The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 13 , Issue SupplementI
Showing 1-13 articles out of 13 articles from the selected issue
  • Naoto WADA, Hiroshi MORIOKA, Mizuho INAZU, Masaki MIYAMOTO, Takayoshi ...
    1988 Volume 13 Issue SupplementI Pages 1-20
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Acute toxicity of cefodizime sodium (THR-221) was examined in mice of both sexes, rats of both sexes (including 5-day-old young), and male dogs. The LD50 values of THR-221 (mg/kg) were as follows : (1) mice : intravenous, 7200 for males and 5000 for females ; intraperitoneal, 10500 for males and 11000 for females ; subcutaneous, 17500 for males and 16500 for females ; and oral, 28000 for males and 29000 for females. (2) rats (adult) : intravenous, 7000 for males and 8200 for females ; intraperitoneal, 9500 for males and 8800 for females ; subcutaneous, 17000 for males and 15500 for females ; oral, more than 20000 for both sexes ; and intramuscular, more than 3200 for both sexes. (3) 5-day-old rats : subcutaneous, 5278 for males and 5314 for females. (4) male dogs: intravenous, more than 5000. Major changes in general conditions observed in mice and rats were decreased spontaneous activity, lying prone, respiratory changes, staggering gait, clonic or clonic-tonic convulsions, and cyanosis, and in the animals dosed orally, diarrhea or salivation was also noted. The changes in 5-day-old rats were respiratory changes, agony, loss of reflex to an external stimulus, and congestion at the injection site, and those in dogs were vomiting, dryness of the nose, and soft or mucous stools. Autopsies on the mice and rats which died revealed hemorrhage on the brain surface. In addition, the followind were seen : intraperitoneal retention of fluid and dark red spots on the abdominal wall (i.p.), subcutaneous retention of fluid or jellylike material and hemorrhage at the injection site (s.c.), and retention of fluid and dark red spots on the mucosa in the digestive tract (mice p.o.). In 5-day-old rats which died, the subcutaneous tissue at the injection site showed hemorrhage macroscopically and inflammatory changes microscopically. Hematological and blood chemical tests performed in dogs showed an increase in white blood cells and changes suggesting anemia, increases in GOT, LDH and ALP activities, and slight changes in urea nitrogen and inorganic phosphorus. In one animal given a low dose of 2500 mg/kg, an increase in GPT activity was also seen. However, these changes were all trandient. Microscopic findings in dogs were slight inflammatory changes in the subcutaneous tissue around the injection site.
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  • Setsuko ABE, Mizuho INAZU, Ryuhji YAJIMA, Hiroshi MORIOKA, Takayoshi K ...
    1988 Volume 13 Issue SupplementI Pages 21-42
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    One-month subacute intravenous toxicity study of cefodizime sodium (THR-221) in rats was carried out with dose levels of 2000, 1000 and 500mg/kg/day. Sixteen males and 16 females were used per group (including the control group). THR-221 caused neither death nor change in general conditions at any dose level throughout the study, except that decreased spontaneous activity appeared only transiently in a part of the animals given 2000 mg/kg/day. Increases in water intake were observed in all compound groups, and transient decreases in food consumption were seen at an early stage of the administration period. However, the compound did not affect the body weight at any dose level. In urinalysis, the urine sediments in all THR-221 groups contained an increased number of epithelial cells as compared with the controls. At autopsy, dilation of the cecum was observed in all THR-221 groups, and jn a part of the rats with this change, red spots or reddening of the serous membrane of the organ also appeared. Light microscopy revealed brown granules in the epithelium of renal tubules in all compound groups (with dose-dependent incidences) and congestion or hemorrhage in the cecum in some compound-treated animals. Electron microscopy on the kidney showed small bodies (considered to be lysosomes) in the tubular epithelium in all compound groups. No other changes related to THR-221 were observed. From the present results that no marked toxic signs were seen at any dose level, the toxicologically non-effective dose of THR-221 for rats of both sexes is considered to be more than 2000 mg/kg/day.
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  • Shigeki NAKANO, Hideaki YADA, Kenzi IRIMURA, Kyouko KUROKAWA, Tomio HI ...
