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Disappearance of migraine during the use of warfarin and of phenprocoumon has been described in sporadic case reports. Treatment with heparin has also been associated with a reduction of migranous headaches. Recently, the Netherlands Pharmacovigilance Foundation LAREB received a case report concerning the diminution of migrainous headaches associated with the use of the vitamin K antagonist, acenocoumarol.
OBJECTIVE: The aim of our study was to investigate the possible effect of acenocoumarol, which is indicated for nonneurological disease, on headache. BACKGROUND: It has been suggested that anticoagulation can have beneficial effects in the control of migraine attacks. METHODS: Four hundred randomized patients on oral anticoagulant therapy were asked to complete a questionnaire regarding their headaches. RESULTS: Headache was present before or during oral anticoagulation in 166 (66 migraineurs and 100 nonmigraineurs) of 326 respondents. The major finding was that oral anticoagulation produced improvement in 63% of patients with migraine versus 38% of patients with nonmigranous headache. Improvement was related to the severity of migraine but not to age. CONCLUSIONS: Oral anticoagulant therapy can improve migraine. The way in which anticoagulant therapy acts on migraine is unknown, but potential mechanisms include its effect on platelet aggregability and pharmacological effects such as suppression of enhanced nitric oxide.
Vitamin K antagonists are most commonly used in long-term thrombosis prophylaxis and the use in patients with cardiovascular disease seems to be increasing. By interfering with the normal hemostatic mechanism, an increased risk of bleeding will arise and administration of human plasma or prothrombin complex concentrates may be necessary. It can be difficult to normalize hemostasis using plasma and prothrombin complex concentrates, because these may be associated with thromboembolic side-effects. The level of factor VII, one of the vitamin-K-dependent coagulation factors, decreases during oral anticoagulant therapy and the administration of recombinant factor VIIa normalizes the prolonged prothrombin time in warfarin-treated rats. After administration of acenocoumarol (International Normalized Ratio > 2), decreased levels of factor X and factor IX (19-46%), protein C (2-20%) and factor VII (4-17%) were found in 28 healthy volunteers. After one dose of recombinant factor VIIa (5, 10, 20, 40, 80, 120, 160, 240, or 320 microg/kg) the International Normalized Ratio and prothrombin time normalized, which may imply an effect on bleeding in individuals receiving oral anticoagulant therapy. The lowest dose (5 microg/kg) normalized the International Normalized Ratio for 12 h and doses > 120 microg/kg normalized it for 24 h. Fragment 1+2 stayed within its normal range in all dose groups, indicating that no systemic coagulation occurred.
The pharmacokinetics and pharmacodynamics of racemic acenocoumarol (AC), the amino (AM) and acetamido (AA) derivative were investigated in healthy volunteers after administration of a single oral (10 mg) dose. All three coumarins were rapidly absorbed from the gastrointestinal tract. The elimination half-lives were 10.9, 10.4, and 4.1 h, for AC, AM and AA, respectively. After the oral administration of AC, no AM and AA was detected in the plasma, and less than 1% of the dose was recovered in the urine (0-24 h) as AM. Renal clearance was the main route of elimination of AM and AA; the former by glomerular filtration, the latter by active excretion. Binding to serum proteins was the highest for AC (1.52% free). AM and AA were less tightly bound (about 3% free). AM or AA did not interfere with the AC plasma protein binding. The oral administration of AC resulted in a rise in prothrombin time with a maximum effect at 24 to 30 h. No anticoagulant activity was observed upon the administration of AM and AA. The results indicate that the compounds AM and AA, if they are formed out of AC at all, do not contribute to the anticoagulant activity of AC.
Although the oral anticoagulant acenocoumarol (AC) is very effectively metabolized by the intestinal microflora to its amino metabolite, under clinical conditions this route of AC-disposition is of no importance because the compound is rapidly absorbed from its pharmaceutical application form. Only when the gastro-intestinal absorption is retarded, for instance by using a capsule as vehiculum, are appreciable amounts of reduced metabolites recovered in urine.
