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PubMed2004

The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon.

Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarin anticoagulant metabolism. The variant alleles CYP2C9*2 and CYP2C9*3 are associated with an increased response to warfarin. However, an effect on acenocoumarol dose requirements appears to be absent for the CYP2C9*2 allele and the consequences for the metabolism of phenprocoumon have not yet been established. We investigated CYP2C9 polymorphisms in relation to the international normalized ratio (INR) during the first 6 weeks of treatment and its effect on the maintenance dose in a cohort of 1124 patients from the Rotterdam Study who were treated with acenocoumarol or phenprocoumon. There was a statistically significant difference in first INR between patients with variant genotypes and those with the wild-type. Almost all acenocoumarol-treated patients with a variant genotype had a significantly higher mean INR and had a higher risk of an INR > or = 6.0 during the first 6 weeks of treatment. A clear genotype-dose relationship was found for acenocoumarol-treated patients. For patients on phenprocoumon, no significant differences were found between variant genotypes and the wild-type genotype. Individuals with one or more CYP2C9*2 or CYP2C9*3 allele(s) require a significantly lower dose of acenocoumarol compared to wild-type patients. Phenprocoumon appears to be a clinically useful alternative in patients carrying the CYP2C9*2 and *3 alleles.

Acenocoumarol↗
PubMed2005

Effect of low-intensity acenocoumarol on frequency and severity of migraine attacks.

OBJECTIVE: To investigate the effect of low-intensity acenocoumarol treatment (target INR 1.5 to 2.0) on the frequency and severity of migraine attacks. BACKGROUND: The positive effect of anticoagulation on migraine has been described in case reports and observational studies. METHODS: We conducted a randomized, open, crossover study in migraine patients. After a run-in period of 8 weeks, all patients received acenocoumarol or propranolol during a period of 12 weeks and, after a washout period of 2 weeks, propranolol or acenocoumarol during a second period of 12 weeks. RESULTS: Nineteen patients fulfilling the criteria were included. In 12 patients with complete data collection, only one good responder could be noted. In the other patients, treatment with low-intensity acenocoumarol did not show improvement of migraine symptoms compared with the run-in period. Treatment with propranolol showed a trend towards improvement compared with the run-in period. No serious adverse events were observed. CONCLUSIONS: Overall, low-intensity acenocoumarol treatment has no prophylactic effect in migraine patients.

Acenocoumarol↗
PubMed2004

The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon.

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

Acenocoumarol↗
PubMed2003

Acenocoumarol-induced Henoch-Schönlein purpura.

OBJECTIVE: To report a probable case of Henoch-Schönlein purpura associated with acenocoumarol therapy. CASE SUMMARY: A 76-year-old white woman was prescribed acenocoumarol for chronic atrial fibrillation. Two months after starting therapy, the patient came to our hospital's emergency department because of abdominal pain associated with vomiting. Physical examination revealed multiple round, confluent, purpuric lesions with some vesicles and an area of residual pigmentation. Lesions were present predominantly on the legs and gluteus, and also on the abdomen and arms. Skin biopsy of the lesions was compatible with leukocytoclastic vasculitis with deposition of immunoglobulin A. An upper intestinal endoscopy was done and identified purpuric mucosal lesions in the fundus, body, and antrum of the stomach and the duodenal bulb. Renal function was not affected, although proteinuria (1.26 g/day) was found and microscopic hematuria was observed. DISCUSSION: The most likely cause of the Henoch-Schönlein purpura in this case was considered to be acenocoumarol because of the close temporal relationship between exposure to the drug and onset of symptoms, as well as the rapid resolution of the symptoms and signs after acenocoumarol was discontinued. The oral anticoagulant was the only identifiable precipitant that the patient encountered before the Henoch-Schönlein purpura developed. An objective causality assessment revealed that the adverse drug event was probable. CONCLUSIONS: This case report illustrates a probable association between Henoch-Schönlein purpura and acenocoumarol. As of December 2003, this reaction had not been previously reported. Clinicians should be aware of this potential adverse effect of a widely used drug.

