A double blind study of phenprocoumon prophylaxis after myocardial infarction.
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[Drug information: coagulation inhibiting agents. II. Indirectly-acting anticoagulants. Coumarin derivatives: dicumarol, phenprocoumon (Marcoumar), warfarin (Marevan). Indandione derivatives: phenindione (Dindevan)].
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Anticoagulants↗
[The treatment basis for anticoagulants in horses].
The pharmacokinetics of racemic phenprocoumon were studied in 8 adult horses after the single intravenous and oral administration of 0.75 mg/kg. After i.v. administration the plasma concentration of phenprocoumon showed a biphasic decline in time. The pharmacokinetics were calculated on the two-compartment open model. The average plasma half-life (beta-phase) was 22 hours, the apparent volume of distribution was 0.61 l/kg, Cltot was 25.2 ml/kg/h (13.9-40.9 ml/kg/h). The systemic bioavailability of oral phenprocoumon was 97.6%, Tmax was found to be 4-12 hours. The effect of phenprocoumon on the coagulation system was determined by the activity of Factor X, the Quick's one stage prothrombin time and the PTT. Factor X showed the most marked effect. A reduction of the content of Factor X was seen over 7-9 days, it decreased to 11-33%. Quick's one stage prothrombin time was reduced over 4-8 days, the lowest values were 22-55%. The PTT showed only a small reaction on the single administration of 0.75 mg/kg phenprocoumon. Differences in the effect on the coagulation between the i.v. and the oral administration could not be observed. In comparison to warfarin, phenprocoumon showed a longer t0.5 (beta) and produced a markedly longer hypothrombogenic reaction. Therefore phenprocoumon appeared to be more suitable for a long term anticoagulation therapy in horses than the structurally related warfarin.
Administration, Oral↗
Unstable anticoagulation in the course of amitriptyline treatment.
A potential drug-drug interaction between the tricyclic antidepressant amitriptyline and the oral anticoagulant phenprocoumon, causing intensified hypo- and/or hyperprothrombinemic effects, was investigated. In seven patients simultaneously receiving amitriptyline and phenprocoumon the course of the Quick values and the amitriptyline and phenprocoumon dosages were registered. The resulting data represented graphically was additionally compared with data and diagrams gained from a control group of seven phenprocoumon patients not receiving amitriptyline. Whereas in the control group the average Quick values (or the target International Normalized Ratio) lay within the required therapeutic range, massive fluctuations were seen in the amitriptyline-treated patients. These fluctuations did not disappear until the amitriptyline medication was discontinued. Whether our findings are actually due to a clinically relevant drug-drug interaction needs to be investigated in further controlled studies based on a larger number of patients, the more so as no comparable investigations and only few references to this subject are to be found in the literature. Should an amitriptyline influence on the frequently prescribed coumarin derivative be proven, an increased risk of rethrombosis or bleeding complications in patients receiving both amitriptyline and phenprocoumon would appear to be indicated.
Adult↗
[Studies of the interractions of cyclamate with phenprocomon (author's transl)].
The effect of cyclamate on the anticoagulant activity of phenprocoumon was investigated in rats after single oral doses of phenprocoumon, cyclamate, or phenprocoumon/cyclamate. By means of high pressure liquid chromatrography [HPLC] the change of the concentration of phenprocoumon per unit time in sera was determined. The anticoagulant acitivity of phenprocoumon was determined by the extension of the prothromin-time (Quick-test). It was found that cyclamate gives rise to an elevated of phenprocoumon in the blood, and a reduction of the anticoagulanting potency.
4-Hydroxycoumarins↗
Spectroscopic study of the interaction of coumarin anticoagulant drugs with polyvinylpyrrolidone.
