General pharmacological profile of the novel muscarinic receptor agonist SNI-2011, a drug for xerostomia in Sjögren's syndrome. 4th communication: Effects on gastrointestinal, urinary and reproductive systems and other effects.
A novel muscarinic receptor agonist, SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), is a candidate therapeutic drug for xerostomia in Sjögren's syndrome. The general pharmacological properties of this drug on the gastrointestinal, urinary and reproductive systems and other tissues were investigated in mice, rats guinea pigs, rabbits and dogs. 1. Gastrointestinal system: SNI-2011 did not cause any effects on the gastrointestinal system, i.e. the intestinal transport of charcoal meal in mice, the secretion of gastric and bile juices, and the formation of ulcer induced by water immersion restraint in rats. 2. Urinary and reproductive systems: SNI-2011 augmented the spontaneous movement of rat pregnant uterus in vivo at 0.3 mg/kg i.v. or higher, and this effect was not observed in the non-pregnant uterus. SNI-2011 increased the spontaneous movement of isolated guinea pig bladder (3 x 10(-6) mol/l or higher) and increased the in vivo spontaneous movement of rat bladder (0.3 mg/kg i.v. or higher). SNI-2011 caused increases in rat urine volume, pH and urinary excretion of Na+ and Cl- at 30 mg/kg p.o. 3. Others: SNI-2011 had no effect on the vascular permeability in mice, hematological parameters and blood coagulation in rats. SNI-2011 had neither hemolytic nor anti-inflammatory effect. These results suggest that SNI-2011 has muscarinic effects on the gastrointestinal, urinary and reproductive systems and other tissues at the doses approximately 10-fold higher than the doses needed for saliva secretion.
Arisawa
Hirohiko
H
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., Tochigi, Japan. hm-arisawa@sannet.ne.jp
Fukui
Kenji
K
Imai
Eiichi
E
Fujise
Nobuaki
N
Masunaga
Hiroaki
H
D000818:Animals; D000893:Anti-Inflammatory Agents; D002319:Cardiovascular System / Q000187:drug effects; D018592:Cross-Over Studies; D004064:Digestive System / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018721:Muscarinic Agonists / Q000494:pharmacology*; D011247:Pregnancy; D011812:Quinuclidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects; D012859:Sjogren's Syndrome / Q000150:complications*; D013876:Thiophenes; D014566:Urogenital System / Q000187:drug effects; D014987:Xerostomia / Q000188:drug therapy* / Q000209:etiology*
D000893:Anti-Inflammatory Agents; D018721:Muscarinic Agonists; D011812:Quinuclidines; D013876:Thiophenes; C059240:cevimeline