sirolimus and Chemical-and-Drug-Induced-Liver-Injury

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

We performed a systematic review and meta-analysis of fatigue, hepatic and metabolic toxicities associated with everolimus intake in patients with solid tumors.. Eligible studies included randomized trials of patients with solid tumors on everolimus describing events of fatigue, hyperlipidemia, hyperglycemia and elevated alanine aminotransferase (ALT).. After the exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade fatigue, hyperglycemia, hyperlipidemia and elevated ALT were 1.31 (p < 0.002), 3.06 (p < 0.0001), 2.54 (p = 0.0001) and 2.96 (p < 0.003), respectively.. Our meta-analysis demonstrates that everolimus is associated with a significantly increased risk of all-grade fatigue, hyperglycemia, hyperlipidemia and elevated ALT.

Topics: Chemical and Drug Induced Liver Injury; Everolimus; Fatigue; Humans; Neoplasms; Protein Kinase Inhibitors; Risk Factors; Sirolimus

Acrylamide (ACRL) was demonstrated to induce hepatotoxicity and programmed cell death (PCD). Rapamycin (RAPA)-induced autophagy had been reported to limit the progression of hepatocellular injury in experimental models. This research was designed to study two death pathways involved in ACRL-induced hepatotoxicity and the modulating effect of RAPA on the resulting hepatic injury. Thirty-six adult male rats were divided into three groups: control group, ACRL-treated group (20 mg kg/day), and the last group co-treated with ACRL plus RAPA (0.5 mg kg/day). Drugs were administered for 21 days via oral gavage. Blood samples were collected to assess alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Livers were dissected; parts were used for detection of superoxide dismutase (SOD) and malondialdehyde (MDA) tissue levels. Other parts were processed for hematoxylin and eosin, Masson's trichrome staining, immunostaining for microtubule-associated proteins 1A/1B light chain 3B (LC3), ubiquitin-binding protein (p62), caspase-3, and receptor-interacting protein kinase 1 (RIPK1). ACRL induced a significant elevation in ALT, AST, MDA levels, and reduction in the SOD level. ACRL also induced hepatocellular injury, fibrosis, and defective autophagy indicated by elevation of LC3 and p62 and increased p62/LC3 ratio. Moreover, it increased the apoptotic (caspase-3) and necroptotic (RIPK1) markers expression. RAPA significantly reduced liver enzymes, oxidative stress, fibrosis, and improved liver histology. Moreover, RAPA decreased p62/LC3 ratio indicated enhanced autophagy, and significantly reduced caspase-3 and RIPK1 expression. In conclusion, RAPA maintained autophagic activity which may save the hepatocytes from PCD and enhance cell viability.

Topics: Acrylamide; Animals; Apoptosis; Autophagy; Caspase 3; Chemical and Drug Induced Liver Injury; Fibrosis; Male; Necroptosis; Rats; Sirolimus; Superoxide Dismutase

Vinyl chloride (VC) is a prevalent environmental toxicant that is rapidly metabolized within the liver. Its metabolites have been shown to directly cause hepatic injury at high exposure levels. We have previously reported that VC metabolite, chloroethanol (CE), potentiates liver injury caused by lipopolysaccharide (LPS). Importantly, that study showed that CE alone, while not causing damage per se, was sufficient to alter hepatic metabolism and increase mTOR phosphorylation in mice, suggesting a possible role for the mTOR pathway. Here, we explored the effect of an mTOR inhibitor, rapamycin, in this model. C57BL/6 J mice were administered CE, followed by rapamycin 1 h and LPS 24 h later. As observed previously, the combination of CE and LPS significantly enhanced liver injury, inflammation, oxidative stress, and metabolic dysregulation. Rapamycin attenuated not only inflammation, but also restored the metabolic phenotype and protected against CE + LPS-induced oxidative stress. Importantly, rapamycin protected against mitochondrial damage and subsequent production of reactive oxygen species (ROS). The protective effect on mitochondrial function by rapamycin was mediated, by restoring the integrity of the electron transport chain at least in part, by blunting the deactivation of mitochondrial c-src, which is involved mitochondrial ROS production by electron transport chain leakage. Taken together, these results further demonstrate a significant role of mTOR-mediated pathways in VC-metabolite induced liver injury and provide further insight into VC-associated hepatic damage. As mTOR mediated pathways are very complex and rapamycin is a more global inhibitor, more specific mTOR (i.e. mTORC1) inhibitors should be considered in future studies.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chlorides; Ethanol; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Sirolimus; Vinyl Chloride

Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases.\ The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.\ To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.

