REPEATED ADMINISTRATION OF SL-84.0418, A NEW ORAL ANTIHYPERGLYCEMIC AGENT - A PHASE-I STUDY

SL 84.0418 is an alpha(2)-adrenoceptor antagonist that has been propos ed as an oral antihyperglycaemic agent for its ability to reduce gluco se-evoked hyperglycaemia. The aim of the present study was to evaluate the pharmacological activity and safety of SL 84.0418 in healthy volu nteers after repeated administrations. Ten male subjects (mean age 25 +/- 3.1 years; mean bodyweight 77 +/- 11.7kg) took part in this open s tudy. SL 84.0418 was administered as a single 10mg oral dose for 7 con secutive days, 1 hour after a standard breakfast. Pharmacological acti vity was assessed through plasma glucose and insulin concentrations, d etermined immediately before and 2 and 4 hours after administration on days 1, 3 and 7. The safety evaluation was based on: (a) daily physic al examination (including bodyweight, blood pressure and heart rate); (b) basal and final routine blood tests as well as electrocardiographi c findings; (c) adverse events spontaneously reported by the subjects. On days 1, 3 and 7, two hours after drug administration, a significan t increase in plasma insulin levels associated with a significant (exc ept for day 3) decrease in plasma glucose levels was observed. Plasma insulin and glucose levels returned to baseline levels 4 hours after a dministration. SL 84.0418 was well tolerated by all subjects with no c linically relevant adverse events. Physical examination, bodyweight an d laboratory tests were unchanged during treatment. Cardiovascular par ameters were not significantly modified, except for minor, asymptomati c variations in diastolic blood pressure in the supine position (78 +/ - 4.2 and 71 +/- 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 +/- 10.1, 83 +/- 15.0 and 83 +/- 12.0 beats/minute on days 0, 1 and 2, re spectively). We conclude that SL 84.0418 is an orally active insulin-r eleasing agent that was well tolerated in healthy volunteers after adm inistration of 10mg once daily for 7 days.