Okada M, Ekimoto H, Ito J, Takahashi K
Nihon Gan Chiryo Gakkai Shi. 1989 Apr 20;24(4):793-7.
In order to find a method to ameliorate pulmonary toxicity of peplomycin (PEP), microscopic changes of the lung following PEP administration and effect of anti-platelet aggregating agents on the toxicity was investigated in mice. When PEP was administered intravenously once a day for 7 days, microthrombi mainly composed of aggregated platelets and fibrin appeared in the capillaries of the lung in an early phase before severe pulmonary edematous lesions and fibrosis occurred. Combination therapy of anti-platelet aggregating agents such as phthalazinol, dipyridamole, ticlopidine and indomethacin suppressed these toxic changes. Especially, ticlopidine was the most effective and superior to prednisolone used clinically for amelioration of the toxicity. Microthrombi, preceding edematous lesions, were considered to be attributed to damages of endothelium by PEP, because PEP itself did not develop platelet aggregation in vitro and ex vivo. Therefore, the microthrombi are likely to produce congestion of pulmonary microcirculation leading to edematous lesions by increase of permeability, and to play significant roles in the development of pulmonary fibrosis in a late phase. Anti-platelet aggregating agents such as ticlopidine are concluded to ameliorate the lung toxicity by preventing microcirculation impairment with the microthrombus.
为了找到一种改善培普利霉素（PEP）肺毒性的方法，研究了小鼠给予PEP后肺的微观变化以及抗血小板聚集剂对该毒性的影响。当每天静脉注射PEP一次，连续7天时，在严重肺水肿病变和纤维化出现之前的早期，肺毛细血管中出现了主要由聚集的血小板和纤维蛋白组成的微血栓。酞嗪酮、双嘧达莫、噻氯匹定和吲哚美辛等抗血小板聚集剂的联合治疗抑制了这些毒性变化。特别是，噻氯匹定最为有效，优于临床上用于改善毒性的泼尼松龙。在水肿病变之前出现的微血栓被认为是由于PEP对内皮的损伤所致，因为PEP本身在体外和体内均不会引起血小板聚集。因此，微血栓可能会导致肺微循环充血，通过增加通透性导致水肿病变，并在后期肺纤维化的发展中起重要作用。得出结论，噻氯匹定等抗血小板聚集剂可通过预防微血栓引起的微循环损伤来改善肺毒性。
