The intravenous infusion of I.C.I. 50172 in doses up to 20 mg reduced, although not significantly, the increase in heart rate produced by the infusion of isoprenaline in healthy volunteers; the response to adrenaline was significantly reduced. The infusion of 1 mg propranolol abolished these responses After the pre‐treatment of subjects with atropine or hexamethonium, I.C.T. 50172 produced a significant reduction in an isoprenaline tachycardia. This reduction was not competitive and did not exceed 50%. The intravenous injection of 4 mg I.C.I. 50172 reduced an exercise tachycardia; its effect was less than that of 4 mg propranolol. This difference became greater as the doses of the two drugs were increased. The dextro isomer of propranolol had no effect on the exercise tachycardia; I.C.I. 45763 reduced it to the same extent as propranolol. The intravenous injection of I.C.I. 50172 reduced the increase in heart rate produced by tilting a normal subject from the supine to 80° head‐up position. After the administration of atropine, I.C.I. 50172 almost abolished the response. In the presence of atropine, I.C.I. 50172 was as active as propranolol in reducing the increase in heart rate on tilting. The reason for the differences in the effects of I.C.I. 50172 on the increases in heart rate brought about by the three procedures is not clear. The increase in forearm blood flow produced by the infusion of isoprenaline into the brachial artery was not reduced by the intra‐arterial administration of I.C.I. 50172.

No abstract

1 In a double‐blind, placebo controlled study, the efficacy of Ro 15‐ 1788, a new benzodiazepine antagonist, in blocking the cognitive, psychomotor and subjective effects of diazepam, was investigated in a group of six healthy male volunteers. 2 The central effects of orally administered diazepam (40 mg) were most pronounced 1 h after dosing and persisted for 9 h with decreasing severity. 3 Concurrent oral administration of Ro 15‐1788 (200 mg) completely prevented the impairment in cognitive and psychomotor function observed after diazepam alone. 4 The duration of action of Ro 15‐1788 was shorter than that of diazepam. 5 Plasma diazepam levels after administration of the diazepam/antagonist combination were very similar to those observed following diazepam alone.

The benzodiazepines are typified by a profile of side effects which includes drowsiness, ataxia and incoordination. Ro 15-1788, an imidazodiazepine derivative, exhibits marked antagonism of the behavioural and biochemical effects of the benzodiazepines in animals and man. It is devoid of any behavioural activity in animals, except at very high doses. In the present study the effects of single rising oral doses of Ro 15-1788 on cognitive, psychomotor and subjective function in man have been assessed using a battery of psychometric tests designed to identify the sedative action of the benzodiazepines. At all doses up to 600 mg, Ro 15-1788 demonstrated none of the classical behavioural effects of the benzodiazepines.