Immunization to Block the Effects of Nicotine

免疫阻断尼古丁的影响

• 批准号: 7811168
• 负责人: PAUL R PENTEL
• 金额: $ 63.86万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7811168
• 关键词: Address; Animals; Antibodies; Antigens; Area; Binding; Blood; Brain; Breathing; Chemicals; Cigarette; Clinical Trials; Cocaine; Data; Development; Dose; Dose-Rate; Drug Kinetics; Evaluation; Exposure to; Feasibility Studies; Funding; Future; Goals; Grant; Heroin; Human; Immunization; Immunoglobulin A; Immunoglobulin G; Immunotherapy; Individual; Inhalation Exposure; Intake; Intervention; Lung; Measures; Mediating; Methods; Modeling; Monoclonal Antibodies; National Institute of Drug Abuse; Nicotine; Nicotine Dependence; Nose; Passive Immunization; Pharmaceutical Preparations; Pharmacology; Phase; Pre-Clinical Model; Preclinical Testing; Public Health; Published Comment; Rattus; Recovery; Role; Route; Serum; Simulate; Smoke; Smoker; Smoking; System; Testing; Tissues; Tobacco Dependence; Tobacco smoke; Translations; Treatment Protocols; United States National Institutes of Health; Vaccination; Vaccines; Work; absorption; addiction; cigarette smoking; cigarette smoking; clinically relevant; immunogenicity; insight; interest; killings; novel; novel strategies; parent grant; pharmacokinetic model; pre-clinical; preclinical study; public health relevance; response; smoking cessation; tool; vaccine efficacy; vaccine evaluation

DESCRIPTION (provided by applicant): This is a response to Notice Number NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The goal of this revision supplement is to extend our studies of nicotine vaccine efficacy in rats by introducing methods for the delivery of nicotine through inhalation of cigarette smoke. Smoking cessation medications have added substantially to our ability to treat tobacco addiction, but their efficacy is limited and new types of medications are needed. Nicotine vaccines elicit nicotine-specific antibodies which bind nicotine and alter its access to brain. Three nicotine vaccines have shown preliminary efficacy in Phase I-II clinical trials, but efficacy is closely correlated with the serum antibody titer and current vaccines do not reliably produce sufficiently high titers in all individuals. The parent grant DA10714 is using rat models of nicotine addiction to study novel means of enhancing vaccine efficacy. Like essentially all current animal studies of nicotine addiction, DA10714 models tobacco addiction using parenteral (i.v. or s.c.) administration of pure nicotine. In contrast, smokers take in nicotine by inhalation and as one of over 4,000 chemicals present in cigarette smoke. The adequacy of using such artificial dosing paradigms to model cigarette smoking is unknown and largely untested. We have adapted and characterized methods for inhalation exposure of rats to smoke simulating the smoking of 1 cigarette or periods of heavier smoking. In this revision supplement we propose to use these methods to study the effects of nicotine vaccines on the absorption and distribution of nicotine inhaled in cigarette smoke. The purposes of doing so are to 1) expand the range of preclinical models available to study nicotine vaccines, 2) assess whether inhalation models provide novel information for vaccine evaluation, 3) examine the specific role of route-specific factors such as pulmonary antibody in mediating nicotine vaccine efficacy, and 3) develop quantitative models which can be more generally used to study the contributions of the inhaled route and other smoke constituents to tobacco addiction and treatment medications development. Nicotine vaccines are an attractive initial candidate for such study because vaccination is a pharmacokinetic intervention, and accurate pharmacokinetic modeling of nicotine intake may be important in understanding and exploiting its efficacy. Aim 1 will test the hypothesis that vaccination is effective in reducing nicotine distribution to brain over a range of clinically relevant dosing conditions. Aim 2 will test the hypotheses that vaccination is more effective in reducing the distribution to brain of inhaled compared to i.v. nicotine, and that such differences are in part mediated by the presence of pulmonary mucosal or tissue antibody. Because heroin and cocaine are also often smoked, the results of this study may inform ongoing efforts to develop vaccines for these addictions as well. PUBLIC HEALTH RELEVANCE: Cigarette smoking kills 5 million people worldwide yearly. Current medications are helpful for smoking cessation but are incompletely effective. We are studying the use of a nicotine vaccine to help smokers quit, which acts by binding nicotine in blood and reducing its access to brain. Rat models of tobacco addiction use nicotine delivered intravenously, which is informative but does not accurately model the human route of intake of nicotine by inhalation from cigarette smoke. This proposal will develop and study the utility of delivering nicotine to rats via exposure to cigarette smoke, and assess whether it allows better evaluation of nicotine vaccine efficacy and can expedite its further development.

