COMPUTER-CONTROLLED INFUSION OF ORG-21465, A WATER-SOLUBLE STEROID IVANESTHETIC AGENT, INTO HUMAN VOLUNTEERS

ORG 21465 has been found to possess anaesthetic properties in humans a nd its pharmacokinetics are known. We performed this study to confirm the characteristics associated with its administration and to define i ts pharmacodynamic profile, in particular to explore the relationship between sedation, anaesthesia, excitation and plasma drug concentratio ns. A water soluble preparation of ORG 21465 was administered to six m ale volunteers as a series of three 15-min computer-controlled, pharma cokinetic model-driven infusions targeting three exponentially increas ing plasma concentrations: 0.5, 1 and 2 mu g ml(-1). The clinical char acteristics of the resultant sedation and anaesthesia were observed. P lasma concentrations of ORG 21465 were measured during and for 500 min after the infusions and the EEG recorded. A sigmoid e-max effect comp artment pharmacodynamic model was fitted to the plasma concentrations and an EEG derivative (spectral edge frequency (SEF)). Anaesthesia wit h ORG 21465 was associated with involuntary movements in all subjects. A steady state concentration of 1180 ng ml(-1) depressed SEF by 50%, the Hill factor describing the sigmoid nature of the concentration-res ponse curve was 1.42 and the equilibration rate constant of the biopha se was 0.112 min(-1). Anaesthesia with ORG 21465 was found to be unsat isfactory because of involuntary movements and slow equilibration with the biophase.