC is had inhibitory action; When concentration was 12.5 and 50 μ mol/L, two kinds of medicines all had tangible inhibited proliferation (P＜0.01) to HUVEC, and the OD value is respectively 0.59 ± 0.04,0.42 ± 0.03 (artesunate) and 0.50 ± 0.04,0.36 ± 0.03 (dihydroartemisinine); The OD value descend have dose dependent, each medication group difference have significance (P＜0.05, n=3).Drug level (μ mol/L) is seen ginseng Fig. 4 (n=3), wherein (▲) artesunate, (■) dihydroartemisinine with the relation of cell survival rate (%). (2) influence that HUVEC is moved The cell migration experimental result shows, under the effect of artesunate and dihydroartemisinine, the quantity that the HUVEC migration enters injured exposed area obviously reduces, referring to Fig. 5, Fig. 7 .1, among Fig. 5: (▲) artesunate, (■) dihydroartemisinine, among Fig. 7 .1: (a) solvent control, (b) 2.5 μ M dihydroartemisinines, (c) 50 μ M dihydroartemisinines. The cell number of normal saline and DMSO matched group HUVEC migration is 256 ± 28 and 258 ± 29.When drug level was 0.5 μ mol/L, the migration inhibitory action was not obvious, and artesunate and dihydroartemisinine group cell migration number are 252 ± 46 and 241 ± 23 (P＞0.05); When concentration is 2.5,12.5,50 μ mol/L, significant difference (P＜0.01) is arranged between medication group and the matched group, artesunate and dihydroartemisinine group migrating cell number are respectively 182.6 ± 25,88.7 ± 11,7.6 ± 6 and 147 ± 18,45 ± 9,1.5 ± 1.The relation of drug level (μ mol/L) and cell migration rate (%) is referring to Fig. 5 (n=3). (3) artesunate and dihydroartemisinine are to the influence of HUVEC tubule molding HUVEC grew in collagen gel substrate 2 ~ 3 days the time, and cell becomes spindle shape by original polygon, and in gel-type vehicle elongation growth, be linear array and form tubular structure, a plurality of tubular structures are interconnected to form tridimensional network.Referring to Fig. 6, Fig. 7 .2, among Fig. 6: (▲) artesunate, (■) dihydroartemisinine, among Fig. 7 .2: (a) solvent control, (b) 12.5 μ M dihydroartemisinines, (c) 50 μ M dihydroartemisinines. Behind the 48h, the tubule total length is 4.90 ± 0.55mm and 5.18 ± 0.65mm in normal saline and each visual field of DMSO matched group; When drug level was 0.5 μ mol/L, little length of tube of medication group and matched group did not more all have significant difference (P＞0.05); When drug level was 2.5 μ mol/L, dihydroartemisinine group tubule total length was 3.85 ± 0.35mm, presented obvious suppression effect (P＜0.05); When concentration was 12.5,50 μ mol/L, two kinds of medicines all had significant tubule inhibitory action (P＜0.01).Artesunate and dihydroartemisinine group tubule total length are respectively 3.47 ± 0.32mm, 1.30 ± 0.08mm and 1.65 ± 0.73mm, 0.42 ± 0.02mm.Relation between drug level (μ mol/L) and the tubule formation rate (%) is referring to Fig. 6 (n=3). The partial reference document that the present invention relates to: [1]Folkman?J.Angiogenesis?in?cancer，rheumatoid?and?disease.Nat?Med1995，1：27-31. [2]Kim?KJ，Li?B，Winer?J.Inhibition?of?vascular?endothelial?growth?factor-inducedangiogenesis?suppresses?tumor?growth?in?vivo.Nature?1993，362：841-844. [3]Klayman?DL.Qinghaosu(artemisinin)：an?antimalarial?drug?from?China.Science1985，228：1049-1055. [4]Benakis?A，Paris?M，Loutan?L，et?al.Pharmacokinetics?of?artemisinin?andartesunate?after?oral?administration?in?healthy?volunteers.Am?J?Trop?Med?Hyg1997，56：17-23. [5]Efferth?T，Dunstan?H，Sauerbrey?A，et?al.The?anti-malarial?artesunate?is?alsoactive?against?cancer.Int?J?Oncol?2001，18：767-773. [6]Moore?JC，Lai?H，Li?JR，et?al.Oral?administration?of?dihydroartemisinin?andferrous?sulfate?retarded?implanted?fibrosarcoma?growth?in?the?rat.Cancer?Lett1995，98：83-87. [7]Jaffe?EA，Nachman?RL，Becker?CG，et?al.Culture?of?human?endothelial?cellsderived?from?umbilical?veins.Identification?by?morphologic?and?immunologiccriteria.J?Clin?Invest?1973，52：2745-2756. [8]Satake?S，Kuzuya?M，Ramas?MA，et?al.Angiogenic?stimuli?are?essential?forsurvival?of?vascular?endothelial?cells?in?three-dimensional?collagen?lattice.Biochem?Biophys?Res?Commun?1998，244：642-646. [9]Weidner?N，Sample?JP，Folkman?J，et?al.tumor?angiogenesis?andmetastasis-correlation?in?invasive?breast?carcinoma.N?Engl?J?Med?1991，324，1-8. [10]Klagsbrun?M，Moses?MA.Molecular?angiogenesis.Chem?Biol?1999，6：217-224. [11]Ferrara?N，Houck?I，Jakeman?L，et?al.Molecular?and?biological?properties?of?thevascular?endothelial?growth?factor?family?of?proteins.Endocr?Rev?1999，13：18-42. [12]Shen?BO，Lee?DR，Zioncheck?TF?Vascular?endothelial?growth?factor?governsendothelial?nitric-oxide?synthase?expression?via?KDR/Flk-1?receptor?and?aprotein?kinasa?C?signaling?pathway.J?boil?Chem?1999，274：33057-33063. [13]Claffey?KP，Brow?LF，Aguila?LF?Expression?of?vascular?permeability?factor/vascular?endothelial?growth?factor?by?melanoma?cells?increases?tumor?growth，angiogenesis，and?experimental?metastasis.Cancer?Res?1996，56：172-182. All documents that the present invention mentions are all quoted in application as a reference, are just all quoted as a reference separately as each piece document.Should understand in addition, the present invention is described in conjunction with most preferred embodiment, yet after having read foregoing of the present invention, those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims institute restricted portion equally. https://patents.google.com/patent/CN1208061C/en?oq=CN1208061C青蒿琥酯和二氢青蒿素在抗血管生成药

CN1145224A青蒿素作为抗真菌剂的应用---外用治疗手足癣、头皮癣、体癣、头皮屑等浅表真菌感染 CN1145224A Application of artemisinin as an antifungal agent---Topically treating superficial fungal infections such as tinea pedis, tinea capitis, tinea corporis, and dandruff. 青蒿素作为抗真菌剂的应用 本发明涉及将一种现有的抗疟药青蒿素作为抗真菌药应用，为青蒿素提供了新的用途。通过对青蒿素抗菌作用研究表明，青蒿素具有良好的抗真菌作用，其抗菌谱及作用与目前常用的广谱抗真菌药酮康唑相似，对某些真菌的作用可强于酮康唑。青蒿素可以制成各种制剂，现作为外用剂治疗手足癣、体癣、头癣等浅部真菌感染，还可以用于头皮屑的防治。青蒿素对癣病的疗效优于酮康唑且不良反应较小。 青蒿素作为抗真菌剂的应用 本发明涉及将一种现有的抗疟药青蒿素作为抗真菌药的应用，为中药治疗真菌感染性疾病提供了一种新的药物。 青蒿素系我国从中药黄花蒿中提取的有效单体成分(倍半萜内酯过氧化物)，有优良的抗疟作用。已被世界卫生组织推荐为新抗疟药，目前临床用于治疗疟疾(竺心影主编：药理学第三版，北京：人民卫生出版社，1993：370)。真菌感染尤其是浅部真菌感染-癣病是一种常见病，目前的治疗药物常用的有克霉唑、咪康唑、酮康唑、氟康唑等，均系人工合成品，不良反应较大，主要毒性有贫血、皮疹及胃肠道反应等(江明性主编：药理学第三版，北京：人民卫生出版社，1989年：348)。现有文献报导是将青蒿油搽剂应用于癣病的治疗，用鲜青蒿加水蒸馏获得青蒿油，其主要成份是按油精、青蒿酮、左旋樟脑、侧柏酮、丁香烯以及其它倍半萜衍生物(陈德宇等：青蒿油搽剂抗真菌作用实验及疗效观察，中国皮肤病学杂志，1990；4(1)：18-19)。 本发明的目的在于利用我国中草药资源开发新药，研究“老药新用”，从现有抗疟药青蒿素寻找出新的作用和应用。 本发明通过对青蒿素的体外抗真菌作用研究，证实青蒿素的抗菌谱及作用与目前常用的广谱抗真菌药酮康唑相似，且对某些真菌的作用强于酮康唑。药效学试验结果表明，青蒿素具有良好的抗真菌作用，对真菌属菌株均呈现抑制或杀灭作用，其中对石膏样毛菌、石膏样小孢子菌作用最强；其次对紫色毛癣菌、许兰氏毛癣菌、紫状表皮癣菌、曲霉菌作用均比酮康唑强或近似；对白色念珠菌抑菌作用略低于酮康唑、杀菌作用接近酮康唑(见附件：青蒿素制剂的体外抗菌作用)。临床应用证明青蒿素可以作为抗真菌药用于治疗真菌感染性疾病。