warfarin and coumarin

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA.

Topics: Acenocoumarol; Animals; Anticoagulants; Clinical Trials as Topic; Coumarins; Fever; Hemorrhage; Humans; International Normalized Ratio; Phenprocoumon; Rats; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

Three new oral anticoagulants have been evaluated in large registration trials and are now available in many jurisdictions for patients with atrial fibrillation. Questions arise whether these drugs are equally effective and safe for all patients. Now when we are moving away from decades with only one orally available drug for anticoagulation there is opportunity to tailor the therapy according to patient characteristics and preferences. This review addresses the interaction of various patient characteristics with the treatment and what features can assist the physician in the choice of anticoagulant for the individual patient.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Coumarins; Dabigatran; Female; Hematology; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Renal Insufficiency; Sex Factors; Warfarin

Coumarins belong to drugs widely used and the spectrum of their use is going to grow. From this point of view and/or because the coumarins are adminstrated in patients who are treated for the other diseases--medical or surgical--at the same time, it is necessary to modify, interrupt or replace peroral anticoagulant treatment in the dependence on various aspects. It requires to compound different algorithms for given situations solution. It is always to decide, if the situation is imperative from the view of solution planed, what risk brings proposed treatment and what is the risk of anticoagulant treatment modification.

Topics: Anticoagulants; Coumarins; Hemorrhage; Humans; International Normalized Ratio; Postoperative Hemorrhage; Preoperative Care; Risk Factors; Thromboembolism; Vitamin K; Warfarin

Excessive anticoagulation is a frequent complication of anticoagulant therapy. The risk of hemorrhage approximately doubles for each one point increase in the International Normalized Ratio (INR) above 3.0. Reducing a prolonged INR to within the desired therapeutic range requires that oral anticoagulants be withheld. In addition, vitamin K may be administered. Since this latter treatment can produce rapid reductions in the INR, it must be carefully tailored to meet individual needs, balancing the risk of bleeding against the potential risk of causing thromboembolism.. To review available literature on the management of coumarin-associated coagulopathy in asymptomatic patients, a Medline search was carried out and papers published in English from 1966 and 2003 were identified. All available information on the management of asymptomatic patients presenting with coumarin-associated coagulopathy was analyzed.. Following the results of clinical studies that only used an elevated INR as a surrogate end-point for the risk of bleeding, low dose oral vitamin K appears as the preferable strategy for rapidly restoring therapeutic INR levels in asymptomatic patients who present with an excessively prolonged INR due to warfarin therapy. For the treatment of patients with asymptomatic acenocoumarol-induced coagulopathy, vitamin K does not add any benefit to the strategy of simply withholding oral anticoagulant treatment.. Large randomized trials using clinical end-points are now required to provide evidence-based treatment recommendations for patients with coumarin-associated coagulopathy.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Costs and Cost Analysis; Coumarins; Hemorrhage; Humans; International Normalized Ratio; Risk Factors; Vitamin K; Warfarin; Withholding Treatment

Oral anticoagulants are the most commonly used agents in the long-term prophylaxis and treatment of arterial and venous thrombotic disorders. As new and expanded indications for their use, such as the prevention of recurrent myocardial infarction or the treatment of systemic embolism in atrial fibrillation, are developed, the use of oral anticoagulants is rising. Also, in North America, oral anticoagulants are used commonly for preventing venous thromboembolism following orthopedic surgery. This article reviews the pharmacology of warfarin sodium, the most commonly used oral anticoagulant in North America, and discusses practical aspects of the use of this agent in thrombotic disorder management.

Topics: Anticoagulants; Coumarins; Humans; International Normalized Ratio; Thrombosis; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Coumarins; Drug Interactions; Food; Heart Valve Prosthesis; Humans; Myocardial Infarction; Thromboembolism; Venous Thrombosis; Warfarin

In patients with mechanical prosthetic heart valves, long-term anticoagulant therapy is mandatory to prevent thromboembolic phenomena. Anticoagulation is also necessary in patients with mitral valvular disease and atrial fibrillation. The risk of maternal thromboembolic events is heightened during pregnancy because of the patient's hypercoagulable state. Controversy exists concerning the appropriate treatment of these patients. No method of anticoagulation is risk free. Coumarin derivatives provide adequate protection against thromboembolism and should be used during pregnancy in patients with mechanical prostheses. The administration of coumarin derivatives in the first trimester is associated with an incidence of 26.7% of spontaneous abortion and a risk of 4.1% of coumarin embryopathy. Heparin does not cross the placental barrier and it is the obvious therapeutic alternative. The teratogenic effects of the coumarinics are prevented if these agents are discontinued and replaced by heparin from before the 6th until the end of the 12th week of gestation. However, subcutaneous unfractionated heparin, in the doses that have been employed, does not provide adequate prophylaxis against thromboembolism in these women. In patients treated with heparin, the incidence of spontaneous abortion is similar to that observed when the mothers are treated with coumarin agents. In order to avoid the delivery of an anticoagulated infant, intravenous heparin in full doses, should be substituted for the coumarin agent in the last two weeks of gestation.When anticoagulant therapy is not necessary, the course of pregnancy in women with bioprostheses is similar to that of the general population. However, the short duration of tissue valves is a clear disadvantage for these women

