Lobeline Clinical Study in ADHD

描述(由申请人提供)：此STTR1期申请的目的是获得概念验证证据，支持洛贝林治疗成人注意缺陷多动障碍(ADHD)的适应症。对ADHD的神经生物学研究表明，脑多巴胺(DA)和去甲肾上腺素(NE)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，但也不是没有局限性或风险。洛贝林是临床前研究中发现的一种非刺激性生物碱，通过与囊泡单胺转运体(VMAT2)相互作用改变DA和NE的神经传递，并作为烟碱受体拮抗剂。洛贝林可抑制尼古丁和苯丙胺引起的多动。临床前研究表明，洛贝林降低了甲基苯丙胺的强化作用，表明它不会增加滥用药物的使用。此外，洛贝林在临床试验中被发现是安全的。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成人ADHD患者的生理和行为影响。将特别强调对注意力、冲动和工作记忆的测试。此外，还将评估与滥用责任和药物耐受性有关的主观影响。我们假设洛贝林将减少注意力不集中和冲动，并增强患有ADHD的成年人的工作记忆。我们希望洛贝林能得到很好的耐受性，并且不会导致与滥用责任相关的自我报告措施的变化。哌醋甲酯将被评估为阳性对照，以证实注意力不集中、冲动和工作记忆等指标对治疗药物效果敏感。拟议的研究结果将提供概念证明，洛贝林具有作为治疗ADHD的有效非刺激性药物的潜力。如果洛贝林对注意力和记忆力的结果指标有改善，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来治疗成人注意缺陷多动障碍。这项研究将评估洛贝林改善ADHD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，洛贝林将接受副作用和滥用责任的评估。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，这些试验旨在确定洛贝林是否是治疗成人ADHD的有用和有效的治疗方法。

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.