    1988 Volume 13 Issue SupplementI Pages 43-90
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A subacute toxicity study of cefodizime sodium (THR-221), a new cephem antibiotics, was carried out using male and female beagle dogs. THR-221 was intravenously administered to the dog at dose levels of 500, 1000 and 2000 mg/kg/day for 5 weeks, followed by 4 weeks recovery period. Cefotetan (CTT) as a reference drug was administered in the same manner at a dose level of 2000 mg/kg/day. The summarized results obtained are as follows : 1. Vomiting and salivation were observed in dogs given 1000 and 2000 mg/kg/day of THR-221. However, it caused no deaths or significant effects on body weight and food consumption in all groups treated with THR-221. 2. No toxicological changes associated with the administration of THR-221 were found in urinary and hematological examinations. 3. In serum biochemical examinations, increase or tendencies of increase of albumin and A/G ratio, probably due to the antibacterial action of THR-221, were detected at all dose levels of THR- 221. 4. There were no dose-related changes in hepatic and renal function, fecal occult blood, ophthalmological, electrocardiographic and auditory examinations, absolute and relative organ weights. 5. Histopathological examinations revealed fibrosis or granulation in perivascular area of injection sites, particularly in males given 2000 mg/kg/day of THR-221. 6. After 4 webks of recovery period, above-mentioned changes were generally disappeared and it was suggested that these were reversible ones. 7. In groups treated with CTT (2000 mg/kg/day), damages were recognized mainly in erythron values, liver and kidney, as compared with the same dose of THR-221. Therefore the toxicity of THR-221 was less than that of CTT. 8. From these results, the non toxic effective dose level and the toxic dose level of THR-221 were estimated to be 500 mg/kg/day and more than 2000 mg/kg/day respectively, for male and female dogs.
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  • Naoto WADA, Mizuho INAZU, Ryuhji YAJIMA, Takashi SUGISAKI, Masaki MIYA ...
    1988 Volume 13 Issue SupplementI Pages 91-122
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Six-month chronic subcutaneous toxicity study of cefodizime sodium (THR-221) in rats was carried out with dose levels of 3000, 1000, 300 and 100 mg/kg/day. The systemic change observed was slightly decreased spontaneous activity, which appeared only in a very few animals. At the injection site of the animals at 1000 and 3000 mg/kg/day, various cutaneous changes (subcutaneous retention of fluid, incrustation, loss of hair and perforation) were observed. The body weight gains of the males at 1000 and 3000 mg/kg/day were depressed from 1 month of administration onward, but the food consumption was not affected in any group. The water intakes at 1000 and 3000 mg/kg/day were increased. Hematological findings were signs of anemia, a slight decrease in red blood cell count or increases in platelet and/or reticulocyte counts in all THR-221 groups. At 3000 mg/kg/day, increases in white blood cell and neutrophil counts and a decrease in lymphocyte count were also observed. Plasma chemistry revealed decreases in total protein amount and, albumin (A) or globulin (G) amounts, and a decrease or increase in A/G ratio in all compound groups. Autopsy revealed dilation of the cecum and hematoma, dark red spots and yellowish brown spots in the subcutaneous tissue at the injection site in all THR-221 groups. Hypertrophy of the spleen was also noted at 300-3000 mg/kg/day. Changes in organ weights were a decrease in liver weight in all compound groups and an increase in spleen weight at 3000 mg/kg/day. Microscopically, the following were observed : brown granules or hyaline droplets in the epithelium of renal tubules ; hemorrhage and inflammatory changes in the subcutaneous tissue at the injection site ; and an increased number of lymphocytes or granulocytes in the spleen and bone marrow. Urinalysis and ocular and auditory tests showed no changes related to THR-221. From the present results, the toxicologically non-effective doses of THR-221 are considered to be 300 mg/kg/day for male rats and more than 1000 mg/kg/day for female rats.
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  • Shigeru KOHDA, Hiroshi NISHIKAWA, Masaki SANO, Minoru TSUCHITANI, Kohj ...
