In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the administered dose of labetalol. Labetalol was rapidly absorbed from the gastrointestinal tract and peak plasma concentrations occurred two hours after oral administration. There was a linear correlation (r = 0.84) between the logarithm of the plasma concentration and the maximum inhibition of exercise tachycardia at two hours. After intravenous administration there was an immediate reduction in systolic and diastolic blood pressure with a concomitant small increase in heart rate. There was a rapid decline in the associated plasma concentration but the pharmacological effects were maintained in excess of two hours. Our findings are consistent with those of others who have studied the relationship between pharmacological events and plasma concentrations after single doses of other adrenoceptor blocking drugs.

1In healthy male volunteers after single oral doses, AH 5158 produced inhibition of exercise induced tachycardia, falls in systolic and diastolic pressure at rest and in response to exercise, which are probably related to combined f-and a-adrenoceptor antagonism. 2 At increasing doses from 100 mg to 400 mg there exists a dose related antagonistic effect, though the dominant effect of,-adrenoceptor antagonism is more easily demonstrable than is a antagonism. 3 As indicated by the pattern of pharmacological effects, absorption of the oral drug is good and the duration of action of a 400 mg dose is approximately 8 hours. 4 Despite being administered in j3-adrenoceptor blocking doses, AH 5158 had no adverse effects upon peak expiratory flow at rest or in response to exercise. 5It is concluded that the pharmacological profile of this combined a-and ,B-adrenoceptor antagonism suggests a potential therapeutic role as an antihypertensive drug.

SUMMARY The pharmacokinetics and gastric antisecretory effects of a new histamine H2-receptor antagonist, ranitidine hydrochloride, have been investigated in healthy subjects. In the pharmacokinetic study six subjects received 20 mg, 40 mg, and 80 mg ranitidine, both orally and intravenously. Plasma levels of ranitidine were dose-related and in most subjects after oral drug the concentration time curve was bimodal. The estimated elimination half-life was 140 minutes and the bioavailability of the oral drug was about 50%. Five subjects received bolus intravenous injections of ranitidine 20 mg, 40 mg, and 80 mg during continuous gastric stimulation with pentagastrin. There was a dose-related reduction in acid output (P <0.05).Recently, the aminomethylfuran derivative, raniti- (Fig. 1) has been described as a potent H2-antagonist.1 In vivo and in vitro studies have shown that ranitidine is a competitive H2-antagonist without significant activity at histamine H1-receptors or at cholinergic receptors. In experimental animals gastric secretion stimulated by histamine, pentagastrin or a test meal was inhibited by ranitidine. It was effective by both parenteral and oral routes and was approximately four to five times more potent than cimetidine. In the present two studies we investigated the effects of ranitidine in healthy volunteers. Methods SUBJECTSEleven healthy men were studied in two groups. In the first study there were six subjects with a mean age of 27 years (range of 23 to 31 years) and a mean weight of 69 kg (range of 58 kg to 76 kg). There were five subjects in the second study with a mean age of 29 years (range of 25 years to 35 years) and a mean weight of 71 kg (range of 63 kg to 76 kg). Informed consent was obtained from each volunteer. TEST PROCEDURESIn both studies the subjects fasted overnight and the Received for publication 18 October 1979 tests began between 9 and 10-30 am. The first study investigated the acceptability and pharmacokinetics of ranitidine hydrochloride after oral and intravenous administration. Each subject received on different occasions and by both routes 20 mg, 40 mg, and 80 mg measured as base, except one subject who did not receive the highest intravenous dose. The intravenous drug was diluted to 20 ml with normal saline and was injected into an antecubital vein over a period of two minutes. Blood samples were obtained through a Butterfly needle which was inserted into a vein in the other arm and kept patent with heparinised saline. The times of blood samples were pre-drug and 2, 5, 15, 30 and 45 minutes and 1, 1 , 2, 3, 4, 5, 6, 7, and 24 hours after administration of the drug. The subjects were supine during the intravenous injection and for the following hour, after which they were ambulant but rested semi-reclining for 15 minutes before the time of each blood sample. Pulse rate and blood pressure, using a Hawksley random zero sphygmomanometer, were also recorded at these times. A lead 2 electrocardiogram was recorded during the injection and for oneminute periods at the ...

I Intravenously administered phentolamine provoked immediate decreases in diastolic blood pressure but increases in heart rate and cardiac output. 2 These immediate circulatory effects had largely disappeared twenty minutes after administration and at this time phentolamine did not inhibit increases in blood pressure which were provoked during hand immersion in ice-cold water. 3 Log dose-response curves of noradrenaline induced increases in systolic and diastolic pressure 20 min after intravenous phentolamine were shifted to the right in a parallel manner compared with the curves before phentolamine administration. 4 It was concluded that the immediate and short acting effects induced by phentolamine are due to a non-specific vasodilator effect but in addition phentolamine causes a longer acting a-adrenoceptor blockade at vascular adrenoceptor sites. However, by producing both pre-and post-synaptic aadrenoceptor blockade this may explain why this drug exerts only a weak antihypertensive effect.

1 The effects of oral propranolol (80 mg), labetalol (400 mg) and placebo on blood pressure, pulse rate and FEV1 at rest and after inhaled histamine, have been compared in six healthy male volunteers. 2 At 90 and 120 min after ingestion propranolol reduced the pulse rate and labetalol reduced the blood pressure, thus confirming absorption of each drug. 3 At 120 min propranolol reduced resting FEV1 and enhanced the fall in FEV1 after histamine, whereas the alterations in FEV1 after labetalol did not differ from placebo. 4 These findings suggest that labetalol is less likely than propranolol to cause bronchoconstriction in asthmatic patients.