Fornai Matteo, Colucci Rocchina, Antonioli Luca, Ghisu Narcisa, Tuccori Marco, Blandizzi Corrado, Del Tacca Mario
Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 2009 Mar;379(3):305-13. doi: 10.1007/s00210-008-0355-y. Epub 2008 Oct 14.
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.
非甾体抗炎药会延迟胃溃疡的愈合，而质子泵抑制剂抵消这种有害作用的能力存在争议。本研究评估泮托拉唑在吲哚美辛存在的情况下对实验性胃溃疡愈合的影响。用醋酸诱导胃溃疡的大鼠，单独或与吲哚美辛（3微摩尔/千克/天）联合，口服泮托拉唑（15微摩尔/千克/天）或法莫替丁（20微摩尔/千克/天）3天或7天。对溃疡组织进行处理以评估溃疡面积、丙二醛、增殖细胞核抗原（PCNA）和裂解的半胱天冬酶-3。对幽门结扎大鼠的实验表明，泮托拉唑和法莫替丁在胃酸分泌的等效抑制剂量下使用（分别为-67.9%和-64.5%）。吲哚美辛在第3天和第7天均延迟溃疡愈合（分别比对照溃疡大+22和+35平方毫米）。在第3天，泮托拉唑在促进吲哚美辛治疗动物的溃疡愈合方面比法莫替丁更有效（分别比吲哚美辛组小-53.6和-31.6平方毫米）。吲哚美辛使溃疡中的丙二醛水平和半胱天冬酶-3活化增加（分别比对照溃疡高+79%和+3.7倍），这些作用被泮托拉唑抵消（分别比吲哚美辛组低-77.9%和-3.5倍），但未被法莫替丁抵消。溃疡PCNA表达的增加（比正常高+2.5倍）在泮托拉唑或法莫替丁单独或与吲哚美辛联合使用时进一步增强（分别比正常高+8.6和+10.3倍）。用受试药物对溃疡动物进行7天治疗后获得了类似结果。得出的结论是，除了抑制胃酸外，泮托拉唑对溃疡愈合还发挥非酸依赖性作用，这可归因于组织氧化和细胞凋亡的减少。