目前已作为外用制剂用于治疗手足癣、体癣、头癣等浅部癣菌病，还可用于防治头皮屑，效果均好。青蒿素治疗癣病疗效优于酮康唑，其不良反应小，未见特殊毒性反应。 本发明青蒿素与现有技术青蒿油虽都能用于治疗癣病，但两药有效成份不同，青蒿素是从青蒿中提取的有效单体成分倍半萜内酯过氧化物，而青蒿油中成份较多，其中次要成份倍半萜衍生物未特指哪一种衍生物；其次青蒿素还可用于治疗头皮屑。青蒿素配制方便，可以直接利用现有的药用青蒿素制备成各种制剂供使用，而青蒿油须用青蒿蒸馏提取后再配制成搽剂。本发明青蒿素作为抗真菌剂应用，目前尚未见国内外文献报导。 青蒿素可制备成各种剂型应用，目前作为外用剂如搽剂、喷雾剂、洗剂等应用。青蒿素外用制剂的组成：青蒿素2-5％、二甲基亚砜20-80％、丙二醇30-60％、乙醇30-70％、食用香精0.05-0.5％，其制备方法：将青蒿素以乙醇溶解，加透皮吸收促进剂二甲基亚砜和丙二醇混合、过滤，再加香精搅匀即得。 本发明从青蒿素寻找到新的作用，为青蒿素“老药新用”提供了新的用途，使青蒿素不仅作为抗疟药应用，还可作为抗真菌药应用，为青蒿素临床应用开拓了新的前景。 实施例： 1、外用剂配方及制备： ①搽剂：青蒿素4g、二甲基亚砜30g、丙二醇30g、乙醇(95％)40g、食用香精0.3％，将青蒿素溶于乙醇中，加二甲基亚砜、丙二醇混匀，再加食用香精搅匀，灌装即得。 ②洗剂：青蒿素3g，用70％乙醇配成3％溶液。 2、应用： ①猫体癣：将青蒿素搽剂涂于患部，用药一次，两日后痊愈。 ②孙××，手足癣：将青蒿素搽剂涂于患部每日一次，应用三天后均痊愈。 ③吴××，头皮屑：青蒿素洗剂适量与洗发剂配合使用，3次后头屑消除。 1、一种抗疟药青蒿素作为抗真菌剂的应用，其特征在于青蒿素具有良好的抗真菌作用，可以作为抗真菌药用于真菌感染性疾病的治疗，还可用于头皮屑的防治。 2、据权利要求1所述的青蒿素的应用，其特征在于青蒿素尤其适用于浅部真菌感染性疾病-癣病的治疗。 3、据权利要求1所述的青蒿素的应用，其特征在于青蒿素可以制成各种剂型应用，如搽剂、喷雾剂、洗剂等外用剂用于癣病。 https://patents.google.com/patent/CN1145224A/zh?oq=CN1145224A青蒿素作为抗真菌剂的应用---外用治疗手足癣、头皮癣、体癣、头皮屑等浅表真菌感染 Application of arteannuin as antifungal agent The artabsin used as antimalarial originally can be used as antifungal medicine, which is externally applied for treating superficial fungus infections such as hand and foot tinea, favus of scalp, body ringworm and dandruff with curative effect similar to or higher than ketoconazole. Arteannuin is as the application of antifungal The present invention relates to of the application of a kind of existing antimalarial arteannuin, for the treatment by Chinese herbs fungal infectious disease provides a kind of new medicine as antifungal agent. The effective monomer component that Herba Artemisiae Annuae prime system China extracts from the Chinese medicine Herba Artemisiae annuae (sesquiterpene lactones peroxide) has good malaria effect.Be new antimalarial by world health organisation recommendations, at present clinical be used for the treatment of malaria (the Zhu Xinying chief editor: pharmacology's third edition, Beijing: the People's Health Publisher, 1993:370).Fungal infection especially mycotic infection of superficial part-tinea is a kind of commonly encountered diseases, present medicine is commonly used clotrimazole, miconazole, ketoconazole, fluconazol etc., all be the synthetic product, untoward reaction is bigger, main toxicity has (Jiang Mingxing chief editor: pharmacology's third edition such as anemia, erythra and gastrointestinal reaction, Beijing: People's Health Publisher, 1989: 348).Existing reported in literature is the treatment that the Herba Artemisiae Annuae oil liniment is applied to tinea, add the water distillation with bright Herba Artemisiae Annuae and obtain Herba Artemisiae Annuae oil, its Main Ingredients and Appearance is by olein, artemisia ketone, left-handed Camphora, absinthol, Flos Caryophylli alkene and other sesquiterpene derivative (Chen Deyu etc.: experiment of Herba Artemisiae Annuae oil liniment antifungic action and observation of curative effect, China's dermatological magazine, 1990; 4 (1): 18-19). The objective of the invention is to utilize China's Chinese herbal medicine resource developing new drug, research " old medicine is newly used " is sought effect and the application that makes new advances from existing antimalarial arteannuin. The present invention confirms that the antimicrobial spectrum