PHASE I/II STUDY OF OLTIPRAZ IN HIV INFECTED INDIVIDUALS

奥替拉唑在 HIV 感染者中的 I/II 期研究

• 批准号: 6245423
• 负责人: PAUL S LIETMAN
• 金额: $ 2.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-05 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6245423
• 关键词: AIDS therapy; HIV infections; clinical research; clinical trial phase I; human subject; human therapy evaluation; reverse transcriptase inhibitors; thiones

This translational research was built upon a series of discoveries made at The Johns Hopkins Medical Institutions. The late Dr. Ernest Bueding found that oltipraz, as an anti-schistosomal agent, caused a depletion in schistosomal glutathione concentration and a simultaneous increase in host organ glutathione concentration. His colleagues, Drs. Thomas Kensler and Paul Talalay have studied oltipraz as a cancer chemopreventive agent based on its ability to increase host cell glutathione concentrations. Dr. Hans Prochaska, a former graduate student of Dr. Paul Talalay's, made the pivotal discoveries for our project (again based on the ability of oltipraz to increase glutathione in cells and on the observation by others that HIV infected patients have depleted glutathione stores) by showing that oltipraz inhibits HIV replication in cells in vitro, that this inhibition occurs in both acutely infected cells and chronically infected cells, that this enzyme was irreversibly inhibited and that a specific metabolic product preferentially inhibits chronically infected cells while the parent drug preferentially inhibits acutely infected cells. These remarkable findings suggest that the parent drug is active as an irreversible inhibitor of the HIV reverse transcriptase while a metabolite is an irreversible inhibitor of some transcriptional event subsequent in the viral life cycle to integration of the proviral DNA. Our study illustrates the translation of these discoveries into an efficiently performed and rigorously conducted Phase I/II study that serves as a "proof-of-principle" study to address the hypothesis that oltipraz has anti-HIV activity as defined by a >50% fall in p24 antiviral antigenemia in humans at doses that are acceptable with respect to toxicity. Twenty-four HIV-infected subjects with a screening p24 antigenemia of >50 pg/ml were randomly assigned to three groups. One group of 6 received placebo and the other two groups of 9 received either 125 mg oltipraz q.d. or 500 mg. oltipraz once a week p.o. for 2 weeks as inpatients in our adult inpatient GCRC and for 2 additional weeks as ambulatory patients in our adult Outpatient GCRC. The study was double- blinded and the blind was not broken until all case reports had been completed and all clinical decisions made. The clinical portion of the study was completed in November of 1996. The primary end-point data, i,e. p24 antigenemia, were completed in January of 1997, along with quantitative cultures and the plasma glutathionine-S-transferase levels. The plasma and red blood cell glutathionine levels and the drug and metabolite levels are still outstanding.

这项翻译研究建立在一系列发现 在约翰·霍普金斯医疗机构。 已故的欧内斯特博士 发现oltipraz是一种抗雪剂剂，引起了枯竭 在血吸虫的谷胱甘肽浓度和同时增加 在宿主器官谷胱甘肽浓度中。 他的同事，博士。托马斯 Kensler和Paul Talalay研究了Oltipraz作为癌症 化学预防剂基于增加宿主细胞的能力 谷胱甘肽浓度。 汉斯·普拉卡斯卡（Hans Prochaska）博士，曾任毕业生 保罗·塔拉莱（Paul Talalay）博士的学生为我们的 项目（再次基于Oltipraz增加谷胱甘肽的能力 在细胞和其他人的观察中，艾滋病毒感染患者 通过表明oltipraz抑制HIV来耗尽谷胱甘肽商店） 在体外的细胞中复制，这种抑制在两者中都发生 急性感染的细胞和长期感染的细胞，该酶 被不可逆转地抑制和特定的代谢产物 优先抑制长期感染的细胞，而父母 优先抑制急性感染的细胞。 这些了不起的 调查结果表明，父毒药活跃为不可逆的 HIV逆转录酶的抑制剂，而代谢产物是一种 某些转录事件随后发生的不可逆抑制剂 病毒生命周期与病毒DNA的整合。 我们的研究说明了这些发现转化为 有效地执行并严格地进行了I/II期研究 作为“原理证明”研究，以解决以下假设 Oltipraz具有抗HIV活性，如p24降低> 50％ 可以接受 尊重毒性。 二十四名HIV感染受试者，具有筛查的P24抗原血症 > 50 pg/ml被随机分配给三组。 一组6 接受安慰剂，另外两个9组收到了125毫克 Oltipraz Q.D.或500毫克。 Oltipraz每周一次在2周 我们成人住院GCRC的住院患者，再加上2周 我们成人门诊GCRC的卧床患者。 该研究是双重的 盲目，盲人并没有破坏，直到所有病例报告 完成和所有临床决定。 该研究的临床部分于1996年11月完成。 主要终点数据i，e。 p24抗原血症已完成 1997年1月，以及定量文化和等离子体 谷胱甘肽-S-转移酶水平。 血浆和红细胞 谷胱甘肽水平以及药物和代谢物水平仍然是 杰出的。