A novel opioid receptor antagonist for treating abuse and overdose

一种用于治疗滥用和过量的新型阿片受体拮抗剂

基本信息

批准号：
10561706
负责人：
CHARLES P FRANCE
金额：
$ 49.24万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561706
关键词：
Acute Address Adverse effects Agonist Attenuated Behavioral Binding Buprenorphine Cessation of life Clinical Cocaine Data Dissociation Dose Drug Kinetics Effectiveness FDA approved Fentanyl Food Goals Health Personnel Heroin Infusion procedures Injections Marketing Metabolism Methadone Methocinnamox Monkeys Naloxone Naltrexone Opioid Opioid Antagonist Opioid Receptor Opioid agonist Overdose Patients Pharmaceutical Preparations Pharmacotherapy Pilot Projects Plasma Procedures Property Reporting Route Self Administration Testing Therapeutic Ventilatory Depression Withdrawal abuse liability analog antagonist carfentanil fentanyl analog improved nonhuman primate novel novel strategies opioid abuse opioid epidemic opioid mortality opioid overdose opioid use overdose death pharmacologic prevent receptor remifentanil respiratory rural area

项目摘要

ABSTRACT Deaths from opioid overdose continue to rise; from 2015-2016, there was a 28% increase in the number of fatal overdoses. Fentanyl derivatives are inexpensive, easy to synthesize, potent, and marketed to unsuspecting abusers as heroin or other drugs. Moreover, the effects of fentanyl derivatives are reportedly more difficult to reverse with naloxone, compared with reversal of heroin. Pharmacotherapies for opioid abuse include the µ opioid receptor agonists methadone and buprenorphine that are effective in many patients, although both drugs have limitations, including diversion and abuse, and they can have serious unwanted effects, including respiratory depression and death. The opioid receptor antagonists naltrexone and naloxone avoid the abuse liability and adverse effects of methadone and buprenorphine; however, short durations of action and surmountability limit their effectiveness. A medication with a longer duration of action that prevents and reverses the effects of opioids in a manner that is not surmounted by increasing doses of agonist could improve significantly treatment of abuse and save lives by providing insurmountable extended protection after rescue from overdose. Our pilot studies in monkeys show that the pseudoirreversible, µ opioid receptor selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses as well as protects against respiratory depression by heroin, with a single injection being effective for a week or longer. Proposed studies build on these compelling data and examine the long-term antagonist properties and the pharmacokinetics of MCAM in combination with commonly abuse opioids, including ultra-potent fentanyl analogs. MCAM is hypothesized to be better than naloxone and naltrexone in reversing and preventing the effects of opioid receptor agonists and, in particular, high efficacy agonists that exert behavioral effects when occupying relatively few opioid receptors. Its pseudoirreversible binding is expected to make antagonism by MCAM more difficult to surmount and to provide longer antagonist action than the currently used opioid receptor antagonists. Aim 1 will characterize long-term antagonism of heroin self-administration by MCAM in a food/drug choice procedure. Aim 2 will examine the ability of MCAM to antagonize the positive reinforcing and respiratory depressant effects of fentanyl and ultra- potent analogs alone and in mixtures with heroin or cocaine. Aim 3 will characterize the pharmacokinetic profile of MCAM, heroin, fentanyl and its derivatives, and cocaine, alone and in mixtures. Using a highly translatable species, this project will examine a novel opioid receptor antagonist that has the potential to save lives by preventing and reversing the adverse, and often lethal, effects of opioids. The availability of another safe, effective, and long-acting treatment could be advantageous for many patients (e.g., problems with compliance would be reduced by an extended-release, pseudoirreversible antagonist) and in many treatment settings (e.g., rural areas where the opioid epidemic is worsening and regular contact with treatment providers is not practical).

抽象的 2015年至2016年间，阿片类药物过量导致的死亡人数持续上升，死亡人数增加了28% 芬太尼衍生物价格低廉、易于合成、效力强，并且销售给毫无戒心的人。此外，据报道，芬太尼衍生物的作用更难以确定。与逆转海洛因相比，纳洛酮逆转阿片类药物滥用的药物疗法包括 µ。阿片受体激动剂美沙酮和丁丙诺啡对许多患者有效，尽管这两种药物有局限性，包括转移和滥用，并且可能会产生严重的不良影响，包括阿片受体拮抗剂纳曲酮和纳洛酮可避免滥用。美沙酮和丁丙诺啡的责任和不良反应；然而，作用持续时间短且可克服性限制了其作用持续时间较长的药物，可以预防和治疗。以增加激动剂剂量无法克服的方式逆转阿片类药物的作用，可以改善通过在救援后提供难以克服的扩展保护来显着治疗虐待并挽救生命我们对猴子的初步研究表明，μ阿片受体具有伪不可逆选择性。拮抗剂甲氧肉桂酸 (MCAM) 可减少海洛因但不会减少可卡因的自我给药，减少对海洛因的选择在食物/药物选择过程中使用瑞芬太尼，并通过以下方式逆转并防止呼吸抑制：拟议的研究建立在这些引人注目的基础上。数据并检查 MCAM 的长期拮抗特性和药代动力学常见滥用的阿片类药物，包括超强效的芬太尼类似物，被重新认定为优于阿片类药物。纳洛酮和纳曲酮逆转和预防阿片受体激动剂的作用，特别是当占据相对较少的阿片受体时发挥行为作用的高效激动剂。假不可逆结合预计会使 MCAM 的拮抗作用更难以克服和提供目标 1 具有比目前使用的阿片受体拮抗剂更长的拮抗作用。目标 2 将检查 MCAM 在食物/药物选择程序中对海洛因自我给药的拮抗作用。 MCAM 拮抗芬太尼和超强药物的正增强和呼吸抑制作用的能力单独的有效类似物以及与海洛因或可卡因的混合物将表征药代动力学特征。单独使用或混合使用 MCAM、海洛因、芬太尼及其衍生物和可卡因。该项目将研究一种新型阿片受体拮抗剂，该拮抗剂有可能通过以下方式拯救生命：预防和扭转阿片类药物的不利且通常是致命的影响提供另一种安全、有效的药物。有效且长效的治疗可能对许多患者有利（例如，依从性问题）会被缓释、假不可逆拮抗剂减少）并且在许多治疗环境中（例如，阿片类药物流行日益恶化的农村地区，定期与治疗提供者联系并不现实）。