Role of prostaglandins and nitric oxide in gastric damage induced by metamizol in rats

Sánchez, Susana; Martín, Maria J.; Ortíz, Pablo; Motilva, Virginia; Herrerias, Juan Manuel; Lastra, Catalina Alarcón de la

doi:10.1007/pl00000319

Cited by 15 publications

(10 citation statements)

References 47 publications

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“…However, 3 of 12 volunteers treated with the high dose of dipyrone developed relevant lesions, suggesting a dose-dependent mucosa-damaging effect in some individuals probably due to the somewhat higher and sustained inhibition of COX-1. Moreover, other mechanisms such as diminished glutathione metabolism (58) or inhibition of the nitric oxide/cyclic guanosine monophosphate pathway and nitric oxide synthase activity (59), which have been suggested to contribute to high-dose dipyrone-elicited weak mucosal lesions in rats, appear feasible.…”

Section: Discussionmentioning

confidence: 99%

Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic

Hinz¹,

Cheremina²,

Bachmakov³

et al. 2007

FASEB j.

124

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Dipyrone (INN, metamizol) is a common analgesic used worldwide. Its widespread prescription or over-the-counter use in many countries (e.g., Brazil, Israel, Mexico, Russia, Spain) requires insight into its mode of action. This study therefore addressed the impact of its metabolites 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA) on peripheral cyclooxygenases (COX). Pharmacokinetics of metabolites and ex vivo COX inhibition were assessed in five volunteers receiving dipyrone at single oral doses of 500 or 1000 mg. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured in vitro and ex vivo in human whole blood as indices of COX-1 and COX-2 activity. In vitro, metabolites elicited no substantial COX-1/COX-2 selectivity with MAA (IC50=2.55 micromol/L for COX-1; IC50=4.65 micromol/L for COX-2), being approximately 8.2- or 9-fold more potent than AA. After administration of dipyrone, MAA plasma concentrations remained above the IC50 values for each isoform for at least 8 h (500 mg) and 12 h (1000 mg) postdose. COX inhibition correlated with MAA plasma levels (ex vivo IC50 values of 1.03 micromol/L [COX-1] and 0.87 micromol/L [COX-2]). By contrast, plasma peak concentrations of AA after the 1000 mg dose were 2.8- and 6.5-fold below its IC50 values for COX-1 and COX-2, respectively. Maximal inhibitions of COX-1 and COX-2 were 94% and 87% (500 mg), 97% and 94% (1000 mg). Taken together, dipyrone elicits a substantial and virtually equipotent inhibition of COX isoforms via MAA. Given the profound COX-2 suppression by dipyrone, which was considerably above COX-2 inhibition by single analgesic doses of celecoxib and rofecoxib, a significant portion of its analgesic action may be ascribed to peripheral mechanisms. In view of the observed COX-1 suppression, physicochemical factors (lack of acidity) rather than differential COX-1 inhibition may be responsible for dipyrone's favorable gastrointestinal tolerability compared with acidic COX inhibitors.

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Section: Discussionmentioning

confidence: 99%

Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic

Hinz¹,

Cheremina²,

Bachmakov³

et al. 2007

FASEB j.

124

View full text Add to dashboard Cite

show abstract

“…Two isoforms of COX have been identified: COX-1, a constitutive enzyme that appears to be responsible for the production of PGs that are physiologically important for homeostatic functions, and COX-2, an inducible isoform, dramatically upregulated during certain processes synthesizing PGs, mediating inflammation, fever and pain [34,35]. However, many studies in recent years have suggested that COX-2 can contribute to gastric mucosal control at least in some circumstances such as adaptive response of gastric mucosa to a topical irritant [36], colonization by Helicobacter pylori [37], healing of chronic gastrointestinal ulcer [38] or defense mechanisms in the damage induced by NSAIDs [39,40].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Modulates the Effects of Gastric Injury in Rats: Role of Prostaglandins and Nitric Oxide

Deogracias¹,

Alarcón‐de‐la‐Lastra²,

Jimenez³

et al. 2003

Neurosignals

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Experimental evidence has been presented connecting melatonin with the prevention or treatment of gastrointestinal disorders either by the scavenging properties of active oxygen or by receptor-mediated stimulation of gene expression of neutralizing enzymes. Prostaglandins and nitric oxide are important neuroimmunomodulators in digestive physiology and different studies have indicated that the protective properties of melatonin may be explained by prostaglandin and/or nitric oxide mechanisms. The aim of the present study was to examine the effect of intraperitoneal administration of melatonin on in vivo changes in PGE₂, generated in gastric mucosal lesions by ischemia-reperfusion. Cyclic GMP nucleotide was also studied as an index of the principal enzymatic activity involved in the metabolism of nitric oxide, the nitric oxide synthase. The different immunological tests showed that the intraperitoneal administration of melatonin prevents the postischemic decrease in prostaglandins. The concentration of this eicosanoid in the rat mucosa treated with 20 mg·kg^–1 of melatonin was significantly higher (p < 0.05) than that in the control rats. The amount of cyclic GMP in the stomach decreased because of ischemia-reperfusion. In treated animals however, a marked increase occurred in concentrations of GMP, but the difference was not statistically significant. The results suggest that the mechanism of protection afforded by melatonin against lesions induced by gastric ischemia-reperfusion may be due to stimulation of the synthesis of eicosanoid protectors during the ischemic process.

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“…Due to their role in the pathophysiological mechanisms underlying some relevant inflammatory disorders, the possible interaction between NO and PG biosynthetic pathways has been studied to verify a possible combined approach in the treatment of many disease states (Fig. 4) (Abramson et al, 2001;Mebazaa et al, 2001;Beierwaltes, 2002;Davel et al, 2002;Gallo et al, 2002;Naoki et al, 2002;Sanchez et al, 2002;Shinmura et al, 2002;Takeuchi et al, 2002;VayssettesCourchay et al, 2002;Kawabe et al, 2003;Slomiany and Slomiany, 2003).…”

Section: A Nitric Oxide/cyclooxygenase Reciprocal Interactionsmentioning

confidence: 99%

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

Muscoli²,

et al. 2005

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Role of prostaglandins and nitric oxide in gastric damage induced by metamizol in rats

Abstract: In addition to inhibition of PG synthesis, damage induced by metamizol was associated with an inhibition of the NO/cGMP pathway and cNOS activity. In contrast, diclofenac-induced gastric damage was associated with an increase of the inflammatory response.

Cited by 15 publications

References 47 publications

Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic

Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic

Melatonin Modulates the Effects of Gastric Injury in Rats: Role of Prostaglandins and Nitric Oxide

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

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