Harvard Medical School, Deaconess Hospital, and Massachusetts General Hospital, Boston, Massachusetts.
J Clin Rheumatol. 1996 Jun;2(3):135-40. doi: 10.1097/00124743-199606000-00005.
New information about the mechanisms of action of nonsteroidal antiinflammatory drugs (NSAIDs) offers potential opportunities to minimize the complications of these commonly used drugs. Traditionally, the accepted mode of action of the NSAIDs has been the inhibition of prostaglandin synthesis through either reversible or irreversible binding to cyclooxygenase (COX). However, drugs that are weak prostaglandin synthesis inhibitors in vitro have been demonstrated to be equally as effective in vivo as other "stronger" COX inhibitors in treating inflammatory diseases, suggesting the importance of other actions of these drugs. Various NSAIDs have been used for years to palliate pain and inflammation in many different disease processes; unfortunately, they have not been demonstrated to alter the natural history of disease such as rheumatoid arthritis. Perhaps that is because prostaglandins do not play a large role in most inflammatory diseases; alternatively, it might be attributable to the inability of NSAIDs to exert their full effects because of their potential toxic reactions.An understanding of the effects of cyclooxygenase inhibition has been further complicated by the recently described second isoenzyme of prostaglandin synthase. One form of cyclooxygenase appears to be important in the maintenance of normal physiologic functions (COX-1), whereas the other form is induced primarily in sites of inflammation (COX-2). Even if inhibition of cyclooxygenase is only one mechanism of action for these drugs, with only some of the potential toxic effects modulated by the inhibition of prostaglandin synthesis such as inhibition of COX-1, an understanding of the actions of the two isoforms of cyclooxygenase is an important step in further delineating the inflammatory cascade. Ideally, the treatment of inflammation could be improved by inhibiting the effects of COX-2 without inhibiting COX-1 activity. Thus, some potential side effects of the NSAIDs might be alleviated. The presently available NSAIDs all affect both COX-1 and COX-2, although not equally. There are also data describing some of the NSAIDs as less toxic to the gastrointestinal mucosa because of their chemical composition. These data are typically based on in vitro experiments that use varying methodologies, making it difficult to compare the effects of any one NSAID between studies.This paper presents a brief review of several of the newly described effects of the NSAIDs and concentrates on the possible implications of the experimentally observed COX-2-selective effects of these clinically useful antiinflammatory agents.
关于非甾体抗炎药（NSAIDs）作用机制的新信息为将这些常用药物的并发症最小化提供了潜在的机会。传统上，NSAIDs 的作用模式一直是通过可逆或不可逆地与环氧化酶（COX）结合来抑制前列腺素合成。然而，体外弱前列腺素合成抑制剂已被证明与其他“更强” COX 抑制剂一样有效，可用于治疗炎症性疾病，这表明这些药物的其他作用很重要。各种 NSAIDs 多年来一直用于缓解许多不同疾病过程中的疼痛和炎症；不幸的是，它们并没有被证明能够改变疾病的自然病程，例如类风湿关节炎。也许是因为前列腺素在大多数炎症性疾病中不起重要作用；或者，这可能归因于 NSAIDs 由于潜在的毒性反应而无法发挥其全部作用。对环氧化酶抑制作用的理解由于最近描述的前列腺素合酶第二种同工酶而变得更加复杂。一种形式的环氧化酶似乎对维持正常生理功能很重要（COX-1），而另一种形式主要在炎症部位诱导（COX-2）。即使环氧化酶抑制仅是这些药物的一种作用机制，并且只有一些潜在的毒性作用通过抑制前列腺素合成来调节，例如 COX-1 的抑制，对两种同工酶的作用的理解是进一步阐明炎症级联的重要步骤。理想情况下，可以通过抑制 COX-2 的作用而不抑制 COX-1 的活性来改善炎症的治疗。因此，一些 NSAIDs 的潜在副作用可能会减轻。目前可用的 NSAIDs 都影响 COX-1 和 COX-2，尽管程度不同。也有数据描述了一些 NSAIDs 对胃肠道黏膜的毒性较小，因为它们的化学成分。这些数据通常基于使用不同方法学的体外实验，使得很难在研究之间比较任何一种 NSAID 的效果。本文简要回顾了 NSAIDs 的一些新描述的作用，并集中讨论了这些临床上有用的抗炎药物中实验观察到的 COX-2 选择性作用的可能影响。
