Inhibitory effects of ramosetron, a potent and selective 5-HT3-receptor antagonist, on conditioned fear stress-induced abnormal defecation and normal defecation in rats: comparative studies with antidiarrheal and spasmolytic agents.
We examined the effect of ramosetron, a potent serotonin (5-HT)(3)-receptor antagonist for irritable bowel syndrome with diarrhea, on conditioned fear stress (CFS)-induced defecation and normal (non-stressed) defecation in rats and compared ramosetron with the antidiarrheal agent loperamide and the spasmolytic agents trimebutine and tiquizium. Ramosetron, loperamide, trimebutine, and tiquizium significantly inhibited CFS-induced defecation in a dose-dependent manner with ED(50) (95% confidence limit) values of 0.019 (0.01 - 0.028), 9.4 (4.0 - 22), 850 (520 - 2,400), and 300 (190 - 450) mg/kg, respectively. A significant effect of ramosetron on CFS-induced defecation appeared at 10 min after dosing and was sustained for 8 h. In contrast, loperamide, trimebutine, and tiquizium significantly inhibited CFS-induced defecation between 1 - 8, 1 - 4, and 1 - 8 h after administration, respectively. High doses of ramosetron did not affect normal defecation, whereas loperamide, trimebutine, and tiquizium significantly inhibited this process. In conclusion, ramosetron has potent, rapid-onset, and long-lasting inhibitory effects on CFS-induced defecation in rats, but does not influence normal defecation. The present findings indicate that ramosetron will be a useful therapeutic agent for irritable bowel syndrome with diarrhea, showing greater efficacy and safety than other antidiarrheal and spasmolytic agents.
Hirata
Takuya
T
Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma, Inc., Tsukuba, Ibaraki, Japan. takuya.hirata@jp.astellas.com
Funatsu
Toshiyuki
T
Keto
Yoshihiro
Y
Akuzawa
Shinobu
S
Sasamata
Masao
M
Miyata
Keiji
K
D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D003214:Conditioning, Classical; D003672:Defecation / Q000187:drug effects*; D005239:Fear; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013312:Stress, Physiological / Q000150:complications* / Q000503:physiopathology; D014287:Trimebutine / Q000494:pharmacology
D000930:Antidiarrheals; D001562:Benzimidazoles; D010276:Parasympatholytics; D011807:Quinolizines; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D008139:Loperamide; C030950:thiaton; C071315:ramosetron; D014287:Trimebutine