cyproterone and Chemical-and-Drug-Induced-Liver-Injury

We hypothesized that a drug's clinical signature (or phenotype) of liver injury can be assessed and used to quantitatively develop a computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and Polygonum multiflorum using data from published case series, to develop DILI-CAT scores for each drug.. Drug specific phenotypes were made up of the following three clinical features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation system was developed with points allocated depending on the variance from the norm (or "core") for the 3 variables in published datasets.. The four drugs had significantly different phenotypes based on latency, R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus < 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also significantly different among drugs (cyproterone [median 12.4] and Polygonum multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median 1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected, because of phenotypic overlap, AMX/CLA and cefazolin could not be well differentiated.. DILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes for DILI adjudication. The data provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could enhance causality assessment methods.

Topics: Amoxicillin-Potassium Clavulanate Combination; Causality; Cefazolin; Chemical and Drug Induced Liver Injury; Computers; Cyproterone; Humans

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

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

A 70-year-old man with prostatic adenocarcinoma received cyproterone acetate 200 mg per day. Three months later, mild fatigue and anorexia with elevation of the alanine aminotransferase (ALT) level to 1311 U/L, total bilirubin level to 14 mg/dL and prothrombin time of 15/11.9 seconds developed. At that time the aspartate aminotransferase (AST) level was only 82 U/L. Viral hepatitis and autoimmune markers were all negative. This hepatitis resolved quickly after cyproterone therapy was discontinued. One and a half years later, the patient was prescribed cyproterone 100 mg daily at another hospital where staff were unaware of his previous history. General malaise, upper abdominal pain and jaundice developed two months later. Laboratory studies at emergency room revealed an AST of 245 U/L, ALT of 255 U/L, total bilirubin of 8.2 mg/dL, amylase of 6055 U/L, prothrombin time of 15.2/11.1 seconds and platelet count of 68000 cells/mL. Although cyproterone was discontinued, the patient died of multiple organ failure 20 days after admission. This case report presents a rare situation with marked elevation of the ALT level without AST level elevation. This finding suggests that cyproterone may induce specific damage to the plasma membrane, and the mitochondria are not involved in the initial stage.

Topics: Aged; Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cyproterone; Hepatitis; Humans; Jaundice; Male

In a recent study in rats, alanine aminotransferase (ALT), the preferred plasma biomarker of hepatocellular injury in rats, was ineffective at detecting marked hepatic necrosis produced by acetaminophen (Human and Experimental Toxicology 19, 277-83, 2000). In contrast, glutamate dehydrogenase (GLDH) was markedly elevated. Accordingly, these enzymes were comprehensively evaluated as plasma biomarkers of hepatocellular injury in rats using several other models of hepatic injury, including partial hepatectomy and exposure to methapyrilene, dexamethasone, cyproterone, isoniazid, lead nitrate, and Wyeth-14643. Other enzymes also evaluated were aspartate aminotransferase (AST), sorbitol dehydrogenase (SDH), and the hepatobiliary marker alkaline phosphatase (ALP). Compared to plasma ALT increases, plasma GLDH increases were up to 10-fold greater, up to 3-fold more persistent, and occurred at times following hepatocellular injury when plasma ALT was not increased. Plasma GLDH activity was not inhibited by the test compounds, whereas ALT was substantially inhibited by both isoniazid and lead nitrate. While plasma GLDH activity was unaffected by induction, ALT was induced by cyproterone and dexamethasone, and ALP was induced by Wyeth-14643 and partial hepatectomy. GLDH was concluded to be a more effective biomarker of acute hepatic injury than ALT, AST, SDH or ALP in the rat, based primarily on the large increase following hepatocellular injury, prolonged persistence in the blood following injury, high sensitivity for detection of injury (including pre-necrotic injury), high tissue specificity, and lower susceptibility to inhibition or induction.

Topics: Acute Disease; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Biomarkers; Chemical and Drug Induced Liver Injury; Cyproterone; Dexamethasone; Glutamate Dehydrogenase; Hepatectomy; Isoniazid; L-Iditol 2-Dehydrogenase; Lead; Liver; Male; Methapyrilene; Nitrates; Pyrimidines; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity

Three procedures were used to stimulate hepatocyte proliferation in the rat without reducing liver mass, resulting in a supplementary growth which differs from the regenerative growth observed after loss of liver mass by hepatectomy or toxic necrosis. They were: (a) the ingestion of cyproterone, a cytochrome P450 inducing drug (b) the injection of an irritant which provokes glycogenesis and synthesis of acute-phase proteins (c) the injection of albumin-bound bilirubin leading to elimination of glucuronated bilirubin in bile. This ensuing supplementary growth was studied in the rat under several conditions of hepatic proliferation: 1. In normal adult rats, in which hepatocyte proliferation is very low, the effect on proliferation was either weak or undetectable. 2. In suckling rats, with a rapid body and liver growth, all the stimulants provoked a synchronized wave of proliferation with a steep increase of the percentage of S-phase hepatocytes from 4.5% in controls to 15-30% in treated rats. This increase was followed by a compensatory period of low proliferation during which a treatment with a second stimulant was much less effective. 3. In 2/3 hepatectomized adult rats, the proliferation induced by cyproterone was higher than the spontaneous regenerative proliferation alone and additional to it during all of the regenerative process. The proliferation induced by acute inflammation was competitive with the synchronous spontaneous proliferation during the early period of synchronized proliferation following surgery, suggesting that both are similar acute responses. Differently, during the late period of lower and unsynchronized regenerative proliferation, the proliferation provoked by acute inflammation was additional to the spontaneous one. A stimulation of proliferation by injection of the albumin-bilirubin complex was observed during the late period after 2/3 hepatectomy. The highest level of stimulation occurred when the liver growth and the hepatocyte proliferation were already high. This suggests that these stimulants are not complete mitogenic stimuli and need cofactors which are present during the spontaneous growth or, alternatively, that the effect of stimulants is opposed by an inhibitory mechanism present in the adult rat.

Topics: Acute-Phase Reaction; Age Factors; Alanine Transaminase; Albumins; Androgen Antagonists; Animals; Animals, Suckling; Bilirubin; Caseins; Cell Division; Chelating Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Energy Metabolism; Glycogen; Hepatectomy; Hepatocytes; Liver; Liver Diseases; Liver Regeneration; Male; Organ Size; Rats; Rats, Wistar

Topics: Aged; Aged, 80 and over; Carcinoma; Chemical and Drug Induced Liver Injury; Cyproterone; Humans; Male; Prostatic Neoplasms

Topics: Aged; Chemical and Drug Induced Liver Injury; Cyproterone; Humans; Male; Prostatic Neoplasms

Cyproterone acetate (CPA) is a widely used drug in the treatment of advanced prostatic carcinoma. Although it is generally well tolerated, liver toxicity has been recognised as a complication of long-term use. We report 3 patients with severe hepatocellular damage due to CPA therapy, 2 with fatal fulminant hepatitis.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Humans; Male; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Humans; Male; Prostatic Neoplasms

A case of severe acute hepatitis caused by cyproterone acetate in a 71 year old man with prostatic carcinoma is reported with a review of the literature on hepatic reactions to this drug. The association between the use of cyproterone acetate and liver abnormalities is poorly documented. This is the fourth published report of adverse hepatic reaction to cyproterone acetate and it substantiates other evidence that cyproterone acetate is potentially hepatotoxic. Monitoring of liver function tests should be mandatory in patients receiving high doses of cyproterone acetate; the drug should be withdrawn immediately if abnormal liver function tests are found.

Topics: Adenocarcinoma; Aged; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Humans; Liver; Male; Prostatic Neoplasms

Regarding a case of little-differentiated adenocarcinoma of prostate in a 79-year old male patient undergoing antiandrogenic corticosteroid therapy (cyproterone acetate), the authors describe a rare complication related to treatment with the drug. Cytolytic icterus, without cholestasis, occurred eleven weeks after starting the treatment without metastasis of the primary cancerous lesion, and regressed when administration of the antiandrogenic agent was interrupted. This description is compatible with toxic hepatitis. This is a rare complication, which should be differentiated from stasis icterus consecutive to treatment with progestogens. Its diagnosis precludes also primary or drug-induced secondary tumors or degenerative hepatic lesions. A knowledge of this complication by the urologist is important, so the latter might not conclude too hastily to metastatic extension of primary cancer of prostate. Withdrawal of the patient from antiandrogenic therapy is mandatory, and management should incorporate complete biological investigation of liver function, CT scans and, depending upon the case, liver biopsy as the only means of studying this exceptionally rare complication.

Topics: Adenocarcinoma; Aged; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Humans; Male; Prostatic Neoplasms

Topics: Aged; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Female; Hepatic Encephalopathy; Humans; Male

A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Drug Evaluation; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Middle Aged

Topics: Acute Disease; Aged; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Cyproterone; Cyproterone Acetate; Female; Humans