Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in a rat model

Tharusan Thevathasan, Stephanie D. Grabitz, Peter Santer, Paul Rostin, Oluwaseun Akeju, James D. Boghosian, Monica Gill, Lyle Isaacs, Joseph F. Cotten, Matthias Eikermann

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)e140-e147
JournalBritish Journal of Anaesthesia
Volume125
Issue number1
DOIs
StatePublished - Jul 2020
Externally publishedYes

Keywords

  • anaesthesia
  • analgesics
  • delayed emergence
  • fentanyl
  • muscle rigidity
  • opioid reversal
  • postoperative complications
  • respiratory depression

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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