Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Br J Anaesth. 2020 Jul;125(1):e140-e147. doi: 10.1016/j.bja.2020.02.019. Epub 2020 Mar 30.
We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS.
Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 μg kg over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5-200 mg kg) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG).
Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50 and ED90) were 1.7 and 15.6 mg kg, respectively. Higher effective doses were needed for recovery of righting reflex (ED50: 9.6 mg kg; ED90: 86.1 mg kg), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity.
Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.
我们假设 Calabadion 1（一种非循环的葫芦[n]脲分子容器）可逆转芬太尼引起的呼吸抑制和中枢神经系统功能障碍。
在雄性 Sprague-Dawley 大鼠中进行了实验。静脉输注芬太尼（12.5 或 25μg/kg 持续 15 分钟），随后静脉推注 Calabadion 1（0.5-200mg/kg）或安慰剂。主要结局是通过气动描记法和动脉血气分析分别评估通气和呼吸抑制的逆转。关键次要结局是通过翻正反射、平衡梁试验和肌电图（EMG）定量评估芬太尼引起的中枢神经系统功能障碍的影响。
Calabadion 1 逆转了芬太尼引起的呼吸抑制，终点为分钟通气量、pH 值和 Paco（P=0.001）。与安慰剂相比，Calabadion 1 剂量依赖性地（P 趋势<0.001）逆转了芬太尼引起的通气不足{81.9[5.1]（均值[标准误差均值]）与 45.5[12.4]ml/min；P<0.001}、酸中毒（pH 值 7.43[0.01]与 7.28[0.04]；P=0.005）和高碳酸血症（Paco 43.4[1.6]与 63.4[8.1]mmHg；P=0.018）。逆转呼吸抑制 50%和 90%所需的有效 Calabadion 1 剂量分别为 1.7 和 15.6mg/kg。恢复翻正反射需要更高的有效剂量（ED50：9.6mg/kg；ED90：86.1mg/kg），Calabadion 1 可加速恢复（4.6[0.3]与 9.0[0.7]分钟；P<0.001）。Calabadion 1 还显著加速了完全功能性运动的恢复和肌肉僵硬的逆转。
Calabadion 1 选择性和剂量依赖性地逆转了芬太尼的呼吸系统和中枢神经系统副作用。
