OBJECTIVETo investigate the effect of low-dose carvedilol combined with candesartan in the prevention of acute and chronic cardiotoxicity of anthracycline drugs in adjuvant chemotherapy of breast cancer.

METHODSForty patients were randomly divided into two groups: the experimental group with chemotherapy plus low-dose carvedilol combined with candesartan (20 cases) and control group with chemotherapy alone (20 cases). The same chemotherapy was given to the two groups. All the 40 patients had no contraindication for carvedilol and candesartan. Patients of the experimental group received low-dose carvedilol from 2.5 mg orally twice a day at first cycle to 5 mg twice a day gradually if no side reactions, and candesartan 2.5 mg orally once a day. Electrocardiogram, ultrasonic cardiogram, arrhythmia, troponin and non-hematologic toxicity were recorded and compared after the second, forth and sixth cycle of chemotherapy. Each cycle included 21 days.

RESULTSLVEF was decreased along with the prolongation of chemotherapy in the experimental group and control group. LVEDD and LVESD showed no significant changes in the experimental group, but gradually increased in the control group. After four and six cycles of chemotherapy, LVEF were (57.00 ± 5.13)% and (45.95 ± 3.68)%, respectively, in the control group, significantly lower than that of (67.00 ± 5.13)% and (57.50 ± 2.57)%, respectively, in the experimental group (P < 0.05). After six cycles of chemotherapy, LVEDD and LVESD were (50.00 ± 10.48) mm and (35.01 ± 2.99) mm, respectively, in the control group, significantly higher than those before chemotherapy (P < 0.05) and experimental group (P < 0.001). The rate of ST segment and T wave abnormalities was 80.0% in the control group after six cycles of chemotherapy, significantly higher than that of 25.0% after four cycles of chemotherapy (P = 0.001) and 10.0% after two cycles of chemotherapy (P < 0.001). The reduction of QRS voltage, arrhythmia and abnormal troponin were 55.0%, 45.0% and 45.0%, respectively, in the control group, significantly higher than those in the experimental group (20.0%, P < 0.05), (10.0%, P = 0.010) and (10.0%, P < 0.05), respectively. The rate of abnormal expression of troponin was 45.0% in the control group, significantly higher than the 10.0% in the experimental group (P < 0.05).

CONCLUSIONSThe use of low-dose carvedilol combined with candesartan can reduce the acute and chronic cardiotoxicity of anthracycline drugs, and with tolerable toxicities. This may provide a new approach to prevent cardiotoxicity of anthracycline drugs in adjuvant chemotherapy of breast cancer.

Adrenergic beta-Antagonists ; administration & dosage ; pharmacology ; Adult ; Aged ; Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Arrhythmias, Cardiac ; chemically induced ; Benzimidazoles ; administration & dosage ; pharmacology ; Breast Neoplasms ; drug therapy ; surgery ; Carbazoles ; administration & dosage ; pharmacology ; Chemotherapy, Adjuvant ; Cyclophosphamide ; adverse effects ; therapeutic use ; Electrocardiography ; drug effects ; Epirubicin ; adverse effects ; therapeutic use ; Female ; Fluorouracil ; adverse effects ; therapeutic use ; Humans ; Mastectomy, Radical ; Middle Aged ; Propanolamines ; administration & dosage ; pharmacology ; Stroke Volume ; drug effects ; Tetrazoles ; administration & dosage ; pharmacology ; Troponin ; metabolism