Acenocoumarol↗
PubMed1991

Comparison of the rat liver microsomal metabolism of the enantiomers of warfarin and 4'-nitrowarfarin (acenocoumarol).

1. Rat liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) has been studied. The enantiomers of both compounds were hydroxylated mainly at the 6- and 7-positions. Acenocoumarol enantiomers were much better substrates for cytochromes P-450 than the corresponding warfarin enantiomers; Km values for the 6- and 7-hydroxylations were 2 to 19 times lower for R- and S-acenocoumarol than for warfarin. 2. Formation of the 6-, 7-, and 8-hydroxy-metabolites of warfarin was stereoselective for the R-enantiomer (the R/S ratio for total intrinsic clearance was about 3). 4'-Hydroxylation was not stereoselective. In contrast, formation of acenocoumarol metabolites was stereoselective for the S-enantiomer (the S/R ratio for total intrinsic clearance was about 3). 3. From the effects of phenobarbitone and methylcholanthrene induction, and inhibition by cimetidine, on in vitro metabolism of the enantiomers of both compounds, it was concluded that the differences between warfarin and acenocoumarol can be explained partly by the involvement of different enzymes.

Acenocoumarol↗
PubMed2004

[Long-term therapy with anticoagulants in patients with nonvalvular atrial fibrillation (prospective follow-up). Part I. Effect of 12-month therapy with acenocoumarol on content of d-dimer, frequency of thrombosis and parameters of hemodynamics of left auricle].

AIM: To assess frequency of left auricular thrombosis and effect of long-term therapy with acenocoumarol on auricular hemodynamics and system of hemostasis and to elucidate predictors of effective therapy with acenocoumarol in patients with nonvalvular atrial fibrillation. MATERIAL: Patients (n=100) with nonvalvular atrial fibrillation and at least 1 risk factor of thromboembolic complications. METHODS: Transesophageal echocardiography and measurement of blood D-dimer levels were carried out before and after 1 year of acenocoumarol therapy. RESULTS: Initial prevalence of left auricular thrombosis was 75%. The use of acenocoumarol for 12 months resulted in significant reduction of frequency of left auricular thrombosis. This was associated with improvement of parameters of intraatrial hemodynamics and lowering of elevated blood D-dimer levels. Clinical-instrumental predictors of presence of left auricular thrombosis and its dynamics during therapy with acenocoumarol were also elucidated.

Acenocoumarol↗
PubMed2004

[A patient with lessened sensitivity to acenocoumarol during a period of enteral feeding].

A 69-year-old man was operated on for a subdural haematoma which had developed during the use of acenocoumarol. Directly after the operation the patient was started on enteral feeding. The acenocoumarol was restarted at a later stage. The dose of acenocoumarol needed for an appropriate level of blood-dilution was twice as high during the period of enteral feeding than it had been preoperatively. After the transition from enteral feeding to oral feeding it was possible to lower the dose of acenocoumarol. The need for a higher dose was probably due to enhanced binding of the proteins in the enteral feeding. The patient was admitted to a nursing home. The combination of acenocoumarol and enteral feeding occurs frequently in patients being rehabilitated. It is important to monitor the blood-dilution when starting and stopping enteral feeding.

Acenocoumarol↗
PubMed1982

The incidence of deep venous thrombosis in patients with an acute myocardial infarction treated with acenocoumarol or indobufen.

