抗艾滋病药物的研究进展

为了遏止AIDS的迅猛流行 ,降低AIDS的发病和致死 ,针对HIV 1感染的各个环节 ,人们研制出一系列抗病毒药物 ,取得了一些成功的治疗经验 ,提出药物研究的重点方向是 :有多个作用靶点、能作用于感染病毒的细胞、调节机体免疫等。目前正利用丰富的中草药资源 。

应激性心肌病

急性扩张性心肌病临床上较为少见,但是经常会引起危及生命的心血管事件.其临床表现多样,包括心源性休克、室性心律失常、类似急性心肌梗死(AMI)的胸痛,早期诊断时应该注意除外一些潜在的、可逆转的病因,包括心脏毒性物质,例如大量酒精、可卡因、抗逆转录病毒制剂;营养缺乏(维生素B1、硒、肉碱);内分泌紊乱(甲状腺机能减退及亢进);莱姆心肌炎(lymecarditis);超敏性反应(hypersensitivity reactions);围产期疾病;以及心动过速所致的心肌病等[1].新近有人发现一种可能不同于以上情况的急性扩张性心肌病,即应激性心肌病(stress cardiomyopathy)[2].

A convenient synthesis of 1-alkyl-5-amino-6-phenylethyluracils as potential non-nucleoside HIV-1RT inhibitors

1-Alkyl-5-amino-6-phenylethyluracils （1a, 1b） were synthesized as potential non-nucleoside HIV-1RT inhibitors. A convenient synthetic procedure was developed for the preparation of 1-alkyl-5-amino or 5-aminosubstituted-6-phenylethyluracils, which were synthesized in three or four steps from 6-methyluracil in good yield. The development of a one-pot reaction that simultaneously removed the benzyl protection group and reduced the nitro group greatly improved the yield of the synthesis. Compounds 1a and 1b are analogs of MKC-442, which is an efficient inhibitor of HIV-1 reverse transcriptase, 1a and 1b were tested for their inhibition of HIV-1RT, and moderate activity was found for 1a.

医务人员艾滋病病毒职业暴露防护工作指导原则(试行)

根据卫生部2004年1月报告,目前全国HIV感染者已有84万人;据国内外专业人士估计,到2010年,中国感染HIV的人数将会超过1亿。2004年12月1日是第17个“世界艾滋病宣传日”,今年宣传的主题是“关注妇女,抗击艾滋”。护理人员是开展艾滋病健康教育的主力军,同时在工作中又可能会接触到艾滋病病毒,因此掌握艾滋病的相关知识和防护技能尤为重要。本刊特刊登国家卫生部于今年6月颁布的《医务人员艾滋病病毒职业暴露防护工作指导原则(试行)》和1篇对护理人员进行HIV/AIDS教育效果方面的论文,以期对大家的工作有所帮助。

Indinavir Resistance Evolution in One Human Immunodeficiency Virus Type 1 Infected Patient Revealed by Single-Genome Amplification

Human Immunodeficiency Virus Type 1 exists in vivo as quasispecies, and one of the genome's characteristics is its diversity. During the antiretroviral therapy, drug resistance is the main obstacle to effective viral prevention. Understanding the molecular evolution process is fundamental to analyze the mechanism of drug resistance and develop a strategy to minimize resistance. Objective: The molecular evolution of drug resistance of one patient who had received reverse transcriptase inhibitors for a long time and had treatment which replaced Nevirapine with Indinavir was analyzed, with the aim of observing the drug resistance evolution pathway. Methods: The patient, XLF, was followed-up for six successive times. The viral populations were amplified and sequenced by single-genome amplification. All the sequences were submitted to the Stanford HIV Drug Resistance Database for the analysis of genotypic drug resistance. Results: 149 entire protease and 171 entire reverse transcriptase sequences were obtained from these samples, and all sequences were identified as subtype B. Before the patient received Indinavir, the viral population only had some polymorphisms in the protease sequences. After the patient began Indinavir treatment, the variants carrying polymorphisms declined while variants carrying the secondary mutation G73S gained the advantage. As therapy was prolonged, G73S was combined with M46I/L90M to form a resistance pattern M46I/G73S/L90M, which then became the dominant population. 97.9% of variants had the M46I/G73S/L90M pattern at XLF6. During the emergence of protease inhibitors resistance, reverse transcriptase inhibitors resistance maintained high levels. Conclusion: Indinavirresistance evolution was observed by single-genome amplification. During the course of changing the regimen to incorporate Indinavir, the G73S mutation occurred and was combined with M46I/L90M.