Topics: Chemical and Drug Induced Liver Injury; Congenital Hyperinsulinism; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Sirolimus; Sulfonylurea Receptors

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

Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC

Topics: Acetaminophen; Animals; Autophagy; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Protective Agents; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Quinolines; Stereoisomerism; Structure-Activity Relationship; Triazoles

To explore the role of mammalian target of rapamycin (mTOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic condition.. Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon (CCl4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin (2 mg/kg per day). The QTc intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles were isolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-mTOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor (TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-mTOR protein.. Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight (P < 0.001). A significant prolongation in QTc intervals occurred in cirrhotic rats exposed to CCl4 (P < 0.001), while this prolongation was decreased with rapamycin treatment (P < 0.01). CCl4-induced cirrhosis caused a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-mTOR expression in left ventricles. Phosphorylated-mTOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-mTOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment.. In this study, we demonstrated a potential role for cardiac mTOR in the pathophysiology of cirrhotic cardiomyopathy. Rapamycin normalized the inotropic effect and altered phosphorylated-mTOR expression and myocardial localization in cirrhotic rats.

Topics: Action Potentials; Animals; Carbon Tetrachloride; Cardiomyopathies; Cardiotonic Agents; Chemical and Drug Induced Liver Injury; Heart Rate; Isoproterenol; Liver Cirrhosis, Experimental; Male; Myocardial Contraction; Myocardium; Papillary Muscles; Phosphorylation; Protein Kinase Inhibitors; Rats, Wistar; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ-producing Th1 cells and more Foxp3(+) Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1-mTOR signaling axis as a potential therapeutic target in hepatic injury.

Topics: Animals; CD11b Antigen; Cell Differentiation; Cells, Cultured; Chemical and Drug Induced Liver Injury; Female; Fingolimod Hydrochloride; Immunoblotting; Immunosuppressive Agents; Liver; Male; Mice; Mice, Inbred C57BL; Myeloid Cells; Nitric Oxide; Nitric Oxide Synthase Type II; omega-N-Methylarginine; Propylene Glycols; Receptors, Chemokine; Receptors, Lysosphingolipid; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sirolimus; Sphingosine; T-Lymphocytes, Regulatory; Th1 Cells; TOR Serine-Threonine Kinases

Topics: Acute Disease; Adult; Chemical and Drug Induced Liver Injury; Fatal Outcome; Fever; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Sirolimus; Transplantation, Homologous

Recent advances in human embryonic and induced pluripotent stem cell-based therapies in animal models of hepatic failure have led to an increased appreciation of the need to translate the proof-of-principle concepts into more practical and feasible protocols for scale up and manufacturing of functional hepatocytes. In this study, we describe a scalable stirred-suspension bioreactor culture of functional hepatocyte-like cells (HLCs) from the human pluripotent stem cells (hPSCs). To promote the initial differentiation of hPSCs in a carrier-free suspension stirred bioreactor into definitive endoderm, we used rapamycin for "priming" phase and activin A for induction. The cells were further differentiated into HLCs in the same system. HLCs were characterized and then purified based on their physiological function, the uptake of DiI-acetylated low-density lipoprotein (LDL) by flow cytometry without genetic manipulation or antibody labeling. The sorted cells were transplanted into the spleens of mice with acute liver injury from carbon tetrachloride. The differentiated HLCs had multiple features of primary hepatocytes, for example, the expression patterns of liver-specific marker genes, albumin secretion, urea production, collagen synthesis, indocyanin green and LDL uptake, glycogen storage, and inducible cytochrome P450 activity. They increased the survival rate, engrafted successfully into the liver, and continued to present hepatic function (i.e., albumin secretion after implantation). This amenable scaling up and outlined enrichment strategy provides a new platform for generating functional HLCs. This integrated approach may facilitate biomedical applications of the hPSC-derived hepatocytes.

