Background

We hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS.

Methods

Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 μg kg⁻¹ over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5–200 mg kg⁻¹) 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).

Results

Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco₂ (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⁻¹; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco₂ 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_Res and ED90_Res) were 1.7 and 15.6 mg kg⁻¹, respectively. Higher effective doses were needed for recovery of righting reflex (ED50_CNS: 9.6 mg kg⁻¹; ED90_CNS: 86.1 mg kg⁻¹), 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.

Conclusions

Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.

中文翻译：

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Calabadion 1在大鼠模型中选择性逆转芬太尼对呼吸和中枢神经系统的影响。

背景

我们假设Calabadion 1（一种无环葫芦[ n ] uril分子容器）可以逆转芬太尼引起的呼吸抑制和中枢神经系统功能障碍。

方法

实验是在雄性Sprague-Dawley大鼠中进行的。芬太尼（12.5或25微克公斤的恒定速率静脉内输注^-1在15分钟内）施用，接着Calabadion 1（0.5-200毫克千克的静脉推注^-1）或安慰剂。主要结果是通气和呼吸抑制的逆转，分别通过气动描记术和动脉血气分析进行评估。关键的次要结局是通过扶正反射，平衡束测试和肌电图（EMG）量化对芬太尼诱导的中枢神经功能障碍的影响。

结果

Calabadion 1在每分钟通气，pH和P a co ₂的端点上逆转了芬太尼诱导的呼吸抑制（P = 0.001）。与安慰剂相比，卡拉巴第1剂量依赖性地（趋势<0.001的P）逆转了芬太尼引起的通气不足[81.9 [5.1]（平均值[平均值的标准误差]）对45.5 [12.4] ml min ^-1；P <0.001}，酸中毒（pH 7.43 [0.01] vs 7.28 [0.04]；P = 0.005）和高碳酸血症（P a co ₂ 43.4 [1.6] vs 63.4 [8.1] mm Hg；P= 0.018）。使呼吸抑制逆转50％和90％所需的有效Calabadion 1剂量（ED50 _Res和ED90 _Res）分别为1.7和15.6 mg kg ^-1。恢复直立反射需要更高的有效剂量（ED50 _CNS：9.6 mg kg ^-1； ED90 _CNS：86.1 mg kg ^-1），这由Calabadion 1加速（4.6 [0.3] vs 9.0 [0.7] min；P < 0.001）。Calabadion 1还可以显着加速全部功能活动性的恢复和肌肉僵硬度的逆转。

结论

Calabadion 1选择性地并剂量依赖性地逆转了芬太尼的呼吸系统和CNS副作用。