In a randomized double blind clinical trial, we compared indobufen, an antiplatelet drug, with acenocoumarol for the prevention of deep venous thrombosis (D.V.T.) in patients with acute myocardial infarction. Therapy was started on admission and continued for 10 days. All patients were screened daily with impedance plethysmography (I.P.G.) and 125I-fibrinogen leg scanning. Diagnosis of D.V.T. was made when either one or both tests became positive. 74 patients were randomized to treatment with indobufen (200 mg b.i.d.) and 76 patients to acenocoumarol (controlled by thrombotest). The incidence of venous thrombosis in patients with indobufen was 11% and in those treated with acenocoumarol 9%. Major bleeding was observed in 2 patients treated with acenocoumarol. In the indobufen group, no bleeding complications or other serious side-effects were observed. The majority of patients developed thrombosis after the first week of admission. For patients with and without thrombosis, there was no significant difference between the two treatment groups concerning the age, the coronary prognostic index, the maximum C.P.K. value, mobility, incidence of congestive heart failure and the site or extent of the infarct. In this study no clinical or laboratory (fibrinogen, platelet count and anti-thrombin III) parameter, either alone or in combination, was of predictive value for the development of D.V.T. It can be concluded that indobufen appears to be as good as acenocoumarol for the prevention of D.V.T. in patients with acute myocardial infarction. Because it is safe and easy to administer, indobufen seems to be preferable. Prophylaxis is required for at least 10 days.

Acenocoumarol↗
PubMed1986

Apparent dose dependency of the hepatic (S)-acenocoumarol clearance in the rat: a study using open liver biopsies.

Saturable hepatic uptake processes may account for the apparent dose-dependent clearance of 4-hydroxycoumarins. We investigated the dose dependent clearance and dose dependent liver distribution of the (S)-enantiomer of acenocoumarol (4-hydroxy-3-[1-4-nitrophenyl)-3-oxobutyl]coumarin) in the rat applying the in situ liver biopsy technique. The drug was administered by constant-rate infusion. At infusion rates below 0.6 microgram/min, blood clearance appeared to be dose dependent, i.e., clearance of (S)-acenocoumarol declined gradually from 6.5 mL/min at a 0.15 microgram/min infusion rate to 3.9 mL/min at a 0.6 micrograms/min infusion rate. From 0.6 microgram/min up to the highest input tested, i.e., 15 micrograms/min, clearance was almost constant, 3.5 mL/min. At low infusion rates the steady-state liver concentration of (S)-acenocoumarol rose steeply in a convex way with infusion. Scatchard analysis of steady-state liver concentrations in relation to steady-state blood concentrations revealed a hepatic binding site for (S)-acenocoumarol, exhibiting a capacity of 1.4 microgram/g of liver tissue.

Acenocoumarol↗
PubMed1985

Prospective study of the potentiation of acenocoumarol by amiodarone.

The influence of oral amiodarone on the anticoagulant effect of the coumarin derivative acenocoumarol has been investigated prospectively in 10 patients with normal renal, hepatic and haematological function and who were not in cardiac failure. The daily dose of acenocoumarol was sufficient to produce a prothrombin activity of 25 to 35%. When the prothrombin time had become stable amiodarone 600 mg/d was administered for 1 week followed by 400 mg/d for the next 3 weeks. A decrease in prothrombin activity from 30.5 to 20.2% was observed, associated with a decrease in vitamin K coagulation factors, after a mean of 4 days following commencement of amiodarone. In 6 patients a prothrombin activity less than 20% required a 60% reduction in the dose of acenocoumarol after 1 week of amiodarone 600 mg, and a 33% reduction after 3 weeks of amiodarone 400 mg. There was no correlation between the plasma amiodarone and the decrease in prothrombin activity. Inhibition of acenocoumarol metabolism by amiodarone is the most likely explanation of these findings.

Acenocoumarol↗
PubMed1994

Determination of acenocoumarol in human plasma by capillary gas chromatography with mass-selective detection.

A method for the determination of acenocoumarol in human plasma by capillary gas chromatography-mass-selective detection is described. After addition of a structurally related analogue as the internal standard, the compounds are extracted from plasma at acidic pH into toluene, back-extracted with a basic solution and re-extracted from hydrochloric acid solution with toluene, which is then evaporated to dryness. The compounds are converted into their methyl derivatives, which are determined by gas chromatography using a mass-selective detector at m/z 324 for acenocoumarol and m/z 338 for the internal standard. The reproducibility and accuracy of the method were found to be suitable over the acenocoumarol concentrations range 2.2-74 nmol/l. The method could be considered as selective for acenocoumarol in the presence of its major metabolites in plasma.

