1) Premature and newborn infants were given single intramuscular injections of Cephaloridine and' Cephalothin in doses of 25 mg per kg of body weight.
The blood level was highest 30 minutes after injection of Cephaloridine and cause to be low or none at 12 hours, but the level of Cephalothin was highest at 1 hour, coming to be low at 8 hours.
During the first 8 hours of administration of Cephaloridine the high blood level was proportional to the age and the weight of infants. The blood level of Cephalothin decreased more rapidly than that of Cephaloridine.
2 ) In premature and newborn infants 25. 8 to 54. 0% of a dose of Cephaloridine given was excreted in 12-hour uring, but 87. 0% of Cephalothin was excreted.
3) Cephaloridine and Cephalothin are more effe c t ive against Staph. aureus. 86. 8% and 81. 6% of the strains were inhibited by O. 3 9 or less mcg/ml of Cephaloridine and Cephalothin.
4) It appears from the data given above that in premature and/or newb o rn infants, the intramuscular administration of Cephaloridine in doses of 20. 0 to 25. 0 mg per kg body weight every 8 or 12 hours; and that of Cephalothin in the same doses every 6 hours may be more effective than that hereto fore. in use.

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Pharmacological actions of 5-fluorouracil (Fu), an antipyrimidine agent, were investigated. In mice, LD50 were the doses of 730 ( sc), 1, 010 ( ip) and 41. 6 ( ic) mg/kg respectively. Chroni c convulsion, lateral turning or rotation of the whole body were observed in application of Fu in the brain of mice and its CD₅₀ was the dose of 18. 15 mg/kg. For subacute toxicity, the rates of death w ere 50% during 30-40 days in the group of 20 mg/kg and 10∼50% during 50∼60 days in the group of 5∼10 mg/kg/day respectively. At that time decrease of testis weight and increase of spleen weight were noticed. The movement of the excised frog heart was accelerated at the dose of 0. 2 mg/ml of Fu, and inhibited at 2 mgiml. The mov e ment of the excised rabbit intestine was accelerated at the dose of 1 mcg/ml of Fu and inhibited at 0. 5 mg/ml. it has no effec t on the excised auricular vessels of the rabbit and dose of 1 mg/m1 of Fu increased the permeability of rabbit skin vessels. Temporary fall of blood pressu r e and decrease of respiration were observed at the dose of 10 mg/kg of Fu in the urethane-anesthetised rabbit. Bradycardia (lengthens of PQ inter val) took place at the dose of 4 mg/kg of Fu and tachycardia (shortens of ST interval) at the dose of 20 mg/kg. Local irritation of Fu was not observed. Fu, therefore, has not remarkab l e pharmacological actions at the therapeutic doses.

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In vitro antimycotic activities of 171 nitrofura n compounds having various chemical structures were tested.
It was found that heterocyclic vinyl compounds exhibited the superior antimycotic activity as well as the superior antibacterial activity. The relationship between structure and activity of these compounds was discussed and following results were shown.
1) The 5-nitro group was essential for the activ ity.
2) Substitution of the other ring for the fura n ring markedly reduced the activity.
3) Conversion of tertiary N on heterocycles to quaternary ammonium salt r educed the activity.
4) Substitution in the 1-position of the vinyl chain reduced the activity.
5) Benzheterocycle compounds except for quinolines were less act ive than the corresponding heterocycle compounds.
6) Conversion of N on a pyridine ring to N-oxide reduced the activity.
7) When a heterocycle was a pyrimidine, the activity was weak.

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In vitro antitrichomonal activities of 171 nitr ofuran compounds having various chemical structures: were tested.
It w as found that heterocyclic vinyl compounds exhibited the superior antitrichomonal activity as well. as the superior antibacterial and antimycotic activities. The relationship between structure and activity of these compounds - was discussed and following results were shown.
1) The 5-nitro group was essential for the activity.
2) Being irrespective of conversion of N to N-oxide, the activity was markedly reduced by conversion of tertiary N to quaternary ammonium salt on heterocycles containing N.
3) Substitution in the 1-position of the vinyl chain reduced the activity.
4) Nitrothiophene compounds showed the similar activity to nitro furan compounds.
5) Acetylation of an amino group in heterocycles did not decrease the activity but increase it im some cases

