(1) When 20.8-34.7mg/kg body welght of CS-1170 were instilled intravenously for 30 minutes to one hour, peak levels were obtained on completion of the intravenous drip in the range 85.7-1,117.3 μg/ml.
(2) The half life was 22-49 minutes which is very rapid.
(3) The kidney clearance was 6.8-104.8ml/min.
(4) The total clearance was 5.9-111.5ml/min, showing oorrelation with the kidney clearance.
(5) The apparent distributional capacity was 0.3-4.3liters, showing a strong correlation with body weight.

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The intravenous preparation of CS-1170 was administered in 9 cases of pediatric disease and was excellent or good in 5 cases (55.6%). It was poor in 3 of 4 cases of Mycoplasma pneumonia. We think that the dose of 50mg/kg/day can exert an effect regardless of the intensity of symptoms. Through our present experiences with the excellent or good cases, an intravenous drip or intratracheal injection for 3-5 days is efrective. Although there was no abnormality in the biochemistry or electrolyte findings before or after administration, eruption developed in one of the cases in which the drug was administered for 6 days.

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CS-1170 was administered in 6 cases of infections in the pediatric field and the clinical response was excellent in 3, fair in 1, poor in 1 and unknown in one. Cases of acute purulent osteomyelitis which was cured by the present drug were described in detail. Each case is summarized in Table 1.

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1. CS-1170 was administered for the purpose of prophylaxis during cardiac catheterization in patients with heart disease, and its blood levels were measured.
2. The mean blood level (Moni-Trol I standard) after one intravenous shot of 20mg/kg was 53.6mcg/ml in catheterized children aged below 6 and 66.9mcg/ml in catheterized children aged above 10 at 30 minutes, and 1.95mcg/ml and 5.2mcg/ml respectively at 6 hours.
3. The mean half life of the blood level was 1.09 hours in catheterized children aged below 6, 1.37 hours in catheterized children aged above 10, and 0.71 hours in infections children.
4. The urinary excretion seemed satisfactorily high although there was a great variation.
5. The clinical efficacy was 88.9%.
6. The bacteriological efficacy was 100% for E. coli, Klebsiella, Proteus mirabilis and Staphylococcus aureus and was 0% for Staphylococcus epidermidis.
7. Although GOT and GPT were elevated in one case as a side effect, they rapidly returned to normal after discontinuation of administration.

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CS-1170 was administered in a total of 11 cases including respiratory infections, urinary-tract infections, and subacute bacterial endocarditis. It was effective in all of the cases; markedly effective in a case of bronchopneumonia with underlying DOWN'S syndrome and infantile spasm and in 2 cases of urinary-tract infections with E. coli. The fact that it was effective for urinary-tract infection with E. coli which showed no sensitivity to ampicillin or cefazolin demonstrates the clinical significance and usefulness of CS-1170 which is said to have a strong antibacterial activity for bacterial producing β-lactamase. No side effect was observed.

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CS-1170 was tried in children with various infections, and the following results were obtained. Some studies on the drug's pharmacokinetics were also made, and the results were as shown below:
1. The time course of serum concentration following one-shot intravenous injections of 30mg/kg in 8 patients aged between 3 and 13 was studied. The results were: 53.4μg/ml, 23.4μg/ml, 6.6μg/ml,1.8μg/ml and 0.5μg/ml at 30 minutes, 1 hour, 2 hours, 4 hours and 6 hours after the drug administration, respectively. Urinary recovery rate was 36% to 69.8% by 2 hours after, 10.9% to 70% by 2 to 4 hours after, 0.6% to 5.4% by 4 to 6 hours after the administration, and by 8 hours after the injection 91.3% of the drug was excreted in the urine.
2. Of 13 cases including 8 cases of bronchopneumonia, 2 cases of urinary tract infections, a case each of suppuration in the neck, lymphadenitis and pyothorax, CS-1170 was found to be effective in 10 cases (83.3%), while effectiveness of the drug was undeterminable in one case.
3. No remarkable side effect including allergic symptom such as eruption was observed, though transient elevation of GOT and GPT was noted in one case.

