PHASE I STUDIES OF THE DDC AS A SINGLE AGENT OR WITH AZT

DDC 作为单一药物或与 AZT 联合使用的 I 期研究

• 批准号: 3874499
• 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/3874499
• 关键词: AIDS; AIDS therapy; antiAIDS agent; antiviral agents; blood brain barrier; clinical trials; combination chemotherapy; deoxycytidine; drug adverse effect; drug design /synthesis /production; human immunodeficiency virus 1; human subject; human therapy evaluation; leukopenia; nucleoside analog; thrombocytopenia; tissue /cell culture; virus antigen; zidovudine; AIDS; AIDS therapy; antiAIDS agent; antiviral agents; blood brain barrier; clinical trials; combination chemotherapy; deoxycytidine; drug adverse effect; drug design /synthesis /production; human immunodeficiency virus 1; human subject; human therapy evaluation; leukopenia; nucleoside analog; thrombocytopenia; tissue /cell culture; virus antigen; zidovudine

In previous annual reports, the first development of anti-retroviral drugs belonging to the dideoxynucleoside family was outlined. One such drug (AZT) has now achieved prescription status. Two others, ddC and ddA, have continued in our development effort. The goal is to find drugs which, alone or in combination, have a better therapeutic index than AZT alone. In a Phase I dose-seeking trial, we administered 5 dose regimens of 2',3'-dideoxycytidine (ddC), a cytidine analogue with potent in vitro activity against human immunodeficiency virus (HIV) which had never previously been given to man, to 20 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). ddC was administered intravenously for 2 weeks and then orally for 4 or more weeks. ddC was well absorbed from the gut and crossed the bloodbrain barrier in these patients. Ten of the 15 patients who received 0.03mg/kg to 0.09 mg/kg ddC every 4 hrs had increases in their absolute number of T4(+) cells at week 2 (p<0.05); in many of the patients, however, these rises were not sustained. Eleven of 13 evaluable patients had a fall in their serum HIV p24 antigen by week 2 of therapy (p<0.01); in a few patients, the p24 antigen subsequently rose to baseline while in most the decline was sustained. Dose related toxiciteis included a transient symptom complex of cutaneous eruptions, fever, and mouth sores; thrombocytopenia; and neutropenia. A late toxicity appearing after 6 to 14 weeks on ddC was reversible painful peripheral neuropathy. These results suggest that ddC has activity against HIV in vivo and has a different toxicity profile than 3'-azido-2',3'-dideoxythymidine (AZT). Based on these different toxicity profiles, we subsequently administered a regimen of AZT (200 mg orally every 4 hrs for 7 days) alternating with ddC (0.03 mg/kg every 4 hrs for 7 days) as a feasibility study. The regimen appears active and has less toxicity than either agent alone. Some patients have taken this combination for 3 years.

在先前的年度报告中，抗逆转录病毒药物的首次发展 概述了属于二乙基核苷家族。一种这样的药物（AZT） 现在已经达到了处方状态。 DDC和DDA的另外两个 继续我们的发展工作。目的是找到一个独自一人的药物 或结合使用，与仅AZT相比，具有更好的治疗指数。在 第一阶段寻求剂量试验，我们管理了5剂治疗方案 2'，3'-二氧辛丁丁（DDC），一种具有有效体外的胞苷类似物 针对人类免疫缺陷病毒（HIV）的活性 先前已将其给予20例获得免疫缺陷的患者 综合征（AIDS）或与AIDS相关的复合物（ARC）。 DDC被管理 静脉注射2周，然后口服4个或更长时间。 DDC很好 从肠道中吸收并越过这些患者的血脑屏障。 在接受0.03mg/kg至0.09 mg/kg DDC的15例患者中，有10名每4小时 第2周的T4（+）细胞的绝对数量增加（p <0.05）； 但是，在许多患者中，这些升高并未持续。十一人 13个可评估的患者到第2周的血清HIV P24抗原的血清HIV P24抗原下降 治疗（p <0.01）;在一些患者中，p24抗原随后上升 在大多数下降中持续下降的基线。剂量相关 毒性包括皮肤喷发的短暂症状复合物， 发烧和口疮；血小板减少症；和中性粒细胞减少。晚期毒性 在DDC上6至14周后出现是可逆的疼痛外围 神经病。这些结果表明DDC在体内具有针对HIV的活性 并且具有与3'-azido-2'，3'-二氧甲酰胺的毒性特征不同的毒性特征 （AZT）。基于这些不同的毒性特征，我们随后 管理AZT方案（每4小时口服200 mg，持续7天） 与DDC交替（每4小时每4小时每4小时）交替使用可行性 学习。该方案显得活跃，毒性较少 独自的。一些患者将这种组合持续了3年。