Acenocoumarol↗
PubMed1998

Jaundice associated with acenocoumarol exposure.

A 69-year-old man developed cholestatic liver enzyme disturbances three and a half weeks after starting treatment with acenocoumarol because of a deep venous thrombosis in his leg. Serological testing showed no signs of recent viral infections. A presumptive diagnosis of hepatotoxicity caused by the use of acenocoumarol was made and the anticoagulant was replaced by low molecular weight heparin. Three weeks after withdrawal of the acenocoumarol, the enzymes had improved. The patient made a full recovery within two months. This case suggests a causal relationship between acenocoumarol exposure and liver damage.

Acenocoumarol↗
PubMed2000

Sensitive stereospecific determination of acenocoumarol and phenprocoumon in plasma by high-performance liquid chromatography.

We describe a normal-phase HPLC method for the stereospecific determination of R- and S-acenocoumarol and R- and S-phenprocoumon with S-warfarin as internal standard. The compounds were separated using a Whelk-O1 chiral stationary phase, detected by UV at 310 nm and quantified in the internal standard mode. Linearity was verified for acenocoumarol in the range of 15-2000 microg/l and for phenprocoumon from 15 to 2200 microg/l, respectively. The detection limits were 5 microg/l for all compounds. The recovery was >84% for R- and S-acenocoumarol and >74% for R- and S-phenprocoumon. The imprecision (C.V.) (50-1800 microg/l) for R- and S-acenocoumarol was <4.7% within-day and <7.8% between-day. For R- and S-phenprocoumon the respective values were <5.6% and <5.9%. The accuracy for all compounds was 96.5-110%.

Acenocoumarol↗
PubMed2006

Patients who take uneven doses of acenocoumarol exhibit significant fluctuating levels of anticoagulation.

Acenocoumarol is the most widely used oral anticoagulant in Spain. In clinical practice it is usual to cut 4 mg tablets into halves and quarters, so that the total weekly dose may be uniformly distributed. Nevertheless, many patients are told to take uneven doses (e.g. 1/2 tablet one day and 1/4 tablet the next day). The impact of these variations in dosage over the stability of anticoagulation is unknown. We carried out a prospective study comparing a group of 40 patients taking uneven doses of acenocoumarol and another group of 10 patients with uniform doses. All patients were within the therapeutic range at inclusion in the study. The International Normalized Ratio (INR) was determined over two consecutive days in every patient to assess possible fluctuations of anticoagulation. Patients receiving an uneven dosage showed a greater variability of the INR value over two consecutive days, as opposed to patients receiving uniform doses. Variation of the INR resulted in a dose change in 27.5% of cases with uneven dosage and in none of the uniform dose cases. Consistent association was found between every INR value and the dose administered to the patient 2 days before (P < 0.01). Patients who take uneven doses of acenocoumarol exhibit significant fluctuating levels of anticoagulation. This fact has to be considered before making any change in the acenocoumarol dose. The INR value obtained depends greatly on the dose administered 2 days before determination of the INR.

Acenocoumarol↗
PubMed2006

A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9.

AIMS: To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity. Methods A patient, highly sensitive to acenocoumarol, and previously determined to carry only a single CYP2C9*3 allele, was genotyped for additional functionally defective alleles in the CYP2C9 and VKORC1 genes. Family members were also analyzed to trace the pedigree. Results The acenocoumarol-sensitive patient was found to possess, in addition to CYP2C9*3 allele, a CYP2C9*11 allele and the VKORC1 AA diplotype which were all traced back through the parental lines. Conclusions Acenocoumarol sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the CYP2C9 and VKORC1 genes. The study provides additional data in support of diminished CYP2C9 activity due to the presence of the rare *11 allele.

Acenocoumarol↗
PubMed1983

Acenocoumarol and its amino and acetamido metabolites. Comparative pharmacokinetics and pharmacodynamics in the rat.

