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Notes: Summary This study reports an approach to the investigation of new intravenous anaesthetic agents. Minaxolone (0.5%) was administered to healthy young adult volunteers in three different phases of study: (i) Subanaesthetic constant-rate infusion of 0.01 mg·kg−1min−1 for 120 min; (ii) Subanaesthetic and anaesthetic infusion regimens of 0.05 mg·kg−1 min−1 for 60 min, followed immediately by 0.020 mg·kg−1min−1 for 60 min; approximately four weeks later the same subjects received infusions of 0.01 mg·kg−1min−1 and 0.015 mg·kg−1min−1 respectively for the same period of time; (iii) Bolus injections of 10 mg and 40 mg over 1 min, at 2 h apart. Similar pharmacokinetic parameters were derived from all three different regimens, most notably characterised by high total body clearance (1.6 to 3.2l·min−1), correlating with rapid lucid clinical recovery of CNS function. Renal clearance was less than 0.5% of total body clearance, which was consistently 2 to 3 times the clearance of indocyanine green. Terminal half-life was short. The subanaesthetic infusion regimen of minaxolone produced a sleep-like state from which subjects were rousable, obeyed commands readily and maintained verbal contact with investigators, while remaining amnesic throughout. This occurred at blood minaxolone concentration of 0.14 to 0.15 mg·l−1. In the second stage, general anaesthesia was induced at a mean blood minaxolone concentration of 0.24 mg·l−1 (SD 0.11). Intravenous bolus injections of 40 mg minaxolone invariably induced anaesthesia with mean blood concentrations of 0.49 mg·l−1 (SD 0.29) 2 min postinjection. Onset of anaesthesia was very rapid, mean 55 s (SD 10), with a consistent duration of anaesthesia (mean 23 min, SD 3). Recovery was very rapid and lucid, without any tendency to lapse back into sleep again. Generally, the incidence of adverse effects was greatest with anaesthetic bolus doses and least with subanaesthetic infusions. Whilst only mild excitatory movements were observed in 60% of subjects who received the subanaesthetic infusion, these increased in frequency and intensity with the anaesthetic infusions and occurred with the greatest severity in all subjects who received the 40 mg bolus injection. Tachycardia invariably was noted in all phases of study. A remarkably high incidence of respiratory upsets, in the form of tachypnoea, hyperventilation, apnoea, hiccoughs and laryngospasm, was observed with the 40 mg bolus dosage. Minaxolone, therefore, whilst possessing pharmacokinetic properties desirable of an IV anaesthetic agent, had disturbing clinical effects which may limit its clinical use. Using this approach, studies in only 15 volunteer subjects were successful in describing the pharmacokinetics, blood concentration-response relationships as well as the incidence and nature of side effects. On the basis of these data, it was possible to determine that the new drug, minaxolone, did not show sufficient promise to warrant further development. This methodology would seem to provide a useful model in the investigation of new intravenous anaesthetics to optimise patient safety and development costs.