Geis G S
Department of Clinical Research, G.D. Searle & Co., Skokie, Illinois 60077, USA.
J Rheumatol Suppl. 1999 Apr;56:31-6.
Nonsteroidal antiinflammatory drugs (NSAID) are effective for the relief of pain and inflammation, yet their use is tempered by the development of side effects, primarily in the gastrointestinal (GI) tract. It is now known that inhibition of the enzyme cyclooxygenase (COX) is the principal mechanism for both the efficacy and the toxicity of NSAID. Recent research has shown that COX exists as at least two isoenzymes, COX-1 and COX-2. Compelling evidence suggests that COX-1 synthesizes prostaglandins that are involved in the regulation of normal cell activity (including G1 cytoprotection), whereas COX-2 appears to produce prostaglandins mainly at sites of inflammation. These findings led to the search for compounds that would inhibit COX-2 without affecting COX-1. Several agents are under investigation in this new therapeutic category, including celecoxib (SC-58635). Celecoxib was developed as an antiinflammatory and analgesic agent, and has been studied in preclinical studies and in clinical trials. This paper focuses on the results of 5 key clinical trials of celecoxib: an efficacy trial in dental pain, a 2 week osteoarthritis (OA) efficacy trial, a 4 week rheumatoid arthritis (RA) efficacy trial, a one week endoscopic study of GI mucosal effects, and a 10 day study of effects on platelet function. The arthritis trials identified celecoxib doses that were effective in treating OA and RA and that were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, no ulcers occurred in subjects receiving celecoxib or placebo, whereas 19% of subjects receiving naproxen developed gastric ulcers. In the platelet effects trial, no statistically significant difference from placebo was seen in the effect of celecoxib on platelet aggregation or bleeding time. In contrast, naproxen caused statistically significant reductions in platelet aggregation and a statistically significant increase in bleeding time. These preliminary trials show that celecoxib achieves analgesic and antiinflammatory efficacy in arthritis through specific COX-2 inhibition without showing evidence of two of the toxic effects of COX-1 inhibition associated with NSAID.
非甾体抗炎药（NSAID）对缓解疼痛和炎症有效，但其使用因副作用的出现而受到限制，主要是在胃肠道（GI）。现在已知抑制环氧化酶（COX）是NSAID疗效和毒性的主要机制。最近的研究表明，COX至少以两种同工酶COX-1和COX-2的形式存在。有力证据表明，COX-1合成参与正常细胞活动调节（包括G1细胞保护）的前列腺素，而COX-2似乎主要在炎症部位产生前列腺素。这些发现促使人们寻找能够抑制COX-2而不影响COX-1的化合物。几种药物正在这一新的治疗类别中进行研究，包括塞来昔布（SC-58635）。塞来昔布被开发为一种抗炎和镇痛药，并已在临床前研究和临床试验中进行了研究。本文重点关注塞来昔布的5项关键临床试验结果：一项牙科疼痛疗效试验、一项为期2周的骨关节炎（OA）疗效试验、一项为期4周的类风湿性关节炎（RA）疗效试验、一项为期一周的GI黏膜效应内镜研究以及一项为期10天的血小板功能影响研究。关节炎试验确定了对治疗OA和RA有效的塞来昔布剂量，并且在标准关节炎量表上与安慰剂有区别。在上消化道内镜研究中，接受塞来昔布或安慰剂的受试者未出现溃疡，而接受萘普生的受试者中有19%出现胃溃疡。在血小板效应试验中，塞来昔布对血小板聚集或出血时间的影响与安慰剂相比无统计学显著差异。相比之下，萘普生导致血小板聚集有统计学显著降低，出血时间有统计学显著增加。这些初步试验表明，塞来昔布通过特异性抑制COX-2在关节炎中实现了镇痛和抗炎疗效，而未显示出与NSAID相关的COX-1抑制的两种毒性作用的证据。
