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PubMed1975

[Attempted murder with phenprocoumon (marcumar)(author's transl)].

The first known case of attempted murder by means of a coumarine-containing drug, administered by a nurse to her husband, is reported. Small doses of phenprocoumon were regularly added to his food or drinks. He was admitted to hospital with a severe haemorrhagic diathesis which, at first, was thought to be a familial haemorrhagic disease, his mother having died of recurrent hypoprothrombinaemia a few years earlier, the cause of her bleeding trouble never having been established. The wife was sentenced to eight years imprisonment.

Adult↗
PubMed1999

Phenprocoumon from a neurosurgical perspective.

A 9-year series of 45 intracranial and spinal hematomas in patients under oral anticoagulant treatment with phenprocoumon was analyzed and compared to data from the literature. In 42% of the patients, International Normalized Ratio (INR) values >4.5 were found on admission, 36% were older than 70 years and most patients (38%) were under long-term treatment after cardiac valve replacement. Patients who recovered did not report to have given informed consent at the start of anticoagulant therapy. Because an average of five serious hemorrhages are reported/year from German neurosurgical departments, it can be estimated that about 650 intracerebral or intraspinal hematomas, including about 250 fatalities/year occur in Germany under oral anticoagulant treatment. These complications reach the same incidence than spontaneous hematomas either from aneurysms or angiomas. Standards for indications, clinical control, quality INR testing and INR targets not exceeding 4.0, and collecting more data on incidences and causative factors of complications may be an important contribution to reduce these fatalities.

Anticoagulants↗
PubMedDate not supplied

[Severe hereditary protein C deficiency in a newborn infant with fulminant purpura--successful treatment with phenprocoumon].

A newborn baby was born with scrotal hematoma and a diagnosis of testicular torsion was made. This diagnosis proved false, when the hematoma was resorbed after a few days and other hematomas developed instead (abdomen, elbow, foot, scalp). A total of nine hemorrhagic episodes were observed, most of them occurring on the scalp. All lesions were sharply delineated, started with red to purple discoloration and then turned to bluish-black indicating gangrene. Histology revealed extensive bleeding into the corium, fibrin thrombi within the capillaries, and complement and IgG in the small arterial walls. Each bleeding was associated with hypofibrinogenemia and thrombocytopenia. A diagnosis of hereditary protein C deficiency was made. Blood levels were consistent with heterozygosity of both the parents and homozygosity of the child. Bleedings were controlled by Cohn fraction I and heparin. It was impossible, however, to prevent further hemorrhage by continuous i.v. heparin. In addition aprotinin, epsilon-aminocaproic acid, AT III, and prednisone were ineffective. Continuous remission finally could be sustained with oral phenprocoumon.

4-Hydroxycoumarins↗
PubMed1993

[Measurement of prothrombin fragment F1+2 for monitoring the anticoagulant effect of phenprocoumon].

It was the aim of this study to ascertain whether the plasma level of prothrombin fragment F1+2 is a suitable indicator of the anticoagulant effect of coumarin derivatives. The F1+2 levels were measured in 164 patients (100 women, 64 men; mean age 63.3 [34-83] years) in whom stable anticoagulation had been achieved with phenprocoumon, comparing the results with those obtained in healthy subjects (28 women, 19 men; mean age 54.6 [25-72] years) without anticoagulation. There was a significant reduction (P < 0.0005) in F1+2 plasma levels with oral anticoagulation (0.45 + 0.23 vs. 0.67 + 0.32 nmol/l). Even on a low degree of anticoagulation (international normalized ratio [INR] < 2.0) the F1+2 value was reduced to within the normal range (0.32-1.2 nmol/l). These results indicate that changes in the plasma level of prothrombin fragment F1+2 are directly dependent on the degree of oral anticoagulation and that this measure seems suitable for the monitoring of the anticoagulant effect. This is also true for oral anticoagulation of mild degree (INR < 2.0) in which the effect cannot be satisfactorily measured by the thromboplastin time (Quick test).

Administration, Oral↗
PubMed2001

Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs.

