Cardiovascular Drugs and Therapy 18 269–277 2004 C  2004 Kluwer Academic Publishers. Manufactured in The United States BASIC PHARMACOLOGY Intrapericardial Ibutilide Administration Fails to Terminate Pacing-Induced Sustained Atrial Fibrillation in Dogs Andr ´ as Vereckei 1 , J. Cristopher Gorski 2 , Michael Ujhelyi 3 , Rahul Mehra 3 , and Douglas P. Zipes 4 1 3rd Department of Medicine, Semmelweis University, School of Medicine, Budapest; 2 Indiana University, Department of Medicine, Clinical Pharmacology Division, Indianapolis, Indiana; 3 Medtronic Inc., Minneapolis, Minnesota; 4 Department of Medicine, The Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana Summary. Purpose: The hypothesis that intrapericardial (ip.) ibutilide administration would terminate pacing- induced sustained atrial fibrillation (AF) and ibutilide dis- tribution were tested. Methods and results: Sustained (≥24 hours) AF was in- duced by 59 ± 20 day rapid atrial pacing in 19 dogs. Af- ter sustained AF was present, the atrial pacemaker was turned off and 9 open chest dogs received 0.015 mg/kg ibutilide (37 ◦ C) in 30 ml saline into the pericardial sac. Ten control dogs received 30 ml saline (37 ◦ C) ip. QT in- tervals, right ventricular monophasic action potential du- ration at 90% of repolarization (RV-MAPD 90 ), AF mean cycle length (AFCL m ), systolic- and diastolic intraarterial blood pressures, intrapericardial-, right atrial- and ventric- ular pressures, cardiac output and ibutilide concentrations were measured. If AF persisted after the 1st drug infusion, dual site rapid atrial pacing (DRAP) simultaneously from the high right atrium and coronary sinus was performed to terminate AF. If it was ineffective, a 2nd ip. drug in- fusion in the same fashion as the 1st one, was attempted. There was no significant difference in AF termination [5/9 (56%) in ibutilide treated and 3/10 (30%) in control dogs] between the two groups. DRAP never terminated AF. The AF duration did not differ between the two groups. Com- pared with control, ibutilide treatment prolonged signifi- cantly AFCL m ( p < 0.001) and non-significantly QT, RV- MAPD 90 . No significant difference was found in systolic and diastolic blood pressure and cardiac output between the two groups. The two orders of magnitude greater ibu- tilide concentration in the pericardial fluid than that in the femoral vein decreased rapidly over time, drug concen- tration was greatest in the atria, smaller in the ventricu- lar myocardium, with a trend decreasing from the epi- to endocardium. Conclusions: Despite a significant atrial electrophysio- logical effect, ip. delivery of ibutilide did not result in higher AF termination rate compared with control. Key Words. intrapericardial administration, ibutilide, atrial fibrillation Introduction Intrapericardial (ip.) administration of drugs is an im- portant potential application of targeted drug delivery. Targeted drug delivery i.e. directing drug action to the organ/region in need, that renders possible to maxi- mize the desired local effect and minimize the systemic side effects, can be achieved by biological or physical means. Biologically targeted drug therapy depends on unique properties of the drug and the organ/region to be treated, physical means of targeted drug delivery is the use of physical barriers for drug delivery, such as ip. antiarrhythmic drug administration [1–3]. The peri- cardial sac represents a natural physical barrier and provides a drug receptacle to restrict drug delivery to the heart. Ip. drug delivery can be applied to treat dis- orders involving superficial tissues of the heart such as atrial and ventricular epicardial tissue, cardiac ner- vous system, coronary vasculature with the possibility of achieving significant local efficacy, prolonged dura- tion of action with lower doses and less toxicity. The therapeutic importance of ip. drug administration is un- derscored by recent demonstration of the efficacy of ip. administered angiogenic [4–9], anti-ischemic [10], an- tiarrhythmic agents [1,11–14] and gene vectors [15–17]. Supported in part by the Herman C. Krannert Fund, Indiana University School of Medicine, National Heart Lung and Blood Institute of the National Institutes of Health, SCOR HL52323 and Medtronic Inc. Address for correspondence: Andr ´ as Vereckei, M.D., 3rd Depart- ment of Medicine, Semmelweis University, School of Medicine, Budapest, K ´ utv ¨ olgyi ´ ut 4, Hungary 1125. Fax: 36-1-225-0196; E- mail: vereckei@kut.sote.hu 269