Clinical Pharmacology of Nicotine Enantiomers

尼古丁对映体的临床药理学

基本信息

批准号：
10570635
负责人：
NEAL L BENOWITZ
金额：
$ 70.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570635
关键词：
Affect Analytical Chemistry Animals Area Behavior Blood Pressure Blood flow Carbon Cardiovascular system Catecholamines Clinical Pharmacology Consumption Cross-Over Studies Deuterium Drug Kinetics Electronic cigarette Half-Life Heart Rate Human Image Isomerism Label Liquid substance Lung Manufacturer Marketing Metabolic Metabolism Methodology Nicotine Optics Outcome Measure Pathway interactions Pattern Pharmacology Pharmacology Study Plasma Process Property Qualifying Regulation Research Rewards Self Administration Skin Standardization Synthesis Chemistry Time Tobacco Urine Withdrawal Symptom Youth abuse liability animal data cardiovascular effects craving electronic cigarette user electronic liquid enantiomer experience interest nicotine self-administration pharmacokinetics and pharmacodynamics pharmacologic response stable isotope tobacco control tobacco products tobacco regulation tobacco-free vaping

项目摘要

Summary/Abstract Recently a number of electronic cigarettes (EC) brands have claimed to use liquids that are “tobacco-free”, meaning they contain “synthetic” nicotine. Such products are not currently subject to existing FDA tobacco control regulations and might be marketed to youth and others as cleaner and less harmful than EC that contain nicotine derived from tobacco. E-cigarette manufacturers may use synthetic nicotine as a way to avoid ongoing FDA regulatory processes for ECs. Nicotine is a chiral compound with one asymmetric carbon atom and can exist as two mirror image forms termed enantiomers or optical isomers, the levorotatory (S)-isomer and the dextrorotatory (R)-isomer. While nicotine from tobacco is almost exclusive (S)-nicotine, most synthetic nicotine is comprised of racemic (S)- and (R)- nicotine. Animal studies indicate that (S)- nicotine is more potent than (R)- nicotine for most pharmacological effects, but the relative potency for different effects varies considerably. Animal data also find differences in rates and pathways of metabolism of the two nicotine enantiomers. Very little information exists on the human pharmacology of R nicotine or racemic nicotine. Understanding the relative abuse potential, cardiovascular effects and metabolic differences of the nicotine enantiomers and their racemic mixture is important for appropriate FDA regulation of synthetic nicotine products. We propose to conduct a human clinical pharmacology study using stable isotope methodology to compare pharmacokinetics and pharmacodynamics of vaped (S)- and (R)- nicotine and racemic nicotine. We will synthesize and prepare for human administration deuterium labeled (S)- and (R)- nicotine. In a crossover study, experienced EC users will on three separate days vape (S)-, (R)- or racemic nicotine both in standardized sessions (15 puffs, one every 30 sec) and in a 90 min ad libitum use session. Outcome measures will include pharmacokinetics, pulmonary retention, patterns of nicotine metabolism, subjective and cardiovascular responses, and nicotine self-administration. Of particular interest will be how in racemic nicotine mixtures (as found in many synthetic nicotine products), the presence of (R)- nicotine affects the pharmacology and self-administration of (S)- nicotine.

摘要/摘要最近，一些电子烟（EC）品牌声称使用的液体是 “不含烟草”，意味着它们含有“合成”尼古丁，此类产品目前不受管制。符合 FDA 现行烟草控制法规，并可能作为清洁剂向青少年和其他人推销且比含有来自电子烟制造商的尼古丁的 EC 危害更小。可能会使用合成尼古丁作为避免 FDA 对 EC 进行持续监管程序的一种方式。尼古丁是一种具有一个不对称碳原子的手性化合物，可以以两个镜像存在称为对映异构体或旋光异构体、左旋 (S) 异构体和右旋异构体的形式 (R)-异构体虽然烟草中的尼古丁几乎都是 (S)-尼古丁，但大多数是合成尼古丁。由种族 (S)- 和 (R)- 尼古丁组成。动物研究表明 (S)- 尼古丁含量更高。大多数药理作用均强于 (R)-尼古丁，但不同药理作用的相对效力动物数据还发现新陈代谢率和途径存在很大差异。关于 R 的两种尼古丁对映体的人类药理学信息很少。了解尼古丁或种族尼古丁的相对滥用潜力、心血管影响。尼古丁对映体及其种族混合物的代谢差异对于 FDA 对合成尼古丁产品的适当监管。我们建议使用稳定同位素方法进行人体临床药理学研究比较电子烟 (S)- 和 (R)- 尼古丁的药代动力学和药效学我们将合成并准备用于人体给药的氘标记（S）- 和(R)-尼古丁。在交叉研究中，经验丰富的 EC 用户将在三天内分别吸食 (S)-、(R)- 或外消旋电子烟标准化疗程（15 口，每 30 秒 1 口）和 90 分钟随意使用中的尼古丁结果测量将包括药代动力学、肺潴留、模式。尼古丁代谢、主观和心血管反应以及尼古丁自我给药。特别令人感兴趣的是种族尼古丁混合物（如在许多合成尼古丁中发现的那样）如何产品），(R)-尼古丁的存在会影响(S)-尼古丁的药理学和自我给药尼古丁。