[in Japanese]

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Anthracycline antibiotic oxaunomycin was obtained through photochemical conversion of precursor metabolite D788-1 which was produced by a blocked mutant strain RPM-5 of Streptomyces sp. D788, purified as a crystalline hydrochloride and physicochemically characterized.

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The technique of protoplast fusion which optimized prototrophic recombination in aclacinomycin-producing Streptomyces galilaeus was studied and applied to the construction of new anthracycline analog-producing recombinant upon genetic cross of two specific mutants blocked in aclacinomycin biosynthesis. Thus, 2-hydroxyaclacinomycin-producing recombinant was obtained by the protoplast fusion.

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Anthracycline antibiotics 2-hydroxyaclacinomycins A and B were isolated and purified from the culure broth of a recombinant strain which was produced by protoplast fusion of two aclacinomycinbrocked mutants. 2-Hydroxyaclacinomycin B is a new compound for which chemical structure and the biologial activity in vitro were determined. 2-Hydroxyaclacinomycins had a stronger antitumor activity against murine leukemic L1210 cells in mice than the parent antibiotic aclacinomycins.

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About 30 antitumor anthracycline antibiotics were tested for their susceptibilities to reductive deglycosidation at C-7 catalyzed by rat liver microsomal NADPH-cytochrome P-450 reductase, xanthine oxidase, cytochrome C reductase and DT-diaphorase. Enzymatic activities to reduce the C-7 position of anthracycline antibiotics were similar among the four redox enzymes although a few exceptions were observed with DT-diaphorase. Among therapeutic use of anthracyclines, aclacinomycin A (ACM-A, aclarubicin) and daunomycin (daunorubicin) were found to be highly sensitive to the redox enzymes tested while adriamycin (ADM, doxorubicin) and THP-ADM (pirarubicin) were resistant to enzymatic reductive deglycosidation. When glycosidic and hydroxylated analogs of ACM-A were compared it was found that anthracyclines with smaller glycoside residues were more sensitive to the redox enzymes and the presence of hydroxyl groups on the aglycone moiety decreased the reductive deglycosidation activities. Thus, the aglycone, aklavinone, was most rapidly reduced to 7-deoxyaklavinone. 1-Hydroxy-, 2-hydroxy-, 11-hydroxy-and 1, 11-dihydroaclacinomycins A were more resistant to the redox enzymes than ACM-A. Especially, 2-hydroxyaclacinomycins were completely insensitive to the enzymatic reduction. THP-ADM, 4'-substituted analog of ADM, was more resistant to the redox enzymes than ADM itself. These results show that the presence of a hydroxyl group, its position on aglycone, the presence of 4'-substituent on aminosugar and its length in the anthracycline molecule play important roles on the C-7 reduction by the redox enzymes. Relationship between reductive deglycosidation susceptibilities and cell-growth inhibitory activities of anthracycline antibiotics are also discussed.

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A clinical study was undertaken to determine the effects of combination antibiotic therapy in 104 patients with infections associated with hematological disorders.
All patients were treated with sulbactam/cefoperazone (SBT/CPZ) plus an aminoglycoside as an empiric therapy for fever. The overalle fficacyr ate of the therapy was 63.5%. Efficacy rat es were 61.2%and 71.9%when initialn eutrophilc ounts were lesst han 500/mm³ and over 500/mm³, respectively.N o significandti fferencew as found between the cases in which initialluys ed a ntibiotics were continued (efficacyr ate 62.5%) and those in which antibioticwse re switched during the course oftherapy (65.6%).Antibiotic therapy with SBT/CPZ plus an aminoglycoside provides adequate antibiotico verage againsti nfectionsa ssociatedw ith hematologicald isorders. This combination was highly effective ven in the neutropenic periods of febrilep atients.

