Hinz B, Brune K
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen.
Anaesthesist. 2000 Nov;49(11):964-71. doi: 10.1007/s001010070032.
The therapeutic and unwanted side effects of non-steroidal antiinflammatory drugs (NSAIDs) are attributable to inhibition of the cyclooxygenase (COX) enzyme which catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a 'housekeeping' enzyme in most tissues. In contrast, COX-2 can be upregulated by various proinflammatory agents, including endotoxin, cytokines and growth factors. Whereas many of the side effects of NSAIDs (e.g. gastrointestinal ulceration and bleeding, platelet dysfunctions) are due to a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic and antipyretic effects of NSAIDs. Thus, the hypothesis that specific inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of specific inhibitors of the COX-2 enzyme as a new class of anti-inflammatory and analgesic agents with improved gastrointestinal tolerability. However, the simple concept that COX-2 is an exclusively proinflammatory and inducible enzyme cannot be supported any longer. Recently, COX-2 was shown to be also expressed under basal conditions in organs such as the ovary, uterus, brain, spinal cord, kidney and bone, suggesting that this isoenzyme may play a more complex physiological role than was expected. The present review assesses concept and molecular mechanism underlying specific COX-2 inhibition as well as indications, pharmakokinetics and unwanted side effects of the recently approved specific COX-2 inhibitors celecoxib and rofecoxib. Moreover, recent advances in COX-2 research, with particular emphasis on new insights into physiological functions of this isoenzyme will be discussed.
非甾体抗炎药（NSAIDs）的治疗作用和不良副作用归因于对环氧化酶（COX）的抑制，该酶催化前列腺素合成的第一步。20世纪90年代初，COX被证明以两种不同的同工型存在。COX-1在大多数组织中作为一种“管家”酶组成性表达。相比之下，COX-2可被多种促炎剂上调，包括内毒素、细胞因子和生长因子。虽然NSAIDs的许多副作用（如胃肠道溃疡和出血、血小板功能障碍）是由于COX-1活性受到抑制，但抑制COX-2衍生的前列腺素可促进NSAIDs的抗炎、镇痛和解热作用。因此，特异性抑制COX-2可能具有与NSAIDs相似的治疗作用，但不会引起不良副作用这一假说，是开发COX-2酶特异性抑制剂作为一类具有更好胃肠道耐受性的新型抗炎和镇痛药的理论基础。然而，COX-2是一种完全促炎且可诱导的酶这一简单概念已不再成立。最近发现，COX-2在卵巢、子宫、脑、脊髓、肾和骨等器官的基础条件下也有表达，这表明该同工酶可能发挥比预期更复杂的生理作用。本综述评估了特异性COX-2抑制的概念和分子机制，以及最近批准的特异性COX-2抑制剂塞来昔布和罗非昔布的适应证、药代动力学和不良副作用。此外，还将讨论COX-2研究的最新进展，特别强调对该同工酶生理功能的新见解。
