PHASE I/II STUDY OF OLTIPRAZ IN HIV INFECTED INDIVIDUALS

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 Kenalor和Paul Talalay研究了oltipraz作为癌症化疗药物， 基于其增加宿主细胞谷胱甘肽的能力的预防剂 浓度的 汉斯·普罗查斯卡博士，博士的前研究生。 保罗塔拉雷的，为我们的项目作出了关键的发现（再次 基于奥替普拉增加细胞中谷胱甘肽的能力， 根据其他人的观察，艾滋病毒感染者 通过显示奥替普拉抑制HIV复制 在体外细胞中，这种抑制作用发生在急性感染的 细胞和慢性感染细胞，这种酶是不可逆的 抑制，并且特定代谢产物优先抑制 慢性感染的细胞，而母体药物优先 抑制急性感染细胞。 这些显著的发现表明， 母体药物作为HIV的不可逆抑制剂具有活性， 而代谢物是不可逆的抑制剂 在病毒生命周期中的一些转录事件， 前病毒DNA的整合。 我们的研究说明了主题发现转化为一个 有效开展并严格实施了1/11期研究， 提供了一个“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感染者，筛查p24抗原基因组为 >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， 在我们的成人门诊GCRC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 antiganamia，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。

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 Kenalor and Paul Talalay have studied oltipraz as a cancer chemo- proventive 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 an 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 transcriptane 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 theme discoveries into an efficiently performed and rigorously conducted Phase 1/11 study that serves an 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 antigenomia 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 antiganamia, were completed in January of 1997, along with quantitative cultures and the plasma glutathionine-S-transferase levels.