dicumarol and Drug-Hypersensitivity

Topics: Administration, Oral; Anaphylaxis; Anticoagulants; Dicumarol; Disseminated Intravascular Coagulation; Drug Evaluation; Drug Hypersensitivity; Female; Fibrinolytic Agents; Heparin; Humans; Male; Pregnancy; Streptokinase; Thromboembolism; Time Factors

Topics: Alcohol Oxidoreductases; Catalase; Cholinesterases; Dicumarol; Diseases in Twins; Drug Hypersensitivity; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Environment; Female; Genetic Diseases, Inborn; Glaucoma; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins; Humans; Infant, Newborn; Intraocular Pressure; Isoniazid; Malignant Hyperthermia; Mutation; Pharmaceutical Preparations; Pharmacogenetics; Phenylthiourea; Phenytoin; Pregnancy; Protein Binding; Racial Groups; Warfarin

Topics: Adult; Aged; Alcohol Oxidoreductases; Antipyrine; Asian People; Child, Preschool; Cholinesterases; Cyanides; Dicumarol; Diseases in Twins; Drug Hypersensitivity; Erythrocytes; Favism; Female; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins; Humans; Isoniazid; Liver; Male; Metabolism, Inborn Errors; Middle Aged; Pharmacogenetics; Phenylbutazone; Phenylthiourea; Phenytoin; Pregnancy; Primaquine; Twins; Warfarin

Topics: Abnormalities, Drug-Induced; Animals; Dicumarol; Dogs; Drug Hypersensitivity; Drug Tolerance; Ethnology; Genetics; Genetics, Medical; Glucosephosphate Dehydrogenase Deficiency; Glucosephosphates; Guinea Pigs; Hemoglobins; Hemoglobins, Abnormal; Humans; Isoniazid; Metabolism; Mice; Mutation; Pharmacogenetics; Pharmacology; Rabbits; Rats; Research; Succinylcholine; Thalidomide; Toxicology

1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma. 5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect. Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils. 6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone. 7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity.

Topics: Adult; Animals; Anti-Infective Agents; Cattle; Cysteine; Dicumarol; Drug Hypersensitivity; Enzyme Inhibitors; Erythrocytes; Flow Cytometry; Glutathione; Haptens; Humans; Leukocytes, Mononuclear; Lymphocytes; Male; Middle Aged; Neutrophils; NF-kappa B; Oxidation-Reduction; Protein Binding; Serum Albumin; Sodium Azide; Sulfamethoxazole; Transcription Factor AP-1

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

Topics: Diarrhea; Dicumarol; Drug Hypersensitivity; Female; Humans; Middle Aged; Muscle Cramp; Myocardial Infarction

Topics: Animals; Coumarins; Dicumarol; Drug Hypersensitivity; Female; Genetic Variation; Humans; Male; Microsomes, Liver; Pharmacogenetics; Rabbits; Rats; Warfarin