Topics: Activins; Albumins; Animals; Biological Transport; Bioreactors; Carbocyanines; Carbon Tetrachloride; Cell Culture Techniques; Cell Differentiation; Cell- and Tissue-Based Therapy; Chemical and Drug Induced Liver Injury; Collagen; Endoderm; Hepatocytes; Lipoproteins, LDL; Liver; Male; Mice; Pluripotent Stem Cells; Sirolimus; Spleen; Transplantation, Heterotopic

Calcineurin inhibitors at elevated serum concentrations frequently cause mild elevation of the liver chemistries. Although rare, severe hepatotoxicity is their serious complication. A 54-year-old man with end-stage renal disease due to chronic glomerulonephritis without biopsy received a renal allograft from the deceased donor. Eleven days after transplantation severe liver injury (AST up to 421 IU/L, ALT 1242  IU/L, and GGT 212 IU/L) with the serum bilirubin within the normal range was recorded. Tacrolimus trough level was 5.5 ng/mL. Liver ultrasound and color-Doppler of the portal system were normal. Liver failure completely resolved after withdrawal of the calcineurin inhibitor and switch to sirolimus. After 9 months of follow-up our patient has excellent graft and liver function. Awareness of the possible association of tacrolimus use with hepatotoxicity is important to timely discontinuation of the causative agent, and to introduce sirolimus as the rescue therapy.

Topics: Chemical and Drug Induced Liver Injury; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus; Tacrolimus

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

Autophagy is a lysosomal degradation pathway for bulk cytosolic proteins and damaged organelles, and is well known to act as a cell survival mechanism. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing necrosis due to mitochondrial damage. We recently found that pharmacological induction of autophagy by rapamycin protects against, whereas pharmacological suppression of autophagy by chloroquine exacerbates, APAP-induced liver injury in mice. Autophagy is induced to remove APAP-induced damaged mitochondria and thus attenuates APAP-induced hepatocyte necrosis. To our surprise, we found that liver-specific Atg5 knockout mice are not more susceptible, but are resistant to APAP-induced liver injury due to compensatory effects. Our work suggests that pharmacological modulation of autophagy is a novel therapeutic approach to ameliorate APAP-induced liver injury. Moreover, our work also suggests that caution needs to be exercised when using genetic autophagy gene knockout mice for pathophysiological studies.

Topics: Acetaminophen; Animals; Autophagy; Chemical and Drug Induced Liver Injury; Humans; Mice; Mice, Knockout; Mitochondria; Models, Biological; Protective Agents; Sirolimus

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Sirolimus is currently used as an immunosuppressive agent in kidney transplantation due to its lack of nephrotoxicity and antiproliferative properties. However, a large number of side effects has been described with the use of m-Tor inhibitors. Most are reversible when treatment is withdrawn. Hepatotoxicity is one of these side effects, considered as a benign condition and resulting generally in a transitory and small increase in transaminase levels. We report here, to the best of our knowledge, the first case of severe sirolimus-induced acute hepatitis confirmed by liver biopsy, in a renal transplant recipient. This condition was completely cured in few weeks after sirolimus withdrawal.

Topics: Acute Disease; Biopsy; C-Reactive Protein; Chemical and Drug Induced Liver Injury; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Sirolimus

Liver injury induced by concanavalin A (Con A) is often used as a model to study the pathophysiology of immune mediated liver injury. Rapamycin (Rapa) is an effective immunosuppressant widely used for preventing immune activation and transplant rejection. However, the effect of Rapa on liver injury caused by Con A has not been carefully examined. In the present study, we examined the effect of Rapa on liver injury caused by Con A.. Mice received intraperitoneal Rapa injection before Con A intravenous administration. The liver injury was examined by measuring serum transaminase and pathology, and the level of cytokines was detected by enzyme linked immunosorbent assay (ELISA).. In the present study, we examined the effect of Rapa on liver injury after Con A injection in mice. We found that the treatment of mice with Rapa protected the liver from Con A-induced injury. Pretreatment with Rapa dramatically ameliorated Con A-induced mortality. This protection was associated with reduced transaminase levels in the blood and further confirmed by liver histology. ELISA showed that Rapa suppressed pro-inflammatory cytokines IFN-gamma and TNF-alpha production as compared with the untreated controls. Furthermore, intrahepatic lymphocyte proliferation was significantly inhibited.. These findings suggested that Rapa has the therapeutic potential for treatment of immune-mediated liver injury in the clinic.