The interaction of coumarin anticoagulants with polyvinylpyrrolidone (PVP) was investigated using a fluorescence technique. The fluorescence intensities of warfarin and phenprocoumon were greatly enhanced following binding to PVP, while the fluorescence of 4-hydroxycoumarin was little enhanced in the presence of PVP. The enhanced fluorescence of warfarin and phenprocoumon bound to PVP can be explained by their incorporation into the hydrophobic environment in the PVP and by a decrease in the internal rotation of the alpha-substituted benzyl group in the drugs. The binding parameters of warfarin and phenprocoumon were estimated by the Klotz method; the binding constants for phenprocoumon and warfarin were found to be 2.6 X 10(4) and 2.2 X 10(4) M-1, respectively. The 13C-NMR measurements suggest the lactone moiety in the 4-hydroxycoumarin and the substituted benzene ring play an important role in the binding to PVP.
4-Hydroxycoumarins↗
Stereoselective metabolism of conformational analogues of warfarin by beta-naphthoflavone-inducible cytochrome P-450.
Previous studies have shown that the structurally related oral anticoagulants warfarin and phenprocoumon are regioselectively hydroxylated in the 6- and 8-positions by hepatic microsomes obtained from 3-methylcholanthrene (3-MC) or beta-naphthoflavone (BNF) pretreated rats. Stereoselectivity for hydroxylation is also observed and favors (R)-warfarin but (S)-phenprocoumon. The possibility that the stereoselectivity of warfarin hydroxylation is a function of the solution conformation of the drug was tested with conformationally restricted analogues. In these experiments the analogues were incubated with microsomes obtained from BNF-pretreated rats and any stereoselectivity associated with 6- and 8-hydroxylation was determined. The R enantiomer of cyclocoumarol, the cyclic ketal analogue of warfarin, was found to be selectively hydroxylated, in contrast to the S enantiomer of warfarin 4-methyl ether, the ring-opened analogue. The latter compound is known to have a preferred solution conformation similar to that of phenprocoumon. The results suggest that at the active site of BNF-induced cytochrome P-450 (R)-warfarin is metabolized in its cyclic hemiketal tautomer, a form which spatially mimics the preferred solution conformation of (S)-phenprocoumon.
Animals↗
Course of thrombin activation markers in patients implanted with Palmaz-Schatz stents: first experiences with a post-interventional anticoagulation regimen.
Following implantation of coronary Palmaz-Schatz stents, 29 patients were anticoagulated with a combination of heparin, phenprocoumon and aspirin following a standard protocol. After removing the arterial and venous lines, post-interventional intravenous (i.v.) heparin treatment started with 1500 IU/h for patients > 80 kg and 1250 IU/h for patients < 80 kg. Heparin was monitored by the activated partial thromboplastin time (aPTT) and adjusted by increasing or reducing i.v. heparin by 250 IU/h to maintain the aPTT within the therapeutic range. Phenprocoumon therapy began the day after stent implantation (day 2) and lasted for 3 months. aPTT, Heptest, prothrombin fragment F1 and 2 (F1.2) and thrombin-antithrombin III complexes (TAT) were monitored at standard intervals for 10 days (mean monitoring time: 9.7 +/- 2.3 days). Anticoagulation was efficient with aPTT levels remaining within the therapeutic range on day 9 and the simultaneous, moderate-onset oral anticoagulation within the therapeutic range of the International Normalized Ratio (INR; 2.15-4.80) on day 8 on average, the mean INR being 2.43 +/- 0.76. On day 4, F1.2 levels were significantly higher than on the day of stenting (1.16 +/- 0.30 nmol/l vs 1.04 +/- 0.53 nmol/l; P < 0.005). F1.2 levels fell after day 5, the difference becoming significant from day 8 on (P < 0.05). F1.2 was negatively correlated with the Heptest (P < 0.05) and fell significantly as a function of the INR during phenprocoumon administration (P < 0.001). After phenprocoumon therapy was discontinued over 3 weeks, 25 patients were followed up by angiography. Despite adequate anticoagulation, mean F1.2 levels in patients showing restenosis at follow-up angiography were significantly higher (P < 0.005) than in those without restenosis. In one patient who developed subacute stent thrombosis, clotting factors were determined 20 min before stent occlusion. The levels of F1.2 and TAT were less than all other patients on this day (F1.2: 0.98 nmol/l vs 1.11 +/- 0.40 nmol/l; TAT: 2.7 micrograms/l vs 3.21 +/- 3.38 micrograms/l). Thus, neither F1.2 nor TAT predicted the occurrence of thrombotic stent failure in individuals. Efficient anticoagulation by a combination of anticoagulants is imperative for stent implantation. Using only current routine methods, this way of monitoring anticoagulation is effective for managing combined anticoagulation therapy.
