Restoring The Mechanical Properties of the Respiratory System as a Treatment of Fentanyl Overdose-Induced Hypoventilation using Kappa Agonists

使用 Kappa 激动剂恢复呼吸系统的机械特性来治疗芬太尼过量引起的通气不足

• 批准号: 10410611
• 负责人: Philippe A Haouzi
• 金额: $ 20.3万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410611
• 关键词: Abdominal Muscles; Acute; Acute respiratory failure; Agonist; Airway Resistance; Alveolar; Animals; Bolus Infusion; Breathing; Cardiopulmonary Resuscitation; Central Sleep Apnea; Cessation of life; Chest wall structure; Chronic; Chronic Kidney Failure; Complex; Depressed mood; Development Plans; Dose; Exposure to; Fatal Outcome; Fentanyl; Formulation; Frequencies; Goals; Hour; Human; Hyperactive behavior; Hypoventilation; Hypoxemia; Hypoxia; Individual; Injections; Intoxication; Intravenous; Japan; Lead; Life; Literature; Mammals; Mechanical ventilation; Metabolism; Modeling; Morphine; Movement; Mus; Muscle; Muscle Contraction; Muscle Rigidity; Naloxone; Neurons; Opioid; Opioid Antagonist; Opioid agonist; Overdose; Oxygen Consumption; Pain; Patients; Periodicity; Pickwickian Syndrome; Pontine structure; Pruritus; Publishing; Pulmonary Gas Exchange; Rattus; Recovery; Respiratory Failure; Respiratory Mechanics; Respiratory System; Risk; Risk Factors; Rodent; Rodent Model; Route; Secondary to; Skeletal Muscle; Speed; Stimulant; Survival Rate; Testing; Tidal Volume; Ventilatory Depression; Withdrawal; addiction; chronic respiratory disease; dosage; efficacy study; fentanyl overdose; improved; kappa opioid receptors; locus ceruleus structure; mass casualty; mechanical properties; mu opioid receptors; opioid overdose; prevent; respiratory; respiratory oxygen; ventilation

ABSTRACT Mu-opioid agonist overdose is associated with immediate and prolonged tetanic and rhythmic contractions of the inspiratory and expiratory muscles that impede respiratory movements for hours. This effect, referred to as opioid induced chest wall rigidity, is a critical mechanism contributing to the lethality of opioid-induced hypoventilation. Mu-opioid-induced muscle “rigidity” is produced by neurons in the locus coeruleus and can be suppressed by kappa-opioid receptor agonists, but not by current ventilatory stimulants. The objective of our proposal is to demonstrate, following an overdose by the mu-opioid receptor agonist fentanyl, that kappa-opioid receptor agonists 1- restore the alteration of passive respiratory mechanics and suppress the hypermetabolism produced by fentanyl induced muscle rigidity, 2- prevent a fatal outcome in unsedated rats. We will test nalfurafine, the only commercially available kappa agonist, and show that it counteracts the ventilatory effects of a fentanyl overdose. If efficacy is demonstrated in rodents, we will pursue these efficacy studies in non-anesthetized large mammal models and will test intravenous as well as intranasal route. Our ultimate goal is to obtain FDA approval for nalfurafine as a treatment of mu-opioid receptor agonist-induced hypoventilation, treatment that could be used in indications ranging from mass casualty to individual victims of opioid intoxication.

抽象的 Mu-阿片受体激动剂过量与立即和长期的强直性和节律性收缩有关。 吸气和呼气肌肉会阻碍呼吸运动数小时。这种作用称为阿片类药物 引起的胸壁僵硬是导致阿片类药物引起的通气不足致死的关键机制。 Mu-阿片类药物引起的肌肉“僵硬”是由蓝斑神经元产生的，可以通过以下方式抑制： kappa-阿片受体激动剂，但不是目前的通气兴奋剂。我们建议的目标是 证明，在过量服用 mu-阿片受体激动剂芬太尼后，κ-阿片受体 激动剂 1- 恢复被动呼吸力学的改变并抑制产生的代谢亢进 通过芬太尼诱导的肌肉僵硬，2-可防止未镇静大鼠的致命结果。我们将测试纳芙拉芬 唯一市售的 kappa 激动剂，并表明它可以抵消芬太尼的通气作用 过量。如果在啮齿动物中证明了疗效，我们将在非麻醉的大型动物中进行这些功效研究 哺乳动物模型并将测试静脉内和鼻内途径。我们的最终目标是获得 FDA 批准 对于纳芙拉芬作为 mu-阿片受体激动剂引起的通气不足的治疗，治疗可能是 用于从大规模伤亡到阿片类药物中毒个体受害者的适应症。