ADMINISTRATION OF 2',3'-DIDEOXYINOSINE (DDI) FOR SEVERE HIV INFECTION

2,3-双脱氧肌苷 (DDI) 治疗严重 HIV 感染

• 批准号: 3874491
• 负责人: R YARCHOAN
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874491
• 关键词: AIDS; AIDS dementia complex; AIDS therapy; HIV infections; antiAIDS agent; antiviral agents; clinical trials; dihydroxypropoxymethylguanine; dosage; drug administration routes; drug adverse effect; drug design /synthesis /production; helper T lymphocyte; human immunodeficiency virus; human subject; human therapy evaluation; inosine; nucleoside analog

A Phase I trial of 2',3'-dideoxyadenosine (ddA) was initiated in February of 1988. ddA is a pro-drug of 2',3'-dideoxyinosine (ddI). Whereas ddA is metabolized in the stomach adenine (which can cause renal toxicity). In contrast, ddl is metabolized to hypoxanthine. Thus, ddl appeared to be the preferred form for oral use. With this background, a Phase I trial of ddl was initiated in July of 1988. By July of 1989, it was apparent that: 1) the maximum tolerated dose for long-term therapy was approximately 10 mg/kg/day; 2) doses of 3 of 10 mg/kg were associated with anti-HIV activity; 3) dose-limiting toxicities were painful peripheral neuropathy, pancreatitis and hepatitis; 4) doses of 3 of 10 mg/kg/day were well tolerated in the majority of patients with AIDS or AIDS-related complex and were associated with long-term clinical and laboratory improvement. Based primarily on the results of this study (with supportive evidence from 2 other Phase I studies), 3 Phase II/III trials of ddl, sponsored by the NIAID and Bristol-Myers Squibb Company were launched in October of 1989 in medical centers around the country. In addition, the FDA enabled patients who could not tolerate AZT or had failed AZT to receive ddl under the mechanisms of a Treatment IND or open label protocol, respectively. At present, more than 10,000 patients have received ddl throughout the United States under these protocols. We are continuing to follow our Phase I patients receiving ddl. We have learned that survival can be excellent with this drug - 80% of AIDS patients entered on the study are alive at 20 months. In addition, we have observed that patients with AIDS dementia can have improvement on ddl. Finally, we have observed that patients with extensive prior AZT use have limited CD4 rises on ddl, whereas they do respond with decreases in HIV p24 antigen. We are now exploring the combination of ddl and DHPG (a drug used for retinitis) and ddl used with interferon.

2月启动了2'3'-二氧化丙氨酸（DDA）的I期试验 1988年。DDA是2'，3'-二维氨酸（DDI）的亲药。而DDA是 在胃腺嘌呤中代谢（可能导致肾脏毒性）。在 对比度，DDL代谢为低黄嘌呤。因此，DDL似乎是 首选的口服使用形式。在此背景下，DDL的I期试验 于1988年7月开始。到1989年7月，很明显：1） 长期治疗的最大耐受剂量约为10 mg/kg/day; 2）10 mg/kg中的3剂与抗HIV有关 活动; 3）限制剂量的毒性是疼痛的周围神经病， 胰腺炎和肝炎； 4）10 mg/kg/天的3剂量很好 在大多数患有艾滋病或艾滋病相关复合物的患者中， 与长期临床和实验室改进有关。基于 主要基于这项研究的结果（有2个支持证据 其他I期研究），DDL的3期II/III试验，由 Niaid和Bristol-Myers Squibb Company于1989年10月在 全国各地的医疗中心。此外，FDA启用了患者 谁无法忍受AZT或未能在AZT下接收DDL 治疗IND或开放标签方案的机制。在 目前，整个联合的10,000多名患者已收到DDL 根据这些协议的状态。我们将继续遵循第一阶段 接受DDL的患者。我们了解到生存可以很好地 该药物-80％的艾滋病患者进入研究时还活着20 月份。此外，我们已经观察到患有艾滋病痴呆症患者可以 在DDL上有所改进。最后，我们观察到患有 大量的事先AZT使用的CD4在DDL上的上升有限，而它们确实有限 HIV P24抗原的降低响应。我们现在正在探索 DDL和DHPG（用于视网膜炎的药物）和DDL的组合 干扰素。