Adult↗
The effect of different oral anticoagulants on diphenylhydantoin (DPH) and tolbutamide metabolism.
The effect of bishydroxycoumarin, phenprocoumon, warfarin and phenindione on the metabolism of diphenylhydantoin (DPH) and tolbutamide has been studied in 54 patients. The half-lives of DPH and tolbutamide in blood following i.v. injections were studied in 33 patients before and after one week of anticoagulant treatment. Bishydroxycoumarin increased the mean half-life values of DPH from 8.8 to 37.4 hours and of tolbutamide from 4.9 to 17.5. Phenprocoumon prolonged DPH half-life from a mean value of 9.9 to 14.0 hours but did not change the tolbutamide half-life. Warfarin and phenindione did not affect DPH or tolbutamide half-lives. Steady state concentration studies in 21 patients showed a rise in serum DPH during bishydroxycoumarin and phenprocoumon treatment but not during treatment with warfarin and phenindione. A rise in serum tolbutamide was noted during treatment with bishydroxycoumarin. These findings suggest that bishydroxycoumarin inhibits the betabolism of DPH and tolbutamide and that phenprocoumon inhibits DPH metabolism. No effect on DPH and tolbutamide metabolism could be demonstrated following administration of warfarin and phenindione.
Coumarins↗
Cyclic interconversion of vitamin K1 and vitamin K1 2,3-epoxide in man.
The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1-2,3-epoxide were studied in two healthy subjects without and with 12 h pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concentration-time profile was adequately fitted by a biexponential equation, with an average terminal half-life of 2.0 and 1.15 h for the administered vitamin K and its 2,3-epoxide respectively. While vitamin K1 was measurable in plasma following administration of vitamin K1-2,3-epoxide, the epoxide was not detectable following administration of vitamin K1. Following pretreatment with phenprocoumon and after intravenous administration of vitamin K1, both the average half-life and area under the plasma concentration-time profile of vitamin K1 were marginally reduced to 1.5 h and 1.76 mg l-1 h respectively, while the plasma concentration of vitamin K1-2,3-epoxide was readily measurable and its half-life markedly prolonged to 14.7 h. Following pretreatment with phenprocoumon and after oral administration of vitamin K1-2,3-epoxide, no vitamin K1 was detectable in plasma and the half-life of the epoxide was 13.8 h. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1-2,3-epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs, obtained by Carlisle & Blaschke (1981).
Adult↗
Vitamin K metabolism in a patient resistant to vitamin K antagonists.
We investigated various pharmacokinetic and pharmacodynamic parameters in a 63-year-old man, resistant to warfarin, fluindione, acenocoumarol and phenprocoumon. Daily doses of up to 30 mg of the long-acting phenprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg/l) but the international normalized ratio remained around 1. The plasma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an accelerated metabolism of the drug. The level of vitamin K1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentrations were low, demonstrating that the gamma-carboxylation of the precursors of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased under oral anticoagulation, correlated to the vitamin K concentration (r2 = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower than that of 22 warfarin-sensitive patients, suggesting an absence of blockade of the vitamin K reductase by phenprocoumon. This resistance to all the molecular forms of the vitamin K antagonists is most likely due to a reduced affinity of the drugs to a mutant vitamin K reductase.
Drug Resistance↗
Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial.
BACKGROUND: Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring. METHODS AND RESULTS: In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours' and < or =1 year's duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively; P=0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively; P=0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm. CONCLUSIONS: Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.
Administration, Oral↗
Prediction of pharmacokinetic drug/drug interactions from In vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants.
