ANTIBODY-BASED THERAPY FOR PHENCYCLIDINE ABUSE

描述：(申请人摘要) 本研究项目的目的是研究其原理和机制。 参与苯环利定(PCP)滥用的抗体治疗。研究 来自本实验室的研究表明，小鼠抗PCP单抗Fab 抗体片段(抗PCP Fab)可逆转PCP诱导的PCP 对大鼠的行为影响。这些研究表明，抗PCP Fab 是一种特定职业的敌手，对几个成员有效 芳基环己胺类药物，并逆转五氯苯酚的毒性 以剂量依赖的方式。此外，反PCP Fab戏剧性地改变了 处置五氯酚，并使五氯酚迅速重新分配到 大脑。接下来的一系列实验将用来检验这种疗法。 在大型动物模型中，狗。这些研究将检验这一假设 抗五氯苯酚Fab以一种可以 由药代动力学/药效学模型预测。因此， 药代动力学研究将检查抗PCP Fab的能力 改变五氯苯酚的处置，行为研究将调查 抗PCP Fab逆转PCP的毒性。公狗和母狗 将在这些研究中被用来确定是否存在犬类性别 治疗上的差异。来自联合药代动力学/ 在大鼠和狗身上的药效学模型将被用于扩大治疗 对人类来说。因此，这些数据应该为 针对其他滥用药物的抗体疗法的发展。

DESCRIPTION: (Applicant's Abstract) The goal of this research project is to study the principles and mechanisms involved in antibody-based therapy for phencyclidine (PCP) abuse. Studies from this laboratory have shown that a murine monoclinal anti-PCP Fab antibody fragment (anti-PCP Fab) is capable of reversing PCP-induced behavioral effects in rats. These studies demonstrate that the anti-PCP Fab is a class-specific antagonist that is effective against several members of the arylcyclohexylamine drug class and that it reverses PCP-induced toxicity in a dose-dependent manner. Also, the anti-PCP Fab dramatically alters the disposition of PCP and produces a rapid redistribution of PCP out of the brain. The next series of experiments will be used to examine the therapy in a large animal model, the dog. These studies will test the hypothesis that the anti-PCP Fab reverses PCP-induced toxicity in a manner that can be predicted by a pharmacokinetic/pharmacodynamic model. Consequently, the pharmacokinetic studies will examine the ability of the anti-PCP Fab to alter the disposition of PCP, and the behavioral studies will investigate the anti-PCP Fab reversal of PCP-induced toxicity. Male and female dogs will be used in these studies to determine if there are any canine sex differences in therapy. Data from the combined pharmacokinetic/ pharmacodynamic models in rats and dogs will be used to scale-up the therapy to humans. Therefore, the data should provide important information for the development of antibody-based therapy for other drugs of abuse.