Drug-induced disorders of the stomach and duodenum

Gore, Richard M.; Levine, Marc S.; Ghahremani, Gary G.

doi:10.1007/s002619900432

Cited by 16 publications

(4 citation statements)

References 31 publications

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“…Gastrointestinal adverse drug reactions (GADRs) represent around 67% of adverse drug reactions (ADRs) described on drug labels and account for 23% of adverse events encountered in phase I studies . Motility‐related GADRs such as diarrhea and constipation are common side‐effect profiles of marketed drugs, and account for a high proportion of ADRs encountered during the development of new chemical entities . Gastrointestinal adverse drug reactions can be dose limiting preclinically and/or clinically, affect patient compliance, or even lead to compound discontinuation .…”

Section: Introductionmentioning

confidence: 99%

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials

Keating

Ewart

Grundy

et al. 2014

Neurogastroenterology Motil

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BackgroundMotility-related gastrointestinal (GI) adverse drug reactions (GADRs) such as diarrhea and constipation are a common and deleterious feature associated with drug development. Novel biomarkers of GI function are therefore required to aid decision making on the GI liability of compounds in development.MethodsFifteen compounds associated with or without clinical GADRs were used to assess the ability of an in vitro colonic motility bioassay to predict motility-related GADRs. Compounds were examined in a blinded fashion for their effects on mouse colonic peristaltic motor complexes in vitro. For each compound concentration-response relationships were determined and the results compared to clinical data. Compounds were also assessed using GI transit measurements obtained using an in vivo rat charcoal meal model.Key ResultsWithin a clinically relevant dosing range, the in vitro assay identified five true and three false positives, four true and three false negatives, which gave a predictive capacity of 60%. The in vivo assay detected four true and four false positives, four false and three true negatives, giving rise to a predictive capacity for this model of 47%.Conclusions & InferencesOverall these results imply that both assays are poor predictors of GADRs. Further analysis would benefit from a larger compound set, but the data show a clear need for improved models for use in safety pharmacology assessment of GI motility.

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Section: Introductionmentioning

confidence: 99%

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials

Keating

Ewart

Grundy

et al. 2014

Neurogastroenterology Motil

View full text Add to dashboard Cite

show abstract

“…Many drug compounds are known to cause gastro-intestinal disorders [110], the cause being locally high concentrations and resultant pH/osmotic effects or more mechanism-based effects. Many drug compounds are known to cause gastro-intestinal disorders [110], the cause being locally high concentrations and resultant pH/osmotic effects or more mechanism-based effects.…”

Section: B Irritation Potentialmentioning

confidence: 99%

Chemical and Physicochemical Approaches to Solve Formulation Problems

Lieberman

Vemuri

2015

The Practice of Medicinal Chemistry

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“…They include altered GI transit, which can manifest itself as diarrhea and/or constipation (Ghahremani 1999;Gore et al 1999;Lat et al 2010). GI AEs and ADRs can affect the GI tract in different ways, giving rise to a wide range of effects including nausea and vomiting, ulceration, inflammation of the intestine, altered fecal output, and abdominal pain/discomfort.…”

Section: List Of Abbreviationsmentioning

confidence: 99%

Principles of Safety Pharmacology

2015

Handbook of Experimental Pharmacology

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Drug-induced disorders of the stomach and duodenum

Cited by 16 publications

References 31 publications

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials

Chemical and Physicochemical Approaches to Solve Formulation Problems

Principles of Safety Pharmacology

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