acenocoumarol 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

The anticoagulant therapy with acenocoumarol is generally associated with a high risk of bleeding and thromboembolic events.. We applied eight already existing acenocoumarol dosing algorithms to Bulgarian patients with low acenocoumarol dose requirements and investigated which of these algorithms would predict most precisely the dose anticoagulant.. Two patients with Bulgarian origin were referred to the outpatient clinical laboratory of "St. Ekaterina" University Hospital for Cardiovascular Surgery and Cardiology, Sofia, Bulgaria. After obtaining written informed consent, both patients were genotyped for polymorphisms in genes for Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase (VKORC1), Apolipoprotein E (APOE), and Cytochrome P450 4F2 (CYP4F2).. All applied acenocoumarol dosing algorithms predicted relatively similar doses of coumarin anticoagulant in both patients. However, van Schie et al.'s algorithm allowed more accurate calculation of the optimal dose in our patients with extremely low acenocoumarol requirements. Genotyping of selected polymorphic variants in CYP2C9 and VKORC1 showed that both patients were compound heterozygotes for CYP2C9 (CYP2C9*2/*3) and homozygotes for both variants in VKORC1 (VKORC1 1173 T/T, and VKORC1-1639 A/A). This combination of genotypes suggested high sensitivity to acenocoumarol leading to the low anticoagulant dose requirements (0.25 and 1 mg/day, respectively) needed to reach the target International Normalized Ratio of 2.5-3.5.. The genotyping of polymorphic variants in VKORC1 and CYP2C9, together with clinical and demographic parameters, can serve for more precise definition of the individual starting and maintenance doses of coumarin derivatives in each patient.

Topics: Acenocoumarol; Algorithms; Anticoagulants; Aortic Valve; Bulgaria; Coumarins; Dose-Response Relationship, Drug; Female; Genotype; Humans; Male; Middle Aged; Mitral Valve; Pharmacogenetics; Polymorphism, Single Nucleotide; Thromboembolism

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

Vitamin K is an essential cofactor for the synthesis of several blood coagulation factors. It has been suggested that the apolipoprotein E (ApoE) genotype has profound effects on vitamin K status. Therefore, we investigated whether this common genetic polymorphism influenced dose requirements and effects of coumarin anticoagulants.. We did a cohort study in 1637 patients from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon.. To attain the same level of anticoagulation, patients with genotype epsilon4/epsilon4 and genotype epsilon3/epsilon4 required respectively 3.4 mg (95%CI: -6.0 to -0.9) and 0.8 mg (95%CI: -1.6 to 0.1) acenocoumarol per week less than patients with genotype epsilon3/epsilon3. Patients homozygous for the epsilon2 allele required 3.5 mg (95%CI: 0.1 to 6.9) acenocoumarol per week more than patients with genotype epsilon3/epsilon3. The acenocoumarol maintenance dose showed a gene dose effect of the epsilon4 allele, but not of the epsilon2 allele. No significant dose difference was observed for phenprocoumon, possibly because of low numbers.. The ApoE genotype affects the dose requirements of acenocoumarol.

Topics: Acenocoumarol; Aged; Alleles; Anticoagulants; Apolipoproteins E; Blood Coagulation; Cohort Studies; Coumarins; Female; Genotype; Homozygote; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Time Factors; Vitamin K

A complex of neodymium(III) with 4-hydroxy-3[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (acenocoumarol) was synthesized by mixing water solutions of neodymium(III) nitrate and the ligand (metal to ligand molar ratio of 1:3). The complex was characterized and identified by elemental analysis, conductivity, IR, 1H NMR and mass spectral data. DTA and TGA were applied to study the composition of the compound. Elemental and mass spectral analysis of the complex indicated the formation of a compound of the composition NdR3 x 6H2O, where R = C19H14NO6-) The reaction of neodymium(III) with acenocoumarol was studied in detail by the spectrophotometric method. The stepwise formation of three complexes, vis., NdR2+, NdR2+ and NdR3 was established in the pH region studied (pH 3.0-7.5). The equilibrium constants for 1:1, 1:2 and 1:3 complexes were determined to be log K1 = 6.20 +/- 0.06; log K2 = 3.46 +/- 0.07 and log K2) = 2.58 +/- 0.05, respectively.

Topics: Acenocoumarol; Coumarins; Drug Stability; Lanthanoid Series Elements; Neodymium

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

Topics: Acenocoumarol; Anticoagulants; Coronary Disease; Coumarins; Peripheral Vascular Diseases; Thromboembolism; Vascular Diseases

Topics: Acenocoumarol; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coronary Disease; Coumarins; Humans

Topics: Acenocoumarol; Anticoagulants; Coronary Artery Disease; Coronary Disease; Coumarins; Humans

Topics: Acenocoumarol; Cardiovascular Diseases; Cerebellum; Coumarins; Myocardial Infarction

Topics: Acenocoumarol; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Coumarins; Humans; Prothrombin

Topics: Acenocoumarol; Anticoagulants; Coumarins; Humans

Topics: Acenocoumarol; Anticoagulants; Coumarins

Topics: Acenocoumarol; Coumarins

Topics: Acenocoumarol; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coumarins; Female; Genitalia; Genitalia, Female; Gynecology; Humans; Obstetric Labor Complications; Obstetrics; Pregnancy; Thromboembolism

Topics: 4-Hydroxycoumarins; Acenocoumarol; Anticoagulants; Coumarins; Humans

Topics: Acenocoumarol; Anticoagulants; Cesarean Section; Coumarins; Diagnosis, Differential; Female; Hematoma; Humans; Pregnancy; Thrombosis

Topics: Acenocoumarol; Anticoagulants; Coumarins; Humans

Topics: Acenocoumarol; Angina Pectoris; Coumarins; Humans

Topics: Acenocoumarol; Anticoagulants; Coumarins; Phenylbutazone; Thromboembolism

Topics: Acenocoumarol; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Coumarins; Humans

Topics: Acenocoumarol; Anticoagulants; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coumarins; Myocardial Infarction; Thrombosis

Topics: Acenocoumarol; Anticoagulants; Coumarins; Thromboembolism

Topics: Acenocoumarol; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coumarins; Humans

Topics: Acenocoumarol; Anticoagulants; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coumarins; Thromboembolism

Topics: Acenocoumarol; Anticoagulants; Antifibrinolytic Agents; Coumarins; Humans; Vitamin K

Topics: Acenocoumarol; Coumarins

Topics: Acenocoumarol; Analgesia; Anesthesia; Anesthesia and Analgesia; Anticoagulants; Coumarins; Female; Genital Diseases, Female; Gynecology; Humans; Labor, Obstetric; Obstetrics; Pain Management; Pregnancy

Topics: Acenocoumarol; Anticoagulants; Coumarins; Dicumarol

Topics: Acenocoumarol; Anticoagulants; Coumarins; Thromboembolism

Topics: Acenocoumarol; Coumarins; Research

Topics: Acenocoumarol; Anticoagulants; Coumarins; Humans; Thromboembolism

Topics: Acenocoumarol; Coumarins

Topics: 4-Hydroxycoumarins; Acenocoumarol; Anticoagulants; Coumarins; Thromboembolism

Topics: Acenocoumarol; Coumarins

Topics: Acenocoumarol; Anticoagulants; Coumarins; Thromboembolism

Topics: Acenocoumarol; Anticoagulants; Coumarins; Thromboembolism

Topics: 4-Hydroxycoumarins; Acenocoumarol; Animal Experimentation; Animals; Coumarins

Topics: 4-Hydroxycoumarins; Acenocoumarol; Coumarins