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PubMedDate not supplied

[Anticoagulation with phenprocoumon in early childhood: dosage, complications, effectiveness].

The dose-response relationship of the Vitamine-K-antagonist Phenprocoumon (Marcumar) was studied in a group of 11 children and 10 adults receiving anticoagulation postoperatively after mechanical valve replacement. The dose in children was found to be lineally correlated to the body surface area and similar to that in adults (saturation dose: 16.0 +/- 3.2 mg/m2; maintenance dose: 11.2 +/- 1.6 mg/m2/week). During the follow up period (265 patient months) one child died from mitral valve thrombosis, two children developed traumatic haematomas, and in one child interactions with 2 other drugs were observed. The incidence of thrombembolism or serious bleeding complications was 4.5 and 9.0 instances per 100 patient-years, respectively. The efficiency of prothrombin time control was established over a six months period and showed 70.3% of the values within, 23.% above, and 6.5% below the therapeutic range. During this period, the prothrombin time was measured 2.5 times per patient and month at the average. We conclude from our experience, that an anticoagulation therapy with Phenprocoumon can be performed in children with only mildly elevated risk of bleeding complications as effectively as in adults provided it is monitored closely.

4-Hydroxycoumarins↗
PubMed1999

Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon.

Anticoagulants of the cumarin-type (warfarin, phenprocoumon, and acenocoumarol) are drugs for the long-term treatment and prevention of thromboembolic disorders. Because of their narrow therapeutic range, many patients have bleedings of variable severity or have recurrent thrombotic events. For this reason, the study of the pharmacokinetic parameters of phenprocoumon (PPC), considering its influence on blood clotting factors, is of high interest. The elimination kinetics of PPC, its interaction with phytomenadion (vitamin K), and the pharmacokinetic behavior of the anticoagulant under steady-state conditions have been investigated in studies with healthy volunteers and patients taking anticoagulants. The maintenance dose and the plasma levels of PPC were correlated with prothrombin time (PT) in 89 patients treated with PPC. Varying parameters in each patient (e.g., elimination kinetics of PPC, activity of the cumarin-dependent blood-clotting factors, endogenous phytomenadion stores), render it impossible to use a different means of monitoring than that of PT determination.

Administration, Oral↗
PubMed1979

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↗
PubMed2006

Safety and efficiency of perilesional sclerotherapy in leg ulcer patients with postthrombotic syndrome and/or oral anticoagulation with phenprocoumon.

BACKGROUND: The positive effects of perilesional sclerotherapy for venous leg ulcers is well documented. Although many patients with venous leg ulcers require oral anticoagulation or have had a deep vein thrombosis, the effects of these factors on perilesional sclerotherapy are unknown. The aim of this study was to review effects of oral anticoagulation and/or postthrombotic syndrome on perilesional sclerotherapy. PATIENTS AND METHODS: 28 patients with venous leg ulcers were observed. 12/28 had a postthrombotic syndrome, 5/12 were on oral anticoagulants (phenprocoumon with INR 2-3). During each treatment session, 1 ml sclerosing foam (1:5, polidocanol 2 %, method of Tessari) was injected. Treatment was continued until all extrafascial veins in the 15cm surrounding the ulcer were closed. RESULTS: Closure of the perilesional veins was achieved in all patients with 2.5 +/- 1.8 injections. In 10 of 28 patients (35.7 %), just one injection was needed. More injections were needed, both in patients with postthrombotic syndrome (3.3 +/- 2.1 vs. 1.8 +/- 1.3) and on anticoagulation with phenprocoumon (4.2 +/- 1.2 vs. 2.1 +/- 1.7). There were only two complications: an ascending phlebitis up to the accessory saphenous vein and a superficial erosion at an injection site which healed within 1 week. CONCLUSIONS: Perilesional sclerotherapy with foam is a safe and efficient therapy for patients with chronic venous leg ulcers even with postthrombotic syndrome and/ or ongoing anticoagulation.

