Nobuo Aikawa and Akira Karasawa
Department of Pharmacology, Pharmaceutical Research Institute, Kyowa
Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka
411, Japan
Abstract: 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.
Keywords: KW-5617, Loperamide, Diarrhea, Zaldaride, Gastrointestinal
propulsion