Effects of pantoprazole on ulcer healing delay associated with NSAID treatment.
Nonsteroidal anti-inflammatory drugs delay gastric ulcer healing, and the ability of proton pump inhibitors to counteract this detrimental effect is debated. This study evaluates the effects of pantoprazole on experimental gastric ulcer healing in the presence of indomethacin. Rats with acetic-acid-induced gastric ulcers were orally treated for 3 or 7 days with pantoprazole (15 micromol/kg/day) or famotidine (20 micromol/kg/day), alone or in combination with indomethacin (3 micromol/kg/day). Ulcerated tissues were processed to assess ulcer area, malondialdehyde, proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Experiments on pylorus-ligated rats indicated that pantoprazole and famotidine were employed at equivalent inhibitory doses on gastric acid secretion (-67.9% and -64.5%, respectively). Indomethacin delayed ulcer healing both at days 3 and 7 (+22 and +35 mm(2) vs control ulcer, respectively). At day 3, pantoprazole was more effective than famotidine in promoting ulcer healing in indomethacin-treated animals (-53.6 and -31.6 mm(2) vs indomethacin, respectively). Malondialdehyde levels and caspase-3 activation in ulcers were increased by indomethacin (+79% and +3.7 folds vs control ulcer, respectively), and these effects were counteracted by pantoprazole (-77.9% and -3.5 folds vs indomethacin, respectively), but not famotidine. Increments of ulcer PCNA expression (+2.5 folds vs normal) were enhanced further by pantoprazole or famotidine, alone or in combination with indomethacin (+8.6 and +10.3 folds vs normal, respectively). Similar results were obtained after 7-day treatments of ulcerated animals with test drugs. It is concluded that, along with acid suppression, pantoprazole exerts acid-independent effects on ulcer healing, which can be ascribed to a decrease in tissue oxidation and apoptosis.
Fornai
Matteo
M
Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Colucci
Rocchina
R
Antonioli
Luca
L
Ghisu
Narcisa
N
Tuccori
Marco
M
Blandizzi
Corrado
C
Del Tacca
Mario
M
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019342:Acetic Acid; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D015738:Famotidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005744:Gastric Acid / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D000077402:Pantoprazole; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013276:Stomach Ulcer / Q000378:metabolism / Q000517:prevention & control*; D014945:Wound Healing / Q000187:drug effects*
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D018809:Proliferating Cell Nuclear Antigen; D054328:Proton Pump Inhibitors; D015738:Famotidine; D000077402:Pantoprazole; D053148:Caspase 3; D019342:Acetic Acid