RRC ID 52184
Author Inoue T, Takemura M, Fushimi N, Fujimori Y, Onozato T, Kurooka T, Asari T, Takeda H, Kobayashi M, Nishibe H, Isaji M.
Title Mizagliflozin, a novel selective SGLT1 inhibitor, exhibits potential in the amelioration of chronic constipation.
Journal Eur J Pharmacol
Abstract Chronic constipation is a highly common functional gastrointestinal disorder that adversely affects patient quality of life. At present, limited therapeutic options are available for the treatment of chronic constipation, which indicates the need for new therapeutic agents. Herein, we report the potential of mizagliflozin, a novel selective sodium glucose co-transporter 1 (SGLT1) inhibitor, for the amelioration of chronic constipation. Mizagliflozin's inhibitory activity against SGLTs was evaluated by an in vitro assay of cells transiently expressing SGLTs. The safety profile of an initial single dose (2-160mg, orally) and multiple doses (2-20mg, orally, once daily immediately prior to breakfast on Days 1 and 13, and three times daily immediately prior to every meal on Days 3-12) of mizagliflozin was determined by performing a phase I study in healthy male subjects. In addition, the effect of mizagliflozin and lubiprostone on fecal wet weight was compared using a dog model of loperamide-induced constipation and rat model of low-fiber-diet-induced constipation. Mizagliflozin potently inhibited human SGLT1 in a highly selective manner. The results of the phase I study showed mizagliflozin increased stool frequency and loosened stool consistency; these effects increased progressively with an increase in the dosage and the number of doses of mizagliflozin. In addition, the oral administration of mizagliflozin increased fecal wet weight in a dog model of loperamide-induced constipation and a rat model of low-fiber-diet-induced constipation, similar to lubiprostone. These results suggest the potential use of a novel selective SGLT1 inhibitor, mizagliflozin, for the amelioration of chronic constipation.
Volume 806
Pages 25-31
Published 2017-7-5
DOI 10.1016/j.ejphar.2017.04.010
PII S0014-2999(17)30252-2
PMID 28410751
MeSH Amides / pharmacology* Amides / therapeutic use Animals Chronic Disease / drug therapy Clinical Trials, Phase I as Topic Constipation / chemically induced Constipation / drug therapy* Dietary Fiber / pharmacology Dogs Dose-Response Relationship, Drug Glucosides / pharmacology* Glucosides / therapeutic use Humans Loperamide / pharmacology Male Pyrazoles / pharmacology* Pyrazoles / therapeutic use Rats Sodium-Glucose Transporter 1 / antagonists & inhibitors*
IF 3.263
Times Cited 13
Human and Animal Cells COS-7(RCB0539)