Treatment of Fentanyl Overdose-Induced Respiratory Failure by Low-Dose Dexmedetomidine

小剂量右美托咪定治疗芬太尼过量所致呼吸衰竭

基本信息

批准号：
10701905
负责人：
Philippe A Haouzi
金额：
$ 60.18万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10701905
关键词：
Abdomen Acceleration Acute Acute respiratory failure Adrenergic Agents Airway Resistance Animals Breathing Central Sleep Apnea Cessation of life Chest wall structure Depressed mood Dexmedetomidine Dose FDA approved Fatal Outcome Fentanyl Goals Hour Human Hypoventilation Hypoxemia Hypoxia Induced Heart Arrest Infusion procedures Injections Intention Intranasal Administration Intravenous Lead Life Mammals Mechanical ventilation Mediating Mental Depression Metabolism Modeling Movement Muscle Muscle Contraction Muscle Rigidity Neurons Opioid Opioid agonist Outcome Oxygen Consumption Pathway interactions Phase Pontine structure Positioning Attribute Rattus Respiratory Failure Respiratory Mechanics Respiratory System Rodent Sedation procedure Skeletal Muscle Stimulant Structure Survival Rate Tidal Volume Time Toxic effect Ventilatory Depression alpha 2 agonist awake dosage efficacy study fentanyl overdose improved intravenous administration intravenous injection locus ceruleus structure opioid exposure opioid mortality opioid overdose prevent respiratory restoration sedative sheep model ventilation

项目摘要

SUMMARY The objective of our proposal is to demonstrate that the restoration of respiratory mechanics and of the metabolism by low doses of the central alpha-2 agonist dexmedetomidine results in an increase in ventilation and prevents the fatal outcome of an opioid overdose. Death by opioid overdose is the consequence of an acute respiratory failure mediated by a direct and indirect inhibition of the medullary respiratory neurons. This inhibition is associated with immediate and prolonged tetanic contractions of the inspiratory and expiratory muscles and an increase in upper-airway resistance that impede respiratory movements for hours. Opioid-induced muscle “rigidity” is produced via neurons in the locus coeruleus and can be suppressed by central alpha-2 agonist agents. Our preliminary results, obtained in sedated and non- sedated rats, show that infusion of low doses of the central alpha-2 agonist dexmedetomidine restores chest wall compliance and suppresses the hypermetabolism produced by fentanyl-induced muscle rigidity, while increasing minute ventilation. The objective of our proposal is to demonstrate that administration of dexmedetomidine, after opioid exposure, prevents a fatal outcome. If efficacy is demonstrated in rodents, we intend to pursue efficacy studies in a non- anesthetized sheep model of fentanyl overdose. This model will allow us to establish the doses of dexmedetomidine needed to produce a beneficial effect without sedation. The effects of intravenous and intranasal dexmedetomidine will be examined. Our intention is to obtain, via 505(b)2 pathway, an FDA approval for non-sedative doses of dexmedetomidine as a treatment of opioid overdose.

概括我们提案的目的是证明呼吸技工的恢复和低剂量的中央α-2激动剂右美托咪定的代谢导致通风增加并防止阿片类药物过量的致命结果。阿片类药物过量死亡是直接和间接介导的急性呼吸衰竭的结果抑制髓质呼吸神经元。这种抑制与立即和延长的四烷型有关吸气和到期肌肉的收缩以及障碍的上流阻力的增加呼吸运动数小时。阿片类药物诱导的肌肉“刚性”是通过基因座的神经元产生的并且可以被中央α-2激动剂剂抑制。我们的初步结果，在镇静和非 - 镇静大鼠表明，低剂量的中央α-2激动剂右美托咪定的输注可恢复胸部墙壁依从性并抑制芬太尼诱导的肌肉刚度产生的超定代谢，而增加通风。我们建议的目的是证明右美托胺的给药，阿片类药物暴露后，防止致命结果。如果在啮齿动物中证明了效率，我们打算在非 - 麻醉的芬太尼过量的绵羊模型。该模型将使我们能够确定右美托咪定需要产生有益的效果而无需镇静。静脉和将检查鼻内右美托咪定。我们的目的是通过505（b）2途径获得FDA批准用于非辅助剂量的右美托咪定作为阿片类药物过量的治疗。