The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 21 , Issue SupplementI
Showing 1-17 articles out of 17 articles from the selected issue
  • Ryuji ENDO
    1996 Volume 21 Issue SupplementI Pages 1-14
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The histopathological examination of a male ddY mouse given an intraperitoneal injection of the crude extract containing 169 μg/ml of tetrodotoxin (TTX) prepared from the ovary of Takifugu porphyreus was carried out. Two crude exract solutions (0.42 and 0.21 μg/ml) were prepared; one kills an animal in 10 min (group 1), and other kills it in 40 min (group 2) after the injection. As a result, a remarkable inflaction of the gall bladder was observed macroscopically in both groups. By light microscopic observed, both groups showed the congestion in the brain, heart, liver, gall bladder, lung and kidneys, while nerve cells were characterized by the vacuolation and disappearance of Nissl's body only in group 2, probably because of the mitochondrial degeneration. Electron microscopically, a part of cristae of mitochondria and ribosome of endoplasmic reticulum disappeared or vacuolated in the nerve cells of group 2. This was also observed in a part of pre and postsynaptic mitochondoria of synapse. However, little significant changes were observed in group 1 and in other tissues of group 2. These results show that a cytopathological change of mice by TTX is mainly detected in nerve tissues when a small amount of TTX is administered to the animals.
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  • Shinji SUGIMOTO, Miho IMAWAKA, Kazuyuki KURATA, Kenichi KANAMARU, Taka ...
    1996 Volume 21 Issue SupplementI Pages 15-32
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A procedure for recording the electroretinogram (ERG) in mice with a coiled stainless steel-type electrode was developed in order to examine retinal toxicity. Mice received a single i.v. of sodium iodate (SI), a retinotoxic compound, via the tail vein at a dose of 12.5, 25 or 50 mg/kg, and the ERG was recorded periodically for 28 days after dosing. In addition, the retina was examined histopathologically on day 30 after dosing. 1. The mice were anesthetized with mixed anesthetics of urethane, xylazine and ketamine after 30 to 60 min of dark-adaptation. Sixteen responses to repetitive 1.2 J light stimuli at a frequency of 0.2 or 0.1 Hz were averaged by a microcomputer. Body temperature of the mice was kept constant at 37 to 38 °C using a thermostatically controlled heating mat. Under these conditions, stable ERG a-wave, b-wave, oscillatory potentials and c-wave could be recorded for 28 days. 2. SI at doses of 25 mg/kg or more caused depression of the amplitudes of the oscillatory potentials, and enhancement of the a- and b-wave amplitudes, while the c-wave was already extinguished on day 1 after dosing. Following these changes, the amplitudes of the a- and b-wave decreased from day 3 or 7 after dosing. These changes did not recover until day 28 after dosing. 3. Upon histopathologic examination of the retina, folding of the outer nuclear layer, disarrangement of the rods and cones, decrease of the visual cells and swelling and decrease of the pigment epithelial cells were observed with SI at 25 mg/kg or more. 4. Using this recording technique, it was confirmed that a stable ERG was recorded repeatedly for 28 days in mice, and the effects of SI on the ERG could be detected. Histopathologic findingd in the retina revealed the abnormal portions were correlated well with the changes in the ERG. These results indicate that the ERG recording procedure developed in this study is useful for evaluating retinal toxicity in mice.
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  • Hiroshi SHIMAZU, Yuji ISHIKAWA, Yasuyuki NISHIGUCHI, Masaru YOSHIDA, K ...