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).
Cutaneous necrosis is an infrequent but well-documented complication of oral anticoagulants. In the pathogenesis of cutaneous necrosis induced by oral anticoagulants recent hypotheses favour the combined role of local factors and a transient unbalance of coagulation mechanisms leading to an hypercoagulable state. There exists a genetic factor that determines a decreased level of two vitamin-K dependent glycoproteins, namely protein C and protein S. We present the case of an obese woman that developed an extensive cutaneous necrosis while receiving acenocoumarol for a deep venous thrombosis. She had an heterozygous deficit for protein C. The histopathologic findings of vessel thrombi and red blood cell extravasation were consistent with the clinical picture. A biopsy specimen taken from an initial lesion disclosed images of leucocytoclastic vasculitis. We reviewed the literature focusing on the pathogenesis and the histopathology of the disease.
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.
The effect of pentobarbitone anaesthesia and the effect of hypothermia associated with the anaesthesia on the blood clearance of indocyanine green (ICG) and of S(-)-acenocoumarol (AC) was investigated in male Wistar rats using the constant rate infusion technique. During anaesthesia, body temperature was regulated by heat supply. At normothermia (rectal temperature of 37.5 degrees C), pentobarbitone anaesthesia decreased ICG clearance from 8.0 +/- 1.7 ml min-1 (mean +/- s.e.m., n = 3) in the conscious state to 4.3 +/- 0.6 ml min-1 and AC clearance from 4.9 +/- 0.4 ml min-1 to 3.4 +/- 0.3 ml min-1. Hypothermia further reduced the clearances of the compounds to 0.9 +/- 0.1 and 2.5 +/- 0.2 ml min-1 for ICG and AC, respectively. The effect of hypothermia was reversible. The results show that pharmacokinetic constants obtained in the anaesthetized animal may differ greatly from those in the conscious one. If pharmacokinetic experiments are performed in the anaesthetized animal, body temperature should be controlled and a slight hyperthermia is most favourable. Our pharmacokinetic data on ICG seriously question the use of this drug to estimate liver blood flow in the rat.
According to theory, the regional increase in drug concentration during target organ directed drug delivery as compared with systemic drug delivery is related to the quotient of the clearance of the drug and the blood flow of the target organ. We investigated the steady-state pharmacokinetic disposition of S-acenocoumarol in plasma, liver, testis, and kidney following its administration (constant rate infusion by an osmotic minipump) directly into the testis or the kidney of rats. The effects of clearance induction (phenobarbitone treatment) on the disposition of the drug were also investigated. The results confirm the theory of target-directed drug delivery.
In 11 patients on steady anticoagulation with a daily dose of acenocoumarol, prothrombin time, factor VII and protein C were measured 2 and 16 h after the daily intake of acenoumarol. Prothrombin time (expressed as International Normalised Ratio) increases significantly, factor VII and protein C decrease between the two samples. These results suggest that a daily dose of acenoumarol is associated with fluctuation of the anticoagulant effect.
Treatment with the direct thrombin inhibitor argatroban (ARG) is often followed by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol (AC) are frequently used in Europe. The standard monitoring test for VKA, pro-thrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the International Normalized Ratio (INR) obtained during combined treatment does not reflect the true effect of the VKA. A similar interference of the VKA on the activated partial thromboplastin time (aPTT), a monitoring assay for direct thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of either 1.0, 2.0 or 3.0 microg/kg/min ARG (days 1, 3, 4 and 5) before initiation of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A linear relationship (INR(ARG+VKA) = intercept + slope * INR (VKA alone)) was observed between the INR measured "on" and "off" ARG. The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR (ARG+VKA) and INR (VKA alone)) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13. There was a close correlation between plasma levels of ARG and aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation of the ECT induced by argatroban. In conclusion, ARG at doses up to 2 microg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA, as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is necessary to monitor ARG in the critical transition period, the ECT which is not influenced by VKA can be used as an alternative to the aPTT.
