Attenuation of cardiotoxicity of daunomycin using a complex with heparin.

Daunomycin (DM) is one of the most important antitumor agents. However, the cardiotoxicity of DM limits it's clinical use. We have made an ionic complex with heparin to decrease the cardiotoxicity. Cardiotoxicities of DM and DM-heparin complex were compared in hamsters. On the electrocardiogram (ECG), two of the four hamsters given DM showed the serious abnormality, bidirectional ventricular premature contraction, while the hamsters given DM-heparin or saline had no abnormalities. On pathological examination, cardiac tissue in hamsters given DM showed deposition of basophilic materials, mild eosinophilic change of myofibrils and microvascuolization, whereas no change was observed in hamsters given DM-heparin complex or saline. Acute toxic effects on survival rates and body weights were more profound in DM-infused mice than in DM-heparin-infused mice. DM and DM-heparin complex showed similar anticancer activity both in vivo and in vitro. Thus, the present study suggests that the DM-heparin complex may attenuate the cardiotoxicity of DM without affecting it's antitumor effect in humans.

[Tissue levels of pirarubicin (THP) in dogs following intra-arterial infusion].

The blood and tissue levels of pirarubicin (THP) were studied in dogs by HPLC analysis. The THP (1.5 mg/kg) was infused from the bifurcation of internal iliac artery. We measured the concentration of THP after 1 or 2 hours of intra-arterial infusion (IA) and compared with the concentration of THP administered intravenously (IV). The plasma levels of THP following IA rapidly disappeared the same as for IV. The blood cell level of THP following both IA and IV was significantly higher than the plasma level. The bladder mucosa and muscle levels of THP following IA were about 8 times as high as that of IV. The bladder muscle level of THP 2 hours after IA was about twice as high as after 1 hour and the same as the bladder mucosa level of THP after both 1 and 2 hours. It is considered that THP by the present method may have the transition from the mucosa to the muscle in the bladder. In the other intrapelvic tissues (perivesical adipose tissue, pelvic lymph node and prostate), IA also had higher concentrations compared with IV. However, the extrapelvic tissues (heart, liver and kidney) levels of THP following IA were the same as those for IV. It was concluded that THP was a reasonable agent for IA chemotherapy for bladder cancer.

[Cardiotoxicity study of ME2303 with the interval intravenous injections to rats].

Cardiotoxic effects of ME2303 were studied upon interval intravenous administrations to rats in comparison with those of doxorubicin (ADR). ME2303 at two dose levels of 3 and 9 mg/kg/day or ADR at a dose levels of 3 mg/kg/day was injected once a week for 3 weeks to female Sprague-Dawley rats (SPF) of 5-weeks of age. ADR depressed body weight gain, decreased food intake and increased water intake. Microscopic observation on the myocardial tissues revealed that ADR caused necrosis and cell infiltration, edema and disarrangement of myofibrils in some of ADR-treated rats. On the other hand, ME2303 showed no significant effects except that some decrease of food intake was observed at a dose level 9 mg/kg/day. No changes in left ventricular functions were observed in perfused hearts isolated from ADR- or ME2303-treated rats. However, about 133 ng/g of ADR remained in the hearts even at 1 week after the final administration whereas ME2303 or its metabolites were not detected, suggesting that ADR may cause disturbance of ventricular function and more cardiomyopathy after a longer term than 1 week following the final administration. These results suggest that the cardiotoxicity of ME2303 is weaker than that of ADR in rats.

Histo-chemical studies on the anti-ulcer effect of bamboo grass in rats.

Oral administration of a hot-water extract (Folin) of bamboo grass (Sasa albomarginata Makino & Shibata) significantly reduced the incidence of water-immersion and restraint stress-, ethanol-induced and indomethacin-induced gastric ulcers in rats. Histological examination of the Folin-treated gastric mucosa showed that microscopic blood clots overlaid the superficial epithelium, maintaining the cellular integrity of gastric mucosa, especially against stress ulcer. In addition, Folin suppressed the incidence of hyperaemia and a decline of acid mucopolysaccharides in the ethanol-induced ulcer. Folin suppressed a release of histamine from rat mast cells, and stabilized erythrocytes and accelerated their agglutination under acid conditions. These results suggest that a microscopic haemostatic effect of Folin reinforced by a membrane-stabilizing effect might be responsible for the prevention of the gastric lesions.

[Toxicological studies on (2''R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic. Its acute toxicity in beagle dogs].