    1996 Volume 21 Issue SupplementI Pages 33-44
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Single-dose toxicity studies of prulifloxacin, a new antibacterial agent, were conducted in mice, rats and dogs. In addition, a single-dose toxicity study of (±)-6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1, 3]thiazeto[3, 2-a]quinoline-3-carboxylic acid (NM394), an active metabolite of prulifloxacin, was performed in rats. Prulifloxacin was administered orally, intraperitoneally (i.p.) or subcutaneously (s.c.) to mice and rats, and orally to dogs. NM394 was administered intravenously (i.v.) to rats. When prulifloxacin was administered orally or s.c., LD50 values were more than 5000 mg/kg in both sexes of mice and rats ; when it was administered i.p., LD50 values were 1757 mg/kg in male mice, 1652 mg/kg in female mice, 915 mg/kg in male rats, and 1076 mg/kg in female rats. The lethal doses of this drug were more than 5000 mg/kg in both sexes of dogs by the oral route. The LD50 values of NM394 were 226 mg/kg in male rats and 238 mg/kg in female rats by the i.v. route. In mice, the major clinical signs observed following the administration of prulifloxacin were sedation, oligopnea, abnormal gait, piloerection, closed eye and tremor by the i.p. route and a scab at the site of injection by the s.c. route; in rats, decreased spontaneous locomotor activity by any of the three routes, oligopnea, lacrimation, hypothermia, piloerection and abnormal gait by the i.p. route, and a scab at the site of injection by the s.c. route; and in dogs, vomiting, reddening of the skin, and loose stool by the oral route. When NM394 was administered i.v., rats showed clonic convulsion and dyspnea. The site of injection was hyperemic, swollen and necrotic. Mice showed a decrease in body weight or an inhibition in weight gain when prulifloxacin was administered i.p. and rats showed the same effects when prulifloxacin or NM394 was administered by any of the above-mentioned routes. Macroscopic findings detected following the i.p. administration of prulifloxacin in mice were pale color of the liver and spleen, thickening of the liver, and adhesion of intra-abdominal organs; and in rats, hydrothorax; congestion and edema of the lung, adhesion of intra-abdominal organs, swelling of the kidney accompanied by fine yellowish-white foci, and atrophy of the testis. When NM394 was administered i.v. to rats, congestion of the lung was macroscopically observed.
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  • Nobuo NISHIMURA, Kazuya FUKUDA, Susumu YAMAZAKI, Kazutoshi TAMURA, Yas ...
    1996 Volume 21 Issue SupplementI Pages 45-70
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Male and female rats were given the test material orally for 4 weeks at doses of 0 (control), 30, 300 and 3000 mg/kg. After discontinuation of the treatment; a 4-week recovery test was also conducted. There was one case of death in the 3000 mg/kg group. Grayish green and soft feces, unkempt fur, transient deep respiration and decreased body weight gain were observed in the 3000 mg/kg group. Decreased food consumption and increased water intakd were seen in the 300 and 3000 mg/kg groups. Ophthalmoscopic examination failed to show any abnormalities related to the treatment. In urinalysis, crystalline substance in the urinary sediments, cloudy urine and decreased Na+ excretion were observed in the 300 and 3000 mg/kg groups. Increased urine volume, lowered urine specific gravity and decreased K+ and Cl- excretions were seen in the 3000 mg/kg group. Hematologic examination showed decreased Hb, Ht, MCV and MCH and increased WBC in the 3000 mg/kg group. Blood chemical examination revealed increased BUN and decreased K+ and Cl- in the 3000 mg/kg group, and decreased K+ and γ-globulin in the 300 mg/kg group. Pathological changes caused by the treatment were as follows. Cecal weight was increased in all dose groups. Cecal distention and swelling of its absorptive cells were seen in the 300 and 3000 mg/kg groups. In kidney, tubular nephrosis with crystalline substance was observed in the 300 and 3000 mg/kg groups, and its organ weight was increased in the 3000 mg/kg group. The above-mentioned changes were reversible except for decreased γ-globulin, increased BUN and urine volume, and lowered urine specific gravity. Ulcer and small cavities associated with proliferation of fibrous tissue in the femoral articular cartilage were observed in the 3000 mg/kg group at the end of recovery period of 4 weeks. Plasma levels and urinary concentrations of active metabolite of the test material were indreased in all dose groups with dose-related manner, whereby no sex difference was observed. No effects caused by the repeated dosing were seen in the plasma concentrations. Increased cecal weight in the 30 mg/kg group was considered to be attributable to the pharmacological effect of the test material. The results show that the NOAEL of prulifloxacin is 30 mg/kg for 4-week repeated dose toxicity in rats.
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  • Shigehito ODA, Makoto IDE, Kazutoshi TAMURA, Mariko NAGATANI, Yasuhiro ...
