Fixed dose analgesic combination with non-opioid mechanism to prevent opioid misuse

固定剂量镇痛与非阿片类药物机制的组合可防止阿片类药物滥用

• 批准号: 9912257
• 负责人: ARTOUR GOMTSIAN
• 金额: $ 22.23万
• 依托单位: SYNVENTA, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912257
• 关键词: Absence of pain sensation; Address; Adrenergic Agents; Adrenergic Receptor; Adult; Adverse effects; Agonist; Analgesics; Antihypertensive Agents; Back; Benefits and Risks; Biological; Blood Pressure; Body Temperature; Cardiovascular Physiology; Clinical; Clonidine; Dose; Drug Combinations; FDA approved; Funding Opportunities; Heat Losses; Human; Hyperthermia; Hypotension; Induced Hyperthermia; Knowledge; Medical; Methods; Monitor; Opioid; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Physiologic Thermoregulation; Probability; Property; Protocols documentation; Publishing; Rattus; Risk; Safety; Small Business Innovation Research Grant; TRPV1 gene; Telemetry; Testing; Withdrawal Symptom; base; chronic pain; clinical development; combat; experience; experimental study; lofexidine; non-opioid analgesic; novel; opioid misuse; opioid overdose; opioid withdrawal; pre-clinical; prescription opioid misuse; presynaptic; prevent; programs; receptor; response; sex

PROJECT SUMMARY / ABSTRACT With nearly 116 mln people suffering from chronic pain in the US alone and the global market projected to reach $83 bln by 2024, there is both a major unmet medical need and a significant commercial opportunity. Dominated by opioid drugs, this field also suffered from alarming consequences of opioid drug overuse and misuse. Antagonists acting at TRPV1 receptor have long been recognized as one of the most promising novel classes of non-opioid analgesics. Several drug companies have developed highly selective and potent compounds. Initial tests in humans have confirmed pharmacodynamic profile expected for this class of agents (i.e. analgesia). However, despite an overall good safety and tolerability, there were significant effects on thermoregulation resulting in clinically meaningful hyperthermia and partial loss of heat sensitivity. These effects have led to the discontinuation of essentially all of the advanced programs in the field of TRPV1 antagonists. In this regard, and in line with funding opportunity RFA-DA-19-019, the current application proposes to conduct a set of preclinical proof of concept studies in rats to support the claims that, at doses that have minimal, clinically acceptable or negligible impact on cardiovascular function, a2 adrenoceptor agonists can diminish thermoregulatory effects of TRPV1 receptor antagonists. In Phase 1, we will demonstrate that (Aim 1) presynaptically acting a2 adrenoceptor agonists such as lofexidine can prevent or diminish the hyperthermic responses to TRPV1 receptor antagonists; (Aim 2) at the doses controlling thermoregulatory effects of TRPV1 receptor antagonists, a2 adrenoceptor agonists have minimal or acceptable effects on hypotension.

项目总结/摘要 仅在美国就有近1.16亿人患有慢性疼痛，全球市场预计 到2024年达到830亿美元，既有一个重大的未满足的医疗需求，也有一个重大的商业机会。 这一领域以阿片类药物为主，阿片类药物过度使用也造成了令人震惊的后果， 误用作用于TRPV 1受体的拮抗剂长期以来被认为是最有前途的新型药物之一， 非阿片类镇痛药的种类。几家制药公司已经开发出高选择性和有效的 化合物.在人体中的初步试验证实了这类药物的预期药效学特征 (i.e.镇痛）。然而，尽管总体上具有良好的安全性和耐受性， 体温调节导致临床上有意义的体温过高和热敏感性的部分丧失。这些影响 已经导致TRPV 1拮抗剂领域基本上所有高级项目的中止。在 在这方面，根据资助机会RFA-DA-19-019，目前的申请建议进行一次 在大鼠中进行的一组临床前概念验证研究，以支持以下声明：在具有最小临床 对心血管功能的影响可接受或可忽略，α 2肾上腺素受体激动剂可减少 TRPV 1受体拮抗剂的体温调节作用。 在第1阶段，我们将证明（目标1）突触前作用的α 2肾上腺素受体激动剂，如 洛非西定可预防或减轻TRPV 1受体拮抗剂的热反应; 控制TRPV 1受体拮抗剂、α 2肾上腺素受体激动剂的体温调节作用的剂量， 对低血压的影响极小或可接受。