Comparison of the minimal lethal doses,cardiac toxicities,and cardiodepressor effects of tricyclic antidepressants and UP 614-04, a potential antidepressant

The cardiotoxic and hemodynamic effects of intravenously administered UP 614-04, imipramine, clomipramine, and amitriptyline were compared using guinea pigs and dogs. In guinea pigs, determinations of minimal lethal dose and electrocardioraphic changes indicated that UP 614-04 was much less cardiotoxic than the three tricyclic antidepressants tested. In dogs, both imipramine and clomipramine exerted more pronounced effects than UP 614-04 on hemodynamic parameters. However, all three agents had qualitatively similar dose–response characteristics in that low doses produced slight increases in systolic blood pressure and heart rate, intermediate doses did not alter haemodynamic parameters, and high doses produced marked cardiodepressor effects. Imipramine and clomipramine were also much more potent than UP 614-04 in potentiating the pressor action of intravenously administered norepinephrine. Taken together, these results have indicated that UP 614-04 is about five times less cardiotoxic and about four to eight times less potent as a cardiodepressor than imipramine or clomipramine.