    1988 Volume 13 Issue SupplementI Pages 123-175
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The chronic intravenous toxicity of cefodizime sodium (THR-221) was studied in beagle dogs. Groups of 6 males and 6 females were treated with THR-221 at doses of 0 (saline), 200, 400, 800 and 1600 mg/kg/day for 6 months. The THR-221 related symptoms were vomiting, excessive drinking behavior and salivation. The paleness of the visible mucosa and discoloration of vascular color by funduscopy due to systemic anemia were observed in one animal each of 800 and 1600 mg/kg/day groups. Body weight was depressed transiently or continuously in a few animals of 400 - 1600 mg/kg/day groups. The hematological, serum chemical and urinalysis findings in a few animals of 400 - 1600 mg/kg/day groups revealed decreases in RBC count, PCV and hemoglobin, an increase in reticulocyte count, a decrease in WBC count, a decrease in platelet count, slight increase in TP. and albumin, a decrease in AlP, and an increase in urinary Na. Light microscopically, deposition of hemosiderin and increased extramedullary hematopoiesis in the liver and spleen, and deposition of fibroid substance in the white pulp of the spleen and diffuse fibrosis in the bone marrows were detected in a few animals of 800 and 1600 mg/kg/day groups. Electron microscopically, no significant toxic changes were observed. The maximum nontoxic doses of THR-221 are estimated as 200 mg/kg/day in male and less than 200 mg/kg/day in female.
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  • Masashi AKAIKE, Teruo KITATANI, Kazuo TAKAYAMA, Takayoshi KOBAYASHI
    1988 Volume 13 Issue SupplementI Pages 177-190
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Cefodizime sodium (THR-221) was intravenously administered to mice of both sexes at dose levels of 300, 1000, 2000 and 3000 mg/kg/day, and its effects on the fertility of male and female mice and on their offspring were examined. Twenty-four males and 24 females were used per dose and as a control group. The males were dosed for 9 weeks prior to mating and through the mating period, and the females were treated from 2 weeks before mating through day 6 of gestation. Cesarean sections were performed on all pregnant mice in each group (16-23) on day 18 of gestation. Of the parental mice, 1, 2 and 1 males died at 0 (control), 2000 and 3000mg/kg/day, respectively, and 5 females died at 3000 mg/kg/day. Inflammatory changes in the skin at the injection site were observed in the males at 3000 mg/kg/day. In the males, the kidney weight at 3000 mg/kg/day and the spleen weights at 2000 and 3000 mg/kg/day increased, and the thymus weight at 3000 mg/kg/day decreased, as compared with the control values. No differences appeared between any compound-treated group and the control group in the following maternal and fetal parameters : copulation rate, conception rate, and body and placental weights, crown-rump length and sex ratio of the live fetuses. External, visceral and skeletal examinations on the live fetuses revealed no compound-related abnormalities. From the present results, it is considered that the no-effect doses of THR-221 for the parental mice and the fetuses are 1000 and 3000 mg/kg/day, respectively.
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  • Teruo KITATANI, Masashi AKAIKE, Kazuo TAKAYAMA, Takayoshi KOBAYASHI
    1988 Volume 13 Issue SupplementI Pages 191-214
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Cefodizime sodium (THR-221) was intravenously administered at dose levels of 300, 1000 and 3000 mg/kg/day to pregnant mice on days 6-15 of gestation covering the period of organogenesis, and its effects on the dams (F0)and the fetal and postnatal development and fertility of their offspring (F1) were examined. In each group including a control group, 21-24 of the 33-38 F0 dams were submitted to cesarean section on day 18 of gestation, and the remaining 12-14 animals were allowed to litter normally and nurse their offspring until day 21 of lactation. In the F0 dams, no compound effects were seen in general conditions, body weight, food consumption, numbers of corpora lutea and implantations or duration of gestation. The thymus weights of the cesarean sectioned dams at 1000 and 3000 mg/kg/day were less than the control values, but no difference appeared in weights of the other main organs between any treatment group and the control group. No gross visceral abnormalities were noted at any dose. In F1 near-term fetuses, the compound administration exerted no effects on their development at any dose, except the decreased body weight and crown-rump length noted at 3000 mg/kg/day. No difference occurred in incidence of fetuses with external, visceral or skeletal anomalies between any treatment group and the control group. Normally delivered F1 offspring in the treatment groups exhibited no changes from the controls in postnatal development, reflexes, 21-day survival index or behavioral test performance. Skeletal examination on F1 offspring which died during lactation and autopsies on the other animals at the end of study revealed no compound-related abnormalities. The fertility of the F1 mice was normal at all doses, and there were no compound effects on the F1 dams or their near-term fetuses or newborn pups. From the present results, it is considered that the no-effect doses of THR-221 for the maternal mice and their offspring are 300 and 1000mg/kg/day, respectively.
