TREATMENT OF AIDS VACUOLAR MYELOPATHY WITH METHIONINE

蛋氨酸治疗艾滋病空泡性脊髓病

• 批准号: 6448561
• 负责人: Alessandro DiRocco
• 金额: $ 8.57万
• 依托单位: BETH ISRAEL MEDICAL CTR (NEW YORK)
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6448561
• 关键词: AIDS therapy; HIV infections; S adenosylmethionine; aminoacid metabolism; clinical research; clinical trials; human subject; human therapy evaluation; methionine; methylation; myelin basic proteins; myelinopathy; nervous system disorder chemotherapy; neuropsychological tests; spinal cord disorders; vitamin B12

White matter vacuolization of the spinal cord is present in approximately 30 percent of patients with AIDS. The vacuolization is progressive, and a significant number of patients develop symptoms of myelopathy. In the later stages of the disease, AIDS-associated vacuolar myelopathy (VM) may lead to severe spastic paraparesis and incontinence. Its pathogenesis is unknown, probably related to metabolic abnormalities rather than caused by direct HIV infection. Abnormal metabolism of the B-12 dependent trans-methylation pathway may play an important role in the pathogenesis of VM. Hypomethylation of myelin basic protein is considered responsible for the spinal cord vacuolization in vitamin B-12 deficiency. Vacuolization of the spinal cord indistinguishable from the AIDS associated VM and the myelopathy of vitamin B12 deficiency is present in other toxic and metabolic diseases affecting trans-methylation, and can be induced experimentally by interfering with the production of methionine or its active metabolite S-adenosyl-methionine (SAM). HIV infection and cytokine activation may lead to decreased production and increased consumption of methionine and SAM. Based on the hypothesis that VM is related to abnormal methionine metabolism, and our pilot data suggesting beneficial effect of methionine treatment in VM, we are conducting a double-blind, placebo-controlled clinical trial with methionine 6g/day vs. placebo. The trial has an enrollment goal of 50 patients. In the three years since the beginning of the study, we have enrolled 40 patients. In this revised competitive renewal application we present progress data on the clinical trial and baseline clinical and biochemical observations. In particular, we report severe reduction of CSF levels of SAM in patients with VM compared to HIV- and HIV+ non myelopathic controls, offering additional evidence for a metabolic disorder in the pathogenesis of VM. We request to complete the clinical trial and the metabolic observations of the study.

大约30％的艾滋病患者中存在脊髓的白质真空化。 液泡是进行的，大量患者会出现骨髓病的症状。 在该疾病的后期，与艾滋病相关的液泡骨髓病（VM）可能导致严重的痉挛性麻痹和尿失禁。 它的发病机理未知，可能与代谢异常有关，而不是由直接HIV感染引起。 B-12依赖性反甲基化途径的异常代谢可能在VM发病机理中起重要作用。 髓磷脂碱性蛋白的低甲基化被认为是维生素B-12缺乏症的脊髓液泡的原因。 脊髓与相关的VM无法区分的脊髓和维生素B12缺乏症的骨髓病没有区别，在影响反甲基化的其他有毒和代谢性疾病中存在，可以通过干扰甲基氨酸或其活性代谢物s-亚adenenosymethionine（Sam）来实验引起。 HIV感染和细胞因子激活可能会导致蛋氨酸和SAM的产生和消耗量增加。基于VM与异常的蛋氨酸代谢有关的假设，以及我们的试验数据表明蛋氨酸治疗在VM中的有益效果，我们正在对甲硫酸甲氨酸6G/天/天进行双盲，安慰剂对照临床试验。 该试验的入学目标是50名患者。 自从研究开始以来的三年中，我们已经招募了40名患者。 在此修订后的竞争更新应用中，我们介绍了临床试验以及基线临床和生化观察的进度数据。 特别是，我们报告说，与HIV和HIV+非骨髓性对照相比，VM患者的CSF水平严重降低了SAM水平，为VM发病机理提供了代谢性疾病的其他证据。 我们要求完成该研究的临床试验和代谢观察结果。