Topics: Animals; Cell Proliferation; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytoprotection; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Immunosuppressive Agents; Inflammation Mediators; Injections, Intraperitoneal; Interferon-gamma; Interleukin-4; Liver; Liver Diseases; Lymphocyte Activation; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Sirolimus; Time Factors; Transaminases; Tumor Necrosis Factor-alpha

Because of its side-effects, long-term administration of ticlopidine limits the use of the sirolimus-eluting stent (SES) in Japan.. Side-effects of ticlopidine occurred in 41 (9.3%) of 440 patients who underwent SES implantation. The majority were liver dysfunction (4.5%) and rash (3.6%). One patient died from severe liver dysfunction. Neutropenia occurred in 3 patients (0.7%). It is remarkable that 28% of side-effects occurred >8 weeks after the initiation of ticlopidine.. Ticlopidine has a relative high rate of side-effects. Clopidogrel should be approved for prevention of stent thrombosis as soon as possible.

Topics: Aged; Blood Vessel Prosthesis Implantation; Chemical and Drug Induced Liver Injury; Coronary Thrombosis; Dose-Response Relationship, Drug; Drug Implants; Drug-Related Side Effects and Adverse Reactions; Exanthema; Female; Humans; Immunosuppressive Agents; Incidence; Japan; Male; Middle Aged; Platelet Aggregation Inhibitors; Retrospective Studies; Sirolimus; Stents; Ticlopidine

The aim of our paper was to describe hepatotoxicity of sirolimus (SRL) in a kidney graft recipient. We report the case of a 30-year-old male after kidney transplantation, treated with steroids, cyclosporin A and SRL, with steroid-resistant acute rejection in anamnesis. At 16th month after transplantation, elevation of serum aminotransfereases was observed. After exclusion of common reasons of this condition, liver biopsy was performed. Nonspecific changes were observed, with probability of drug-induced injury. SRL was changed to mycophenolate mofetil, which was followed by quick normalization of serum aminotransferase levels. Hepatoxicity is a rare complication of SRL therapy and may be connected with some diagnostic and/or therapeutic problems. Conversion to another immunosuppressant seems to be an appropriate procedure in this condition.

Topics: Acute Disease; Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Sirolimus; Steroids

Sirolimus is an immunosuppressant that exerts anti-rejection activity by inhibiting T-cell activity and is used to treat chronic rejection and calcineurin-related nephrotoxicity. Unlike tacrolimus and cyclosporine, it has no effect on calcineurin activity in liver transplant recipients.. To report correlates of survival outcomes in a series of patients with putative sirolimus-related hepatotoxicity after liver transplant.. We retrospectively reviewed the medical records of patients who underwent a liver transplant for chronic hepatitis C virus (HCV) and who received sirolimus immunosuppressive therapy between November 2000 and November 2003. Extracted data included sirolimus serum concentrations, frequency of sirolimus-related adverse effects, drug-related clinical hepatitis, and survival outcomes.. Ten patients were found to have been treated with sirolimus for either renal insufficiency (n = 6) or chronic rejection (n = 4). Six patients had liver biopsies, while the remaining 4 patients were clinically diagnosed with rejection. Two of the 6 patients demonstrated changes consistent with sinusoidal congestion and one with eosinophilia, consistent with an allergic drug reaction. HCV viral load increased slightly, from 600 000 to 700 000 IU/mL. Mean baseline transaminase levels were 45 IU/L for aspartate aminotransferase and 50 IU/L for alanine aminotransferase, with peak levels of 210 and 180 IU/L, respectively. The time to transaminase increase was a mean of 21 days when sirolimus was added, with resolution within 27 days (mean) after its discontinuation. No changes were evident in antiviral therapy. Combination sirolimus and tacrolimus concentrations were maintained at >10 ng/mL; average monotherapy with sirolimus was 12 ng/mL, and average time on therapy was 25 weeks.. Sirolimus-related hepatotoxicity is an important complication after liver transplant. Immediate recognition is critical to avoid confusion with other causes of abnormal serum aminotransferases after liver transplant, and discontinuation of the drug may be required.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Liver Transplantation; Retrospective Studies; Sirolimus; Survival Rate