PRELIMINARY INVESTIGATIONS OF THE CLINICAL-PHARMACOLOGY OF 3 SHORT-ACTING NONDEPOLARIZING NEUROMUSCULAR BLOCKING-AGENTS, ORG 9453, ORG 9489 AND ORG 9487

Three muscle relaxants, Org 9453, Org 9489 and Org 9487, short-acting in animals, were investigated to establish their profiles in humans. Potency, time course of action, and pharmacokinetic behaviour were studied in 90 healthy patients during fentanyl/halothane/N2O anaesthesia. Neuromuscular function was monitored mechanomyographically. Plasma and urine concentrations (three patients per compound) were measured by HPLC, and these data were analyzed by iterative linear least square regression analysis. The ED(90) valuesfor Org 9453, Org 9489 and Org 9487 were 1.4, 0.45 and 1.15 mg kg(-1) respectively. The onset times of Org 9453 (1.5 mg.kg(-1), 1.1 X ED(90)), Org 9489 (0.9 mg.kg(-1) 2 X ED(90)) and Org 9487 (1.5 mg.kg(-1), 1.3 X ED(90)) were 1.2, 1.6 and 1.5 min, and the durations until 25% twitch recovery were 8.6, 22.0 and 8.9 min, respectively. Clearances of these doses were 6.9, 5.8, and 11.1 ml.kg(-1).min(-1), and mean residence times 26, 79, and 41 min, respectively. Mean renal excretion (parent compound and metabolites) within 24 hr amounted to 5, 11.3 and 12.2% respectively. No side effects other than a moderate short-lasting decrease of blood pressure and a concomittant increase in heart rate were noted. It is concluded that Org 9453 and Org 9487 are short-acting muscle relaxants in humans.