The Japanese Journal of Antibiotics
Online ISSN : 2186-5477
Print ISSN : 0368-2781
ISSN-L : 0368-2781
Volume 39, Issue 12
Displaying 1-15 of 15 articles from this issue
  • HIROYUKI KOBAYASHI
    1986 Volume 39 Issue 12 Pages 3129-3139
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
  • SATOSHI KOBAYASHI, KATSUMI TAKAI, AKINOBU INOUE
    1986 Volume 39 Issue 12 Pages 3140-3147
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Aminoglycoside and β-lactam antibiotics are often used in combination. This paper reports a high performance liquid chromatographic determination method for each of astromicin (ASTM) and cefsulodin (CFS) in blood samples of several species.
    The procedure for ASTM included purification with CM-Sephadex, separation on a reversed phase column (C-18) and derivatization with o-phthalaldehyde (OPA).
    The procedure for CFS included deproteinization with methanol, centrifugation, filtration and separation on a reversed phase column (C-18).
    Either of the drugs did not affect the determination of the other. The detection limits were 0.1μ/ml for ASTM and 0.5μg/ml for CFS. These sensitivities seem good enough for a clinical application of the method considering usual dosage levels of the drugs.
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  • SATOSHI KOBAYASHI, KATSUMI TAKAI, SATOE MASUDA, AKINOBU INOUE
    1986 Volume 39 Issue 12 Pages 3148-3155
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Combination therapy of aminoglycoside and β-lactam antibiotics is often used clinically because of its effectiveness. This paper reports a high performance liquid chromatographic (HPLC) determination method for each of astromicin (ASTM) and cefoperazone (CPZ) in blood samples of several species.
    The procedure for ASTM included purification with CM-Sephadex, separation on a reversed phase column (C-18) and derivatization with o-phthalaldehyde (OPA).
    The procedure for CPZ included deproteinization with methanol, centrifugation and separation on a reversed phase column (C-18).
    Either of the drugs did not affect the determination of the other. The detection limits were 0.1μg/ml for ASTM and 0.5μg/ml for CPZ. These sensitivities seem good enough for a clinical application of the method considering usual dosage levels of the drugs.
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  • SATOSHI KOBAYASHI, KATSUMI TAKAI, SATOE MASUDA, AKINOBU INOUE
    1986 Volume 39 Issue 12 Pages 3156-3163
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Aminoglycoside and β-lactam antibiotics are often used in combination, and many synergistic effects have been reported. We describe here a high performance liquid chromatographic determination method for each of astromicin (ASTM) and piperacillin (PIPC) in blood samples of several species.
    The procedure for ASTM included purification with CM-Sephadex, separation on a reversed phase column (C-18) and derivatization with o-phthalaldehyde (OPA).
    The procedure for PIPC included deproteinization with acetonitrile, centrifugation and separation on a reversed phase column (C-18).
    Either of the drugs did not affect the determination of the other. The detection limits were 0.1μg/ml for ASTM and 0.5μg/ml for PIPC. These sensitivities seem good enough for a clinical application of the method considering usual dosage levels of these drugs.
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  • I. ACUTE TOXICITY TEST IN MOUSE, RAT AND DOG
    TOYOHIKO MORINO, KOUICHI SANO, HITOMI HARA, KEIKO MOTOYAMA, KAZUHIKO I ...
    1986 Volume 39 Issue 12 Pages 3164-3178
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Acute toxicity of isepamicin (HAPA-B), a new aminoglycoside antibiotic, in mice, rats and dogs was examined in comparison with amikacin (AMK) and gentamicin (GM).
    1. Intravenous LD50 values of HAPA-B were 234 mg/kg in male and 236 mg/kg in female for mice, 489 mg/kg in male and 476 mg/kg in female for rats and 720-864 mg/kg for dogs. Those of AMK were 183 mg/kg in male and 181 mg/kg in female for mice, 420 mg/kg in male and 417 mg/kg in female for rats. Those of GM were 50 mg/kg in male and 47 mg/kg in female for mice, 119 mg/kg in male and 124 mg/kg in female for rats.
