Lobeline Clinical Study in ADHD

描述（由申请人提供）：本次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）适应症的概念证明证据。ADHD的神经生物学研究提示大脑多巴胺（DA）和去甲肾上腺素（NE）的异常，可能还有尼古丁受体的异常。目前可用的兴奋剂药物可以逆转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。红血碱是一种非刺激性生物碱，在临床前研究中显示，它通过与水泡单胺转运蛋白（VMAT2）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，洛贝林减少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，红血莲在临床试验中被证明是安全的。在拟议的初步概念验证，人体实验室研究中，将评估一系列剂量的洛贝林对ADHD成人的生理和行为影响。我们将特别强调对注意力、冲动和工作记忆的任务测量。此外，还将评估与滥用责任和药物耐受性有关的主观影响。我们假设洛贝林会减少注意力不集中和冲动，并增强ADHD成人的工作记忆。我们希望lobeline能够被很好地容忍，并且不会在与滥用责任相关的自我报告措施中产生变化。将哌醋甲酯作为阳性对照进行评估，以证实注意力不集中、冲动和工作记忆的测量对治疗药物的影响是敏感的。拟议研究的结果将提供概念证明，洛贝林有潜力作为一种有效的非兴奋剂药物治疗多动症。如果洛贝林能改善注意力和记忆力，我们将进行一项人体临床试验，以证明洛贝林对多动症人群的疗效。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。该研究将评估洛比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，还将评估洛贝林的副作用和滥用风险。从拟议的研究中获得的信息将为后续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。

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.