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A new compound ( 2-P-aminobenzene sulfonam ide-3-methoxypyrazine) “Sulfalene (Polycidal)”, a longacting sulfonamide, was proved to have a relatively broad antibacterial spectrum against gram-positive and negative microorganisms in vitro.
By the pretreatment of the dru g to mice, protective effect against the bacterial infection (Salmonella enteritidis or E. con) was surely observed.
The concentrations of the drug absorbed in plasma and tissues or excreted in urine after the oral administration were chemically and biologically determined and the comparatively high concentrations of the drug were determined 1∼4 hours after the administration and the effective dose were also demonstrated even at 24∼48 hours after the administration.
The binding of the drug to plasma or tissu e proteins varies with the concentration of drug present, as has been shown to be true for sulfa drugs in general. The degree of binding to proteins is rather less, however, than that with other sulfa drugs.

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Antibacterial activity in vitro of thiophenicol (TP), a new antibiotic, was examined and comparedl with that of chloramphenicol (CP). The blood level and urinary excretion of those two antibiotics after oral administration was determined. Clinically, TP was administered to 19 patients with infectious diseases of the respiratory, billiary or urinary tracts. The results obtained were as follow.:
1) Against 15 standard strains of gram positive or negative bacteria, antibacterial activity of TP in vitro was subordinated to CP.
2) Both TP and CP had maintained approximately same level in the blood after administration, although, TP had higher urinary output.
3) Twelve of nineteen patients received TP administration had apparent susceptability to this antibiotic. As a side effect of TP, gastrointestinal disturbance was observed in few patients. To urinary tract infection, TP was considered to be predominant to CP in this study.

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1) Experimental cholecystitis in dogs was produced by injecting E. coil (NIHJ and C-43 strain) and 5% sodium desoxycholate into the gallbladder. In postmortem examination, bile usually contained about 10⁶/m1 of E. coil possessing same susceptibility patterns to the original microorganisms. Pathological studies of these. gallbladders revealed signs of inflammation.
2) The produced cholecystitis was treated with th ree antibiotics?chloramphenicol (CP), kanamycin (KM), aminobenzyl-penicillin (AB-PC)--for 1 week. More or less effects were obtained from the treatment with these drugs with the exception of KM. Especially, AB-PC group was most successfully treated. The cholecystitis produced with E. coil susceptible to CP responded more effectively than those with the microorganism moderately resistant to this antibiotic. In addition to these results, the observation of the blood and biliary concentration of these three antibiotics (100 mg/kg 1. m. ) for 24 hours, revealed the fact that the latter played more important role in the treatment of experimen tal cholecystitis.
3) Injecting E. coli adapted to 2% desoxycholate, in vitro, more severe inflammation was produced than the cases with unadapted microorganism.
4) Determination of hemaggl utinin titer was carried out in order to study the process of inflammation. In normal dogs without infection, average H. A. titer of 2² has obtained. In non-treated group without chemotherapy, significant high titer up to 2⁸ was observed on 7 th day. In the treated group, fluctuation of the titer was observed in proportion to the effects of treatment. The grade and process of inflammation may be evaluated by the method of hemagglutination reaction.

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Antirickettsial activities against R. orientalis of tetracycline, demethylchlortetracycline, methacycline, aminobenzylpenicillin, cephaloridine, cephalothin, mikamycin, spiramycin and acetylspiramycin were evaluated. Demethylchlortetracycline and methacycline were more effective, mikamycin, spiramycin and acetylspiramycin were less effective than tetracycline in the treatment of the mice inoculated. with R. orientalis. Aminobenzylpenicillin, cephaloridine and cephalothin had no effect on the infected mice. In clinical use, demethylchlortetracycline and methacycline were administered 33 mg twice daily and then on defervescence once daily for about 3 weeks until the total amount reached 1 g. This dosage was two third of tetracycline applied to small-dose long-term treatment. All six patients were cured without incurring relapse. In three cases mikamycin was administered daily 1g dose, followed by reduced daily 0. 5 g dose after subsidence of fever, and all of these three cases showed relapse after 1 to 3 days. In the use of mikamycin, spiramycin and acetylspiramycin, oral daily dose less than 1 g would be inadequate for the treatment of tsutsugamushi disease.