Topics: Abortion, Spontaneous; Adult; Anticoagulants; Coumarins; Female; Fetus; Gestational Age; Heart Valve Prosthesis; Heparin; Humans; Injections, Intravenous; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Factors; Thromboembolism; Time Factors; Warfarin

In general, the current recommendations for treating and prophylaxing thrombotic patients with hereditary defects are similar to those for thrombotic individuals without a defect. Determinations as to the need for long-term anticoagulation require that a clinical assessment be made regarding the relative benefit in preventing thrombotic episodes versus the risk of increased bleeding. With our newly found ability to identify genetic risk factors in a substantial fraction of patients with venous thrombosis and pulmonary embolism, it will be possible to perform rigorously designed studies to determine whether they should be managed with more prolonged or intense anticoagulation after a thrombotic event or more aggressive prophylactic regimens in high risk situations such as a total hip replacement.

Topics: Abnormalities, Drug-Induced; Anticoagulants; Antithrombin III; Antithrombin III Deficiency; Blood Proteins; Coumarins; Disease Susceptibility; Drug Eruptions; Factor V Deficiency; Female; Fibrinolytic Agents; Genetic Predisposition to Disease; Humans; Infant, Newborn; Male; Necrosis; Pregnancy; Pregnancy Complications, Hematologic; Prevalence; Protein C; Protein S Deficiency; Puerperal Disorders; Purpura; Recurrence; Risk; Thrombolytic Therapy; Thrombosis; Warfarin

The various stages involved in the transport, pharmacological action and elimination of warfarin involve the specific binding of warfarin to a chiral macromolecular complex. However, it seems that the degree of stereoselectivity is variable, which presumably reflects the importance of the side-chain in binding to each type of macromolecule. It would appear that there is greater stereoselective control in the interaction of warfarin with cytochrome P-450 enzymes than that observed for interaction with the receptor, vitamin K1 epoxide reductase. Indeed, warfarin has been developed as a powerful stereochemical probe for in vitro studies of the terminal enzyme in the mixed-function oxidase system, cytochrome P-450. Warfarin undergoes hydroxylation in the 6, 7 and 8-positions of the aromatic ring which must interact with the active (haemoprotein) portion of the molecule, leaving the side-chain, which contains the chiral centre, free for recognition by the substrate binding site. In vitro studies indicate that the interaction of warfarin at its receptor, vitamin K1 epoxide reductase, is completely non-stereoselective. This suggests that only the 4-hydroxycoumarin ring portion of the drug binds to the enzyme. Consistent with this hypothesis, salicylate, which can mimic part of the 4-hydroxycoumarin ring system, produces hypothrombinaemia by inhibition of vitamin K1 epoxide reductase. These findings suggest that the coumarin ring system is largely responsible for the pharmacodynamic properties of warfarin, whereas the side-chain dictates the disposition and metabolism of the drug.

Topics: Animals; Coumarins; Cytochrome P-450 Enzyme System; Protein Binding; Stereoisomerism; Tissue Distribution; Warfarin

In acute pancreatitis (AP), pancreatic damage leads to local vascular injury, manifesting as endothelial damage and activation, increased vascular permeability, leukocyte rolling, sticking and transmigration to pancreatic tissue as well as activation of coagulation. Previous studies have shown that pretreatment with heparin or acenocoumarol inhibits the development of AP. The aim of the present study was to check the impact of pretreatment with warfarin, an oral vitamin K antagonist, on the development of ischemia/reperfusion-induced AP in rats. AP was induced by pancreatic ischemia followed by reperfusion of the gland. Warfarin (90, 180 or 270 µg/kg/dose) or vehicle were administered intragastrically once a day for 7 days before induction of AP. The effect of warfarin on the severity of AP was assessed 6 h after pancreatic reperfusion. The assessment included histological, functional, and biochemical analyses. Pretreatment with warfarin given at a dose of 90 or 180 µg/kg/dose increased the international normalized ratio and reduced morphological signs of pancreatic damage such as pancreatic edema, vacuolization of acinar cells, necrosis and the number of hemorrhages. These effects were accompanied by an improvement of pancreatic blood flow and a decrease in serum level amylase, lipase, pro-inflammatory interleukin-1β and plasma level of D-dimer. In contrast, pretreatment with warfarin given at a dose of 270 µg/kg/dose led to an increase in severity of pancreatic damage and biochemical indicators of AP. In addition, this dose of warfarin resulted in deaths in some animals. Pretreatment with low doses of warfarin inhibits the development of AP induced by pancreatic ischemia followed by reperfusion.

