General pharmacological studies on T-1982 produced the following results.
On central nervous system, subcutaneous injection of T-1982 at dose of 2,000 mg/kg hastened the onset of pentetrazole-induced tonic extensor in mice.T-1982 had no effect on spontaneous motor activity, pentobarbital hypnosis, body temperature or EEG in mice or rabbits, and also did not show moter incoordinate, anticonvulsive or analgesic activity in mice at intravenous doses of 250, 1,000 mg/kg or subcutaneous doses of 500-2,000
mg/kg. On motor and sensory nervous systems, no effect of T-1982 was noted on spinal reflex, neuromuscular junction, conduction anesthesia or surface anesthesia in rats or rabbits.
On respiratory, cardiovascular and autonomic nervous systems, T-1982 caused transient increase of respiratoryrate, slight hypotension and transient increase of femoral blood flow in dogs at intravenous doses of 250-1,000mg/kg.However, it caused a slight hypertensive tendency in rabbits.Heart rate and ECG in dogs or rabbits, blood pressure response to epinephrine, isoproterenol, acetylcholine or histamine in dogs, nictitating membranein cats and pupil size in mice were not affected after intravenous injection of T-1982.No effect was found onisolated guinea pig atrium or rabbit descending aorta following T-1982 application.
On renal function in rats, T-1982 caused an increase of PSP excretion but had no effect on urine volume or electrolytes excretion at intravenous doses of 250-1,000 mg/kg.
T-1982 prolonged bleeding time in mice at intravenous doses of 500-1,000 mg/kg, but did not show hemolytic property and inhibitory activity on blood coagulation or platelet aggregation in vitro experiments.
Spontaneous movement and tone of isolated stomach, ileum, colon, uterus, was deferens or trachea and acetylcholine-, histamine-, nicotine-or barium chloride-induced contraction of ileum were not affected following T-1982 application.Intestinal propulsion of barium meal in mice, gastric secretion and carrageenin-induced edema in rats were not affected after intraveonus injection of T-1982.
T-1982 increased bile secretion in rats dose-dependently at intravenous doses of 31.3 125 mg/kg.The local irritative activity of T-1982 in rats was slightly milder than cefoxitin and moderately milder than cefmetazole after intradermal injection.
In conclusion, these results suggest that T-1982 would not cause any adverse effects at its estimated clinical doses of 10-20 mg/kg (500-1,000 mg/man).

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The local irritation effect of T-1982 after the intramuscular injection into the musculus vastus lateralis was examined in rabbits.
T-1982 was dissolved by the way of clinical use and was injected singly into the musculus vastus lateralis. Then the degree of muscular injury at the time of 2 days and 7 days after the injection was judged from muscle weight ratio, gross local observation and histological observation.
The degree of muscular injury caused by T-1982 was compared with that of saline, 0.75% acetic acid and 6%acetic acid.
On the degree of muscular injury of T-1982 was almost equal to that of 0.75% acetic acid, but milder than 6% acetic acid.
From these, it was concluded that the local irritation effect of T-1982 was grade 3.

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The distribution of T-1982, a new semisynthetic cephamycin antibiotic, was studied with whole body autoradiography in normal male mice, pregnant mice and experimental pyelonephritic mice following a single intravenous administration of 80 mg/kg of ¹⁴C-T-1982.
1.In normal male mice, the radioactivity was distributed at high concentration in the liver, kidney, lung, gastrointestinal tracts, skin, salivary gland, tongue and muscle, but was hardly observed in the central nervous system that composed of the brain and spinal cord.
2.In pregnant mice, the radioactivity was hardly observed in the fetuses.
3.In experimental pyelonephritic mice, considerable radioactivity was concentrated on the acute inflammatory area.

