Saito T, Ukai K, Masuda T, Nakagawa T, Kimura K, Fujii M, Wakatsuki K, Saeki M, Kasai H
Department Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan.
Arzneimittelforschung. 1997 Dec;47(12):1375-82.
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.
在实验动物中研究了新型胆囊收缩素-A拮抗剂洛西格列胺（(+/-)-4-(3,4-二氯苯甲酰胺基)-N-(3-甲氧基丙基)-N-戊基戊二酸，CR 1505，CAS 107097-80-3）对中枢神经系统、自主神经系统、心肺系统、胃肠系统、血液系统及其他系统的一般药理学特性。1. 中枢神经系统：静脉注射洛西格列胺30mg/kg时，6只小鼠中有1只出现眼睑下垂，但静脉注射3mg/kg和10mg/kg时，小鼠的总体行为无变化。洛西格列胺对小鼠的运动活性、硫喷妥钠诱导的催眠、抗惊厥活性、镇痛活性及大鼠直肠温度变化均无影响。2. 自主神经系统：在体外，浓度为10(-4)和3×10(-4)mol/L的洛西格列胺可轻微抑制豚鼠离体回肠中激动剂诱导的收缩及未孕大鼠离体子宫的自发性节律性收缩。但洛西格列胺对未孕大鼠离体子宫中催产素诱导的收缩无影响。3. 心肺系统：洛西格列胺对麻醉犬的心率和心电图无影响。但静脉注射30mg/kg时，可轻微升高血压并降低呼吸频率。此外，静脉注射剂量超过3mg/kg时，洛西格列胺可轻微降低股动脉血流量。另一方面，它对豚鼠离体心房的收缩力或收缩速率及兔离体主动脉的静息张力无影响。4. 胃肠系统：静脉注射10mg/kg和30mg/kg时，洛西格列胺可增加麻醉大鼠的胆汁分泌，静脉注射3mg/kg、10mg/kg和30mg/kg时，可增加麻醉犬的胆汁分泌。然而，总胆汁酸输出量不受洛西格列胺影响。另一方面，洛西格列胺对大鼠的胰腺分泌、胃分泌和胃排空及小鼠的肠道转运活性无影响。5. 血液学：在体外，在无牛血清白蛋白的样品中，浓度超过1.9×10(-3)mol/L时洛西格列胺出现溶血，而在有牛血清白蛋白的样品中，浓度超过6.9×10(-3)mol/L时洛西格列胺出现溶血，且与无白蛋白条件相比，其最大效力较弱。另一方面，在体内，洛西格列胺对溶血无影响。此外，它对血小板聚集、凝血酶原时间和活化部分凝血活酶时间无影响。6. 其他药理作用：洛西格列胺对豚鼠的局部麻醉活性及小鼠的肾功能无影响。这些结果表明，在药理有效剂量下，洛西格列胺似乎对中枢神经系统、自主神经系统、心肺系统、胃肠系统、血液系统及其他系统无严重副作用。
