ANTIBODY-BASED THERAPY FOR METHAMPHETAMINE ABUSE

描述（申请人摘要）： 该项目的长期目标是开发基于抗体的 治疗滥用合成兴奋剂的药物， 甲基苯丙胺（METH）。 治疗是迫切需要的，因为反复使用 这些药物会导致心血管问题，严重的抑郁症， 精神病和暴力行为 这些新药物可以用于 治疗计划的康复成瘾者或在急诊室设置为 迅速逆转药物过量 该提案中的实验是 旨在系统地检验单克隆抗体 (MAb)它们的抗原结合片段（Fab）可用于治疗 一系列与兴奋剂滥用有关的医疗问题。 虽然 最终的目标是选择一种单克隆抗体，可以用于治疗所有的 该项目的主要重点将是 METH. 因此，将选择针对METH的高亲和力MAb， 将在非哺乳动物中产生200-400 g单克隆抗METH IgG 生物反应 在IgG和Fab的生产和纯化后， 临床前试验将开始。 评估抗体用于 治疗成瘾，一个全面的系列研究， 将在大鼠中进行被动免疫（用单克隆IgG） 人类“狂欢”吸毒的模式。 这些研究将包括行为 METH重复给药后免疫治疗的有效性评价 在很长一段时间内。 用于评价抗METH Fab的使用 治疗药物过量，一个综合的系列药代动力学，行为， 各种治疗后的神经化学研究将 进行。 最后，研究了药物的药代动力学和行为效应， 抗METH Fab对METH毒性的影响将在狗中以毒性剂量进行研究。 为将治疗扩大到人类做准备。 这些综合研究 药物代谢动力学，行为和神经化学变化， 基于抗体的治疗将作为一个原型模型， 治疗其他药物滥用的影响。

DESCRIPTION (Applicant's Abstract): The long-term objective of this project is to develop antibody-based medications for the treatment of abuse of synthetic stimulants like methamphetamine (METH). A treatment is badly needed since repeated use of these drugs can lead to cardiovascular problems, severe depression, psychosis, and violent behavior. These new medications could be used in a treatment plan for a recovering addict or in an emergency room setting for rapidly reversing a drug overdose. The experiments in this proposal are designed to systematically test the hypothesis that monoclonal antibodies (MAb) and their antigen binding fragments (Fab) could be used to treat a range of medical problems associated with stimulant abuse. Although the eventual goal is to select a MAb that could be used for treating all of the METH-like synthetic stimulants, the main focus of the project will be on METH. Therefore, high affinity MAb against METH will be selected, and 200-400 g of monoclonal anti-METH IgG will be generated in a non-mammalian bioreactor. After production and purification of the IgG and Fab, preclinical testing will begin. To assess the potential use antibodies for treating addiction, a comprehensive series of studies following active and passive immunization (with the monoclonal IgG) will be conducted in a rat model of human "binge" drug use. These studies will include the behavioral evaluation of the effectiveness of immunotherapy after repeated METH doses over an extended period of time. For evaluating the use of anti-METH Fab for treating overdose, an integrated series of pharmacokinetic, behavioral and neurochemical studies after various types of treatments will be conducted. Finally, the pharmacokinetic and behavioral effects of the anti-METH Fab on METH toxicity will be studied in dogs at toxic doses in preparation for scaling up the therapy to humans. These integrated studies of pharmacokinetic, behavioral and neurochemical changes after antibody-based therapy will serve as a prototypic model that can be applied to treating the effects of other drugs of abuse.