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Cutaneous Photosensitization
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
The distribution of phototoxic reactions has changed significantly since 1981, with benoxaprofen and other NSAIDs causing the majority of problems.17 As a result, phototoxicity predictive tests have become increasingly important in the development of new NSAIDs. This type of testing, in contrast to irritation testing, is not a routine procedure for all new chemicals entering the market and therefore, much less experience is apparent in this area of skin testing. Accordingly, it is necessary to ascertain what screening tests are available and how sensitive they are, as well as to identify the reference standards that are to be used to determine the specificity of a phototoxicity test.17
Models of Toxicity Screening Using Cultured Cells
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
Roberta L. Grant, Daniel Acosta
Over the past several years, we have been able to demonstrate that a primary culture system of rat hepatocytes is a useful experimental model for comparing the relative toxicity of known hepatotoxins with those of unknown compounds. In one study, four nonsteroidal anti-inflammatory agents (NSAID), benoxaprofen, orpanoxin, aspirin, and ibuprofen, were compared with that of indomethacin.17 The relative toxicity of these compounds was evaluated on an equimolar basis at concentrations of 100 to 1000 μM. This concentration range was similar to the therapeutic concentrations of most of these agents. Three different measures of cytotoxicity were employed: lactate dehydrogenase (LDH) release, a measure of plasma membrane integrity; levels of urea, an indicator of a liver specific function; and viability, based on dye exclusion of trypan blue or erythrocin B.
Confessions from an insider
Published in Peter C. Gøtzsche, Richard Smith, Drummond Rennie, Deadly Medicines and Organised Crime, 2019
Peter C. Gøtzsche, Richard Smith, Drummond Rennie
Lilly ignored or trivialised the harms and failed to inform the authorities of liver failure and deaths, which a subsequent court case described as ‘standard practice in the industry’.24,25 Lilly published a paper in the BMJ that claimed that no cases of jaundice or deaths had been reported, but this wasn’t true.22 Furthermore, benoxaprofen causes other horrible harms, e.g. photosensitivity in 10% of patients and loosening of the nails from the nailbed in 10%, but it was approved despite this and despite insufficient animal toxicology studies, in violation of the Food and Drug Administration’s (FDA’s) own rules. When independent researchers found that benoxaprofen accumulated in the elderly, Lilly tried to prevent the study from being published and, as always, the UK drug regulator’s action was grossly inadequate and allowed Lilly to trivialise the problem. These omissions proved fatal for some elderly patients, and the drug was withdrawn after only 2 years on the market.
A cysteine trapping assay for risk assessment of reactive acyl CoA metabolites
Published in Xenobiotica, 2022
Nobuyuki Kakutani, Satoru Kobayashi, Toshio Taniguchi, Yukihiro Nomura
Pooled human liver microsomes (n = 50, mixed gender) were purchased from Sekisui XenoTech, LLC (Kansas City, KS, USA). Trizma® hydrochloride solution (pH 7.4, 1 M), magnesium solution (1 M), KCl, CoA, ATP, Triton X-100, ibufenac, tolmetin, repaglinide, furosemide, zomepirac, mefenamic acid, and diclofenac were purchased from Sigma-Aldrich (St Louis, MO, USA). Acetonitrile (MeCN), glutathione (GSH), lysine, ibuprofen, fenclozic acid, indomethacin, and naproxen were purchased from Fujifilm Wako Pure Chemical Corporation (Osaka, Japan). Dithiothreitol (DTT), meclofenamic acid, probenecid, gemfibrozil, and febuxostat were purchased from Tokyo Chemical Industry (Tokyo, Japan). Benoxaprofen was purchased from Toronto Research Chemicals (Toronto, Ontario, Canada). TAK-875 was synthesised by Japan Tobacco, Inc. [35S]cysteine (Cys) and Ultima Flo M were purchased from PerkinElmer Life and Analytical Science (Boston, MA, USA). Formic acid (FA) and dimethyl sulfoxide (DMSO) were purchased from Nacalai Tesque (Kyoto, Japan). An Acquity C18 BEH column and XBridge BEH C18 column were purchased from Waters Corporation (Milford, MA, USA). The stock solutions of test compounds were prepared in DMSO or 50% water/MeCN at a concentration of 100 mM before each assay.
Current insights in the complexities underlying drug-induced cholestasis
Published in Critical Reviews in Toxicology, 2019
Neel Deferm, Tom De Vocht, Bing Qi, Pieter Van Brantegem, Eva Gijbels, Mathieu Vinken, Peter de Witte, Thomas Bouillon, Pieter Annaert
DIC poses a major hurdle for the pharmaceutical industry and regulatory authorities, since it is a leading cause of both attrition and post-approval withdrawal of drugs (van Tonder et al. 2013). Indeed, approximately 30% of all drugs withdrawals, due to hepatotoxic adverse events, were reported to induce cholestatic liver injury (Figure 1). Examples include benoxaprofen and troglitazone. Benoxaprofen was withdrawn in 1982, the same year it was marketed, while troglitazone was withdrawn in 1999, only two years after it reached the market (Onakpoya et al. 2016). Troglitazone accrued approximately $700 million per year in the US, stressing the fact that drug withdrawals lead to huge financial losses for the pharmaceutical industry (van Tonder et al. 2013).