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号通知的回应，NIH宣布可为竞争性修订申请提供恢复法案资金。这一修订版附录的目的是通过引入通过吸入香烟烟雾传递尼古丁的方法来扩大我们对尼古丁疫苗在大鼠身上有效性的研究。戒烟药物大大增加了我们治疗烟草成瘾的能力，但它们的效果有限，需要新型药物。尼古丁疫苗诱导尼古丁特异性抗体，这些抗体结合尼古丁并改变其进入大脑的途径。三种尼古丁疫苗在第一-第二阶段临床试验中显示出初步疗效，但疗效与血清抗体效价密切相关，目前的疫苗并不能可靠地在所有人身上产生足够高的效价。家长资助DA10714正在使用尼古丁成瘾的大鼠模型来研究提高疫苗效力的新方法。就像目前所有关于尼古丁成瘾的动物研究一样，DA10714使用静脉注射建立烟草成瘾模型。或S.C.)服用纯尼古丁。相比之下，吸烟者通过吸入尼古丁，并将其作为香烟烟雾中存在的4000多种化学物质之一。使用这种人工给药范例来模拟香烟吸烟的充分性是未知的，而且在很大程度上还没有经过测试。我们已经调整和表征了大鼠吸入暴露于烟雾的方法，模拟一支香烟的吸烟或重度吸烟的时期。在这个修订版的附录中，我们建议使用这些方法来研究尼古丁疫苗对香烟烟雾中吸入的尼古丁的吸收和分布的影响。这样做的目的是：1)扩大可用于研究尼古丁疫苗的临床前模型的范围；2)评估吸入模型是否为疫苗评估提供了新的信息；3)检查特定路线的因素，如肺部抗体在调节尼古丁疫苗效力方面的具体作用；以及3)开发可更普遍地用于研究吸入路线和其他烟雾成分对烟草成瘾和治疗药物开发的贡献的定量模型。尼古丁疫苗是这类研究的一个有吸引力的初始候选者，因为疫苗接种是一种药代动力学干预，准确的尼古丁摄入量的药代动力学模型对于理解和利用其疗效可能是重要的。目的1将验证一种假设，即在一系列临床相关的剂量条件下，接种疫苗在减少尼古丁分布到大脑中是有效的。目的2将验证接种疫苗比静脉注射更有效地减少吸入性药物在脑内分布的假说。这种差异在一定程度上是由肺粘膜或组织抗体的存在所调节的。由于海洛因和可卡因也经常被吸烟，这项研究的结果可能会为正在进行的开发这些成瘾的疫苗的努力提供参考。 与公共健康相关：全世界每年有500万人死于吸烟。目前的药物对戒烟有帮助，但并不完全有效。我们正在研究使用尼古丁疫苗来帮助吸烟者戒烟，这种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发挥作用。烟草成瘾的大鼠模型使用静脉注射尼古丁，这是有信息的，但不能准确地模拟人类通过从香烟烟雾中吸入尼古丁的途径。这项建议将开发和研究通过暴露在香烟烟雾中向老鼠传递尼古丁的效用，并评估它是否可以更好地评估尼古丁疫苗的效力，并可以加快其进一步发展。