Lobeline Clinical Study in ADHD

洛贝林治疗多动症的临床研究

• 批准号: 7497074
• 负责人: Mark S Kleven
• 金额: $ 7.66万
• 依托单位: YAUPON THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497074
• 关键词: Acute; Adult; Adverse effects; Adverse event; Alkaloids; Amphetamines; Animal Experiments; Animal Model; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Behavioral Symptoms; Blood Pressure; Brain; Clinical; Clinical Research; Clinical Trials; Cocaine; Committee Members; Conduct Clinical Trials; Corpus striatum structure; Data; Date Available; Desire for food; Development; Dopamine; Dose; Double-Blind Method; Feasibility Studies; Growth; Heart Rate; Human; Hyperactive behavior; Ilex vomitoria; Impulsivity; Laboratory Study; Learning; Lobelia; Lobeline; Measures; Memory; Methamphetamine; Methylphenidate; Neurobiology; Neurocognitive Deficit; Nicotine; Nicotinic Receptors; Norepinephrine; Outcome Measure; Patient Self-Report; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phase; Physiological; Placebo Control; Population; Purpose; Range; Rate; Recording of previous events; Research; Rewards; Risk; Safety; Self Administration; Self-Administered; Short-Term Memory; Small Business Technology Transfer Research; Study Subject; Suicide; Symptoms; Therapeutic; cigarette smoking; concept; drug of abuse; improved; inattention; neural circuit; neurotransmission; novel; pre-clinical; preclinical study; receptor function; smoking cessation; vesicular monoamine transporter

DESCRIPTION (provided by applicant): The purpose of this STTR Phase 1 application is to obtain proof-of-concept evidence that supports the indication of lobeline for the treatment of adult Attention Deficit Hyperactivity Disorder (ADHD). Research on the neurobiology of ADHD implicates abnormalities in brain dopamine (DA) and norepinephrine (NE) and possibly in nicotinic receptors. Currently available stimulant medications reverse the core behavioral symptoms and neurocognitive deficits that characterize ADHD, but are not without limitations or risks. Lobeline is a nonstimulant alkaloid shown in preclinical studies to alter DA and NE neurotransmission by interacting with the vesicular monoamine transporter (VMAT2) and acts as a nicotinic receptor antagonist. Lobeline inhibits hyperactivity induced by nicotine and amphetamine. Preclinical studies demonstrate that lobeline decreases the reinforcing effects of methamphetamine, suggesting that it will not increase the use of drugs of abuse. Furthermore, lobeline has been found to be safe in clinical trials. In the proposed initial proof- of-concept, human laboratory study, the physiological and behavioral effects of a range of doses of lobeline will be assessed in adults with ADHD. Particular emphasis will be made to task measures of attention, impulsivity and working memory. In addition, subjective effects related to abuse liability and drug tolerability will be assessed. We hypothesize that lobeline will decrease inattention and impulsivity and enhance working memory in adults with ADHD. We expect lobeline to be well tolerated and not to engender changes in self- report measures associated with abuse liability. Methylphenidate will be evaluated as a positive control to provide confirmation that the measures of inattention, impulsivity and working memory are sensitive to therapeutic drug effects. Results from the proposed study will provide proof-of-concept that lobeline has potential as an efficacious non-stimulant medication for ADHD. If improvements on outcome measures of attention and memory are obtained with lobeline, we will advance to a human clinical trial to demonstrate the efficacy of lobeline in an ADHD population. This project supports the development of a safe and effective non-stimulant medication for the treatment of adult Attention Deficit Hyperactivity Disorder. The study will evaluate the ability of lobeline to improve the hallmark symptoms of ADHD, including inattention, impulsivity and memory problems. Also, lobeline will be assessed for side-effects and abuse liability. Information obtained from the proposed study will inform subsequent clinical trials aimed at determining if lobeline is a useful and efficacious treatment for adult ADHD.

描述（由申请人提供）：本STTR I期申请的目的是获得支持洛贝林治疗成人注意缺陷多动障碍（ADHD）适应症的概念验证证据。对ADHD的神经生物学研究表明，大脑多巴胺（DA）和去甲肾上腺素（NE）可能存在异常，尼古丁受体也可能存在异常。目前可用的兴奋剂药物逆转了ADHD的核心行为症状和神经认知缺陷，但并非没有限制或风险。洛贝林是一种非刺激性生物碱，在临床前研究中显示通过与囊泡单胺转运蛋白（VMAT 2）相互作用改变DA和NE神经传递，并作为烟碱受体拮抗剂。洛贝林抑制尼古丁和安非他明引起的多动症。临床前研究表明，洛贝林降低了甲基苯丙胺的强化作用，这表明它不会增加滥用药物的使用。此外，在临床试验中发现洛贝林是安全的。在拟议的初步概念验证、人类实验室研究中，将在患有ADHD的成人中评估一系列剂量的洛贝林的生理和行为效应。将特别强调注意力，冲动和工作记忆的任务措施。此外，还将评估与滥用倾向和药物耐受性相关的主观效应。我们假设，洛贝林将减少注意力不集中和冲动，并增强工作记忆的成人多动症。我们期望洛贝林能够被很好地耐受，并且不会引起与滥用责任相关的自我报告措施的变化。哌醋甲酯将作为阳性对照进行评价，以确认注意力不集中、冲动和工作记忆的测量值对治疗药物效应敏感。拟议研究的结果将提供概念验证，即洛贝林有潜力作为ADHD的有效非兴奋剂药物。如果用洛贝林可以改善注意力和记忆力的结果，我们将进行人体临床试验，以证明洛贝林在ADHD人群中的疗效。该项目支持开发一种安全有效的非兴奋剂药物，用于治疗成人注意力缺陷多动障碍。这项研究将评估洛贝林改善多动症标志性症状的能力，包括注意力不集中，冲动和记忆问题。此外，洛贝林将评估副作用和滥用责任。从拟议的研究中获得的信息将为随后的临床试验提供信息，旨在确定洛贝林是否是一种有用和有效的成人ADHD治疗方法。