BACKGROUND: The risk of hemorrhage when coumarin anticoagulants are used sharply increases when the international normalized ratio (INR) is > or = 6.0. Such overanticoagulation may be caused by drug interactions. We performed a case-control study among previously stable outpatients of an anticoagulation clinic using phenprocoumon or acenocoumarol to identify changes in the use of potentially interacting drugs related to overanticoagulation. METHODS: Three hundred case patients with INR values > or = 6.0 were compared with 302 randomly selected matched control subjects with INR values within the target zone. Information on changes in the use of 87 potentially interacting drugs in the 4 weeks before the index day was collected by interviewing patients and by reviewing the anticoagulant medical record. RESULTS: Forty-five potentially interacting drugs were not used in the 4-week study period, and only 15 drugs were used by at least 10 patients. For a number of drugs, too few patients had a relevant change in use to judge their association with overanticoagulation. A course of a combination product of sulfamethoxazole and trimethoprim strongly increased the risk of overanticoagulation (adjusted odds ratio, 24.2; 95% confidence interval [CI], 2.8 to 209.1; population attributable risk percentage [PAR%], 5.7%), especially in patients receiving acenocoumarol. Penicillins were associated with a risk of overanticoagulation of 2.4 (95% CI, 1.00 to 5.5); the corresponding PAR% was 3.4%. The effect was confined to amoxicillin (INN, amoxicilline) plus clavulanic acid. CONCLUSION: Drug interactions as a cause of overanticoagulation predominantly concerned antibacterial drugs. If possible, the use of sulfamethoxazole-trimethoprim and amoxicillin plus clavulanic acid should be avoided in patients receiving coumarins. If there is no therapeutic alternative available, increased monitoring of INR values is warranted to prevent overanticoagulation and potential bleeding complications.

Acenocoumarol↗
PubMed2004

Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo.

The effect of cytochrome P450 (CYP) 2C9 polymorphisms on the stereoselective biotransformation of the oral anticoagulant phenprocoumon (PPC) to inactive, monohydroxylated metabolites was studied in vitro and in vivo. In human liver microsomes, the (S)-7-hydroxylation--being the major metabolic pathway--was significantly compromised in a gene-dose-dependent manner in samples expressing the CYP2C9*2 or CYP2C9*3 allele. The CYP2C9*3/*3 genotype corresponded to an almost fourfold lower (S)-7-hydroxylation rate than CYP2C9*1/*1 (wild-type). The intrinsic clearance of human recombinant CYP2C9*2 and CYP2C9*3 for the (S)-7-hydroxylation was 28.9 and 50.9% lower than of CYP2C9*1, respectively. The area under the plasma concentration-time curve (AUC) of PPC metabolites after oral intake of 12 mg racemic PPC was significantly lower in volunteers expressing the CYP2C9*2 or CYP2C9*3 allele. Increasing plasma AUC metabolic ratios (parent compound/metabolite) in CYP2C9*2 and CYP2C9*3 variant allele carriers were found for each hydroxylation reaction and the CYP2C9*3/*3 genotype corresponded to an about 10-fold higher metabolic ratio of PPC (S)-7-hydroxylation relative to CYP2C9*1/*1. CYP2C9 polymorphisms cause a markedly compromised PPC (S)-7-hydroxylation. However, PPC metabolism appears overall less influenced by CYP2C9 genotype compared with other oral anticoagulants and it may thus be a valuable alternative for therapeutic anticoagulation of patients expressing CYP2C9 variant alleles.

Alleles↗
PubMed2004

Effects of vitamin K antagonist phenprocoumon on activated partial thromboplastin time measurement of direct thrombin inhibitors.

The activated partial thromboplastin time (aPTT) is currently the most common test used to measure the anticoagulation intensity of heparins and direct thrombin inhibitors (DTIs). Vitamin K antagonists variably affect aPTT reagents. Interactions between heparin and DTIs occur during concurrent therapy. Three DTIs (lepirudin, argatroban, melagatran) and one unfractionated heparin (liquemin) were added to normal plasma (NP) samples (n = 23) and to vitamin K antagonist plasma (VKAP) samples (n = 23) of patients treated with phenprocoumon. Lepirudin and argatroban were added at concentrations from 300 to 3000 ng/ml, melagatran from 30 to 1000 ng/ml, and unfractionated heparin from 0.016 to 0.48 IU/ml. Wave parameters of clotting time and aPTT ratio curves were evaluated by multivariate analysis for inhibitors, aPTT reagents and NP and VKAP samples. Normal ranges resulting from NP samples were 34.5 +/- 1.0 s with Pathromtin SL and 33.9 +/- 0.8 s with Platelin LS. Normal ranges using VKAP were 52.8 +/- 2.6 s (Pathromtin SL) and 44.2 +/- 1.1 s (Platelin LS) (P < 0.0001). Variance analysis showed that inhibitors, plasmas (NP versus VKAP) and reagents influenced the wave characteristics of aPTT (s) (P < 0.0001) and aPTT ratios (P < 0.0001). Distinct statistical differences between aPTT reagents on one hand and normal versus vitamin K antagonist plasma on the other hand make a comparison of reported aPTT results difficult, especially during overlapping therapy with vitamin K antagonists.