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Passage of CS-1170 into the cerebrospinal fluid (CSF) after a single intravenous administration of 100mg/kg was studied in the staphylococcal meningitis in rabbits, and the following results were obtained.
1) Two experiments were done, each being conducted on 6 rabbits, and (a) the blood and (b) CSF levels of CS-1170 (c) CSF/serum ratio were determined at the specified hours in the parentheses, i.e., 1, 11/2 and 2 hours. In experiment I,(a) 91.5μg/ml,(b) 16.8μg/ml and (c) 18.4% (1/2 hr); (a) 18.6μg/ml,(b) 2.57μg/ml and (c) 18.6% (1hr); (a) 7.2μg/ml,(b) 0.27μg/ml and (c) 4.2% (11/2 hr); (a) 4.2μg/ml,(b) 0μg/ml (2 hrs.). In experiment II,(a) 132.7μg/ml,(b) 9.1μg/ml, and (c) 6.9% (1/2hr); (a) 41.1μg/ml,(b) 5.0μg/ml and (c) 12.2% (1 hr); (a) 9.3μg/ml,(b) 0.8μg/ml and (c) 8.6% (11/2 hr); (a) 1.3μg/ml,(b) 0μg/ml (2 hrs.). Blood level and CSF/serum ratio at 1/2 hr were not decreased compared to those of cephaloridine and cefazolin, respectively, but were lower after 1 hour.
2) Ten consecutive determinations were made on 7 rabbits at 15-minute interval for 2 hours and a half. Mean blood level (μg/ml) at each time was 208.9 (15 min), 112.4 (30 min), 66.7 (45 min), 41.4 (60 min), 25.9 (75 min), 15.6 (90 min), 10.0 (105 min), 6.9 (120 min), 6.2 (135 min) and 4.2 (150min), respectively, and mean CSF level was 12.1 (15 min), 12.6 (30 min), 7.5 (45 min), 5.2 (60 min), 3.9 (75 min), 1.4 (90 min) and undetectable thereafter.
3) Based on the foregoing data, each half-life of blood and CSF level (T 1/2) and Area under curve (AUC) of CSF/serum ratio were calculated. Blood T 1/2 was 24 minutes and that of CSF 20.6 minutes, respectively, suggesting a faster disappearance of CS-1170 from the CSF. An AUC of CSF/serum ratio was 9.4% (-1hr), 10.0% (-11/2 hrs.) and 9.6% (-2 hrs.) and did not show any increase, reflecting that T 1/2 in blood and CSF was almost similar.
4) In each experiment, an individual variation in CSF concentration was remarkable and therefore the passage of CS-1170 appeared to be unpredictable.
5) In order to determine whether or not this antibiotic may be chosen in the treatment of purulent meningitis, necessity of further investigations on the dosage was indicated by the above studies.

