Nicotine delivery to rodents with lung alveolar region-targeted aerosol tech

描述（由申请人提供）：本申请是对NIH/PSH 2010-2“SBIR/STTR资助申请的综合征集”的回应，该申请根据NIDA 2“药物滥用研究的替代药物给药剂型的开发”。通过烟草的使用，尼古丁是美国使用最频繁的成瘾性药物之一，也是导致疾病、残疾和死亡的主要可预防原因。为了了解尼古丁对大脑和身体的多种影响，并开发更有效和更安全的戒烟和治疗烟草相关疾病的药物，需要尼古丁依赖动物模型。目前可用于体内动物模型的尼古丁施用方法具有许多局限性。尼古丁无法到达肺部的气体交换区域（肺泡）;因此，动脉尼古丁水平升高的时间过程和幅度与吸烟时的人类不可比较。这项资助的目标是开发一种非侵入性的方法和工具包，用于将尼古丁输送到啮齿动物模型中，以确保足够和可控的量进入循环和大脑，与尼古丁进入吸烟人体的速度相同。目标1。开发一种新的啮齿类动物尼古丁给药方法，并通过动物试验进行验证。我们将通过测定空气中的半数致死浓度（LC 50）和诱导神经行为变化（包括癫痫发作）的半数有效浓度（EC 50）来证明尼古丁递送的有效性。我们将优化尼古丁给药参数，以确保啮齿动物血液中尼古丁浓度的时间过程与吸烟时人体血液中的药代动力学特征相似。目标2.用开发的方法设计和设计啮齿动物的尼古丁输送系统。暴露系统将提供两种选择：用于准确和急性尼古丁研究的约束暴露系统，以及用于慢性研究的家庭笼内自由移动暴露系统。这些系统将被纳入本公司开发的SmartCageTM平台，该平台可以自动定量监测尼古丁暴露期间的啮齿动物行为，这是成瘾研究的强大工具。该项目的第一阶段将开发一种非侵入性和有效的方法来管理尼古丁的啮齿动物，从而创建动物模型，非常类似的时间过程和尼古丁的血液浓度在人类吸烟。我们将提供一个重要的工具，研究吸烟的急性尼古丁影响和慢性影响使用家庭笼。该方法将对烟草相关疾病和尼古丁成瘾研究领域产生重大影响。这项研究将对尼古丁替代疗法（NRT）戒烟具有重要意义。第一阶段项目将为第二阶段项目奠定基础，该项目将开发用于大鼠和小鼠的商业产品系列，并有可能用于大麻、可卡因、海洛因等其他滥用药物。 公共卫生相关性：由于烟草的使用，尼古丁是最常用的成瘾药物之一，也是美国疾病、残疾和死亡的主要可预防原因。这样的工具包将确保对进入循环和大脑的尼古丁量的控制，允许设计实验，其中尼古丁对人体的影响可以更准确地建模。这种方法将为动物研究提供一个强大的工具，以了解尼古丁对大脑和身体的众多影响。此外，该方法将作为开发更有效，更安全的戒烟药物和治疗烟草相关疾病的平台。

DESCRIPTION (provided by applicant): This application is in response to NIH/PSH 2010-2 'Omnibus solicitation for SBIR/STTR Grant Application' under NIDA 2, "Development of Alternate Drug Delivery Dosage Forms for Drugs Abuse Studies". Through the use of tobacco, nicotine is one of the most heavily used addictive drugs and the leading preventable cause of disease, disability, and death in the U.S. To understand the numerous effects of nicotine on the brain and body, and to develop more effective and safer medications for smoking cessation and for treatment of tobacco- related diseases, nicotine dependent animal models are required. Currently available nicotine application methods for in vivo animal models have a number of limitations. Nicotine fails to reach the gas-exchange region in the lungs (the alveoli); therefore, the time course and magnitude of the rise in arterial nicotine levels are not comparable to those of humans when smoking cigarettes. The goal of this grant is to develop a non-invasive method and toolkit for delivering nicotine to rodent models that ensure an adequate and controllable amount entering circulation and the brain at the same rate nicotine enters the bodies of humans smoking cigarettes. Aim 1. To develop a novel nicotine delivery method for rodents and to validate it with animal testing. We will demonstrate the effectiveness of nicotine delivery by determining median lethal concentration (LC50) in air and median effective concentration (EC50) for the induction of neurobehavioral changes including seizures. We will optimize the parameters of nicotine delivery to ensure the time course of blood nicotine concentrations in rodents resembles the pharmacokinetic profile in human blood when smoking cigarettes. Aim 2. Design and engineer the nicotine delivery systems for rodents with the method developed. The exposure systems will provide two options: a restraint exposure system for accurate and acute nicotine studies, and free-moving exposure systems inside home cages for chronic studies. These systems will be incorporated into the SmartCageTM platform developed by our Company that can automatically and quantitatively monitor rodent behavior during nicotine exposure, a powerful tool for addiction studies. This Phase I project will develop a noninvasive and effective method to administer nicotine to rodents, thereby creating animal models that closely resemble the time course and magnitude of nicotine blood concentrations in humans smoking cigarettes. We will provide an important tool for studying the acute nicotine effects of smoking cigarettes and chronic effects using home cages. This method will have a significant impact on the field of tobacco-related disease and nicotine addiction research. This study will have important implications in nicotine replacement therapy (NRT) for smoking cessation. This Phase I project will lay the groundwork for a Phase II project developing a commercial product series for rats and mice, with a potential for other drugs of abuse such as marijuana, cocaine, heroin and beyond. PUBLIC HEALTH RELEVANCE: As a result of tobacco usage, nicotine is one of the most heavily used addictive drugs and the leading preventable cause of disease, disability, and death in the U.S. The goal of the proposed project is to develop a toolkit to administer nicotine to rodents. Such a toolkit will ensure control over the amount of nicotine entering circulation and the brain, allowing for the design of experiments in which the effects of nicotine in humans may be more accurately modeled. This method will provide a powerful tool for animal research to understand the numerous effects of nicotine on the brain and body. Furthermore, this method will serve as a platform to develop more effective and safer medications for smoking cessation and treatment of tobacco-related diseases.