Administration, Oral↗
PubMed1977

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↗
PubMed1988

Sex-related differences in disposition and response to phenprocoumon in rats.

The pharmacokinetics and the pharmacological response to phenprocoumon have been studied in female and male inbred Lewis-Wistar rats. A significantly lower clearance was found in female than in male rats (7.9 +/- 1.4 vs 24.5 +/- 2.5 mL h-1 kg-1, respectively; t = 15.09, P less than 0.001) as well as a lower apparent volume of distribution (288 +/- 46 vs 617 +/- 105 mL kg-1; t = 7.58, P less than 0.001) and a longer half-life (25.5 +/- 3.4 vs 17.5 +/- 1.8 h; t = 5.16, P less than 0.001). The binding of phenprocoumon was higher in female than in male rats (fu: 0.0096 +/ 0.0008 vs 0.0124 +/- 0.0007, respectively; t = 6.66, P less than 0.001). The total (C) as well as the unbound concentration (Cu) needed to elicit a 50% decrease in the prothrombin complex synthesis rate was substantially higher in female rats: C50 was 377 +/- 98 ng mL-1 in female and 155 +/- 29 ng mL-1 in male rats (t = 5.32, P less than 0.001), whereas Cu50 was 3.6 +/- 0.7 ng mL-1 in female and 1.9 +/- 0.3 ng mL-1 in male rats (t = 5.50, P less than 0.001). However, because of the lower clearance and volume of distribution and the longer half-life in female rats, the female rats experienced a higher cumulative effect than male rats to 0.34 mg kg-1 i.v. doses.

4-Hydroxycoumarins↗
PubMed2000

Pneumatosis cystoides intestinalis: an unexpected finding in intestinal bleeding under therapy with phenprocoumon.

Pneumatosis cystoides intestinalis is a rarely observed disorder on plain abdominal X-ray or colonoscopy examination. Although causing few complaints in adults, it can nevertheless lead to gastrointestinal bleeding. In the reported case, gastrointestinal bleeding was observed with coinciding pneumatosis and phenprocoumon therapy. After stopping anticoagulant therapy, pneumatosis vanished completely, thus suggesting that phenprocoumon is probably a further cause of the cystic disease. In the known list of drugs able to provoke pneumatosis, this case adds a new mechanism of affliction different to either immunosuppression or gas production.

Aged↗
PubMed1993

Comparative plasma disposition and anticoagulant activities of racemic phenprocoumon and its metabolites in rats.

The anticoagulant phenprocoumon (PH) and its metabolites 6-hydroxy-, 7-hydroxy- and 4'hydroxy-phenprocoumon (6-OH-PH, 7-OH-PH and 4'-OH-PH, respectively) were separately administered intravenously as racemates to rats in order to measure the potential effects of the major metabolites of PH on coagulation. Plasma samples were assayed for total concentrations of the administered compounds and the corresponding prothrombin times; kinetic parameters and anticoagulant activities were estimated using a pharmacodynamic model based on the rate of synthesis of clotting factors. The relative potencies were in the order PH > 4'-OH-PH > 6-OH-PH > 7-OH-PH the latter showing no activity. Patients on PH therapy showed lower plasma concentrations of metabolites than of PH; in humans the metabolites of PH will not contribute significantly to the overall anticoagulant activity of the drug.

Animals↗
PubMed1977

Interaction study between phenprocoumon and flurbiprofen.

The effects of flurbiprofen on various coagulation and haemostasis parameters were studied in 19 patients adequately anticoagulated on a fixed dose of phenprocoumon. Laboratory controls were performed 5 times at weekly intervals. Flurbiprofen 50 mg 3-times daily was given for 2 weeks after an initial control period of 2 weeks. The last control followed 1 week after cessation of flurbiprofen. All changes observed during the administration of flurbiprofen were quantitatively moderate; some reached statistical significance. The prothrombin time (%) Factor II and Factor X values fell; Factor II values remained unchanged. Factor IX values fell only in the first week on flurbiprofen and reached control values thereafter. Phenprocoumon concentration remained constant throughout. There was no change in spontaneous platelet aggregation. Although there was a slight, statistically significant increase in the Ivy bleeding time, it remained within the normal range. These findings suggest that the interference of flurbiprofen with oral anticoagulation is minimal and probably of no clinical relevance.

