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PubMed1997

Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery.

OBJECTIVE: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both. METHODS: We therefore followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve replacement. INR values were determined frequently. At the 4th and around the 24th day after starting treatment with phenprocoumon, we also measured the total and unbound plasma concentration of phenprocoumon. RESULTS: The dose requirement to obtain the desired anticoagulant effect was significantly lower in the older patients than in the younger patients (26.3 vs. 37.3 micrograms.kg-1.day-1). The total plasma concentration (2.19 vs. 2.43 micrograms.ml-1), the percentage unbound drug in the plasma (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng.ml-1) did not differ significantly between older and younger patients. The dose-adjusted INR (INR/dose) was higher in the older patients (110 vs. 67) but the INR adjusted for the unbound plasma concentration (INR/Cuss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older patients had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml.kg-1.h-1). CONCLUSIONS: Older patients (> 70 years) require a dose approximately 30% lower than younger patients (< 160 years). Pharmacokinetic reasons (reduced metabolic clearance) are mainly responsible for the lower dose requirement of the older patients after heart valve surgery.

Adult↗
PubMed1997

Severe bleeding in two patients due to increased sensitivity of factor IX activity to phenprocoumon therapy.

Two male patients with severe and recurrent bleeding episodes under phenprocoumon therapy are reported. Both patients exhibited a strong decrease of their factor IX activities below 1% of normal, whereas the activities of the vitamin K-dependent factors prothrombin, VII, and X were found to be within or above the expected therapeutic ranges of 20-40%. Upon removal of phenprocoumon and substitution with vitamin K, the factor IX activities increased to 85% and 55%, respectively. Reexposition to phenprocoumon in one patient confirmed the rapid and selective decrease of the factor IX activity. These findings provide the first report of an abnormally high sensitivity of factor IX activity to oral anticoagulant therapy.

Adult↗
PubMed2004

Determination of phenprocoumon, warfarin and their monohydroxylated metabolites in human plasma and urine by liquid chromatography-mass spectrometry after solid-phase extraction.

A high-performance liquid chromatography-mass spectrometry (HPLC-MS) method for the quantification of phenprocoumon, warfarin, and their known monohydroxylated metabolites in human plasma and urine was developed using a simple, selective solid-phase extraction scheme. Chromatographic separation was achieved on a reversed-phase Luna C18 column and step gradient elution resulted in a total run time of about 13 min. Limits of quantification (LOQ) were < or = 40 nM for the parent compounds and < or = 25 nM for the metabolites and the limit of detection (LOD) was < or = 2.5 nM for all analytes. Average recovery was 84% (+/- 3.7) and 74% (+/- 13.2) in plasma and urine, respectively. Intra- and inter-day coefficients of variation were < or = 8.6 and < or = 10.6% in plasma and urine, respectively. The method was successfully applied to the analysis of phenprocoumon samples from four healthy volunteers and should prove useful for future comparative studies of warfarin and phenprocoumon pharmacokinetics.

Anticoagulants↗
PubMed1982

Determination of the anticoagulant phenprocoumon in human plasma and urine by high-performance liquid chromatography.

The determination of the anticoagulant phenprocoumon in plasma, after acidification and extraction with 1,2-dichloroethane was effected through isocratic high-performance liquid chromatography; a C18 reversed-phase column was used as stationary phase using aqueous acetonitrile as eluent and UV detection at 313 nm; p-chlorophenprocoumon was used as internal standard. A high proportion of phenprocoumon in urine is eliminated as the glucuronide and must be hydrolyzed enzymatically before extraction; the same column and detector as for plasma were used, but with gradient elution. The method was used in the range 0.1-5 mg/1, the sensitivity was 0.1 mg/1 for plasma and 0.02 mg/1 for urine, the precision was in the range 3-5% and the absence of interference due to other anticoagulants, drugs or endogenous compounds allows the specific determination of phenprocoumon in plasma and urine from patients and volunteers in clinical relevant cases, drug interaction, compliance, toxicological and pharmacokinetic studies.

4-Hydroxycoumarins↗
PubMed2000

Inhibition of phenprocoumon anticoagulation by carbamazepine.

