Elliott S N, McKnight W, Davies N M, MacNaughton W K, Wallace J L
Department of Pharmacology, University of Calgary, Alberta, Canada.
Life Sci. 1998;62(1):77-91. doi: 10.1016/s0024-3205(97)01040-0.
Gastric ulceration associated with the use of NSAIDs is most frequently observed in elderly women, the same sector of society most likely to be receiving therapy for osteoporosis. As some anti-osteoporosis medications have been suggested to irritate the upper gastrointestinal mucosa, we evaluated the ability of one such drug, alendronate, to damage the gastric mucosa and to influence the severity and healing of gastric ulcers in rodents. The effects of alendronate on indomethacin-induced antral ulceration was evaluated in the rabbit, while effects on ulcer healing and on the formation of gastric erosions was evaluated in the rat. Effects of alendronate on gastric acid secretion, blood flow and prostaglandin synthesis were also evaluated. Alendronate caused erosions in the rabbit stomach, but not antral ulceration. However, at the highest doses tested (80 mg) alendronate increased the incidence and size of indomethacin-induced antral ulcers. Alendronate also enhanced indomethacin-induced gastric damage in the rat, and delayed gastric ulcer healing. These effects of alendronate were not attributable to changes in gastric acid secretion, blood flow, prostaglandin synthesis or the pharmacokinetics of indomethacin. The damaging effects of alendronate on the stomach were due to topical irritant effects and could be observed at concentrations as low as 4 mg/ml within 30 min of oral administration or topical superfusion. These results support preliminary clinical evidence that alendronate can damage the gastric mucosa. While gastric injury may be a rare occurrence in patients taking this drug, concomitant use of alendronate and NSAIDs may increase the incidence or severity of ulceration.
与使用非甾体抗炎药相关的胃溃疡最常见于老年女性，而这一社会群体也是最有可能接受骨质疏松症治疗的人群。由于一些抗骨质疏松药物被认为会刺激上消化道黏膜，我们评估了其中一种药物阿仑膦酸钠对啮齿动物胃黏膜的损伤作用以及对胃溃疡严重程度和愈合的影响。在兔子身上评估了阿仑膦酸钠对吲哚美辛诱导的胃窦溃疡的影响，同时在大鼠身上评估了其对溃疡愈合和胃糜烂形成的影响。还评估了阿仑膦酸钠对胃酸分泌、血流量和前列腺素合成的影响。阿仑膦酸钠在兔子胃中引起糜烂，但未导致胃窦溃疡。然而，在测试的最高剂量（80毫克）下，阿仑膦酸钠增加了吲哚美辛诱导的胃窦溃疡的发生率和大小。阿仑膦酸钠还增强了吲哚美辛在大鼠中诱导的胃损伤，并延迟了胃溃疡的愈合。阿仑膦酸钠的这些作用并非归因于胃酸分泌、血流量、前列腺素合成或吲哚美辛的药代动力学变化。阿仑膦酸钠对胃的损伤作用是由于局部刺激作用，在口服给药或局部灌注30分钟内，低至4毫克/毫升的浓度即可观察到。这些结果支持了阿仑膦酸钠可损伤胃黏膜的初步临床证据。虽然服用该药物的患者中胃损伤可能很少见，但同时使用阿仑膦酸钠和非甾体抗炎药可能会增加溃疡的发生率或严重程度。
