Immunopharmacotherapy for Methamphetamine Addiction

描述（由申请人提供）：d-甲基苯丙胺（冰毒）的滥用和成瘾会干扰个人健康、职业表现、人际关系和财务状况的许多方面。冰毒滥用和冰毒交易的行为后果也使美国的法律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。目前治疗冰毒成瘾的方法不是完全有效的，也没有批准的药物治疗冰毒成瘾的存在。最近使用免疫治疗方法治疗可卡因和尼古丁成瘾的早期临床试验取得了成功，这激发了人们对开发治疗甲基苯丙胺成瘾的类似方法的兴趣。拟议的研究将创建针对甲基安非他明（MCV）的候选活疫苗，并在一系列体内模型中评估最有希望的候选疫苗。将合成约束甲基半抗原，以产生大约六种MCV候选物。将评估mcv在小鼠和大鼠中产生具有特定甲基安非他明活性的合适抗体滴度。还将在恒河猴中进行试点研究，以确定在该物种中产生高抗体滴度的最佳参数。然后将在大鼠中评估最有效的mcv子集，以确定改变甲基苯丙胺体内药代动力学的潜力。然后将对顶级MCV候选药物在猴子体内的药代动力学活性进行类似的评估。据推测，有效的免疫将导致甲基苯丙胺在外周的隔离和大脑中甲基苯丙胺水平的降低。进一步的研究将利用无线电遥测系统确定MCV免疫是否可以改变大鼠和猴子对甲基安非他明挑战的心脏、高热和高运动反应。最后，将确定MCV免疫是否可以通过大鼠静脉自我给药程序减弱甲基苯丙胺的强化特性。

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.