PHASE I/II STUDY OF OLTIPRAZ IN HIV INFECTED PATIENTS

这项转化研究是建立在一系列发现的基础上， 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， 体内谷胱甘肽浓度和宿主体内谷胱甘肽浓度的同时增加 器官谷胱甘肽浓度。 他的同事托马斯肯斯勒博士和 Paul Talalay研究了oltipraz作为癌症化学预防剂， 增加宿主细胞谷胱甘肽浓度的能力。 汉斯 普罗查斯卡是保罗·塔拉雷博士的前研究生， 我们项目的关键发现（再次基于 oltipraz增加细胞中的谷胱甘肽和其他人的观察 HIV感染者已经耗尽了谷胱甘肽储存）， oltipraz在体外细胞中抑制HIV复制， 在急性感染细胞和慢性感染细胞中均发生抑制 细胞，这种酶被不可逆地抑制， 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的细胞。 这些显着的发现表明母体药物作为一种药物具有活性 HIV逆转录酶的不可逆抑制剂， 是一些转录事件的不可逆抑制剂， 病毒的生命周期到前病毒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抗病毒药物降低>50% 在人类中以毒性方面可接受的剂量进行抗血药试验。 24例筛选p24抗原血症>50的HIV感染受试者 pg/ml随机分为三组。 一组6人， 安慰剂组和另外两组9人接受125 mg奥替普拉q.d. 或500毫克。oltipraz每周一次p.o.作为住院病人在我们的 成人住院GCRC和另外两周的门诊患者 在我们的成人门诊GCRC中。 这项研究是双盲的， 在完成所有病例报告和所有临床 做出的决定 研究的临床部分于1996年11月完成。 的 主要终点数据，即，p24抗原血症，于1月完成 1997年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 药物和代谢物水平仍然很高

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 glutatbione 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 antigemia 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 two 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.