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Absorption, distribution and excretion of sodium 7β-[(2R, 3S)-2-(4-ethy1-2, 3-dioxo-l-piperazinecarboxamido)-3-hydroxybutanamido]-7 α-methoxy-3-[(1-methyl-1 H-tetrazol-5-y1) thiomethyl]-3-cephem-4-carboxylate (T-1982) were studied in rats and mice using of ¹⁴C-T-1982.
1.The binding rate of ¹⁴C-T-1982 to serum protein was about 16% in mouse, 27% in rat and 50% in human.
2.After intravenous administration to mice and rats, blood levels of radioactivity diminished rapidly. While, after subcutaneous administration to mice and intramuscular administration to rats, blood levels reached rapidly to high concentration and, declined gradually in comparison with intravenous studies.
3.Radioactivity after parenteral administration to rats and mice was distributed high into kidney, following by liver, stomach, heart, lung and ovarium, but low into brain.In new born rats, tissue levels diminished slower than that of adult rats.
4.With regard to oral administration to mice, almost all radioactivity was found in feces.This result suggested that T-1982 was hardly absorbed from gastrointestinal tracts.Urinary excretion rate after intravenous administration was about 60% in mice and 19% in rats, and the other radioactivity was found in feces.
5.In rats, radioactivity was excreted in bile at biliary excretion rate of about 80% after intravenous administration.
6.After intravenous administration to nursed rats, radioactivity was hardly detected in gastrointestinal tracts of sucklings.And from the study on distribution of radioactivity in pregnant mice, it was suggested that T-1982 scarcely passed placenta.
7.Excretion pattern after multiple administration to rats was similar to that of single administration. This result suggested that T-1982 did not produce accumulation of it in body.

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Piperacillin (PIPC) was administered to 4 cases with obstetrical and gynecological infections and the follow ing results were obtained.
1.PIPC was administered by intravenous drip infusion with 4 g per day for 7-14 days. The clinical efficacy was excellent in 2 cases with postoperative parametritis and good in 2 other cases, 1 with infectious ovarian cystoma and 1 with intrauterine infection.In the latter 2 cases surgical treatment was combined.
2.In laboratory findings GOT and GPT were slightly elevated in 2 cases. The relation between the drug and the abnormality was unclear because these rises may be considered due to the anesthesia or the operation itself.

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Piperacillin (PIPC) was administered to patients with obstetrical and gynecological infectious diseases and we studied its clinical effect and tissue distribution.
1.Clinical results
PIPC was administered to 26 patients at a dose of 2-4 g per day (twice a day) by dripping infusion over a period of 3-10 days (total 8-30 g). These included 16 cases with intrauterine infection, 1 with adnexitis, 4 with pelvic inflammatory disease and 5 with infections of the external genitalia.The clinical results were excellent in 11 cases, good in 13 cases and poor in 2 cases so that the overall efficacy rate was 92.3%.
For bacteriological study 33 strains were isolated from 20 patients.These included Gram positive bacteria (6 strains), Gram negative bacteria (23 strains) and anaerobes (4 strains).After PIPC treatment 32 strains (including S.epidermidis 4 strains, E.coli 12 strains, K.pneumoniae 3 strains, E.aerogenes 2 strains, P.aeruginosa2 strains and anaerobes 4 strains, etc.) disappeared except for 1 strain of K.pneumoniae which perisisted.The disappearance rate was 97.0%.
The only side effect observed was a slight case of malaise during the first administration day, however the relationship between the appearance of this symptom and the drug was unclear.No adverse reaction in laboratory findings was observed.
2.Tissue distribution
We determined the tissue concentration from 90 to 240 minutes after dripping infusion for 1 hour at a dose of 2 g.PIPC concentrations in these tissues including the endometrium, myometrium, cervix uteri, portio vaginalis, oviduct and ovary showed the highest level (18.0-11.7 μg) at 90 minutes after the beginning of administration.These values were 48.6-31.6% in respect to the uterine arterial blood level (37 itgiml at 90 minutes after infusion).

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The following trial was conducted as a fundamental study in the application of piperacillin (PIPC) in the field of obstetrics and gynecology.
A dose of 1 g was administered to 10 patients by intravenous injection and the concentrations of PIPC in the serum and the various tissues of the uterus were measured. This data was analyzed by the computer.
1.These concentrations were analyzed based on a two-or three-compartment model.We obtained the pharmacokinetic parameters and described the simulation curves.Correspondence was observed between the calculated and the actually determined concentrations.
2.PIPC was rapidly distributed to the tissues of the uterus and exhibited high concentrations. Transfer to these tissues correlated well with serum concentrations.

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Fundamental and clinical studies were made on piperacillin (PIPC) and the results were obtained as follows.
Serum and uterine tissue concentrations of PIPC were obtained from 36 to 215 minutes after intravenous single shot of 2g of PIPC.The cervix uteri, endometrium and corpus uteri showed the highest antibiotic levels of 38.0, 43.0 and 33.0mcg/g, respectively, at 65 minutes after injection, and oviduct and ovary showed the highest levelof 31.5 and 28.5mcg/g at 36 minutes.Its concentrations were sufficiently effective against the major pathogens (Gram-negative bacilli and anaerobes) demonstrated in the field of obstetrics and gynecology.
PIPC was administered 6 patients, including 3 of pelvic peritonitis (isolated organism was E.coil 1), 2 of acute endometritis (Klebsiella sp. 1, Peptococcus sp.+Bacteroides sp.1) and 1 of acute adnexitis, in a dosage of 1 or 2g twice or 3 times a day for a period of 5 to 8 days by intravenous administration or intravenous drip infusion.Clinical response was obtained excellent in 1 and good in 5.No adverse reaction was observed in any of the cases treated with PIPC, nor was there any marked changes in the laboratory findings.

