Miller Thomas L, Mathews Jeanette, Dungan George C, Pergolizzi Joseph V, Raffa Robert B
Clinical Development, Enalare Therapeutics, Princeton, USA.
Research and Development, Enalare Therapeutics, Princeton, USA.
Cureus. 2024 Nov 30;16(11):e74826. doi: 10.7759/cureus.74826. eCollection 2024 Nov.
Xylazine exacerbates the respiratory depression induced by fentanyl. Because xylazine is a non-opioid, it is resistant to reversal by opioid receptor antagonists such as naloxone (e.g., Narcan), thereby complicating attempts at treatment of fentanyl overdose. Antagonists of large-conductance potassium BK (big potassium) channels (BK) in the carotid bodies reverse drug-induced hypoxia (decreased pO) and hypercapnia (increased pCO). In animals and human volunteers, the selective BK antagonist ENA-001 reverses the respiratory depression induced by opioids and non-opioids, i.e., it is an "agnostic" respiratory reversal agent. Given the seriousness of xylazine plus fentanyl combination (XFC) overdose, the present pilot study in rats was designed to evaluate the potential of a single intravenous bolus of ENA-001 to mitigate the acute respiratory depression induced by a prior intravenous bolus infusion of an XFC. XFC-induced respiratory depression was manifested as a decrease in pO and an increase in pCO. ENA-001, but not the vehicle, rapidly reversed these XFC-induced changes. Based on the results of this pilot study, the "agnostic" nature of ENA-001 respiratory stimulation appears to extend to XFC-induced overdose. Given the urgent clinical need, additional study seems warranted.
赛拉嗪会加剧芬太尼引起的呼吸抑制。由于赛拉嗪是非阿片类药物，它对阿片受体拮抗剂（如纳洛酮，例如盐酸纳洛酮）的逆转作用具有抗性，从而使芬太尼过量中毒的治疗变得复杂。颈动脉体中大电导钾通道（BK，大钾通道）的拮抗剂可逆转药物诱导的低氧血症（pO降低）和高碳酸血症（pCO升高）。在动物和人类志愿者中，选择性BK拮抗剂ENA-001可逆转阿片类药物和非阿片类药物引起的呼吸抑制，即它是一种“非特异性”呼吸逆转剂。鉴于赛拉嗪加芬太尼联合用药（XFC）过量中毒的严重性，本大鼠初步研究旨在评估单次静脉推注ENA-001减轻先前静脉推注XFC引起的急性呼吸抑制的潜力。XFC引起的呼吸抑制表现为pO降低和pCO升高。ENA-001而非溶媒迅速逆转了这些由XFC引起的变化。基于该初步研究的结果，ENA-001呼吸刺激的“非特异性”性质似乎也适用于XFC引起的过量中毒。鉴于迫切的临床需求，似乎有必要进行更多研究。
