Soestolol: A potentially short acting Type III anti-arrhythmic

Project Summary AbstractAn ester of a beta blockeresmololwas introducedyears ago to facilitate the use of beta blockers in the acute care settingIV beta blockers have a long half life and this discouraged their use acutelyEsmololbecause of its short half life became a very commercially successful agentcurrently seeing increased clinical useAnti arrhythmic agents cause significant side effects and may cause severe arrhythmiasSotalol is a drug often used to treat supraventricular arrhythmiasbut its prolongation of the QT interval and the specter of life threatening arrhythmias such as Torsade de Pointe ventricular tachycardia limits its useHaving a sotalol like agentbut with a half life of minutes would be clinically usefulIf excessive QT prolongation is observedor ventricular arrhythmias developthe short acting agent could be stopped and it would quickly dissipateenhancing patient safetyWe have synthesized a sotalol conjurer with an ester linkagewhich would be rapidly hydrolyzed in the blood by circulating esterase yielding a drug with a short half lifeThe studies outlined in this initial grant would demonstrate anti arrhythmic activities of the new agentsoestololin animal models of supraventricular and ventricular arrhythmiasWe also plan to develop an assay for the drug based on our sotalol assay to verify thatindeedthe kinetic half life is shortAdditionallyby following QT effectswe will determine that the biologic half life is equally short as the kinetic half lifeSoestololif it indeed is an effective anti arrhythmic with a short half lifewill be a commercial successas well as contributing significantly to patient care and safety Project NarrativeThe mainstay anti arrhythmia therapies are amiodarone and sotalol and these drugs are often used for the treatment of supraventricular arrhythmias in pediatric patientsas well as adultsAmiodarone is very long acting and has a very large number of adverse side effectsSotalol can cause serious ventricular arrhythmias in some patientsmaking its use problematicWe propose to study a very short acting version of IV Sotalol that would have a half life of minutesPhysicians could stop the infusion of the sort half life sotalol and we believe it would dissipate in minutesreversing excessive QT prolongation that can lead to serious adverse arrhythmiasAdditionallyif the patient became bradycardichypotensiveor went into heart failurestopping the drug could rapidly and safely reverse these adversitiesSoestolol has the promise of a breakthrough anti arrhythmic therapy