Cefazolin (CEZ) concentration in the bone marrow of tibia was examined1, 2 and 3 hours after intramuscular injection of 1g.
CEZ concentration in the bone marrow of tibia 1 hour after injection was 59.9±10.31μg/ml. Ratio to serum was 101.7%.CEZ concentration in the bone marrow of tibia 2 hours after injection was 42.5±7.77μg/ml.Ratio to serum was 102.7%.CEZ concentration in the bone marrow of tibia 3 hours after injection was 33.9±7.75μg/ml.Ratio to serum was 102.7%.
Penetration capacity of CEZ into the bone marrow of tibia was excellent.

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In the clinical studies on cefadroxil against acute infectious diseases in the otorhinolaryngological field, the following results were obtained:
(1) In 10 cases of various infections, excellent was 2 cases and good was 8 cases, efficacy rate being 100%.
(2) No side effects were observed subjectively, and no abnormal findings were demonstrated with laboratory tests.
(3) Cefadroxil may be expected to be a highly effective and safe agent for the therapy of otorhinolaryngological infections.

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The cardiotoxic effect of aclacinomycin A or adriamycin given by a single intravenous injection was evaluated in golden hamsters by electrocardiography (ECG) and electron microscopy.
Aclacinomycin A caused slight ECG alterations at a dose of 75 mg/kg or 100 mg/kg such as bradycardia, Ta wave formation, ST segment depression and T wave flattening.On the other hand, adriamycin caused moderate to remarkable alterations in ECG at a dose of 3.13 mg/kg or 6.25mg/kg, such as arrhythmia, bradycardia, auriculoventricular block, bundle branch block, ST segment changes and T wave flattening.
Alterations in ultrastructure of the myocardium caused by aclacinomycin A at a dose of 25 mg/kg contained some cardiac cells with mild changes, ie, dilations of sarcoplasmic reticulum and swelling of mitochondria.At a dose of 100mg/kg, it caused moderate to remarkable alterations such as separation of myofilaments, appearance of myelin figures, and decreases in intramitochondrial granules and glycogen particles.Adriamycin, however, gave remarkable changes even at a dose of 6.25 mg/kg which involved separation of myofilaments, lower electron-density of mitochondrial matrix, vacuolization and swelling of capillary endothelial cells.From these findings, both antibiotics may cause cardiotoxicity by similar mechanism.But aclacinomycin A affected the heart milder than adriamycin.

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Male golden hamsters were treated with aclacinomycin A or adriamycin by daily intraperitoneal injections for 15 consecutive days, and then allowed to be recovered for 15 days.Dose levels of aclacinomycin A and adriamycin were1.5, 2.0and3.0 mg/kg, and 0.17and0.5mg/kg, respectively. General toxicity, electrocardiogram (ECG), blood biochemical analysis and light microscopic and electron microscopic examinations were studied.The two drugs produced body weight loss at a dose of3.0mg/kg and0.5mg/kg, respectively.Death occurred in hamsters treated with aclacinomycin A at the highest dose (4/6 animals).In ECG study, aclacinomycin A-treated hamsters showed reversible QRS duration prolongation and T wave flattening at a dose of1.5or2.0mg/kg. Adriamycin-treated animals at a dose of0.5mg/kg showed R wave amplitude elevation during dosing period, and PR interval prolongation, R wave amplitude elevation and S wave amplitude reduction during recovery period.
Blood biochemical analysis demonstrated reversible elevation of lactate dehydrogenase and αhydroxybutyrate dehydrogenase activities in aclacinomycin A-treated hamsters at a dose of2.0mg/kg, and an increase in lipoperoxide in adriamycin-treated animals at a dose of0.5mg/kg during dosing period.
Histologically, both drugs produced separation of myofilaments, swelling of mitochondria, dilation of sarcoplasmic reticulums and decreases in glycogen and lipid particles in myocardium.But aclacinomycin A-treated hamsters rarely showed these alterations after recovery period, whereas adriamycin-treated animals showed separation and necrosis of myofilaments, fibrosis of muscle fibers and formation of myelin figure even after recovery period.These results suggested that cardiotoxicity caused by aclacinomycin A was reversible and milder than that by adriamycin.

