An ester of a beta blocker, esmolol, was introduced 30 years ago to facilitate the use of beta blockers in the acute care setting. IV beta blockers have a long half-life and this discouraged their use acutely. Esmolol, because of its short half-life became a very commercially successful agent, currently seeing increased clinical use. Anti-arrhythmic agents cause significant side effects and may cause severe arrhythmias. Sotalol is a drug often used to treat supraventricular arrhythmias, but its prolongation of the QT interval and the specter of life threatening arrhythmias such as Torsade de Pointe ventricular tachycardia limits its use. Having a sotalol like agent, but with a half-life of minutes would be clinically useful. If excessive QT prolongation is observed, or ventricular arrhythmias develop, the short acting agent could be stopped and it would quickly dissipate, enhancing patient safety. We have synthesized a sotalol conjurer with an ester linkage, which would be rapidly hydrolyzed in the blood by circulating esterase yielding a drug with a short half-life. The studies outlined in this initial grant would demonstrate anti-arrhythmic activities of the new agent, soestolol, in animal models of supraventricular and ventricular arrhythmias. We also plan to develop an assay for the drug based on our sotalol assay to verify that, indeed, the kinetic half-life is short. Additionally, by following QT effects, we will determine that the biologic half-life is equally short as the kinetic half-life. Soestolol, if it indeed is an effective anti-arrhythmic with a short half-life, will be a commercial success, as well as contributing significantly to patient care and safety.
Public Health Relevance Statement: Project Narrative The mainstay anti-arrhythmia therapies are amiodarone and sotalol and these drugs are often used for the treatment of supraventricular arrhythmias in pediatric patients, as well as adults. Amiodarone is very long acting and has a very large number of adverse side effects. Sotalol can cause serious ventricular arrhythmias in some patients, making its use problematic. We propose to study a very short acting version of IV Sotalol that would have a half-life of minutes. Physicians could stop the infusion of the sort half-life sotalol and we believe it would dissipate in minutes, reversing excessive QT prolongation that can lead to serious adverse arrhythmias. Additionally, if the patient became bradycardic, hypotensive, or went into heart failure, stopping the drug could rapidly and safely reverse these adversities. Soestolol has the promise of a breakthrough anti-arrhythmic therapy.
NIH Spending Category: Cardiovascular; Heart Disease; Women's Health
Project Terms: Acute; Adrenergic beta-Antagonists; Adult; Alternative Therapies; Amiodarone; Animal Model; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Area; Arrhythmia; Atrial Fibrillation; base; Biological; Biological Assay; Blood; Cardiac; Caring; Cavia; Chemicals; Child; Clinical; Coronary Occlusions; Dose; dronedarone; Drug effect disorder; Drug Kinetics; esmolol; esterase; Esters; Female; Grant; Half-Life; Heart failure; hemodynamics; High Pressure Liquid Chromatography; Hydrolysis; in vivo; Incidence; Infusion procedures; innovation; Isoproterenol; Kinetics; Lead; Life; male; Measures; Modeling; Modification; mortality; New Agents; Patient Care; patient safety; Patients; pediatric patients; Pharmaceutical Preparations; Pharmacological Treatment; Physicians; Preparation; Property; Rattus; Reporting; response; side effect; Sotalol; success; Supraventricular Arrhythmia; Testing; Therapeutic; Torsades de Pointes; Ventricular Arrhythmia; Ventricular Tachycardia
