A CCK receptor antagonist
Loxiglumide is a cholecystokinin (CCK) receptor antagonist that inhibits CCK-8 binding to central and peripheral CCK receptors with Ki values of 9.1 and 0.33 μM, respectively.1 It inhibits CCK-8-induced release of acetylcholine from isolated guinea pig gallbladder (IC50 = 10 nM).2 Loxiglumide (50 μM) reduces the invasion of PANC-1 and MiaPaCa-2 human pancreatic cancer cells by 83.1 and 82.9%, respectively, in vitro.3 Loxiglumide (10-5,000 μM) reduces DNA synthesis in PC-TI and PC-YY human pancreatic cancer cells in a concentration-dependent manner (IC50s = 160 and 74 μM, respectively).4 It reduces the tumor growth rate by 37.5 and 38%, respectively, in PC-TI and PC-YY mouse xenograft models when administered at a dose of 250 mg/kg. Loxiglumide is toxic to mice with LD50 values ranging from 440 to 500 mg/kg dependent on the route of administration. In a rat model of acute pancreatitis, loxiglumide (50 mg/kg, s.c.) reduces serum concentrations of CCK, amylase, and lipase by greater than 60%, as well as tissue hemorrhaging and acinar cell necrosis.5
1.Setnikar, I., Bani, M., Cereda, R., et al.Pharmacological characterisation of a new potent and specific nonpolypeptidic cholecystokinin antagonistArzneimittelforschung37(6)703-707(1987) 2.Rakovska, A., Sgaragli, G., Mantovani, P., et al.Effect of loxiglumide (CR 1505) on CCK-induced contractions and 3H-acetylcholine release from guinea-pig gallbladderNeuropeptides25(5)271-276(1993) 3.Hirata, M., Itoh, M., Tsuchida, A., et al.Cholecystokinin receptor antagonist, loxiglumide, inhibits invasiveness of human pancreatic cancer cell linesFEBS. Lett.383(3)241-244(1996) 4.Nio, Y., Tsubono, M., Morimoto, H., et al.Loxiglumide (CR 1 505), a cholecystokinin antagonist, specifically inhibits the growth of human pancreatic cancer lines xenografted into nude miceCancer72(12)3599-3606(1993) 5.Tani, S., Itoh, H., Koide, M., et al.Involvement of endogenous cholecystokinin in the development of acute pancreatitis induced by closed duodenal loopPancreas8(1)109-115(1993)
Animal experiment: | Rats[1] At 24 h after induction of acute hemorrhagic pancreatitis, rats are divided into four different treatment groups: standard rat chow (AP-C); standard rat chow with pancreatic rest (AP-R); standard rat chow with pancreatic stimulation (AP-S); and standard rat chow with pancreatic rest, followed by pancreatic stimulation (AP-R/S). Rats in the AP-C group receive 2 mL/kg body weight saline orally (po) via an orogastric tube twice daily (09:00 and 21:00 h) for 10 d; the AP-R group receive 50 mg/kg body weight of CCK-1 receptor antagonist Loxiglumide dissolved in 2 mL distilled water po twice daily for 10 d; the AP-S group receive 25 mg/kg body weight protease inhibitor Camostat, which is known to stimulate endogenous CCK release, dissolved in 2 mL distilled water po twice daily for 10 d; and the AP-R/S group receive 50 mg/kg body weight Loxiglumide twice daily for the first 5 d followed by 25 mg/kg body weight camostat twice daily for the next 5 d. Rats are fed ad libitum. On day 12 at 24 h after the last treatment and overnight fasting, pancreatic exocrine function and histological examination of the pancreas are performed. |
参考文献: [1]. Jia D, et al. Effect of endogenous cholecystokinin on the course of acute pancreatitis in rats. World J Gastroenterol. 2015 Jul 7;21(25):7742-53. | |
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