title: Effects of KW-5617 (zaldaride maleate), a potent and selective calmodulin inhibitor, on secretory diarrhea and on gastrointestinal propulsion in rats.
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.
authors.affiliation: Department of Pharmacology, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Aikawa
authors.forename: A
authors.initials: A
authors.lastname: Karasawa
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003967:Diarrhea / Q000188:drug therapy*; D015232:Dinoprostone / Q000008:administration & dosage; D005746:Gastric Emptying / Q000187:drug effects*; D008139:Loperamide / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010528:Peristalsis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000930:Antidiarrheals; D001562:Benzimidazoles; D002147:Calmodulin; C052087:CGS 9343B; D008139:Loperamide; D015232:Dinoprostone