title: Timing of treatment with ICRF-187 and its effect on chronic doxorubicin cardiotoxicity.
abstract: Studies were conducted to evaluate whether the timing of administration of ICRF-187 [(+)-1,2-bis(3,5 dioxopiperazinyl-1-yl)propane] would influence the degree of cardioprotection provided by this agent against the development of doxorubicin-induced chronic cardiomyopathy. Beagle dogs (8.5-14 kg) received either doxorubicin alone (1.75 mg/kg, i.v., n = 8), doxorubicin (1.75 mg/kg) simultaneously with ICRF-187 (35 mg/kg, i.v., n = 8), or doxorubicin (1.75 mg/kg) followed 2 h later by ICRF-187 (35 mg/kg, n = 8). Control animals received ICRF-187 (35 mg/kg, n = 4) or saline (n = 4). All animals received a course of seven treatments, each given 3 weeks apart, and were killed 3 weeks after the last treatment. Semiquantitative grading of histologic sections of myocardium showed that as compared with animals treated with doxorubicin alone, the incidence and the severity of the doxorubicin-induced myocardial lesions were reduced in the two groups of animals given doxorubicin plus ICRF-187. However, protection was significantly better in dogs receiving ICRF-187 and doxorubicin simultaneously than in those given ICRF-187 2 h after doxorubicin. These observations were interpreted as indicating that the timing of administration of ICRF-187 with respect to that of doxorubicin is an important factor in determining the degree of cardioprotection and that there is a "time window" in which ICRF-187 exerts optimal effects.
authors.affiliation: Division of Research and Testing, Food and Drug Administration, Laurel, MD 20708.
authors.forename: E H
authors.initials: EH
authors.lastname: Herman
authors.forename: V J
authors.initials: VJ
authors.lastname: Ferrans
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control*; D004285:Dogs; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005260:Female; D008297:Male; D011929:Razoxane / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D011929:Razoxane; D004317:Doxorubicin