Clinical Therapeutics/Volume 30, Number 4, 2008 Effects of Carvedilol on Left Ventricular Function and Oxidative Stress in Infants and Children with Idiopathic Dilated Cardiomyopathy: A 12-Month, Two-Center, Open-Label Study Milica Bajcetic, MD, PhD1; Aleksandra Nikolic Kokic, PhD2; Milan Djukic, MD, PhD3; Jovan Kosutic, MD, PhD4;Jadranka Mitrovic, MD3; Dejan Mijalkovic, MSc2; IdaJovanovic, MD, PhD3; Slavko Simeunovic, MD, PhD3; Mihajlo B. Spasic, PhD2; and Ranka Samardzic, MD, PhD1 1Department of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, Universityof Belgrade, Belgrade, Serbia; 2Department of Physiology, Institute for Biological Research "Sinisa Stankovic," Belgrade, Serbia; 3Department of Pediatric Cardiology, University Children's Hospital, Belgrade, Serbia; and 4Department of Pediatric Cardiology, Mother and Ch//d Institute, Belgrade, Serbia ABSTRACT Objectives: This study was conducted to determine the effects of carvedilol adjunct to standard treatment on left ventricular function (LVF), estimated as ejection fraction (EF) and fractional shortening (FS) on echo- cardiography, in children with idiopathic dilated car- diomyopathy (DCM). A secondary end point was to characterize the antioxidant potential of carvedilol. Methods: Hospitalized children aged _<16years with clinically stable DCM and advanced congestive heart failure (HF) with modified New York Heart Associa- tion Classification for Children (NYHAC) functional classes II to IV and EF <40% were enrolled in this pro- spective, 12-month, 2-center, open-label study. Oral carvedilol was added to a standard regimen of an angiotensin-converting enzyme inhibitor, a diuretic, and digoxin in a dose-escalation design. Systolic and dia- stolic blood pressure (BP), heart rate (HR), and modi- fied NYHAC were assessed before (baseline) and at 1, 3, 6, and 12 months of adjunct carvedilol treatment. EF and FS were analyzed before and at 6 and 12 months of carvedilol treatment. At each study visit, tolerability was assessed in terms of adverse events (AEs), treatment- emergent signs and symptoms, physical examination including vital sign measurement (BP, HR, and body temperature), and laboratory analysis. Antioxidative enzyme activity was evaluated by measuring erythro- cyte copper/zinc superoxide dismutase (SOD), cata- lase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activity at baseline and 1, 3, 6, and 12 months of adjunct carvedilol treatment. For assessment of antioxidative enzyme activity, a con- trol group comprised 29 age-matched healthy children. Results: Twenty-one children (12 boys, 9 girls; age range, 7 months to 16 years; 100% white) completed the study. Four patients discontinued carvedilol at the beginning of the study due to severe arrhythmia which required amiodarone therapy (2 patients), bradycar- dia and hypotension (1), and bronchospasm (1). Carve- dilol (0.4 mg/kg/d in children _<62.5 kg or 25 mg/d in children >62.5 kg) was associated with significant decreases from baseline in systolic BP (130 [4] vs 123 [3] mm Hg; P < 0.05), diastolic BP (85 [4] vs 77 [4] mm Hg; P < 0.05), and HR (81 [4] vs 65 [4] bpm; P < 0.001) after the first month of addition to stan- dard therapy. At 6 months, there were significant im- provements from baseline in EF (37.2% [2.4%] vs 50.2% [2.3%]; P < 0.001) and FS (18.37% [2.00%] vs 23.58% [0.90%]; P < 0.001). Modified NYHAC class was significantly improved in 80% of children (2.9 vs 2.3; P < 0.001) at 12 months. The highest dose of carve- dilol (0.8 mg/kg/d in children _<62.5 kg or 50 mg/d in children >62.5 kg) was well tolerated in all 21 chil- dren. No serious AEs that necessitated study drug dis- continuation (tiredness, headache, vomiting) were ob- served. At baseline, mean (SE) erythrocyte SOD activity (2781 [116] vs 2406 [102] U/g Hb; P < 0.05) and GR Accepted for pubfication February 22, 2008. doi:l 0.1016/j.clinthera.2008.04.007 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved. 702 Volume 30 Number 4