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Transient acquired resistance to the coumarin anticoagulants phenprocoumon and acenocoumarol.

A 62-year-old man developed resistance to coumarin congeners during treatment with phenprocoumon (Marcoumar) and acenocoumarol (Sintrom), requiring at least triple the usual therapeutic dose and plasma concentration of phenprocoumon for satisfactory anticoagulation. After 8 months on this high dosage, the patient suddenly developed haemorrhagic diathesis. The medication was therefore discontinued. The resistance could not be ascribed to impaired absorption or enhanced metabolism.

4-Hydroxycoumarins↗

The binding of phenprocoumon to human plasma proteins.

By in vitro experiments with equilibrium dialysis and 5 micrograms PPC per ml an average of 99.7 +/- 0.2% was bound to serum proteins. The binding in a solution with the albumin concentration which was present in the serum samples did not differ from this binding or from the binding in plasma where coagulation was prevented with either heparin or citrate. The binding constant in albumin solutions at 37 degrees was 4.5 +/- 0.31/mol x 10(-5) and an average of 1.16 +/- 0.04 primary binding sites was found. The association constant for the PPC albumin interaction was temperature dependent and the results of thermodynamic calculations suggested a combined ionic and non-polar type of binding as the change in enthalpy contributed with 40% of change in free energy. A large positive entropy change was found (15.79 Kcal/mol/degree K). The addition of phytomenadione to albumin solutions and of menadione to plasma caused a considerable decrease in the protein bound fraction of PPC, indicating the relevance of a study concerning the possible clinical consequences of these interactions.

4-Hydroxycoumarins↗

Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats.

The elimination, distribution and anticoagulant activity of S(-)-, R(+)-, and R,S(+/-)- phenoprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0.6 mg kg-1. From the plasma concentrations which elicited the same anticoagulant effect, S(-)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocouman. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(-)-enantiomer was shorter (12-5 h) than that of R(+)-phenprocoumon (17-8 h). No differences were observed in the apparent volume of distribution. However, the mean liver:plasma concentration ratio was higher for the S(-)-(6-9) than for the R(+)-enantiomer (5-2). At a total concentration of 16-8 microgram ml-1 the percentage of unbound drug in rat serum was significantly higher for the S(-)- (1-13%) than that for the R(+)-enantiomer (0.76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(-)- over the R(+)-enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.

4-Hydroxycoumarins↗

Prognosis of prophylactic anticoagulant treatment in ischaemic stroke.

Two groups of patients who had a stroke, prolonged reversible ischaemic neurological deficit or transient ischaemic attacks were compared; one group was treated with anticoagulants (phenprocoumon) and a matched control group was treated with other substances. Results showed a similar survival rate in both groups, but significantly fewer recurrences were seen in the surviving patients treated with anticoagulants.

4-Hydroxycoumarins↗

The effect of daily administration of naproxen on the prothrombin complex activity in patients under long-term therapy with phenprocoumon.

Out of a total of 150 patients attending an out-patient clinic for anticoagulant therapy, 12 had disorders which normally would indicate a prolonged use of an antirheumatic drug. To 6 of these patients, naproxen (1/4 g twice daily) was given while anticoagulant treatment with phenprocoumon was continued in an unchanged dosage schedule (average dose 2.1 mg/day). On the average, the prothrombin complex activity (PP%) was reduced to a stable level 10--20% below that obtained during a 2-month period before the naproxen treatment was started. No bleeding episodes or other effects were observed. Thus the simultaneous administration of naproxen caused no problems for the maintenance of a stable anticoagulant therapy.

4-Hydroxycoumarins↗

On the interaction between the anti-inflammatory substance proquazone (RU 43-715) and phenprocoumone.

In a double blind study on 20 anticoagulated patients, the influence of the anti-inflammatory drug 1-isopropyl-4-phenyl-7-methyl-2 (1H) quinazolone on the degree of hypocoagulability was examined. In comparison to a placebo group, there was no statistical difference in the Quick precentage, in coagulation factors II, VII, and X, and in platelet aggregation induced by collagen and by epinephrine respectively. In addition, no increased bleeding tendency could be observed during the study.

4-Hydroxycoumarins↗