PubMed · 16387231
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B Zane Horowitz, Robert G Hendrickson, Charisse Pizarro-Osilla. 2006. Not so fast!. https://doi.org/10.1016/j.annemergmed.2005.05.039
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Although antioxidants are used to treat an overdose of the analgaesic/antipyretic drug APAP (acetaminophen), roles of antioxidant enzymes in APAP-induced hepatotoxicity remain controversial. Our objective was to determine impacts of knockout of SOD1 (superoxide dismutase; Cu,Zn-SOD) alone or in combination with selenium-dependent GPX1 (glutathione peroxidase-1) on APAP-induced hepatotoxicity. All SOD1-null (SOD1-/-) and SOD1- and GPX1-double-knockout mice survived an intraperitoneal injection of 600 mg of APAP per kg of body mass, whereas 75% of WT (wild-type) and GPX1-null mice died within 20 h. Survival time of SOD1-/- mice injected with 1200 mg of APAP per kg of body mass was longer than that of the WT mice (934 compared with 315 min, P<0.05). The APAP-treated SOD1-/- mice had less (P<0.05) plasma ALT (alanine aminotransferase) activity increase and attenuated (P<0.05) hepatic glutathione depletion than the WT mice. The protection conferred by SOD1 deletion was associated with a block of the APAP-mediated hepatic protein nitration and a 50% reduction (P<0.05) in activity of a key APAP metabolism enzyme CYP2E1 (cytochrome P450 2E1) in liver. The SOD1 deletion also caused moderate shifts in the APAP metabolism profiles. In conclusion, deletion of SOD1 alone or in combination with GPX1 greatly enhanced mouse resistance to APAP overdose. Our results suggest a possible pro-oxidant role for the physiological level of SOD1 activity in APAP-mediated hepatotoxicity.
Raman spectra of a set of coated pharmaceutical tablets were analyzed for the purpose of calibrating the spectra to tablet coating thickness. Acetaminophen tablets were coated with a hydroxypropylmethylcellulose/polyethylene glycol film coating whose thickness was varied from 0 to 6% weight gain. Coatings were also prepared with two concentrations of TiO2 at several film thicknesses. The resulting spectral data set was analyzed using several different multivariate calibration procedures. The procedures examined in this study included spectral correction followed by target factor analysis, spectral correction with baseline subtraction followed by principal component regression, and first derivative computation followed by principal component regression. The results demonstrate that target factor analysis is a viable method for calibration of Raman spectra to tablet coating thickness. Calibration based on derivative spectra resulted in linear correlation that was equal to that of the results of target factor analysis for coatings without TiO2. However, target factor analysis was found to be superior to other methods when TiO2 was present in the tablet coatings. The effect of sample fluorescence on each of these chemometric methods was also examined. It was found that when photobleaching of fluorescent impurities due to exposure to the Raman excitation source was controlled, the tablet coating thickness could be calibrated to the intensity of the fluorescence signal. The results also demonstrate that for the samples examined here, calibration by target factor analysis is insensitive to variation in fluorescent intensity when the tablet coating emission spectrum is included in the matrix of target vectors.
Predicted environmental concentrations for five commonly used pharmaceuticals were calculated using data from the UK Department of Health according to risk assessment guidelines proposed by the European Agency for the Evaluation of Medicinal Products. Surface waters from the South-East of England were analysed and results were compared with predicted concentrations and findings from other studies from the UK and Europe. It was found that the efficacy of these predictions varied and was hampered by a shortage of data for many of the drugs. Ibuprofen, paracetamol and salbutamol were detected and quantified in all locations sampled. Ibuprofen was consistently found at the highest concentrations (up to 3 microg l(-1)). Levels up and downstream of two wastewater treatment works were compared in order to investigate the link between sewage discharge and environmental concentrations of pharmaceuticals. Results from one site demonstrated a considerable increase in concentrations of ibuprofen, salbutamol and paracetamol downstream from the treatment works; however, no link was established for a second works.