CYP2C9 is involved in the metabolism of the oral anticoagulants warfarin, phenprocoumon, and acenocoumarol. It is also responsible for the 5'-hydroxylation of the nonsteroidal anti-inflammatory drug lornoxicam. Therefore, lornoxicam and the oral anticoagulants are potential inhibitors of their metabolism. Their inhibitory potency was investigated in microsomes from six human livers. An approach to predict pharmacokinetic interactions of lornoxicam from in vitro inhibition data was developed. Where possible, the forecasts were verified by comparison with data from clinical interaction studies. The following increases in steady-state plasma concentrations or areas under the plasma concentration-time curve of the oral anticoagulants by concomitant lornoxicam medication were predicted (values in parentheses are for healthy volunteers): (S)-warfarin, 1. 58-fold (1.32-fold for racemate); racemic-acenocoumarol, 1.28-fold (1.09-fold); (R)-acenocoumarol, 1.10-fold (1.0-fold); racemic-phenprocoumon, 1.11-fold (1.18-fold); and (S)-phenprocoumon, 1.13-fold (1.24-fold). Lornoxicam 5'-hydroxylation was competitively inhibited in vitro by both phenprocoumon (K(i) = 1.2 +/- 0.4 microM) and acenocoumarol (K(i) = 5.5 +/- 3.5 microM). The present results indicate that relatively close predictions of the interactions of lornoxicam with oral anticoagulants from in vitro data are possible under the assumption that hepatic lornoxicam concentrations are similar to its total plasma concentrations. The degree of pharmacokinetic interactions exhibited by oral anticoagulants and lornoxicam is dependent on the respective contribution of CYP2C9 to their total clearance.
Acenocoumarol↗
[The influencing of rat-tail tumors with and without irradiation].
In a collective of 200 Wistar rats, the influence of anticoagulants upon the rat tail tumor (Walker 256 carcinosarcoma) was checked with and without irradiation. After implantation of the tumor and development of a certain definite tumor volume, the animals were divided into four different groups of 50 rats each. The first one was the control group without any manipulation, the second received an one-stage X-irradiation with 2500 R SD directed to the tail tumor, the third was treated with an oral dose of Phenprocoumon which was added to the daily drinking quantity (0.1 mg/kg body weight), and the fourth group was given an one-stage X-irradiation together with the oral Phenprocoumon treatment. The influence of these different treatments on the growth of the primary tumor, on the incidence of metastases and on the death rate was checked up. The best therapeutical effect was observed with combined radiation and Phenprocoumon treatment. The therapy resulted in an almost complete growth rate depression of the primary tumor, in an early tendency of remission of the primary tumor, a 42 per cent decrease of the incidence of metastases to the lung, and a 42 per cent increase of the survival rate. With regard to the frequency of metastases and to the survival rate, treatment with Phenprocoumon alone showed significantly better results as sole radiation treatment.
Animals↗
Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized anticoagulation clinics in the Netherlands: a randomized clinical trial.
BACKGROUND: Several studies have demonstrated that patient self-management of oral anticoagulant therapy (OAT) can improve treatment quality. However, most of these studies were not conducted within a specialized anticoagulation care system. The objective of the present study was to determine whether patient self-management of OAT improves the quality of care delivered by anticoagulation clinics. METHODS: In this randomized study by 2 Dutch anticoagulation clinics 341 patients aged between 18 and 75 years and receiving long-term OAT were divided into 4 groups: an existing routine care group of patients untrained in self-management; a routine care group of trained patients; a group managed weekly at an anticoagulation clinic where international normalized ratios were measured by trained patients; and weekly patient self-management. A 2-step randomization procedure was followed: first, a Zelen-design randomization was performed to distribute patients (without informing them) to the existing care group or to receive training in self-management; second, trained patients were randomized to the 3 other study groups. RESULTS: Only 25.6% of invited patients agreed to participate in the training program. Patients who remained in the existing care group were within the international normalized ratio target range 63.5% of the time. The type of coumarin taken was a major predicting factor of OAT quality. In all study groups phenprocoumon outperformed acenocoumarol by 11.6% (95% confidence interval [CI], 6.6%-16.5%). Weekly management with phenprocoumon led to a 6.5% improvement (95% CI, 0.0%-13.1%) in time in the international normalized ratio target range when patients were managed at an anticoagulation clinic and to an 8.7% improvement (95% CI, 1.6%-15.9%) when patients were self-managed. Weekly management with acenocoumarol did not improve the quality of OAT. CONCLUSION: With selected patients, the quality of OAT obtained through patient self-management is at least as high as that delivered by specialized physicians at anticoagulation clinics. Weekly management of OAT with long-acting phenprocoumon has to be preferred at anticoagulation clinics or, where possible, through patient self-management.
