PHASE I/II STUDY OF OLTIPRAZ IN HIV INFECTED PATIENTS

奥替拉唑治疗 HIV 感染患者的 I/II 期研究

• 批准号: 6245480
• 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/6245480
• 关键词: AIDS therapy; HIV infections; antiprotozoal agents; clinical research; clinical trial phase I; human subject; 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 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.

这项翻译研究是建立在一系列发现的 约翰·霍普金斯医疗机构。 已故的欧内斯特博士发现 那个oltipraz作为一种抗距离剂，导致 血吸虫的谷胱甘肽浓度和宿主同时增加 器官谷胱甘肽浓度。 他的同事，博士。托马斯·肯斯勒（Thomas Kensler）和 保罗·塔拉莱（Paul Talalay）研究了oltipraz作为癌症化学预防剂的基础 关于它增加宿主细胞谷胱甘肽浓度的能力。 汉斯博士 Prochaska是Paul Talalay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观察 艾滋病毒感染的患者通过显示出来的谷胱甘肽商店耗尽） Oltipraz抑制了细胞中细胞中的HIV复制，这就是 抑制作用发生在急性感染的细胞和慢性感染 细胞，该酶不可逆地抑制 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。 这些了不起的发现表明，母体药物是活跃的 HIV逆转录酶的不可逆抑制剂，而代谢产物 是随后发生的某些转录事件的不可逆抑制剂 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抗病毒降低> 50％的抗HIV活性 人类的抗血症以毒性可接受的剂量。 二十四名HIV感染受试者，筛查P24抗原血症> 50 PG/mL被随机分配给三组。 一组6组收到 安慰剂和其他9组收到了125毫克Oltipraz Q.D. 或500毫克。 Oltipraz每周一次在我们的住院病人2周中 成人住院GCRC，另外两周作为门诊患者 在我们的成人门诊GCRC中。 这项研究是双盲的，盲目的 直到所有病例报告都完成和所有临床 做出的决定。 该研究的临床部分于1996年11月完成。 一月份完成了主要终点数据，即P24抗原血症 1997年的定量培养物和血浆谷胱甘肽-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出色。