(2"R)-4'-O-Tetrahydropyranyladriamycin (THP), a new antitumor antibiotic of anthracycline derivative, was given intravenously to male and female Beagle dogs, followed by observations for 2 weeks. The doses were 0.125, 0.25, 0.5 and 1.0 mg/kg. Observations were performed on mortality, clinical signs, body weight and temperature, food and water consumption, ECG, ophthalmoscopy, testicular measurement, hematology, serum biochemistry, urinalysis, autopsy, histopathology and electron microscopy. The results were as follows. All animals of 1 mg/kg-treated group died but there were no deaths in other groups. All the levels of doses caused vomiting and diarrhea. Furthermore, the highest dose caused bloody diarrhea and decreases in food consumption, motility and body weight, followed by death. These effects may be related to histopathological changes in mucosa of digestive tract. Some changes in water consumption, urine volume and renal histopathology were sporadically observed after treatment, but they were not treatment-related. These results suggest that a treatment with THP does not significantly cause renal disturbance. There were no treatment-related changes in body temperature, ophthalmoscopical observation and testicular measurement. THP produced flattening of T wave and prolongation of QRS interval only at high doses of more than 0.5 mg/kg for males and of 1 mg/kg for females but did not cause any histopathological or electron microscopical changes in hearts. It seems that the abnormalities caused by THP in ECG traces are due to the deterioration of general conditions rather than the direct effect on heart. High doses produce the significant changes in platelet, WBC, Hb, Neutro. (Seg.), Mono., Hb, RBC and Lymph. and further regressive changes in thymus, spleen and bone marrow. These results suggest that THP causes some effects on hemopoietic tissues. The sporadic changes in serum biochemistry and urinalysis were neither related to the treatment nor to the changes in organ weight, autopsy, histopathology and electron microscopy. Therefore, it is likely that THP does not cause toxicological effect on the other tissues and organs except hemopoietic tissues.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-1. Toxicity of metabolites of miocamycin: acute toxicity of Mb1 in mice.

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic isolated from a culture broth of Streptomyces mycarofaciens. MOM is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. The object of this study was to evaluate acute toxicity in male and female mice after single oral administration of Mb1, a metabolite of MOM, at a dose level of 5,000 mg/kg as the maximum physically applicable dose. Observations were kept for 1 week after administration. In conclusion, Mb1 exhibited no acute toxicity in present study. The LD0 values were estimated as more than 5,000 mg/kg.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-2. Toxicity of metabolites of miocamycin: acute toxicity of Mb1 in rats.

Acute toxicity studies on miocamycin (MOM), non-crystalline solid, and its metabolite Mb1 were performed in mice in the previous studies. In the present studies, we evaluated acute toxicity of Mb1 in male and female rats after single oral administration at the maximum physically applicable dose of 5,000 mg/kg. Observations were continued for 1 week after treatment. It is concluded that LD0 values of Mb1 were estimated more than 5,000 mg/kg.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-3. Toxicity of metabolites of miocamycin: subacute toxicity of Mb1 in rats.

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous study, LD0 values of Mb1 were estimated more than 5,000 mg/kg in male and female rats as Mb1 did not exhibited any lethal toxicity even at the maximum physically applicable dose of 5,000 mg/kg. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb1 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxicity was observed in this subacute toxicity study on Mb1 in rats.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-4. Toxicity of metabolites of miocamycin: acute toxicity of Mb2 in mice.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites. At previous study, LD0 values of Mb1 were estimated more than 5,000 mg/kg in male and female mice. The object of this study was to evaluate acute toxicity in male and female mice after single oral administration of Mb2, a metabolite of MOM, at a dose level of 5,000 mg/kg as the maximum physically applicable dose. It is concluded that LD0 values of Mb2 were estimated more than 5,000 mg/kg.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-5. Toxicity of metabolites of miocamycin: acute toxicity of Mb2 in rats.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites. At previous study, LD0 values of Mb1 were estimated more than 5,000 mg/kg in male and female rats. The object of this study was to evaluate acute toxicity in male and female rats after single oral administration of Mb2, a metabolite of MOM. It is concluded that LD0 values of Mb2 were estimated more than 5,000 mg/kg.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-6. Toxicity of metabolites of miocamycin: subacute toxicity of Mb2 in rats.

Miocamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. At previous study, the acute and subacute toxicity of Mb1 and acute toxicity of Mb2 were performed that those metabolites did not exhibit any lethal toxicity even at the maximum physically applicable dose. The object of this study was to examine subacute toxicity in male and female rats after repeated p.o. administration of Mb2 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is, therefore, concluded that Mb2 exerted no toxic effects in this subacute toxicity.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-7. Toxicity of metabolites of miocamycin: acute toxicity of Mb6 in mice.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites. In the present studies, we evaluated acute toxicity and estimated LD50 values of Mb6, one of the main metabolites of MOM, in male and female mice after single oral administration. Observations were continued for 1 week after treatment. The LD50 values were calculated according to Litchfield-Wilcoxon's method. It is concluded that LD50 values of Mb6 were 4,150 mg/kg (3,577.6 approximately 4,814.0 mg/kg) in male mice and 4,000 mg/kg (3,389.8 approximately 4,720.0 mg/kg) in female mice, respectively.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-8. Toxicity of metabolites of miocamycin: acute toxicity of Mb6 in rats.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous studies, we estimated LD50 values of Mb6 in male and female mice after single oral administration. The LD50 values were 4,150 mg/kg in male mice and 4,000 mg/kg in female mice, respectively. In the present studies, we evaluated acute toxicity and estimated LD50 values of Mb6 in male and female rats after single oral administration. Observations were continued for 1 week after treatment. It is concluded that LD0 values of Mb6 in male and female rats, were estimated more than 5,000 mg/kg as Mb6 did not exhibit any manifest acute toxicity even at the maximum physically applicable dose of 5,000 mg/kg.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-9. Toxicity of metabolites of miocamycin: subacute toxicity of Mb6 in rats.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. It is also known that LD50 values of Mb6 were 4,150 mg/kg in male mice and 4,000 mg/kg in female mice but LD0 values in male and female rats were estimated more than 5,000 mg/kg. The object of this study was to examine subacute toxicological effects in male and female rats after repeated oral administration of Mb6 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxicity was observed in this study with Mb6 in male and female rats after oral administration at dosage levels of 125, 250, 500 and 1,000 mg/kg for 5 weeks.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-10. Toxicity of metabolites of miocamycin: acute toxicity of Mb12 in mice.

We evaluated acute toxicity and estimated LD50 values of Mb12, one of the main metabolites of MOM, in male and female mice after single oral administration. Observations were continued for 1 week after treatment. The LD50 values were calculated according to Litchfield-Wilcoxon's method. It is concluded that LD50 values of Mb12 were 5,750 mg/kg (4,914.5-6,727.5 mg/kg) in male mice and 4,950 mg/kg (4,194.9-5,841.0 mg/kg) in female mice, respectively.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-11. Toxicity of metabolites of miocamycin: acute toxicity of Mb12 in rats.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous studies, LD50 values of Mb12 were 5,750 mg/kg in male mice and 4,950 mg/kg in female mice, respectively. The object of this study was to evaluate acute toxicity in male and female rats after single oral administration of Mb12. Observations were continued for 1 week after treatment. It is concluded that LD0 values of Mb12 were estimated more than 5,000 mg/kg.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-12. Toxicity of metabolites of miocamycin: subacute toxicity of Mb12 in rats.

Miocamycin (MOM) is a derivative of midecamycin and is metabolized into 4 main metabolites of Mb1, Mb2, Mb6 and Mb12. In the previous study, LD0 values of Mb12 in male and female rats were estimated more than 5,000 mg/kg. The object of this study was to evaluate subacute toxicity in male and female rats after repeated oral administration of Mb12 for 5 weeks at a daily dosage of 125, 250, 500 and 1,000 mg/kg. It is concluded that no manifest toxic effects were caused by Mb12 even at the highest dosage level of 1,000 mg/kg/day for 5 weeks to male and female rats.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miokamycin). Part I-1. Acute toxicity in mice.

Miokamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic isolated from a culture broth of Streptomyces mycarofaciens. The objective of this study was to determine the acute toxicity of MOM, non-crystalline solid, in male and female mice (Jcl-ICR, SPF, 5-week-old) after single i.p., and p.o. administration of this material at a dose level of 5,000 mg/kg as the maximum physically applicable dose. MOM, non-crystalline solid, exhibited no acute toxicity in the present study. LD0 values were estimated as more than 5,000 mg/kg in each route of administration.

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miokamycin). Part I-2. Acute toxicity in rats.

Miokamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic isolated from a culture broth of Streptomyces mycarofaciens. The object of this study was to determine the acute toxicity in male and female rats (Wistar, 5-week-old) after single i.p., s.c. and p.o. administration of MOM, non-crystalline solid, at a dose level of 5,000 mg/kg as the maximum physically applicable dose. Observations were kept for 1 week after administration. In conclusion, no animal died during an observation period for 1 week so that the LD0 values were estimated to be more than 5,000 mg/kg in all routes of administration.