Nornicotine as a Treatment for Nicotine Addiction

去甲尼古丁治疗尼古丁成瘾

• 批准号: 6891732
• 负责人: Michael T Bardo
• 金额: $ 54.71万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891732
• 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疗法复发率很高，因此需要替代戒烟剂。当前第二阶段 STTR 拨款申请的总体目标是为天然产物 R(+)-降尼古丁作为口服有效的替代戒烟剂的开发提供支持数据。吸烟者还会接触来自烟草的生物碱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，并且具有独特的药理学特征。我们实验室的最新数据表明，R(+)-降烟碱比 S(-)-降烟碱在体外刺激大鼠伏核切片释放多巴胺 (DA) 方面更有效，并且 R(+)-降烟碱在该检测结果低于 S(-)-尼古丁和 S(-)-降烟碱，表明 R(+)-降烟碱是烟碱受体的部分激动剂介导 DA 释放的亚型（含 a6）。重要的是，我们发现静脉注射时 R(+)-降尼古丁减少。在大鼠中，尼古丁自我给药比 S(-)-降尼古丁更有效。这些临床前结果为确定 R(+)-降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 Therapeutics, Inc. 已接近向 FDA 提交研究性新药 (IND) 申请的阶段，以进行 R(​​+)-降尼古丁的 1 期人体临床试验。拟议的研究将全面评估 R(+)-降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以提供安全信息，作为 IND 提交要求的一部分。 FDA 批准后，将采用随机、安慰剂对照、剂量递增设计，对因吸烟行为而经常接触降尼古丁的健康吸烟者进行口服 R(+)-降尼古丁的一期安全性研究。这项安全性研究将在肯塔基大学钱德勒医学中心的普通临床研究中心 (GCRC) 进行。将在给药前和给药后多个时间点测量 R(+)-降烟碱的心血管、表现和主观影响，并确定行为影响和血浆 R(+)-降烟碱水平之间的关系。这项 1 期安全性研究的结果将为未来 R(+)-降尼古丁的临床疗效研究提供信息。