A cyclodextrin formulation to improve use of the anaesthetic tribromoethanol (Avertin)

Abstract

Objective: Efficacy and safety concerns have been raised in the literature with the use of tribromoethanol (Avertin) for anaesthesia in rats and mice when administered by intraperitoneal injection. Despite the controversy, it remains in common usage as an anaesthetic agent in laboratory rodents for short-term surgical procedures. Cyclodextrins have been shown to improve drug solubility and were investigated here as an improved anaesthetic formulation for mice. Materials and Methods: The phase solubility of TBE with HP-β-CD was estimated. The efficacy of two anaesthetic regimens were compared in this study; the conventional tribromoethanol (TBE) formulation solubilized in tertiary amyl alcohol and a HP-β-CD cyclodextrin formulation containing TBE. Mice (n=6) were administered the formulations by IP injection and the pharmacodynamic parameters of time to induction of anaesthesia, duration of anaesthesia and recovery time were measured using a combined reflex score. Results and Discussion: Phase solubility studies showed a linear increase in the solubility of TBE with increasing HP-β-CD concentration and suggested > 1:1 binding of the drug in the cyclodextrin complex. At a dose of 260 mg/kg the standard TBE formulation appeared to produce deeper anaesthesia than the cyclodextrin formulation, with a minimum average CRS of 1.8 compared to 5.2. No post-mortem pathology was observed in mice that received either the conventional or cyclodextrin formulation. Conclusion: The cyclodextrin TBE formulation did not conclusively provide an improved anaesthetic response at a dose of 260 mg/kg compared to the conventional formulation. The improved solubility of TBE with HP-β-CD and the reduced variability in anaesthetic response warrants the further investigation of this formulation. This study has also identified the value of using the anticholinergic atropine in association with TBE for anaesthesia.