Everts B, Währborg P, Hedner T
Department of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, Sweden.
Clin Rheumatol. 2000;19(5):331-43. doi: 10.1007/s100670070024.
The prostaglandin series of bioactive compounds is formed by the interaction of two distinct but related enzymes, cyclo-oxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutive form which is present mainly in the gastric mucosa, kidney and platelets. COX-2 is mainly an inducible form, although also to some extent present constitutively in the CNS, the juxtaglomerular apparatus of the kidney and in the placenta during late gestation. Both isoforms contribute to the inflammatory process, but COX-2 is of considerable therapeutic interest as it is induced, resulting in an enhanced formation of prostaglandins, during acute as well as chronic inflammation. Conventional NSAIDs inhibit both isoforms to a similar extent and in an approximately equal dose and concentration range. The two recently developed and clinically available selective COX-2 inhibitors, celecoxib and rofecoxib, are about 100-1000 times more selective on the COX-2 than on the COX-1 isoform. In Europe rofecoxib is today indicated for the symptoms and signs of osteoarthritis, whereas celecoxib is indicated for both osteoarthritis and rheumatoid arthritis. The major clinical interest of these drugs has been related to the lower incidence of gastrointestinal bleeding which, with the conventional COX-1/COX-2 agents has been a source of hospitalisation, disablement and death, especially in the elderly. Clinical trials have convincingly demonstrated that celecoxib and rofecoxib in clinical use induce very few gastrointestinal complications compared to conventional and non-selective NSAIDs. However, the well known contraindications for NSAIDs, such as late pregnancy, aspirin-induced asthma, congestive heart failure and renal dysfunction, will so far apply also to the COX-2 inhibitors. Compared to the traditional and non-selective NSAIDs, COX-2 inhibitors may provide an insight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecoxib and rofecoxib, knowledge about their clinical usefulness in various inflammatory disease states and pain disorders is increasing. For the many patients suffering from such conditions, the selective COX-2 inhibitors are likely to become a significant addition to the therapeutic arsenal of analgesic and anti-inflammatory drugs.
生物活性化合物前列腺素系列是由两种不同但相关的酶——环氧化酶-1（COX-1）和环氧化酶-2（COX-2）相互作用形成的。COX-1是一种组成型形式，主要存在于胃黏膜、肾脏和血小板中。COX-2主要是一种诱导型形式，不过在中枢神经系统、肾脏的肾小球旁器以及妊娠晚期的胎盘中也有一定程度的组成型存在。两种同工型都参与炎症过程，但COX-2具有相当大的治疗意义，因为在急性和慢性炎症期间它会被诱导，导致前列腺素生成增加。传统的非甾体抗炎药（NSAIDs）对两种同工型的抑制程度相似，且在大致相同的剂量和浓度范围内。最近研发并已临床应用的两种选择性COX-2抑制剂塞来昔布和罗非昔布，对COX-2的选择性比对COX-1同工型高约100 - 1000倍。在欧洲，罗非昔布目前用于治疗骨关节炎的症状和体征，而塞来昔布则用于治疗骨关节炎和类风湿关节炎。这些药物的主要临床意义在于胃肠道出血的发生率较低，而使用传统的COX-1/COX-2药物时，胃肠道出血一直是住院、致残和死亡的一个原因，在老年人中尤为如此。临床试验令人信服地证明，与传统的非选择性NSAIDs相比，临床使用的塞来昔布和罗非昔布引起的胃肠道并发症极少。然而，到目前为止，NSAIDs众所周知的禁忌证，如晚期妊娠、阿司匹林诱发的哮喘、充血性心力衰竭和肾功能不全，同样也适用于COX-2抑制剂。与传统的非选择性NSAIDs相比，COX-2抑制剂可能为其他治疗领域提供思路，如胃肠道癌症和痴呆症，目前正在探索其与COX-2机制的潜在相关性并进行临床试验。随着塞来昔布和罗非昔布在临床上迅速被接受，关于它们在各种炎症性疾病状态和疼痛病症中的临床效用的知识也在不断增加。对于许多患有此类病症的患者来说，选择性COX-2抑制剂很可能会成为镇痛和抗炎药物治疗武器库中的重要补充。
