EVALUATION OF PROTEIN BASED MEDICATIONS AGAINST COCAINE

描述：(申请人摘要)在治疗中有用的药物疗法 事实证明，可卡因滥用的罪魁祸首很难确定。传统的 受体拮抗剂的方法似乎不适合可卡因作为 原因有很多。这项建议旨在评估五种基于蛋白质的 可能有效地阻断行为和毒性影响的药物 可卡因。这些药物中有三种是已经提出的抗体 在小鼠身上对抗可卡因。第四种药物是丁酰胆碱酯酶， 分解血液中可卡因的酶。第五种药物是一种小说 催化抗体，单抗15A10，可结合结合和 新陈代谢。这些药物中的每一种都被认为是为了降低发病率。 可卡因进入大脑，要么通过隔离过程，要么通过 快速崩溃的过程，或者两者兼而有之。大脑入侵率的下降 应该同时降低可卡因的毒性和滥用责任。这个测试 毒性的程序包括评估几种剂量的 这些药物中的每一种都可以阻止可卡因引起的血压升高 老鼠和老鼠。作为对照，一种结构和作用类似于 可卡因，但没有BChE和Mab 15A10作用的酯桥，将是 与可卡因平行评估。可卡因拮抗的持续时间，a 一种药物的关键方面，将使用血压进行评估 在小鼠身上进行试验。治疗可卡因滥用的测试程序是 大鼠静脉注射给药的研究。这里也是，剂量-反应曲线 可卡因和Win 35065将被确立，并试图改变这些 向右的曲线将与五个管理每一个一起绘制 药物。BChE和Mab 15A10产生能力的研究 增加可卡因代谢物蛋氨酸甲酯的计划是 证明这两种药物都会增加可卡因的比率 新陈代谢。

DESCRIPTION: (Applicant's Abstract) Pharmacotherapies useful in the treatment of cocaine abuse have proven very difficult to identify. The traditional receptor antagonist approach does not appear appropriate for cocaine for a number of reasons. This proposal is designed to evaluate five protein-based medications that may be effective in blocking the behavioral and toxic effects of cocaine. Three of these medications are antibodies that have been raised against cocaine in mice. A fourth medication is butyrylcholinesterase, the enzyme that breaks down cocaine in the blood. The fifth medication is a novel catalytic antibody, Mab 15A10, which may combine the properties of binding and metabolizing. Each of these medications is postulated to act to reduce the rate of cocaine entry into the brain, either by a process of sequestration, or by a process of rapid breakdown, or both. This decrease in rate of brain entry should decrease both the toxicity and the abuse liabililty of cocaine. The test procedures for toxicity involve evaluation of the ability of several doses of each of these medications to block cocaine-induced blood pressure increases in rats and mice. As a control, a drug with a similar structure and action as cocaine, but without the esteratic bridge where BChE and Mab 15A10 act, will be evaluated in parallel with cocaine. The duration of cocaine antagonism, a critical aspect of a medication, will be evaluated using the blood pressure assay in mice. The test procedure for treatment of the abuse of cocaine is intravenous self-administration studies in rats. Here too, dose-response curves with cocaine and WIN 35065 will be established, and attempts to shift these curves to the right will be made with administration of each of the five medications. Studies in which the ability of BChE and Mab 15A10 to produce increases in the cocaine metabolite, egconine methyl ester are planned to demonstrate that both of these medications increase the rate of cocaine metabolism.