1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10,20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times. The maximum effect (34.4 + 2.2%) occurred after 40 mg.3 There was a small decline in effect from the peak to 24 h when 40 mg produced a 23.3+2.7% reduction and a further decline to 48 h when there was a 14.6 + 1.8% reduction. 4 Plasma levels of betaxolol were measured in these studies. The peak plasma concentration occurred between 3 and 8 h with different doses. The plasma elimination half-lives after 10, 20 and 40 mg were 11.4 + 2.5, 15.9 + 4.9 and 15.1 + 3.1 h. 5 The effects of 40 mg betaxolol, 200 mg atenolol, 160 mg propranolol, 160 mg oxprenolol, 400 mg sotalol and placebo on an exercise tachycardia were compared in five subjects who received all treatments in random order. 6 There was no significant difference in the maximum reduction produced in an exercise tachycardia by the different drugs. 7 The effect of all drugs decreased with time. The effect of oxprenolol had worn off at 24 h but at 48 h only atenolol and betaxolol produced significant reductions in the exercise tachycardia. 8 Plasma concentrations of the different drugs were measured and plasma elimination half-lives determined. The half-life for betaxolol was 24.5 h which was longer than that for any of the other drugs. 9 These observations show that betaxolol is a potent f-adrenoceptor antagonist with a long duration of effect on an exercise tachycardia and a long plasma elimination half-life.

Beta adrenoceptor blockers differ mainly in their plasma elimination half-lives (t 1/2 s). It has been assumed that drugs with longer t 1/2 will have a longer duration of effect on exercise tachycardia. Several factors may influence the duration of action of beta blockers; we have investigated the contribution of plasma elimination t 1/2 and dose by comparing the effects on an exercise tachycardia in healthy subjects of placebo, 25, 50, 100, and 200 mg of atenolol and of sotalol, and 50, 100, 200, and 400 mg metoprolol. Subjects exercised before and at 2, 3, 6, 8, 24, 33, and 48 hr after oral doses of each drug. Plasma samples for measurement of drug concentration were drawn before each exercise period. Twenty-four hours after 50, 100, and 200 mg atenolol and 50, 100, 200, and 400 mg sotalol there were reductions in an exercise tachycardia; at this time reductions were greater after the larger doses. The plasma elimination t 1/2s of atenolol were between 7.2 +/0 1.0 hr. Although 50, 100, and 200 mg metoprolol induced the same reductions in an exercise tachycardia 2 hr after drug as 25, 50, and 100 mg atenolol and 50, 100, and 200 mg sotalol, these doses were without effect at 24 hr. Metoprolol 400 mg reduced exercise tachycardia at 24 hr but the effect was less than that of the three largest doses of atenolol and sotalol. The plasma elimination t 1/2 for metoprolol was between 3.6 +/- 0.6 and 5.0 +/- 1.8 hr. These results show that duration of cardiac beta blocking of cardiac beta blocking activity of atenolol, sotalol, and metoprolol is determined by the elimination t 1/2 and dose.

A Valsalva manoeuvre is probably the mechanism by which our patient initially reverted his rhythm when jumping from a height or firing a shotgun. He brought his electric fence to the hospital and used it to stop a tachycardia. Electrocardiography showed that the fast rhythm persisted for three beats after the shock, implying that the mechanism of action was probably stimulation of the vagus. Our patient's use of the diving reflex and his do it yourself "electric cardioversion" are, however, a little extreme for standard medical teaching.

The aim of this ongoing study is to determine whether or not there is a difference in terms of efficacy between lower dose and higher dose streptokinase (STK) regimens used in the systemic thrombolytic therapy of acute myocardial infarction. Acute infarction patients are randomized to low dose (600,000 I.U.) or high dose (1,500,000 I.U.) STK delivered over 30 minutes. To date 52 cases have been serially paired and analysed statistically by the method of sequential analysis. One response taken to be of primary importance as an indirect indicator of clot lysis in assessment of treatment is the time to onset of recession of the ST segment towards the isoelectric baseline on the ECG.Another response is the ratio of fibrinogen/fibrin degradation products formed per unit of plasma fibrinogen. This is a direct measurement of plasmin activity. Treatment preference per low dose/high dose pairing is plotted in Figures 1 and 2 respectively for each response. No chart entry is made where there is no marked preference. In both instances, though statistical significance (p < 0.05) has not yet been reached, the trend is strongly in favour of low dose STK or, at a minimum, no difference between the doses. Not least, this has economic implications also.

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