Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
J Pharmacol Exp Ther. 2011 Sep;338(3):850-9. doi: 10.1124/jpet.111.183293. Epub 2011 Jun 24.
Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.
最近的临床研究表明，选择性 5-羟色胺（5-HT）再摄取抑制剂（SSRIs）与非甾体抗炎药（NSAIDs）同时使用会有引起不良反应的风险。我们研究了 SSRIs 对吲哚美辛引起的大鼠胃窦病变的影响。大鼠禁食 24 小时后恢复进食 1 小时，然后在恢复进食后 1 小时给予吲哚美辛（30mg/kg 皮下注射），6 小时后处死。帕罗西汀（1-10mg/kg）在给予吲哚美辛前 30 分钟口服给予。吲哚美辛引起了再喂养大鼠的胃窦病变。帕罗西汀剂量依赖性地加重了这些病变，尽管它本身不会引起损伤。当其他 NSAIDs 如双氯芬酸、氟比洛芬和洛索洛芬与帕罗西汀一起给予，或当吲哚美辛与其他抗抑郁药如氟伏沙明和米那普仑一起给予，而不是与丙咪嗪或马普替林一起给予时，也得到了类似的结果。外源性 5-HT 也加重了吲哚美辛引起的胃窦损伤，而帕罗西汀的加重作用被 5-HT3 拮抗剂昂丹司琼减弱，但不是其他 5-HT 受体亚型的拮抗剂。吲哚美辛加帕罗西汀对胃分泌没有影响，但显著降低了黏膜超氧化物歧化酶（SOD）活性和 GSH 含量。抗分泌（酸或胃蛋白酶）剂和黏膜保护剂以及 SOD 和别嘌醇显著预防了吲哚美辛加帕罗西汀引起的胃窦损伤。这些结果表明，SSRIs 加重了 NSAID 引起的胃窦病变，可能是通过激活 5-HT3 受体，而加重的机制可能涉及酸/胃蛋白酶的腐蚀性作用以及抗氧化系统受损。