    Intraperitoneal LD50 values of HAPA-B were 2,244 mg/kg in male and 2,272 mg/kg in female for mice, 1,664 mg/kg in male and 1,591 mg/kg in female for rats.
    Intramuscular LD50 values of HAPA-B were 2,508 mg/kg in male and 2,632 mg/kg in female for mice, 2,088 mg/kg in male and 2, 111 mg/kg in female for rats and>1,800 mg/kg for dogs. Those of AMK were 1,247 mg/kg in male and 1,334 mg/kg in female for mice, 2,324 mg/kg in male and 2,244 mg/kg in female for rats. Those of GM were 359 mg/kg in male and 360 mg/kg in female for mice, 559 mg/kg in male and 557 mg/kg in female for rats.
    Subcutaneous LD50 values of HAPA-B were 3,321 mg/kg in male and 3,320 mg/kg in female for mice, 3,451 mg/kg in male and 3,392 mg/kg in female for rats.
    Oral LD50 values of HAPA-B were more than 5,000 mg/kg in mice and rats.
    2. Ataxia, acratia, dyspnea and convulsions were observed following administration by all routes, except for oral route, of all drugs in mice, rats and dogs.
    3. The cause of early death was due to respiratory paralysis which is the typical acute toxic sign of aminoglycoside antibiotics, and that of late death was due to renal injuries.
    4. BUN and creatinine values of surviving dogs after day 14 increased after administration by either intravenous or intramuscular routes.
    5. Disintegration, necrosis and calcification of epithelial cells of the proximal convoluted tubuli were observed in rats which died during the course of the study, and atrophy, dilatation and eosinophilic degeneration in epithelial cells of the proximal convoluted tubuli and thickening of BOWMAN'S capsule were observed in surviving dogs.
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  • II. INTRAMUSCURAL SUBACUTE TOXICITY TEST IN RAT
    TOYOHIKO MORINO, HARUKO ENDO, KAZUMI SHIRAIWA, KOUICHI SANO, MASAMI MI ...
    1986 Volume 39 Issue 12 Pages 3179-3200
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Subacute toxicity in the rat of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was examined in comparison with amikacin (AMK). Daily doses of 12.5, 25, 100 and 300mg/kg of HAPA-B or 25 and 100mg/kg of AMK were injected intramuscularly for 28 days.
    1. No animal died and there were no changes in general symptoms except for hemorrhage at injection sites of both drugs.
    2. Decreases in body weight gain and food consumption were observed in males and females in the HAPA-B 300mg/kg dose group. Water consumption was increased in males in the HAPA-B 300mg/kg and AMK 100mg/kg dose groups.
    3. Elevations of serum creatinine and/or BUN in males and females were occasionally observed in the HAPA-B 300mg/kg and AMK 100mg/kg dose groups, and elevation of GOT, which seemed to be due to muscle injuries, was occasionally observed in a no dose-dependent manner with either drug.
    4. Increases in kidney and caecum weights of males and females in the HAPA-B 100, 300mg/kg and AMK 25, 100mg/kg dose groups and increases in adrenal relative-weights in males and females in the HAPA-B 300mg/kg dose group were observed.
    5. At necropsy, discoloration and enlargement of the kidney were observed in a dose-dependent manner at or above 100mg/kg with either drug.
    6. Histopathological findings indicated degeneration and necrosis in epithelial cells of the proximal convolute tubuli and thickening of basement membrane. Electron microscopic findings indicated an increase in number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convolute tubuli with both drugs.
    7. The above results suggest that HAPA-B has renal toxicity like other aminoglycoside antibiotics but its toxicity was lower than AMK. The non-toxic dose of HAPA-B in this test was 12.5mg/kg.
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  • IV. INTRAMUSCULAR SUBACUTE TOXICITY TEST IN DOG
    DAISUKE NAKANISHI, KOUICHI SANO, KAZUHIKO IIZUKA, MASAMI MIURA, TOYOHI ...
    1986 Volume 39 Issue 12 Pages 3201-3244
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    The subacute toxicity in the dog of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was studied in comparison with amikacin (AMK).