Topics: Acute Disease; Animals; Anticoagulants; Coumarins; Ischemia; Male; Pancreas; Pancreatitis; Rats; Rats, Wistar; Reperfusion Injury; Warfarin

In this study, we report an innovative approach aiming to assess the binding affinity between drug molecules and human serum albumin by combining nanoporous anodic alumina rugate filters (NAA-RFs) modified with human serum albumin (HSA) and reflectometric interference spectroscopy (RIfS). NAA-RFs are photonic crystal structures produced by sinusoidal pulse anodization of aluminum that present two characteristic optical parameters, the characteristic reflection peak (λPeak), and the effective optical thickness of the film (OTeff), which can be readily used as sensing parameters. A design of experiments strategy and an ANOVA analysis are used to establish the effect of the anodization parameters (i.e., anodization period and anodization offset) on the sensitivity of HSA-modified NAA-RFs toward indomethacin, a model drug. To this end, two sensing parameters are used, that is, shifts in the characteristic reflection peak (ΔλPeak) and changes in the effective optical thickness of the film (ΔOTeff). Subsequently, optimized NAA-RFs are used as sensing platforms to determine the binding affinity between a set of drugs (i.e., indomethacin, coumarin, sulfadymethoxine, warfarin, and salicylic acid) and HSA molecules. Our results verify that the combination of HSA-modified NAA-RFs with RIfS can be used as a portable, low-cost, and simple system for establishing the binding affinity between drugs and plasma proteins, which is a critical factor to develop efficient medicines for treating a broad range of diseases and medical conditions.

Topics: Aluminum Oxide; Biosensing Techniques; Coumarins; Crystallization; Electrodes; Humans; Indomethacin; Nanopores; Optical Phenomena; Photons; Salicylic Acid; Serum Albumin, Human; Sulfadimethoxine; Warfarin

Despite recent progress in antithrombotic therapy, there's still an unmet medical need for safe and orally available anticoagulants. Encouraged by the marked antithrombotic and anticoagulant activities of some coumarin derivatives, twenty-three new N-coumarinyl-4-amidinobenzamides 4a-f and 6-heterocycle substituted coumarin derivatives 5, 6a,b, 10a-e, 12a-e and 14a-d were synthesized and evaluated for their in vivo antithrombotic activity. The most active congeners were the unsubstituted amidine 4a (36.5 s), coumarinyl oxadiazole 5 (42.3 s), bis coumarinyl oxadiazole 6b (37.8 s) and coumarinyl pyrazole 10b (38.5 s) that presented prothrombin time (PT) values comparable to the reference drug warfarin (42.3 s). Furthermore, docking studies were undertaken to gain insight into the possible binding mode of these compounds with the coagulation factor Xa (FXa) binding site.

Topics: Animals; Anticoagulants; Binding Sites; Coumarins; Factor Xa; Factor Xa Inhibitors; Fibrinolytic Agents; Male; Mice; Molecular Docking Simulation; Molecular Structure; Prothrombin Time; Structure-Activity Relationship; Warfarin

Polymorphisms in CYP2C9 can vary the rate of metabolic clearance of oral anticoagulants, risking toxicity in patients. The present study focused on exploring the genetic etiology of idiopathic hyper sensitivity to coumarin anticoagulants in a patient who presented with multiple bleeding episodes and supra-elevated International Normalized Ratios.. Bidirectional gene sequencing of CYP2C9 and VKORC1 was carried out. Using allele-specific polymerase chain reaction, the identified novel variant was genotyped in 309 patients on anticoagulation therapy. The pharmacoproteomic significance of the novel genetic variant was elucidated by structural demonstration of binding of coumarin molecules within the mutant CYP2C9 204His protein model and in silico bioinformatic evolutionary analyses. Three-dimensional structure model of the mutant protein was constructed on the basis of the published X-ray crystal structure of human CYP2C9 protein (Protein Data Bank, 1R9O).. The patient was identified to have a novel heterozygous missense mutation in exon 4 of CYP2C9 gene (g.9172A > C; p.Asn204His; CYP2C9*57). The variant was absent in the 309 genotyped patients. In silico bioinformatic analyses indicated the variant to have a deleterious effect on the protein. Analysis of 3D structure model of the mutant protein revealed that the substituted His204 led to restricted binding of the coumarin drug within the binding site of CYP2C9 enzyme, thereby inhibiting its metabolic clearance and thus explaining the enhanced pharmacologic effect and bleeding in the patient.. The study elucidates the structurally deleterious role of the novel CYP2C9*57 missense mutation in coumarin toxicity.

Topics: Acenocoumarol; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Base Sequence; Binding Sites; Coumarins; Cytochrome P-450 CYP2C9; Female; Flurbiprofen; Genotype; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Molecular Docking Simulation; Mutation, Missense; Protein Binding; Warfarin

Coumarin and warfarin, two substances which are intensively metabolized in animals and humans, were tested for teratogenicity and embryo lethality in a 3-day in vitro assay using zebrafish embryos. Warfarin is a coumarin derivative, but in contrast to the mother substance warfarin has anticoagulant properties. Both substances produced teratogenic and lethal effects in zebrafish embryos. The LC(50) and EC(50) values for coumarin are 855 μM and 314 μM, respectively; the corresponding values for warfarin are 988 μM and 194 μM. For coumarin, three main or fingerprint endpoints (malformation of head, tail and growth retardation) were identified, whereas malformation of tail was the only fingerprint endpoint of warfarin. The analysis of the ratios between the zebrafish embryo effect concentrations of both substances and human therapeutic plasma concentrations confirmed the teratogenic potential of warfarin, as well as the equivocal status of coumarin.

