Sex disparity and drug-induced liver injury.

Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.

Sorafenib for the treatment of recurrent hepatocellular carcinoma after liver transplantation?

BACKGROUND: There are scarce data on the use of sorafenib for the treatment of recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT). PATIENTS AND METHODS: Ten patients were treated with sorafenib after OLT following the Italian Drug Agency guidelines: they had well-compensated liver function (Child-Pugh class A in the case of cirrhosis), intermediate-or advanced-stage HCC, good general condition (performance status 0), and not suitable for loco-regional therapies. Patients with HCC recurrence after OLT were treated with sorafenib (400 mg twice daily). Adverse events (AEs) were assessed using National Cancer Institute Common Toxicity Criteria of Adverse Events (NCI-CTCAE) v3.0 with tumor responses evaluated acording to modified Response Evaluation Criteria in Select Tumors) criteria. RESULTS: Median duration of treatment was 10 months (range, 2-18). Seven patients (70%) received an additionally targeted therapy with mTOR inhibitors as part of their immunosuppressive regimen. Most common grade 3 AEs included diarrhea (50%), hand-foot skin reaction (30%), and fatigue (20%). Sorafenib had to be discontinued in 3 patients (30%) due to AEs and 4 additional patients (40%) required a dose adjustment. No deterioration of liver graft function occurred. Three patients (30%) stopped treatment due to radiological progression of HCC, whereas 3 are still using the drug. Median time to progression was 8 months (range, 2-16). Median survival from start of therapy was 18 months (range, 4- 36). CONCLUSION: Our preliminary results suggest that sorafenib is a safe effective therapy for recurrent HCC after OLT.

Comparison between nifedipine and carvedilol in the treatment of de novo arterial hypertension after liver transplantation: preliminary results of a controlled clinical trial.

There is no controlled clinical trial on the treatment of de novo arterial hypertension after liver transplantation (LT) a common complication using calcineurin inhibitors (CNI) for immunosuppressive therapy. The aim of this study was to compare the efficacy and safety of nifedipine, a calcium channel blocker, and carvedilol, an alpha1- and beta-blocker. The study included 50 patients who developed arterial hypertension after LT. The data on the first 30 patients who have completed 12-month follow-up are reported herein. Eighteen patients received nifedipine, and 12 patients received carvedilol. Patients were evaluated monthly at the outpatient clinic for 1 year. If patients developed severe adverse effects to nifedipine, they were switched to carvedilol and vice versa (therapy failure). The two groups were similar for clinical features, indications for LT, immunosuppressive therapy, and baseline blood pressures. A failure of treatment was observed in 9 of 18 patients treated with nifedipine (50.0%) and one of 12 patients treated with carvedilol (8%, P < .025). Nifedipine was effective in 4 of 18 patients, carvedilol, in 4 of 12 patients (22.21% vs 33.3%, P = NS). Two of the nine nonresponders to nifedipine responded to carvedilol. The efficacy of monotherapy was observed in 11 of 40 randomized patients (27.5%). Carvedilol monotherapy is as effective as nifedipine but far better tolerated.

Aprotinin efficacy on intraoperative bleeding and transfusion requirements in orthotopic liver transplantation.

BACKGROUND: Bleeding complications frequently occur during orthotopic liver transplantation (OLT), particularly in patients with liver cirrhosis. Enhanced fibrinolytic activity in plasma was seen to play a key role in the development of the hemostatic disorder and of hemorrhages. Aprotinin, a serine protease inhibitor, has been used in the prevention and/or treatment of hyperfibrinolytic states. STUDY DESIGN AND METHODS: In the present study, the effect of aprotinin on bleeding complications and transfusion requirements was investigated in OLT patients with liver cirrhosis. Seven consecutive cirrhotic patients undergoing OLT were infused with aprotinin following an original protocol (1,000,000-KIU intravenous loading dose plus 500,000 kallikrein-inhibitory units per hour until skin closure). Seven previous cirrhotic OLT patients not receiving aprotinin were used as controls. RESULTS: In the treated group, a significant decrease in the number of transfused units of packed red cells (48.7%, p < 0.01), fresh-frozen plasma (24.4%, p < 0.05), platelets (35.9%, p < 0.01), and autologous blood (55.2%, p < 0.01) was observed as compared with the control group. Moreover, the mean length of operation was significantly shorter in the aprotinin-infused patients than in untreated patients (8.3 +/- 1.2 vs. 10.1 +/- 1.8 hours, respectively; p < 0.01)). In the aprotinin-treated group, the antifibrinolytic efficacy was confirmed by the lack of increase in D-dimer levels and decrease of fibrinogen in plasma; on the contrary, these changes were always seen in the group not receiving aprotinin. CONCLUSION: Infusion of aprotinin during OLT in cirrhotic patients can be recommended for the prevention of hyperfibrinolysis-triggered bleeding, thus reducing transfusion requirements. A possible protective effect on the primary nonfunction of the grafted liver is suggested.