Coruzzi G, Menozzi A, Dobrilla G
Department of Human Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology, University of Parma, Parma, Italy.
Curr Drug Targets Inflamm Allergy. 2004 Mar;3(1):43-61. doi: 10.2174/1568010043483971.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently associated with serious adverse effects related to the inhibition of cyclooxygenase (COX) in tissues where prostanoids exert physiological effects, such as gastric mucosal defence, renal homeostasis and platelet aggregation. The discovery of a second COX isoform (COX-2) specifically induced in pathological tissues led to the development of selective COX-2 inhibitors, believed to have an improved safety profile compared to traditional NSAIDs. Animal studies, however, have revealed a protective role for the COX-2 enzyme in the stomach, kidney, heart, vasculature and reproductive system, and therefore, the safety of COX-2 selective inhibitors needs to be reassessed. On the other hand, new therapeutic indications have emerged as a result of the role played by COX-2 overexpression in cancer or Alzheimer's disease. A second approach aimed at obtaining safer NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional NSAIDs chemically linked to NO-releasing moieties retain the therapeutic efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional therapeutic applications in cardiovascular diseases, Alzheimer's disease and cancer have been suggested. Animal data, however, need to be confirmed in large clinical trials. Finally, the increase in endogenous NO via a selective increase in inducible NO synthase in the gastric mucosa is the mechanism underlying the good gastric tolerability and the gastroprotective effects of the non-selective NSAID amtolmetin guacyl, documented to date in the rat.
非甾体抗炎药（NSAIDs）的使用常常与严重不良反应相关，这些不良反应与在前列腺素发挥生理作用的组织（如胃黏膜防御、肾脏内环境稳定和血小板聚集）中抑制环氧化酶（COX）有关。在病理组织中特异性诱导产生的第二种COX同工型（COX-2）的发现，促使了选择性COX-2抑制剂的研发，人们认为与传统NSAIDs相比，其安全性有所改善。然而，动物研究表明COX-2酶在胃、肾、心脏、血管系统和生殖系统中具有保护作用，因此，COX-2选择性抑制剂的安全性需要重新评估。另一方面，由于COX-2过表达在癌症或阿尔茨海默病中所起的作用，出现了新的治疗适应症。旨在获得更安全NSAIDs的另一种方法基于一氧化氮（NO）的胃保护作用。与释放NO的部分化学连接的传统NSAIDs保留了母体NSAIDs的治疗效果，但没有其不良反应。此外，还提出了在心血管疾病、阿尔茨海默病和癌症中的其他治疗应用。然而，动物数据需要在大型临床试验中得到证实。最后，通过选择性增加胃黏膜中诱导型NO合酶来增加内源性NO，是迄今为止在大鼠中记录的非选择性NSAID安托美汀胍基良好胃耐受性和胃保护作用的潜在机制。
