[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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Subacute toxicity of josamycin was investigated on the rats of both sexes. Josamycin (base) was administered orally at the doses of 0.1, 0.3, 1.0 and 3.0g/kg body weight for 5 weeks. No deleterious effects were observed on their behaviour, growth curve, food intake and organ weight except for the female liver, where slight increase of weight was observed and s-GPT and alkaline phosphatase activities of the serum were also slightly elevated in the female. No histopathological chages attributable to medication with josamycin were observed in brains, thoracic or abdominal viscera of the rats examined at the end of the study.
Josamycin (base) was administered orally to pregnant mice and rats and its effect on the fetus was investigated according to the test method admitted by the Ministry of Public Health and Welfare. Josamycin was given orally at the daily doses of 0.3 and 3.0g/kg to pregnant ICR-JCL mice from 7 th day to 13th day and pregnant Wistar rats from 8th day to 14th day of gestation. The mortality rate of mouse fetuses was higher in the 3.0g/kg group than in the control group. Rate of growth retardation of mouse fetuses was higher in the 3.0g/kg group than in the control group. No teratogenic effect was observed on the fetuses nor on the youngs.

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Following oral administration of 100mg/kg each of four macrolides, josamycin, erythromycin, leucomycin and spiramycin, their serum levels in dogs were determined microbiologically. The serum level of josamycin was 26.2mcg/ml and 31.0mcg/ml 1 hour and 2 hours after administration, respectively. By these times josamycin and spiramycin gave higher levels than erythromycin and leucomycin. However, by 8 and 24 hours after administration spiramycin gave the highest level among them.
In the experiment on mice, tritiated josamycin at the dose of 200mg/kg was given orally and distribution of the radioactivity and of the antibacterial activity in tissues was determined. By 1 hour after administration, 47% of the radioactivity was recovered in the intestine, 17% in the urine, 3.2% in the liver and 2.4% in the bile. The radioactivity per unit weight was highest in the bile, followed by the small intestine, large intestine, feces, stomach and liver in that order. By 3 hours after administration, 42% was found in the intestine, 26% in the urine, 8.5% in the lungs, 3.3% in the liver, 3.2% in the muscles and 1.3% in the heart. The radioactivity per unit weight was highest in the lungs, then it decreased in the order heart > bile > thymus > feces > large intestine > liver > small intestine > kidney and stomach. Recovery rates of total radioactivity at 1 and 3 hours after administration were 73% and 88% respectively. Distribution of josamycin in plasma, urine and several organs as computed from the data obtained by radioactivity and antibacterial activity went parallel, but the former gave much larger figures than the latter.
The above data lead to the conclusion that josamycin is readily absorbed from the digestive tract, but decomposed relatively fast, losing its antibacterial activity.

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Multidimentional observations in mice indicated sedative activity of josamycin, and several sympathomimetic or parasympathomimetic profiles at higher doses. Behavior changes about the same as in mice were also observed in cats. Josamycin caused drop of the blood level and depression of the respiration in anesthetized cats injected with 100mg/kg intravenously. Electrocardiograms indicated various kinds of effects, such as prolongation of PP-and PQ-intervals and arrhythmia at 1.0mg/kg. On isolated heart preparation of guinea-pig, an increase in the coronary flow, transient depression of the amplitude of contraction and slight decrease of heart rate were observed at1mg/kg and higher doses of josamycin. No definite activity was observed on the uterus preparation of rat. Josamycin (0.01mg/ml and higher concentration) dose-dependent decrease in contractility of the isolated ileum of rabbit. A nonspecific antispasmolytic effect against acetylcholine, histamine and barium was also observed. In electroencephalogram, there was no convulsion pattern, but slow waves of low amplitude were observed. Josamycin did not cause any neuromuscular blocking effect on the indirectly stimulated diaphragm-phrenic nerve preparation of rat. The body temperature remained unaltered in rabbit injected various doses of josamycin. Only higher doses of josamycin decreased urinary excretion of rat. Josamycin, at 100mg/kg intradermally injected had irritant effect on the skin of rabbit almost equivalent to 0.1mg/ml of histamine.

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Medicating josamycin (JM) to 40 male and 40 female Wistar rats by the use of oral syringe, chronic toxicity of JM was examined for 189 days (6 months) period beginning from January 18 to August 4, 1968. The drug was given at the daily doses of 3,000mg/kg, 1,000mg/kg and 300mg/kg suspended in 1% CMC solution, and administered orally by oral syringe.
One animal in the group administered with daily doses of 3,000mg/kg, two in the group administered with 1,000mg/kg, and one in the group administered with no drug were dead. The histological examination in these dead animals showed only pneumonia and any direct relationship to the drug was not found.
With regard to the growth curves, the tendency was similar in all the groups as well as in the control group. The body weights of the male rats in 300mg/kg group were lower from the 1st to 6th week, and those in 1,000mg/kg group were lower from the 20th to 26th week and at the final period. These values, however, remained within the normal range in Wistar rats. In the female rats, no significant difference was found as compared with the control group.
The hematological and the biochemical findings in the serum showed no significant changes.
No significant histological changes were observed in regards of the chronic toxicity of JM.

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