ANTITUMOR THERAPY, ANTIEMETICS AND BRAIN RECEPTORS

恶心和呕吐是患者常见且严重的毒性反应。 接受癌症化疗。关于这方面的信息很少 化疗所致呕吐的分子机制 其治疗的药理学。药物引起的恶心和呕吐被认为是 主要通过呕吐性抗肿瘤药物与 化学感受器触发区(最后区)中的多巴胺能受体 大脑。已知止吐剂的主要类别为吩噻嗪。 结合并拮抗大脑中的多巴胺受体。长期的 这项建议的目标是：1)确定人类的受体类型 化学感受器触发区和呕吐中枢以及呕吐的相互作用 使用多巴胺放射性配基结合技术与这些受体结合的药物， 以及2)更有效地使用吩噻嗪作为止吐剂 通过研究这些药物的药代动力学、毒性和疗效 病人体内的药剂。该提案的具体目的是将 用放射性配基研究化学感受器触发区的多巴胺受体 结合技术，以确定是否有其他受体 人类化学感受器触发区和呕吐中心的类型 合适的放射性配基结合分析，以表征相互作用 具有这些受体类型的呕吐型抗肿瘤药物，以表征 汉防己甲素口服给药后的药代动力学 治疗恶心呕吐，并研究其毒性、疗效和安全性。 抗呕吐药吩噻嗪在AS患者体内的药代动力学 给药剂量和给药程序的功能。的主要方法论 这些研究将是放射性配基结合分析，它提供了 确定大脑区域的受体类型，确定呕吐剂是否具有抗肿瘤作用 药物与这些受体相互作用，并提供一种定量检测 生物样品中低浓度吩噻嗪的测定 体液。这些研究的结果有望提供更好的 对呕吐及其预防的认识是新建筑设计的理论基础 止吐化疗的方法，以及更难用的 吩噻嗪止吐剂。

Nausea and vomiting are frequent and serious toxicities in patients receiving cancer chemotherapy. There is little information available on the molecular mechanisms of chemotherapy induced emesis or in the pharmacology of its treatment. Drug-induced nausea and vomiting is thought to occur primarily via interaction of emetic antitumor agents with dopaminergic receptors in the chemoreceptor trigger zone (area postrema) of the brain. The major class of antiemetic agents, phenothiazines, are known to bind to and antagonize dopamine receptors in the brain. The long-term goals of this proposal are: 1) to characterize receptor types in the human chemoreceptor trigger zone and emetic center, and the interaction of emetic agents with these receptors using dopamine radioligand binding techniques, and 2) to provide more efficacious use of phenothiazines as antiemetic agents by studying the pharmacokinetics, toxicity and efficacy of these agents in patients. The specific aims of the proposal are to characterize dopamine receptors in the chemoreceptor trigger zone using radioligand binding techniques, to determine the presence or absence of other receptor types in the human chemoreceptor trigger zone and emetic center using appropriate radioligand binding assay, to characterize the interaction of emetic antitumor agents with these receptor types, to characterize the pharmacokinetics of phenothiazines following oral administration for the treatment of nausea and vomiting and to study the toxicity, efficacy, and pharmacokinetics of phenothiazines as antiemetic agents in patients as a function of dose and schedule of administration. The major methodology in these studies will be radioligand binding assays which provide the means to characterize receptor types in brain regions, determine if emetic antitumor agents interact with these receptors, and provide a quantitative assay for the determination of low concentrations of phenothiazines in biological fluids. Results of these studies will hopefully provide a better understanding of emesis and its prevention, a rationale for design of new approaches to antiemetic chemotherapy, and more dfficacious use of phenothiazine antiemetic agents.