warfarin and Hepatitis

1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

Topics: Acetamides; Aldehyde Oxidase; Animals; Chimera; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Hepatitis; Humans; Liver; Mice; Mice, SCID; Mice, Transgenic; Pharmaceutical Preparations; Pharmacokinetics; Pyrimidines; Rats; Urokinase-Type Plasminogen Activator; Warfarin

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

gamma-Carboxyglutamic acid residues on prothrombin are synthesized from glutamic acid on a prothrombin precursor in the liver through a vitamin K-dependent carboxylase. In the absence of vitamin K or in the presence of vitamin K antagonists, an inert form of prothrombin - abnormal prothrombin - circulates in the blood. We have developed specific immunoassays for native and abnormal human prothrombin. The prothrombin concentration in our normal subjects was 108 +/- 19 microgram per milliliter. The abnormal-prothrombin concentration varied over four orders of magnitude between the limits of detection in normal plasma and the level in patients with cirrhosis (0 to 5 microgram per milliliter), acute hepatitis (0 to 33 microgram per milliliter), or vitamin K deficiency (32 to 100 microgram per milliliter) and in those treated with sodium warfarin (12 to 65 microgram per milliliter). These studies indicate that abnormal prothrombin is not a component of normal plasma but appears in a variety of hepatic and nutritional disorders characterized by impaired hepatic vitamin-K-dependent carboxylation.

Topics: Adult; Aged; Carbon-Carbon Ligases; Epitopes; Female; Hepatitis; Humans; Ligases; Liver; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Prothrombin; Prothrombin Time; Vitamin K Deficiency; Warfarin

Two groups of patients were observed for evidence of acute radiation hepatitis during "high dose" radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes on liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.

Topics: Adult; Aged; Female; Hepatitis; Hodgkin Disease; Humans; Male; Middle Aged; Neoplasms; Radiation Injuries; Radiation Tolerance; Radiotherapy Dosage; Radiotherapy, High-Energy; Remission, Spontaneous; Warfarin

Topics: Adult; Age Factors; Cholecystitis; Chromium Alloys; Follow-Up Studies; Gastrointestinal Hemorrhage; Hepatitis; Hip; Hip Dislocation; Hip Joint; Humans; Joint Prosthesis; Middle Aged; Molecular Weight; Peripheral Nervous System Diseases; Polyethylenes; Postoperative Complications; Prosthesis Design; Surgical Wound Infection; Thromboembolism; Urinary Tract Infections; Warfarin

Topics: Anticoagulants; Biopsy; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Guanethidine; Hepatitis; Humans; Hydrochlorothiazide; Hypertension; Methylprednisolone; Polyarteritis Nodosa; Thrombophlebitis; Warfarin