Jackson L M, Hawkey C J
Department of Medicine, University Hospital Nottingham, England.
Drugs. 2000 Jun;59(6):1207-16. doi: 10.2165/00003495-200059060-00001.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for substantial morbidity and mortality as a result of the complications associated with gastroduodenal ulcers, such as perforation and bleeding. The central mechanism leading to the gastroduodenal toxicity of NSAIDs is their ability to inhibit mucosal prostaglandin synthesis. Recent recognition that there are 2 isoforms of the enzyme cyclooxygenase (COX) responsible for prostaglandin synthesis has enabled the development of drugs capable of sparing the gastric mucosa. The inducible COX-2 enzyme is responsible for some aspects of pain and inflammation in arthritis while the constitutive COX-1 enzyme appears responsible for most of the gastro-protective prostaglandin synthesis in the stomach and duodenum. Drugs selective for COX-2 probably act by binding to a pocket in the enzyme that is present in COX-2 but not in COX-1. As a result, drugs that have little or no COX-1 activity across their therapeutic dosage range have been developed. Two drugs that are claimed to be highly selective or specific in their ability to inhibit COX-2, rofecoxib and celecoxib, are now available on prescription in the US and rofecoxib is available in Europe. Short term volunteer studies of 7 days' duration and patient studies of 6 months' duration have shown these drugs to have a level of gastroduodenal injury that is similar or equivalent to that seen with placebo, whereas high rates of damage and ulceration are seen with nonselective NSAIDs. In addition, there appear to have been fewer perforations, clinical ulcers and bleeds in the phase III clinical trials of these agents, compared with nonselective NSAIDS. However, more experience will be needed before this promise can be confirmed. In addition, COX-2 inhibitors share the adverse effects of NSAIDs outside the gastrointestinal tract that are dependent on COX-2 inhibition.
非甾体抗炎药（NSAIDs）由于与胃十二指肠溃疡相关的并发症（如穿孔和出血）而导致大量发病和死亡。导致NSAIDs胃十二指肠毒性的核心机制是它们抑制黏膜前列腺素合成的能力。最近认识到有两种负责前列腺素合成的环氧化酶（COX）同工型，这使得能够开发出可保护胃黏膜的药物。诱导型COX-2酶负责关节炎疼痛和炎症的某些方面，而组成型COX-1酶似乎负责胃和十二指肠中大部分具有胃保护作用的前列腺素合成。对COX-2有选择性的药物可能通过与COX-2中存在但COX-1中不存在的酶口袋结合而起作用。结果，已开发出在其治疗剂量范围内对COX-1几乎没有或没有活性的药物。两种据称在抑制COX-2能力方面具有高度选择性或特异性的药物，罗非昔布和塞来昔布，目前在美国可凭处方获得，罗非昔布在欧洲也可获得。为期7天的短期志愿者研究和为期6个月的患者研究表明，这些药物的胃十二指肠损伤水平与安慰剂相似或相当，而非选择性NSAIDs则会出现高比率的损伤和溃疡。此外，与非选择性NSAIDs相比，这些药物在III期临床试验中的穿孔、临床溃疡和出血似乎较少。然而，在这一前景得到证实之前，还需要更多的经验。此外，COX-2抑制剂在胃肠道外也有NSAIDs依赖于COX-2抑制的不良反应。
