RESUMEN
The cardioprotective potentials of prenylamine (a calcium antagonist) and of a combination of vitamins A and E (a singlet oxygen quencher and a free radical scavenger, respectively) were evaluated in rabbits given chronically large doses of Adriamycin (ADM) (10.8 mg/kg body weight for 9 to 11 weeks). Among ADM-treated rabbits, 8 of 10 showed post-treatment ECG changes; in rabbits treated with ADM and prenylamine, changes were found in a smaller number (5 of 10); and in animals treated with ADM and vitamins A and E, the incidence was only one in six (p less than 0.05). Heart homogenates from ADM-treated rabbits showed an increased hydroperoxide-initiated chemiluminescence (expressed as cpm/mg protein X 10(-3)) of 77 +/- 4 compared to control animals (52 +/- 1) (p less than 0.01). Prenylamine administration did not alter hydroperoxide-initiated chemiluminescence in ADM-treated rabbits, whereas treatment with a combination of vitamins A and E showed a significant decrease in hydroperoxide-initiated chemiluminescence in control (40 +/- 2) and ADM-treated rabbits (42 +/- 1). Microscopically, myocardial fibers had mild to severe hydropic vacuolization of sarcoplasm, which led to progressive myocytolysis. A total of 103 +/- 13 damaged fibers were detected over 700 counted fibers. Myocardial damage was lowered to 47 +/- 16 by administration of prenylamine and to 28 +/- 8 by administration of vitamins A and E. It is suggested that ADM leads to myocardial lipid peroxidation (ameliorated by vitamins A and E) with membrane damage and to an increase in calcium permeability, the latter being counteracted by prenylamine.
Asunto(s)
Doxorrubicina/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Prenilamina/uso terapéutico , Vitamina A/uso terapéutico , Vitamina E/uso terapéutico , Animales , Sinergismo Farmacológico , Electrocardiografía , Femenino , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/prevención & control , Peróxido de Hidrógeno/metabolismo , Mediciones Luminiscentes , Masculino , Miocardio/patología , ConejosRESUMEN
Adriamycin (ADM) and 4'-epiadriamycin (4'-ADM) were given to mice in a single dose of 15 mg/kg body weight (i.p.). Twenty-five mice were alloted to 3 groups. One group (Group I; n = 8) was given ADM; another group (Group II; n = 9) was similarly treated with 4'-ADM, and a control group (n = 8) received an equivalent volume of 0.9% NaCl solution. Mice were sacrificed 4 days after the described treatment. A complete autopsy was carried out in each animal. Hydroperoxide-initiated chemiluminescence and malonaldehyde formation were measured in mouse heart homogenates. Control mice showed a maximal photoemission of 52 +/- 2 (X 10(-3)) (mean values +/- S.E.M.) cpm/mg protein and a formation of 20 +/- 4 nmol malonaldehyde/g organ after a 2 hr-incubation. The ADM-treated mice showed a 24% enhanced hydroperoxide-initiated photoemission and a 370% increased malonaldehyde formation. The 4'-ADM-treated mice showed a 15% increased hydroperoxide-stimulated chemiluminescence and an 85% increased malonaldehyde formation. Vitamin A (5000 IU), vitamin E (85 IU) and vitamins A and E (same doses as before) given as a single dose i.p. 1 day before doxorubicin administration were able to decrease the hydroperoxide-initiated chemiluminescence by 24%, 26% and 44%, respectively. Microscopically, only scarce isolated microvacuolated subendocardial fibers were found in the ADM-treated animals. Our data showing that 4'-ADM lacks a statistically significant effect in increasing heart peroxidation as compared to ADM may explain its lower myocardial toxicity.
Asunto(s)
Doxorrubicina/farmacología , Cardiopatías/inducido químicamente , Peróxidos Lipídicos/metabolismo , Miocardio/metabolismo , Animales , Fenómenos Químicos , Química , Doxorrubicina/toxicidad , Epirrubicina , Femenino , Humanos , Malondialdehído/metabolismo , Ratones , Vitamina A/farmacología , Vitamina E/farmacologíaRESUMEN
Adriamycin (ADM) is an effective antineoplastic drug. However, ADM induces alterations in cardiac function which limit the safe dose which can be administered. As it was suggested that ADM-induced cardiomyopathy is related to a calcium mediated necrosis and/or an increase in lipid peroxidation, the cardioprotective potential of prenylamine (PNL) (a well known calcium antagonistic drug) was evaluated in rabbits given chronically large doses of ADM. Twenty five rabbits were allotted to 4 groups. Group I (PNL-ADM) was given 334 +/- 82 mg of PNL and 12.2 +/- 3.8 mg of ADM, group II (water-ADM) 14.4 +/- 4.6 of ADM, group III (PNL-saline) 280 +/- 91 mg of PNL and group IV (water-saline), same doses as ADM and PNL. Rabbits were sacrificed between 38 and 65 days after the beginning of the trial. In group I weight increased only 13% and in group II, 39% (p less than 0.01). Correlation coefficients were significant for variations of weight and ADM-doses (r = 0.875). In group II 8/10 rabbits showed post-treatment electrocardiographic changes, while group I changes were found in a lesser extent (5/10). Heart homogenates from ADM-treated rabbits showed an increased lipoperoxidation (74 +/- 5 cpm/mg protein X 10(-3) as compared with the control animals (58 +/- 6 cpm/mg protein X 10(-3) (p less than 0.05), while PNL treatment did not alter myocardial lipoperoxidation. Microscopically, myocardial fibers had from mild to severe hydropic vacuolization of sarcoplasm which led to progressive myocytolysis. Myocardial damage was lower in group I (ADM-PNL), 41.7 +/- 7.6 than in group II (water-ADM), 104 +/- 10.8 (p less than 0.05). It is suggested that ADM-peroxidation effects lead to lipoperoxidation with membrane damage and increase in Ca++ permeability, the latter being counteracted by PNL.