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

利用肺泡区域靶向气雾剂技术向啮齿类动物输送尼古丁

• 批准号: 8130191
• 负责人: XUESI Max SHAO
• 金额: $ 24.04万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130191
• 关键词: Acute; Adverse effects; Aerosols; Air; Air Pressure; Alveolar; Animal Experimentation; Animal Model; Animal Testing; Animals; Applications Grants; Behavior; Blood; Blood Circulation; Brain; Breathing; Caliber; Cessation of life; Chemicals; Chronic; Cigarette; Cocaine; Computers; Deposition; Development; Devices; Disease; Dosage Forms; Drug Administration Routes; Drug Delivery Systems; Drug Kinetics; Drug abuse; Effectiveness; Ensure; Fetus; Gases; Generations; Goals; Grant; Heroin; Home environment; Hour; Human; Human body; Injection of therapeutic agent; Intravenous; Kinetics; Liver; Lung; Marijuana; Metabolism; Methods; Modeling; Monitor; Mus; National Institute of Drug Abuse; Nebulizer; Neuronal Plasticity; Nicotine; Nicotine Dependence; Nose; Oral; Pharmaceutical Preparations; Phase; Pulmonary alveolar structure; Pump; Rattus; Research; Rodent; Rodent Model; Route; Schedule; Seizures; Self Administration; Series; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Smoker; Smoking; Solutions; Stimulus; Structure of mucous membrane of nose; System; Systems Development; Technology; Time; Tissues; Tobacco; Tobacco use; United States National Institutes of Health; Withholding Treatment; absorption; addiction; base; brain circulation; cigarette smoking; cigarette smoking; design; disability; drinking water; drug of abuse; engineering design; in vivo; neurobehavioral; nicotine replacement; novel; particle; pregnant; research study; response; restraint; smoking cessation; subcutaneous; tool; vapor

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.

描述(由申请人提供)：本申请是对NIH/PSH 2010-2“NIDA 2，”药物滥用研究替代给药剂型的开发“下的”SBIR/STTR资助申请的综合征集“的回应。由于烟草的使用，尼古丁是美国最常用的成瘾药物之一，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众多影响，并开发更有效、更安全的戒烟和治疗烟草相关疾病的药物，需要建立尼古丁依赖动物模型。目前可用于体内动物模型的尼古丁应用方法有许多局限性。尼古丁无法到达肺部的气体交换区域(肺泡)；因此，动脉尼古丁水平上升的时间进程和幅度无法与吸烟时的人类相比。这笔赠款的目标是开发一种非侵入性的方法和工具包，将尼古丁输送到啮齿动物模型中，以确保足够和可控的尼古丁进入循环和大脑的速度与尼古丁进入吸烟者身体的速度相同。目的1.建立一种新型的啮齿动物尼古丁给药方法，并通过动物实验进行验证。我们将通过测定空气中的半数致死浓度(LC50)和诱发包括癫痫发作在内的神经行为变化的半数有效浓度(EC50)来证明尼古丁释放的有效性。我们将优化尼古丁给药参数，以确保啮齿动物体内尼古丁浓度的时间进程与吸烟时人血中的药代动力学曲线相似。目的2.用所开发的方法设计和设计啮齿动物尼古丁递送系统。暴露系统将提供两个选项：用于准确和急性尼古丁研究的限制性暴露系统，以及用于慢性研究的家庭笼子内的自由移动暴露系统。这些系统将被整合到我们公司开发的SmartCageTM平台中，该平台可以自动和定量地监测尼古丁暴露期间的啮齿动物行为，这是一种用于成瘾研究的强大工具。这个第一阶段的项目将开发一种非侵入性的有效方法来给啮齿动物注射尼古丁，从而创建与吸烟的人的尼古丁血液浓度的时间过程和大小非常相似的动物模型。我们将为研究吸烟的急性尼古丁影响和使用家庭笼子的慢性影响提供重要工具。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)戒烟有重要意义。这一第一阶段项目将为第二阶段项目奠定基础，该项目为大鼠和小鼠开发商业产品系列，并有可能开发其他滥用药物，如大麻、可卡因、海洛因和其他药物。 公共卫生相关性：由于烟草的使用，尼古丁是美国最常用的成瘾药物之一，也是导致疾病、残疾和死亡的主要可预防原因。拟议项目的目标是开发一种工具包，用于给啮齿动物注射尼古丁。这样的工具包将确保控制尼古丁进入血液循环和大脑的数量，从而允许设计实验，在实验中，尼古丁对人类的影响可能会得到更准确的模拟。这种方法将为动物研究提供强大的工具，以了解尼古丁对大脑和身体的众多影响。此外，这一方法将成为开发更有效和更安全的戒烟和治疗烟草相关疾病的药物的平台。