Adult↗
Left atrial thrombi despite anticoagulant and antiplatelet therapy.
To investigate risk factors for embolization in patients with echocardiographically detected left atrial thrombi and to evaluate thrombus development, we examined 29 patients with transesophageal and transthoracic echocardiography at two points during a follow-up of 18 months. We compared patients with a history of possible arterial embolization (n = 13) with those without (n = 16) in regard to age, gender, left atrial dilatation, localization of the thrombus in the left atrial cavity, spontaneous echo contrast, and atrial fibrillation. Eight patients were treated with aspirin, 20 with phenprocoumon. Only left atrial spontaneous contrast was associated with thromboembolism (10/15 patients with spontaneous contrast experienced arterial embolism; p = 0.038). In six patients arterial embolism occurred after thrombus detection (14% per patient per year). Four of these patients were treated with phenprocoumon, two with aspirin. At reexamination, one thrombus was detected in the patient without anticoagulant treatment and one thrombus was detected in the 8 patients treated with aspirin (13%), compared with ten thrombi detected in the 20 patients (50%) treated with phenprocoumon (p = NS). In 17 patients no thrombus was seen at reexamination. Since only 2 patients had undergone thrombectomy and 3 experienced arterial embolism during follow-up, thrombi disappeared under medical therapy in 12 patients. Patients with left atrial thrombi have a high risk of arterial embolization despite proper anticoagulative or antiplatelet treatment. Embolization occurs significantly more often if spontaneous echo contrast can be visualized. Left atrial thrombi can be reduced in size by the administration of antiplatelet and anticoagulative agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Lack of interaction between tramadol and coumarins.
The objective of this study was to investigate whether the central analgesic tramadol influences the effects of the coumarin anticoagulant phenprocoumon during multiple-dose administration. Nineteen patients receiving long-term anticoagulant therapy who had been in a stable hypothrombinemic state for at least 3 months completed a double-blind, placebo-controlled, crossover study. Tramadol was administered in the usual therapeutic dose of 50 mg three times daily. The average daily phenprocoumon dose was identical for individual patients in both treatment periods. The equivalence ratio (tramadol/placebo) of the international normalized ratio (INR) values was 0.99 (90% confidence interval 0.89-1.10), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). Therefore, tramadol does not affect INR in patients being treated with phenprocoumon. These data suggest a lack of interaction between tramadol and coumarin anticoagulants.
Aged↗
Main comedications associated with major bleeding during anticoagulant therapy with coumarins.
OBJECTIVE: To study the main comedications associated with major bleeding during anticoagulant therapy with coumarins in a non-selected population under everyday circumstances. METHODS: The study population for this retrospective cohort study included all new users of phenprocoumon or acenocoumarol aged 40-80 years, during the period 1992-2000 in the PHARMO Record Linkage System. All patients were followed until the last dispensing of phenprocoumon or acenocoumarol, the first bleeding complication requiring hospitalization, death, or the end of the study period. The number of days on coumarins alone and the number of days on coumarins in combination with several potentially interactive drugs during follow-up were determined for each patient. RESULTS: The inclusion criteria of this study were met by 19,935 new users of phenprocoumon or acenocoumarol. During follow-up, 552 patients were hospitalized for bleeding. Of all potentially interactive drugs started during anticoagulant therapy by at least 50 patients and with at least five bleedings, antibacterial drugs were associated with a four to seven times increased risk of bleeding. Among non-steroidal anti-inflammatory drugs, naproxen had the highest relative risk. Antithrombotic salicylates and tramadol were associated with a three times increased risk of bleeding. CONCLUSION: Antibacterial drugs, non-steroidal anti-inflammatory drugs, antithrombotic salicylates and tramadol were the main potentially interactive drugs associated with major bleeding during anticoagulant therapy with coumarins under everyday circumstances.
Acenocoumarol↗