BURROUGHS WELLCOME’s BW15AU INCREASES CARDIAC OUTPUT IN HEART FAILURE
BURROUGHS WELLCOME's BW15AU INCREASES CARDIAC OUTPUT IN HEART FAILURE patients, results of a dosetitration study suggest. "Acute administration of the compound was associated with a significant increase in cardiac index, a significant decline in pulmonary vascular resistance and a modest decrease in pulmonary artery wedge pressure," study investigator Kirkwood Adams, University of North Carolina at Chapel Hill, reported Nov. 17 at the American Heart Association's 65th Scientific Sessions in New Orleans. The dose-titration study of BW15AU, a vasodilator and analog of epoprostenol (BW's Flolan), involved 12 patients classified as having NYHA Class III or Class IV heart failure. Patients had to have had the Class III or IV heart failure symptoms for at least three months prior to enrollment and a resting left ventricular ejection fraction of less than or equal to 35%, Adams explained. The objective of the study was to evaluate the acute hemodynamic effects of sequential dose titration of BW15AU in patients with severe heart failure. BW15AU was titrated initially at an I.V. dose of 5 nanograms/kilogram/minute. "The dose was next raised to 10 ng/kg/minute and subsequently increased in increments of 10 ng/kg/minute until the patient developed an adverse event," Adams said. The maximal tolerated dose (MTD) was administered for 90 minutes during a maintenance segment and additional hemodynamic measurements were taken at 15-minute intervals. During a washout phase, the infusion was stopped and serial hemodynamic measurements were obtained over a 90-minute period. * Reporting the changes in hemodynamic variables between vehicle and the MTD of BW15AU, Adams stated: "There was a modest but definite decline in systolic blood pressure from 116 mmHg to 106 mmHg, which was significant." He continued: "There was a minor and insignificant increase in heart rate from 91 beats per minute to 95 beats per minute at [MTD]." There also was a "significant decline in systemic vascular resistance from the vehicle infusion to the maximum tolerated dose of BW15AU," Adams said. "Likewise, there was a reduction in pulmonary vascular resistance from vehicle to [MTD], which was highly significant as well." The reduction in pulmonary resistance continued unchanged during the maintenance infusion but reversed rapidly after the drug was stopped. The cardiac index "increased significantly from vehicle" to MTD, Adams reported, noting that this increased output was sustained during the 90-minute maintenance infusion. In the washout phase, "there was a rampant return of cardiac index towards the levels reported during the vehicle infusion." Additionally, "there was a modest reduction in wedge pressure noted from vehicle to maximal tolerated dose, which continued during the maintenance infusion." The hemodynamic results "suggest that additional studies of BW15AU are warranted," Adams stated. The drug has a short half-life which apparently would necessitate chronic administration, such as through a transdermal device. Burroughs said that it plans to conduct Phase II trials of BW15AU for treatment of heart failure and is exploring the possibility of putting the drug in a transdermal patch. Flolan is in Phase III trials for congestive heart failure and primary pulmonary hypertension. An NDA for Flolan's use as replacement for heparin in hemodialysis has been pending at FDA since 1986.
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