Acenocoumarol Therapy Research Articles

Lack of effect of cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol.

The kinetics and dynamics of single doses (5 mg p.o.) of the optical isomers of acenocoumarol (R-AC and S-AC) were followed in healthy subjects and the effect on them of cimetidine 800 mg/day was also investigated. The AC enantiomers differed greatly in their pharmacokinetics. The mean residence time (MRT) of R-AC was about 10 times longer than that of S-AC, 15 h vs 1.2 h. There was no difference in the volume of distribution. Depression of blood clotting activity (Thrombotest) was observed only after administration of R-AC. The inactivity of S-AC as a vitamin K antagonist must be ascribed to its short MRT. Cimetidine did not affect the acute oral kinetics of R- and S-AC, nor did it affect the anticlotting activity of R-AC. The urinary excretion pattern of the 6- and 7-hydroxylated AC metabolites was not altered during cimetidine treatment. Although the present studies showed no effect of cimetidine on the pharmacokinetics and dynamics of acenocoumarol, the findings of Serlin et al. suggest that cimetidine should not be administered during acenocoumarol therapy.

Effect of age and sex on acenocoumarol requirements.

A group of 690 patients (337 males and 353 females) on long-term acenocoumarol therapy was studied. 62.8% of the values of the prothrombin ratio were within the chosen therapeutic range (1.8 to 2.7), 21.9% were below 1.8 and 15.3% were above 2.7. The daily maintenance dose, expressed on a weight basis, was found to significantly decrease with increasing age. The daily maintenance dose taken by females was significantly higher than the dose taken by males (P less than 0.05); the differences between males and females were maximal among patients aged between 21 and 50 years, and disappeared at older ages. Two hundred and twenty-eight haemorrhagic episodes in 160 patients were recorded during a total of 7797 months of follow-up. No lethal haemorrhages were observed. The overall incidence of bleeding episodes among females (3.6%) was higher than among males (2.2%) (P less than 0.001), even if menorrhagia was excluded (P less than 0.01).

The potentiation of acenocoumarol anticoagulant effect by amiodarone.

Out of 690 patients (337 males and 353 females) on long-term acenocoumarol therapy, 80 (35 males and 45 females) were taking amiodarone. Forty patients had started amiodarone treatment while being treated with acenocoumarol. Of these, nine patients had begun amiodarone treatment while taking acenocoumarol. The relation between the daily dose of acenocoumarol and the prothrombin ratio (AC dose/PR ratio) has been considered a useful indicator to study the interaction between amiodarone and acenocoumarol. Differences of acenocoumarol daily dose between takers and non-takers of amiodarone were statistically significant (t = 5.35; P less than 0.001) for the whole population, for all the age groups, and also among males (t = 2.43; P less than 0.01) as well as among females (t = 5.38; P less than 0.001). Out of 40 patients chronically treated with acenocoumarol in whom amiodarone was instituted, 32 showed a decrease of the AC dose/PR ratio, while in eight patients no change was recorded (paired t-test, t = 5.82; P less than 0.001). In 15 patients who were being concomitantly treated with acenocoumarol and amiodarone, amiodarone was discontinued. An increase of the AC dose/PR ratio was recorded (paired t-test, t = 4.01; P less than 0.001). Nine patients had started treatment with amiodarone while receiving acenocoumarol and a decrease of the AC dose/PR ratio was documented; amiodarone was discontinued some months later, and an increase of the AC dose/PR ratio was seen.