Topics: Animals; Anticoagulants; Coumarins; Embryo, Nonmammalian; Teratogens; Warfarin; Zebrafish

Dicumarinic oral anticoagulants have a narrow therapeutic range and a great individual variability in response, which makes calculation of the correct dose difficult and critical. Genetic factors involved in this variability include polymorphisms of genes that encode the metabolic enzyme CYP2C9 and the target enzyme vitamin K epoxide reductase complex 1 (VKORC1); these polymorphisms can be associated with reduced enzymatic expression. We examined the frequency of the most relevant variants encoding CYP2C9 (alleles *1, *2 and *3) and VKORC1 (SNP -1639A>G) in the Argentinian population. Molecular typing was performed by PCR-RFLP on a randomly selected sample of 101 healthy volunteers from the Hospital Italiano de Buenos Aires gene bank. Fifty-seven subjects were identified as homozygous for CYP2C9*1 and 14 for *2, while 24 and 5 were heterozygous for *2 and *3 alleles; one individual was a composite heterozygote (*2/*3). When we examined VKORC1, 21 subjects were AA homozygous, 60 were AG heterozygotes and 20 were GG homozygotes. This is the first analysis of genotypic frequencies for CYP2C9 and VKORC1 performed in an Argentinian population. These allele prevalences are similar to what is known for Caucasian population, reflecting the European ancestor of our patient population, coming mostly from Buenos Aires city and surroundings. Knowledge of this prevalence information is instrumental for cost-effective pharmacogenomic testing in patients undergoing oral anticoagulation treatment.

Topics: Adult; Aged; Anticoagulants; Argentina; Aryl Hydrocarbon Hydroxylases; Coumarins; Cytochrome P-450 CYP2C9; Drug Administration Schedule; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Male; Middle Aged; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Single Nucleotide; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin; Young Adult

The action of the coumarin-type drugs and related compounds is reviewed to their VKOR antagonistic effects. In our study, twenty 3-pyridinyl, pyrimidinyl and pyrazolyl-4-hydroxycoumarin derivatives were synthesized. A comparative in vivo (CT, PT determination) and in vitro (measurement of PIVKA-II levels) anticoagulant study with respect to warfarin showed that the synthesized compounds have different anticoagulant activities, the most prospective compounds were the 3-pyrazolyl-4-hydroxycoumarin derivatives.

Topics: 4-Hydroxycoumarins; Administration, Oral; Anticoagulants; Biomarkers; Coumarins; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Lethal Dose 50; Molecular Structure; Platelet Aggregation Inhibitors; Protein Precursors; Prothrombin; Structure-Activity Relationship; Warfarin

Warfarin is often used as a site-specific probe for examining the binding of drugs and other solutes to Sudlow site I of human serum albumin (HSA). However, warfarin has strong binding to HSA and the two chiral forms of warfarin have slightly different binding affinities for this protein. Warfarin also undergoes a slow change in structure when present in common buffers used for binding studies. This report examined the use of four related, achiral compounds (i.e., coumarin, 7-hydroxycoumarin, 7-hydroxy-4-methylcoumarin, and 4-hydroxycoumarin) as possible alternative probes for Sudlow site I in drug binding studies. High-performance affinity chromatography and immobilized HSA columns were used to compare and evaluate the binding properties of these probe candidates. Binding for each of the tested probe candidates to HSA was found to give a good fit to a two-site model. The first group of sites had moderate-to-high affinities for the probe candidates with association equilibrium constants that ranged from 6.4 x 10(3)M(-1) (coumarin) to 5.5 x 10(4)M(-1) (4-hydroxycoumarin) at pH 7.4 and 37 degrees C. The second group of weaker, and probably non-specific, binding regions, had association equilibrium constants that ranged from 3.8 x 10(1)M(-1) (7-hydroxy-4-methylcoumarin) to 7.3 x 10(2)M(-1) (coumarin). Competition experiments based on zonal elution indicated that all of these probe candidates competed with warfarin at their high affinity regions. Warfarin also showed competition with coumarin, 7-hydroxycoumarin and 7-hydroxy-4-methycoumarin for their weak affinity sites but appeared to not bind and/or compete for all of the weak sites of 4-hydroxycoumarin. It was found from this group that 4-hydroxycoumarin was the best alternative to warfarin for examining the interactions of drugs at Sudlow site I on HSA. These results also provided information on how the major structural components of warfarin contribute to the binding of this drug at Sudlow site I.

Topics: Binding Sites; Binding, Competitive; Chromatography, High Pressure Liquid; Coumarins; Drug Stability; Humans; Kinetics; Magnetic Resonance Spectroscopy; Molecular Probes; Serum Albumin; Umbelliferones; Warfarin

