Pretreatment with ICRF-187 allows a marked increase in the total cumulative dose of doxorubicin tolerated by beagle dogs.
To study the influence of ICRF-187 on the functional and morphological effects of very large cumulative doses of doxorubicin, adult beagle dogs were given doxorubicin (1.75 mg/kg i.v.) either alone or 15 min after ICRF-187 (25 mg/kg, i.v.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg, i.v.) or 0.9% saline without doxorubicin. Of eight animals receiving doxorubicin alone, two died after a total dose of 12.25 mg/kg and three died after 14 mg/kg; three others were in poor condition at the time of euthanasia after 14 mg/kg. Of eight animals receiving both ICRF-187 and doxorubicin, one died after 35 mg/kg, two died after 43.75 mg/kg and one died after 52.5 mg/kg; two dogs were euthanatized after 43.75 mg/kg because of difficulties encountered in giving i.v. injections, and two dogs survived a total dose of 52.5 mg/kg. All control dogs survived. None of the treatment or control groups developed consistent echocardiographic changes or alterations in mean arterial pressure. Dogs given ICRF-187 and doxorubicin developed PQ interval prolongation after 300 days and ventricular premature beats after 500 days. Each animal receiving doxorubicin alone had severe myocardial lesions (lesion score 3+). Of the animals given ICRF-187 and doxorubicin, one that received 35 mg/kg doxorubicin had no lesions; of four given 43.75 mg/kg, three had no lesions and one had minimal lesions (lesion score 1+); of three given 52.5 mg/kg, one had minimal (lesion score 1+) and two had moderate (lesion score 2+) lesions. Control animals had no myocardial lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Herman
E H
EH
Division of Drug Biology, Food and Drug Administration, Washington, DC 20204.
Ferrans
V J
VJ
Young
R S
RS
Hamlin
R L
RL
D000818:Animals; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D004361:Drug Tolerance; D004452:Echocardiography; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced*; D008099:Liver / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011929:Razoxane / Q000008:administration & dosage / Q000494:pharmacology*
D010879:Piperazines; D011929:Razoxane; D004317:Doxorubicin