1 The elimination and anticoagulant activity of a single intravenous dose of warfarin (1.0‐1.2 mg/kg) without and with concomitant cholestyramine treatment (about 4 g three times daily) was studied in five healthy male subjects. 2 Cholestyramine treatment decreased the biological half‐life of plasma warfarin (from a mean value of 2 days − 1.3 days) and increased the total clearance of this drug (from a mean value of 37 ml kg‐1 day‐1–53 ml kg‐1 day‐1). 3 The total anticoagulant effect per dose of warfarin, as measured by the area under the effect v time curve, was also reduced by cholestyramine (average reduction of about 25%). 4 Warfarin possibly undergoes enterohepatic recycling in man which can be interrupted by cholestyramine.

1 The free fraction of azapropazone in the plasma of 37 healthy volunteers ranged from 0.0027 to 0.0070 (0.0044 + 0.0009, mean s.d.). The principal binding protein was found to be albumin. 2 In 27 patients with various degrees of renal failure the free fraction values of azapropazone were markedly enhanced (0.0260 + 0.0239, mean + s.d.) and increased more than tenfold in some patients. There was a weak correlation (r = 0.46, P<0.05) between the free fraction and the clearance of endogenous creatinine. Such correlation was not found for serum creatinine, serum albumin, serum uric acid and serum urea nitrogen. 3 In 32 patients with chronic liver disease the free fraction values of azapropazone were also markedly higher (0.0210 + 0.0242, mean + s.d.) than in healthy subjects. There were statistical significant correlations between the free fraction values and the prothrombin complex activity in the plasma (r = 0.40, P<0.05) and the total bilirubin concentration in the plasma (r = 0.90, P<0.001), respectively. Such correlation was not found for serum albumin, serum glutamic oxalacetic transaminase, serum -y-glutamyl transpeptidase and serum alkaline phosphatase. 4 In patients with kidney and liver disease the free fraction values of azapropazone correlated well with those of the anticoagulant drug phenprocoumon (r = 0.93, P<0

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In a randomized, controlled study 10 male patients with angiographically confirmed ischaemic heart disease received AQ-A 39 (falipamil), a heart rate reducing agent in a single intravenous dose (2 mg kg-1) in comparison to propranolol (0.1 mg kg-1). Both drugs reduced heart rate in supine position slightly. The rise of heart rate induced by orthostasis was diminished by AQ-A 39 to 4 +/- 2 beats min-1 and by propranolol 9 +/- 2 beats min-1. After submaximal exercise heart rate during placebo was 129 +/- 3, during AQ-A 39 113 +/- 3 and during propranolol 103 +/- beats min-1. Systolic arterial pressure decreased by propranolol only. The double product obtained by placebo was 231 +/- 10 while it was for 194 +/- 9 after AQ-A 39 and 158 +/- 6 mmHg min-1 after propranolol, respectively. Both substances increased exercise time as compared to placebo. Furthermore, AQ-A 39 increased noradrenaline plasma levels in the upright position and after submaximal exercise compared to the values obtained following placebo. The dose of isoproterenol necessary to induce an increase of heart rate by 20 beats min-1 was after AQ-A 39 4.2 times greater and following propranolol 9.2 times greater than during placebo. The results suggest that AQ-A 39 will be useful in the short term management of patients with ischaemic heart disease.

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The effect of iv digoxin on normal sinus node function was studied after pharmacologic autonomic blockade (AB) in ten patients. Sinus cycle length (SCL), sinus node recovery time (SNRT) and sinoatrial conduction time (SACT) were determined before and after AB with propranolol (0.2 mg/kg body weight) and atropine sulfate (0.04 mg/kg body weight) iv, and 15 min, 30 min, and 45 min after 1 mg iv digoxin. AB resulted in a significant decrease (P less than 0.01) in SCL (916 +/- 158 to 716 +/- 120 ms), in SNRT (1,229 +/- 221 to 871 +/- 190 ms), and in SACT (79 +/- 34 to 44 +/- 10 ms). Fifteen minutes after iv digoxin there was no significant change observed in SCL (716 +/- 120 to 708 +/- 92 ms), in SNRT (871 +/- 190 to 864 +/- 148 ms), or in SACT (44 +/- 10 to 46 +/- 15 ms). Similar results were obtained 30 min after digoxin administration. It is concluded that a single therapeutic dose of digoxin has no direct effect on electrophysiologic parameters of normal intrinsic sinus node function.