Shunji Hosokawa

Chronic effects of a novel synthetic anthracycline derivative (SM-5887) on normal heart and doxorubicin-induced cardiomyopathy in beagle dogs

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.

Carcinogenicity studies of oxolinic acid in rats and mice

A chronic feeding study was conducted to determine the carcinogenic potential of oxolinic acid, an antimicrobial agent, in rats and mice. Oxolinic acid was administered in the diet to Wistar rats (0, 30, 100, 300 or 1000 ppm; 50 rats/dose/sex) for 104 wk and to ICR mice (0, 50, 150 or 500 ppm; 50 mice/dose/sex) for 78 wk. Clinical signs, body weight, food consumption, autopsy findings and histopathological data were noted. Mortality was unaffected by oxolinic acid administration in neither species. In rats, body weight gain was suppressed in both sexes at 1000 ppm. Histopathological examinations conducted after autopsy at 104 wk revealed a slight increase in benign Leydig cell tumours of the testis at 1000 ppm, which did not appear until late in the lifetime of rats. No other treatment-related neoplastic lesions were observed in rats. Non-neoplastic lesions in males at 1000 ppm included Leydig cell hyperplasia and tubular atrophy of the testes. In mice, decreased body weight gain was observed in both sexes at 500 ppm, but no non-neoplastic or neoplastic lesions attributable to the treatment with oxolinic acid occurred in either sex. In conclusion, oxolinic acid induced benign Leydig cell tumours of the testis in rats at the highest dose level tested (1000 ppm). The no-effect level for tumour induction was confirmed to be 300 ppm (10.9 mg/kg/day) in rats. None was induced in mice.

Effect of chronic l-DOPA administration on serum luteinizing hormone levels in male rats

We examined whether the repeated oral administration with a high dose of L-3-(3,4-dihydroxyphenyl)-alanine (L-DOPA) in 0.5% carboxymethyl cellulose increases serum luteinizing hormone (LH) levels in male rats. Serum LH levels were increased 4 h after a single administration of 1000 mg/kg L-DOPA to male rats, and returned to control levels within 8 h after administration. Four hours after a single administration, serum LH levels were significantly increased by L-DOPA at 1000 mg/kg, but not at 20, 100 or 200 mg/kg. Decreases in body weight and relative weight of the prostate were observed after 7 and 14 days of administration of 1000 mg/kg per day L-DOPA, but no changes were observed in weight of the testis, epididymis or seminal vesicle. The administration of L-DOPA at 500 or 1000 mg/kg per day for 7 or 14 days resulted in increased basal serum LH levels and decreased basal serum prolactin levels 24 h after the last administration. Serum testosterone levels tended to be higher in treated than in control rats. The levels of two metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in rats treated with 500 mg/kg per day tended to be slightly higher than those in control rats after 7 days of administration. Levels of DA, DOPAC and HVA were significantly increased after 7 and 14 days of administration of 1000 mg/kg per day and after 14 days of administration of 5000 mg/kg per day. The level of norepinephrine, but not its metabolite 3-methoxy-4-hydroxyphenylglycol, was significantly increased after only 7 days of administration of 1000 mg/kg per day. No significant changes were observed in levels of 5-hydroxytryptamine or its metabolite 5-hydroxyindole-3-acetic acid with administration of 500 or 1000 mg/kg per day. These findings suggest that a prolonged treatment with a high dose of L-DOPA in male rats induces release of LH from the pituitary, resulting in sustained elevation of LH levels in peripheral circulation.