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Fundamental and clinical studies were made on CS-1170, a new cephamycin, and the following results were obtained.
1) MICs of CS-1170 to 42 strains of Klebsiella pneumoniae biovar. oxytoca were lower than those of cefazolin and distributed in a narrower range, suggesting that this antibiotic is less susceptible to β-lactamase. Although cefazolin had a higher antibacterial activity against 14 strains of Staphylo-coccus aureus, CS-1170 was superior against 9 strains of E. coli, 4 strains of Salmonella, 2 strains of Proteus and 3 strains of Klebsiella pneumoniae. MICs to 3 out of 5 strains of Enterobacter and 8 strains of Pseudomonas aeruginosa were higher than 100βg/ml with both CS-1170 and cefazolin.
2) Blood levels of CS-1170 were determined in 11 children. After a single intravenous injection of 20-30 mg/kg, either by one shot injection or by a continuous drip infusion over 30 minutes, peak levels were 60-80 βg/ml and blood levels were maintained over 10βg/ml at least for the next 2 hours. Urinary concentrations determined in 2 patients were higher than 1,000βg/ml 4 hours after an intra-venous injection, and urinary recovery was almost complete by 6 hours. Cerebrospinal fluid (CSF) concentrations in a single case of purulent meningitis of CS-1170 were as follows: approximately 1.6βg/ml 80 minutes after an injection of 7.5mg/kg on the 2nd day of treatment, undetectable 80 minutes after injections on the 3rd and 5th days, 3.3βg/ml 60 minutes after an injection of 50mg/kg on the 7th day and undetectable 60 minutes after an injection of 12.5 mg/kg on the 9th day, respectively.
3) CS-1170 was given to 31 children with bacterial infections. They ranged in age from 9 days to 12 years, about two-thirds being infants. In most cases daily dose was 40-80mg/kg, divided in three and given by one shot injection in 4 cases, a 30-minute continuous drip infusion in 16 and a 60-minute continuous drip infusion in 11. The overall efficacy rate was 90.3%: excellent in 19 cases, good in 3 and failure in 3; sinuitis (1 case), failure; tonsillitis (4), excellent in 2 and good in 2; bronchitis (2), excellent in 2; pneumonia (7), excellent in 5 and good in 2; empyema (2), good in 1 and failure in 1; purulent meningitis (1), excellent; peritonitis (1), failure; sepsis (2), good in 2; SSS syndrome (4), excellent in 2 and good in 2; and urinary tract infection (7), excellent in 7.
4) Adverse reactions included mild diarrhea in 1 and eosinophilia in 1, respectively. Minimal elevations of GOT and GPT noted in 4 cases were insignificant and did not appear to be related to this drug.
5) Based on the above results it was concluded that CS-1170 is an excellent new antibiotic with few adverse reactions and has broader indication in the treatment of bacterial infections in children. The recommended dose in general is 20-30mg/kg 3 to 4 times a day and preferably should be given by a 30-minute continuous drip infusion.
6) However, as there is a possibility that the passage of CS-1170 into the CSF may be insufficient, further studies are required as to the application of this antibiotic to the treatment of purulent meningitis.

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The acute toxicity of sodium fosfornycin (FOM-Na), a new antibiotic in ICR mice and Wistar rats has been investigated.
The LD₅₀ values in mice were: 1,230 (male), 1,225 (female) mg/kg by i. v., 2,175 (m), 2,467 (f) mg/kg by i. p.; 2,625 (m), 2,662 (f) mg/kg by i. m.; 5,100 (m), 6,150 (f) mg/kg by s. c. and 8,020 (m), 7,300 (f) mg/kg by p.o.
The LD₅₀ values in rats were: 1,650 (m), 1,560 (f) mg/kg by i. v.; 2,060 (m), 2,000 (f) mg/kg by i. p.; 2,630 (m), 2,460 (f) mg/kg by i. m.; 5,100 (m), 4,320 (f) mg/kg by s. c. and 4,700 (m), 4,550 (f) mg/kg by p.o.
Animals dosed only i. v. died within 2 minutes. Signs of toxicity in mice or rats given FOM-Na were similar and included motor activity depression, reduced respiration and occasionally tremors. Surviving mice or rats given FOM-Na developed no pathological changes of the drug specificity.

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FOM-Na solution in distilled water for injection, J. P., with its pH adjusted to 7.0±0.2 with diluted hydrochloric acid, was administered to rats and rabbits for subacute toxicity test. The results revealed the following:
1. It was intraperitoneally administered to Wistar rats each weighing 100±10g at their age of 5 weeks, and intravenously into auricular veins of male albino rabbits each weighing about 3kg, for 35 successive days except Sundays through one administration per day. There was no death in rats of both sexes with the doses less than 1,000mg/kg, while 3/10 males and 5/10 females died with the dose of 2,000mg/kg. In terms of general conditions, both stretched physical position and vocalization were noted, which were presumed to be attributable to the stimuli of the administration. In the postmortem examination mutual adhesion of organs in the peritoneum was noted, while in the lightmicroscopic examinations histological proliferation and adhesion were found out in the hepatic capsules or serous membrane of the intestine etc., but no abnormalities were detected in the other organs.
In the mean body weights, there were no significant differences between the control group and the groups of males with doses less than 500mg/kg and females with doses less than 1,000mg/kg whereas in the groups of males with doses more than 1,000mg/kg and the females with a dose of 2,000mg/kg, a trend of reduced weight gain was noted in comparison with the control group. The feed intake also was reduced as the dose was elevated.
In terms of the male group hematology, the In. P increased with doses higher than 250mg/kg, while BUN was reduced in the groups with a dose of 250mg/kg and doses higher than 1,000mg/kg, and Na was reduced in the groups with doses from 125 up to 500mg/kg. In the female groups, the loss of Hgb and rise in the Cl were noted in the doses higher than 500mg/kg while the loss of WBC was noted in almost all the treated groups.
However, none of these changes was suggestive of specific abnormalities when compared with the photomicroscopic findings and our hematological background data.
2. There were no significant changes in the general conditions of any group of rabbits. Their mean body weights and their mean feed intakes proceeded almost similarly with those of the control group. In the hematological and histopathological tests also, no specific abnormal finding was experienced, which were deemed to be attributable to the administration of FOM-Na.

