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HEMOLYTIC ANEMIA STUDIES OF HEMOLYTIC ANEMIA

溶血性贫血溶血性贫血的研究

基本信息

批准号：
2735074
负责人：
DAVID J. JOLLOW
金额：
$ 24.74万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-07-01 至 2001-06-30
项目状态：
已结题

项目摘要

The clinical use of dapsone has expanded over the last decade. Dapsone is now the drug of choice for certain autoimmune-associated disorders such as dermatitis herpetiformis, and is an important component of prophylaxis and chemotherapy for opportunistic infections, such as P. carnii pneumonia, in AIDS patients. In both situations, dapsone's hemotoxicity; viz, methemoglobinemia and hemolytic anemia, are dose limiting in therapy. Over the life of this grant, we have used a rat model to identify the hemotoxic metabolites (N-hydroxydapsone [DDS-NOH] and N-acetyl-N-hydroxydapsone [MADDS-NOH]) of the drug and to gain insight into the mechanism underlying the hemolytic response. We now propose to test the hypothesis that the insight gained with the rat model can be used to reduce the severity of dapsone-induced hemotoxicity in humans and hence improve the therapeutic ratio of the drug. Four aims are presented. The first will examine whether the mechanistic concepts developed with rat red cells applies to human cells, and if so, the relative responsiveness of human vs rat red cells. Parameters to be examined include heme oxidation (methemoglobin formation); oxy- and/or thiyl-radical production; glutathione and protein mixed disulfide formation (G-SS-G and Pr-SS-G); formation of hemoglobin- skeletal protein adducts and of other membrane-bound hemoglobin monomers and polymers; echinocyte formation; and susceptibility to macrophage ingestion. The second aim will characterize the effect of inhibitors of dapsone N-hydroxylation in rat hepatic microsomal preparations and, for selected inhibitors, on dapsone N-hydroxylation in the acute and chronic rat models of dapsone hemotoxicity, as a prelude to the clinical studies. The third aim will determine if the severity of hemotoxicity in volunteers and patients receiving single doses of dapsone can be correlated with blood levels of DDS-NOH+MADDS-NOH, and with their CYP3A4 phenotypic status. The fourth aim will examine she capacity of inhibitors of CYP3A4 (which has been implicated in the N-hydroxylation of dapsone in humans) to suppress both blood DDS-NOH+MADDS-NOH levels and hemotoxicity. Potential inhibitors to be tested include cimetidine, ketaconazole, grapefruit juice, and trimethoprim. Further studies will determine if the extent of binding of hemoglobin monomers and polymers to membrane components can be used to develop a quantitative assay to assess the severity of a hemolytic response occurring in patients during chronic dapsone therapy.

在过去的十年里，氨苯砜的临床应用已经扩大。氨苯砜是现在，治疗某些自身免疫相关疾病的首选药物，如疱疹样皮炎，是预防和治疗疱疹的重要组成部分。化疗治疗机会性感染，如卡氏肺炎艾滋病患者。在这两种情况下，氨苯砜的血液毒性；即，高铁血红蛋白血症和溶血性贫血是治疗中的剂量限制。完毕在这笔赠款的生命中，我们使用了一种老鼠模型来鉴定血液毒素代谢物(N-羟基氨苯砜[DDS-NOH]和N-乙酰-N-羟基氨苯酮 [MADDS-NOH])，并深入了解其潜在的机制溶血反应。我们现在建议检验这样的假设通过大鼠模型获得的洞察力可以用来降低氨苯砜对人体的血液毒性，从而提高治疗效果药物的比例。提出了四个目标。第一个将检查是否用大鼠红细胞发展出来的机械概念适用于人类细胞，如果是这样的话，人与大鼠红细胞的相对反应性。要检查的参数包括血红素氧化(高铁血红蛋白形成)；氧和/或硫基自由基的产生；谷胱甘肽和蛋白质混合二硫键形成(G-SS-G和Pr-SS-G)；骨骼蛋白加合物和其他膜结合的血红蛋白单体和聚合物；棘细胞形成；巨噬细胞易感性摄取。第二个目标将描述抑制剂的作用。氨苯砜N-羟化在大鼠肝微粒体制剂中的作用急性和慢性氨苯砜N-羟化作用的选择性抑制剂氨苯砜血液毒性大鼠模型，作为临床研究的前奏。第三个目标将确定志愿者血液毒性的严重程度而接受单剂量氨苯砜治疗的患者可以与 DDS-NOH+MADDS-NOH的血液水平及其与细胞色素P3A4表型的关系状态。第四个目标是检测细胞色素P3A4抑制剂的抑制能力。 (这与人体内氨苯砜的N-羟基化有关) 抑制血液DDS-NOH+MADDS-NOH水平和血液毒性。潜力待检测的抑制剂包括西咪替丁、酮康唑、葡萄柚果汁和甲氧苄氨嘧啶。进一步的研究将确定是否会有血红蛋白单体和聚合物与膜组件的结合可以是用于建立一种定量分析方法来评估溶血的严重程度氨苯砜慢性治疗过程中患者的反应。