HEMODYNAMIC-EFFECTS AND CONCENTRATION EFFECT RELATIONSHIP OF A GRADED INFUSION OF PIROXIMONE IN PATIENTS WITH SEVERE HEART-FAILURE

Piroximone is a new phosphodiesterase III inhibitor that combines inotropic and vasodilator properties. To elucidate the optimal dose regimen and the dose-concentration-effect relationships, we studied eight patients with congestive heart failure of New York Heart Association class IV during a continuous multistage infusion over a 24-h period followed by a 4-h washout. After a bolus of 0.5 mg/kg, infusions at a rate of 2.5, 5.0, and 10.0 mug/kg/min for 8 h each were given to determine the maintenance dose of piroximone required to achieve an increase in cardiac index greater-than-or-equal-to 30%. Serial assessment of hemodynamics, plasma piroximone levels, and ventricular ectopic beats was performed. Following the loading dose and at higher infusion rates (5 and 10 mug/kg/min) Piroximone produced significant hemodynamic changes compared to baseline, i.e., a maximum increase in cardiac index from 2.2 +/- 0.4 to 3.6 +/- 0.8 L/min/m2 (67 +/- 21%), decreases in right atrial pressure from 14 +/- 3 to 9 +/- 3 mm Hg (40 +/- 16%), pulmonary capillary wedge pressure from 29 +/- 5 to 23 +/- 7 mm Hg (28 +/- 18%), pulmonary vascular resistance from 249 +/- 93 to 151 +/- 59 (45 +/- 19%), and systemic vascular resistance from 1,330 +/- 442 to 752 +/-272 dyn s/cm5 (44 +/- 19%). Piroximone increased the heart rate by 10% at the highest dose and produced a decrease in mean arterial pressure by 13%. There was a slight increase in ventricular ectopy in two patients (2.2 and 3 VPBs/min) and no change in the remaining six. Two hours after discontinuation of the piroximone infusion, hemodynamic parameters returned to baseline in parallel to decreasing plasma levels. Plasma concentrations of piroximone reached a steady state at infusion rates of 2.5 and 5.0 mug/kg/min but continued to rise disproportionately at the highest dose. The terminal elimination half-life was 1.4 +/- 0.3 h. Our findings indicate a close relationship between piroximone plasma concentrations and hemodynamic effects in patients with severe congestive heart failure. The rising plasma concentrations at an infusion rate of 10 mug/kg/min are suggestive of nonlinear pharmacokinetics, with the risk of excessive accumulation during prolonged administration.