Anticoagulant Phenprocoumon Research Articles

Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status.

The mechanism of cephalosporin-induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N-methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl-thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3-epoxide in response to a 10-mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA-II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef-associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub-normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional-vitamin K status predisposes to hypoprothrombinemia.

Rheological and Anticoagulant Therapy of Patients with Chronic Peripheral Occlusive Arterial Disease (COAD)

In the course of a six-month study, a three-subgroup cohort of 113 patients (103 m, 10 f, mean age 58 +/- 8 years) with angiographically proven occlusive peripheral arterial disease (COAD) Fontaine stage II was analyzed regarding the therapeutic (improvement of walking performance) and prophylactic (prevention of new vascular events) effects of oral treatment with three different drug regimens. Group A (38 patients) was treated with the anticoagulants phenprocoumon or acenocoumarol; group B (32 patients), with the same anticoagulants plus pentoxifylline--800-1200 mg per day; and group C (43 patients) received irregular treatment with various vasodilators, such as xanthinolnicotinate, naftidrofuryl, pyridylmethanol, and others. At the end of the trial period a significant increase in systolic ankle pressure index and walking distance was observed in group B whereas the two other groups showed minor changes only. The elevated plasma fibrinogen concentration in group B was also significantly decreased. The percentage of atherosclerotic complications such as new arterial thrombosis in the lower limbs, newly appeared stenocardia, myocardial infarction, transient ischemic attack (TIA), and stroke was highest in group C (20%), relatively lower in group A (10%), and lowest in group B (3%). The percentage of hemorrhagic complications was minimal, with no significant differences between group A and group B. These complications were mild and disappeared quickly. The combined therapy with anticoagulants and pentoxifylline had a marked therapeutic and probably prophylactic effect as regards thromboembolic complications in patients with COAD and other localizations of atherosclerosis.

Studies on the metabolism of oral anticoagulants

The metabolites of the oral anticoagulant phenprocoumon are characterized as the 7,4′ and 6-hydroxyphenprocoumons in human plasma and urine using liquid chromatography and gas chromatography-mass spectrometry. The author's own work and that of others are reviewed and the metabolic stereoselectivity of phenprocoumon and its metabolism is compared with that of warfarin.

Identification of phenprocoumon metabolites in human urine by high-performance liquid chromatography and gas chromatography—mass spectrometry

The oral anticoagulant phenprocoumon is eliminated in urine mainly as the glucuronide conjugate to an extent of 20% of the dose. The urine from patients undergoing phenprocoumon therapy was investigated and the following metabolites were isolated and identified: 7-hydroxyphenprocoumon as the main component, and 4′-hydroxyphenprocoumon and 6-hydroxyphenprocoumon as conjugates. They were characterized by high-performance liquid chromatography and, after methylation, by gas chromatography—mass spectrometry

Phenylbutazone and Sulfinpyrazone Interaction With Oral Anticoagulant Phenprocoumon

To compare the marked hypoprothrombinemic augmentation in man of racemic warfarin sodium by the pyrazolons phenylbutazone and sulfinpyrazone with that of the coumarin anticoagulant phenprocoumon, these interactions were studied prospectively in six normal subjects. Large single doses of racemic phenprocoumon, 0.6 mg/kg orally, were administered with and without daily phenylbutazone, 300 mg, or sulfinpyrazone, 400 mg, beginning three days before phenprocoumon and continuing for 14 days. Daily blood samples were drawn for phenprocoumon content and one-stage prothrombin time. Phenylbutazone markedly increased both the phenprocoumon concentrations and prothrombin times, whereas sulfinpyrazone did not.

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 C 10 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/l, the sensitivity was 0.1 mg/l for plasma and 0.02 mg/l 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.

A specific and sensitive method for the determination of the anticoagulant phenprocoumon in plasma

A specific thin-layer chromatographic assay for phenprocoumon has been developed with a sensitivity of 5 ng/ml of plasma, using only 0.2 ml. This sensitivity is more than 20 times higher than that of the published methods. The drug is extracted from acidified plasma, an aliquot of the extract is applied to a silica-gel thin-layer plate and separated from interfering substances. The quantity of phenprocoumon is determined by fluorescence densitometry in situ. The standard deviation of the whole procedure is less than ± 3%. The new procedure permits pharmacokinetic studies withlow doses of phenprocoumon to be performed on volunteers. Furthermore, due to the high sensitivity of the method, it is possible to determine the free drug fraction of this highly protein-bound substance in the plasma of patients. It was shown that, in the therapeutic concentration range, phenprocoumon is bound by about 99.5% to the plasma proteins. Since the assay is simple and quick to perform, a large series of plasma samples can be analysed without any problems.

ChemInform Abstract: SYNTHESIS AND THIN‐LAYER CHROMATOGRAPHIC, ULTRAVIOLET, AND MASS SPECTRAL PROPERTIES OF THE ANTICOAGULANT PHENPROCOUMON AND ITS MONOHYDROXYLATED DERIVATIVES

Chemischer InformationsdienstVolume 6, Issue 35 Heterocyclic Compounds ChemInform Abstract: SYNTHESIS AND THIN-LAYER CHROMATOGRAPHIC, ULTRAVIOLET, AND MASS SPECTRAL PROPERTIES OF THE ANTICOAGULANT PHENPROCOUMON AND ITS MONOHYDROXYLATED DERIVATIVES L. R. POHL, L. R. POHLSearch for more papers by this authorR. HADDOCK, R. HADDOCKSearch for more papers by this authorW. A. GARLAND, W. A. GARLANDSearch for more papers by this authorW. F. TRAGER, W. F. TRAGERSearch for more papers by this author L. R. POHL, L. R. POHLSearch for more papers by this authorR. HADDOCK, R. HADDOCKSearch for more papers by this authorW. A. GARLAND, W. A. GARLANDSearch for more papers by this authorW. F. TRAGER, W. F. TRAGERSearch for more papers by this author First published: September 2, 1975 https://doi.org/10.1002/chin.197535227AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume6, Issue35September 2, 1975 RelatedInformation

Synthesis and thin-layer chromatographic ultraviolet, and mass spectral properties of the anticoagulant phenprocoumon and its monohydroxylated derivatives.

Phenprocoumon and all of its aromatic monohydroxylated derivatives have been synthesized and analyzed by TLC, uv, and chemical ionization mass spectroscopy. By utilization of various combinations of these analytical techniques all of the titled compounds can be uniquely identified.

Collaborative Study of a Semiautomated Method for the Analysis of Acenocoumarol, Phenprocoumon, and Potassium Warfarin Tablets

This collaborative study was undertaken to determine if the anticoagulants acenocoumarol, phenprocoumon, and potassium warfarin could be analyzed by the automated analysis system described in the collaborative study for the analysis of sodium warfarin and dicumarol. Collaborators were supplied with a composited tablet sample of each anticoagulant. Results agreed well with the National Formulary methods for phenprocoumon and potassium warfarin, and an unpublished method for acenocoumarol. For acenocoumarol, coefficients of variation on individual sets of data ranged from 0.30 to 1.94% For phenprocoumon, coefficients of variation ranged from 0.52 to 1.20%. For potassium warfarin, coefficients of variation ranged from 0.54 to 1.79%. The results of this study show that acenocoumarol, phenprocoumon, and potassium warfarin can be analyzed by the official AOAC method for the analysis of sodium warfarin and dicumarol tablets.