The elimination, distribution and anticoagulant activity of racemic acenocoumarol, its amino (AM) and acetamido (AA) derivative were determined in male Wistar rats after subcutaneous injection of a single dose of 2 mg kg-1. The effect of daily administration of acenocoumarol on the prothrombin complex activity (PCA) was also investigated. A rapid onset of the hypothrombogenic effect was observed for all three derivatives with the half-life of decline of PCA = 3.6 h. The duration of the hypothrombogenic effect was short for the drug and its AA derivative and long for the AM compound (normalization at about 24 and 70 h, respectively), parallelling the half-life of elimination of the compounds of, 3.3, 4, and 8 h respectively. Daily administration of acenocoumarol for 8 days showed no change in the kinetics of the anticoagulant effect. Elimination of the drug is solely by metabolism. Reduction of the 4'-nitro group was not a metabolic route of importance; the amount of its two derivatives cumulatively excreted in urine over 5 days accounted for 2-3% of the dose only. Elimination of AM derivative is mainly by acetylation to AA, the compound which itself is eliminated by renal excretion. The distribution of acenocoumarol between liver and plasma was determined. The liver to plasma ratio was higher than 1 beyond 10 min after administration. The elimination rate of the drug from liver was slower than from plasma giving an increase in liver to plasma ratio in time. Plasma protein binding was extensive, being the highest for the drug; 1.81, 2.84 and 3.89% free for drug, AM, and AA derivative, respectively.

Acenocoumarol↗
PubMed1987

The biliary excretion of acenocoumarol in the rat: stereochemical aspects.

Within 24 h, 50% of a single dose of the acenocoumarol enantiomers was recovered in bile and 20% in urine of Wistar rats. The elimination products were mainly (greater than 90%) the 6- and 7-hydroxyacenocoumarol as conjugates in the bile but free in the urine. Only R-acenocoumarol, free and conjugated, was excreted in bile. There were no gross differences between the enantiomers in metabolic pattern or in the amount of metabolites formed. A significant difference was observed for the biliary excretion of the 7-hydroxy metabolite; the ratio of free and conjugated 7-hydroxyacenocoumarol was three times higher for the S- than for the R-isomer. An unknown third metabolite was recovered in bile in higher amounts with the S- than with the R-acenocoumarol. Only traces of this metabolite were recovered from urine. The data show an extensive biliary excretion of acenocoumarol and demonstrate stereoselective mechanisms in the excretion processes.

Acenocoumarol↗
PubMedDate not supplied

Changes in bone density during long-term administration of low-molecular-weight heparins or acenocoumarol for secondary prophylaxis of venous thromboembolism.

BACKGROUND: Indications for long-term anticoagulation are expanding. Osteoporosis is a complication which can develop after prolonged treatment with unfractionated heparin and is probably multifactorial. Data on osteoporosis associated with low-molecular-weight heparins (LMWH) are contradictory. Vitamin K participates in bone metabolism and since oral anticoagulants antagonize vitamin K, their use may also increase the risk of osteoporosis. AIM: To assess and compare the effects of long-term secondary venous thromboembolic prophylaxis with LMWH or acenocoumarol on bone structure. METHODS: We assessed bone mineral density (BMD) by densitometry in 86 patients receiving LMWH or acenocoumarol for 3-24 months. The initial BMD was compared to the final result expressed as the percentage difference. The Z-score was also assessed and defined for individual patients as the number of standard deviations of BMD from its ideal value calculated for age and sex groups. RESULTS: Excessive decrease in BMD was evidenced, which seemed to relate to the duration as well as type of treatment. At 1 and 2 years of follow-up, the mean decrease in BMD of the femur was 1.8% and 2.6% in patients on acenocoumarol and 3.1 and 4.8% in patients on enoxaparin, respectively. CONCLUSIONS: Long-term exposure to treatment and prophylaxis of venous thromboembolism cause a modest but progressive decrease in BMD, more evident in patients on LMWH than on acenocoumarol. It might be advisable to perform densitometry before starting long-term anticoagulation and to repeat it every 12 months, especially in patients with concomitant risk factors for osteoporosis in order to identify patients in need of its prophylaxis.

Acenocoumarol↗