Nornicotine as a Treatment for Nicotine Addiction

描述(由申请人提供)：由于目前可用的药物疗法复发率高，需要替代戒烟剂。目前第二阶段STTR赠款申请的总体目标是为开发天然产品R(+)去甲尼古丁作为一种口服有效的替代戒烟药物提供支持数据。吸烟者还会接触到来自烟草的生物碱去甲尼古丁和尼古丁代谢物。与尼古丁相比，去甲尼古丁在脑内的滞留时间较长，具有独特的药理作用。本实验室最近的研究表明，R(+)-去甲烟碱在体外刺激大鼠伏隔核脑片释放多巴胺(DA)的作用强于S(-)-去甲烟碱，而在本实验中，R(+)-去甲烟碱的作用弱于S(-)-烟碱和S(-)-去甲烟碱，提示R(+)-去甲烟碱是介导DA释放的烟碱受体亚型(A6)的部分激动剂。重要的是，我们发现R(+)-去甲尼古丁静脉注射减少。在大鼠中，尼古丁自身给药比S(-)-去甲尼古丁更有效。这些临床前结果为确定R(+)-去甲尼古丁作为人类戒烟剂的潜在治疗益处奠定了基础。为了实现这一目标，Yaupon治疗公司已经接近可以向FDA提交研究新药(IND)申请，以进行R(+)-去甲尼古丁的第一阶段人体临床试验的阶段。拟议的研究将全面评估R(+)-去甲尼古丁的口服生物利用度。此外，作为FDA要求的一部分，临床前毒理学将作为IND提交要求的一部分来提供安全信息。FDA批准后，将在因吸烟行为而定期接触去甲尼古丁的健康烟草吸烟者中，采用随机、安慰剂对照、剂量递增设计进行口服R(+)-去甲尼古丁的第一阶段安全性研究。这项安全性研究将在肯塔基大学钱德勒医学中心的综合临床研究中心(GCRC)进行。将在给药前和给药后的多个时间点测量R(+)-去甲尼古丁的心血管效应、性能和主观效应，并确定行为效应与血浆R(+)-去尼古丁水平的关系。这项第一阶段安全性研究的结果将为未来R(+)-去甲尼古丁的临床疗效研究提供信息。

DESCRIPTION (provided by applicant): Alternative tobacco cessation agents are needed due to the high rate of relapse with currently available pharmacotherapies. The overall goal of the current Phase II STTR grant application is to provide supporting data towards the development of the natural product, R(+)-nornicotine, as an orally-effective, alternative tobacco use cessation agent. Smokers are also exposed to alkaloidal nornicotine from tobacco and as a nicotine metabolite. Compared to nicotine, nornicotine has a long residence time in brain and a unique pharmacological profile. Recent data from our laboratory demonstrate that R(+)-nornicotine is more potent than S(-)-nornicotine in stimulating dopamine (DA) release from rat nucleus accumbens slices in vitro, and that the efficacy of R(+)-nornicotine in this assay is less than that of both S(-)-nicotine and S(-)-nornicotine, suggesting that R(+)-nornicotine is a partial agonist at nicotinic receptor subtypes (a6-containing) mediating DA release. Importantly, we found that R(+)-nornicotine decreased i.v. nicotine self-administration more potently than S(-)-nornicotine in rats. These preclinical results set the stage for determining the potential therapeutic benefit of R(+)-nornicotine as a tobacco use cessation agent in humans. Toward this goal, Yaupon Therapeutics, Inc., is close to the stage at which an Investigational New Drug (IND) application to the FDA can be submitted to conduct a Phase 1 human clinical trial with R(+)-nornicotine. The proposed studies will fully assess the oral bioavailability of R(+)-nornicotine. In addition, as part of the FDA requirements, preclinical toxicology will be performed to provide safety information as part of the IND submission requirements. Following FDA approval, a Phase 1 safety study of oral R(+)-nornicotine will be conducted using a randomized, placebo-controlled, dose-escalation design in healthy tobacco smokers who are exposed regularly to nornicotine as a result of smoking behavior. This safety study will be conducted in the General Clinical Research Center (GCRC) at the University of Kentucky Chandler Medical Center. The cardiovascular, performance and subjective effects of R(+)-nornicotine will be measured before and at multiple time points after dose administration, and the relationship between behavioral effects and plasma R(+)-nornicotine levels will be determined. The results from this Phase 1 safety study will inform future clinical efficacy studies with R(+)-nornicotine.