Development of a Flunitrazepam Immunization Strategy

描述(申请人提供)：虽然免疫药物疗法的想法并不新鲜，但它在药物滥用治疗中的应用近年来受到了极大的关注。为了评估针对滥用药物的被动免疫的效果，我们将评估针对氟硝西潘的单抗(MAb)缓解药物引起的精神运动和认知障碍的能力。在小鼠模型下，我们将使用运动活动和情境学习试验来验证单抗的能力，该单抗因其与氟硝西潘的高结合亲和力而被选中，以隔离药物并阻断其作用。上面的结果将与第二组实验进行比较，其中包括乙醇联合注射和氟硝西潘。评估免疫接种是否仍然可以挽救受损的行为，这增加了研究的相关性，因为氟硝西潘通常是以多种药物组合的形式摄入的。我们假设，该单抗将挽救氟硝基安定治疗的小鼠以及与其他CMS抑制剂联合治疗的小鼠的运动协调和学习能力受损。这项研究将验证免疫药物治疗的模型，并测试与涉及氟硝西潘的多药过量病例相关的免疫策略。除了扩大免疫药物治疗的领域外，该项目还对公共健康和福祉有直接影响。氟硝西潘被广泛用于通过损害受害者的认知和记忆来促进性侵犯，根据NIDA和DBA的出版物，与海洛因、可卡因和酒精一起滥用。鉴于记录在案的性侵犯案件的数量以及与氟硝西潘和其他CMS镇静剂联合使用而导致的死亡人数，进一步研究预防氟硝西潘中毒和使用这种强效苯二氮卓类药物的多药模式是合理的。

DESCRIPTION (provided by applicant): While the idea of immunopharmacotherapy is not new, its application to the treatment of drug abuse has received much attention in recent years. In order to assess the efficacy of passive immunization against an abused drug, we will evaluate the ability of monoclonal antibodies (mAb's) raised against flunitrazepam to alleviate drug-induced psychomotor and cognitive impairments. Under a mouse model, we will employ locomotor activity and contextual learning assays to validate the ability of a mAb, selected for its high binding affinity to flunitrazepam, to sequester the drug and block its effect. The above results will be compared to a second set of experiments incorporating ethanol coadmistration with flunitrazepam. Assessing whether immunization still rescues impaired behavior adds relevancy to the study given that flunitrazepam is usually ingested in polydrug combinations. We have hypothesized that the mAb will rescue the impaired motor coordination and learning seen in flunitrazepam-treated mice, and in mice receiving flunitrazepam in conjunction with other CMS depressants. This study will validate a model for immunopharmacotherapy as well as test an immunization strategy relevant in polydrug overdose cases involving flunitrazepam. In addition to extending the field of immunopharmacotherapy, this project has direct implications into public health and well being. Flunitrazepam is widely used in facilitating sexual assault by impairing the victim's cognition and memory, and according to publications from NIDA and the DBA, coabused with heroin, cocaine, and alcohol. Given the number of documented sexual assault cases as well as fatalities associated with combining flunitrazepam and other CMS sedatives, further examination into the prevention of flunitrazepam intoxication and of polydrug models involving this potent benzodiazepine is justified.