Paracetamol [acetaminophen]-induced gastrotoxicity: revealed by induced hyperacidity in combination with acute or chronic inflammation

Abstract

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-beta-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxicity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Cryopreserved Human Intestinal Mucosal Epithelium: A Novel In Vitro Experimental System for the Evaluation of Enteric Drug Metabolism, Cytochrome P450 Induction, and Enterotoxicity

“…Because drug metabolism is a key determinant of toxicity due to metabolic activation and detoxification, an in vitro enteric system with drug metabolism capacity similar to that in the gastrointestinal tract in vivo would be ideal for the early evaluation of gastrointestinal toxicity in drug development. We therefore embarked on the development of an in vitro enterotoxicity assay with CHIM using two nonsteroidal antiinflammatory drugs known to be associated with gastrointestinal toxicity, acetaminophen (Rainsford and Whitehouse, 2006) and naproxen (Curtarelli and Romussi, 1973). Both acetaminophen and naproxen have been associated with upper gastrointestinal bleeding and perforations.…”

What Do Patients in Rheumatologic Care Know About the Risks of NSAIDs?

“…However, a recent study has suggested that side effects due to acetaminophen treatment are underrecognized, and further studies are therefore needed to investigate this issue. 11 The main sources of information were the professionals (rheumatologist and general practitioner) and written material (package leaflet and patient hand-outs). Patients had great confidence in information from the health care system.…”

Adjuvant arthritis 50 years on: the impact of the 1956 article by C. M. Pearson, ‘Development of arthritis, periarthritis and periostitis in rats given adjuvants’

“…Fifty years on, reports are still being published indicating how helpful the adjuvant arthritis has been for probing new therapies e. g. a TNF antagonist plus/minus parathyroid hormone [35] or drug toxicity e. g. paracetamol [36]. It has also facilitated studies of lipoxygenase inhibitors (especially those present in natural products), not recognised in acute assays for NSAIDs but showing anti-infl ammatory activity in adjuvant-arthritic rats [37,38].…”