Exercise capacity, hemodynamic, and neurohumoral changes following acute and chronic administration of flosequinan in chronic congestive heart failure

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Abstract
We evaluated the responses to 90 minutes and 8 days of therapy with a new long-acting vasodilator flosequinan in ten patients with moderate chronic congestive heart failure in an open, uncontrolled study. Acute administration of 100 mg orally resulted in a decrease of preload, with a reduction of left ventricular end-diastolic volume, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and right atrial pressure. Following the acute administration, we found no significant changes of heart rate, cardiac index, stroke volume, peripheral vascular resistance, ejection fraction, and dp/dt. Chronic application for 8 days (100 mg/day) showed persistent effects on preload, with a significant decrease of pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. After 8 days of treatment, cardiac index was significantly increased from 2.2±0.2 l/min/m2 to 2.8±0.2 l/min/m2 (p=0.013) and stroke volume from 57±10 ml to 74±9 ml (p=0.022). Peripheral vascular resistance decreased by 28%. After 8 days, bicycle exercise capacity increased significantly from 383±44 sec to 422±43 sec (p=0.01) and the patients were able to increase their walking distance over a 6-minute exercise test from 426±46 m to 477±33 m (p=0.007), with a concomitant decrease of dyspnea (p=0.013). Plasma renin concentration showed only a rise 90 minutes after the acute administration on day 8 of the study, and atrial natriuretic peptide and 6-keto-prostaglandin F1-alpha decreased significantly. Plasma norepinephrine, epinephrine, dopamine, and prostaglandin E2 did not change. After 8 days body weight was reduced from 76.5±2.1 kg to 75.1±2.4 kg. These data indicate that flosequinan is effective in patients with heart failure during a relatively short duration of treatment, improving cardiac performance and exercise capacity and acting primarily on preload, and it may have cumulative vasodilator effects on arterial vessels during chronic therapy. We observed no substantial stimulation of neurohumoral factors and no fluid retention.

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