detorubicin and Heart-Failure

Six anthracycline antibiotics with demonstrated antitumor activity in human or experimental tumor systems were studied. The purpose of this investigation was to compare the cardiotoxic potential of these compounds and to characterize the myocardial pharmacokinetics in order to provide a possible explanation for differences in cardiotoxicity. Groups of rabbits received i.v. injections of drug at maximally tolerated treatment doses with respect to lymphohematopoietic toxicity for periods of 11 or 16 weeks and were evaluated histopathologically for the development of myocardial damage. Following a single i.v. administration of the different anthracyclines to rabbits, the amount of parent drug and metabolites accumulating in the heart at various times was determined by high-pressure liquid chromatography and fluorometry. Adriamycin (ADR), daunorubicin (DNR), and detorubicin produced similar severe cardiomyopathy with frequent congestive heart failure at approximately equal dose levels. Three additional antibiotics, rubidazone and the N-L-leucyl derivatives of ADR and DNR (N-L-leucyl-adriamycin and N-L-leucyl-daunorubicin), produced significantly less severe lymphohematopoietic toxicity, thus permitting the administration of 3 to 3.5 times the ADR and DNR treatment doses. Chronic treatment with these anthracyclines also resulted in significantly less cardiomyopathy, especially in the case of N-L-leucyl-daunorubicin and rubidazone. This reduced cardiomyopathy correlated with lower total myocardial drug accumulation but, more importantly, with lower amounts of DNR or ADR accumulation in the heart. These findings suggest that the degree of anthracycline myocardial toxicity may be directly related to the relative qualitative and quantitative accumulation of drug metabolites in the myocardium.

Topics: Animals; Antibiotics, Antineoplastic; Chromatography, High Pressure Liquid; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Female; Fluorometry; Glycosides; Heart Diseases; Heart Failure; Injections, Intravenous; Kinetics; Myocardium; Naphthacenes; Rabbits

A 58-year-old man with subcutaneous metastases from a naevocarcinoma was prescribed 1 138 mg/m2 of a new anthracylic derivative, dietoxy-acetoxy-daunorubicine, at doses of 180 mg every three weeks. Irreversible cardiac failure occurred nine months after starting treatment, and was considered to be due to the toxic effects of the compound. He improved for a short period after very high doses of vasodilatators but death occured very shortly afterwards. Histological examination revealed severe subendocardial fibrosis, disseminated interstitial fibrosis, and degenerative and necrotic lesions of the myocytes. The authors discuss the factors involved in the cardiotoxicity of the anthracyclines: total dose, intervals between doses, associated risk, factors (age, radiotherapy). Even at usual doses signs of myocardial dysfunction are found in one third of patients treated, with the presence of histological lesions in all these cases, but clinical cardiac failure is rarely observed.

Topics: Cardiomyopathies; Daunorubicin; Heart Failure; Humans; Male; Melanoma; Middle Aged; Myocardium; Skin Neoplasms