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A survey of purulent meningitis in infancy and childhood from 1980 through 1986 was made by sending questionnaires to 32 pediatric institutions in Aichi, Gifu and Shizuoka prefectures. Case cards of 125 patients were collected and analyzed. The results are summarized as follows:
1. The sex ratio (male/female) was 1.78. The age distribution for all patients was as follows: younger than 1 month, 24.8%; 1-12 months, 32.8%; 1 year, 19.2%; 2-5 years, 16.0%; older than 6 years, 7.2%. Nearly 3/4 of all purulent meningitis cases occurred in infancy.
2. The isolation rate of causative organisms was 71.2%. The 4 major causative organisms were Haemophilus sp.(28 cases), Streptococcus pneumoniae (14 cases), Streptococcus agalactiae (13cases), and Escherichia coli (12 cases). Haemophilus sp. was dominant in patients over 3 months of age, and S. pneumoniae was noted in all age groups. The latter 2 were dominant under 3 months of age.
3. The outcome of 125 cases was as follows: cured, 73 cases (58.4%); improved, 26 cases (20.8%); dead, 15 cases (12.0%); unknown, 11 cases (8.8%). As to the outcome by age, the mortality of infants within 1 month old was the highest, 29.0%, and then decreased with increasing age. As to the outcome by causative organisms, Haemophilus sp. and E. coli were associated with good outcome, whereas S. pneumoniae and S. agalactiae with poor outcome.
4. Among several antibiotics, ampicillin was the most frequently used in 94 cases, followed by cefotaxime in 50 cases.
5. As to the initial antibiotic treatment, 51 cases were treated with penicillins (PCs)(including PCs+aminoglycosides (AGs)), 9 cases with cephalosporins group I, II, IV,(CEPs I, II, IV)(including CEPs I, II, IV+AGs), 25 cases with CEPs V (including CEPs V+AGs) and 31 cases with CEPs V+PCs (including CEPs V+PCs+AGs). No significant differences were observed in the outcome among these initial treatment group.
6. Compared with the initial treatments of CEPs V or CEPs V+PCs groups, other antibiotics were used more frequently in those of PCs + AGs and CEPs I, II, IV groups. In the light of this analysis, the initial treatments of purulent meningits with PCs+AGs or CEPs I, II, IV were not so effective as those with CEPs V or CEPs V+PCs.

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Combination antibiotic therapies using piperacillin (PIPC) were evaluated in 60 episodes of severe infections in 38 neutropenic patients with hematologic malignancies.
1.The overall efficacy rate was 46.7%. Efficacy rates were 30% in patients with pneumonia, 60% in patients with sepsis and 50% in patients with suspected sepsis in which causative organisms were not identified.
2.Eradication rates were 44.4% for Gram-negative bacilli, 50% for Pseudomonas aeruginosa and 22.2% for Gram-positive cocci.
3. Efficacy rates were 33.3% in patients with initial count of neutrophil less than 100/μl, 60% in patients with those 100 to 500/μl and 66.7% in patients with those higher than 500/μl. Initial neutrophil counts correlated well with efficacies of PIPC on severe infection in patients with hematologic malignancies.
4.Mild increases of transaminase were observed in 2 cases.
From these results it is concluded that PIPC is one of the most important antibiotics in the treatment of severe infections in neutropenic patients with hematologic malignancies.

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A total of 43 patients, c omprising 41 patients with oral candidiasisa nd 2 with esophageal candidiasis, w ere treated with miconazole (MCZ) gel to assess its efHcacy and safety intreating upper digestivet ractm ycosis. The efHcacy of the drug was evaluablei n 33 of them, consistingo f32 patientsw ith oral candidiasisa nd 1 with esophageal candidiasis.T he clinicale Mcacy rate of the drug against oral candidiasisw as 87.5% (28/32 patients), a nd the clinicalr esponse was good in the 1 evaluable patient with esophageal candidiasis
The safety of the drug was assessed in 40 patients. In 3 (7.5%) of them, nausea occurred as an adverse event, but was not particularly serious in any of them. No abnormal laboratory test values caused by the drug were observed. The results suggested that MCZ gel would be a very useful drug in treating oral and esophageal candidiasis.

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Clinical effects of combined use of aztreonam (AZT), amikacin (AMK) and clindamycin (CLDM) in 46 cases with infectious diseases in obstetrics and gynecology were retrospectively studied in 2 groups, and the following results were obtained.
1. No significant difference in efficacy rates was noted between AZT plus CLDM treated group (n=25) and AMK plus CLDM treated group (n=21)(96.0% vs. 95.2%), while rate of excellent efficacy was slightly higher in AZT plus CLDM group than AMK plus CLDM group (24.0% vs. 14.3%).
2. No significant difference in bacteriological clinical effects was also noted between the 2 groups, while bacteriological eradication rate was higher in the AZT plus CLDM group than in the other group (76.2% vs. 50.0%), and the difference was particularly clear in the eradication rates of aerobic, Gram-negative bacteria (88.9% vs. 30.0%).
3. Subjective and objective side effects, and abnormalities of clinical test results were not found in either group.