4-Hydroxycoumarins↗
PubMed1988

Microbial models of mammalian metabolism: production of novel alpha-diketone metabolites of warfarin and phenprocoumon using Aspergillus niger.

1. The coumarin anticoagulants warfarin and phenprocoumon were metabolized by Aspergillus niger via oxidative ring cleavage to yield the corresponding alpha-diketone metabolites. 2. Structural identification was based upon physical, spectral, and chromatographic comparisons of isolated metabolites and synthetic standards generated by the oxidative cleavage of warfarin or phenprocoumon with pyridinium chlorochromate. 3. This pathway of metabolism has been previously observed for coumarin anticoagulants in mammalian systems.

4-Hydroxycoumarins↗
PubMed1976

[Studies on the interactions of chlordiazepoxide, nitrazepam, and diazepam with phenprocoumon (author's transl)].

The interaction of benzodiazepine derivatives with phenprocoumon (Marcumar) was investigated after a single dose of the combination of phenprocoumon/diazepoxide (Librium), phenprocoumon/diazepam (Valium) and phenprocoumon/nitrazepam (Mogadan) had been applied to rats. By means of the high pressure liquid chromatography (HPLC) the change of concentration of these pharmaceutical agents per unit time in serum was determined and related to the corresponding change of prothrombin-time. Hence it can be concluded that the benzodiazepine derivatives influence the distribution of phenprocoumon in the organism.

4-Hydroxycoumarins↗
PubMed2002

[Initiation of oral anticoagulant treatment: comparison between different dosage regimens of warfarin and phenprocoumon].

A high "loading dosage" is often given during initiation of oral anticoagulant treatment in order to reach sufficient anticoagulation within short time. Increased bleeding risk as well as a transient prothrombotic tendency are complications of this treatment schedule. The aim of our study was to find proper dosage regimens of phenprocoumon and warfarin allowing initiation of oral anticoagulant treatment in a short time. For 50% of the patients 7.5 mg warfarin daily resulted in stable INR values within 4 days. Patients receiving higher (10 mg) or lower (5 mg) daily dosages of warfarin or 6 or 9 mg phenprocoumon daily during the first days of therapy reached the therapeutic range significantly later. Furthermore, no significant differences of prothrombin fragment F 1+2 were observed, indicating that no enhanced thrombin formation occurred. Thus, initiation of oral anticoagulant treatment using 7.5 mg warfarin daily is a simple and safe dosage regimen.

Administration, Oral↗
PubMed2002

Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants.

BACKGROUND: Several case reports associated combined use of coumarins and antibacterial drugs with overanticoagulation. Despite the fact that these drugs are frequently prescribed concurrently, there is little quantitative information on the risks of such complications. OBJECTIVE: To study which antibacterial drugs are associated with overanticoagulation during therapy with coumarins. DESIGN: Population-based cohort study in a sample of the Rotterdam Study. SUBJECTS: All patients who were treated with acenocoumarol or phenprocoumon in the study period from April 1, 1991 through December 31, 1998 and for whom INR data were available. METHODS: Patients were followed until an INR >/= 6.0, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of an INR >/= 6.0 in relation to concomitant use of an oral anticoagulant and antibacterial drugs after adjustment for several potentially confounding factors such as age, gender, hepatic dysfunction, malignancies, and heart failure. RESULTS: Of the 1,124 patients in the cohort, 351 developed an INR >/= 6.0. The incidence rate was 6.9 per 10,000 treatment days. Sulfamethoxazole combined with trimethoprim most strongly increased the risk of overanticoagulation with an adjusted relative risk of 20.1 (95% CI: 10.7-37.9). Stratification showed that the induction period of overanticoagulation varied between different antibacterial drugs. CONCLUSION: In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, several antibacterial drugs strongly increased the risk of overanticoagulation. Awareness of these drug interactions and more frequent monitoring of INR values during the initial stages of antibacterial drug therapy are warranted to minimize the risk of bleeding complications.