of arteannuin and effect are similar to broad-spectrum antifungal medicine ketoconazole commonly used at present, and the effect of some fungus is better than ketoconazole by the external antifungic action research to arteannuin.Results of pharmacodynamic test shows that arteannuin has good antifungic action, the fungi bacterial strain is all presented suppress or killing action, and is wherein the strongest to achorion gypseum, microsporon gypseum effect; Secondly all strong or approximate to Trichophyton violaceum, trichophyton, purple shape epidermophyton, aspergillosis effect than ketoconazole; The Candida albicans bacteriostasis (is seen Appendix: the vitro antibacterial activity of arteannuin preparation) near ketoconazole a little less than ketoconazole, bactericidal action.Clinical practice proof arteannuin can be used as antifungal agent and is used for the treatment of fungal infectious disease.Be used for the treatment of superficial part ringworm such as tinea manus and pedis, tinea corporis, tinea capitis at present as external preparation, also can be used for preventing and treating the dandruff, effect is all good.Arteannuin treatment tinea curative effect is better than ketoconazole, and its untoward reaction is little, does not see the specific toxicity reaction. Though arteannuin of the present invention and prior art Herba Artemisiae Annuae oil can both be used for the treatment of tinea, but two medicine active ingredient differences, arteannuin is the effective monomer component sesquiterpene lactones peroxide that extracts from Herba Artemisiae Annuae, and composition is more in the Herba Artemisiae Annuae oil, and wherein less important composition sesquiterpene derivative does not refer in particular to any derivant; Secondly arteannuin also can be used for treating the dandruff.The arteannuin preparation is convenient, can directly utilize existing medicinal arteannuin to be prepared into various preparations for use, and Herba Artemisiae Annuae oil must be with being mixed with liniment behind the Herba Artemisiae Annuae distillation extraction again.Arteannuin of the present invention is used as antifungal, has not yet to see the domestic and foreign literature report. Arteannuin can be prepared into various dosage forms and use, at present as application such as external agent such as liniment, spray, lotions.The composition of arteannuin external preparation: arteannuin 2-5%, dimethyl sulfoxide 20-80%, propylene glycol 30-60%, ethanol 30-70%, edible essence 0.05-0.5%, its preparation method: with arteannuin with dissolve with ethanol, add Percutaneous absorption enhancer dimethyl sulfoxide and mixed with propylene glycol, filtration, add essence again and stir evenly promptly. The present invention searches out new effect from arteannuin, for arteannuin " old medicine is newly used " provides new purposes, arteannuin is not only used as antimalarial, also can be used as antifungal agent and uses, for new prospect has been opened up in the arteannuin clinical practice. Embodiment: 1, external agent prescription and preparation: 1. liniment: arteannuin 4g, dimethyl sulfoxide 30g, propylene glycol 30g, ethanol (95%) 40g, edible essence 0.3%, arteannuin is dissolved in the ethanol, add dimethyl sulfoxide, propylene glycol mixing, add edible essence again and stir evenly, fill is promptly. 