Immunopharmacotherapy for Methamphetamine Addiction

描述（由申请人提供）：滥用和成瘾，d-甲基苯丙胺（METH）干扰个人健康，职业表现，人际关系和财务状况的许多方面。甲基苯丙胺滥用和甲基苯丙胺贸易的行为后果也使整个美国的法律的和紧急医疗资源紧张。因此，甲基苯丙胺是一个日益严重的公共卫生问题。目前用于METH成瘾的治疗方法不完全有效，并且不存在用于METH成瘾的批准的药物疗法。最近在使用免疫方法治疗可卡因和尼古丁成瘾的早期临床试验中取得的成功激发了人们对创造类似方法治疗甲基苯丙胺成瘾的兴趣。拟议的研究将创建METH（MCV）特异性的候选活性疫苗，并在体内模型级联中评估最有希望的候选疫苗。将合成受约束的METH半抗原以产生约6个MCV候选物。将评价MCV在小鼠和大鼠中产生具有特异性METH活性的适当抗体滴度。还将在恒河猴中进行初步研究，以确定在该物种中产生高抗体滴度的最佳参数。然后将在大鼠中评价最有效MCV的子集，以确定改变体内METH药代动力学的潜力。然后将在猴中类似地评价最佳MCV候选物的药代动力学活性。据推测，有效的免疫接种将导致METH在外周中的隔离和脑中METH水平的降低。进一步的研究将使用无线电遥测系统确定MCV免疫是否可以改变大鼠和猴对METH攻击的心脏、高热和过度运动反应。最后，将使用大鼠静脉内自我给药程序确定MCV免疫是否可以减弱METH的增强性质。

DESCRIPTION (provided by applicant): The abuse of, and addiction to, d-methamphetamine (METH) interferes with many aspects of personal health, vocational performance, interpersonal relationships and financial well being. Behavioral consequences of METH abuse and the METH trade also strain legal and emergency medical resources throughout the US. METH is therefore a growing public health concern. Current therapeutic approaches for METH addiction are less than completely effective and no approved pharmacotherapies for METH addiction exist. Recent successes in early clinical trials using immunotherapeutic approaches for cocaine and nicotine addiction have motivated interest in creating similar approaches for methamphetamine addiction. The studies proposed will create candidate active vaccines specific for METH (MCV) and evaluate the most promising candidates in a cascade of in vivo models. Constrained METH haptens will be synthesized to create approximately six MCV candidates. MCVs will be evaluated for the generation of suitable antibody titer with specific METH activity in mice and rats. Pilot studies in rhesus macaque monkeys will also be undertaken to determine optimal parameters for generating high antibody titers in this species. A subset of the most effective MCVs will then be evaluated in rats to determine the potential for altering METH pharmacokinetics in vivo. The top MCV candidate will then be similarly evaluated for pharmacokinetic activity in monkeys. It is hypothesized that effective immunization will result in sequestration of METH in the periphery and a lowering of METH levels in brain. Further studies will determine if the MCV immunization can modify cardiac, hyperthermic and hyperlocomotor responses to METH challenge in rats and monkeys using a radiotelemetric system. Finally, it will be determined if MCV immunization can attenuate the reinforcing properties of METH using a rat intravenous self-administration procedure.