Fujimura H, Tsurumi K, Hasegawa J, Yanagihara M, Hiramatsu Y, Maekawa K
Nihon Yakurigaku Zasshi. 1982 Mar;79(3):123-36.
We reported in our previous paper that TN-762, a potent inhibitor of prostaglandin biosynthesis, has marked inhibitory activity on acute experimental inflammation. In this paper, the anti-inflammatory, analgesic, and antipyretic activities of TN-762 were assessed in animal models, and compared with those of indomethacin, ketoprofen and ibuprofen. TN-762 inhibited the sustained paw edema induced by mustard in rats during administration for 3 days, but after final administration, the inhibitory activity was decreased rapidly and was less then that of ketoprofen and indomethacin. TN-762 also inhibited the proliferation of granuloma induced by means of cotton pellet and granuloma pouch methods, and the adjuvant arthritis in rats. The inhibitory activity of the compound on inflammatory proliferation was more potent than that of ibuprofen, but slightly less than that of ketoprofen and less than about 1/10 times that of indomethacin. Indomethacin markedly inhibited the body weight gain at a high dose, while TN-762 did not affect it. Therefore, TN-762 was proven to have an inhibitory effect on subacute and chronic inflammation at low doses without toxic effects, but the compound appeared to have a less of an inhibitory effect on secondary or late stages of inflammation than on primary stage inflammation. TN-762 inhibited the acute paw edema induced by nystatin, and the inhibitory activity was the same as that of ketoprofen and indomethacin. The pathogenesis of nystatin edema has been considered to be due to lysosomal labilization. This result suggests that TN-762 has a potent membrane stabilizing action which is considered to be one of the necessary mechanisms in anti-inflammatory action. On the other hand, TN-762 showed the same potent analgesic effect as ketoprofen and indomethacin as observed by the acetic acid writhing and modified Haffner's methods in mice and by the Randall-Selitto's method in rats. However the antipyretic effect of TN-762 was significantly less than that of ketoprofen and indomethacin.
我们在之前的论文中报道，前列腺素生物合成的强效抑制剂TN - 762对急性实验性炎症具有显著的抑制活性。在本文中，在动物模型中评估了TN - 762的抗炎、镇痛和解热活性，并与吲哚美辛、酮洛芬和布洛芬进行了比较。TN - 762在大鼠连续给药3天期间抑制了芥子油诱导的持续性爪肿胀，但在末次给药后，抑制活性迅速下降，且低于酮洛芬和吲哚美辛。TN - 762还抑制了棉球法和肉芽肿袋法诱导的大鼠肉芽肿增殖以及佐剂性关节炎。该化合物对炎症增殖的抑制活性比布洛芬更强，但略低于酮洛芬，约为吲哚美辛的1/10。高剂量时吲哚美辛显著抑制体重增加，而TN - 762对其无影响。因此，已证明TN - 762在低剂量时对亚急性和慢性炎症具有抑制作用且无毒性作用，但该化合物对炎症继发或后期阶段的抑制作用似乎比对初级阶段炎症的抑制作用小。TN - 762抑制了制霉菌素诱导的急性爪肿胀，其抑制活性与酮洛芬和吲哚美辛相同。制霉菌素水肿的发病机制被认为是由于溶酶体不稳定。这一结果表明TN - 762具有强大的膜稳定作用，这被认为是抗炎作用的必要机制之一。另一方面，通过小鼠醋酸扭体法、改良哈夫纳法以及大鼠兰德尔 - 塞利托法观察到，TN - 762显示出与酮洛芬和吲哚美辛相同的强效镇痛作用。然而，TN - 762的解热作用明显低于酮洛芬和吲哚美辛。
