CERC-501 Kappa Antagonist for Nicotine Dependence

CERC-501 尼古丁依赖性 Kappa 拮抗剂

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：烟草每年与艾滋病毒，非法毒品，酒精，机动车事故和与枪支有关的死亡人数的总和造成更多的死亡。虽然戒烟疗法的商业化增强了禁欲，但长期禁欲率很低。 Kappa鸦片接收器（Kor）拮抗作用有可能解决与尼古丁戒断有关的情绪改变，包括烦躁，焦虑和抑郁。 KOR通过慢性物质暴露来更新，并被认为参与介导压力引起的毒品寻求行为的恢复。迄今为止的数据支持了新的共识，即KOR拮抗剂具有抗抑郁药样的作用，减少过量的物质消耗，并减少戒断药物的行为和迹象（尼古丁，酒精，海洛因）。像CERC-501这样的高度选择性，口服，每天一次，耐受性良好的Kappa拮抗剂的可用性将代表用于物质使用障碍（包括尼古丁依赖性）的承诺治疗方法。迄今为止，临床研究表明，CERC-501安全，有选择地阻止了健康的成年人中的Kor。在动物研究中，CERC-501证明了抗抑郁药样的作用，并减少了尼古丁 - 尼古丁大鼠的痛觉过敏，体征和开放式行为。 Cerecor的CERC-501计划包括注册以帮助戒烟治疗。该提案的主要目的是在1B/2A期的人类实验室研究中生成数据，表明CERC-501可以提高相对于安慰剂的抵抗吸烟的能力，这是通过第一次香烟的时间和在寻求繁重吸烟者的非治疗中的自我管理香烟数量来衡量的（特定的目标1）。此处提出的范式先前已由其他人（McKee等人，2012; Roche等，2014）进行了验证，以测量在受控环境中吸烟的吸烟者中吸烟者中的吸烟行为（第一烟的时间；吸烟数量）。该模型似乎对“现实世界”吸烟中继的危险因素敏感，尼古丁依赖的严重程度以及吸烟所达到的享乐效应程度。建议每天使用CERC-501进行稳定的健康吸烟者在员工观察下进行dod，然后进入临床研究病房进行过夜的尼古丁禁欲。节制18小时后，将向受试者提供吸烟提示，并每5分钟获得一次奖励，以免吸烟。一旦建立了失误的时间，他们将被允许随意抽烟。 CERC-501对尼古丁戒断，情绪，狂热，焦虑和渴望的状态测量的影响以及其在该队列中的安全性和耐受性的影响（具体目的2和3）。