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  • Osamu YAMAKITA, Masahiro KOIDA, Mitsuhiro SHINOMIYA, Shigenori KATAYAM ...
    1988 Volume 13 Issue SupplementI Pages 215-229
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Peri- and postnatal study of cefodizime sodium (THR-221), a new developed cephem-type antibiotics, was carried out with ICR mice. THR-22l at dose levels of 0, 300, 1000 and 3000 mg/kg/day were administered intravenously to pregnant and delivered dams from day 15 of gestation through day 21 of lactation. No changes in body weights of dams in all treated groups but slight decrease in food consumptions of 3000 mg/kg/day group were observed. Treated sites, tails of a few dams in this group, were affected with inflammatory lesions because of repeated dosing. Neonates from dams treated with 3000 mg/kg/day were slightly decreased in body weight at birth. At term sacrifice of F 1 of 10 weeks age, absolute and relative spleen weights were decreased in male 3000 mg/kg/day group and in female 1000 and 3000 mg/kg/day group. No effects on other physical, behavioral or reproductive ability examinations of F 1 offspring were showed. It is suggested that no effect dose level of THR-221 is 1000 mg/kg/day and that of F 1 offspring is 300 mg/kg/day.
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  • Minoru TAKEMOTO, Kohya MATSUO, Shinji KATOH, Ryouichi YOSHIDA
    1988 Volume 13 Issue SupplementI Pages 231-243
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The antigenicity studies of a β-lactam antibiotic, cefodizime sodium (THR-221), were examined in mice and guinea pigs and the following results were obtained. 1)In passive cutaneous anaphylaxis (PCA) with sera from BALB/c or C3H/He mice, a slight PCA reaction was observed only in BALB/c mice by using THR-221-ovalbumin (OVA) plus Freund's complete adjuvant (FCA) as the immunogen and THR-221 itself as the eliciting antigen. 2)Immunological cross-reactivity between THR-221 and CTX was present at the rat PCA reaction. 3)Antibodies against THR-221 were detected by PCA in guinea pigs. The anti-THR-221 antibodies gave PCA responses smaller than those of CMZ by using antibiotic plus FCA as the immunogen and the antibiotic-bovine serum albumin (BSA) as the eliciting antigen. 4)In the observation of active systemic anaphylaxis (ASA), no symptoms were observed in guinea pigs sensitized with THR-221 and provoked with THR-221-BSA. On the other hand, guinea pigs sensitized with THR-221 plus FCA by injecting THR-221-BSA showed fetal anaphylactic reactions. 5)The results of passive hemagglutination (PHA) also indicated that the PHA titer of THR-221 was lower than that of CMZ. 6)Protein binding property of THR-221 with human serum albumin was lower than other β-lactam antibiotics. 7)Antibodies against THR-221-OVA by using THR-221-BSA as the eliciting antigen were detected in any tests above mentioned. It is concluded from these results that immunological activity of THR-221 was equivalent to the other β-lactam antibiotics.
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  • Akinobu OHUCHIDA, Ryouichi YOSHIDA
    1988 Volume 13 Issue SupplementI Pages 245-256
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The mutagenicity of cefodizime sodium (THR-221) was investigated by the reverse mutation test using seven bacterial strains (Salmonella typhi-murium strains TA100, TA98, TA1535, TA1537 and TA1538, and Echerichia coli strains WP2 and WP2uvrA) and the chromosomal aberration test with cultured Chinese hamster lung (CHL) cells. The reverse mutation test was carried out in dose range from 0.0025 to 5.0 μg/plate in the absence and presence of mammalian metabolic activation system. Antibacterial effects were observed at concentrations more than 0.25 μg/plate, and no significant increases in the number of revertants were observed at the dose levels where antibacterial effects were not detected. THR-221 caused no increases in the number of chromosomal aberrants at dose levels of 0.75, 1.5, 3.0 and 6.0 mg/ml in the absence and presence of the metabolic activation. These results indicate that THR-221 has no mutagenic activity.
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  • Osamu YAMAKITA, Masahiro KOIDA, Mitsuhiro SHINOMIYA, Kenzi IMAMURA, Ma ...
