当前位置: X-MOL 学术Clin. Pharmacol. Ther. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Development of a Translational Model to Assess the Impact of Opioid Overdose and Naloxone Dosing on Respiratory Depression and Cardiac Arrest
Clinical Pharmacology & Therapeutics ( IF 6.3 ) Pub Date : 2022-06-29 , DOI: 10.1002/cpt.2696
John Mann 1 , Mohammadreza Samieegohar 1 , Anik Chaturbedi 1 , Joel Zirkle 1 , Xiaomei Han 1 , S Farzad Ahmadi 1 , Amy Eshleman 2 , Aaron Janowsky 2 , Katherine Wolfrum 2 , Tracy Swanson 2 , Shelley Bloom 2 , Albert Dahan 3 , Erik Olofsen 3 , Jeffry Florian 1 , David G Strauss 1 , Zhihua Li 1
Affiliation  

In response to a surge of deaths from synthetic opioid overdoses, there have been increased efforts to distribute naloxone products in community settings. Prior research has assessed the effectiveness of naloxone in the hospital setting; however, it is challenging to assess naloxone dosing regimens in the community/first-responder setting, including reversal of respiratory depression effects of fentanyl and its derivatives (fentanyls). Here, we describe the development and validation of a mechanistic model that combines opioid mu receptor binding kinetics, opioid agonist and antagonist pharmacokinetics, and human respiratory and circulatory physiology, to evaluate naloxone dosing to reverse respiratory depression. Validation supports our model, which can quantitatively predict displacement of opioids by naloxone from opioid mu receptors in vitro, hypoxia-induced cardiac arrest in vivo, and opioid-induced respiratory depression in humans from different fentanyls. After validation, overdose simulations were performed with fentanyl and carfentanil followed by administration of different intramuscular naloxone products. Carfentanil induced more cardiac arrest events and was more difficult to reverse than fentanyl. Opioid receptor binding data indicated that carfentanil has substantially slower dissociation kinetics from the opioid receptor compared with nine other fentanyls tested, which likely contributes to the difficulty in reversing carfentanil. Administration of the same dose of naloxone intramuscularly from two different naloxone products with different formulations resulted in differences in the number of virtual patients experiencing cardiac arrest. This work provides a robust framework to evaluate dosing regimens of opioid receptor antagonists to reverse opioid-induced respiratory depression, including those caused by newly emerging synthetic opioids.

中文翻译:

开发转化模型以评估阿片类药物过量和纳洛酮剂量对呼吸抑制和心脏骤停的影响

为了应对合成阿片类药物过量导致的死亡人数激增,人们加大了在社区环境中分发纳洛酮产品的力度。之前的研究已经评估了纳洛酮在医院环境中的有效性;然而,在社区/急救人员环境中评估纳洛酮给药方案具有挑战性,包括逆转芬太尼及其衍生物(芬太尼)的呼吸抑制作用。在这里,我们描述了结合阿片类 mu 受体结合动力学、阿片类激动剂和拮抗剂药代动力学以及人类呼吸和循环生理学的机制模型的开发和验证,以评估纳洛酮剂量以逆转呼吸抑制。验证支持我们的模型,该模型可以定量预测纳洛酮从阿片类药物 mu 受体置换阿片类药物体外,体内缺氧性心脏骤停和阿片类药物引起的人类呼吸抑制来自不同的芬太尼。验证后,使用芬太尼和卡芬太尼进行过量模拟,然后使用不同的肌内注射纳洛酮产品。卡芬太尼诱发了更多的心脏骤停事件,并且比芬太尼更难逆转。阿片受体结合数据表明,与所测试的其他九种芬太尼相比,卡芬太尼与阿片受体的解离动力学要慢得多,这可能是逆转卡芬太尼困难的原因。从具有不同配方的两种不同纳洛酮产品肌肉注射相同剂量的纳洛酮导致经历心脏骤停的虚拟患者数量的差异。
更新日期:2022-06-29
down
wechat
bug