中药逆转胃癌多药耐药作用的研究进展

化疗是临床胃癌治疗的主要方式,恶性肿瘤的发展致使多药联合治疗引发了多药耐药,对化疗效果造成巨大负面影响,对抑制癌细胞和维持患者生命造成极大威胁,也是患者预后不良的重要原因之一,因此,选择合理的多药耐药逆转药物制剂已经成为抗癌战线的重要任务之一。中药单体作为目前有效逆转胃癌多药耐药的天然产物制剂,充分发挥药效范围广而强、不良反应小、靶向功能多项化等优点,已经成为现代抗癌药物的主要研究热点。本研究通过查阅分析胃癌方面抗肿瘤多药耐药逆转治疗作用机制,对中药逆转胃癌多药耐药治疗的相关机制进行总结,在所得研究综述的基础上为进一步治疗及新药的研发创新提供依据。

药品

葛兰素史克艾滋病新药在美获批 8月12日，葛兰素史克公司宣布，其研制的Tivicay 50mg片剂在美国获FDA批准上市。据悉，Tivicay为每日一次的口服药物，是HIV整合酶抑制剂，旨在与其他抗逆转录病毒制剂联合用于既往已治疗过、或初冶HIV—1成人和12岁及以上、体重至少40千克的儿童感染者。

预防HIV传播的药物干预

对于HIV感染的治疗现己进行了大量的研究，但在世界范围内仍有14，000人新感染HIV，因此预防新感染的发生仍是很重要的任务。目前，预防HIV感染的手段包括教育和保护措施，如安全套或暴露后给予预防性药物（暴露后预防[PEP]）。未来的选择可能包括暴露前的预防（PREP）的口服抗逆转录病毒制剂、局部的杀微生物制剂及疫苗。在本次大会上，Robert Grant博士总结了目前抗HIV感染化学预防的研究现状。

第十三届国际HIV耐药会议概况

第13届国际HIV耐药会议已于2004年6月8日～12日在西班牙的加拿利群岛举行。与会者对在HIV耐药相关性突变的了解、检测以及临床开发应用方面的进展进行了回顾，同时亦对可供应用与研究的抗逆转录病毒治疗制剂的活性——包括核苷／非核苷类逆转录酶抑制剂、蛋白酶抑制剂(PIs)、整合酶抑制剂、病毒适应性以及治疗预后、HIV耐药研究的最新进展等工作给予肯定。

新型口服抗凝剂治疗患者的临床管理

使用维生素K拮抗剂（VKAs）是抗凝治疗和预防血栓性疾病的传统疗法,但是该疗法的效果个体差异大,容易受食物和药物影响,需要凝血监测。因此,VKAs逐渐被新型口服抗凝剂（NOACs）所代替。目前主要有两类NOACs,它们通过抑制凝血因子Ⅹa（FⅩa）或凝血酶发挥作用[1]。NOACs和VKAs同样有效,且出血并发症发病率更低。

Route improvement of 3-substituted-4-(2-methylcyclohexyloxy)-6-phenethylpyridinone

trans-3-Isopropyl-4-（2-methylcyclohexyloxy）-6-phenethylpyridin-2（1H）-one, as reverse transcriptase （NNRTIs）, exhibited significant potent activity not only against wild-type HIV-1 strains but also on mutant strains. For furthering study this compound, the original synthetic route should be shorten to improve the total yield. In this report, we designed an efficient synthetic strategy to obtain the target compound with higher yield.

