Erickson R A, Rivera N
Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, California 90822.
Dig Dis Sci. 1992 Dec;37(12):1833-9. doi: 10.1007/BF01308076.
Combination therapy with difluoromethylornithine (DFMO) and a nonsteroidal antiinflammatory drug (NSAID) has been proposed for the chemoprevention of colonic neoplasia. The purpose of this study was to examine whether DFMO would affect NSAID-mediated intestinal injury. Male Sprague-Dawley rats were gavaged with 20 mg/kg of indomethacin, after seven days of exposure to drinking water with or without 2% DFMO. The rats were killed 24 or 48 hr later, and the small intestine removed for macroscopic and microscopic quantitation of intestinal injury by computerized image analysis. Seven days of DFMO alone had no effect on overall mucosal thickness, but did increase the depth of proximal intestinal crypts. Forty-eight hours after indomethacin, DFMO treatment decreased the number of indomethacin-induced ulcers and percent of the surface area ulcerated. However, DFMO also decreased the mucosal thickness, villus height, and crypt depth in indomethacin-treated rats. Thus although DFMO decreases macroscopic intestinal ulceration by indomethacin, the reduction in villus and crypt height suggests that it also impairs the mucosa's ability to recover from microscopic indomethacin-induced damage. This study shows DFMO does impact NSAID-mediated intestinal injury and therefore human trials with combinations of DFMO and NSAIDs should include monitoring for small intestinal injury.
已有人提出用二氟甲基鸟氨酸（DFMO）与一种非甾体抗炎药（NSAID）联合治疗来进行结肠肿瘤的化学预防。本研究的目的是检验DFMO是否会影响NSAID介导的肠道损伤。将雄性Sprague-Dawley大鼠在饮用含或不含2% DFMO的水7天后，灌胃给予20 mg/kg的吲哚美辛。24或48小时后处死大鼠，取出小肠，通过计算机图像分析对肠道损伤进行宏观和微观定量。单独给予DFMO 7天对整体黏膜厚度没有影响，但确实增加了近端肠隐窝的深度。吲哚美辛给药48小时后，DFMO治疗减少了吲哚美辛诱导的溃疡数量和溃疡表面积百分比。然而，DFMO也降低了吲哚美辛处理大鼠的黏膜厚度、绒毛高度和隐窝深度。因此，尽管DFMO可减少吲哚美辛引起的宏观肠道溃疡，但绒毛和隐窝高度的降低表明它也损害了黏膜从吲哚美辛诱导的微观损伤中恢复的能力。本研究表明DFMO确实会影响NSAID介导的肠道损伤，因此DFMO与NSAIDs联合的人体试验应包括对小肠损伤的监测。