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The antibacterial activity of sulfamethoxypyrazine in vitro has indicated sensitivity to Gram-positive and negative bacteria as well as sulfisomezole and sulfamethoxypyridazine which were used as control drugs, and in its antibacterial effect, any marked difference between them was not observed, however rather slight effect on particular bacteria was noticed.
Further, with reference to the distribution fo r sensitivity of clinical isolated bacteria, the resistant bacteria with 61% of appearance rate was observed in pathogenicity of Staphylococcus in case of M. I. C. with 10 times of the standard strain being regarded as resistance and a majority of both E. coli and Shigella were found to be resistant bacteria.
The cross resistance among those three drugs was also realized.
It is interesting that the treatment effect on mouse experim ental infection, differing from antibacterial activity in vitro, has shown more striking effect than with sulfisomezole and sulfamethoxypyridazine.
This is bacause of the superiority in both transition within internal organs and long activity of sulfamethoxypyrazine and we are presently studying on this point.
In the treatment experiment for mouse experimental infection we observed only as for one-time administration and it is presumed that further effect might be increased with continuous administration of the drug and future clinical results will be expected.

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Basic studies on sulfamethoxypyrazine (SMP), a new sulfonamide, were performed in comparison with sulfadimethoxine (SDM) and sulfisomezole (SIM). The results of Report I are summarized as follows. 1) In vitro antibacterial activities of SMP were as effective as SDM, but less than that of SIM. 2) The affinity of SMP in human plasma and its adsorption rate on human erythrocytes we re less than SDM and SIM. 3) N⁴-Acetyl derivative of SMP was easily soluble as well as N⁴-acetyl SIM at pH 6. 0∼8. 0 in buffer solution. 4) Acute toxicities (LD₅₀) of SMP in mice were 1, 160 mg/kg (i. v. ), 1, 590 m g/kg (s. c. ), and 1, 7101 mg/kg (p. 0. ). 5) ED₅₀ of SMP in infected mice were superior to other three sulfonamides. The results were 54 mg/kg on Staphylococcus, 70 mg/kg on Streptococcus, and 115 mg/kg on Salmonella.

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Distribution of sulfamethoxypyrazine (SMP) by oral administration in human (1 gjman) and in aniraat (100 m g/kg) was observed in comparison with suLfadimethoxine (SDM) and sulfisomezole (SIM). The results of Report II are summarized as follows.
1) Blood levels of SMP in men were sh o wn by the occurrence of peak value (45 m cgiml) in 5 hours, and this was foliwed by the slow disappearance as well as SDM, but the concentration in each time was higher than SDM and SIM.
2) In the case of SMP and SDM, a bout 20% of the administered dose were excreted in the human, urine in 24 hours, but on the contrary SIM showed the recovery of more than 90%.
3) Bile concentrations of SMP in rats were as high as SIM and more than th ose of SDM.
4) Tissue distributions of SMP in rabbits showed similar pattern with SDM.

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Drug resistance and biological properties of 261 strains of gram negative bacteria were investigated. These strains were isolated in 1965 from patients at 14 hospitals, with the cooperation of 16 participating laboratories. The strains included Escherichia coli (44. 1%), Pseudomonas aeruginosa (25. 3%), Proteus (11. 5%), Klebsiella (8. 8%) and others (10. 3%). It was found that almost all of these strains were multiply resistant. The strains harboring transmissible drug-resistance-factor “R” included E. coli, Proteus and Klebsiella, which belong to the Enterobacteriaceae. This report also oonfirms similar findings in suggesting that R factors are widely distributed in gram negative bacteria of clinical significance.

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A new antibiotic, lincomycin, has been discovered in fermentation broths of Streptomyces linconensi var. linconensis sp. n. by MASON, DIETZ and DE BOER, and characterized by HERR and BERGEY in, 1963 in Research Laboratories, The Upjohn Company.
Lincomycin shows in vitro activity compara ble to that of macrolide group antibiotics mainly against gram-positive microorganisms, and it is not cross-resistant with any of the major known antibiotics.. Consequently, the case reports on bacillary dysentery treated with lincomycin are rare yet in Japan. Numerous bacteriologically confirmed cases of shigellosis were treated with lincomycin alone or lincomycin in combination with kanamycin. It proved excellent on trial. The results obtained were as follows: 1) The minimal inhibitory concentration of lincomycin against Sh igella strains was mostly 200 to 400 mcg/ml.
2) The antibacterial activity of lincomycin increased at alkaline pH.
3) When used for the treatment of bacillary dysentery in dose of 2. 0 g daily for an adult for a period of 5 days, lincomycin exerted a favorable effect on the appearance of bacilli in the stool. However, the bacterial reappearance cases were seen in 5 of 45 cases treated with the antibiotic (11. 1%).
4) The stool levels of lincomycin following oral administration of 2. 0 g of the dru g daily were found to be, though varying significantly depending on individuals, an extremely high concentration reaching 3, 000 to 7, 000 mcgIg. The stool levels of the antibiotic were lower in bacterial reappearance cases than in non-reappearance cases.
5) No synergism was found i n the test of in vitro activity of lincomycin combined with kanamycin.
6) Disappearance of bacilli was earlier in cases treated with combined use of 1. 0 g of lincomycin and 1. 0 g of kanamycin daily for an adult than in cases treated with lincomycin alone. The bacterial reappearance cases were found in 24 of 618 cases treated with lincomycin combined with kanamycin (3. 9%). The result was most excellent compared with several other combined treatments such as macrolide and kanamycin, nalidixic acid and kanamycin or nalidixic acid and macrolide.
7) No side effects were observed in all the treated cases.

