Immunopharmacotherapy for Methamphetamine Addiction

描述(由申请人提供)：滥用和沉迷于d-甲基苯丙胺(冰毒)干扰了个人健康、职业表现、人际关系和经济福祉的许多方面。冰毒滥用和冰毒贸易的行为后果也给美国各地的法律和紧急医疗资源带来了压力。因此，冰毒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并不完全有效，而且还没有批准的冰毒成瘾药物疗法。最近在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中取得的成功，激发了人们创造类似方法治疗甲基苯丙胺成瘾的兴趣。拟议的研究将创造针对冰毒(MCV)的候选活性疫苗，并在一系列体内模型中评估最有希望的候选疫苗。受约束的甲基半抗原将被合成以产生大约六个MCV候选。将评估MCV在小鼠和大鼠中产生具有特定冰毒活性的合适抗体滴度。还将对恒河猴进行初步研究，以确定在该物种中产生高抗体效价的最佳参数。然后，将在大鼠身上评估最有效的MCV的子集，以确定改变冰毒在体内药代动力学的可能性。然后，将对排名靠前的MCV候选药物在猴子身上进行类似的药代动力学活性评估。据推测，有效的免疫将导致冰毒在外周的隔离，并降低大脑中的冰毒水平。进一步的研究将确定MCV免疫是否可以利用无线电遥测系统改变大鼠和猴子对冰毒攻击的心脏、体温和运动亢进反应。最后，将通过大鼠静脉注射自我给药程序来确定MCV免疫是否可以减弱冰毒的增强特性。

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.