acenocoumarol and Drug-Hypersensitivity

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Drug Hypersensitivity; Humans; Hypersensitivity, Delayed; Lymphocyte Activation; Male

The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults.. All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate.. Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).. DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Topics: Acenocoumarol; Age Factors; Aged; Allopurinol; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hematologic Agents; Hemorrhage; Humans; International Normalized Ratio; Italy; Male; Prevalence; Proton Pump Inhibitors; Warfarin

Topics: Acenocoumarol; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Diclofenac; Drug Hypersensitivity; Humans; Male; Middle Aged; Urticaria

To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity. Methods A patient, highly sensitive to acenocoumarol, and previously determined to carry only a single CYP2C9*3 allele, was genotyped for additional functionally defective alleles in the CYP2C9 and VKORC1 genes. Family members were also analyzed to trace the pedigree. Results The acenocoumarol-sensitive patient was found to possess, in addition to CYP2C9*3 allele, a CYP2C9*11 allele and the VKORC1 AA diplotype which were all traced back through the parental lines. Conclusions Acenocoumarol sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the CYP2C9 and VKORC1 genes. The study provides additional data in support of diminished CYP2C9 activity due to the presence of the rare *11 allele.

Topics: Acenocoumarol; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Drug Hypersensitivity; Female; Humans; Male; Mixed Function Oxygenases; Pedigree; Polymorphism, Genetic; Vitamin K Epoxide Reductases; Warfarin

Topics: Acenocoumarol; Aged; Cross Reactions; Drug Hypersensitivity; Female; Fibrinolytic Agents; Hepatitis; Humans; Phenprocoumon; T-Lymphocytes, Helper-Inducer; Warfarin

Our objective was to study the pharmacokinetics of R - and S -acenocoumarol in a subject who was highly sensitive to the anticoagulant effect of acenocoumarol. The subject was found to be heterozygous for CYP2C9*3.. The plasma pharmacokinetics of the acenocoumarol enantiomers was established after an oral dose of 8 mg of racemic acenocoumarol. Urine was collected to establish the formation clearance of the 6- and 7-hydroxy metabolites of R - and S -acenocoumarol.. The pharmacokinetics of S -acenocoumarol in this subject differed greatly (oral clearance, 6%-10%; half-life of elimination, 400%-500%) from the values of a [wt/wt] control and from population values. R -acenocoumarol clearance was at the lower level of population values. The apparent formation clearances of the metabolites were low-approximately 10% of control activity for the hydroxylations (6- and 7-) of S -acenocoumarol and for the 7-hydroxylation of R -acenocoumarol. The rate of the 6-hydroxylation of R -acenocoumarol was about 50% of control values.. The presence of even one copy of CYP2C9*3 reduces profoundly the metabolic clearance of S -acenocoumarol. As a result the first-pass effect of elimination is abolished and the maintenance time is increased. S -Acenocoumarol, which is normally clinically inactive, will now exert main anticoagulant activity.

Topics: Acenocoumarol; Adolescent; Alleles; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Drug Hypersensitivity; Exons; Genotype; Heterozygote; Humans; Male; Stereoisomerism; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Dicumarol; Drug Hypersensitivity; Ethyl Biscoumacetate; Female; Humans; Phenindione; Pregnancy; Warfarin

Topics: Acenocoumarol; Anticoagulants; Drug Hypersensitivity; Hematologic Diseases; Humans; Hypersensitivity; Liver