PMID- 18498919
OWN - NLM
STAT- MEDLINE
DCOM- 20081118
LR  - 20190923
IS  - 0149-2918 (Print)
IS  - 0149-2918 (Linking)
VI  - 30
IP  - 4
DP  - 2008 Apr
TI  - 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.
PG  - 702-14
AB  - 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 echocardiography, in 
      children with idiopathic dilated cardiomyopathy (DCM). A secondary end point was 
      to characterize the antioxidant potential of carvedilol. METHODS: Hospitalized 
      children aged <or=16 years with clinically stable DCM and advanced congestive 
      heart failure (HF) with modified New York Heart Association Classification for 
      Children (NYHAC) functional classes II to IV and EF <40% were enrolled in this 
      prospective, 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 diastolic blood pressure (BP), 
      heart rate (HR), and modified 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 erythrocyte copper/zinc superoxide dismutase (SOD), 
      catalase (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 control 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), bradycardia and hypotension (1), 
      and bronchospasm (1). Carvedilol (0.4 mg/kg/d in children <or=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 standard therapy. At 6 months, there were significant improvements 
      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 carvedilol (0.8 mg/kg/d in children <or=62.5 kg or 50 mg/d in children >62.5 
      kg) was well tolerated in all 21 children. No serious AEs that necessitated study 
      drug discontinuation (tiredness, headache, vomiting) were observed. At baseline, 
      mean (SE) erythrocyte SOD activity (2781 [116] vs 2406 [102] U/g Hb; P<0.05) and 
      GR activity (5.3 [0.3] vs 3.0 [0.2] micromol nicotinamide adenine dinucleotide 
      phosphate [NADPH]/min/g Hb; P<0.001) were significantly higher in children with 
      DCM who received standard therapy compared with healthy controls.CAT activity 
      (12.7[0.9] vs 18.5 [1.0]U/g Hb; P<0.001) was significantly lower, while GSH-Px 
      was unchanged. At 6 and 12 months of therapy, carvedilol plus standard treatment 
      was associated with significant decreases from baseline in SOD (2516 [126] and 
      2550 [118], respectively, vs 2781 [116] U/g Hb; both, P<0.001) and GR (4.7 [0.3] 
      and 4.1 [0.2], respectively, vs 5.3 [0.2] micromol NADPH/min/g Hb; P<0.05 and 
      P<0.001) and increased CAT (16.9 [1.0] and 16.4 [0.7], respectively, vs 12.7 
      [0.9] U/g Hb; both, P<0.001). CONCLUSIONS: These pediatric patients with DCM 
      treated for 12 months with carvedilol (up to 0.8 mg/kg/d in children <or=62.5 kg 
      or 50 mg/d in children >62.5 kg) were found to have significant improvements in 
      LVF and symptoms of HF. Twelve months of carvedilol therapy was associated with 
      antioxidant enzyme activities near those observed in healthy children.
FAU - Bajcetic, Milica
AU  - Bajcetic M
AD  - Department of Pharmacology, Clinical Pharmacology and Toxicology, School of 
      Medicine, University of Belgrade, Belgrade, Serbia. mbajcetic@doctor.com
FAU - Kokic Nikolic, Aleksandra
AU  - Kokic Nikolic A
FAU - Djukic, Milan
AU  - Djukic M
FAU - Kosutic, Jovan
AU  - Kosutic J
FAU - Mitrovic, Jadranka
AU  - Mitrovic J
FAU - Mijalkovic, Dejan
AU  - Mijalkovic D
FAU - Jovanovic, Ida
AU  - Jovanovic I
FAU - Simeunovic, Slavko
AU  - Simeunovic S
FAU - Spasic, Mihajlo B
AU  - Spasic MB
FAU - Samardzic, Ranka
AU  - Samardzic R
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Carbazoles)
RN  - 0 (Propanolamines)
RN  - 0K47UL67F2 (Carvedilol)
RN  - EC 1.11.1.6 (Catalase)
RN  - EC 1.11.1.9 (Glutathione Peroxidase)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.8.1.7 (Glutathione Reductase)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adrenergic beta-Antagonists/administration & dosage/*therapeutic use
MH  - Blood Pressure/drug effects
MH  - Carbazoles/administration & dosage/*therapeutic use
MH  - Cardiomyopathy, Dilated/blood/*drug therapy/physiopathology
MH  - Carvedilol
MH  - Catalase/blood
MH  - Child
MH  - Child, Preschool
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Follow-Up Studies
MH  - Glutathione Peroxidase/blood
MH  - Glutathione Reductase/blood
MH  - Heart Rate/drug effects
MH  - Humans
MH  - Infant
MH  - Male
MH  - Oxidative Stress/*drug effects
MH  - Propanolamines/administration & dosage/*therapeutic use
MH  - Prospective Studies
MH  - Stroke Volume/drug effects
MH  - Superoxide Dismutase/blood
MH  - Treatment Outcome
MH  - Ventricular Function, Left/*drug effects/physiology
EDAT- 2008/05/24 09:00
MHDA- 2008/11/19 09:00
CRDT- 2008/05/24 09:00
PHST- 2008/02/22 00:00 [accepted]
PHST- 2008/05/24 09:00 [pubmed]
PHST- 2008/11/19 09:00 [medline]
PHST- 2008/05/24 09:00 [entrez]
AID - S0149-2918(08)00146-X [pii]
AID - 10.1016/j.clinthera.2008.04.007 [doi]
PST - ppublish
SO  - Clin Ther. 2008 Apr;30(4):702-14. doi: 10.1016/j.clinthera.2008.04.007.