SL 84.0418 is an agr;2-adrenoceptor antagonist that has been proposed as an oral antihyperglycaemic agent for its ability to reduce glucose-evoked hyperglycaemia. The aim of the present study was to evaluate the pharmacological activity and safety of SL 84.0418 in healthy volunteers after repeated administrations. Ten male subjects (mean age 25 plusmn; 3.1 years; mean bodyweight 77 plusmn; 11.7kg) took part in this open study. SL 84.0418 was administered as a single 10mg oral dose for 7 consecutive days, 1 hour after a standard breakfast. Pharmacological activity was assessed through plasma glucose and insulin concentrations, determined immediately before and 2 and 4 hours after administration on days 1, 3 and 7. The safety evaluation was based on: (a) daily physical examination (including bodyweight, blood pressure and heart rate); (b) basal and final routine blood tests as well as electrocardiographic findings; (c) adverse events spontaneously reported by the subjects. On days 1, 3 and 7, two hours after drug administration, a significant increase in plasma insulin levels associated with a significant (except for day 3) decrease in plasma glucose levels was observed. Plasma insulin and glucose levels returned to baseline levels 4 hours after administration. SL 84.0418 was well tolerated by all subjects with no clinically relevant adverse events. Physical examination, bodyweight and laboratory tests were unchanged during treatment. Cardiovascular parameters were not significantly modified, except for minor, asymptomatic variations in diastolic blood pressure in the supine position (78 plusmn; 4.2 and 71 plusmn; 9.6mm Hg on days 0 and 3, respectively) and in heart rate in the standing position on the first 2 days of treatment (74 plusmn; 10.1, 83 plusmn; 15.0 and 83 plusmn; 12.0 beatssol;minute on days 0, 1 and 2, respectively). We conclude that SL 84.0418 is an orally active insulin-releasing agent that was well tolerated in healthy volunteers after administration of 10mg once daily for 7 days.
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