Cumulative hemodynamic response to short-term treatment with flosequinan (BTS 49465), a new direct-acting vasodilator drug, in severe chronic congestive heart failure

Pharmacologic tolerance develops rapidly to the hemodynamic effects of many vasodilator drugs used in the treatment of congestive heart failure. We evaluated the responses to 3 days of therapy with a new long-acting vasodilator drug, flosequinan (BTS 49465), in 16 patients with severe chronic heart failure. On each of the 3 days, flosequinan (100 or 150 mg orally) produced marked increases in cardiac index and decreases in left ventricular filling pressure, mean right atrial pressure, and systemic vascular resistance (all p less than 0.01) without significant changes in heart rate. Whereas the effects of flosequinan on right and left ventricular filling pressures on the first and third days were similar, cardiac index was higher and systemic vascular resistance was lower after the third dose than after the first dose of the drug, indicating the occurrence of a cumulative vasodilator effect on arterial resistance vessels. Since all hemodynamic changes persisted for longer than 24 h after each dose of the drug, the daily administration of flosequinan also produced a progressive improvement in the hemodynamic state recorded before each dose of the drug. These data indicate that pharmacologic tolerance does not develop to the effects of flosequinan during short-term therapy with the drug in patients with severe chronic heart failure. Instead, further hemodynamic improvement may occur because of a cumulative vasodilator effect that results from the drug's prolonged duration of action.