Tharusan Thevathasan1, Stephanie D Grabitz2, Peter Santer3, Paul Rostin1, Oluwaseun Akeju1, James D Boghosian1, Monica Gill1, Lyle Isaacs4, Joseph F Cotten1, Matthias Eikermann5. 1. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA. 2. 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. 3. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 4. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA. 5. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, Essen, Germany. Electronic address: meikerma@bidmc.harvard.edu.
Abstract
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.
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.
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