KW-5617 (
zaldaride maleate), 1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin -4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one
maleate, is a selective
calmodulin inhibitor. We studied the effects of KW-5617 on secretory
diarrhea and gastrointestinal propulsion in rats, as compared with those of
loperamide, a conventional anti-diarrheal
drug.
Diarrhea was induced in rats either by 16,16-dimethyl
prostaglandin E2 (500 microg/kg, i.p.) or by
castor oil (1 ml/100 g
body weight, p.o.). In the 16,16-dimethyl
prostaglandin E2 model, KW-5617 at the doses of 3 mg/kg (p.o.) and higher ameliorated the
diarrhea. Similarly,
loperamide improved the
diarrhea, the activity of
loperamide being equivalent to that of KW-5617. In the
castor oil model, KW-5617 significantly delayed the onset of
diarrhea at the doses of 3 mg/kg (p.o.) and higher, while
loperamide delayed the onset of
diarrhea at the doses of 0.3 mg/kg (p.o.) and higher. KW-5617 only at the high doses of 30 and 100 mg/kg (p.o.) reduced gastric emptying, small intestinal propulsion, proximal colonic propulsion and distal colonic propulsion. In contrast,
loperamide at its anti-diarrheal doses inhibited gastrointestinal propulsion. Our results show that KW-5617, unlike
loperamide, at its anti-diarrheal doses does not exert anti-propulsive effects in rats. KW-5617 may be a useful
drug for the treatment of
diarrhea in terms of less side effects such as
constipation.