Acenocoumarol↗
PubMed2006

[Off label use in long-term anticoagulation after liver transplantation due to phenprocoumon-induced hepatic failure].

BACKGROUND: Drug therapy should be individualised according to criteria of efficacy, adverse effects, and treatment adherence. This is particularly important at the interface of inpatient and ambulatory care. Aspects of drug approval (labelling) and individual refunding by health care insurances should also be taken into account. CASE REPORT: A patient (male, 61, painter) showed elevated transaminases after treatment with phenprocoumon because of a deep vein thrombosis in 1999. Transaminases normalized completely after discontinuation of excluded. After a recurrent thrombosis in 2003 phenprocoumon was prescribed again followed by recurrent elevation of transaminases and subsequent cholestatic hepatitis progressing to fulminant hepatic failure that required liver transplantation. After transplantation the patient's general state of health was good and liver function nearly normal. Anticoagulation was indicated beyond the postoperative phase because of recurrent deep vein thrombosis and atrial fibrillation. A low molecular weight heparin was chosen for long-term treatment. CONCLUSION: A low molecular weight heparin appears to be the most appropriate way to maintain effective and safe anticoagulation in this patient. Coumarins carry a residual risk of an extrahepatic, immunologically mediated cross sensitization. Long-term use of ximelagatran (which has been withdrawn meanwhile) may also cause liver damage. For heparinoids, hirudines, and other drugs affecting coagulation like platelet aggregation inhibitors, therapeutic evidence is not sufficient. Though subcutaneous application of heparin is a disadvantage for the patient, therapeutic alternatives do not have better documented efficacy or less hepatotoxic potential. The low molecular weight heparin fulfils the criteria for refunding set by federal jurisdiction.

Anticoagulants↗
PubMed1991

Effects of the oral anticoagulant phenprocoumon on blood coagulation and thrombogenesis induced by rabbit aorta subendothelium exposed to flowing human blood: role of dose and shear rate.

We investigated the effect of oral anticoagulation on thrombogenesis induced by the subendothelium of rabbit aorta. Eighteen healthy volunteers underwent a 2-week treatment with the oral coumarin preparation phenprocoumon to a target international normalized ratio (INR) of 5. By using an ex-vivo perfusion chamber system, the interaction between flowing blood and exposed subendothelium was measured at low (50 sec-1) and high (650 sec-1) wall shear rates. The low shear rate simulated blood flow in venous vessels and the high shear rate simulated blood flow in arterial vessels. Deposition of fibrin, platelets, and platelet thrombi on subendothelium was quantified by morphometric and immunologic techniques. Fibrin deposition prevailed at the low shear rate (183 +/- 57 ng/mm2 vs 46 +/- 16 ng/mm2, low vs high shear rate; mean +/- SEM; p less than 0.01). In contrast, the interaction of platelets with subendothelium was more intense at high shear rates when compared with low shear rates, as indicated by higher platelet adhesion (44% +/- 2% vs 9% +/- 1% coverage of subendothelium with platelets, p less than 0.001) and platelet thrombus volumes (3.6 +/- 0.4 microns 3/microns 2 vs 1.3 +/- 0.3 microns 3/microns 2, p less than 0.001). Fibrin deposition on subendothelium was substantially reduced even at a low intensity of anticoagulation (reduction by 60% at INR 2.1 and by 75% at INR 3.7) and was abolished after high coumarin doses (INR 5.2). In contrast, a significant inhibition of platelet thrombus formation could be achieved only by high doses of phenprocoumon (INR 5.2). Our data indicate that relatively low doses of oral anticoagulants (INR between 2 and 3.5) substantially inhibit the fibrin formation on subendothelium prevailing at venous shear conditions, whereas a high intensity of anticoagulation (INR 4 to 5) is necessary to inhibit the formation of platelet-rich thrombi prevailing at arterial shear conditions.

