STUDIES OF HEMOLYTIC ANEMIA
溶血性贫血的研究
基本信息
- 批准号:3341062
- 负责人:
- 金额:$ 14.2万
- 依托单位:
- 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 1988-06-30
- 项目状态:已结题
- 来源:
- 关键词:aniline blood toxicology covalent bond dapsone dosage drug adverse effect drug design /synthesis /production drug metabolism erythrocytes glucose 6 phosphate dehydrogenase deficiency hemolysis hemolytic anemia hemotoxin high performance liquid chromatography membrane lipids methemoglobin primaquine radiation detector radiotracer scintillation spectrometry spectrometry stainings stoichiometry thin layer chromatography toxicant interaction toxin metabolism
项目摘要
Approximately 10% of Black American males experience hemolytic anemia after
exposure to aniline and aniline-related drugs and environmental chemicals.
Enhanced sensitivity is also seen in Americans of Mediterranean decent
(Italian, Greek, Lebanese, etc.), where the hemolytic episode may be
life-threatening. Extensive studies in the 1950's and 1960's revealed that
sensitivity is associated with a relative deficiency of erythrocyte
glucose-6-phosphate dehydrogenase (G6-PD) and led to the concept that
injury resulted from oxidative stress induced by metabolite(s) of aniline
and related compounds. However, the hemolytic metabolite(s) were not
identified and little is known as to their interaction with the RBC. Our
long term objective is to determine the toxicological mechanisms underlying
drug-induced hemolytic anemia. We have developed an animal model that
shows a dose-dependent hemolytic anemia after aniline or dapsone. The
hemolytic response appears to be similar to that of man. We have
identified a metabolite of aniline (pnenylhydroxylamine), which is a) about
15 x more potent than aniline, and b) a direct acting hemotoxin, and hence
may be solely responsible for the hemolytic anemia sen after aniline. The
objectives of the present phase of the studies are a) to identify the
hemolytic metabolites of aniline, phenacetin, dapsone, and primaquine; b)
to identify the metabolic events which determine the formation and delivery
of the ultimate toxins to the red cell and the relationship between
delivery and response; and c) to examine the relevance of concepts
developed in vitro with phenylhydrazine and other hematotoxins for the in
vivo drug-induced hemotoxicity. The initial mechanism studies proposed
here will begin to assess the metabolic basis for the dose/response curves,
the significance of methemoglobin formation in the hemolytic sequence, and
whether hemoglobin and/or the cell membrane can be eliminated as molecular
targets for phenylhydroxylamine and related hemolytic drug metabolites. It
is expected that these studies will provide the basis for a detailed
toxicological assessment of the role of drug metabolism in drug-induced
hemolytic anemia and further our understanding of mechanisms underlying
this type of red cell injury in vivo.
大约10%的美国黑人男性在死后经历溶血性贫血
接触到苯胺及与苯胺有关的药物和环境化学品。
地中海正派的美国人也表现出更强的敏感性
(意大利语、希腊语、黎巴嫩语等),溶血事件可能在哪里
有生命危险。对1950年的S和1960年的S的广泛研究表明,
敏感度与红细胞相对不足有关
葡萄糖-6-磷酸脱氢酶(G6-PD),并导致了
苯胺代谢物S所致氧化应激损伤
以及相关化合物。然而,溶血代谢物(S)不是
但对它们与红细胞的相互作用却知之甚少。我们的
长期目标是确定潜在的毒理学机制
药物引起的溶血性贫血。我们已经开发出一种动物模型,
显示在苯胺或氨苯砜后出现剂量依赖性溶血性贫血。这个
溶血反应似乎与人类相似。我们有
鉴定了一种苯胺的代谢物(对苯羟胺),这是一种约
15倍于苯胺的效力,以及b)直接作用的血球毒素,因此
可能是苯丙胺后发生溶血性贫血的唯一原因。这个
本阶段研究的目标是:a)确定
苯胺、非那西丁、氨苯砜和伯喹的溶血代谢物;b)
以确定决定形成和传递的代谢事件
终极毒素对红细胞的影响及其与
交付和回应;以及c)审查概念的相关性
用苯肼和其他血毒素体外开发用于体内的
体内药物引起的血液毒性。初步机制研究建议
这里将开始评估剂量/反应曲线的代谢基础,
高铁血红蛋白形成在溶血序列中的意义,以及
是否可以将血红蛋白和/或细胞膜作为分子消除
苯羟胺和相关溶血药物代谢物的靶标。它
预计这些研究将为制定详细的
药物代谢在药物诱导中作用的毒理学评价
溶血性贫血及其发病机制的进一步认识
这种类型的红细胞在体内受到损伤。
项目成果
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