Some adverse actions of chlorothalonil at sublethal levels in rat thymic lymphocytes: Its relation to Zn2.

Chlorothalonil, a polychlorinated aromatic fungicide, is considered non-toxic to small mammals. However, chlorothalonil inactivates sulfhydryl enzymes and depletes cellular glutathione. Chlorothalonil increases intracellular Zn2+ concentration ([Zn2+]i) in mammalian cells possibly because intracellular Zn2+ is released via zinc-thiol/disulfide interchange. The effects of chlorothalonil at sublethal concentrations on the cellular content of nonprotein thiols ([NPT]i) and [Zn2+]i were examined using flow cytometry in rat thymocytes. Low concentrations (0.3-1 µM) of chlorothalonil increased, but high concentrations (3-10 µM) decreased [NPT]i. These effects of chlorothalonil were partly attenuated by an intracellular Zn2+ chelator. Chlorothalonil at 0.3-10 µM increased [Zn2+]i in a concentration-dependent manner, which was largely dependent on the release of intracellular Zn2+. Both the decrease in [NPT]i and increase in [Zn2+]i increase the vulnerability of cells to oxidative stress. Chlorothalonil at 1-10 µM potentiated the cytotoxicity of H2O2 (300 µM). It was also the case for 10 µM pentachloronitrobenzene, but not 10 µM pentachlorophenol. In conclusion, chlorothalonil at low (sublethal) micromolar concentrations is cytotoxic to mammalian cells under oxidative stress.

Adherence to changing from brand-name to generic atorvastatin in newly treated patients: a retrospective cohort study using health insurance claims.

BACKGROUND: Effect of statin therapy has been reported to be associated with patient's adherence. Atorvastatin was available in Japan as a brand-name product beginning in 2000. The first atorvastatin generics were introduced in Japan in November 2011. The objective of this study was to analyze whether changing from a brand-name atorvastatin to a generic product would affect patient adherence. METHODS: We conducted a retrospective cohort study that included adult patients who received newly prescribed brand-name atorvastatin between June 1, 2011 and May 31, 2012, using a health insurance claims database in Japan. Patients were classified by the presence or absence of changing to a generic during the 6 months from December 1, 2011 to May 31, 2012 (the index period). The first prescription date for the generic or brand product during the index period was defined as the index date. Adherence to therapy was assessed by the proportion of days covered (PDC) and persistence of treatment by time to discontinuation. RESULTS: There were 135 patients changing to generic atorvastatin and 147 continuing with the brand-name product. There was no significant difference in decrease of PDC from pre- to post-index date between the changed cohort and continued cohort (-8.6% vs -10.3%, respectively; P = 0.443). After adjusting for baseline covariates, including adherence in pre-index date, no statistically significant differences were observed in the adjusted odds of adherence between the cohorts (adjusted odds ratio = 0.83, 95% confidence interval (CI) = 0.46-1.53). There was also no significant difference in persistence between two cohorts in the 180-day after post-index date. After analysis of a Cox proportional hazard regression model controlling for baseline covariates, including adherence in pre-index date, no statistically significant differences were observed for the hazard of non-persistence between the cohorts (adjusted hazard ratio = 0.96, 95% CI = 0.60-1.53). CONCLUSIONS: Changing from a brand-name atorvastatin to generic product did not affect adherence for patients newly treated with atorvastatin.