Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.
Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.
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DOI：
10.1038/s41598-021-86458-x
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发表时间：
2021-03-26
影响因子：
4.6
通讯作者：
Lewis SJ
中科院分区：
文献类型：
--
作者：
Jenkins MW;Khalid F;Baby SM;May WJ;Young AP;Bates JN;Cheng F;Seckler JM;Lewis SJ
迫切需要开发新的化合物，其防止阿片类药物如芬太尼对分钟通气量的有害影响，同时如果可能的话，保留阿片类药物的镇痛作用。我们报告L-谷胱甘肽乙酯（GSHee）可能是这样一个新的化合物。在这项研究中，我们测量了甩尾潜伏期（TFL），动脉血气（ABG）化学，肺泡-动脉梯度，并通过全身体积描记法测定芬太尼（75 μg/kg，IV）在雄性成年Sprague-Dawley大鼠中引起的反应，这些大鼠在15分钟前接受了GSHee（100 μmol/kg，IV）的推注。GSHee单独给药对TFL、ABG化学和A-a梯度的影响最小，而它引起一些呼吸参数的变化，如呼吸频率增加。在溶剂处理的大鼠中，芬太尼引起（1）TFL增加，（2）pH、pO 2和sO2降低以及pCO 2增加（均提示呼吸抑制），（3）肺泡-动脉压差增加（指示肺中通气-灌注的不匹配），和（4）呼吸参数的变化，例如潮气量的减少，表明有明显的抑郁症状在GSHee预处理的大鼠中，芬太尼引起更长时间的镇痛，ABG化学和肺泡-动脉梯度的相对较小的变化，以及显著较轻的通气抑制。GSHee可能代表一类新型硫酯药物的有效成员，这些药物能够预防强效阿片类药物（如芬太尼）引起的镇痛作用及其对肺部气体交换的有害影响，而不会影响阿片类镇痛。
There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague–Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO2 and sO2 and increases in pCO2 (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
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