Kase Y, Hayakawa T, Togashi Y, Kamataki T
Central Research Laboratories, Tsumura & Co., Inashiki-gun, Ibaraki, Japan.
Jpn J Pharmacol. 1997 Dec;75(4):399-405. doi: 10.1254/jjp.75.399.
For characterization of the mechanism(s) of severe diarrhea due to the anticancer agent, irinotecan hydrochloride (CPT-11), examination was made of the relation of CPT-11-related diarrhea to colonic prostaglandin E2 (PGE2) and water absorption in rats. Acute diarrheal symptoms were observed within 1 hr after the administration of CPT-11 to rats, with increased PGE2 and decreased water absorption in the colon. Treatment with atropine at 1 mg/kg, s.c. was noted to inhibit intestinal PGE2 and the CPT-11-related acute diarrheal symptoms, indicating that these diarrheal symptoms were mediated through the cholinergic nervous system accelerated functionally by CPT-11. On the other hand, daily treatment of CPT-11 at the same dose resulted in chronic diarrheal symptoms in all animals 3 days after CPT-11 treatment. Histopathological changes observed in the descending colon and ileum of the rats included degeneration and necrosis of villi and cryptal cells and a decrease in the number of the goblet cells. Significantly increased PGE2 and impaired water absorption of the descending colon were also observed during the chronic diarrheal stage. It can be considered that the chronic diarrheal symptoms appear as a consequence of the gastrointestinal injury characterized by significant increase in PGE2 accompanied by impaired water absorption.
为了阐明抗癌药物盐酸伊立替康（CPT-11）所致严重腹泻的机制，研究了CPT-11相关性腹泻与大鼠结肠前列腺素E2（PGE2）及水吸收之间的关系。给大鼠注射CPT-11后1小时内观察到急性腹泻症状，同时结肠中PGE2增加，水吸收减少。皮下注射1mg/kg阿托品可抑制肠道PGE2及CPT-11相关性急性腹泻症状，表明这些腹泻症状是由CPT-11功能性加速的胆碱能神经系统介导的。另一方面，以相同剂量每日给予CPT-11，在CPT-11治疗3天后所有动物均出现慢性腹泻症状。大鼠降结肠和回肠的组织病理学变化包括绒毛和隐窝细胞的变性和坏死以及杯状细胞数量减少。在慢性腹泻阶段还观察到降结肠中PGE2显著增加且水吸收受损。可以认为，慢性腹泻症状是胃肠道损伤的结果，其特征是PGE2显著增加并伴有水吸收受损。