2. lotion: arteannuin 3g is made into 3% solution with 70% ethanol. 2, use: 1. cat tinea corporis: the arteannuin liniment is applied to affected part, medication once, recovery from illness after two days. 2. grandson * *, tinea manus and pedis: the arteannuin liniment is applied to affected part once a day, uses after three days all recoveries from illness. 3. Wu * *, the dandruff: the arteannuin lotion is an amount of to be used with shampoo, the bits elimination of 3 postocciput. 1, a kind of antimalarial arteannuin is characterized in that as the application of antifungal arteannuin has good antifungic action, can be used as the treatment that antifungal agent is used for fungal infectious disease, also can be used for the control of the dandruff. 2,, it is characterized in that arteannuin is particularly useful for the treatment of mycotic infection of superficial part disease-tinea according to the application of the described arteannuin of claim 1. 3, according to the application of the described arteannuin of claim 1, it is characterized in that arteannuin can make various dosage forms and use, be used for tinea as external agent such as liniment, spray, lotions. https://patents.google.com/patent/CN1145224A/en?oq=CN1145224A青蒿素作为抗真菌剂的应用---外用治疗手足癣、头皮癣、体癣、头皮屑等浅表真菌感染

CN1116036C一种治疗酒渣鼻及光敏性疾病的含双氢青蒿素的药物组合物---含有双氢青蒿素药物组合物是治疗红斑狼疮和光敏性疾病的有效药物 CN1116036C A pharmaceutical composition containing dihydroartemisinin for treating rosacea and photosensitive diseases---The pharmaceutical composition containing dihydroartemisinin is an effective treatment for lupus erythematosus and photosensitive diseases. 治疗红斑狼疮和光敏性疾病的含双氢青蒿素的药物组合物 本发明涉及含有双氢青蒿素的药物组合物，经药效学、毒理学及临床研究，表明本发明的药物组合物是治疗红斑狼疮和光敏性疾病的有效药物，该药物组合物可以制成各种常用的剂型用于临床，具有高效、安全、无毒副作用的特点。 治疗红斑狼疮和光敏性疾病的含双氢青蒿素的药物组合物 本发明涉及一种用于治疗红斑狼疮和光敏性疾病的药物，特别是用于治疗红斑狼疮和光敏性疾病的含有双氢青蒿素的药物组合物。 红斑狼疮和多形性日光疹等均为光敏性疾病，而红斑狼疮又属免疫性疾病，严重危害人体健康，特别是系统性红斑狼疮往往侵犯结缔组织、血管、内脏、皮肤等多种器官并伴有免疫学异常的全身性疾病。现代医学认为自身免疫性疾病是由机体免疫功能紊乱，导致B细胞功能亢进而产生大量自体抗体，引起免疫复合物在组织，特别是肾小球内基底膜内沉着(狼疮性肾常是致死的原因)导致III型变态反应。 近年来红斑狼疮发病率有不断上升的趋势，据美国Siegel和Fessel对纽约和旧金山人群调查，患病率分别为13.4/10万和50.8/10万。国内上海纺织系统人群调查患病率为70.4/10万(女性则为113.3/10万)故有关本病的流行病学及治疗学研究已日益受到国内外重视。对于该病的治疗，西医多用大剂量皮质类固醇激素以及免疫抑制剂治疗，对部分患者可控制病情，但长期用药则引起严重的毒副作用和并发症，甚至成为本病致死的主要原因。中医采用辨证施治的方针，近年来开发了一些治疗系统性红斑狼疮的药物。例如中国专利申请91103109公开了一种治疗系统性红斑狼疮的药物组合物，其中含有34种中药；中国专利申请94103378公开了一种治疗系统性红斑狼疮的药物组合物，其中含有十多种中药。上述这些中药组合物一般都是处方药，使用时一般都需医生根据患者的实际情况对药物组合物的成分进行取舍。尽管也有中成药，但因为其成分多，制备复杂，因此在实际使用过程中还不是非常方便。双氢青蒿素是青蒿素的还原化合物，其结构式如下：... 我国自七十年代开始，对青蒿素进行了广泛深入的研究，开发出了青蒿素及其衍生物是一类有效的抗疟药物组合物。近年来，随着对青蒿素及其衍生物研究的深入，不断发现了其在新领域中的应用。 本发明的目的是提供一种高效、安全且无毒副作用的治疗红斑狼疮和光敏性疾病的药物组合物。 本发明是基于这样的事实而完成的：本发明人以其发明的双氢青蒿素致力于抗疟研究，结果证明双氢青蒿素在高效、低毒、制备方便等方面均优于其它青蒿素类衍生物，同时又在免疫研究领域取得新发现，即在发现双氢青蒿素具有显著免疫抑制并对细胞免疫及体液免疫具有双向调节作用的基础上，经药效学和临床研究证明双氢青蒿素对红斑狼疮和光敏性疾病具有肯定的疗效，且无明显的毒副作用。 本发明提供了一种用于治疗红斑狼疮和光敏性疾病的含有双氢青蒿素的药物组合物，该组合物含有治疗有效剂量的双氢青蒿素。 本发明的目的是提供一种用于治疗红斑狼疮和光敏性疾病的含有双氢青蒿素的药物组合物，该组合物含有双氢青蒿素1-10重量％。 本发明的药物组合物适用于所有红斑狼疮(系统性红斑狼疮和盘状红斑狼疮)和光敏性疾病(多形性日光疹等)。 本发明的药物组合物可以是任何常用的药剂形式，可以为固体制剂，例如片剂、胶囊、栓剂、粉剂、颗粒剂、透皮软膏、霜剂等，也可以为液体制剂，例如口服液、喷雾剂、注射液等。本发明的药物组合物的制备方式是本领域的普通技术人员所公知的。 按照本发明的药物组合物，优选是将其制成片剂或胶囊，每一片片剂或每一粒胶囊含有20-80mg的双氢青蒿素。 本发明的药物组合物一般为口服给药，也可以经其他途径给药，例如治疗光敏性皮肤病可以使用外用制剂。用量一般为1-5mg/kg体重/天。 本发明的药物组合物可以单独使用。在治疗症状较重的系统性红斑狼疮时，也可以与现有的治疗红斑狼疮和光敏性疾病的其他药物，例如常用的激素类药物组合使用。 