Research Project
6880348
DESCRIPTION (provided by applicant): Digoxin is the first line pharmacologic therapy for CHF and AF. Digoxin increases cardiac contractility and blocks conduction through the AV node slowing the ventricular response to AF and thus slowing the rate of the beating ventricles permitting more time for the heart to fill. The recent Dig trial supports the use of digoxin in the treatment of CHF and the recent AFIRM trial supports the rate control strategy for AF treatment. Digoxin is believed to augment contractility by inhibition of NaK+ATP'ace as well as of AV node delay by this mechanism. However, the inhibition of NaK+ATP'ace is initiated by digoxin binding to the alpha subunit and three different subunits exist. Digoxin is a chiral molecule and it is possible that the chiral isolates of digoxin exhibit different binding affinities for the alpha subunits yielding different effects on cardiac contractility and AV node conduction. In preliminary studies we have been able to isolate two isomers and find differential effects on conduction and contractility. We propose to further expand the preliminary work, confirm the differential action on the two isolates in a second species; both requisite preliminary steps to developing the two compounds as independent pharmaceutical agents. Additionally we propose studies to identify the isolates as to chemical structure, determine their stability in vitro and in vivo as well as develop methods to increase the yield of the isolates at chiral separation. We further propose to determine the toxic to therapeutic ratio of the isolates to see if they offer an advantage to the racemate digoxin compound. The advantage would be a treatment for AF that did not cause cardiac augmentation and vasoconstriction or a treatment for CHF that does not cause heart rate slowing or conduction disturbances.