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This paper concerns how to use various antibiotics in renal failure, in regard to the changes in: metabolic route of antibiotics using dogs with renal impairment produced by injection of mercury bichloride.
Blood, bile and urine samples were collected and bio-assayed following intravenous administration. of penicillin-G (PC-G), pyrrolidinomethyl-tetracycline (PRM-TC), erythromycin (EM), kanamycin (KM) and gentamicin (GNT) after catheterization in hepatic vein and in common bile duct.
Using these data, clearances and rates of removal of drugs from serum (Ks), liver and bile, and kidney (Kr) were calculated.
In normal dogs, rates of decline from serum i. e. half-life of PC-G, KM, GNT and PRM-TC were found mainly due to removal of these antibiotics form the kidney (Kr) with the exception of EM. In renal failure, there were marked decreases of Kr in PC-G, KM, GNT and PRM-TC, where as less decrease in EM.
It was sho wn that hepatic metabolism of PRM-TC and EM were accerelated in renal failure, while hepatic removals of KM and GNT were negligible.
Accordingly, decreases of Ks, i. e. prolo ngations of half-life in renal failure are most prominent in
KM, GNT, and PC-G and in lesser degaee in PRM-TC. EM is practically not influenced. KM, GNT and PRM-TC are more or less toxic and thus may be hazardous in renal failure unless control of dosage schedule.

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Primary or secondary disturbances to various physical functions, especially those related to the reticuloendothelial system in cancer patients may be induced with relation to the malignant growth. The results of a number of investigations suggest that reduction of activities of the general defense mechanisms due to above factor may be favorable to malignant growth.
Therefore, the stimulation of the activities of the defense mechanism could be inhibited by the tumor growth.
With this point of view, the author and his collaborators have studied on the value of activation of the physical functions of a cancer bearing host and its combination with cancer chemotherapy; that is, the effect of administration of stimulating agents to the reticuloendothelial system (including liver tonics, stroma-affecting agents), of massive dose of protein (amino acid preparation), of various bacterial vaccine, and of hormone of the opposite sex.
Thus, it will be summarized that one of th e most promising approaches to cancer therapy at the present time is a combination of anti-cancer chemotherapeutic agents together with agents that stimulate the activities of the defense mechanism of the host.

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In the obstetrical and gynecologic fields the administration of antibiotics should be made carefully, iparticularly in consideration of the influences of the antibiotics on the fetuses.
The concentrations of the antibiotics transferred into various organs of the fetus by the maternal. administration were investigated. In cases of abortion in midgestational months, the antibiotic s were given before the evacuation of the uterine contents and thereby the drugs were apparently transferred into the fetal body the transferred concentrations were high in order of CP>CER>CET>KM and levels of the distribution of the drugs were high in order of kindney>lung≥liver>heart>brain.
In the continued administration there was a slight tendency of the accumulation of the drugs in ikidney. The concentrations of the drugs transferred into the genital organs were almost of the sam e levels in uterus, oviducts and ovaries and very slight in myoma. No specific abnormal finding was observed in the peripheral hemogram or in the clinical symptoms of the new born infants by the 'maternal administration of CP in total doses of 1∼5 g in the 9∼10 th gestational months.
Occurreuces of unfavourable effecs of the antibiotics on the new born infants th rough the lactation: seem to be unprobable because of the slight transfer into the maternal milk.

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