The purpose of the present study was to examine the effects of oxidative stress on ventricular arrhythmias in rabbits with adriamycin-induced cardiomyopathy and the relationship between oxidative stress and ventricular arrhythmia. Forty Japanese white rabbits were randomly divided into four groups (n=10 in each): control group, metoprolol (a selective β1 receptor blocker) group, carvedilol (a nonselective β blocker/α-1 blocker) group and adriamycin group. Models of adriamycin-induced cardiomyopathy were established by intravenously injecting adriamycin hydrochloride (1 mg/kg) to rabbits via the auri-edge vein twice a week for 8 weeks in the adriamycin, metoprolol and carvedilol groups. Rabbits in the control group were given equal volume of saline through the auri-edge vein. Rabbits in the metoprolol and carvedilol groups were then intragastrically administrated metoprolol (5 mg/kg/d) and carvedilol (5 mg/kg/d) respectively for 2 months, while those in the adriamycin and control groups were treated with equal volume of saline in the same manner as in the metroprolol and carvedilol groups. Left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) were measured by echocardiography. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), malondialdehyde (MAD) and superoxide dismutase (SOD) were detected. The left ventricular wedge preparations were perfused with Tyrode's solution. The transmural electrocardiogram, transmural action potentials from epicardium (Epi) and endocardium (Endo), transmural repolarization dispersion (TDR) were recorded, and the incidences of triggered activity and ventricular arrhythmias were obtained at rapid cycle lengths. The results showed that TDR and the serum MDA and NT-proBNP levels were increased, and LVEF and the serum SOD level decreased in the adriamycin group compared with the control group. The incidences of triggered activity and ventricular arrhythmia were significantly higher in the adriamycin group than those in the control group (P<0.05). In the carvedilol group as compared with the adriamycin group, the serum SOD level and the LVEF were substantially increased; the TDR, and the serum MDA and NT-proBNP levels were significantly decreased; the incidences of triggered activity and ventricular arrhythmia were obviously reduced (P<0.05). There were no significant differences in the levels of MDA and SOD, LVEF, TDR and the incidences of triggered activity and ventricular arrhythmia between the adriamycin group and the metoprolol group. It was concluded that carvedilol may inhibit triggered activity and ventricular arrhythmias in rabbit with adriamycin-induced cardiomyopathy, which is related to the decrease in oxygen free radials.
Animals ; Anti-Arrhythmia Agents ; administration & dosage ; Antibiotics, Antineoplastic ; Carbazoles ; administration & dosage ; Cardiomyopathies ; chemically induced ; physiopathology ; prevention & control ; Doxorubicin ; Heart Rate ; drug effects ; Male ; Metoprolol ; administration & dosage ; Oxidative Stress ; drug effects ; Propanolamines ; administration & dosage ; Rabbits ; Treatment Outcome ; Ventricular Fibrillation ; chemically induced ; physiopathology ; prevention & control

BACKGROUND/AIMS: Carvedilol is an antioxidant that inhibits smooth muscle cell proliferation and migration. The aim of this study was to investigate the beneficial effects of carvedilol-loaded stents on 2-year clinical outcomes after stent implantation in patients with coronary artery disease. METHODS: We performed a prospective trial with male subjects to compare the safety and effects of carvedilol-loaded BiodivYsio(R) stents implanted into 20 patients with those of bare-metal BiodivYsio(R) stents implanted into 21 patients for de novo coronary lesions. The primary end point was the degree of neointimal hyperplasia, which was measured by intravascular ultrasound (IVUS) 6 months after the procedure; the secondary end point was major adverse cardiac events (MACE) at 2 years after implantation. All carvedilol and control stents were deployed successfully. RESULTS: A 2-year follow-up was completed for 19 patients (95%) in the carvedilol stent group and 20 patients (95%) in the control stent group. IVUS showed a trend toward a larger luminal area (6.86 +/- 2.59 vs. 5.47 +/- 1.52 mm2, p = 0.267), smaller neointimal area (1.34 +/- 0.70 vs. 2.40 +/- 1.73 mm2, p = 0.18), and reduced net decrease in luminal area (-0.78 +/- 0.97 vs. -1.89 +/- 1.78 mm2, p = 0.106) in the carvedilol stent group compared with the control stent group, respectively. There were no significant differences in the incidence of MACE (10.5 vs. 30.0%, respectively, p = 0.132) between the groups at 2 years after stent implantation. Stent thrombosis did not occur in either group after 2 years. CONCLUSIONS: The carvedilol-loaded stents tended to inhibit neointimal hyperplasia without the occurrence of cardiac death, myocardial infarction, or stent thrombosis at 2-year follow-up.
Aged ; *Angioplasty, Balloon, Coronary ; Carbazoles/*administration & dosage ; Coronary Artery Disease/*therapy ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Propanolamines/*administration & dosage ; Prospective Studies ; *Stents ; Treatment Outcome ; Ultrasonography, Interventional