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).

抽象的阿片类药物过量的死亡继续增加。从2015年至2016年，致命数量增加了28％过量服用。芬太尼衍生物便宜，易于合成，潜力和销售施虐者是海洛因或其他药物。此外，据报道，芬太尼衍生物的影响更难与海洛因相反，与纳洛酮相反。阿片类药物滥用的药物治疗包括µ 阿片类药物激动剂运动酮和丁丙诺啡在许多患者中都是有效的，尽管这两种药物有局限性，包括转移和虐待，它们可能会产生严重的不良影响，包括呼吸抑郁和死亡。阿片受体拮抗剂纳曲酮和纳洛酮避免了滥用方法加多酮和丁丙诺啡的责任和不利影响；但是，行动持续时间短克服性限制了它们的有效性。采取持续时间的药物可防止和以不受增加剂量的激动剂来克服阿片类药物的影响可以改善救援后，通过提供无法克服的扩展保护来显着治疗虐待并挽救生命来自服药过量。我们在猴子中的试点研究表明，伪可逆的µ阿片类药物接收器选择性拮抗剂甲氧激素（MCAM）降低了海洛因，但不会自我管理，降低了选择的选择在食品/药物选择程序中雷依替特尼，逆转并通过海洛因，单一注射持续一周或更长时间。拟议的研究以这些引人注目数据并检查MCAM的长期拮抗剂特性和药代动力学与结合通常滥用阿片类药物，包括超功能的芬太尼类似物。 MCAM假设比纳洛酮和纳曲酮在逆转和防止阿片受体激动剂的影响，尤其是高效激动剂在占据相对较少的阿片类药物受体时会发挥行为影响。伪可逆的绑定预计将使MCAM更难以克服并提供对抗比当前使用的阿片类药物接收器拮抗剂更长的拮抗作用。 AIM 1将以长期为特征 MCAM在食品/药物选择程序中由MCAM自我管理的对抗。 AIM 2将检查 MCAM能够拮抗芬太尼和超级的阳性增强和呼吸抑制作用单独使用海洛因或可卡因混合物中的有效类似物。 AIM 3将表征药代动力学轮廓 MCAM，海洛因，芬太尼及其衍生物和可卡因，单独和混合物。使用高度翻译物种，该项目将检查一个新型的阿片类药物受体拮抗剂，该拮抗剂有可能通过防止和逆转阿片类药物的不利或致命的影响。另一个安全的可用性有效和长效治疗对许多患者可能是有利的（例如，依从性问题在许多治疗环境中，将通过延长的释放，伪可逆的拮抗剂来降低（例如，阿片类药物流行的粗糙区域令人担忧，并定期与治疗提供者接触）。