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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).

摘要阿片类药物过量死亡人数继续上升；从2015-2016年，死亡人数增加了28% 吸毒过量。芬太尼衍生物价格低廉，易于合成，有效，并销售给不知情的人作为海洛因或其他毒品的滥用者。此外，据报道，芬太尼衍生物的影响更难纳洛酮逆转，与海洛因逆转相比。治疗阿片类药物滥用的药物疗法包括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，包括转移注意力和滥用，它们可能会产生严重的有害影响，包括呼吸抑制和死亡。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易感性和不良反应；然而，短期和可克服性限制了它们的有效性。一种作用时间较长的药物，可预防和以一种不能通过增加激动剂剂量来克服的方式逆转阿片类药物的影响可以改善通过在救援后提供难以逾越的延伸保护，显著治疗虐待并拯救生命因为服药过量。我们在猴子身上的先导研究表明，假不可逆、µ阿片受体选择性拮抗剂美索那莫(MCAM)减少海洛因，但不减少可卡因的自我给药，减少对瑞芬太尼在食物/药物选择程序中的作用，逆转并保护呼吸抑制，通过海洛因，单次注射有效一周或更长时间。拟议的研究建立在这些令人信服的基础上数据和检测MCAM的长期拮抗剂性质和药代动力学通常滥用阿片类药物，包括超强效芬太尼类似物。MCAM被假设为比纳洛酮和纳曲酮逆转和预防阿片受体激动剂的作用，尤其是，当占据相对较少的阿片受体时产生行为影响的高效激动剂。它的假不可逆结合预计将使MCAM的拮抗更难克服和提供比目前使用的阿片受体拮抗剂的拮抗作用更长。目标1将描述长期的 MCAM在食物/药物选择过程中对海洛因自我给药的拮抗作用。Aim 2将研究 MCAM拮抗芬太尼和超氧化物歧化酶的正性增强和呼吸抑制作用有效的类似物单独或与海洛因或可卡因的混合物。目标3将描述药物动力学特征 MCAM、海洛因、芬太尼及其衍生物和可卡因的单独和混合使用。使用高度可翻译的物种，这个项目将研究一种新的阿片受体拮抗剂，它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影响，而且往往是致命的。另一个保险箱的可用性，有效、长效的治疗对许多患者可能是有利的(例如，依从性问题会被缓释的假不可逆拮抗剂降低)并且在许多治疗环境中(例如，阿片类药物流行正在恶化的农村地区，与治疗提供者定期接触是不切实际的)。