General pharmacological profile of the novel muscarinic receptor agonist SNI-2011, a drug for xerostomia in Sjögren's syndrome. 3rd communication: effects on respiratory and cardiovascular systems.
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 respiratory and cardiovascular systems were investigated in guinea pigs and dogs. SNI-2011 reduced the contractile force and beating rate of isolated right guinea pig atrium at 1 x 10(-6) mol/l or higher and 3 x 10(-6) mol/l or higher, respectively. SNI-2011 reduced the contractile force of isolated left atrium induced by electric stimulation at 1 x 10(-6) mol/l or higher. In anesthetized dogs, SNI-2011 caused a transient decrease in blood pressure, tachycardia and an increase in femoral arterial blood flow at 0.01 mg/kg i.v. or higher. At 1 mg/kg it caused continuous bradycardia, a decrease in femoral arterial blood flow and an increase in respiration rate in addition to the changes observed immediately after injection. A transient negative T-wave was observed as the only change in the ECG immediately after injection at 1 mg/kg. However, when SNI-2011 was injected intraduodenally, a decrease in femoral arterial blood flow, bradycardia and a tendency to increase respiration rate were observed at doses of 1 to 3 mg/kg. All these events in dogs were antagonized by atropine. These results suggest that oral administration of SNI-2011, that is the clinical administration route, can distinctly reduce the muscarinic effects on the respiratory and cardiovascular systems compared to intravenous administration.
Arisawa
Hirohiko
H
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., Tochigi, Japan. hm-arisawa@sannet.ne.jp
Fukui
Kenji
K
Masunaga
Hiroaki
H
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D011812:Quinuclidines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects*; D012859:Sjogren's Syndrome / Q000150:complications*; D013876:Thiophenes; D014987:Xerostomia / Q000188:drug therapy* / Q000209:etiology*
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D013876:Thiophenes; D001285:Atropine; C059240:cevimeline