描述（由申请人提供）：这是对NOT-OD-09-058的通知号码的回复，NIH宣布了竞争性修订申请的恢复法案资金的可用性。这种修订补充剂的目的是通过引入通过吸入香烟烟来传递尼古丁的方法来扩展我们对大鼠尼古丁疫苗功效的研究。戒烟药物已大大增加了我们治疗烟草成瘾的能力，但是它们的功效是有限的，需要新型的药物。尼古丁疫苗会引起尼古丁特异性抗体，这些抗体结合尼古丁并改变其进入大脑的访问。三种尼古丁疫苗在I-II期临床试验中表现出了初步功效，但是功效与血清抗体滴度密切相关，而当前的疫苗在所有个体中都无法可靠地产生足够高的滴度。父授予DA10714正在使用尼古丁成瘾的大鼠模型来研究增强疫苗功效的新方法。就像目前所有关于尼古丁成瘾的动物研究一样，DA10714模型使用肠胃外（i.v.或s.c.）施用纯尼古丁的烟草成瘾。相比之下，吸烟者通过吸入吸收尼古丁，是香烟烟雾中有4000多种化学物质之一。使用这种人工剂量范式对吸烟进行建模的充分性是未知的，并且在很大程度上未经测试。我们已经适应和表征了吸入大鼠吸入吸烟的方法，以模拟吸烟1烟或较重的吸烟。在此修订补充剂中，我们建议使用这些方法研究尼古丁疫苗对吸入香烟烟雾中尼古丁的吸收和分布的影响。 The purposes of doing so are to 1) expand the range of preclinical models available to study nicotine vaccines, 2) assess whether inhalation models provide novel information for vaccine evaluation, 3) examine the specific role of route-specific factors such as pulmonary antibody in mediating nicotine vaccine efficacy, and 3) develop quantitative models which can be more generally used to study the contributions of the inhaled route and other smoke constituents to烟草成瘾和治疗药物的开发。尼古丁疫苗是该研究的有吸引力的初始候选者，因为疫苗是一种药代动力学干预措施，尼古丁摄入的准确药代动力学建模对于理解和利用其功效可能很重要。 AIM 1将检验以下假设：在一系列临床相关的给药条件下，疫苗接种可有效减少尼古丁分布。 AIM 2将测试与静脉注射相比，疫苗接种在减少吸入大脑的分布方面更有效的假设。尼古丁，这种差异部分是由肺粘膜或组织抗体的存在介导的。由于海洛因和可卡因也经常被吸烟，因此这项研究的结果也可能为开发这些成瘾的疫苗开发持续的努力。 公共卫生相关性：吸烟每年杀死500万人。当前的药物有助于戒烟，但无效。我们正在研究使用尼古丁疫苗来帮助吸烟者戒烟，这些疫苗通过结合血液中的尼古丁并减少其进入大脑的途径来戒烟。烟草成瘾的大鼠模型使用静脉注射的尼古丁，这是有益的，但不能准确地模拟通过吸入香烟烟雾的人类摄入尼古丁的途径。该提案将通过暴露于香烟烟雾来开发和研究将尼古丁传递给大鼠的效用，并评估它是否允许更好地评估尼古丁疫苗的功效，并可以加快其进一步发展。