Preclinical Evaluation of GluR2-3Y Peptide as a Potential New Medication for Poly

描述（由申请人提供）：就经济和社会成本以及个人成本而言，药物滥用和成瘾是北美社会的巨大消耗。迫切需要有效的药物来治疗成瘾。尽管针对某些类型的成瘾（即阿片类药物成瘾）的药物开发取得了进展，但这些药物有明显的缺点。目前仍没有批准的治疗方法来治疗许多类型的成瘾，如甲基苯丙胺或可卡因成瘾。使问题进一步复杂化的是，许多高度成瘾的边缘人群也有非常高水平的多种药物成瘾，也就是说，这些人群中的许多人经常使用多种物质并对其上瘾。这些个体和人群的治疗策略是复杂的，因为每种类型的成瘾背后有不同的机制。针对不同类型成瘾的共同机制的创新策略除了对治疗单一物质成瘾也有用外，可能对治疗这种多种药物成瘾有很大好处。英属哥伦比亚大学的研究人员开发了一种很有前途的先导化合物，作为一种潜在的成瘾疗法。这种肽化合物并不直接针对药物受体，而是针对成瘾行为背后的关联和学习机制。这些学习和联想机制已被证明对成瘾的渴望和复发方面都是至关重要的，而与药物使用的奖励方面无关。该研究项目的长期目标是进行一项使用先导肽化合物的人体临床试验，最初的目标人群是注射吸毒者，其中至少有一部分吸毒者对多种物质上瘾。因此，本文提出的短期目标是进行额外的非临床实验，为后续正式的临床前安全性和毒性计划定位项目，以便迅速向FDA研究新药申请和/或加拿大卫生部临床试验申请进行。研究计划中描述的实验包括在多种药物成瘾的动物模型中进一步测试先导化合物；确定所述先导化合物的最小有效剂量、最大耐受剂量、治疗指数和最佳剂量；先导化合物在动物模型中的全药代动力学和生物分布分析并研究另一种给药方式，即鼻内给药，以潜在地扩大该化合物在更广泛目标人群中的适用性和可行性。

DESCRIPTION (provided by applicant): Substance abuse and addiction represents a huge drain on North American society, in terms of economic and social costs, as well as the human individual cost. The need for effective medications to treat addiction is urgent. Although medications development has progressed for certain types of addiction, namely opioid addiction, these medications have significant drawbacks. There remain no currently approved therapies for many types of addiction such as methamphetamine or cocaine addiction. Further complicating matters is that many marginalized populations suffering from high levels of addiction also have very high levels of polydrug addiction that is, many individuals in these populations regularly use and are addicted to multiple substances. Treatment strategies for such individuals and populations are complex due to the various mechanisms underlying each type of addiction. Innovative strategies that target mechanisms common to different types of addiction may be of great benefit in treating such polydrug addictions, in addition to also be useful for treating single substance addictions. Researchers at The University of British Columbia have developed a promising lead compound as a potential addiction therapy. This peptide compound does not directly target drug receptors, but rather targets the association and learning mechanisms underlying addiction behaviors. These learning and association mechanisms have been shown to be critical for both the craving and the relapse aspects of addiction, and are not related to the reward aspects of drug use. It is a long range goal of the research project to conduct a human clinical trial using the lead peptide compound, with an initial target population of injection drug users where at least a portion of such drug users are addicted to multiple substances. Thus the short term goals proposed herein are to perform additional non-clinical experiments to position the project for a follow-on formal preclinical safety and toxicity program, in order to proceed quickly towards an FDA Investigational New Drug Application and/or Health Canada Clinical Trial Application. The experiments described in the research proposal include further testing of the lead compound in an animal model of polydrug addiction; determination of minimum efficacy dose, maximum tolerated dose, therapeutic index, and optimal dose of the lead compounds; full pharmacokinetic and biodistribution profiling of the lead compound in animal model; and investigation of an alternate mode of delivery, intranasal, to potential expand the applicability and feasibility of using the compound with a broader target population. PUBLIC HEALTH RELEVANCE: The proposed research project is intended to investigate and ultimately provide new medications for the treatment of addiction, in particular for the treatment of patients with multiple substance use disorders. For individuals in marginalized populations such as those found in many inner cities, and particularly in Vancouver's Downtown Eastside, addiction to multiple substances, such as heroin, cocaine, and/or alcohol, is widespread, and has devastating consequences both on the individual and on society. Drug addiction in such communities is very clearly a significant public health issue that requires new and innovative solutions, particularly in communities with high levels of polydrug use and addiction.