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.

这项转化研究是建立在一系列发现的基础上的， 在约翰霍普金斯医疗机构。 已故的欧内斯特·布丁博士 发现奥替普拉作为一种抗溶酶体药物， 同时增加了谷胱甘肽的浓度 在宿主器官谷胱甘肽浓度。 他的同事托马斯博士 Kensler和Paul Talalay将奥替普拉作为癌症进行了研究 基于其增加宿主细胞的能力的化学预防剂 谷胱甘肽浓度。 汉斯·普罗查斯卡博士， 保罗·塔拉雷博士的学生，为我们的研究做出了关键性的发现。 项目（再次基于奥替普拉增加谷胱甘肽的能力 以及其他人观察到的艾滋病毒感染者 已耗尽谷胱甘肽储存），显示奥替普拉抑制艾滋病毒 在体外细胞中复制，这种抑制发生在两个 急性感染细胞和慢性感染细胞，这种酶 被不可逆地抑制了，一种特定的代谢产物 优先抑制慢性感染细胞，而母体药物 优先抑制急性感染细胞。 这些非凡 研究结果表明，母体药物具有不可逆的活性， HIV逆转录酶的抑制剂，而代谢物是 一些转录事件的不可逆抑制剂， 病毒生命周期到前病毒DNA的整合。 我们的研究说明了这些发现转化为 有效执行并严格进行I/II期研究， 作为一个“原理证明”的研究，以解决假设， oltipraz具有抗HIV活性，定义为p24下降>50% 抗病毒抗原血症在人类中的剂量是可接受的， 关于毒性。 24例HIV感染受试者，筛查时p24抗原血症为 >50 pg/ml随机分为三组。 一组6人 接受安慰剂，另外两组9人接受125 mg 奥替普拉或500毫克。oltipraz每周一次p.o.两个星期， 我们的成人住院GCRC的住院患者和额外的2周， 我们的成人门诊GCRC的门诊患者。 这项研究是双重的- 设盲，在所有病例报告完成后才揭盲。 完成所有临床决策。 研究的临床部分于1996年11月完成。 主要终点数据，即。p24抗原血症，完成于 1997年1月，沿着定量培养和血浆 谷胱甘肽-S-转移酶水平。 血浆和红细胞 谷胱甘肽水平和药物和代谢物水平仍然是 非常出色。