Anticoagulants↗
PubMed1980

The binding of furosemide to serum proteins in elderly patients: displacing effect of phenprocoumon.

The percentual binding of furosemide (5 micrograms/ml) was slightly but significantly lower in serum from elderly patients than in serum from normal blood donors (96.5 +/- 0.7 versus 97.9 +/- 0.3). A significant positive correlation was demonstrated between protein binding and albumin concentration in serum. The reduced binding in the elderly could be explained by an observed decrease in the concentration of albumin in the elderly. The percentual binding did not change in samples obtained during the first hour after the intravenous administration of 40 mg furosemide. Of 4-chloro-5-sulfamoyl antranilic acid (CSA) and antranilic acid (A) about 60% were bound to serum proteins in vitro and none of these two compounds affected the protein binding of furosemide. The addition of phenprocoumon (PPC) caused significant decreases in the percentual binding of furosemide in serum (5 microgram/ml) at PPC values of 10 microgram/ml and more. The effect of PPC on the binding of furosemide was studied in vivo in 7 patients receiving 40 mg furosemide intravenously without and with the simultaneous intravenous administration of PPC (3 mg per 10 kg body weight). In good accordance with the in vitro experiments the modest average decrease in furosemide binding, caused by concentrations of PPC not exceeding 6.2 micrograms/ml, was not significant.

4-Hydroxycoumarins↗
PubMedDate not supplied

Subacute liver failure induced by phenprocoumon treatment.

We report on a 39-year-old woman suffering from deep venous thrombosis due to a heterozygous factor-V-Leiden mutation with resistance to activated protein C. Four months after beginning oral anticoagulation, generalized jaundice appeared. Subsequently, subacute liver failure developed necessitating an orthotopic liver transplantation. Histopathology showed features of extensive liver cell necrosis without evidence of a substantial inflammatory infiltrate. Based on histopathology and exclusion of other liver diseases, phenprocoumon-induced liver failure was diagnosed. Five months after transplantation the patient is well with normal liver function tests. Because of the widespread use of oral anticoagulants, not only bleeding complications but also hepatotoxicity should be considered in therapy supervision.

Adult↗
PubMedDate not supplied

Effect of phenprocoumon on monitoring of lepirudin, argatroban, melagatran and unfractionated heparin with the PiCT method.

Prothrombinase-induced clotting time (PiCT) is a clotting-time test for heparins and direct thrombin inhibitors to reduce drawbacks of aPTT. Effects of the direct thrombin inhibitors lepirudin, argatroban, melagatran and of unfractionated heparin (UFH) were investigated in normal and oral anticoagulant plasma samples. Lepirudin showed potentiating interferences with phenprocoumon effects. Melagatran, argatroban and UFH delivered distinct linear additive effects in both plasma sample groups. PiCT ratio reduces differences between both groups with UFH, and argatroban inhibitor-receptor-binding mode plays a role in interaction patterns.

Anticoagulants↗
PubMed1990

Algorithm for short-term prescription of phenprocoumon.

Data from the start of anticoagulation therapy using the coumarin derivative phenprocoumon were obtained retrospectively for 101 patients, and the correct long-term maintenance dose (MD) of the drug was determined. The average loading dose was 23.2 +/- 7.8 mg and the average MD 2.14 +/- 0.99 mg. The physician's prescription on discharge tended to underestimate the true MD by 0.29 +/- 0.64 mg. Significant positive correlations with MD were noted for loading dose and weight and negative correlations for age, serum creatinine, initial prothrombin ratio, and length of treatment pause (days) for patients receiving an excessive loading dose. Using stepwise variance analysis, an algorithm was obtained that predicted the MD: MD = -0.7 + loading dose/10 - treatment pause/7 - age/60 + initial prothrombin ratio. The accuracy (0.02 +/- 0.54 mg) was similar to that of the discharging physician. The algorithm required an average observation period of 5.4 days and the physician's estimate 12.4 days. It is suggested that the use of the algorithm would lead to shorter hospitalization without loss of treatment accuracy.

4-Hydroxycoumarins↗
PubMedDate not supplied

Concentrations of phenprocoumon in serum and serum water determined by high-performance liquid chromatography in patients on oral anticoagulant therapy.