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Subacute cardiotoxic effect of aclacinomycin A or adriamycin given by daily intraperitoneal injections for 5 days was studied in rats by electrocardiography (ECG), blood biochemical analysis, light microscopy and electron microscopy.
Dose levels of aclacinomycin A and adriamycin were 4 and 8 mg/kg, and 2 and 4 mg/kg, respectively. The two drugs caused severe body weight loss at a dose of 8 mg/kg and 4 mg/kg, respectively.Aclacinomycin A-treated rats at a dose of 4 mg/kg showed slight changes in ECG,
whereas adriamycin-treated rats at the same dose showed a heart rate decrease, QRS duration and QT interval prolongation and R and S waves amplitude elevation.
Blood biochemical changes caused by both drugs at a dose of 4 mg/kg were increased in lipoperoxide and α-hydroxybutyrate dehydrogenase activity.
Aclacinomycin A gave slight ultrastructural changes in some cardiac cells such as formation of myelin figure and vacuolization in mitochondria.But adriamycin caused remarkable alterations such as degeneration and destruction of mitochondria, vacuolization of sarcoplasm and disappearance of myofilaments, which were often observed near the capillaries and nuclei.
These results suggest that the two antibiotics caused cardiotoxicity by a similar mechanism. However, the damage produced by aclacinomycin A was milder than that of adriamycin.

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Male and female Wistar rats were treated with aclacinomycin A, a new anthracycline antitumor antibiotic, at 5 dosage levels (0.08, 0.15, 0.3, 0.6and1.2mg/kg-day) by daily intraperitoneal injections for 180 days for a chronic toxicity study. Recovery was also examined for 30days after completion of the administration.
Mortality was as follows: Male5/24, female3/24 in 0.6mg/kg-day dose group and male19/24, female8/24in1.2mg/kg·day dose group.Anorexia, depression of spontaneous activity and unformed feces were observed in rats in0.6and1.2mg/kg·day dose groups after day 90.Body weight gain decreased during the period.No significant change was found in rats receiving the drug at 0.3 and less mg/kg·day, all through the observation period.Remarkable decreases in WBC count were noted in rats in the two highest dose groups on day 90.
Autopsy findings included atrophy of the thymus and hyperemia and hemorrhage in the gastrointestinal tract and mesenteric lymph node in the animals treated at0.6and1.1mg/kg·day in the examination on day90.
Histologically, atrophy of the thymus and hyperplasia of the spleen were observed in the higher dose groups on day 90.But no remarkable abnormalities were found in histological examination on day180.
The changes in general symptom and decrease in body weight gain, which were observed during the dosing period in rats in0.6mg/kg·day dose group, recovered within30days after the drug administration was discontinued but no complete recovery of the WBC count decrease was observed.

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We have been studying physiologically active substances produced by microorganisms which are isolated in our laboratory1).A grain named Aspergillus sp.No.Y-8980which was isolated frorn a soil sample collected at Yoron Island in Kagoshima Prefecture was identified with a Microorganisin classified in Aspergillus, terreus group2) on the taxonomic properties.A. physiologically active substance, produced by the strain was obtained as slightly yellow needle crystals.The substance was melted at127°C and showed [α] ²⁰_D-23.9°C, C₇H₈O₄ (MW: 154.12).From various physico-chemical properties, the substance was identical to terreic acid (5, 6-epoxy-3-hydroxy-ptoluquinone) 8, 4).Moreover, it was found that the substance demonstrated effects on morphological degeneration in HeLa cells as well as inhibition and prolongation of survival.time in EHRLICH ascites carcinoma cells.No report on such anti-tumor effects as above with regards to terreic acid was presented previously This paper describes taxonomy of the producing strain;production, isolation, physico-chemical properties, chemical structure, biological properties and anti-tuinor effects on the substance.

