Nornicotine as a Treatment for Nicotine Addiction

描述（由申请人提供）：由于现有药物治疗的复发率高，需要替代戒烟剂。目前第二期STTR拨款申请的总体目标是为开发天然产物R(+)-去甲尼古丁提供支持数据，R(+)-去甲尼古丁是一种口服有效的替代戒烟剂。吸烟者也会接触到烟草中的去尼古丁生物碱和尼古丁代谢物。与尼古丁相比，去甲尼古丁在脑内停留时间长，具有独特的药理特征。我们实验室最近的数据表明，R(+)-去甲尼古丁在体外刺激大鼠伏隔核切片多巴胺（DA）释放方面比S(-)-去甲尼古丁更有效，并且在本实验中R(+)-去甲尼古丁的效果低于S(-)-尼古丁和S(-)-去甲尼古丁，这表明R(+)-去甲尼古丁是尼古丁受体亚型（含a6）介导DA释放的部分激动剂。重要的是，我们发现R(+)-去甲尼古丁比S(-)-去甲尼古丁在大鼠体内更有效地减少静脉给药。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效益奠定了基础。为了实现这一目标，Yaupon Therapeutics, Inc.已经接近向FDA提交新药研究（IND）申请的阶段，可以进行R(+)-去甲尼古丁的1期人体临床试验。拟议的研究将充分评估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，提供安全性信息。在FDA批准后，口服R(+)-去甲尼古丁的1期安全性研究将在因吸烟行为而经常暴露于去甲尼古丁的健康吸烟者中进行，采用随机、安慰剂对照、剂量递增设计。这项安全性研究将在肯塔基大学钱德勒医学中心的普通临床研究中心（GCRC）进行。在给药前和给药后多个时间点测量R(+)-去甲尼古丁的心血管效应、性能效应和主观效应，并确定行为效应与血浆R(+)-去甲尼古丁水平的关系。这项1期安全性研究的结果将为R(+)-去甲尼古丁的未来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.