Development of a Flunitrazepam Immunization Strategy

描述（由申请人提供）：虽然免疫药物治疗的想法并不新鲜，但近年来其在药物滥用治疗中的应用备受关注。为了评估被动免疫对滥用药物的有效性，我们将评估针对氟硝西泮产生的单克隆抗体（mAb）减轻药物诱导的精神障碍和认知障碍的能力。在小鼠模型下，我们将采用自发活动和上下文学习测定来验证mAb的能力，该mAb因其对氟硝西泮的高结合亲和力而被选择，以螯合药物并阻断其作用。将上述结果与第二组将乙醇与氟硝西泮共给药的实验进行比较。鉴于氟硝西泮通常以多种药物组合的形式摄入，评估免疫接种是否仍能挽救受损的行为增加了研究的相关性。我们假设mAb将挽救在氟硝西泮治疗的小鼠和接受氟硝西泮与其他CMS抑制剂联合治疗的小鼠中观察到的受损的运动协调和学习。本研究将验证免疫药物治疗模型，并测试涉及氟硝西泮的多种药物过量病例相关的免疫策略。除了扩展免疫药物治疗领域外，该项目还直接影响公共卫生和福祉。 氟硝西泮被广泛用于通过损害受害者的认知和记忆来促进性侵犯，并且根据NIDA和DBA的出版物，与海洛因，可卡因和酒精共同滥用。鉴于记录在案的性侵犯病例以及与氟硝西泮和其他CMS镇静剂联合使用相关的死亡人数，有理由进一步研究氟硝西泮中毒的预防和涉及这种强效苯二氮卓类药物的多种药物模型。

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.