Immunization to Block the Effects of Nicotine

描述（由申请人提供）：这是对NOT-OD-09-058号通知的回应，NIH宣布为竞争性修订申请提供恢复法案资金。本修订补充的目的是通过引入通过吸入香烟烟雾递送尼古丁的方法来扩展我们对大鼠尼古丁疫苗有效性的研究。戒烟药物大大提高了我们治疗烟草成瘾的能力，但其疗效有限，需要新型药物。尼古丁疫苗引发尼古丁特异性抗体，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I-II期临床试验中显示出初步疗效，但疗效与血清抗体滴度密切相关，目前的疫苗不能在所有个体中可靠地产生足够高的滴度。DA 10714研究基金正在使用尼古丁成瘾的大鼠模型来研究增强疫苗效力的新方法。与目前所有尼古丁成瘾的动物研究基本相同，DA 10714使用胃肠外（i. v.或s.c.）使用纯尼古丁。相比之下，吸烟者通过吸入尼古丁，尼古丁是香烟烟雾中存在的4,000多种化学物质之一。使用这种人工给药模式来模拟吸烟的充分性是未知的，并且在很大程度上未经测试。我们已经调整和表征了大鼠吸入暴露于烟雾的方法，模拟吸烟1支香烟或更重的吸烟时间。在本修订补充中，我们建议使用这些方法来研究尼古丁疫苗对香烟烟雾中尼古丁吸收和分布的影响。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价提供了新的信息，3）检查途径特异性因素（如肺抗体）在介导尼古丁疫苗有效性中的特定作用，以及3）开发定量模型，该定量模型可以更普遍地用于研究吸入途径和其他烟雾成分对烟草成瘾和治疗药物开发的贡献。尼古丁疫苗是此类研究的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，尼古丁摄入的准确药代动力学建模对于理解和利用其疗效可能很重要。目的1将检验以下假设：在一系列临床相关给药条件下，接种疫苗可有效减少尼古丁向大脑的分布。目的2将检验以下假设：与静脉注射相比，接种疫苗在减少吸入尼古丁向大脑的分布方面更有效，并且此类差异部分由肺粘膜或组织抗体的存在介导。由于海洛因和可卡因也经常被吸食，这项研究的结果可能会为正在进行的开发这些成瘾疫苗的努力提供信息。 公共卫生相关性：吸烟每年导致全球500万人死亡。目前的药物有助于戒烟，但效果不完全。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来发挥作用。烟草成瘾的大鼠模型使用静脉内递送的尼古丁，这是信息丰富的，但不能准确地模拟人类通过吸入香烟烟雾摄入尼古丁的途径。该提案将开发和研究通过暴露于香烟烟雾向大鼠递送尼古丁的效用，并评估它是否可以更好地评估尼古丁疫苗的功效，并加快其进一步开发。

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.