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-Apioid激动剂过量与直接和长时间的破坏和有节奏的收缩有关 吸气和到期肌肉会阻碍呼吸运动数小时。这种作用，称为阿片类药物 诱发的胸壁刚度是导致阿片类药物诱导不足衰减的致死性的关键机制。 MU-阿片类诱导的肌肉“刚度”是由凝座层中神经元产生的，可以被抑制 Kappa-阿片受体激动剂，但不是通过当前的通气刺激物。我们建议的目的是 表明，随着Mu-Apoid受体激动剂芬太尼的过量服用，Kappa-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超定代谢 通过芬太尼诱导的肌肉僵硬，2-防止未培养大鼠的致命结果。我们将测试Nalfurafine， 仅商业可用的喀巴激动剂，并表明它抵消了芬太尼的通气作用 过量。如果在啮齿动物中证明了效率，我们将在非麻醉大型的大型研究中进行这些效率研究 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 对于纳尔列芬作为对mu阿片受体激动剂诱导的不足的治疗，可以是 用于从大规模伤亡到阿片类药物中毒的个体受害者的适应症。