Synthesis and anti-HIV-1 activity evaluation of N-1-alkyl-5-halogeno-6-alkylamino uracils as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

N-1-alkyl-5-halogeno-6-alkylamino uracils,which are novel 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine (HEPT) analogues,were synthesized as the selective and potent non-nucleoside human immunodeficiency virus(HIV)-1 reverse transcriptase inhibitors.Some of the compounds showed potent inhibitory activity against HIV-1 reverse transcriptase.For instance,compounds 1d,1m and 1n exhibited potent anti-HTV-1 activity with the IC_(50) values of 13.3,11.7 and 3.15μM,respectively, which are comparable to that of nevirapine(IC_(50) 8.38μM).

Synthesis and biological evaluation of novel 1-aryl-5-iodo-6-benzyluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

We have synthesized the novel compounds 1a-1i,which are a series of hybrid analogues to 6-benzyl-1-（benzyloxymethyl）- 5-iodouracil,a compound showing strong activity against HIV-1.We also evaluated the activity of these compounds as the inhibitors of HIV-1 reverse transcriptase（HIV-1 RT）,and they have demonstrated moderate activity.

Design, synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual(RT/IN) inhibitors

Three series of novel anti-immunodeficiency virus 1 （HIV-1） dual （RT/1N） inhibitors were rationally designed by introducing a functioning diketo acid （DKA） into pyridin-2-one scaffold. To efficiently analyze inhibitory activity, these compounds were screened against HIV-1 RT and IN respectively via surface plasmon resonance （SPR）, and active compounds were subsequently evaluated by enzyme assay. It was noteworthy that compound A2 exhibited moderate activity against both HIV-1 RT and IN. This result provided information for further development of pyridinone analogues as potent dual HIV-1 inhibitors.

Synthesis and biological evaluation of novel 2-arylalkylthio-5-iodo-6-benzyl S-DABOs as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of novel dihydro-alkylthio-benzyl-oxopyrimidines （S-DABOs） 7a-f have been designed and synthesized with an efficient method. Biological evaluation of their HIV-1 reverse transcriptase inhibitory activities was performed using Nevirapine （NVP） as a reference compound. Among the series, compound 7d shows the highest reverse transcriptase inhibitory activity, which is better than Nevirapine.

Pyridin-2(1H)-ones as HIV-1 NNRTIs:a combinatorial optimization strategy

With rapid spread of HIV(human immunodeficiency virus) on a global scale and increasingly severe drug-resistance of it,it is urgently necessary to develop novel effective anti-HIV drugs.Non-nucleoside reverse transcriptase inhibitor(NNRTIs)is one of the most significant antiretroviral drugs for fighting against HIV infection due to their various structures,unique mode of action,good efficacy and low toxicity.Pyridinone derivatives,a type of NNRTIs,have been reported to achieve remarkable development in the past few decades.In this review,we summarized current drug design and medicinal chemistry efforts toward the development of next-generation pyridinones as HIV-1 NNRTIs.

Synthesis and biological evaluation of indeno[1, 2-b]indole derivatives as dual topoisomerase Ⅰ & Ⅱ inhibitors: novel multidrug resistant reversal anticancer agents

A single compound able to inhibit both TopoⅠandⅡmay present the advantage of improving anti-proliferative activity,with reduced toxic side effects,with respect to the combination of two inhibitors.We designed and synthesized 28 compounds of indeno[1,2-b]indole derivatives as a new class of TopoⅠandⅡinhibitor and successfully identified compound 2-3 j,which showed the most potent cell growth inhibition with IC50=0.74μM against HCT-116 cell line.Compound 2-3 j was also evaluated as a potent topoisomeraseⅠandⅡinhibitor and can induce apoptosis in human colon cancer cells.2-3 j showed potency against a small panel of drug sensitive and multidrug resistant(MDR)cell lines,and it reversed the MDR of K562/A02,MCF-7/Adr,and KB/Vcr cells at 0.5μM,with reversal fold values of 3.2,10.1,and 5.8,respectively.2-3 j might inhibit the function of ABCG2 to increase intracellular drug accumulation and enhance the sensitivity of conventional chemotherapeutic agents for MDR cells.2-3 j could be a promising lead for the development of a new class of antitumor drug acting as inhibitors of TopoⅠ&Ⅱand ABCG2.