PubMed · 10697929
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E Palacios, G Valvassori. 2000. Hemorrhagic labyrinthitis.. https://pubmed.ncbi.nlm.nih.gov/10697929/
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The Long-Evans Cinnamon (LEC) rats accumulate excess copper (Cu) in the liver in a manner similar to patients with Wilson's disease (WD) and spontaneously develop acute hepatitis with severe jaundice. Although hydroxyl radicals (*OH) have been proposed to be a cause of hepatitis by the accumulation of Cu, it is not clear whether or not *OH can be produced in the liver of hepatitic LEC rats in vivo and also can be involved in the onset of hepatitis. In the present study, *OH production in plasma and liver of hepatitic LEC rats was quantified by trapping *OH with salicylic acid (SA) as 2, 3-dihydroxybenzoic acid (2, 3-DHBA). The ratios of 2, 3-DHBA/SA were significantly higher in plasma and liver of hepatitic LEC rats than those of Wistar rats and LEC rats showing no signs of hepatitis. Furthermore, the ratios of 2, 3-DHBA/SA in plasma and liver of hepatitic LEC rats were almost the same as those of Wistar rats treated orally with CuSO(4) (0.5 mmol/kg) 2 h before acetylsalicylic acid (ASA) injection. We also evaluated the protective effects of D-mannitol (a *OH scavenger) treatment against acute hepatitis in LEC rats. D-mannitol (500 mg/kg) was administered intraperitoneally to 10-week-old LEC rats for 3 weeks. D-mannitol treatment suppressed the increases in serum aspartate aminotransferase activity and total bilirubin concentration. In addition, D-mannitol treatment significantly reduced hepatic mitochondrial lipid peroxidation, which is thought to be important in the pathogenesis of Cu-induced hepatotoxicity. These observations suggest that accelerated generation of *OH catalyzed by free Cu in the liver may, at least in part, play a role in the pathogenesis of acute hepatitis in LEC rats.
Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The clinical efficacy of NSAIDs is primarily related to the inhibition of COX-2 activity, whereas much of the toxicity, particularly gastrointestinal toxicity, is related to COX-1 inhibition. In vitro and in vivo assays indicate that both COX-2-specific inhibitors and conventional NSAIDs are equally effective in inhibiting COX-2, suggesting that the clinical efficacy of COX-2-specific inhibitors should be similar to that of conventional NSAIDs. Multiple studies in patients with osteoarthritis, rheumatoid arthritis, and acute pain have now confirmed that the clinical efficacy of COX-2-specific inhibitors is similar to that of conventional NSAIDs.
The use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with upper gastrointestinal bleeding and perforation (UGIB), acute liver injury, acute renal injury, heart failure, and adverse reproductive outcomes. This article summarizes the effects of various factors, such as NSAID dose, duration of treatment, patient age, and ulcer history, on the incidences of these adverse side effects. We used the UK General Practice Research Database to study further the principal safety concern related to NSAIDs, namely, UGIB.