A double-blind crossover trial between diclofenac sodium and placebo was carried out in 32 hospitalized patients who were thought to be stabilized on concurrent anticoagulant therapy with acenocoumarol. The object of the trial was to investigate any possible interaction between diclofenac and anticoagulant by monitoring prothrombin times daily through the four week period. No statistically significant difference between placebo and diclofenac could be shown and some problems of accurately monitoring prothrombin times are discussed.
During repetitive extracorporeal irradiation, heparin treatment is responsible for a very high lymphocytic peak which does not last more than two days. This peak is not observed after using acenocoumarol as anticoagulant. That is why the degree of lymphocyte depletion after RECIB is to be interpreted in function of the anticoagulant used. This peak is temporary. No matter the anticoagulant used, lymphopenia is obtained after 15 days. The level of lymphocytic depletion is independent of the initial lymphocytosis.
Rats received a single subcutaneous dose of the inflammatory agent carrageenin on the top of the skull, followed by oral acenocoumarol for 3 days; in every case, an extensive haematoma was observed on the skull on day 4. The capillary resistance on the depilated dorsal skin was significantly reduced by this combined inflammatory + anticoagulant treatment. Haematoma development was not inhibited by cortisone, non-steroidal anti-phlogistics (piroxicam, proquazone) or benzopyrone derivatives (hesperidin methylchalcone, oligomeric procyanidin). On pretreatment with vitamin K1 for 1 day, followed by daily treatment for 3 days, no haematoma was observed.
Between 1980 and 1985, 2,012 patients treated with acenocoumarol were followed up. 31 of them had intracranial hemorrhage (ICH), representing an incidence of 1.54%. Its mortality rate was as high as 45%. The most common indication of anticoagulant therapy was cardiac valvular disease. No precipitating factors or concomitant hemorrhages in other sites were detected. Most patients with ICH were, at the time of the accident, within the therapeutic anticoagulant range. The most common localization of ICH was intraparenchymal; most of them developed after one year of anticoagulant therapy. In 32% of instances there was previous hypertension and previous stroke in 26%. ICH had a three times greater incidence in patients over 65 years. The patients who died showed larger hematomas than survivors in computed tomography.
The stereoselectivity of the pharmacokinetics and of the pharmacodynamics of the oral anticoagulant acenocoumarol (AC) and of two of its potential metabolites, the amino (AM) and the acetamido (AA) derivatives, were investigated in the rat. The pharmacokinetics and pharmacodynamics were investigated following the acute subcutaneous (1 mg/kg) administration of the pure enantiomers. For AC and AA, the S(-)-enantiomer was preferentially eliminated, whereas for AM the R(+)-enantiomer showed the shortest half-life. The differences in elimination between the AC enantiomers were entirely due to differences in total clearance, 183 +/- 14 and 714 +/- 148 ml X h-1 X kg-1 (+/- SD) for R(+)- and S(-)-AC. Also the differences in elimination between the AM enantiomers were mainly due to differences in body clearance, 50 +/- 13 and 18 +/- 4 ml X h-1 X kg-1 for R(+)- and S(-)-AM. For S(-)-AA the higher total clearance as well as the smaller volume of distribution accounted for its 2-fold higher rate of elimination. Acetylation of AM, i.e. the conversion to AA, which accounted for about 50% of its total clearance was stereoselective for R(+)-AM. The renal clearance of AA which accounted for 50-60% of the AA clearance was not selective for one of the AA enantiomers. Stereoselectivity in plasma protein binding was observed, the differences, however, were small. Thus, stereoselectivity in plasma protein binding did not account for the observed differences in the pharmacokinetics. The differences in anticlotting activity between the enantiomers of AC and AM were determined mainly by their pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)
In two different studies, the relation between plasma concentrations of acenocoumarol and apparent prothrombin levels (Quick test) was investigated, using a new specific analytical method for the assay of the drug. The prothrombin level appeared independent of the plasma concentration of the drug, which is higher in old patients (over 70 years) than in younger patients (under 51 years).