Cardiovascular effects of a newly synthesized cardiotonic agent (TA-064) on normal and diseased hearts

Abstract

A new inotropic agent, TA-064, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol, was shown to have strong effects in experimental animals. Its effectiveness and associated adverse effects were tested in humans invasively (n = 6) and noninvasively (n = 17). Increasing doses of intravenous infusion (1, 2, and 4 micrograms/kg/min) increased plasma levels to 15, 35, and 82 ng/ml, respectively, resulting in marked increases in the peak rate of left ventricular pressure rise (dP/dt) (1,450 +/- 63 to 3,042 +/- 349 mm Hg/s) (mean +/- standard error of the mean [SEM], p less than 0.01) and the ratio of dP/dt to left ventricular pressure at a developed pressure of 40 mm Hg (25 +/- 3 to 39 +/- 2 s-1) (p less than 0.01), with a reduction in left ventricular end-diastolic pressure (12 +/- 2 to 4 +/- 1 mm Hg) (p less than 0.01). Minimal or no changes were seen in heart rate and left ventricular systolic pressure. After a single oral dose (10 mg), the plasma level reached its peak at 90 minutes (16 +/- 9 ng/ml, n = 17). A positive inotropic effect was confirmed echocardiographically in both healthy volunteers (n = 8) and patients with congestive heart failure (CHF) (n = 9) who were maximally treated with conventional regimens: increase in mean velocity of circumferential fiber shortening (healthy volunteers: 1.29 +/- 0.05 to 1.60 +/- 0.11 circ/s [p less than 0.05]; patients with CHF: 0.69 +/- 0.08 to 0.93 +/- 0.09 circ/s [p less than 0.01]), ejection fraction (healthy volunteers: 68 +/- 2 to 75 +/- 2% [p less than 0.05], patients with CHF: 37 +/- 4 to 45 +/- 5% [p less than 0.01]) without change in heart rate. The cardiac index was increased only in the CHF group (2.71 +/- 0.22 to 3.21 +/- 0.24 liters/min/m2) (p less than 0.05). No significant untoward effects were observed. Thus TA-064 is a potent inotropic agent and can be used either parenterally or orally. Salutary effects can be expected in patients with congestive heart failure who are treated with digitalis and diuretic agents.