本发明使用的双氢青蒿素的制备方法是已知的。有关其制备方法已经见诸于文献报道。 以下通过实验例对本发明进行更进一步的说明。但应该理解的是，本发明的实验例只是用于说明而不是限制本发明。药效学实验... https://patents.google.com/patent/CN1116036C/zh?oq=CN1116036C一种治疗酒渣鼻及光敏性疾病的含双氢青蒿素的药物组合物---含有双氢青蒿素药物组合物是治疗红斑狼疮和光敏性疾病的有效药物 Medicinal composition containing dihydroartemisine for treating rosacea and photosensitive diseases The present invention relates to a medical composition containing dihydroartemisinin. Pharmacodynamical, toxicological and clinical research indicates that the medical composition of the present invention is effective medicine for treating lupus erythematosus and photosensitive diseases. The medical composition can be made into various common preparations for clinical application, and has the characteristics of high efficiency, safety and no toxic effect and side effect. The pharmaceutical composition that contains dihydroarteannuin of treatment lupus erythematosus and photosensitive diseases The present invention relates to a kind of medicine that is used for the treatment of lupus erythematosus and photosensitive diseases, especially for the pharmaceutical composition that contains dihydroarteannuin of treatment lupus erythematosus and photosensitive diseases. Lupus erythematosus and polymorphous light eruption etc. are photosensitive diseases, and lupus erythematosus belongs to immune disease, serious harm health, particularly systemic lupus erythematosus (sle) are often invaded multiple organs such as connective tissue, blood vessel, internal organs, skin and with the systemic disease of crucial immunological abnormality.Modern medicine thinks that autoimmune disease is by the body's immunity disorder, cause the B cell function hyperfunction and produce a large amount of autoantibody, cause that immune complex calm (the lupus kidney often is lethal reason) in basement membrane in the tissue, particularly glomerule causes the III allergic reaction type. The lupus erythematosus sickness rate has the trend of continuous rising in recent years, and to New York and San Francisco census of population, prevalence is respectively 13.4/10 ten thousand and 50.8/10 ten thousand according to U.S. Siegel and Fessel.Domestic Shanghai textile department census of population prevalence is that 70.4/10 ten thousand (women then is 113.3/10 ten thousand) are so the epidemiology of relevant primary disease and therapeutics research are subjected to domestic and international attention day by day.For the treatment of this disease, doctor trained in Western medicine is used heavy dose of corticosteroid hormone and immunosuppressant treatment more, and to the part patient may command state of an illness, but long-term prescription then causes serious toxic and side effects and complication, even becomes the lethal main cause of primary disease.The traditional Chinese medical science adopts the policy of determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs, has developed the medicine of some therapy system lupus erythematosus in recent years.For example Chinese patent application 91103109 discloses a kind of pharmaceutical composition of therapy system lupus erythematosus, wherein contains 34 kinds of Chinese medicines; Chinese patent application 94103378 discloses a kind of pharmaceutical composition of therapy system lupus erythematosus, wherein