General pharmacological profile of the novel cholecystokinin-A antagonist loxiglumide.
The general pharmacological properties of a novel cholecystokinin-A antagonist, loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylgl utaramic acid, CR 1505, CAS 107097-80-3) on central nervous system, autonomic nervous system, cardio-respiratory system, gastrointestinal system, hematological and miscellaneous systems were investigated in experimental animals. 1. Central nervous system: At a dose of 30 mg/kg, i.v. loxiglumide showed ptosis in one of 6 mice, but at doses of 3 and 10 mg/kg, i.v. no change on gross behavior in mice. Loxiglumide had no effect on locomotor activity and thiopental-induced hypnosis, anti-convulsive activity, analgesic activity in mice and rectal temperature changes in rats. 2. Autonomic nervous system: In vitro, loxiglumide at concentrations of 10(-4) and 3 x 10(-4) mol/l slightly inhibited agonist-induced contractions in the isolated guinea pig ileum and spontaneous rhythmic contractions in the isolated non-pregnant rat uterus. But loxiglumide had no effect on oxytocin-induced contraction in isolated non-pregnant rat uterus. 3. Cardio-respiratory system: Loxiglumide had no effect on heart rate and electrocardiogram in anesthetized dogs. But it slightly increased blood pressure and decreased the frequency of respirations at a dose of 30 mg/kg, i.v. Furthermore, loxiglumide slightly decreased femoral arterial blood flow at doses of more than 3 mg/kg, i.v. On the other hand, it had no effect on contractile force or contraction rate in the isolated guinea pig atrium and resting tension in the isolated rabbit aorta. 4. Gastrointestinal system: Loxiglumide increased bile secretion at doses of 10 and 30 mg/kg, i.v. in anesthetized rats and at doses of 3, 10 and 30 mg/kg, i.v. in anesthetized dogs. However, total bile acid output was not affected by loxiglumide. On the other hand, loxiglumide had no effect on pancreatic secretion, gastric secretion and gastric emptying in rats and intestinal transport activity in mice. 5. Hematology: In vitro, in the case of samples without bovine serum albumin, at concentrations of more than 1.9 x 10(-3) mol/l loxiglumide showed hemolysis, while in the case of samples with bovine serum albumin, at concentrations of more than 6.9 x 10(-3) mol/l loxiglumide showed hemolysis, and its maximal potency was weak compared to albumin-free conditions. On the other hand, in vivo, loxiglumide had no effect on hemolysis. In addition, it had no effect on platelet aggregation, prothrombin time and activated partial thromboplastin time. 6. Miscellaneous pharmacological actions: Loxiglumide had no effect on local anesthetic activity in guinea pigs and renal function in mice. These results suggest that loxiglumide seems to produce no serious side effects on the central nervous system, autonomic nervous system, cardio-respiratory system, gastrointestinal system, hematological and miscellaneous systems at pharmacologically effective doses.
Saito
T
T
Department Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan.
Ukai
K
K
Masuda
T
T
Nakagawa
T
T
Kimura
K
K
Fujii
M
M
Wakatsuki
K
K
Saeki
M
M
Kasai
H
H
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D004064:Digestive System / Q000187:drug effects; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D011377:Proglumide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects
D006727:Hormone Antagonists; C053737:loxiglumide; D002766:Cholecystokinin; D011377:Proglumide