losartan-potassium and Chemical-and-Drug-Induced-Liver-Injury

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

Topics: Angiotensin II; Animals; Atmospheric Pressure; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia; Indomethacin; Liver; Nephrectomy; Prostaglandins; Rabbits; Rats; Secretory Rate

Etoposide (ETO) and methotrexate (MTX) are two effective chemotherapeutic drugs. However, the clinical use of these drugs is limited by its toxicity in normal tissues, especially in kidney and in liver tissues. Recombinant human erythropoietin (rhEPO), erythropoietin hormone, has also been shown to exert tissue protective effects. The purpose of this study was to explore the protective effect of rhEPO against oxidative stress and genotoxicity induced by ETO and MTX in vivo. Adult male Wistar rats were divided into 10 groups (6 animals each): control group, rhEPO alone group, ETO alone group, MTX alone group and rhEPO + ETO/MTX groups. In rhEPO + ETO/MTX groups, three doses of pretreatment with rhEPO were performed: 1000, 3000 and 6000 IU/kg. Our results showed that rhEPO pretreatment protects liver and kidney tissues against oxidative stress induced by the anticancer drugs. The glycoprotein decreased malondialdehyde (MDA) levels, reduced catalase activity and ameliorated glutathione depletion. Furthermore, we showed that rhEPO administration prevented drug-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, especially at 3000 IU/kg, against ETO- and MTX-induced oxidative stress and genotoxicity in vivo.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Catalase; Chemical and Drug Induced Liver Injury; DNA Damage; Erythropoietin; Etoposide; Glutathione; Kidney; Kidney Diseases; Lipid Peroxidation; Liver; Male; Malondialdehyde; Methotrexate; Protective Agents; Rats, Wistar; Recombinant Proteins

Topics: Adenine; Animals; Autophagosomes; Autophagy; Cell Line; Chemical and Drug Induced Liver Injury; Chromones; Cobalt; Disease Models, Animal; Erythropoietin; Humans; Liver; Liver Function Tests; Mice; Mice, Inbred C57BL; Morpholines; Peptide Fragments; Proto-Oncogene Proteins c-akt; Random Allocation; Reperfusion Injury; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

To investigate the protective effects of helix B surface peptide (HBSP) on acute liver injury induced by carbon tetrachloride (CCl. HBSP is a potential therapeutic agent against acute liver injury induced by CCl

Topics: Alanine Transaminase; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Aspartate Aminotransferases; Carbon Tetrachloride; CD3 Complex; CD8 Antigens; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Chromones; Cytokines; Enzyme Inhibitors; Erythropoietin; Gene Expression; Glutathione Peroxidase; Hepatocytes; Humans; L-Lactate Dehydrogenase; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Morpholines; Multiprotein Complexes; Oxidative Stress; Peptide Fragments; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Erythropoietin (EPO) is the main hormone driving mammalian erythropoiesis, with activity mediated via the surface receptor, EPO-R, on erythroid progenitor cells. Recombinant human EPO is currently used clinically for the treatment of anemia in patients with end-stage renal disease, and in certain cancer patients suffering from anemia induced either by the tumor itself or by chemotherapy. EPO-R expression is also detected in non-erythroid cells, including macrophages present in the peritoneum, spleen, and bone marrow (BM). Here we demonstrate that Kupffer cells (KCs) - the liver-resident macrophages - are EPO targets. We show that, in vitro, EPO initiated intracellular signalling and enhanced phagocytosis in a rat KC line (RKC-2) and in sorted KCs. Moreover, continuous EPO administration in mice, resulted in an increased number of KCs, up-regulation of liver EPO-R expression and elevated production of the monocyte chemoattractant CCL2, with corresponding egress of Ly6C

Topics: Acetaminophen; Animals; Antigens, Ly; Cell Proliferation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Chemokine CCL2; Disease Models, Animal; Erythropoietin; Humans; Kupffer Cells; Liver; Mice; Phagocytosis; Rats; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Up-Regulation

Mitomycin C (MMC) is one of the most effective chemotherapeutic drugs. However, the dose of MMC is greatly limited by its toxicity in normal tissues. Recombinant human erythropoietin (rhEPO), an erythropoietic hormone, has also been shown to exert tissue protective effects. The purpose of this study was to explore the protective effect of rhEPO against MMC-induced heart, liver, and renal dysfunction. Adult male Wistar rats were divided into six groups (with six animals each), namely control, rhEPO alone group, MMC alone group, and rhEPO + MMC group (pre-, co-, and posttreatment conditions). The results showed that MMC induced a marked cardiac, renal, and liver failure characterized by a significant decrease in body weight, organs weight, and organs ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and conjugated and total bilirubin levels in serum. Histological examination showed that MMC caused liver alterations. rhEPO treatment restored body weight, organs weight, and organs ratio as well as serum biochemical parameters and histological damage caused by MMC exposure.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Erythropoietin; Heart Failure; Kidney Function Tests; Liver Function Tests; Male; Mitomycin; Organ Size; Rats, Wistar; Recombinant Proteins; Renal Insufficiency