contains ten plurality of Chinese.Above-mentioned these Chinese medicine compositions all are prescription drugss generally, generally all need the doctor according to patient's practical situation the composition of pharmaceutical composition to be accepted or rejected during use.Although Chinese patent medicine is also arranged, because its composition is many, preparation is complicated, also is not very convenient in actual use therefore.Dihydroarteannuin is the reducing compound of arteannuin, and its structural formula is as follows:... China begins from the seventies, and arteannuin has been carried out research extensively and profoundly, and having developed arteannuin and derivant thereof is the effective antimalarial agent compositions of a class.In recent years, along with to the going deep into of arteannuin and derivant research thereof, constantly found its application in frontier. The purpose of this invention is to provide a kind of efficient, safety and the treatment lupus erythematosus that has no side effect and the pharmaceutical composition of photosensitive diseases. The present invention is based on such fact and finishes: the inventor is devoted to malaria research with the dihydroarteannuin of its invention, the result proves that dihydroarteannuin is efficiently, low toxicity, aspect such as easy to prepare all is better than other artemisinin derivatives, simultaneously obtain new discovery in the immune Research field again, promptly finding that dihydroarteannuin has remarkable immunosuppressant and pair cell immunity and humoral immunization and has on the basis of dual regulation, through pharmacodynamics and clinical research proof dihydroarteannuin lupus erythematosus and photosensitive diseases are had sure curative effect, and do not have obvious toxic and side effects. The invention provides a kind of pharmaceutical composition that contains dihydroarteannuin that is used for the treatment of lupus erythematosus and photosensitive diseases, said composition contains the dihydroarteannuin for the treatment of effective dose. The purpose of this invention is to provide a kind of pharmaceutical composition that contains dihydroarteannuin that is used for the treatment of lupus erythematosus and photosensitive diseases, said composition contains dihydroarteannuin 1-10 weight %. Pharmaceutical composition of the present invention is applicable to all lupus erythematosus (systemic lupus erythematosus (sle) and discoid lupus erythematosus) and photosensitive diseases (polymorphous light eruption etc.). Pharmaceutical composition of the present invention can be any medicine type commonly used, can be solid preparation, and for example tablet, capsule, suppository, powder, granule, transdermal ointment, cream etc. also can be liquid preparation, for example oral liquid, spray, injection etc.Preparation of drug combination mode of the present invention is that those of ordinary skill in the art is known. According to pharmaceutical composition of the present invention, preferably be made into tablet or capsule, each sheet tablet or each capsules contain the dihydroarteannuin of 20-80mg. Pharmaceutical composition of the present invention is generally oral administration, also can for example treat light sensitive dermatoses and can