    1988 Volume 13 Issue SupplementI Pages 257-284
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Four local irritation studies of cefodizime sodium (THR-221), a new developed cephem-type antibiotics, were carried out with NZW rabbits. 1. In eye irritation test, 25% THR-221 water solution had no irritancy on eye mucosa in rabbits. 2. In single injective intramuscular irritation study, regardless of solvents (water or 0.5% lidocaine), 25% THR-221 solution had irritancy equal to 0.75% acetic acid. But recovery process of the muscle injured with THR-221 was faster and better than with 0.75% acetic acid. 3. In five days injective muscular irritation study, the irritancy of 25% THR-221 water solution on the muscle was milder than that of CTT or CET. Histopathological damage with THR-221, necrosis/degeneration of muscle fibers and edema/hemorrhage in interstitium etc., were well recovered. 4. In vessel irritation study, 10% or more THR-221 water solution had irritancy on ear vessel. THR-221, as same as CTT, caused organized thrombi and inflammation at the surrounding area. The degree of irritation of 20% THR-221 solution was slightly stronger than that of 20% CET, but weaker than that of 20% CTT. 5. In a clinical phase, it is to be desired that THR-221 like as CTT or CET shall be avoided repeated intramuscular or intravenous injections at the same site.
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  • Taiji HAYASHI, Akira MARUDEN, Kenzi IRIMURA, Masahiko KUWATA, Ken'ichi ...
    1988 Volume 13 Issue SupplementI Pages 285-327
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Nephrotoxicity of cefodizime sodium (THR-221), a new cephem antibiotic, was studied in rats by comparing its toxic effect with those of other cephem antibiotics including cephaloridine (CER), cefazolin (CEZ) and cefmetazol (CMZ). Each drug was administered single and consecutive 14-day dosage with its alone or in combination with either furosemide or gentamicin. The results are summarized as follows : 1. In the single dosage study, the rats treated with THR-221 at dose levels of 1200mg/kg and more showed slight changes in urinary protein and glucose. In rats treated with CER at a dose of 1200mg/kg, creatinine level in plasma and weights of kidneys were increased, and degeneration and/or necrosis of the renal proximal tubular epithelia were observed. Furthermore, by the consecutive dosage of CER at a dose of 1000mg/kg, remarkable renal responses including increase in urinary protein and glucose, and weights of kidneys, were observed. In addition, histopathological examinations showed degeneration and/or regeneration of the renal proximal tubular epithelia. 2. No enhanced effect of nephrotoxicity by combination with furosemide or gentamicin was observed except in case of combination of CER with furosemide. 3. The above results indicate that the nephrotoxic potency among these four antibiotics on the single and consecutive dosage studies is CER>>THR-221≥CEZ ≒CMZ and CER>>THR-221≒CEZ≒CMZ, in the decreasing order.
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  • Hiroshi MORIOKA, Ryuhji YAJIMA, Mizuho INAZU, Takayoshi KOBAYASHI, Tak ...
    1988 Volume 13 Issue SupplementI Pages 329-360
    Published: June 03, 1988
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Renal effects of cefodizime sodium (THR-221) administered by the intravenous route singly and for 7 consecutive days to male rabbits, were compared, with those of cefazolin sodium (CEZ) and cephalothin sodium (CET). Four animals were used in each group including control groups. In the single-dose study, THR-221 (600 and 1800 mg/kg) and CET (1800 mg/kg) caused no nephrotoxic effects. In the CEZ groups (600 and 1800 mg/kg), find-ings indicative of the decreased renal function were obtained : serum urea nitrogen and creatinine levels increased over the control values, and phenolsulfonphthalein (PSP) retention test showed a delay in PSP excretion from the blood. In addition, the white surface of the kidney was macroscopically observed, and microscopic examination revealed renal proximal tubular changes such as necrosis, hyaline cast and calcification, suggesting renal disorders. The repeated-dose study also showed similar results to those described above. Administration of THR-221 (200 and 600 mg/kg/day) and CET (600 mg/kg/day) caused no effects on the kidney. In the CEZ groups (200 and 600 mg/kg/day), serum chemical and PSP test results suggested the decreased renal function, and macroscopic and microscopic findings included organic changes in the kidney. These results suggest that under the conditions tested THR-221 dose not elicit signs of nephrotoxicity in contrast to CEZ, and behaves almost equally to CET.
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