Clinical Pharmacology of Nicotine Enantiomers

尼古丁对映体的临床药理学

• 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
• 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

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）品牌声称使用液体， “不含烟草”，意味着它们含有“合成”尼古丁。此类产品目前不受 现有的FDA烟草控制法规，并可能向青少年和其他人销售， 并且比含有来自烟草的尼古丁的EC危害更小。电子烟制造商 可能使用合成尼古丁作为一种方式，以避免正在进行的FDA对EC的监管程序。 尼古丁是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的形式，左旋（S）-异构体和右旋（S）-异构体， （R）-异构体。虽然烟草中的尼古丁几乎是唯一的（S）-尼古丁，但大多数合成尼古丁 由外消旋（S）-和（R）-尼古丁组成。动物研究表明，（S）-尼古丁更多 对于大多数药理作用，比（R）-尼古丁更有效，但对于不同的药理作用， 效果差别很大。动物数据也发现了代谢率和代谢途径的差异 两种尼古丁对映异构体。关于R的人体药理学的信息很少 尼古丁或外消旋尼古丁。了解相对滥用潜力，心血管影响 尼古丁对映异构体及其外消旋混合物的代谢差异对于 合成尼古丁产品的适当FDA法规。 我们建议使用稳定同位素方法进行人体临床药理学研究 比较雾化的（S）-和（R）-尼古丁的药代动力学和药效学， 外消旋尼古丁我们将合成并制备用于人类施用的氘标记的（S）- 和（R）-尼古丁。 在交叉研究中，有经验的EC用户将在三个不同的日子vape（S）-，（R）-或外消旋 尼古丁在标准化阶段（15喷，每30秒一喷）和90分钟自由使用 上网时段结果测量将包括药代动力学、肺潴留、 尼古丁代谢、主观和心血管反应以及尼古丁自我给药。 特别感兴趣的是如何在外消旋尼古丁混合物（如在许多合成尼古丁中发现的）中 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。