Noda T, Watanabe T, Kohda A, Hosokawa S, Suzuki T
Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka Prefecture, Japan.
Invest New Drugs. 1998;16(2):121-8. doi: 10.1023/a:1006088907271.
This study was designed to investigate the chronic cardiotoxic potential of SM-5887 and a possible deteriorating effect of SM-5887 on low-grade cardiotoxicity pre-induced by doxorubicin in beagle dogs. In the chronic treatment, beagle dogs of each sex were given intravenously once every 3 weeks, either a sublethal dose of doxorubicin (1.5 mg/kg) or SM-5887 (2.5 mg/kg). The experiment was terminated 3 weeks after the ninth dosing. Animals which received over six courses of doxorubicin demonstrated the electrocardiogram (ECG) changes, decrease of blood pressure and high-grade histopathological cardiomyopathy, while animals which were terminally sacrificed after the SM-5887 administration did not show any changes in ECG, blood pressure and histopathological examinations. To examine a possibly deteriorating cardiotoxic effect of SM-5887, low-grade cardiomyopathy was induced in dogs by four courses of doxorubicin (1.5 mg/kg). Nine weeks after pre-treatment, dogs were given four courses of either doxorubicin (1.5 mg/kg) or SM-5887 (2.5 mg/kg) once every 3 weeks. The low-grade cardiotoxic changes were enhanced by the additional doxorubicin treatment. On the contrary, the SM-5887 treatment did not progress the grade of cardiomyopathy. In conclusion, SM-5887 does not have any potential of chronic cardiotoxicity and deteriorating effect on doxorubicin-induced cardiotoxicity in dogs.
本研究旨在调查SM - 5887的慢性心脏毒性潜力，以及SM - 5887对在比格犬中由阿霉素预先诱导的轻度心脏毒性可能产生的恶化作用。在慢性治疗中，对各性别的比格犬每3周静脉注射一次，给予亚致死剂量的阿霉素（1.5mg/kg）或SM - 5887（2.5mg/kg）。在第九次给药后3周终止实验。接受超过六个疗程阿霉素治疗的动物出现了心电图（ECG）变化、血压下降和高度组织病理学心肌病，而在给予SM - 5887后终末处死的动物在心电图、血压和组织病理学检查中未显示任何变化。为了检查SM - 5887可能的恶化心脏毒性作用，通过四个疗程的阿霉素（1.5mg/kg）在犬中诱导轻度心肌病。预处理9周后，每3周给犬四个疗程的阿霉素（1.5mg/kg）或SM - 5887（2.5mg/kg）。额外的阿霉素治疗增强了轻度心脏毒性变化。相反，SM - 5887治疗并未使心肌病等级进展。总之，SM - 5887对犬没有任何慢性心脏毒性潜力，也不会对比阿霉素诱导的心脏毒性产生恶化作用。
