pyrimidinones and Chemical-and-Drug-Induced-Liver-Injury

In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Gastrointestinal Diseases; Humans; Hypophysitis; Hypothyroidism; Imidazoles; Immunosuppressive Agents; Indoles; Ipilimumab; Melanoma; Mycophenolic Acid; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Sweet Syndrome; Thyrotoxicosis; Tumor Necrosis Factor-alpha; Vemurafenib; Vitiligo

Darunavir, previously known as TMC-114, is a new protease inhibitor (PI) with a high affinity for the HIV-1 protease and strong ability to inhibit its action, even in mutated forms. Consequently, this drug is considered to have great intrinsic potency and a high genetic barrier. At the time of writing, data on the tolerability and safety of darunavir come mainly from studies of late rescue therapy (POWER, DUET), which have included more than 1,600 patients. Recent data, relating to shorter time periods, are also available from studies in early treatment-experienced patients (TITAN) and in treatment-naïve patients (ARTEMIS), increasing experience to a further 600 patients. Lastly, more than 4,000 patients who have received darunavir through the Expanded Access Program have allowed the drug's generally good safety and tolerability profile to be defined. In the studies performed to date, darunavir has been well tolerated, with a better profile than that of the PIs used in control groups in terms of adverse effects such as diarrhea, gastrointestinal tolerability and lipid alterations. Moreover, to date, no unexpected severe adverse effects have been reported.

Topics: Adult; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Darunavir; Drug Therapy, Combination; Dyslipidemias; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Lopinavir; Male; Multicenter Studies as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Salvage Therapy; Sulfonamides

Lopinavir/ritonavir (LPV/r) has been the gold standard in first line rescue treatment for many years. No other boosted protease inhibitor (PI/r) has managed to demonstrate that it is superior to LPV/r. In this regard, the TITAN study compared the efficacy and safety of darunavir (DRV/r) in 595 patients, at a dose of 600/100 mg two times a day against the normal LPV/r dose, combined with at least 2 other optimised antiretroviral drugs. The efficacy of the treatment at 48 weeks (VL<400 copies/mL) was significantly higher in the DRV/r goup compared to the LPV/r group, both in the analysis by protocol (77% vs. 68%), the non-inferiority of DRV/r being demonstrated (estimated difference +9%, 95% CI 2-16), and by intention to treat (77% vs. 67%), the superiority of DRV/r being demonstrated (estimated difference 10%, 95% CI 2-17%). The incidence of diarrhoea and increase in triglycerides was higher in the LPV/r group. The differences in efficacy of both treatments in favour of DRV/r started to be seen from a basal primary mutation in the protease, with these differences increasing as the number of these mutations increased. In patients with virological failure, DRV/r protected the protease and reverse transcriptase against mutations, thus preserving future therapeutic options. We have some theoretical and clinical data available that enables us to consider the possibility of administering DRV/r once a day in some patients with a few mutations in the protease and in those where this dosing regime is considered important. With the results of the TITAN study, DRV/r must be considered the new gold standard in first line rescue, at least in those patients with a primary mutation in the protease.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Darunavir; Diarrhea; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prognosis; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy; Sulfonamides

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Female; Humans; Imidazoles; Liver Function Tests; Melanoma; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index; Skin Neoplasms; Vemurafenib

We report the case of a patient with non-Hodgkin's lymphoma who, during chemotherapy according to the r-CHOP schedule (rituximab-cyclophosphamide-doxorubicin-vincristine and prednisone), showed a hepatic flare with jaundice. Given the patient's state of asymptomatic carrier of HBsAg, we began a treatment of telbivudine (600 mg/die), resulting in a regression of hepatitis flare and negativization of HBV viraemia.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Cyclophosphamide; Cytomegalovirus; Cytomegalovirus Infections; Doxorubicin; Hepatitis B virus; Hepatitis B, Chronic; Humans; Hyperbilirubinemia; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nucleosides; Prednisone; Pyrimidinones; Rituximab; Telbivudine; Thymidine; Vincristine; Viremia; Virus Activation

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

Topics: Adult; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Exanthema; Female; HIV Infections; HIV Protease Inhibitors; Humans; Kidney Diseases; Lopinavir; Myelopoiesis; Pyrimidinones

We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrollment.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Italy; Liver Diseases; Lopinavir; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrimidinones; Ritonavir

Topics: Chemical and Drug Induced Liver Injury; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Liver; Lopinavir; Pyrimidinones; Ritonavir

H2 receptor antagonist-hepatotoxicant interactions were evaluated in male Fischer-344 rats. The H2 receptor antagonists, cimetidine, ranitidine, oxmetidine, and 2-[2-(2-dimethyl-aminomethyl-5-furanylmethyl-thio)-ethylamino]-5-( 6-methyl- 3-picolyl)-4-pyrimidine trihydrohydrochloride (SK&F 93479) were administered (p.o.) at a dose of 0.143 mMoles/kg 30 minutes prior to hepatotoxicant treatment. Submaximal hepatotoxic doses (p.o.) of carbon tetrachloride (795 mg/kg), bromobenzene (748 mg/kg), chloroform (1,190 mg/kg), allyl alcohol (60 mg/kg), galactosamine (200 mg/kg, i.p.), and acetaminophen (1000 mg/kg) were employed. Hepatotoxicity was evaluated by determining serum alanine aminotransferase activity (ALT). Pretreatment with the H2 receptor antagonists did not significantly alter carbon tetrachloride or allyl alcohol hepatotoxicity. Bromobenzene and chloroform toxicities were unaffected by cimetidine, ranitidine, and oxmetidine pretreatment but were potentiated by SK&F 93479. Cimetidine and ranitidine decreased galactosamine mediated hepatotoxicity. Acetaminophen hepatotoxicity was markedly potentiated by ranitidine pretreatment but was unaltered by the other three H2 receptor antagonists. The mechanisms of hepatotoxicity potentiation or protection have not been determined, however, the lack of consistent H2 receptor antagonists effects indicates that it is unlikely that alterations in G.I. pH account for the effects observed. H2 receptor antagonist mediated changes in hepatotoxicant metabolism provide a more plausible mechanism of action, particularly in the cases of SK&F 93479 potentiation of bromobenzene and chloroform and ranitidine potentiation of acetaminophen hepatotoxicity.

Topics: 1-Propanol; Acetaminophen; Animals; Bromobenzenes; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chloroform; Cimetidine; Drug Antagonism; Drug Synergism; Histamine H2 Antagonists; Imidazoles; Liver; Male; Propanols; Pyrimidinones; Ranitidine; Rats; Rats, Inbred F344