A 16-year-old vasectomized male ring-tailed lemur (Lemur catta) with a history of suspected chronic renal failure was evaluated because of extreme lethargy, hyperpnea, and abscess of the right pectoral scent gland.. Examination of the anesthetized patient revealed an impacted right pectoral scent gland with serosanguineous exudate. A CBC and serum biochemical analysis revealed severe anemia, marked azotemia, hyperphosphatemia, and hypocalcemia.. Supportive care (including fluid therapy and phosphorus binder administration) was initiated for renal failure; the affected gland was cleaned, and antimicrobials were administered. The patient received 1 blood transfusion, and darbepoetin alfa was administered weekly to stimulate RBC production. Anemia and azotemia persisted. Three months after treatment started, serum iron analysis revealed that iron deficiency was the probable cause for the lack of a consistent regenerative response to darbepoetin injections. Iron dextran injections resulted in a marked regenerative response; however, serum biochemical analysis results after the second injection were consistent with hepatic injury. Hepatic enzyme activities normalized following discontinuation of iron dextran treatment, but the lemur's Hct declined rapidly despite supplementary iron administration PO. The patient developed severe mandibular osteomyelitis and was euthanized because of poor prognosis. Postmortem evaluation of hepatic iron concentration confirmed iron deficiency.. The family Lemuridae is considered prone to hemosiderosis and hemochromatosis, which delayed rapid diagnosis and treatment of the lemur's disease. Apparent hepatic injury following iron dextran injections further complicated treatment. Findings for this lemur support the use of species-specific total iron binding capacity and total serum iron and ferritin concentrations in evaluation of an animal with suspected iron deficiency.

Topics: Aging; Anemia, Iron-Deficiency; Animals; Blood Transfusion; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Dietary Supplements; Erythropoietin; Hematinics; Iron; Iron-Dextran Complex; Lemur; Male; Renal Insufficiency, Chronic

Topics: Animals; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Cisplatin; Erythropoietin; Kidney Diseases; Protective Agents

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Cisplatin (Cisp) is one of the most effective chemotherapeutic drugs. However, the dose of Cisp is greatly limited by its toxicity. Recombinant human erythropoietin (rhEPO), a hormone that regulates hematopoiesis, has also been shown to exert tissue-protective effects. The purpose of this study was to explore the protective effect of rhEPO against Cisp-induced renal and liver dysfunctions. Adult male Wistar rats were divided into six groups of six each: control, rhEPO-alone group, Cisp-alone group and rhEPO + Cisp group (pretreatment, cotreatment and posttreatment conditions). Our results showed that Cisp-induced a marked renal and liver failure characterized by a significant decrease in body weight, organ weight and organ ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, G-glutamyl transferase, alkaline phosphatase, bilirubin conjugated and bilirubin total levels in serum. Histological examination showed that Cisp caused kidney alterations. rhEPO treatments restored body weight, organ weight and organ ratio as well as serum biochemical parameters changed due to Cisp exposure.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Bilirubin; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Cisplatin; Creatinine; Erythropoietin; gamma-Glutamyltransferase; Kidney Diseases; Protective Agents; Rats; Rats, Wistar; Recombinant Proteins

Topics: Adult; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Erythropoietin; Female; Humans

Evaluation of pharmacologic agents that stimulate fetal hemoglobin production has been done mainly in baboons and macaques. We investigated whether results in transgenic mice can predict the stimulation of fetal hemoglobin in primates, by testing gamma globin induction in response to a new ribonucleotide reductase inhibitor, Didox. A transgenic mouse line carrying the human A gamma gene linked to a locus control region cassette was used. Treatment of transgenic mice with Didox resulted in induction of gamma gene expression as documented by an increase in F reticulocytes and F cells and an elevation of gamma/gamma + beta biosynthetic ratio. Similarly, administration of Didox to a baboon in the nonanemic and chronically anemic state resulted in induction of gamma gene expression as shown by increases in F reticulocytes, F cells, and Hb F. These results suggest that the muLCR-A gamma transgenic mice can be used to screen new pharmacologic compounds for gamma globin inducibility.

Topics: Anemia; Animals; Chemical and Drug Induced Liver Injury; Erythropoietin; Fetal Hemoglobin; Gene Expression; Humans; Hydroxamic Acids; Leukopenia; Mice; Mice, Transgenic; Recombinant Proteins; Reticulocytes; Ribonucleotide Reductases; Thrombocytopenia

Topics: Alanine Transaminase; Anemia; Animals; Aspartate Aminotransferases; Bilirubin; Blood Cell Count; Blood Chemical Analysis; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Dogs; Erythropoietin; Female; Haplorhini; Hematocrit; Iron; Iron Isotopes; Kidney Diseases; Liver; Male; Mice; Necrosis; Nitrosamines; Polycythemia; Species Specificity