Nornicotine as a Treatment for Nicotine Addiction

去甲尼古丁治疗尼古丁成瘾

• 批准号: 7121533
• 负责人: Michael T Bardo
• 金额: $ 36.78万
• 依托单位: YAUPON THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121533
• 关键词: analog; behavior test; biological products; clinical trial phase I; drug abuse chemotherapy; drug addiction antagonist; drug design /synthesis /production; drug screening /evaluation; human subject; human therapy evaluation; insecticides; laboratory rat; nicotine; patient oriented research; pharmacokinetics; smoking cessation; stereoisomer

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.

描述（由申请人提供）：由于目前可用的药物治疗复发率高，因此需要替代戒烟药物。目前的第二阶段STTR资助申请的总体目标是为天然产品R（+）-去甲烟碱的开发提供支持数据，作为口服有效的替代烟草使用戒烟剂。吸烟者也会接触到烟草中的降烟碱和尼古丁代谢物。与尼古丁相比，去甲尼古丁在大脑中的停留时间较长，具有独特的药理学特征。我们实验室的最新数据表明，R（+）-去甲烟碱在体外刺激大鼠延髓核切片释放多巴胺（DA）方面比S（-）-去甲烟碱更有效，并且R（+）-去甲烟碱在该测定中的功效低于S（-）-烟碱和S（-）-去甲烟碱，表明R（+）-去甲烟碱是烟碱受体亚型（含α 6）的部分激动剂，介导DA释放。重要的是，我们发现在大鼠中，R（+）-去甲尼古丁比S（-）-去甲尼古丁更有效地减少静脉内尼古丁自我给药。这些临床前结果为确定R（+）-去甲烟碱作为人类烟草使用戒烟剂的潜在治疗益处奠定了基础。为了实现这一目标，Yaupon Therapeutics，Inc.，已经接近可以向FDA提交研究性新药（IND）申请的阶段，以进行R（+）-去甲尼古丁的1期人体临床试验。拟定研究将全面评估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，将进行临床前毒理学研究，以提供安全性信息，作为IND提交要求的一部分。FDA批准后，将在因吸烟行为而定期暴露于去甲尼古丁的健康吸烟者中，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I期安全性研究。本安全性研究将在肯塔基州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多个时间点测量R（+）-去甲烟碱的心血管、性能和主观效应，并确定行为效应与血浆R（+）-去甲烟碱水平之间的关系。这项I期安全性研究的结果将为未来的R（+）-去甲尼古丁临床疗效研究提供信息。