TY - JOUR
T1 - Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in a rat model
AU - Thevathasan, Tharusan
AU - Grabitz, Stephanie D.
AU - Santer, Peter
AU - Rostin, Paul
AU - Akeju, Oluwaseun
AU - Boghosian, James D.
AU - Gill, Monica
AU - Isaacs, Lyle
AU - Cotten, Joseph F.
AU - Eikermann, Matthias
N1 - Publisher Copyright:
© 2020 British Journal of Anaesthesia
PY - 2020/7
Y1 - 2020/7
N2 - 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% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg−1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg−1; ED90CNS: 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.
AB - 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% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg−1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg−1; ED90CNS: 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.
KW - anaesthesia
KW - analgesics
KW - delayed emergence
KW - fentanyl
KW - muscle rigidity
KW - opioid reversal
KW - postoperative complications
KW - respiratory depression
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U2 - 10.1016/j.bja.2020.02.019
DO - 10.1016/j.bja.2020.02.019
M3 - Article
C2 - 32241547
AN - SCOPUS:85082535191
SN - 0007-0912
VL - 125
SP - e140-e147
JO - British Journal of Anaesthesia
JF - British Journal of Anaesthesia
IS - 1
ER -