Two convenient high-performance liquid chromatography procedures are proposed for the determination of phenprocoumon (Marcumar) in serum (S-PPC) and its unbound fraction in serum water (SW-PPC). S-PPC and SW-PPC were determined in samples from 53 patients undergoing oral anticoagulant therapy who were within the therapeutic interval of the thrombotest. S-PPC concentrations ranged from 0.6 to 5.0 mg/l, SW-PPC from 1.4 to 21.1 micrograms/l. A linear correlation (r = 0.714) was found between S-PPC and SW-PPC concentrations in the patient samples, the mean free fraction being 0.30%. S-PPC and SW-PPC concentrations were intra-individually stable during therapy. A linear correlation (r = 0.710) was observed between S-PPC concentrations and dosage.

Administration, Oral↗
PubMed2004

Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time.

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.

Acenocoumarol↗
PubMed1975

Biotransformation of phenprocoumon in the rat.

The metabolic fate of phenprocoumon [3-(alpha-ethylbenzyl)-4-hydroxycoumarin] in the rat is described. The major metabolites, 4',-6-,7-, and 8-hyproxyphenprocoumon, have been identified yb mass spectrometry, TLC, and uv and compared with authentic smaples. Metabolites are mainly excreted via the feces. The results are compared with those previously reported for warfarin.

Animals↗
PubMed1975

[The reciprocal actions of phenprocoumon (Marcumar) with human serum albumin, erythrocytes and blood].

The binding properties of phenprocoumon (PhC) to human serum albumin (HSA) and to red blood cells (RBC) were determined by using the equilibrium dialysis. Analysis of PhC-binding data to HSA at pH 7.4 and temperatures of 10 degrees C and 27 degrees C resulted in binding constants (k) of 11.8 - 10(4) and 7.0 - 10(4), in free standard enthalpy changes deltaG0 of -6.658 and -6.651 kcal/mol, and in standard enthalpy change TdeltaS0 of 1.386 and 1.469 kcal/mole, respectively. The standard enthalpy change deltaH0 was -5.182 kcal/mole for both temperatures. These results indicate that the binding between PhC and HSA is predominantly effected by hydrophobic interactions. At pH 7.4 the binding to HSA is essentially characeterized by two straight lines of binding, whereas at pH 9 and 10 there are three. With increasing pH more binding sites become free and the affinity of PhC to HSA grows. Studies of binding properties to RBC indicate a strong binding of PhC to hemoglobin (k 7.9 - 10(5)), but only a weak one to red cell membranes (binding ratio hemoglobin to ghosts 66 : 1). In a combined system of HSA and RBC, competition occurs between both components and therefore the strength of binding decreases. At therapeutic PhC-concentrations, 91.7% of the PhC are bound to the whole blood, 20.8% to RBC, and 70.9% to HSA. With increasing concentrations of PhC the binding to RBC declines to 10.5% accompanied by an approximately unchanged binding to whole blood of 92.1%; whereas binding to HSA increases to 81.6%. The affinity of PhC to HSA grows larger than its affinity to RBC. The total binding to blood remains unchanged within a 21-fold range and it is predominantly determined by the affinity of HSA to PhC.

Blood↗
PubMed1986

Heparin and phenprocoumon inhibit kappa-carrageenin induced thrombosis in rats.

The tail thrombosis after kappa-carrageenin injection in rats was significantly inhibited by heparin and phenprocoumon. Heparin was yet effective at doses as low as 150 IU/kg. The present data point to an involvement of blood coagulation in this new model. Injection of cobra venom factor with complement depletion caused no thrombosis inhibition. The differences between the present kappa-carrageenin induced thrombosis model and a disseminated intravascular coagulation after lambda-carrageenin are discussed.

4-Hydroxycoumarins↗
PubMed1988

Adjustment of phenprocoumon dosage utilizing a pharmacokinetic model.

According to a pharmacokinetic model, the adjustment of a phenprocoumon (PPC) standard dosage based on experimentally determined means values of the parameters volume of distribution and biological half-life will yield in more than 50% of the individuals the desired plasma PPC concentration. In 25 patients it was tested, whether the thus derived loading and maintenance doses, 376.8 and 35.2 micrograms PPC per kg b. wt., resp., actually lead to the predicted optimum plasma PPC concentration of 2.0 micrograms/ml. After initiating dosage, the plasma PPC concentrations were determined over a time period of 30 days. As predicted by the model, in 72% of the patients the average steady-state plasma PPC concentrations were within the range of 1.7 and 2.3 micrograms/ml. The data obtained were used to newly calculate mean values of the volume of distribution, the biological half-life, and the total body clearance of PPC. The mean biological half-life of PPC derived was somewhat shorter than that used for the calculation of the standard dose. Quick-values were estimated concomitantly with the plasma PPC concentrations. They revealed an optimum anticoagulation (15-25%) in 96% of the patients.

4-Hydroxycoumarins↗
PubMed1979

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↗