COMPLICATIONS OF HIV DISEASE AGENDA

HIV 疾病议程的并发症

• 批准号: 5205273
• 负责人: Ann Cornwall Collier
• 金额: --
• 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/5205273
• 关键词: AIDS; AIDS therapy; HIV infections; antitubercular agents; biological response modifiers; cachexia; candidiasis; clinical research; comorbidity; cooperative study; cryptosporidiosis; cytomegalovirus; drug resistance; human subject; human therapy evaluation; immunity; medical complication; microorganism disease chemotherapy; opportunistic infections; polymerase chain reaction; secondary infection; tuberculosis; virus load

AIDS patients are widely recognized to be much more susceptible than non- AIDS patients to the side effects of the arylamine antibiotics dapsone (DDS) and sulfamethoxazole (SMX), which are used to treat or protect against Pneumocystis carinii pneumonia (PCP). These arylamines produce a constellation of hematologic (aplastic anemia and methemoglobinemia) and hypersensitivity (fever, rash) reactions which, in AIDS patients, are often severe enough to require withdrawal of the drug, even though PCP is a frequently fatal opportunistic infection in AIDS. The hematologic toxicities can be directly linked to cytochrome P450-dependent oxidation of the arylamine to an arylhydroxylamine, which is further oxidized spontaneously, in a co-oxidation with hemoglobin (in erythrocytes), and possibly by myeloperoxidase (in neutrophils) to a nitroso intermediate, a highly reactive electrophile which covalently binds to proteins producing anemia, neutropenia, and hepatotoxicity, either directly or through an immune mechanism. Intracellular glutathione (GSH) normally affords protection against metabolically-generated electrophiles. However, over the past few years, it has been observed that HIV seropositive individuals are substantially deficient in GSH. Based on these considerations, we propose to: 1) determine in AIDS patients with PCP whether inhibition of cytochrome P450 with cimetidine will inhibit the oxidation of DDS and SMX (using pharmacokinetic techniques), and diminish the toxicity of the arylamines; 2) determine in AIDS patients with PCP whether supplementation of GSH with the precursor N-acetylcysteine will retard the second step in SMX oxidation to the putative toxic electyrophile and diminish toxicity. (This approach is inadvisable for DDS since methemoglobinemia will be promoted); and 3) identify the specific cytochrome P450 isozyme responsible for arylamine N-oxidation in human liver microsomes using specific antibodies and inhibitors, identify a clinically acceptable specific inhibitor in human liver microsomes, and evaluate its effects in vivo as in Specific Aim 1. These studies are linked to existing protocols in the ACTU in which DDS and SMX are administered.

艾滋病患者被广泛认为比非非 - 辅助患者对芳胺抗生素dapsone的副作用 （DDS）和磺胺甲恶唑（SMX），用于治疗或保护 反对肺炎肺炎肺炎肺炎（PCP）。 这些芳胺产生 血液学的星座（性贫血和高铁血红蛋白）和 在艾滋病患者中，高敏性（发烧，皮疹）反应通常是 即使PCP是一个 经常在艾滋病中致命的机会感染。 血液学 毒性可以直接与细胞色素P450依赖性氧化有关 芳基胺至芳羟胺，该芳胺被进一步氧化 自发地与血红蛋白共同氧化（在红细胞中）和 可能是由髓过氧化物酶（在中性粒细胞中）到氮气中间体 高反应性的亲电体，共价与产生蛋白质结合 直接或通过 免疫机制。 细胞内谷胱甘肽（GSH）通常提供 防止代谢生成的电力。 但是，结束了 过去几年，已经观察到HIV血清阳性个体 GSH基本上缺乏。 根据这些考虑，我们 提议：1）在PCP的艾滋病患者中确定是否抑制 用甲苯胺的细胞色素P450将抑制DDS和SMX的氧化 （使用药代动力学技术），并降低 芳胺； 2）确定在PCP的艾滋病患者中是否补充 使用前体N-乙酰半胱氨酸的GSH将延迟第二步 SMX氧化为推定的有毒毒素和毒性降低。 （这种方法对于DDS是不可考虑的 晋升）； 3）确定特定的细胞色素P450同工酶负责 使用特异性 抗体和抑制剂，确定临床上可接受的特异性 人肝微粒体中的抑制剂，并在体内评估其作用 特定目的1。这些研究与ACTU中的现有协议有关 在其中管理DDS和SMX。