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[in Japanese]

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Fundamental and clinical studies on sisomicin, a new aminoglycoside antibiotic were carried out and the following results were obtained.
1. Antibacterial activity of sisomicin was superior to thatof gentamicin, amikacin, cefazolin and ampicillin against S.aureus and Ps.aeruginosa.Against E. coli and K.pneumoniae, it was superior to that of amikacin, cefazolin, ampicillin and equal or slightly superior to that of gentamicin.
2. Mean serum levels of sisomicin were 18.0±0.5 μg/ml, 15.7±1.3 μg/ml, 9.6±0.6 μg/mi, 3.2± 0.4 1.7±0.2 μg/ml and 0.95 μg/ml at 1/2, 1, 2, 4, 6 and 8 hours after a single intramuscular administration of sisomicin 2.0 mg/kg to 3 children.Mean half-life time was 1.6±0.2 hours.Mean urinary recovery was 60.4±7.5% within 6 hours after administration of sisomicin 1.6-2.1 mg/kg to 4 children.
3. Sisomicin was given intramuscularly to 13 children with acute pyelitis (11), acute cystitis (1) and stomatitis gangrenosa and cervical lymphadenitis (1). The daily dose was 2.0-4.2 mg/kg, divided into twice.Clinical response was excellent in 8 andgood in 5.In bacteriological examinations, 13 pathogens (E.coli 9, K.pneumoniae 2, Ps. aeruginosa2) were eradicated after administration. No adverse reactions were observed.

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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A cooperative study in 46 institutions and clinics in Tohoku and Hokkaido districts in Japan was carried out to compare the efficacy, usefulness and safety of cefamandole and cefazolin in treatment of respiratory tract infections by randomized double blind technique.
Two grams of either of the two cephalosporins were given by intravenous drip infusion to the two groups of patients aged over 16 years twicea day for 14 days.
Of a total of 232 patients included in the study, 120 patients were treated with cefamandole and 112 patients with cefazolin. Of these patients treated with either of the both drugs, 27 patients were excluded from evaluation for efficacy. All232 patients were adopted for analysis of side effects.
Characteristics of the population, sex and age distribution, severity of infections and infecting organisms before treatment were similar in eachtreatment group and no statistically significant differences could be found between the two groups. Both groups included nearly equal numbers of patients with underlying diseases or with complications. The patients pre-treated with other antibiotics before the start of the study or treated simultaneously with anti-inflammatory drugs were equally distributed in the both treatment groups.
Clinical cure rate was 69.2% in groups of the patients treated with cefamandole, whereas that in cefazolin treatment group was 62.2%. Thus, there was a difference of 7% in clinical cure rate between two treatment groups, though it was notstatistically significant. In groups of patients with acute bacterial pneumonia or lung abscess, clinical cure rate with cefamandole was76.7%, whereas that with cefazolin was 67.7%. Thus, the clinical cure rate was 9% higher in the group of patients treated with cefamandole, though the difference was again statistically not significant. In the group of patients with infections associated with chronic respiratory diseases, cefamandole cured SO% of the patients treated, whereas cefazolin cured 48.1%.
Comparison of the curves of cumulative distribution of MICsof cefamandole and cefazolin proved the superiority of cefamandole to cefazolin in antimicrobial activities against strains of various species isolated from the patients in the study. Rate of eradication of potential pathogenic microorganisms was 82.4% in the patients with pneumonia or lung abscess who were treated with cefamandole, whereas that was 66.7% in the patients treated with cefazolin.Thus eradication rate was higher by 15.7% in patients treated with cefamandole than in those treated with cefazolin and the difference in eradication rate was statistically significant (P <0.1).In patients with infections associated with chronic respiratory disease, bacterial eradication rate with cefamandole was 76.2%, whereas that with cefazolin was 83.3%.
Taking efficacy and adverse effects into consideration, usefulness of the two cephalosporins in the treatment of respiratory tract infections was evaluated by doctors in charge.In 33.3% of patients treated, cefamandole was evaluated as quite useful in the treatment of pneumonia or lung abscess.In contrast, cefazolin was evaluated as quite useful in only 18.3% of patient treated. This difference was statistically significant (P <0.1).In treatment of patients with infections associated with chronic respiratory disease, cefamandole and cefazolin were evaluated as quite useful or useful in 53.1% and in 51.8% of the patients treated with each drug, respectively.
Frequency and severity of adverse reactions to therapy was quite similar in the cefamandoleand cefazolin-treated groups.Comparison of laboratory test values obtained before, during and after the treatment with both agents showed that the two cephalosporins did not differ from each other in producing test values outside the normal limits and neither cephalosporin caused major toxic hepatic, renal and hematologic reactions.

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