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We conducted experimental and clinical tests on piperacillin (PIPC), a drug with a broad antibacterial spectrum, and achieved the following results.
PIPC exhibited the following rather high therapeutic blood concentraions: 30-60 μg/ml at 1 hour after intravenous injection of 1 g of PIPC, 10, μg/ml at 2 hours after intravenous injection of 2 g of PIPC, 7.2 μg/ml at 1 1/2 hours after the completion of 1 hour dripping infusion of 1 g of PIPC, and 5.6, μg/ml up to 4 hours after the completion of 2 hours dripping infusion of 2 g of PIPC.
The yield to the various uterine tissues is presented in decreasing order: the highest yield to ovary was about 40 50% of the blood level, followed by the uterine cervical region, portio vaginalis, myometrium and oviduct, the lowest yield, about 25-30% of the blood level was found in endometrium.
We conducted a clinical test on 7 patients with infections of the sexual organs and it proved to be excellent in 3, good in 3, and ineffective in 1 case so that the overall efficacy rate was 85.7% The patient in whom PIPC proved ineffective suffered from an underlying disease, namely the end stage of cervical cancer.
One patient suffered from a slight headache but whether this side effect was due to administration of the drug is not clear. Absolutely no abnormal findings during laboratory tests which could be attributed to drug administration were made.
Based on the above results, PIPC was judged to be an extremely useful drug in the treatment of infections in the obstetric and gynecological fields.

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In order to evaluate the clinical efficacy of piperacillin (PIPC) in the obstetrical field, 1 g of PIPC was intravenously administered to 45 normal term gravidas and PIPC concentrations in maternal serum, umbilical cord serum and amniotic fluid were determined. Fifty-three samples of maternal serum, 45 samples of umbilical cord serum and 44 samples of amniotic fluid were obtained at amniotomy and delivery.
The results of these studies are summarized as follows.
1.Mean biological half life of PIPC in maternal serum administered to term gravidas was 61.43 minutes.
2.Placental transfer of PIPC concentration into umbilical cord serum was about 71% of maternal serum concentration after 1 hour.
3.There was no prominent difference in the PIPC concentrations of the amniotic fluid between the ruptured and unruptured cases.Fast transfer of PIPC into the amniotic fluid was recognized, such as 1 cases was already raised to 4.3 μg/ml of PIPC in the amniotic fluid at 1 hour after administration.
4.The maternal serum and amniotic fluid concentration had a contrary relationship, and crossed each other at ca.5 μg/ml of concentration after 2 hours and 50 minutes.
Over a period of 6 hours and 20 minutes, the amniotic fluid concentration gradually increased.

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A total of 16 hospitalized patients underwent surgery for gastroenterological problems in the Department of Gastroenterological Surgery, Kanazawa Medical College Hospital, during the period from April 1981 to September 1981.
After they had undergone partial or total gastroenterological resection, cefoxitin was administered for the prevention of postoperative infections.
The following findings were obtained. 1.Fifteen out of 16 patients responded well with the clinical efficacy of 94 percent.
2.Elevations in S-GOT levels were noted in 3 patients.However, no other abnormalities were evident in the clinical data.
3.These clinical results indicate that cefoxitin is an effective antibiotic for the prevention of postoperative infections in gastroenterological surgery.

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Cefotiam (CTM) is a new synthetic cephem antibiotic developed in Japan. The results of the fundamental and clinical studies are as follows.
1.CTM showed antibacterial activity, in terms of MIC, as strong as those of cephalothin (CET) and cefazolin (CEZ) for Gram-positive cocci, and several times superior to for Gram-negative bacilli.
2.CTM serum levels approximately reached the peaks on completion of 60 minutes intravenous drip infusion of 1 g of this preparation dissolved in 5% glucose solution of 250 ml;the mean value was 65.00 aug/ml. Then the levels dropped rather quickly up to 180 minutes after the start of drip infusion.After that, the levels dropped gradually up to 360 minutes.
3.As for the passage of CTM in the oral tissues, satisfactory passage was observed in both maxillomandibular marrow and gingiva, which adequately exceeded MICs of the clinically isolated strains of oral infections.
4.This preparation was administered 1 g of 2 g daily by intravenous drip infusion in 18 cases of moderate or more serious infections in the field of oral surgery; the clinical efficacy rate obtained was 94.4%.
5.No manifestations of side effect were observed clinically.As for laboratory findings, 1 case of large increases in GOT and GPT (a hepatitis B antigen positive patient) and 2 cases of slight increase in GPT were observed.
On the basis of these results of the fundamental and clinical studies, it was concluded that CTM is an excellent antibiotic for the treatment of oral infections.