    1996 Volume 21 Issue SupplementI Pages 71-88
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in beagle dogs. Male and female dogs were given the test material orally for 4 weeks at doses of 0 (control), 30, 150 and 750 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted. Feces containing white material were seen in the 150 and 750 mg/kg groups. Salivation, prone, lateral or sitting position, gait disturbance, and locomotor depression were observed in the 750 mg/kg group. In this dose group, decreased body weight and food and water consumptions were also observed. There were no treatment-related effects on survival. Ophthalmoscopic and electrocardiographic examinations and urinalysis failed to show any abnormalities related to the treatment. Hematologic examination showed decreased WBC in the 750 mg/kg group. Blood chemical examination revealed increased GPT and α2-globulin in the 750 mg/kg group. Pathological changes caused by the treatment were as follows. Rarefaction of matrix, cavitations and erosions in humeral and femoral articular cartilages, and inflammatory cell infiltration in synovium were seen in the 150 and 750 mg/kg groups. Focal hemorrhage in synovium was also observed in the 750 mg/kg group. In kidney, regeneration of tubular epithelium, inflammatory cell infiltration, fibrosis and crystalline substance in the tubular lumen were observed in the 750 mg/kg group. The above-mentioned changes were satisfactorily reversible except for the changes in the humeral and femoral articular cartilages and in the kidney. Plasma levels and urinary concentrations of active metabolite of the test material were increased in all dose groups with ddse-related manner, whereby no sex difference was observed. No effects caused by the repeated dosing were seen in the plasma concentrations. Toxicological findings were not observed in the 30 mg/kg group. The results show that the NOAEL of prulifloxacin is 30 mg/kg for 4-week repeated dose toxicity in dogs.
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  • Seitaro ISHIBASHI, Motokuni NAKAZAWA, Takeharu TAWARATANI, Hiroshi UCH ...
    1996 Volume 21 Issue SupplementI Pages 89-111
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Male and female rats were given the test material orally for 13 weeks at doses of 0 (control), 30, 170 and 1000 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. Salivation, soft feces, reduced body weight gain and increased water consumption were seen in the 1000 mg/kg group. There were no treatment-related effects on survival and food consumption. Ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. Urinalysis revealed increased urine volume and decreased K+ excretion in the 1000 mg/kg group. Blood chemical examination showed increased BUN, decreased triglyceride, K+, Cl- and total protein in the 1000 mg/kg group. Pathological changes caused by the treatment were as follows. Renal tubular nephrosis with crystalline substante was observed in the 170 and 1000 mg/kg groups. Renal weight was increased and crystalline substance was noted in the lumen of the urinary bladder in the 1OOO mg/kg group. Cecal distention with increased its organ weight was observed in all dose groups and swelling of its absorptive cells was seen in the 170 and 1000 mg/kg groups. Swelling of jejunal goblet cells was observed in the 1000 mg/kg group. In femoral articular cartilage, focal accumulation of chondrocytes, small cavities and proliferation of fibrous tissue were seen in the 170 and 1000 mg/kg groups. The above-mentioned changes were reversible except for renal tubular nephrosis and cecal distention with its increased organ weight, of which the degree and frequency, however, were lowered. The cecal distention in the 30 mg/kg group was considered to be attributable to the pharmacological effect of the test material. The results show that the NOAEL of prulifloxacin is 30 mg/kg for 13-week repeated dose toxicity in rats.
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  • Masaru YOSHIDA, Akitaka KAWAMINAMI, Takeharu TAWARATANI, Hiroshi UCHIM ...
    1996 Volume 21 Issue SupplementI Pages 113-129
    Published: June 05, 1996
    Released: February 21, 2008
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    A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in beagle dogs. Male and female dogs were given the test material orally for 13 weeks at doses of 0 (control), 20, 100 and 500 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. Vomiting, salivation and decreased body weight gain or reduced body weight were seen in the 100 and 500 mg/kg groups. In the 500 mg/kg group, tremor, paresis of posterior limb associated with prone or sitting position and decreased food consumption were also observed. There were no treatment-related effects on survival and water consumption. Ophthalmoscopic, electrocardiographic and hematologic examinations, and urinalysis failed to show any abnormalities .attributable to the treatment. Blood chemical examination showed increased GPT and decreased β- and γ-globulins in the 100 and 500 mg/kg groups, and increased GOT in the 500 mg/kg group. In pathological examination, cavitations and erosions were seen in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups. The above-mentioned changes were satisfactorily reversible except for erosions in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups. No toxicological findings were seen in the 20 mg/kg group. The results show that the NOAEL of prulifloxacin is 20 mg/kg for 13-week repeated dose toxicity in dogs.
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  • Shigeru ISHIDA, Masamichi IKETANI, Susumu YAMAZAKI, Kazutoshi TAMURA, ...
