Franchi A, Di Girolamo G, de los Santos A R, Marti M L, Gimeno M A
Centro de Estudios Farmacológicos y Botánicos (CEFYBO).
Medicina (B Aires). 1998;58(3):291-4.
The non-steroidal anti-inflammatory drugs (NSAIDS) induced ulcerations in the gastrointestinal tract are possibly associated with the reduction in prostaglandin (PGs) synthesis due to the inhibition of cyclooxygenase. On the other hand, it has been shown that 5-lipooxygenase products (5-LO) are ulcerogenic agents. In some cases, the utilization of NSAIDS stimulates 5-LO pathway to an excess of arachidonic acid because of cyclooxygenase inhibition. In these cases, the damage produced by NSAIDS is greater, since not only the cytoprotective PGs decrease but also the products of 5-LO are increased. The object of the present paper was to study the effects of lysine clonixinate (LC) and indomethacin (INDO) on PGs and 5-HETE synthesis. The concentrations used of LC (4 and 6 micrograms/ml) and INDO (0.035 micrograms/ml and 0.35 micrograms/ml) correspond to the plasmatic values reached with oral therapeutic doses for both drugs. The results show that in no case did LC reduce the production of PGE2. On the contrary INDO inhibited significantly the synthesis of PGe2. It is interesting to mention that LC 4 and 6 micrograms/ml inhibited drastically the production of 5-HETE. Only with the higher concentration of INDO did we observe a similar effect. These results may indicate an inhibitory action on 5-LO, the first enzyme in the metabolic pathway of arachidonic acid in the production of HETEs and LTS. We conclude that LC in therapeutic doses has a mechanism of action different from the classical NSAIDS. The data obtained in this study could explain the low incidence in gastrointestinal lesions with LC.
非甾体抗炎药（NSAIDs）引起的胃肠道溃疡可能与环氧化酶受抑制导致前列腺素（PGs）合成减少有关。另一方面，已表明5-脂氧合酶产物（5-LO）是致溃疡因子。在某些情况下，由于环氧化酶受抑制，NSAIDs的使用会刺激5-LO途径产生过量的花生四烯酸。在这些情况下，NSAIDs产生的损害更大，因为不仅细胞保护作用的PGs减少，而且5-LO的产物也增加。本文的目的是研究氯尼辛赖氨酸（LC）和吲哚美辛（INDO）对PGs和5-羟基二十碳四烯酸（5-HETE）合成的影响。所使用的LC浓度（4和6微克/毫升）和INDO浓度（0.035微克/毫升和0.35微克/毫升）分别对应于两种药物口服治疗剂量时达到的血浆值。结果表明，在任何情况下LC都不会降低前列腺素E2（PGE2）的产生。相反，INDO显著抑制了PGE2的合成。值得一提的是，4和6微克/毫升的LC能显著抑制5-HETE的产生。只有在较高浓度的INDO时，我们才观察到类似的效果。这些结果可能表明对5-LO有抑制作用，5-LO是花生四烯酸代谢途径中产生羟基二十碳四烯酸（HETEs）和白三烯（LTS）的第一种酶。我们得出结论，治疗剂量的LC具有与经典NSAIDs不同的作用机制。本研究获得的数据可以解释LC引起胃肠道病变的发生率较低的原因。
