PHASE I/II STUDY OF OLTIPRAZ IN HIV INFECTED INDIVIDUALS

这项翻译研究建立在一系列发现的基础上 在约翰·霍普金斯医疗机构。已故的欧内斯特·布丁博士 发现奥替拉兹作为一种抗血吸虫病药物，导致了 在血吸虫体内谷胱甘肽浓度同时增加 寄主器官中谷胱甘肽的浓度。他的同事托马斯博士 Kensler和Paul Talalay将奥替拉兹作为癌症进行了研究 基于其增加宿主细胞能力的化学预防药物 谷胱甘肽浓度。汉斯·普罗查斯卡博士，前毕业生 保罗·塔拉雷博士的学生，为我们的 项目(再次基于奥替拉兹增加谷胱甘肽的能力 在细胞中和其他人观察到的艾滋病毒感染者 已经耗尽了谷胱甘肽存储)通过显示奥替拉兹抑制艾滋病毒 在体外细胞中的复制，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 被不可逆转地抑制了，一种特定的代谢产物 优先抑制慢性感染细胞，而母药 优先抑制急性感染的细胞。这些不同寻常的 研究结果表明，母体药物具有不可逆转的活性。 HIV逆转录酶的抑制剂，而代谢物是 对随后发生的某些转录事件的不可逆抑制作用 病毒生命周期到整合前病毒DNA。 我们的研究说明了这些发现如何转化为 有效执行并严格执行第一阶段/第二阶段研究 作为一项“原则证明”研究，以解决以下假设 奥替拉兹具有抗HIV活性，其定义是在p24中下降50% 抗病毒抗原血症在人类中的剂量是可以接受的 在毒性方面。 24例p24抗原血症筛查的HIV感染者 50 pg/ml随机分为3组。6人一组 接受安慰剂的另外两组9人接受125毫克 奥替普拉兹q.d.或500毫克。奥替普拉兹每周一次。为期2周，作为 在我们的成人住院GCRC中住院的患者和额外的2周 门诊患者在我们的成人门诊GCRC。这项研究是双重的- 盲人和盲人直到所有的案件报告都被 完成并做出所有临床决定。 这项研究的临床部分于1996年11月完成。 主要终点数据，即p24抗原血症，是在#年完成的。 1997年1月，以及定量培养和血浆 谷胱甘肽-S-转移酶水平。血浆和红细胞 谷胱甘肽水平以及药物和代谢物水平仍然 太棒了。

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.