    HAPA-B at dose levels of 6.25, 25 and 100mg/kg/day and AMK at dose levels of 25 and 100mg/kg/day were given intramuscularly for 30 days.
    1. Only one female dog in the AMK 100mg/kg dose group died on day 29.
    2. The activities of urinary NAG and r-GTP increased dose-relatedly in dogs in the 25 and 100mg/kg dose groups of either drug.
    3. Discoloration and/or enlargement of the kidneys were observed in dogs at 100mg/kg of either drug. Hemorrhage and/or edema at the injection sites were observed in dogs in the 25 and 100mg/kg dose groups of either drug.
    4. Increases of absolute and relative kidney weights were observed in the AMK 100mg/kg group. An increase of relative kidney weights was also observed in the HAPA-B 100mg/kg group.
    5. In microscopic observations, various histopathological changes of renal tubules and tubular epithelium were observed dose-relatedly in the 25 and 100mg/kg groups of both drugs. At a dose of 25mg/kg, there was no significant difference of the incidence and severity of these renal changes between HAPA-B and AMK groups. Desquamation and necrosis of the renal tubular epithelium were observed only in the AMK 100mg/kg group. The necrosis in these changes was considered to be one of the severest possible changes in renal tubules, hence the renal toxicity of HAPA-B was judged to be milder than that of AMK at the dose level of 100mg/kg.
    6. The non-toxic dose of HAPA-B in this study was estimated to be 6.25mg/kg.
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  • VII. INTRAMUSCULAR CHRONIC TEST IN RAT
    HIROKO FUJII, KAZUMI SHIRAIWA, MASAMI MIURA, TOYOHIKO MORINO, KAZUHIKO ...
    1986 Volume 39 Issue 12 Pages 3245-3282
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Chronic toxicity in the rat of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was examined in comparison with amikacin (AMK).
    Daily doses of 3.125, 6.25, 25 and 100mg/kg of HAPA-B or 25 and 100mg/kg of AMK were injected intramuscularly for 6 months, and recovery test was carried out for 2 months after discontinuing the drug.
    1. No animal died and there were no changes in general symptoms except for hemorrhage of injection sites of both drugs.
    2. Decreases in body weight gain and food consumption were observed in 100mg/kg dose group of either drug. Water consumption was markedly increased in males of the AMK 100mg/kg dose group during administration and recovery periods.
    3. Decreases in erythrocytes, hematocrit and hemoglobin were observed in 100mg/kg dose group of either drug. These decreases seemed to be due to renal injury. An increase in the number of platelets was also observed. This was likely caused by the hemorrhage at injection sites. These changes persisted into the recovery period.
    4. Elevation of BUN was observed in the 100mg/kg dose group of either drug. Its value in the AMK 100mg/kg dose group was markedly higher than that in the HAPA-B 100mg/kg dose group and did not decrease back to the normal values even during the recovery period.
    5. An increase of urine volume and a decrease of urine specific gravity were observed in males in the 100mg/kg group of either drug. Furthermore, NAG was elevated in a dose-dependent manner from 25mg/kg with both drugs.
    6. The weight of kidney increased dose-relatedly and significantly in groups administered with 25mg/kg or more of either drug and weight of caecum increased dose-relatedly and significantly in groups administered with 6.25mg/kg or more of HAPA-B or 25mg/kg or more of AMK.
    7. Discoloration and enlargement of the kidney occurred in a dose-dependent manner as observed by necropsy. Eosinophilic granular degeneration, swelling, fatty degeneration, necrosis, calcification in the epithelial cells of the proximal convoluted tubuli, and thickenings of BOWMAN'S Capsule and tubular basement membrane were observed at 25 and 100mg/kg dose groups of either drug. In recovery periods, after the necrosis disappeared, calcification and regeneration were observed in epithelial cells. Electron microscopic findings showed an increase in the number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convolute tubuli with either drug.
    8. The non-toxic dose of HAPA-B in this test is estimated to be 6.25mg/kg, which caused no significant drug-induced changes.
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  • I. FERTILITY STUDY IN RATS (INTRAMUSCULAR ADMINISTRATION)
    MASANORI SASAKI, KIYOMI KAWAGUCHI, HATSUNE YAMADA, YOSHIR KOBAYASHI, H ...