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Susceptibilities to cefotiam of 103 strains of 27 bacterial species were determined by the 2-fold agar dilution method in parallel with the diameter of inhibition zone by the single-disc method, under the experimental condition established by KANAZAWA.
The experiments demonstrated significant correlation between MIC by the dilution method and diameter of inhibition zone in each of conventional assay of the over-night (about 16 hours) incubation, delayed assay (about 24 hours incubation), and rapid assay (about 3-4or 5-6 hours incubation), thus confirming applicability of the singledisc assay for cefotiam.
Analysis of the data obtained by using cefotiam disc containing 30μg revealed the primary regression equation to be: D (diameter, mm) =25.6-10.1 log MIC (μg/ml) in conventional assay, D=32.8-13.2 log MIC (μg/ml) in delayed assay, D=17.2-5.8 log MIC (μg/ml) in 3 s 4 hours rapid assay and D=21.0-7.8 log MIC (μg/ml) in 5-6 hours rapid assay, respectively.
The range of variations in MICs estimated from the diameter of inhibition zone by the disc test was then calculated in comparison with that in MIC determined by the 2-fold agar dilution assays, as reference for the experimental errors which may be involved in the estimation of MIC of cefotiam by the single-disc assay.

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Cyclocytidine (Cyclo-C) was evaluated as an antiviral chemotherapeutic agent in 10 children with herpes-groupvirus infections.The diagnoses of the patients were severe cytomegalovirus (CMV) syndrome with pneumonitis in acute leukemia (2), congenital or infantile CMV infections (3), herpes zoster encephalitis in acute leukemia (1), severe nosocomial varicella in compromised patients (2), varicella pneumonia (1) and acuteencephalitis due to herpes simplex type-1 (1).Cyclo-C was effective in all the cases with acute infections, although it had no benefit on the course of chronic CMV infection with irreversible damages, However, complete or transient ceasing of viral shedding was obtiined in all the 5 cases with CMV infections.
From the present small open study, further evaluation of Cyclo-C as an antiviral agent especially in acute CMV infections is warranted.

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Many strains of cefazolin (CEZ)-resistant Staphylococcus aureus of recent clinical isolates were also resistant to gentamicin (GM). In addition, the antibacterial activity of NTL was found to be stronger than that of GM and stronger than that of CEZ for those resistant strains and especially for those moderately resistant to GM.

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This paper is concerned with fundamental and clinical studies of ceftizoxime, a newly developed cephalosporin derivative, in the field of obstetrics and gynecology.
1.Concentrations of ceftizoxime after administration 1g of ceftizoxime by1hour drip infusion were determined in genital organs in 17 patients and the exudate of pelvic dead space in 6 patients.Simulated maximal concentrations with the ratios to the simulated peak serum levels were as follows: 27.9, μg/g for fundal myometrium with the ratio of 48%, 36.0μg/gfor portio vaginalis with 62%, 17.1tig/g for ovary with 29%, 15.0 iugig for oviduct with 26% and 16.2, μg/ml for the exudate of pelvic dead space with 30%.
2.Minimal inhibitory concentrations of ceftizoxime were determined against clinically isolated organisms from female genital infectious diseases. Ceftizoxime was found to have a potent in vitro activity against Gram negative bacilli;for example, 0.1, μg/mg or low against E.colt and K.pneumoniae.Against P. aeruginosa, P.cepacia and B.fragilis, ceftizoxime had an activity which expected to be effective in the clinical use.
3.We gave ceftizoxime to 6 patients comprising 4 patients with puerperal fever, 1with septic abortion and 1with tubo-ovarian abscess in daily doses of 2to 3 g by b.i.d or t.i.d intravenous drip infusion for 4 12 days.The results of the treatment were ‘excellent’ in 3 patients, ‘good’ in 2, and ‘unevaluatable’ in 1.
4.Adverse reactions occurred in 2 patients who showed eruption during the medication with ceftizoxime. These patients had allergic histories due to penicillin derivatives.
From the above results it is concluded that ceftizoxime is an useful drug for infections in obstetrical and gynecological field.

