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Background. The development of a microcomputer-based device permits quick, simple, and noninvasive quantification of the respiratory sinus arrhythmia (RSA) during quiet breathing.Methods and Results. We prospectively and serially measured the radionuclide left ventricular ejection fraction and the RSA amplitude in 34 cancer patients receiving up to nine monthly bolus treatments with doxorubicin hydrochloride (60 mg/m2). Of the eight patients who ultimately developed symptomatic doxorubicin-induced congestive heart failure, seven (87.5%) demonstrated a significant decline in RSA amplitude; five of 26 subjects without clinical symptoms of cardiotoxicity (19.2%) showed a similar RSA amplitude decline. On average, significant RSA amplitude decline occurred 3 months before the last planned doxorubicin dose in patients destined to develop clinical congestive heart failure.Conclusion. Overall, RSA amplitude abnormality proved to be a more specific predictor of clinically significant congestive heart failure than did serial resting radionuclide ejection fractions. (Circulation 1991;84:697-707)

Compared to doxorubicin, equimolar epirubicin toxicity is reduced by about 50% by the epimerization of a hydrogen and hydroxyl group at the 4' position of the anthracycline sugar moiety. The circadian timing of doxorubicin administration markedly affects its lethal and sub-lethal bone marrow and gut toxicities in mice, as well as the severity of its clinical toxicity. We tested whether the timing of administration of equitoxic epirubicin doses similarly affected the toxicological response in female CD2F1 mice. A large and highly reproducible effect of the circadian stage of administration was documented with best drug tolerance occurring during the first half of the daily rest (light) span of the animals. In addition to this circadian rhythm, a significant seasonal effect was found with significantly fewer deaths occurring after epirubicin was given in the Summer, as compared to the Winter. Safest circadian timing for epirubicin is statistically significantly earlier in the day than for doxorubicin, while their seasonal patterns are quite similar.