    1986 Volume 39 Issue 12 Pages 3283-3290
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Effect of isepamicin (HAPA-B), a new aminoglycoside antibiotic, on fertility and reproductive performance in Wistar rats was studied. The drug was injected intramuscularly to rats at a daily dose of 25, 100 or 200mg/kg. Male rats were treated for 63 days before mating and during the mating period, and female rats were treated for 2 weeks and through the mating period to the 7th day after mating.
    1. In male rats, an inhibition of body weight gain and a development of a pale color and hypertrophy of the kidney were observed in 100 and 200mg/kg dose-groups.
    2. In female rats, inhibition of body weight gain was observed in 100 and 200mg/kg dose-groups and a pale color of the kidney was seen in the 200mg/kg group.
    3. No significant differences were observed in mating and fertility performance of male and female rats between the control and treated groups.
    4. Numbers of corpora lutea, implantation sites and living fetuses in the 200mg/kg group decreased significantly.
    5. No external, visceral and skeletal anomalies due to the treatment of HAPA-B were observed in the live fetuses.
    6. No effect dose levels of HAPA-B found in this study were 25mg/kg on parent rats and 100mg/kg on reproduction ability and their fetuses.
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  • II. TERATOLOGICAL STUDY IN RATS (INTRAMUSCULAR ADMINISTRATION)
    MASANORI SASAKI, KIYOMI KAWAGUCHI, HATSUNE YAMADA, YOSHIRO KOBAYASHI, ...
    1986 Volume 39 Issue 12 Pages 3291-3310
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Teratological study of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was performed in Jcl: Wistar rat. The drug was given intramuscularly to dams at doses of 25, 100 and 200mg/kg from day 7 to 17 after mating. The influence on dams, their fetuses and offspring was studied.
    1. A decrease in food intake and a development of pale color of the kidney of dams at a dose level of 200mg/kg were observed in the prenatal study.
    2. The HAPA-B did not show any influence on prenatal development of fetuses.
    3. In the postnatal study, no effect of HAPA-B on parturition and lactation of dams was seen except that a discoloration of the kidney was observed at autopsy.
    4. However, some differences were observed between the control and treatment groups in postnatal development, behavior and reproduction performance of offspring. Dose-response effects of HAPA-B on offspring were not observed in the postnatal study.
    5. No effect dose levels of HAPA-B established in this study on rat fetuses and offspring were 200mg/kg and 100mg/kg on pregnant rat, respectively.
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  • IV. PERI-AND POST-NATAL STUDY IN RATS (INTRAMUSCULAR ADMINISTRATION)
    HIROSHI KUBOTA, MARIKO SUDA, HATSUNE YAMADA, YOSHIRO KOBAYASHI, HIROSH ...
    1986 Volume 39 Issue 12 Pages 3311-3328
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Peri-and post-natal effect of HAPA-B, a new aminoglycoside antibiotic, was studied in Jd: Wistar rats. The antibiotic was given intramuscularly to dams at doses of 25, 100 and 200mg/kg from day 17 of gestation to 21 days after delivery and throughout lactation. Influences of the drug on dams and their offspring were studied.
    1. A decrease in food intake and an increase in water intake were observed in the 200mg/kg treated group.
    2. At autopsy of dams after weaning, pale discoloration and hypertrophy of the kidney were observed in 100 and 200mg/kg groups.
    3. All other observations including delivery and nursing performance of dams, postnatal development of offspring, behavior and reproduction performance of the offspring were normal.
    4. The no effect dose level of HAPA-B found in this study was 25mg/kg on rat dams and 100mg/kg on the offspring.
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  • YUJI NAKANO, ISAMU NIIMI, YOSHIRO KOBAYASHI, HIROSHI YAMAMOTO
    1986 Volume 39 Issue 12 Pages 3329-3340
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Immunological properties of isepamicin (HAPA-B), a new semisynthetic aminoglycoside, were compared with those of gentamicin (GM). The results are summarized as follows.