Warfarin and acenocoumarols are the most commonly prescribed anticoagulants that is difficult to use because of the wide intra- and interpatient variation in the dose requirements, the narrow therapeutic range and the risk of serious bleeding. Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Mutations in the VKORC1 gene affect the sensitivity of the epoxy reductase enzyme for warfarin. The three main haplotypes of VKORC1 gene, *2, *3, *4, explain most of the genetic variability in warfarin dose among Caucasians. In the current paper we focus on this subject in view of our experience gained during molecular genetic tests for the main VKORC1 haplotypes in Hungarian patients with anticoagulant therapy and unusual clinical response. A total of 28 selected cases were characterized for VKORC1 G-1639A, G9041A and C6009T alleles. Genotyping has been carried out by molecular biology techniques, including PCR-RFLP assay and direct sequencing. In patients undergoing anticoagulant therapy we could identify VKORC1 *1*2, *2*2, *2*3, *1*4, *2*4 and *3*4 haplotypes. Patients with A haplotype group (14% of the studied patients) require much lower warfarin doses than other patients (2.7+/-0.2 mg/day). In our patients we found some with B haplotype group (25%) who require high warfarin dose (6.2+/-0.3 mg/day). There were also subjects bearing the A/B haplotype group (61%) with intermediate warfarin dose (4.9+/-0.2 mg/day), estimated by the haplotype analyses of the VKORC1 gene. Results presented here underline the need of VKORC1 haplotyping in anticoagulated patients with unusual clinical anticoagulant response, and the examination can have further therapeutic consequences.

Topics: Adult; Anticoagulants; Coumarins; Female; Haplotypes; Hemorrhage; Humans; Hungary; Male; Middle Aged; Mixed Function Oxygenases; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Vitamin K Epoxide Reductases; Warfarin; White People

Topics: Aged, 80 and over; Anticoagulants; Cardiac Surgical Procedures; Coumarins; Extremities; Gangrene; Heparin; Humans; International Normalized Ratio; Male; Middle Aged; Necrosis; Thrombocytopenia; Vitamin K; Warfarin

Topics: Anticoagulants; Coumarins; Hemorrhage; Humans; International Normalized Ratio; Thromboembolism; Warfarin

Topics: Administration, Oral; Anticoagulants; Coumarins; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Risk; Thrombosis; Time Factors; Vitamin K 1; Warfarin

Zirconium complexes of mendiaxon, warfarin, coumachlor, and niffcoumar have been synthesized by reaction of the ligands with zirconium chloride in stoichiometric ratio 1:2. The formation of the complexes has been proved on the basis of elemental analysis, IR-spectroscopy, 1H-NMR spectroscopy, and thermal studies. Differential thermal analyses and thermogravimetric analyses have been applied to study the compositions of the new complexes. It is concluded that the lactone- and the keto-carbonyl groups of warfarin, coumachlor, and niffcoumar are bonded to the metal ion as bidentate ligands, but mendiaxon is bonded as monodentate ligand. Cytotoxic screening by MTT-assay was carried out. Among these compounds the zirconium complex of mendiaxon showed highest cytotoxic activity against human promyelocytic leukemic HL-60 cells. The inorganic salt was found to be active against this cell line.

Topics: Antineoplastic Agents; Cell Survival; Coumarins; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Hymecromone; Ligands; Magnetic Resonance Spectroscopy; Organometallic Compounds; Spectrophotometry, Infrared; Warfarin; Zirconium

Topics: Abnormalities, Drug-Induced; Animals; Anticoagulants; Bioprosthesis; Cattle; Coumarins; Female; Heart Valve Prosthesis; Heparin; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Factors; Warfarin

Cerium complexes of Umbellipherone, Mendiaxon, Warfarin, Coumachlor, and Niffcoumar have been synthesized by reaction of the ligands with cerium nitrate in a stoichiometric ratio of 1:2. The formation of the complexes has been proved on the basis of elemental analysis, conductivities, IR spectroscopy, and 1H-NMR spectroscopy. The molecules of the ligands were optimized by means of the semiempirical quantum mechanical method PM3 to the energetically most stable conformers. All the ligands were characterized by molecular and submolecular electronic indices and the putative donor centers are proposed. It is concluded that the lactone- and the keto-carbonyl groups of Warfarin, Coumachlor, and Niffcoumar are bonded to the metal ion as bidentate ligands. The other two coumarins are bonded as monodentate ligands. Conductivity measurements show the non-electrolytic nature of the complexes. Cytotoxic screening by MTT assay was carried out. The cerium complexes were found to be more active than the inorganic salts.

Topics: 4-Hydroxycoumarins; Antineoplastic Agents; Cell Survival; Cerium; Coumarins; Humans; Hymecromone; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Organometallic Compounds; Spectrophotometry, Infrared; Tumor Cells, Cultured; Warfarin

1. Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by 12 recombinant human cytochrome P450 (P450 or CYP) enzymes and by human liver microsomes have been investigated. 2. Arachidonic acid (50 microM) significantly inhibited CYP1A1- and 1A2-dependent 7-ethoxycoumarin O-deethylations, CYP2C8-dependent taxol 6alpha-hydroxylation and CYP2C19-dependent R-warfarin 7-hydroxylation. This chemical also inhibited slightly the xenobiotic oxidations catalysed by CYP1B1, 2B6, 2C9, 2D6, 2E1 and 3A4 in recombinant enzyme systems. 3. Retinol, retinoic acid and cholecalciferol were strong inhibitors for xenobiotic oxidations catalysed by recombinant CYP1A1, 2C8 and 2C19. 4. Dixon plots of inhibitions of CYP1A1-, 1A2-, 2C8- and 2C19-dependent xenobiotic oxidations by arachidonic acid, of CYP1A1-, 2B6- and 2C19-dependent activities by retinol, and of CYP1A1- and 2C19-dependent activities by cholecalciferol indicated that these chemicals inhibit P450 activities mainly through a competitive mechanism. 5. In human liver microsomes, arachidonic acid inhibited CYP1A2-dependent theophylline hydroxylation, CYP2C8-dependent taxol 6alpha-hydroxylation and CYP2C19-dependent omeprazole 5-hydroxylation. Taxol 6alpha-hydroxylation was also inhibited by retinol and retinoic acid, and omeprazole 5-hydroxylation was inhibited by retinol in human liver microsomes. 6. These results suggest that xenobiotic oxidations by P450 enzymes are affected by endobiotic chemicals and that the endobiotic-xenobiotic interactions as well as drug-drug interactions may be of great importance when understanding the basis for pharmacological and toxicological actions of a number of xenobiotic chemicals.