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Fosfomycin sodium FOM-Na, Forocyle-S® were administered at 25mg/kg or 50mg/kg to 15 children between the ages of 3 and 15 through intravenous injection or through 1 hour intravenous drip infusion, and concentrations in blood serum and excretion through urine were examined and a pharmacokinetic analyses were carried out using the one-compartment model.
1. Average concentrations in the blood serum after injections with 25 mg/kg and 50mg/kg were 55.3±6.3μg/ml and 118.8±31.1 μg/kg 30 minutes after injection, respectively, and their half-lives were 1.04±0.15 hours and 0.98±O.17 hours, respectively. six hours after injection, the levels were 2.7±1.6 μg/kg and 6.2±5.5 μg/kg, respectively.
With l hour intravenous dripinfusion of 25mg/kg and 50mg/kg, average concetrations the blood serum were 34.2±14.9 μg/mland 89.7±6.7 μg/ml, respectively, and the irhalf-lives were0.87±0.24 hour and 0.69±0.10 hour, respectively. six hours after the administration, the levels were 2.7±1.8 μg/ml and 6.7±0.8 μg/ml.
There was a clear dose response in the concentration levels in the blood in those given the drug at 25mg/kg and 50mg/kg in either method of administration.
2. Average levels in urine after injection of 25mg/kg and 50mg/kg were 5,778±2,257 μg/ml and 6,268±3,329 μg/ml 0-2 hours after administration, respectively, and average levels at 4-6 hours were 701±765 μg/ml and 1,588±1,324 μg/ml, respectively. Average excretion, ratesinto the urine were 72.8±11.O and 73.9±11.1%, respectively.
In case of l hour drips infusion of 25mg/kg and 50mg/kg, average concentratiOns in th eurine 0-2 hours after administration were 3,570±1,540 μg/ml and 11,800 μg/ml, respectively, and averages fbr 4-6 hours were 211±124 μg/ml and 1,300μg/ml. Average rates of excretion into the urine for the first group was 57.9±16.3% and the second group was 78.4%.
In case of l hour drips infusion of 25mg/kg and 50mg/kg, average concentratiOns in th eurine 0-2 hours after administration were 3,570±1,540 μg/ml and 11,800 μg/ml, respectively, and averages fbr 4-6 hours were 211±124 μg/ml and 1,300μg/ml. Average rates of excretion into the urine for the first group was 57.9±16.3% and the second group was 78.4%.
Clear dose response was observed in changes of drug concentratiOn levels in the urine with 25mg/kg and 50mg/kg doses through either administration method, and in terms of excretion into the urine, no no ticeable differences were observed between the different amounts administered or different administration methods.
3. Average values Of the pharmac0kinetic parameters inthe respective administration quantities and methods Obtained through application of the one-compartment model were 0.678±0.091-1.018 ±0.142hr-1 fbr elimination rate constant (Ke1), and the distribution capacities (Vd) was 0.229± 0.081-0.370±0.084L/kg with no great differences according to administration methods or quan. tities. In terms Of ages there were hardly any differences in Kel were found, but there was a tendency that the greater the age of the subject was, the smaller the value of Vd was obtained.
4. As fbr the average values of area under the time/density curve (AUC) calculated by pharmacokinetic parameter, in the case of either quantity there was no difference between the injection and the lhour drip while fbr both methods Of administration there was aclear dose response among the patients administered either 25mg/kg and 50mg/kg.
The average values for total body clearance and kidney clearance fbr each method and quantity were 3.91±0.39-4.31±1.19ml/min/kg, 2.06-3.28±1.50ml/min/kg, respectively withoutany large differences caused by administration method or quantity.

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An antifungal agent of the imidazole class, miconazole (MCZ)(base), was investigated for itsin vitro antifungal activities against isolates from the oral cavity and esophagus of patients with mycosis, and the following findings were obtained:
1. Those yeast-like fungi which were presumed to be the causative agents were isolated from the oral cavity and esophagus of patients with mycosis, and identified. Candida albicans was the most frequently occurring species, accounting for 71.4% of all the isolates. Less frequently, several other Candida species, such as Candida krusei, Candida tropicalis, Candida lusitaniae and Candida lipolytica were also isolated mostly from patients with polymicrobial infections.
2. The MICs of MCZ against the isolates of Candida species which were obtained from materials from patients with oral and esophageal candidiasis as the presumable causative agent distributed through such a wide range as ≤0.04 to 20μg/ml, and susceptibilities of these isolates to MCZ proved to be no less than those to amphotericin B, which was used as the control drug.
The results suggest that an appropriate preparation of MCZ (base) will be effective in treating mycosis of the oral cavity and esophagus.

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