    1996 Volume 21 Issue SupplementI Pages 131-148
    Published: June 05, 1996
    Released: February 21, 2008
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    A repeated dose toxicity study of (±)-6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1, 3]thiazeto[3, 2-a]quinoline-3-carboxylic acid (NM394), the active metabolite of a new antibacterial agent, prulifloxacin, was conducted in Sprague-Dawley rats. Male and female rats were given the test material intravenously for 4 weeks at doses of 0 (control), 3, 10 and 30 mg/kg. After discontinuation of the treatment, a 4-week recovery test was also conducted. There were no treatment-related effects on survival, clinical signs, body weight and food consumption. Ophthalmoscopic and hematologic examinations failed to show any abnormalities related to the treatment. Increased water consumption was observed in the 10 and 30 mg/kg groups. In these dose groups, increased urine volume and lowered urine specific gravity, and crystalline substancd and small epithelial cells in urinary sediments were seen. Cloudy urine was also seen in the 30 mg/kg group. Blood chemical examination showed decreased γ-globulin in the 10 and 30 mg/kg groups and increased BUN and creatinine in the 30 mg/kg group. Pathological changes caused by the treatment were as follows. In kidney, tubular nephrosis with crystalline substande was observed in the 10 and 30 mg/kg groups and its organ weight was increased in the 30 mg/kg group. Cecal weight was increased in the 30 mg/kg group. The above-mentioned changes were reversible except for decreased γ-globulin. Plasma levels and urinary concentrations of the test material were increased in all dose groups with dose-related manner, whereby no sex differences were observed. No effects caused by the repeated dosing were seen in the plasma concentrations. Toxicological findings were not observed in the 3 mg/kg group. The results show that the NOAEL of NM394 is 3 mg/kg for 4-week repeated dose toxicity in rats.
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  • Toshio IHARA, Atsushi AKUNE, Kazuhiro NAKAMA, Yutaka CHIHAYA, Ryoichi ...
    1996 Volume 21 Issue SupplementI Pages 149-169
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Single-dose and repeated dose toxicity studies of prulifloxacin, a new antibacterial agent, were conducted in aged beagle dogs. I. A single-dose toxicity study: Prulifloxacin was administered orally to aged female dogs at a single-dose of 2500 and 5000 mg/kg. No death occurred in any group. Vomiting was observed in one of two animals at 2500 mg/kg and in both animals at 5000 mg/kg 3-4 hr after dosing. At 5000 mg/kg, vomiting was observed in both animals after feeding on the day after dosing. One animal also showed soft stool. Thereafter, no abnormalities were observed in any animal. No test article related changes were noted in food consumption, water consumption, body weight or pathological examination in any group. The results show that the lethal dose of prulifloxacin is judged to be greater than 5000 mg/kg in aged female dogs. II. A repeated dose toxicity study: Aged male and female dogs were given the test article orally for 4 weeks at doses of 0 (control), 20, 100 and 500 mg/kg. No death occurred in any group. At 500 mg/kg, vomiting was observed every day or intermittently throughout the dosing period and salivation was observed almost every day from day 6 to the end of the dosing onward. Decreases or lack of food and water consumption, and decrease of body weight werd noted at 500 mg/kg. At 100 mg/kg, slight decreases in food consumption and body weight were noted in the females. No abnormalities were noted in ophthalmoscopic or electrocardiographic examination. In urinalysis, decreases in Na+, K+ and Cl- concentrations and the total excretion amount were noted mostly at 500 mg/kg. A low specific gravity was noted in males at 500 mg/kg. In hematology and serum biochemistry, high GPT, BUN and creatinine, and decreases in WBC were noted in both sexes at 500 mg/kg. A high GOT was noted in males; and low Cl- in females at 500 mg/kg. At 100 mg/kg, a high GPT wad noted. Rough surface in the kidney and chronic interstitial nephritis (basophilic change of tubule, atrophy of tubule, thickening of tubular basement membrane, interstitial mononuclear cell infiltration; interstitial focal fibrosis) were increased at 500 mg/kg. No toxicological findings were seen in the 20 mg/kg group. The results show that the NOAEL of prulifloxacin is 20 mg/kg for 4-week repeated dose toxicity in aged dogs.
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  • Tagahiko MORINAGA, Shigenobu FUJII, Shigenori FURUKAWA, Mikito KIKUMOR ...
    1996 Volume 21 Issue SupplementI Pages 171-185
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of fertility and fetal development of prulifloxacin, a new anti-bacterial agent, was conducted in Sprague-Dawley rats. Male rats were given the drug orally from 63 days before mating to the end of mating period. Female rats were given from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 30, 170 and 1000 mg/kg. The females weresacrificed on day 20 of pregnancy for examination of their fetuses. In the 170 mg/kg group, water consumption increased in the female rats, and food consumption decreased and the cecum increased in weight and was enlarged in the males and the females. In the 1000 mg/kg group, body weight gain was suppressed in the males, and food consumption decreased 5 water consumption increased and cecum increased in weight and enlarged in the males and the females. Moreover, this dose caused white spots and rough surface of the kidney in the males. Prulifloxacin had no adverse effects on reproductive function of the parent animals, and also on development of the fetuses. These results show that the NOAEL of prulifloxacin are 30 mg/kg for general toxicity in parent animals, 1000 mg/kg for reproductive function of parent animals and for development of fetuses.