Topics: Arachidonic Acid; Aryl Hydrocarbon Hydroxylases; Cholecalciferol; Coumarins; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1B1; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Ethanolamines; Humans; Isoenzymes; Lauric Acids; Microsomes, Liver; Mixed Function Oxygenases; Nifedipine; Omeprazole; Oxidation-Reduction; Oxidoreductases, N-Demethylating; Paclitaxel; Prostaglandins; Recombinant Proteins; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Theophylline; Tretinoin; Warfarin; Xenobiotics

To describe how oral anticoagulant therapy is performed in a defined catchment area in order to improve the quality of care.. Two study periods of 8 weeks were compared with reference to monitoring sites, i.e. hospital departments and primary health care centres.. The health care district of Umeå in northern Sweden, with 125,300 inhabitants.. Patients on oral anticoagulant therapy at the department of Internal Medicine, Umeå University Hospital, in 1987 (n = 243) were compared with all patients treated in 1990 at health centres (n = 175) and at the department of Internal Medicine (n = 290) in the Umeå district.. The prevalence of treatment failures and complications was calculated per patient year, as well as the relative frequencies of patients within treatment recommendations.. 80-83% of the patients were within treatment recommendations. Treatment failures were 3.6% of hospital patients, and 2.6% of primary care patients. Corresponding figures for bleeding complications were 8.9% and 5.1%, respectively. The differences are partly explained by differences in the studied groups, e.g. age, indications for treatment, and concomitant diseases.

Topics: Administration, Oral; Anticoagulants; Coumarins; Female; Hemorrhage; Humans; Male; Monitoring, Ambulatory; Outcome Assessment, Health Care; Outpatient Clinics, Hospital; Primary Health Care; Rural Health Services; Sweden; Thromboembolism; Warfarin

After transurethral resection (TUR) of superficial bladder tumors, intravesical instillations with BCG are successfully used to lower the recurrence rate. The mechanism of the antitumor activity of BCG is not completely understood. After TUR, a fibrin clot is formed on the damaged urothelium. Fibronectin (FN) is part of the clot. It has been demonstrated that binding of BCG to the bladder wall is mediated by FN, and therefore FN seems necessary for the antitumor activity of BCG. This binding can be inhibited by fibrin clot inhibitors, like aspirin and coumarin. A reduced efficacy of BCG in patients with superficial bladder cancer using these drugs has been described. We studied 183 patients with superficial bladder cancer, treated with one or two 6-week courses of intravesical BCG instillations. Of the 42 patients that used fibrin clot inhibitors, 13 (31%) experienced a recurrent tumor, as compared to 56 (40%) of 141 patients who did not use these drugs (p = 0.28). The mean time to recurrence was the same in both groups. These results did not depend on the BCG strain used (Tice or RIVM, p = 0.92) and were not influenced by the use of antibiotics against urinary tract infections. We conclude that in our study fibrin clot inhibitors have no adverse effect on the efficacy of BCG therapy for superficial bladder cancer.

Topics: Administration, Intravesical; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; BCG Vaccine; Carcinoma in Situ; Carcinoma, Transitional Cell; Coumarins; Dipyridamole; Fibrin; Humans; Male; Random Allocation; Urinary Bladder Neoplasms; Warfarin

The International Sensitivity Index (ISI) for different thromboplastin reagents is obtained by calibration against WHO reference preparations. It is hoped that calculation of the International Normalized Ratio (INR) from the ISI will permit accuracy and conformity in reporting laboratory assays of warfarin effect even across a range of different techniques. We have examined the INR values of 128 warfarin patients obtained by four different techniques in common use, namely venous and capillary Thrombotest and venous and capillary Manchester reagent. Discrepant INR values were obtained. The mean Manchester venous INR values were lower than those obtained by the other three methods (P less than 0.0001). This suggests that patients dosed by reference to Manchester venous INR are liable to receive more warfarin than those dosed by the other methods.

