Setnikar I, Cereda R, Pacini M A, Revel L, Makovec F
Rotta Research Laboratorium, S.p.A., Monza, Italy.
Arzneimittelforschung. 1989 Sep;39(9):1109-14.
Tiropramide hydrochloride and some of its metabolites were studied in vivo for their antispasmodic activities on the following models: gastric emptying in the mouse retarded by cholecystokinin octapeptide (CCK-8) or morphine, progression of intestinal contents in the mouse, spontaneous motility of the colon in the anesthetized rabbit, diarrhea induced by castor oil in the rat, spasm of the sphincter of Oddi provoked by morphine in the guinea pig, contractions of the urinary bladder in the anesthetized rat. On these models tiropramide had an antispasmodic activity at doses of 4-40 mg/kg i.p. or i.v. and of 50-90 mg/kg orally. The potency was greater on "pathological" contractions or spasms and smaller on "physiological" movements. Tiropramide may therefore be regarded as a "eukinetic" antispasmodic agent. Tiropramide in general was more potent than reference agents such as papaverine or flavoxate and was active also after oral administration. The metabolites of tiropramide, i.e. CR 1034, CR 1098 and CR 1166 showed similar pharmacodynamic effects, but their potency was smaller than that of tiropramide. Large doses of tiropramide have depressive actions on the cardiovascular system, which can be seen especially if tiropramide is administered i.v. and are less pronounced after oral administration. The circulatory effects are therefore probably the limiting factor for increasing the parenteral doses of tiropramide in human therapy. Tiropramide was found less toxic than papaverine (LD50). The metabolites of tiropramide were less toxic than the parent compound. The toxicity of the chiralic forms of tiropramide does not differ significantly from that of the racemic substance.
对盐酸替罗哌胺及其部分代谢产物进行了体内研究，观察它们在以下模型中的抗痉挛活性：用八肽胆囊收缩素（CCK - 8）或吗啡使小鼠胃排空延迟、小鼠肠内容物推进、麻醉兔的结肠自发运动、蓖麻油诱导大鼠腹泻、吗啡诱导豚鼠奥迪括约肌痉挛、麻醉大鼠膀胱收缩。在这些模型中，替罗哌胺腹腔注射或静脉注射剂量为4 - 40mg/kg、口服剂量为50 - 90mg/kg时有抗痉挛活性。其效力对“病理性”收缩或痉挛更强，对“生理性”运动较弱。因此，替罗哌胺可被视为一种“促动力性”抗痉挛剂。总体而言，替罗哌胺比诸如罂粟碱或黄酮哌酯等参比药物效力更强，口服给药后也有活性。替罗哌胺的代谢产物，即CR 1034、CR 1098和CR 1166显示出相似的药效学作用，但其效力低于替罗哌胺。大剂量替罗哌胺对心血管系统有抑制作用，尤其是静脉注射时更明显，口服后则不太显著。因此，循环系统效应可能是限制替罗哌胺在人体治疗中增加静脉注射剂量的因素。发现替罗哌胺的毒性低于罂粟碱（LD50）。替罗哌胺的代谢产物毒性低于母体化合物。替罗哌胺手性形式的毒性与外消旋体相比无显著差异。