Administration, Oral↗
PubMed1982

[Influence of (+)-Catechin and Dithiocarb on the Pharmacokinetics of Phenprocoumon, Tolbutamide and Three Inhalation Anesthetics in rats].

Pretreatment with (+)-catechin ((+)-cyanidanol-3, Catergen) (200 mg/kg p.o.) did not alter the elimination of intravenously injected phenprocoumon (0.6 mg/kg) or tolbutamide (100 mg/kg) in rats, while dithiocarb (Sodium diethyl-dithiocarbamate) (200 mg/kg p.o.) prolonged only the elimination half-life of phenprocoumon to a small extent. The metabolism of halothane (100 ppm), enflurane (100 ppm) or methoxyflurane (300 ppm) was studied by measuring the disappearance of the compounds from the atmosphere of a closed exposure system. Pretreatment with (+)-catechin did not impair the metabolic removal of all three anesthetics; in the case of enflurane (+)-catechin caused a small, but significant shortening of the elimination half-life, for enflurane and methoxyflurane the uptake of the compounds into the rats seemed to be impaired under the influence of (+)-catechin. Dithiocarb strongly impaired the in vivo metabolism of halothane and methoxyflurane, whereas that of enflurane remained unaffected.

4-Hydroxycoumarins↗
PubMed1984

Interaction between phenprocoumon and phytomenadion: a pharmacokinetic investigation in healthy volunteers.

In 23 female and male healthy volunteers the pharmacokinetic behaviour of [3H]phenprocoumon and [3H]phytomenadion was investigated. The time-dependent changes in plasma radioactivity and the amount of urinary excretion were measured. Under simultaneous administration of phytomenadion (PHY) in daily doses of 10 mg, the elimination of phenprocoumon (PPC) was not altered (t0.5 beta 141.4 h, CUE50 20.4% of administered dose) as compared with data of previous investigations, while its anticoagulant effect was inhibited. PHY in doses of 10 mg was absorbed quickly and eliminated with a mean half-life of 60.6 h at a total body clearance (Cltot) of 9.3 ml/min and a renal clearance (Clren) of 1.9 ml/min. Under the co-administration of PPC the vitamin was eliminated with a half-life time of 23.1 h (Cltot 16.7 ml/min) and the amount of excreted radioactivity was enhanced (26.3% of administered dose; Clren 4.5 ml/min) as compared with the data of PHY without co-medication. From the experiments it is concluded that (1) PHY inhibits the action of PPC without influencing its pharmacokinetics, and (2) that PPC distinctly changes the pharmacokinetics of PHY and diminishes its pharmacodynamic action as measured by changes in the prothrombin complex activity.

4-Hydroxycoumarins↗
PubMed1978

Individualization of drug dosage during long-term treatment with phenprocoumon (Falithrom).

Pharmacokinetic studies were carried out with 3H-phenprocoumon (3H-PPC) during long-term treatment with phenprocoumon (PPC, Falithrom) in 10 female and male patients with thromboembolic diseases. Additionally, 12 mg 3H-PPC were administered per os to 6 male volunteers. Half-life and pattern of urine metabolites were measured and compared with those in patients. The radioactivity decreased independently of the total PPC plasma concentration, which was estimated fluorometrically. An exponential regression with a high coefficient of determination was found between the mean maintenance dose (PPC) and the area under plasma concentration curve of radioactivity. This procedure is considered to be a method to improve long-term treatment with PPC.

4-Hydroxycoumarins↗