Topics: Animals; Blood Coagulation Tests; Brain Chemistry; Capillaries; Coumarins; False Negative Reactions; Humans; Rabbits; Reagent Kits, Diagnostic; Reference Standards; Thromboplastin; Thrombosis; Veins; Warfarin

Topics: Coumarins; Humans; Terminology as Topic; Warfarin

An in vitro system which expresses all enzyme activities related to vitamin K-dependent carboxylation of blood clotting factors was prepared from livers of rats overdosed with warfarin, difenacoum and dicumarol respectively. In this system, the activities of the two pathways that are known to produce active reduced vitamin K1 cofactor for the carboxylation reaction were measured. Also the ability of high concentrations of vitamin K1 to overcome inhibition of clotting factor synthesis was studied. In the systems prepared from livers of warfarin and difenacoum intoxicated rats, pathway I was inactive. Vitamin K epoxide reductase was also inactive which strongly suggests that this enzyme catalyzes the activity of pathway I in vivo. Reduction of vitamin K1 by pathway II bypassed the inactive pathway I and resulted in carboxylation activity. This pathway therefore mediates the antidotic effect of vitamin K1 in the coumarin intoxicated liver. In the in vitro system prepared from dicumarol intoxicated livers the activity of pathway I was not significantly affected. Dicumarol however was a strong inhibitor when added to liver microsomes in vitro.

Topics: 4-Hydroxycoumarins; Animals; Blood Coagulation Factors; Coumarins; Dicumarol; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Rats; Rats, Inbred Strains; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

In the liver, it appears that there are two different pathways for vitamin K reduction. One pathway is irreversibly inhibited by coumarin anticoagulant drugs. The other pathway has been shown in the present study to be composed of enzymes that are not effected by physiological 'in vivo' concentrations of these drugs. This pathway appears to be responsible for the antidotal effect of vitamin K in overcoming coumarin poisoning. In rat liver the pathway has been shown to be composed of DT-diaphorase (EC.1.6.99.2) and a microsomal dehydrogenase(s). The activity of the microsomal dehydrogenase(s) was 3.6-fold higher with NADH than with NADPH present in the test system. It appears that this enzyme is the physiologically important enzyme in the pathway. In contrast with DT-diaphorase, this enzyme(s) is shown to be tightly associated with the mirosomal membrane. The enzyme(s) is not identical with either of the quinone-reducing enzymes cytochrome P-450 reductase or cytochrome-b5 reductase. Our data thus postulate the existence of an as-yet-unidentified microsomal dehydrogenase that appears to have an important function in the pathway.

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Blood Coagulation; Coumarins; Immunosorbent Techniques; Ligases; Male; Microsomes, Liver; NAD(P)H Dehydrogenase (Quinone); Oxidoreductases; Quinone Reductases; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Vitamin K; Warfarin

Coumarin necrosis, a rare complication of coumarin anticoagulation, typically presents with well-defined purpuric patches that progress to bullae formation and necrosis. The vast majority of those affected are women, and most commonly affected sites are the breasts, buttocks, thighs, and abdomen. We present a male patient who manifested a unique reticulated purpura that progressed to bullae formation on the toes of one foot in addition to more classic lesions on the thigh and calf.

Topics: Coumarins; Humans; Male; Middle Aged; Necrosis; Purpura; Skin; Toes; Warfarin

Clinical use of antibiotics containing a N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of a vitamin K-responsive hypoprothrombinemia. Administration of NMTT to rats decreased the activity of the liver microsomal vitamin K epoxide reductase, increased the liver ratio of vitamin K epoxide to vitamin K, and decreased the rate of metabolism of injected vitamin K epoxide. These responses are the same as those observed following the administration of coumarin anticoagulants. In contrast to the effect of coumarin anticoagulants, NMTT did not inhibit the vitamin K epoxide reductase in vitro. These data suggest that the hypoprothrombinemia which has been observed following use of these antibiotics results from the inactivation of the liver vitamin K epoxide reductase by NMTT or a NMTT metabolite.

Topics: Animals; Azoles; Coumarins; Cytosol; Dithiothreitol; Hypoprothrombinemias; Male; Microsomes, Liver; Mixed Function Oxygenases; Rats; Tetrazoles; Vitamin K; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin

Coagulation studies were carried out on 10 patients who bled during anticoagulant therapy, in whom no other underlying cause for bleeding could be demonstrated, and 10 patients with similar degrees of hypoprothrombinemia who were not bleeding. The average age and sex distribution of the two groups was similar, and no association was noted between the occurrence of hemorrhage and the type of anticoagulant used, the duration of treatment or the nature of the underlying disease. Comparison of the results revealed no differences in the levels of factors II, VII, IX and X or in the glass and silicone (Siliclad) clotting time, the thromboplastin generation test and Thrombotest. It was concluded that all patients on anticoagulant drugs whose prothrombin time is in the therapeutic range or longer are potential bleeders and that one cannot necessarily predict those who will bleed on the basis of coagulation studies.