    1. Rabbits were immunized by HAPA-B or GM with a strong adjuvant, FREUND'S complete adjuvant, and specific Ig G antibodies were found in sera when assayed using PHA and PCA reactions.
    2. In sera from guinea pigs and mice immunized by HAPA-B or GM with aluminum hydroxide gel, no specific Ig G nor Ig E antibody was detected when assayed using PCA reactions.
    3. Specific antibodies (Ig G, Ig E) produced against HAPA-B and GM were confirmed in different animals immunized by chemically introduced antigens of HAPA-B-carrier protein conjugate and GM-carrier protein conjugate, respectively.
    4. Guinea pigs immunized by. HAPA-B or HAPA-B-carrier protein conjugate with aluminum hydroxide gel did not exhibit typical systemic anaphylactic reactions when elicited with HAPA-B alone.
    5. HAPA-B had some immunocross-reactivity with GM.
    6. These results suggested that the antibody-producing activity of HAPA-B was similar to that of GM.
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  • AKIRA SONO, KIMIKO OYAIDE, YOSHIRO KOBAYASHI, HIROSHI YAMAMOTO
    1986 Volume 39 Issue 12 Pages 3341-3348
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    To detect mutagenic activity of isepamicin (HAPA-B), a new aminoglycoside antibiotic, we carried out several mutagenicity tests using microorganisms and cultured mammalian cells.
    Effects of the antibiotic on DNA-lesion induction and repair were examined using the Rec-assay with Bacillus subtilis and a sister-chromatid exchange test with cultured Chinese hamster cells. The drug caused no increase of mutagenicity indices in both tests, suggesting that the antibiotic has no DNA-damaging effect.
    To further investigate the effect of HAPA-B on gene-mutation, we performed the AMES Salmonella/microsome plate assay and the thioguanine resistance mutation test using cultured Chinese hamster cells. In both tests, the antibiotic induced no increase of mutation frequencies over spontaneous levels.
    Clastogenic activities of HAPA-B and its effect on chromosome disjunction were examined by the chromosomal aberration test using cultured Chinese hamster cells. After a short-or long-time exposure, the antibiotic induced neither structural chromosome aberrations nor an increase in the number of tetraploid cells.
    The negative results from these five test systems with different mechanisms strongly suggest the safety of HAPA-B regarding mutagenicity.
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  • KIMIKO OYAIDE, AKIRA SONO, YOSHIRO KOBAYASHI, HIROSHI YAMAMOTO
    1986 Volume 39 Issue 12 Pages 3349-3352
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Mutation frequency tests for isepamicin (HAPA-B), a new aminoglycoside antibiotic, were carried out using Salmonella typhimurium strains TA98, TA100, TA1535 and Escherichta colt WP2uvrA.
    After a 30-minute exposure of bacterial cells at 37°C to HAPA-B in a buffer solution, the cells were washed twice with a buffer solution to minimize the cytotoxicity of the drug. Then washed cells were inoculated on minimum glucose agar plates to determine mutation frequency.
    The results should no significant increase in mutation frequency with increasing HAPA-B concentration; suggesting that the drug has no mutagenicity detectable by this test system.
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  • TERUTOMO KOHIRA, JOB YANO, YOSHIRO KOBAYASHI, HIROSHI YAMAMOTO
    1986 Volume 39 Issue 12 Pages 3353-3368
    Published: December 25, 1986
    Released on J-STAGE: May 17, 2013
    JOURNAL FREE ACCESS
    Local irritative effects of isepamicin (HAPA-B) were studied using muscle and blood vessel of Japanese White rabbits.
    Muscle irritation experiment was carried out with a single dosage of 100mg HAPA-B, 100mg amikacin (AMK), saline, 0.75% acetic acid or 6.0% acetic acid administered into musculus sacrospinalis. Vascular irritation experiment was carried out by allowing HAPA-B to remain in a sealed section of vena retroauricularis for 3 minutes after injection.
    In result, the muscular irritative activity of HAPA-B was less severe than 0.75% acetic acid but more than saline, and almost equal activity to AMK was observed. The HAPA-B caused very slight inflammation while thrombus was not formed. The vascular irritative activity was very little.
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