Sandra Bodeau

Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib

BackgroundSorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking.MethodsWe used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used.ResultsWe observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival.ConclusionThese findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.

N-methyl-2-pyridone-5-carboxamide (2PY)—Major Metabolite of Nicotinamide: An Update on an Old Uremic Toxin

N-methyl-2-pyridone-5-carboxamide (2PY, a major metabolite of nicotinamide, NAM) was recently identified as a uremic toxin. Recent interventional trials using NAM to treat high levels of phosphorus in end-stage renal disease have highlighted new potential uremic toxicities of 2PY. In the context of uremia, the accumulation of 2PY could be harmful—perhaps by inhibiting poly (ADP-ribose) polymerase-1 activity. Here, we review recently published data on 2PY’s metabolism and toxicological profile.

DHEA and progesterone have a protective effect on ribavirin-induced hemolysis

[1] Coilly A, Roche B, Dumortier J, Leroy V, Botta-Fridlund D, Radenne S, et al. Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience. J Hepatol 2014;60:78–86. [2] Aguilera I, Sousa JM, Praena JM, Gomez-Bravo MA, Nunez-Roldan A. Choice of calcineurin inhibitor may influence the development of de novo immune hepatitis associated with anti-GSTT1 antibodies after liver transplantation. Clin Transplant 2011;25:207–212. [3] Coilly A, Furlan V, Roche B, Barau C, Noël C, Bonhomme-Faivre L, et al. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother 2012;56:5728–5734. [4] Fiel MI, Agarwal K, Stanca C, Elhajj N, Kontorinis N, Thung SN, et al. Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus. Liver Transpl 2008;14:861–871. [5] Sebagh M, Castillo-Rama M, Azoulay D, Coilly A, Delvart V, Allard MA, et al. Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults. Transplantation 2013;96:670–678.

Patients treated with first‐generation HCV protease inhibitors exhibit high ribavirin concentrations

Anemia is a well‐known RBV‐related event in HCV therapy which is exacerbated by the addition of telaprevir and boceprevir. This retrospective study evaluated and compared ribavirin exposure and parameters able to influence hemoglobin decrease in a large population of patients treated with dual or triple therapy. Patients on triple therapy had higher ribavirin concentrations at week 12 of treatment (3460 ng/mL vs. 1843 ng/mL; P < .0001). An association was also observed between week 12 eGFR and ribavirin concentration only for patients on triple therapy (P = .002). The proportion of patients with a  >20 mL/min/1.73 m2 decrease in eGFR at week 12 was higher among patients on triple therapy: 32%, 14%, and 5% for boceprevir, telaprevir, and dual therapy, respectively (P = .025 and .026). No correlation was observed between boceprevir and telaprevir concentrations and hemoglobin or eGFR decrease. Exacerbation of anemia in patients on triple therapy is related to higher ribavirin concentrations. We provide an explanation for this increase in plasma RBV concentration. Triple therapy with PEG‐IFN, RBV, and telaprevir or boceprevir will remain the only HCV treatment option for many patients. Our data show that the RBV dose can be decreased while maintaining adequate plasma concentrations and reducing anemia.

The end-of-treatment ribavirin concentration predicts hepatitis C virus relapse.

Background: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse. Methods: Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass-spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers. Results: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 ± 312 ng/mL for relapsers and 2278 ± 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24–∞; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin-28B genotype, and response to previous courses of treatment. Conclusions: Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse.

Does Therapeutic Drug Monitoring of Ribavirin in HCV Genotype 3 Treatment With Sofosbuvir and Ribavirin Still Have a Role