Topics: Acenocoumarol; Anticoagulants; Blood Coagulation Tests; Coumarins; Dicumarol; Drug Therapy; Geriatrics; Hemorrhagic Disorders; Humans; Hypoprothrombinemias; Indans; Phenindione; Prothrombin Time; Warfarin

Topics: Acenocoumarol; Anticoagulants; Coumarins; Dicumarol; Drug Therapy; Ecchymosis; Ethyl Biscoumacetate; Gangrene; Necrosis; Phenindione; Pulmonary Embolism; Purpura; Skin Diseases; Thrombophlebitis; Toxicology; Warfarin

Topics: Amino Acids; Aminoisobutyric Acids; Antimetabolites; Carbon Isotopes; Coumarins; Factor VII; Glycine; In Vitro Techniques; Liver; Metabolism; Naphthoquinones; Pharmacology; Proteins; Rats; Research; Ubiquinone; Vitamin K; Warfarin

Topics: Anticoagulants; Blood Proteins; Coumarins; Dicumarol; Feces; Humans; Hypoprothrombinemias; Male; Pharmacology; Prothrombin Time; Research; Warfarin

Topics: Anticoagulants; Blood; Blood Coagulation Factors; Blood Coagulation Tests; Child; Coumarins; Dicumarol; Diseases in Twins; Drug Tolerance; Genetics, Medical; Geriatrics; Heparin; Humans; Intestinal Absorption; Pharmacology; Phenindione; Vitamin K; Warfarin

Topics: Acenocoumarol; Blood Coagulation Tests; Coumarins; Dicumarol; Factor IX; Factor VII; Factor X; Hematologic Tests; Hemostatics; Humans; Prothrombin; Warfarin

Topics: Administration, Intravenous; Coumarins; Humans; Sodium; Vascular Surgical Procedures; Warfarin

Topics: Anticoagulants; Coumarins; Humans; Male; Metabolism; Pharmacology; Prothrombin Time; Vitamin K 1; Warfarin

Topics: Coumarins; Humans; Peripheral Vascular Diseases; Urticaria; Vascular Diseases; Warfarin

Topics: Blood Circulation; Coronary Vessels; Coumarins; Heart; Papaverine; Warfarin

Topics: Anticoagulants; Bronchi; Bronchodilator Agents; Coumarins; Warfarin

Topics: Coumarins; Hemorrhage; Humans; Neoplasms; Warfarin

Using intravenous sodium warfarin, rabbits were rendered hypoprothrombinemic and subjected to two intravenous injections of Shear's polysaccharide. None of the 9 animals surviving the required period of time developed bilateral renal cortical necrosis or histologic thrombi in the kidney, liver, spleen, or lungs. In a control group of 7 animals treated only with endotoxin, 6 developed bilateral renal cortical necrosis. It is concluded that the prothrombin complex is necessary for the production of the generalized Shwartzman reaction by bacterial endotoxins and that this phenomenon is essentially a process of disseminated intravascular coagulation.

Topics: Animals; Coumarins; Disseminated Intravascular Coagulation; Endotoxins; Hypersensitivity; Kidney; Necrosis; Rabbits; Shwartzman Phenomenon; Sodium; Thrombosis; Warfarin

Topics: Coumarins; Dicumarol; Humans; Sodium; Sodium, Dietary; Thromboembolism; Warfarin

Topics: Anticoagulants; Coronary Disease; Coumarins; Dicumarol; Humans; Myocardial Infarction; Sodium; Warfarin

Topics: Anticoagulants; Coumarins; Humans; Warfarin

Topics: Coumarins; Thromboembolism; Warfarin

Topics: Coumarins; Ions; Sodium; Sodium, Dietary; Warfarin

Topics: Anticoagulants; Coumarins; Sodium; Thromboembolism; Warfarin

Topics: Coumarins; Humans; Warfarin

Topics: Coumarins; Sodium; Warfarin

Topics: Animals; Coumarins; Hyperthyroidism; Hypothyroidism; Prothrombin; Prothrombin Time; Rats; Warfarin

Topics: Anticoagulants; Coumarins; Sodium; Sodium, Dietary; Warfarin

Topics: Anticoagulants; Coumarins; Sodium; Sodium, Dietary; Warfarin

Topics: Anticoagulants; Coumarins; Dicumarol; Sodium; Thromboembolism; Warfarin

Topics: Anticoagulants; Coumarins; Sodium; Warfarin

Topics: Anticoagulants; Coumarins; Warfarin

Topics: Anticoagulants; Coumarins; Humans; Warfarin

Topics: 4-Hydroxycoumarins; Administration, Rectal; Coumarins; Ions; Sodium; Sodium, Dietary; Warfarin

Topics: Coumarins; Poland; Rats; Warfarin

Topics: Anions; Anticoagulants; Coumarins; Ions; Sodium; Sodium, Dietary; Warfarin

Topics: Coumarins; Hemorrhagic Disorders; Insecticides; Warfarin

Topics: Animals; Anticoagulants; Coumarins; Humans; Poisons; Republic of Korea; Rodentia; Warfarin

Topics: Coumarins; Humans; Poisoning; Warfarin

Topics: Anticoagulants; Coumarins; Humans; Prothrombin Time; Warfarin

Topics: Anions; Coumarins; Hypoprothrombinemias; Ions; Prothrombin; Sodium; Sodium, Dietary; Warfarin

Topics: Coumarins; Humans; Hypoprothrombinemias; Prothrombin Time; Sodium; Warfarin

Topics: Animals; Animals, Laboratory; Coumarins; Warfarin

Topics: Coumarins; Rats; Warfarin

Topics: Anticoagulants; Coumarins; Sodium; Sodium, Dietary; Thromboembolism; Warfarin

Topics: Coumarins; Rats; Warfarin

Topics: Coumarins; Dicumarol; Humans; Rodenticides; Suicide, Attempted; Warfarin