Carbamazepine inhibits warfarin and dicoumarol anticoagulation through induction of cytochrome P450-enzymes. Inhibition of phenprocoumon anticoagulation by carbamazepine has been supposed in some reviews, however, without hard empirical evidence. We report a patient who was anticoagulated with phenprocoumon in whom carbamazepine produced a dramatic increase in prothrombin time ratio (Quick). After discontinuation of carbamazepine, Quick-values returned to therapeutic levels. Valproate did not affect phenprocoumol's anticoagulant properties. The potentially hazardous carbamazepine-phenprocoumon interaction should be emphasized in reference drug manuals.

Anticoagulants↗
PubMed2006

VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement.

In a prospective follow-up study of the effects of VKORC1 and CYP2C9 genotypes on the anticoagulation status of patients, we assessed the CYP2C9 and the VKORC1 C1173T genotypes of patients during the initial 6 months of phenprocoumon treatment. We used linear regression models and Cox proportional hazard models to determine the effects of the VKORC1 and CYP2C9 genotypes on phenprocoumon dose requirements, overanticoagulation, and time to achieve stability. Allele frequencies of interest within the cohort (N=281) were 40.8% VKORC1 T-1173, 12.8% CYP2C9*2, and 6.9% CYP2C9*3. In patients with the VKORC1 CC genotype, carriers of a CYP2C9 polymorphism needed dosages that were nearly 30% lower than those for CYP2C9*1/*1 patients (P<0.001). In patients with a VKORC1 polymorphism, differences between carriers of a CYP2C9 polymorphism and CYP2C9*1/*1 were far smaller and largely not statistically significant. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (28.7% and 7.2%, respectively). Carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had a strongly increased risk of severe overanticoagulation (hazard ratio (HR) 7.20, P=0.002). Only carriers of a CYP2C9*2 allele had a decreased chance to achieve stability compared to CYP2C9*1/*1 patients (HR 0.61, P=0.004). In conclusion, the VKORC1 genotype modifies the effect of the CYP2C9 genotype on phenprocoumon dose requirements. A combination of polymorphisms of both genotypes is associated with a strongly increased risk of overanticoagulation, whereas delayed stabilization is mainly associated with the CYP2C9 genotype.

Aged↗
PubMed1998

Increased sensitivity of factor IX to phenprocoumon as a cause of bleeding in a patient with antiphospholipid antibody associated thrombosis.

We report one patient who presented with a spontaneous bleeding complication under phenprocoumon therapy. Oral anticoagulation was initiated due to deep-vein thrombosis which was attributed to an antiphospholipid antibody syndrome. Coagulation analysis revealed a strong and selective reduction of factor IX (F IX) activity to 1%, whereas the other vitamin K-dependent factors (II, VII, X), the prothrombin time and International Normalized Ratio (INR) were within the therapeutic range. After withdrawal of phenprocoumon, all vitamin K-dependent factors including F IX normalized. Because the patient suffered from a recurrence of thrombotic events, he was re-exposed to phenprocoumon and the disproportionate decline of F IX was observed again. These findings indicate an increased sensitivity of F IX to vitamin K antagonists, representing an uncommon mechanism associated with bleeding complications under oral anticoagulant treatment.

Adult↗
PubMed2003

[Phenprocoumon-induced liver failure].

HISTORY: A 61-year-old woman was referred because of painless jaundice, laboratory tests having indicated hepatitis with impaired liver functions. For the past two years she had been taking phenprocoumon because she had atrial fibrillation. INVESTIGATIONS: Serological tests largely excluded infectious, autoimmune or metabolic etiology, so that the diagnosis of drug-induced hepatic disease was made. Liver biopsy showed necrotic liver cells and mild inflammatory reaction. TREATMENT AND COURSE: A perforating duodenal ulcer required urgent surgical intervention, after which liver functions further deteriorated. The patient having refused liver transplantation she was treated symptomatically (oral vitamin K. lactulose, diuretics), phenprocoumon was discontinued and her condition slowly improved. She was discharged after two months. At subsequent examination she was symptom-free, the INR was 1.41, transaminases were normal and ultrasound merely showed a slightly inhomogeneous internal structure. CONCLUSION: Phenprocoumon can cause liver damage even when the drug has been taken for prolonged periods without any problems. A careful history about previously administered drugs should be taken in any case of hepatitis of uncertain etiology.

Anticoagulants↗
PubMed1995

[Phenprocoumon-induced cholestatic hepatitis].