To the Editors: The optimal use of ribavirin in the treatment of hepatitis C with pegylated interferon, particularly by adjusting the dose to body weight and therapeutic drug monitoring of plasma concentrations, has greatly improved the response to treatment. In clinical practice, conventional combination therapy that includes ribavirin is able to significantly reduce relapse rates after treatment. A lower relapse rate is highly dependent on ribavirin concentrations during treatment. Food and Drug Administration has recently approved sofosbuvir, a first-in-class polymerase inhibitor, for the treatment of chronic hepatitis C genotypes 1, 2, 3, or 4. This treatment option allows, for the first time, treatment of infections with genotypes 2 and 3 without using interferon. The recommended regimen is a combination of sofosbuvir 400 mg and weight-based ribavirin dosing. However, closer analysis of the results of 4 phase 3 trials (Fig. 1) in 984 hepatitis C virus (HCV) genotype 2 and 3 mono-infected patients (FISSION, POSITRON, FUSION, and VALENCE), reveals that relapse rates remain fairly high (236/980: 24%). The results of these trials indicate very high end of treatment (ETR) response rates, close to 100% (981/ 984: 99.7% overall). However, sustained virologic response (SVR) rates were much lower (731/984: 74.3%) because of relapse occurring after the ETR. In a more detailed analysis of the results observed in patients with genotypes 2 and 3, the relapse rate was 7% (26/327) for genotype 2 and 32.2% (210/653) for genotype 3. Guidelines for the treatment of genotype 3 indicate that treatment should be continued for 24 weeks, which reduced the relapse rate to 14% (34/249) in the single-arm study evaluating this regimen (VALENCE). FISSION, POSITRON, and FUSION trials provide data from univariate and multivariate logistic regression assessing the factors associated with SVR12 in sofosbuvir plus ribavirin patients. In multivariate analysis, RBV exposure (mg

High metabolic N‐oxidation of voriconazole in a patient with refractory aspergillosis and CYP2C19*17/*17 genotype

kg21

DHEA prevents ribavirin-induced anemia via inhibition of glucose-6-phosphate dehydrogenase

d21) is one of the factors associated with SVR, with an odds ratio of 1.258 (P = 0.002) and 1.469 (P = 0.0119) in the FISSION and FUSION trials, respectively. In these studies, among factors associated with SVR in multivariate analysis (gender, genotype 2 versus 3, the presence or absence of cirrhosis, ribavirin exposure), the only one that can be modulated is ribavirin exposure. In addition, in a study involving 60 naive genotype 1 patients treated with combination therapy sofosbuvir (400 mg) and in the first group ribavirin 1000 or 1200 mg (weightadjusted) or in the second group ribavirin 600 mg, relapse after the ETR was 29% in the first group and 45% in the second. In recent years, with dual therapy and the advent of direct-acting antiviral agents, it has been clearly demonstrated that patients with a more marked reduction of hemoglobin (Hb) during treatment are more likely to achieve higher SVR rates. Very recently, Sulkowski et al, analyzing the NEUTRINO, FISSION, FUSION, and POSITRON clinical trials, showed that SVR was associated with the extent of Hb decrease. For HCV genotype 2–infected patients, SVR rates were .92% across all levels of Hb reduction. However, for HCV genotype 3–infected patients, SVR was determined by the extent of Hb decrease: 63% for patients with a decrease

Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients

3 g/dL and 48% for those with a decrease ,3 g/dL. In fact, anemia during treatment of hepatitis C partially reflects good exposure to ribavirin. However, plasma ribavirin measurements have 2 distinct benefits for the clinician. The first benefit is prevention of overdose, thereby avoiding the risk of accentuating anemia. In practice, deterioration of anemia can be avoided by regularly monitoring the kinetic decrease of Hb during therapy. The second benefit of plasma ribavirin assays, which are probably indicated in the case of sofosbuvir therapy, is to detect patients with subtherapeutic concentrations despite good compliance with treatment, because of the marked interindividual variability of pharmacokinetics even when the dose is adjusted to body weight. In patients for whom interferon is not indicated, sofosbuvir provides the possibility of interferon-free FIGURE 1. Data on the ETR response, SVR, and relapse from phase 3 trials in HCV genotype 2 and 3 mono-infected patients.

Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells

oratory of pharmacology and toxicology, CHU Amiens Picardie, UPJV, INSERM U1088, France,Laboratory of pharmacology and toxicology, Nantes ersity Hospital, France,Department of Pharmacology, EA 4123, Le Kremlin Bicêtre University Hospital, Universite Paris Sud, France,Department linical Hematology, CHU Amiens Picardie, France,Laboratory of pharmacology and toxicology, CHU Amiens Picardie, France and Laboratory of ology, CHU Amiens Picardie, France