CERC-501 Kappa Antagonist for Nicotine Dependence

CERC-501 尼古丁依赖性 Kappa 拮抗剂

• 批准号: 9041849
• 负责人: SANDRA D COMER
• 金额: $ 102.05万
• 依托单位: CERECOR. INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041849
• 关键词: Abstinence; Address; Adult; Affective; Agonist; Alcohols; Anhedonia; Animal Model; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Attenuated; Basic Science; Behavior; Behavioral; Bioavailable; Biological; Brain; Bupropion; Cessation of life; Chronic; Cigarette; Clinical Research; Collaborations; Consensus; Consumption; Controlled Environment; Crossover Design; Cues; Data; Development; Diagnostic; Dopamine; Dose; Double-Blind Method; Drops; Firearms; Funding; Goals; Guidelines; HIV; Heroin; Hour; Human; Hyperalgesia; Illicit Drugs; Institutes; Kentucky; Laboratories; Laboratory Study; Marketing; Measurement; Measures; Mediating; Mental Depression; Modality; Modeling; Moods; New York; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Opioid Receptor; Oral; Outcome Measure; Outpatients; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebos; Play; Prevalence; Rattus; Relapse; Research; Research Personnel; Rewards; Risk Factors; Rodent; Role; Safety; Self Administration; Self-Administered; Severities; Signal Transduction; Smoke; Smoker; Smoking; Smoking Behavior; Stress; Subgroup; Substance Use Disorder; System; Time; Tobacco; Tobacco Dependence; Tobacco use; Universities; Update; Withdrawal; Withholding Treatment; addiction; alternative treatment; cigarette smoking; cohort; commercialization; craving; design; disturbance in affect; drug seeking behavior; drug withdrawal; efficacy testing; hedonic; human subject; improved; meetings; nicotine replacement; novel; novel therapeutics; open field behavior; physical symptom; preclinical study; public health priorities; public health relevance; receptor; reinforcer; relating to nervous system; research clinical testing; secondary outcome; small molecule; smoking cessation; smoking relapse; success; symptomatic improvement; symptomatology; varenicline; vehicular accident; ward

 DESCRIPTION (provided by applicant): Tobacco contributes to more deaths in the US each year than HIV, illicit drugs, alcohol, motor vehicle accidents, and firearm-related fatalities combined. While the commercialization of therapies for smoking cessation has enhanced abstinence, long-term abstinence rates are low. Kappa opiate receptor (KOR) antagonism has the potential to address the mood alterations that are associated with nicotine withdrawal, including irritability, anxiety, and depression. KORs are upregulated by chronic substance exposure and are thought to participate in mediating stress-induced reinstatement of drug-seeking behavior. Data to date support an emerging consensus that KOR antagonists have antidepressant-like effects, reduce excessive substance consumption, and reduce behaviors and signs of drug withdrawal (nicotine, alcohol, heroin). The availability of a highly selective, orally active, once-daily, well-tolerated kappa antagonist like CERC-501 would represent a promising treatment alternative for substance use disorders including nicotine dependence. Clinical studies to date suggest that CERC-501 safely and selectively blocks KOR in healthy adult humans. In animal studies, CERC-501 has demonstrated antidepressant-like effects and reduces the hyperalgesia, somatic signs and open field behaviors of nicotine-withdrawn rats. Cerecor's plans for CERC-501 include its registration as an aid to smoking cessation treatment. The primary objective of the proposal is to generate data in a Phase 1b/2a human laboratory study demonstrating that CERC-501 increases the ability to resist smoking relative to placebo, as measured by time to first cigarette and number of self-administered cigarettes in non-treatment seeking heavy smokers (Specific Aim 1). The experimental paradigm proposed herein has been previously developed and validated by others (McKee, et al 2012; Roche, et al 2014) to measure smoking lapse behaviors (time to first cigarette; number of cigarettes smoked) in smokers undergoing abstinence from cigarette smoking in a controlled environment. The model appears to be sensitive to risk factors for `real world' smoking relapse, the severity of nicotine dependence, and the degree of hedonic effect achieved with smoking. Healthy, heavy smokers are proposed to be dosed under staff observation daily with CERC-501 to steady state, and then admitted to a clinical research ward for overnight nicotine abstinence. After 18 hours of abstinence, the subjects will be presented with a smoking cue, and rewarded for every 5 minutes that they are able to abstain from smoking. Once the time to lapse has been established, they will be allowed to smoke ad libitum. The impact of CERC-501 on state measures of nicotine withdrawal, mood, anhedonia, anxiety, and craving, as well as its safety and tolerability in this cohort will be assessed (Specific Aims 2 and 3).

 描述（由申请人提供）：在美国，烟草每年导致的死亡人数比艾滋病毒、非法药物、酒精、机动车事故和枪支相关死亡人数的总和还多，尽管戒烟疗法的商业化提高了戒烟率，但长期来看。 Kappa 阿片受体 (KOR) 拮抗剂有可能解决与尼古丁戒断相关的情绪变化，包括烦躁、焦虑和抑郁。 KOR 会因慢性物质暴露而上调，并被认为参与介导压力诱导的药物寻求行为的恢复。迄今为止的数据支持一个新的共识，即 KOR 拮抗剂具有抗抑郁样作用，可减少过度的物质消耗，并减少行为和体征。 CERC-501 等高度选择性、口服活性、每日一次、耐受性良好的 kappa 拮抗剂的可用性将成为药物滥用障碍（包括药物滥用障碍）的一种有前途的治疗替代方案。迄今为止的临床研究表明，CERC-501 可安全、选择性地阻断健康成年人体内的 KOR。在动物研究中，CERC-501 已表现出类似抗抑郁的作用，并可减少尼古丁戒断患者的痛觉过敏、躯体症状和旷场行为。 Cerecor 的 CERC-501 计划包括将其注册为戒烟治疗的辅助手段。该提案的主要目标是生成阶段数据。 1b/2a 人体实验室研究表明，相对于安慰剂，CERC-501 提高了抵抗吸烟的能力，通过未接受治疗的重度吸烟者首次吸烟的时间和自行吸食香烟的数量来衡量（具体目标 1）。所提出的范式之前已由其他人开发和验证（McKee 等人，2012 年；Roche 等人，2014 年），用于测量戒烟行为（第一次吸烟的时间；吸第一支烟的时间）在受控环境中戒烟的吸烟者中，该模型似乎对“现实世界”吸烟复发的风险因素、尼古丁依赖的严重程度以及吸烟所达到的享乐效果敏感。建议重度吸烟者在工作人员观察下每天服用CERC-501至稳定状态，然后入住临床研究病房进行过夜尼古丁戒断，戒烟18小时后，将向受试者提供吸烟提示，并在他们能够戒烟的每 5 分钟内给予奖励。 一旦确定了戒烟时间，他们将被允许随意吸烟。 CERC-501 对他们的影响。将评估该队列中尼古丁戒断、情绪、快感缺失、焦虑和渴望的国家措施及其安全性和耐受性（具体目标 2 和 3）。