HISTORY AND CLINICAL FINDINGS: A 78-year-old woman had 4 years age received phenprocoumon as prophylaxis against thromboembolism after implantation of a left total knee prosthesis. Ten weeks later she developed hepatitis with negative hepatitis serology. 6 weeks before her latest hospitalisation a right total knee implantation had been performed and she again received phenprocoumon. She was admitted now because of cholestatic jaundice with rapid deterioration of her general state. There were no significant abnormal findings other than jaundiced skin and sclerae. INVESTIGATION: Bilirubin concentration was clearly elevated to 11.5 mg/dl, and the transaminase activities were increased, together with raised gamma-GT and alkaline phosphatase levels. The Quick value was below 8%. Hepatitis serology was positive for hepatitis A antibodies, but negative for B and C antibodies. No antigens were demonstrated. The eosinophil count was elevated in the differential blood count. Sonography showed a normal-sized liver with slightly dense echo pattern, but no evidence of abscess or dilatation of the bile duct system. Liver biopsy revealed severe acute hepatitis of viral type and discrete eosinophilic infiltration. TREATMENT AND COURSE: After all medication had been discontinued, transaminase activities decreased while bilirubin concentration rose. Thus, prednisone treatment was started (initially 50 mg/d), the dose then gradually reduced. The cholestasis parameters became normal and the patient's general state was much improved so that she could be discharged. CONCLUSION: Cholestatic hepatitis is a rare side effect of phenprocoumon. The associated eosinophilia suggests the cause to be an allergic genesis in the sense of a hypersensitivity reaction.

Aged↗
PubMed1991

Decreased peripheral bone mineral content in patients under anticoagulant therapy with phenprocoumon.

In experimental and clinical studies, conflicting results regarding the effect of oral anticoagulant therapy on bone metabolism have been reported. To measure a possible influence of long-term anticoagulant therapy with phenprocoumon on peripheral bone mass, measurements of peripheral bone mineral content (BMC) and serum osteocalcin levels were performed with single photon absorptiometry in a total of 78 patients on anticoagulant treatment. We studied 43 women (mean age 66 years +/- 2 SEM) and 35 men (mean age 65 years +/- 2 SEM) with a median duration of phenprocoumon therapy of 1 year (1-9 years). In all patients, the medical history gave no symptoms of metabolic bone disease, or diseases or medications causing osteoporosis. Both in the male and female groups, mean peripheral BMC was significantly decreased (male: P less than 0.01, female: P less than 0.003) when compared with corresponding controls. Serum OC-levels measured in 16 patients were also significantly lower than those of the controls (P less than 0.02). Our data of decreased BMC and low serum OC-levels indicate reduced bone mass in patients on long-term anticoagulant therapy with phenprocoumon. This may imply an influence of anticoagulants on bone metabolism resulting in decreased bone formation.

Aged↗
PubMed1982

Cimetidine does not increase the anticoagulant effect of phenprocoumon.

In patients on oral warfarin, nicoumalone and phenindione an increase of the anticoagulant effect has been described during concomitant treatment with cimetidine. Therefore we have investigated the effect of cimetidine on the steady state dynamics of phenprocoumon in ten outpatients. No changes in the anticoagulant effect and the plasma phenprocoumon levels were observed during and after 2 weeks application of cimetidine. The data show that cimetidine does not interact with the metabolism of phenprocoumon in contrast to warfarin.

4-Hydroxycoumarins↗
PubMed1980

Investigations into the binding of phenprocoumon to albumin using fluorescence spectroscopy.

The fluorescence of phenprocoumon is enhanced following interaction with bovine and human serum albumin, allowing the binding parameters for two binding sites to be estimated by a modified Bjerrum method and the Scatchard method. The fluorescence is increased as the pH is raised to 9.0 and also on addition of the drugs ibuprofen and fenoprofen. Chloride ions, phenylbutazone and acenocoumarin seem to displace phenprocoumon from its primary binding site on human serum albumin. Investigations with the enantiomers of phenprocoumon show that the binding sites have some stereospecificity.

4-Hydroxycoumarins↗
PubMed2003

Acenocoumarol is not a safe alternative for anticoagulation in phenprocoumon-induced hepatic failure. Report of two cases.

