Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
PLoS One. 2012;7(4):e35196. doi: 10.1371/journal.pone.0035196. Epub 2012 Apr 9.
Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co-administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co-morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence.
非甾体抗炎药是最常用的处方药和非处方药之一，但它们经常导致严重的胃肠道溃疡和出血，尤其是在老年患者和患有某些合并症的患者中。新型抗炎药很少在模拟高风险人类使用者的动物模型中进行测试，导致对药物真正毒性的低估。在本研究中，我们在预计粘膜防御受损的模型中检查了两种新型 NSAID 和两种常用 NSAID 的作用。萘普生、塞来昔布、ATB-346（一种释放硫化氢和萘普生的化合物）和 NCX 429（一种释放一氧化氮和萘普生的化合物）在健康、关节炎、肥胖和高血压大鼠以及高龄（19 个月）大鼠和同时给予低剂量阿司匹林和/或奥美拉唑的大鼠中进行了评估。除高血压外，在这些模型中给予萘普生时，观察到比健康大鼠更大的胃和/或肠道损伤。当与低剂量阿司匹林和/或奥美拉唑同时给予时，塞来昔布引起的损伤显著增加。相比之下，ATB-346 和 NCX 429，在测试剂量与萘普生和塞来昔布相同有效，可减轻炎症和抑制环氧化酶活性时，在任何模型中均未引起明显的胃或肠道损伤。这些结果表明，人类合并症的动物模型显示出与人类观察到的相同的对 NSAID 诱导的胃肠道损伤的易感性增加。此外，两种释放粘膜防御介质（硫化氢和一氧化氮）的新型 NSAID 在这些粘膜防御受损的模型中不会引起明显的胃肠道损伤。