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An experimental suppurative otitis media in dog was produced to evaluate the therapeutic effects of cefmetazole (CMZ) in this study.
In order to induce a definite case of otitis media, 1.0 mg of dexamethasone was administered intramuscularly to dog, 12 hours before a bacterial inoculation into the middle ear of it.
For inoculation, 5 x 10⁸ live bacteria of S. aureus, strain 571 (UOP) was prepared from its 18 hour-bouillon culture and added 0.9 ml of 5% mucin solution for a total inoculation fluid of 1.0 ml. This fluid was injected into the middle ear on one side by inserting a ‘mouse syringe’ with a swollen tip down the external auditory meatus to pierce the tympanic membrane. On the opposite side, only 1.0 ml of micin solution was injected. In this way, suppurative otitis media which definitely lasted until the 15th day following the bacterial inoculation was realized.
Since in each positive controls, the onset of suppurative otitis media had been confirmed on the 4th day after inoculation, the intravenous administration of CMZ (three times a day; 9: 30, 15: 30, 21: 30) was started at the end of the 4th day and continued through the 7th day. The dogs thus treated were sacrificed on the 10th day after inoculation and the live bacteria count within the middle ear, signs of inflammation on the tympanic cavity, and the accumulation of pus were examined. The therapeutic effect of CMZ was rated as ‘effective’ incase where S.aureus-571 was found to be negative.
All the animals administered a daily dose of 30 mg/kg or above it, were found to be S. aureus-571 free, thusth e satisfactory therepeutic effect of CMZ was demonstrated. Especially, at the daily dose of 120 mg/kg the membrane of the tympanic cavity in all cases exhibited a picture of a radical cure to alm ost the same degree asth e control side membranes, and any signs of inflammation were hardly observed.
The last mentioned phenomena had been observed too by the authors on the treatment of the experimentallyi nduced pyometra in bitches, with CMZ. Thus it is assumed that in treating some suppurative diseases with CMZ, it may be advisable to initiate the administration at relatively large doses in order to achieve generallybetter and quick effect.

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Antibacterial activities of cefmetazole, a new preparation of cephamycin antibiotic, were determined against selected clinical strains of Escherichia coli (27 strains), Klebsiella sp.(27 strains) and Bacteroides fragilis (27strains). Activities were evaluated at bacteriostatic and also bactericidal levels with particular reference to time of exposure of microbes to the drug.
The minimal drug concentrations producing minimal reduction of colony-forming units at time intervals of 3, 6 and 24 hours after exposure to the drug-approximations to the theoretical bacteriostatic concentrationswere designated as 3-h, 6-h and 24-h MRCs, respectively. Conventional MIC yielding no turbidity after incubation of antibiotic-containing broth for 24 hours was also determined. The minimal concentrations of the drug producing 99.9% killing at time intervals of 3, 6 and 24 hours after exposure to the drug were designated as 3-h, 6-h and 24-h MLCs, respectively. Assuming that the apparent mode of action of a drug is bactericidal when the ratio of bactericidal-bacteriostatic concentrations is low (≤4) and bacteriostatic when high (≥8), then cefmetazole appeared to be a bactericidal drug to a considerable number of Gram-negative strains when the exposure time exceeded a period of 6 hours. The data that the mode of action of this drug is bactericidal with such relatively brief exposure times-indicating repid decrease of colony-forming units-would suggest cefmetazole is an excellent antibacterial agent and would be a useful drug in treatment of bacterial infections.

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For the purpose of verifing the effectiveness of peplomycin, one of the derivatives of bleomycin, against carcinoma of the esophagus and the safety of it, the analysis of the data for total 113 cases collected from 25 institutions in Japan was made.
The results are as follows.
It was effective in 19 out of 74 evaluable cases of carcinoma of the esophagus (25.7%).
In case of treatment with peplomycin alone, it was effective in 6 out of 39 cases (15.4%). In case of thecombination treatment with peplomycin and some other therapy, it was effective in 13 out of 35 cases (37.1%).
As for the side effects, the incidence of fever was the highest in both the cases of peplomycin alone and the combination treatment such as 39.6% and 37.0%, respectively. Anorexia, nausea, vomiting, respiratory symptoms and tiredness were found in relatively many cases.
In the clinical laboratory tests, the vital capacity after the treatment tended to be lower than that before the treatment, but there was little change in the hematological tests, pulmonary function test and renal function test.

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