Acenocoumarol has been proposed repeatedly as a safe alternative drug regimen for oral anticoagulation in patients who have suffered phenprocoumon-induced fulminant hepatic failure. The current report describes 2 patients with phenprocoumon-induced hepatic failure, necessitating liver transplantation in 1 case, who showed recurrence of liver damage when oral anticoagulation with acenocoumarol was attempted. Thus, acenocoumarol may not be a safe therapeutic alternative for patients who survived severe phenprocoumon-induced hepatotoxicity.

Acenocoumarol↗
PubMed1980

Effect of induction and inhibition of drug metabolism on pharmacokinetics and anticoagulant activity of the enantiomers of phenprocoumon in rats.

The elimination, distribution and anticoagulant activities of the enantiomers of phenprocoumon were studied in rats following enzyme induction by phenobarbital (pretreatment with 75 mg . kg-1 for 4 days) and enzyme inhibition by chloramphenicol (100 mg . kg-1 h prior to the injection of phenprocoumon and then 50 mg . kg-1 every 12 h). Pretreatment with phenobarbital increased the rate of elimination and decreased the total anticoagulant effect per dose of both enantiomers. It also caused a slight reduction of the liver/plasma concentration ratio of the enantiomers due to the increase of the liver weight and a significant enhancement of the synthesis rate of prothrombin complex activity in non-anticoagulated rats. Chloramphenicol decreased the rate of elimination and enhanced the total anticoagulant effect per dose of both enantiomers. The distribution between plasma and liver remained unaffected. Thus, in rats neither the induction of the phenprocoumon metabolism by phenobarbital nor its inhibition by chloramphenicol appears to be stereoselective.

4-Hydroxycoumarins↗
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↗
PubMed1987

Absence of interaction between ofloxacin and phenprocoumon.

The effect of ofloxacin on steady-state phenprocoumon pharmacodynamics was investigated in 7 healthy male volunteers taking daily sub-therapeutic doses of phenprocoumon. Ofloxacin 200 mg once daily for 7 days did not alter the anti-coagulant response (Quick values) to phenprocoumon after a stabilization phase of 2 weeks. Mean Quick values during the steady-state phase before and during ofloxacin administration were 54% and 52%, respectively. In vitro studies with concentrations of 0 to 100 mg ofloxacin/1 added to plasma also failed to show any interaction. The results indicate, therefore, that ofloxacin does not interfere with vitamin K-dependent coagulation cascade, as seen after other antibiotics.

4-Hydroxycoumarins↗
PubMed2003

Ginger-associated overanticoagulation by phenprocoumon.

OBJECTIVE: To report a case of ginger-phenprocoumon interaction resulting in an elevated international normalized ratio (INR) and epistaxis. CASE SUMMARY: A 76-year-old white European woman on long-term phenprocoumon therapy with an INR within the therapeutic range began using ginger products. Several weeks later, she developed an elevated INR up to 10 and epistaxis. The INR returned to the normal range after ginger was stopped and vitamin K1 was given. DISCUSSION: There have been a number of investigations resulting in conflicting opinions on the effect of ginger on hemostasis, specifically, platelet inhibition. Nevertheless, based on these investigations, recommendations have been issued to refrain from ingesting ginger and other herbals like garlic or ginkgo biloba in situations where bleeding may be critical. An objective causality assessment revealed that the adverse drug event as a result of the phenprocoumon and ginger interaction was probable. CONCLUSIONS: As of writing, this was the first case report that may support an interaction between an oral anticoagulant and ginger together with a brief review of the literature on ginger and hemostasis. As this interaction was observed only by chance, this case highlights the importance of self-control of anticoagulation with coumarins particularly for the detection of unknown interactions.

Aged↗
PubMed1978

[Studies on the interaction of Phenprocoumon with Diazepam and with Nitrazepam (author's transl)].

The influence of Diazepam and Nitrazepam on the anticoagulating activity of Phenprocoumon was studied in rats. It was found that the repeated oral application of Diazepam or Nitrazepam during the treatment with Phenprocoumon did not change the adjusted prothrombin time. The prothrombin time was considerably shortened when the application of Diazepam or Nitrazepam was stopped although Phenprocoumon was still applied. Furthermore, the influence of Chlordiazepoxid, Diazepam and Nitrazepam on the normal prothrombin time was studied. It was found that the treatment with benzodiazepine derivatives had no influence upon the prothrombin time, not only during the treatment, but also after the treatment was stopped.

4-Hydroxycoumarins↗