Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response.
Nonsteroidal anti-inflammatory drugs (NSAID) are well known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and animals too. These effects are related with the inhibition of the enzyme cyclooxygenase, which is the main established mechanism of action for these drugs. Fasted rats were given piroxicam, preferential COX-1 inhibitor (10-20 mg/kg) or meloxicam, preferential COX-2 inhibitor (7.5-15 mg/kg) orally. Six or nine hours (h) later, respectively, the stomach was excised, the severity of the damage assessed and myeloperoxidase (MPO) activity measured, as well as prostaglandin PGE(2) content. Furthermore, in order to assess the effects of these oxicams over previously damaged gastric mucosa, 1 ml of 0.6 N HCl was administered p.o. followed, 1 h after, of the correspondent dose of each NSAID, and the same parameters were determined. Oral administration of both drugs dose-dependently caused acute gastric haemorrhage erosions. Myeloperoxidase activity was significantly increased by piroxicam administration. In addition, PGE(2) content was significantly reduced. The association between the administration of the acid and NSAID caused a worsening of the damage and, while myeloperoxidase activity did not modify by both piroxicam and meloxicam, PGE(2) levels were reduced. These results suggest that the PG derived from both COX-1 and COX-2 pathway plays a beneficial role in the gastroprotection, and thus caution should be exercise in the clinical use of preferential COX-2 inhibitors.
Villegas
Isabel
I
Department of Pharmacology, Faculty of Pharmacy, University of Seville, P. García González Street, 41012-Seville, Spain.
La Casa
Carmen
C
de la Lastra
Catalina Alarcón
CA
Motilva
Virginia
V
Herrerías
Juan Manuel
JM
Martín
María José
MJ
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D006851:Hydrochloric Acid / Q000633:toxicity; D008297:Male; D000077239:Meloxicam; D009195:Peroxidase / Q000378:metabolism; D010894:Piroxicam / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D013843:Thiazines / Q000008:administration & dosage / Q000633:toxicity*; D013844:Thiazoles / Q000008:administration & dosage / Q000633:toxicity*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; D009195:Peroxidase; D015232:Dinoprostone; D006851:Hydrochloric Acid; D000077239:Meloxicam