Chronic toxicity of josamycin propionate was studied by using male and female Wistar-Imamichi rats.
Daily doses of 2,000, 1,000, 300 and 100 mg/kg (expressed as the equivalent weight of josamycin) were given to groups of male and female rats for 194 successive days by an oral syringe.
All animals survived except a male rat given 2,000 mg/kg doses and a male of the control group which were killed from accidental pneumonia. Each group showed almost similar growth curve to that of the control. No significant change was observed both in hematological findings and in biochemical examinations of sera as compared with the control.
Autoptic and histological examinations revealed no significant changes related to toxic effect of the drug.

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[in Japanese]

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Effects of 3', 4'-dideoxykanamycin B (DKB) on the auditory function of guinea pigs were examined by means of PREYER'S pinna reflex method and the evaluation of maximum cochlear microphonics (CM).
Complete loss of the pinna reflex and scarcely visible CM were taken about two weeks in each group of animals given daily dose of 200mg/kg (as base activity) of DKB and 100mg/kgof comparative drug, gentamicin sulfate (GM). It took approximately three weeks to lose the pinna reflex of the animals dosed with 150mg/kg of DKB 80mg/kg of GM, and then remarkably decreased CM was also observed in these groups. There was no change on the reflex of the animals treated with DKB at the dose of 100mg/kg and 50mg/kg for two months, in the former group, however, CM was slightly reduced in the ampitudes, which may indicate that limited injuries were presented in their cochleas. The animals given daily 60mg/kg of GM lost the reflex until four weeks but two in this group, and yet some of them remained the heighest potential in the animals that missed the movement of the pinna.
Based on the mg/kg dosage of the antibiotics, number of days to take abolishing the reflex and the estimation of CM, it was suggested that DKB was nearly a half as auditory toxic as GM.

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Pharmacological effects of DKB, a new aminoglycoside antibiotic, were studied and following results were obtained.
1) In urethane (1g/kg, s.c.) anesthetized rabbit, administration of 10mg/kg (i. v.) of DKB caused a fall of blood pressure and a slight acceleration of respiration. Administration of 20mg/kg of DKB caused decrease in heart rate on ECG. These cardiovascular effects of DKB were retained following the administration of atropine, diphenhydramine, propranolol and sodium nitrite, and after vagotomy and spinal resection. On the isolated rabbit ear preparation, blood vessels were slightly dilated following the administration of 10% DKB.
2) The movements of isolated rabbit intestine and rat uterus in MAGNUS apparatus were inhibited by the administration of 0.005% DKB. The tonus of isolated guinea-pig trachea strip chain in MAGNUS apparatus was relaxed by the administration of 0.01% DKB. These effects of DKB were antagonized by the addition of BaCl₂ and acetylcholine.
3) The responses of the phrenic nerve-diaphragm preparation of rat to nerve stimulation were blocked by the administration of 0.3% DKB. This effect of DKB was antagonized by the addition of CaCl₂ and pentobarbital.
4) At high concentrated of DKB, irritation to the muscle of rat was observed, and permeability of skin vessels were stimulated by the administration of 10% DKB.
5) No significant effects were observed on central nervous system, body temperature, red cell resistance and prothrombin time by the administration of DKB.
6) No antigenicity in rabbit was formed by the administration of DKB. At the therapeutic doses of DKB, no remarkable pharmacological actions were observed.

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The teratogenicity of 3', 4'-dideoxykanamycin B (DKB) was studied using dd strain mice and Donryu strain rats and the following results were obtained:
(1) In mice, 89.7% of mothers died in 400 mg/kg (as base activity) intraperitoneal injection group and 64.1% of mothers in 250 mg/kg intramuscular injection group. In rats, 35.0% of mothers died in 300 mg/kg intramuscular injection group.
(2) In embryonic mortality, no significant difference was observed between the control and medicated group.
(3) In fetal abnormalities in appearance and skeleton, no significant difference was observed between the control and medicated group.
(4) No effect of DKB was observed on birth rate, survival rate, growing body weight and organs of newborns.
(5) No teratogenic effect was observed in mice and rats administered intraperitoneally and intramuscularly with DKB.

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The absorption, excretion, distribution and metabolism of DKB (3', 4'-dideoxykanamycin B) in rats were examined using a radioactive compound.
1) The cumulative urinary excretion curve and the blood concentration curve determined by antimicrobial activity in rats given DKB intramuscularly agreed with those determined by radioactivity and no metabolites were detected on the thin-layer chromatogram of urinary excreted DKB.
From these facts, there appeared no metabolites in most DKB administered.
2) In all tissues except kidney, the amount of DKB decreased with the decrease in blood concentration, and there was only a trace 24 hours after intramuscular administration in rats.
3) When injected intramuscularly into rats, the antibiotic was eliminated very rapidly form the blood and excreted in the urine; 70% of ³H-DKB was recovered within 2 hours and 85% within 24 hours.

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Serum levels, urinary excretions, and tissue distributions of 3', 4'-dideoxykanamycin B (DKB) in rabbits and dogs were examined by cylinder-plate diffusion assay with Bacillus subtilis ATCC 6633 as test organism, comparing with those of gentamicin (GM).
The results obtained in the present study were summarized as follows:
(1) A mean peak serum level of 57.2 mcg (base)/ml was obtained in rabbits given single 20mg (base)/kg dose of DKB intramuscularly. Biological half-life calculated at linear two-compartment model was 1.389 hr. and amount recovered from 8-hour urine was accounted for about 75.0% of given dose. These properties were nearly equal to those obtained after intravenous administration.
(2) When 20 mg (base)/kg dose of DKB was administered to dogs intramuscularly, a mean peak serum level of 58.6 mcg (base)/ml was obtained. Absorption rate constant (3.1149 hr^-1), elimination constant (0.4692 hr^-1), volume of distribution (0.264 L/kg) and biological half-life (1.477 hr) were calculated at same analysis. Urinary excretion of DKB was also studied in same dosage. Amount recovered from 10-hour urine was accounted for about 64.0% of dose given. In comparison with GM, no significant difference in these pharmacodynamic properties was found between these two antibiotics.
(3) Tissue levels after single 50 mg (base) /kg dose of DKB and GM given intramuscularly were estimated in rabbits. Level of DKB in lung was obtained about two times higher than GM, but in the others (brain, thymus, heart, liver, spleen, kidney, muscle and liquid humor), DKB showed a similar tendency to GM.
(4) From these data, it may be suggested that 3', 4'-dideoxykanamycin B has similar pharmacodynamic properties as gentamicin.

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Schizophyllan, a simple glucan produced by Schizophyllum commune, was injected into peritoneal cavity of mice, and the time course changes in lysosomal enzyme activities of the peritoneal exudate cells were estimated.
(1) The levels of acid phosphatase, β-glucuronidase and cathepsin activities began to increase markedly after 24 hours, reached the peak levels between 2-6 days, and then gradually returned to control values by 15 days. There was, however, no increase in alkaline phosphatase or lysozyme activity.
(2) Schizophyllan proved to be more effective than zymosan or glycogen in inducing and maintaining the high levels of lysosomal enzyme activities.
(3) The macrophage monolayers were stained for acid phosphatase. Macrophages taken from schizophyllan-treated mice were much larger in size and more various in shape than those from control mice, containing a great number of acid phosphatase-positive pinocytic vacuoles and lysosome granules.
(4) Macrophages from schizophyllan-treated mice appeared to be more active than control cells in phagocytosis and digestion of heat-killed Saccharomyces cerevisiae.
Schizophyllan is considered to be a powerful stimulant of RES function and also to be an effective inducer of lysosomal enzymes.

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