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.
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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.
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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。
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.
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