Fadolmidine - Favourable adverse effects profile for spinal analgesia suggested by in vitro and in vivo models

Abstract

Fadolmidine is an α₂-adrenoceptor full agonist developed for spinal analgesia with a local mode of action. The purpose of this study was to demonstrate the safety of fadolmidine on known α₂-adrenoceptor-related effects: kidney function, urodynamics and cardiovascular variables. Furthermore, the binding affinity of fadolmidine for the 5-HT₃ receptor prompted functional studies on 5-HT₃. According to the binding affinity data, fadolmidine demonstrated partial agonism on the 5-HT₃ receptor in transfected cells and in guinea pig ileum preparation. However, intravenous (IV) fadolmidine did not produce any 5-HT₃-related hemodynamic effects in anaesthetised rats. In urodynamic studies, intrathecal (IT) fadolmidine interrupted volume-evoked voiding cycles and induced overflow incontinence at high concentrations in anaesthetised rats; however, at the analgesic dose range, the effects were mild. The effects of fadolmidine on kidney function were studied in conscious rats after IV and IT dosing. While IT fadolmidine increased dose-dependent urine output, sodium ion concentration, IV doses increased only sodium ion concentration The effects of IT fadolmidine on heart rate (HR), mean arterial pressure (MAP) and sedation were evaluated in the home cage and in the open field using a telemetry system. In resting conditions, fadolmidine decreased HR dose-dependently and increased initial MAP, whereas in actively moving rats, there were no effects at analgesic doses. The results suggest that at anticipated analgesic clinical doses, IT fadolmidine provides analgesia without significant adverse effects on sedation, MAP or HR and with only modest effects on kidney function and urodynamics.

Keywords: 5-HT(3); Agonist; Fadolmidine; Kidney function; Urodynamics; α(2)-adrenoceptor.