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The following conclusion has been drawn from our study on the toxicological effects of FOM-Na through chronic toxicity tests with Wistar rats and Beagle dogs.
I. Wistar Rats
The results of continued intraperitoneal administration of FOM-Na to rats once a day for 182 successive days revealed that there was no death in both sexes of the group less than 500 mg/kg and that 3 males and 5 females of the group with 1,000mg/kg and all the animals of both sexes of the group with 2,000mg/kg died. The general conditions of these rats of both sexes were found to have been similar to those of the rats in the subacute toxicity test, with no significant differences in mean body weights between the control groups and the groups of males with doses less than 500mg/kg and the group of females with doses less than 1,000mg/kg, but with trends of suppressed weight gain rates in the groups with doses more than the above-mentioned doses comparing those of the control groups. The mean feed intakes were similar to each other of the control groups and the groups of both sexes given doses less than 1,000mg/kg, but the mean feed intake of the groups with a dose of 2,000mg/kg was less than that of the control group, and all the animals of this group eventually died. Changes were noted in TP, Ly, Ne, Cl and K among other hemato-biochemical findings. But, as there was no abnormal light-microscopic finding in any specific organ, and as the hemato-biochemical variations were not found to be particularly remarkable in comparison with our background data, these changes could hardly be attributable to the administration of FOM-Na. However, despite absence of any specific abnormality in the hematological findings, degenerative figures were noted in the renal uriniferous epithelium in the light-microscopic observations particularly in the groups with higher doses of FOM-Na. Changes related to the decrease of resistibility against infections such as pneumonia, hepatic microgranulomatic foci and chronically infected spleen were noted in each groups receiving high doses of FOM-Na.
II. Beagle Dogs
Continued intravenous administration of FOM-Na to Beagle dogs once a day for maximum 182 days resulted occasional vomitting of yellowish watery fluid or bubble-like substances in some animals of the group with more than 250mg/kg. But these symptoms were not always specific for administration of FOM-Na and could be often noted following intravenous injections of antibiotics. It was confirmed by the supplementary test that FOM-Na in lower concentrations and at slower injection rates did not develop these symptoms. Both the mean body weight and mean feed intake in the groups with its administration were similar to those of the control group. In the biochemical tests on serum samples, UA was found to have reduced in the group with 500mg/kg. In the electron-microscopic findings of the kidney, some products degenerative changes or vacuoles were noted in the epithelial cells of the principal tubules and the degenerations or deficiency figures were found in the epithelium of collecting tubules. But as no remarkable changes were noted in the light-microscopic findings, above observations were thought to be such a grade as would not be termed as toxic effects of FOM-Na to kidneys. No abnormalities were detected in the other organs, too.

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[in Japanese]

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NK 631, a new antibiotic of bleomycin analogue, was applied to the treatment of 15 patients with head-and-neck cancers.
The results obtained were slightly better than bleomycin-treated cases.
For the side effect of NK 631, there were no lung disorders in all patients.

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[in Japanese]

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We used only NK 631, a new bleomycin derivative, for 10 cases of primary oral cancer, and obtained following results.
(1) Anti-cancer effects were immediate and as follow: remarkably good in 1 case, efficacious in 8 cases, and none in 1 case.
(2) In clinical examination, peripheral blood, function of kidney, liver, etc. were normal. But attention must be payed to blood gas.
(3) Loss of hair, stomatitis and exanthema were noticed as side effects more clearly than regular bleomycin, but no fever.
As the result of the above, NK 631 is better than regular bleomycin in anti-cancer effect and activity, but more attention should be payed to the side effect.

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[in Japanese]

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[in Japanese]

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