Dvornik D, Lee D K
Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
Clin Rheumatol. 1989 Mar;8 Suppl 1:16-24. doi: 10.1007/BF02214106.
The high concentrations of pro-inflammatory prostaglandins (PGs) produced in the joint during the initial stage of inflammation can be decreased by inhibiting their biosynthesis with nonsteroidal anti-inflammatory drugs (NSAIDs). The commonly encountered gastrointestinal intolerance in human subjects treated with NSAIDs is generally attributed to inhibition of PG synthesis in gastric mucosa, where the natural role of locally biosynthesized PGs is to protect the mucosa from necrosis upon exposure to noxious agents. The action of an ideal NSAID should therefore be tissue specific, i.e., it should inhibit PG formation at the sites of inflammation but not in gastric mucosa, where PGs are needed for cytoprotection. We believe that etodolac, a new, structurally distinct NSAID, meets this criterion, inhibiting PG synthesis in a tissue-specific fashion. Experimental data supporting this interpretation were obtained in rats by demonstrating that daily administration of orally effective anti-inflammatory doses of etodolac had no significant effect on gastric mucosal PGE2 or prostacyclin levels (measured as the stable metabolite, 6-keto-PGF1 alpha). In contrast, naproxen, piroxicam, and aspirin caused a statistically significant PG depletion. The results obtained in rats thus support the view that the favorable gastrointestinal safety profile of etodolac in human patients may be attributable to selective sparing of the cytoprotective PGs in gastric mucosa.
在炎症初始阶段关节中产生的高浓度促炎前列腺素（PGs），可通过使用非甾体抗炎药（NSAIDs）抑制其生物合成来降低。接受NSAIDs治疗的人类受试者中常见的胃肠道不耐受，通常归因于胃黏膜中PG合成的抑制，在胃黏膜中，局部生物合成的PG的天然作用是保护黏膜免受接触有害剂时的坏死。因此，理想的NSAID的作用应该是组织特异性的，即它应该在炎症部位抑制PG形成，但不在胃黏膜中抑制，在胃黏膜中PG对于细胞保护是必需的。我们认为依托度酸，一种新型的、结构独特的NSAID，符合这一标准，以组织特异性方式抑制PG合成。通过证明每日口服有效抗炎剂量的依托度酸对胃黏膜PGE2或前列环素水平（以稳定代谢物6-酮-PGF1α测量）没有显著影响，在大鼠中获得了支持这一解释的实验数据。相比之下，萘普生、吡罗昔康和阿司匹林导致了统计学上显著的PG消耗。因此，在大鼠中获得的结果支持这样的观点，即依托度酸在人类患者中良好的胃肠道安全性可能归因于对胃黏膜中细胞保护PG的选择性保留。