use external preparation through other administrations.Consumption is generally the 1-5mg/kg body weight/day. Pharmaceutical composition of the present invention can use separately.When the heavier systemic lupus erythematosus (sle) of treatment symptom, also can with the other drug of existing treatment lupus erythematosus and photosensitive diseases, for example Chang Yong hormone medicine is used in combination. The preparation method of the dihydroarteannuin that the present invention uses is known.Relevant its preparation method is seen in bibliographical information. Below example further illustrates the present invention by experiment.But it should be understood that experimental example of the present invention just is used for explanation rather than restriction the present invention.Pharmacodynamic experiment... https://patents.google.com/patent/CN1116036C/en?oq=CN1116036C一种治疗酒渣鼻及光敏性疾病的含双氢青蒿素的药物组合物---含有双氢青蒿素药物组合物是治疗红斑狼疮和光敏性疾病的有效药物

CN1105722C含氮杂环自由基的青蒿素衍生物及其制备方法---该衍生物具有抗原虫、抗癌、调节免疫、抗炎、杀虫等作用 CN1105722C Artemisinin derivatives containing nitrogen heterocyclic free radicals and preparation methods thereof---The derivative exhibits anti-parasitic, anti-cancer, immunomodulatory, anti-inflammatory, and insecticidal effects. 含氮杂环基的青蒿素衍生物及其制备方法 一类含氮杂环基的青蒿素衍生物及其制备方法：它们可由乙酰二氢青蒿素(或三氟乙酰二氢青蒿素，次甲基青蒿素，二氢青蒿素，β-溴代蒿乙醚，2，3-环氧蒿丙醚)与氮杂环化合物(或含有羧基的氮杂环化合物，含有羟基的氮杂环化合物)反应生成。经初步药理筛选，发现它们具有抗原虫，抗癌，免疫调节，抗炎，杀虫等作用。 含氮杂环基的青蒿素衍生物及其制备方法 本发明涉及稠环系含有氮原子作为杂环原子的杂环化合物，具体说是含有氮杂环基的青蒿素衍生物及其制备方法。 青蒿素是中药青蒿(植物黄花蒿Artemisia annua L)的抗疟有效成份，有治疗抗药性疟疾和速效、低毒的特点。国内外科学家制备了大量青蒿素的衍生物，其中含氮杂环基的青蒿素衍生物有如下报导：(一)式中，... https://patents.google.com/patent/CN1105722C/zh?oq=CN1105722C含氮杂环自由基的青蒿素衍生物及其制备方法---该衍生物具有抗原虫、抗癌、调节免疫、抗炎、杀虫等作用 Arteannuin derivant containing azacyclic radical and preparation process thereof The present invention relates to arteannuin derivatives containing nitrogen heterocyclic groups and a preparing method thereof. The derivatives can be generated by the reaction of acetyl dihydroarteannuin (or trifluoroacetyl dihydroarteannuin, methenyl arteannuin, dihydroarteannuin, beta-bromoarteether and 2, 3-epoxyartemisic propyl ether) and a nitrogen heterocyclic compound (or a nitrogen heterocyclic compound containing carboxyl or a nitrogen heterocyclic compound containing hydroxyl). Primary pharmacological screening tests find that the derivatives have functions of resisting protozoons and cancer, regulating immunity, resisting inflammation, killing insects, etc. Artemisinin derivative of nitrogen heterocycle and preparation method thereof The present invention relates to condensed ring system and contain the heterogeneous ring compound of nitrogen-atoms as heterocyclic atom, is artemisinin derivative that contains Azacyclyl and preparation method thereof specifically. Artemisinin is the antimalarial effective ingredient of Chinese medicine sweet wormwood (plant Artemisia annua Artemisia annua L), and treatment resistant malaria and characteristics quick-acting, low toxicity are arranged.Scientist has prepared the derivative of a large amount of Artemisinins both at home and abroad, and wherein the artemisinin derivative of nitrogen heterocycle has following report: (1) in the formula,... https://patents.google.com/patent/CN1105722C/en?oq=CN1105722C含氮杂环自由基的青蒿素衍生物及其制备方法---该衍生物具有抗原虫、抗癌、调节免疫、抗炎、杀虫等作用