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  • Tagahiko MORINAGA, Shigenobu FUJII, Shigenori FURUKAWA, Mikito KIKUMOR ...
    1996 Volume 21 Issue SupplementI Pages 187-206
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of the effect of prulifloxacin, a new antibacterial agent, during the period of organogenesis was conducted in Sprague-Dawley rats. Female rats were given prulifloxacin orally at dose levels of 0 (control), 30, 300 and 3000 mg/kg from day 7 to day 17 of pregnancy. Twenty-four or twenty-five female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the pregnant rats (12-15 per dose levels) were allowed to deliver naturally for postnatal examination of their offspring. In the 300 or 3000 mg/kg groups, the food consumption decreased and water consumption increased in the dams. In the 3000 mg/kg group, the body weight gain was suppressed in the dams. In the 300 and 3000 mg/kg groups, the weights of cecum increased and the enlargement of cecum was observed. In the 3000 mg/kg group, white spots and rough surface of the kidney and renal tubular nephrosis with crystalline substance were observed and the weight of the kidney increased in the dams, and the body weight decreased and retarded ossifications in the fetuses. Prulifloxacin had no effect on the number of corpora lutea and implantations, or on fetal mortality, sex ratio, or external and visceral development of the fetuses. Prulifloxacin also did not affect delivery and the number of live newborns and birth index, or have any adverse effects on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality; motor ability, learning ability or reproductive performance. Prulifloxacin also had no adverse effects of the second generation offspring (F2). These results show that the NOAEL of prulifloxacin are 30 mg/kg for general toxicity in mother animals, 3000 mg/kg for pregnancy and delivery of mother animals and 300 mg/kg for development of their offspring.
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  • Tagahiko MORINAGA, Shigenobu FUJII, Shigenori FURUKAWA, Mikito KIKUMOR ...
    1996 Volume 21 Issue SupplementI Pages 207-217
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    A study of the effect of prulifloxacin, a new antibacterial agent, during the period of organogenesis was conducted in New Zealand White rabbits. Female rabbits were given prulifloxacin orally at dose levels of 0 (control), 1O, 30 and 100 mg/kg from day 6 to 18 of pregnancy. Female rabbits were sacrificed on day 29 of pregnancy for examination of their fetuses. In the 30 mg/kg group, food and water consumption decreased. In the 100 mg/kg group, soft stool was observed and body weight gain, food consumption and water consumption decreased. Premature delivery (2/16) occurred and enlargement of cecum and increased weight of cecum wcre observed. The number of fetal death increased in the 100 mg/kg group. However, prulifloxacin had no effects on the number of corpora lutea, implantations and live fetuses, and on body weight, placental weight, sex ratio, and external, visceral and skeletal development of live fetuses. These results show that the NOAEL of prulifloxacin are 10 mg/kg for general toxicity in mother animals; 30 mg/kg for pregnancy of mother animals and for development of fetuses.
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  • Tagahiko MORINAGA, Shigenobu FUJII, Shigenori FURUKAWA, Mikito KIKUMOR ...
    1996 Volume 21 Issue SupplementI Pages 219-230
    Published: June 05, 1996
    Released: February 21, 2008
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    A peri- and postnatal study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Female rats were given prulifloxacin orally at dose levels of 0 (control), 30, 100 and 300 mg/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. Food consumption in the period of pregnancy decreased in the dams given 100 and 300 mg/kg, and food and water consumption during lactational period increased in the dams given 300 mg/kg. The weight of the cecum of the dams increased in 100 and 300 mg/kg groups, and these doses caused enlargement of the cecum. Prulifloxacin had no effects on general sign, delivery, nursing, body weight gain, and kidney. Prulifloxacin also did not affect the number of live newborns and birth index, and have any adverse effects on the postnatal development of the first generation offspring (F1) such as differentiation, functional development, emotionality, motor ability, learning ability and reproductive performance. Prulifloxacin also had no adverse effects on the second generation offspring (F2). These results show that the NOAEL of prulifloxacin are 30 mg/kg for general toxicity in mother animals, 300 mg/kg for pregnancy and delivery of mother animals and development of their offspring.
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  • Chiaki TATEDA, Katsutomo SAKAI, Satoru YAMAKAWA, Takashi NAKASUJI, Toh ...
    1996 Volume 21 Issue SupplementI Pages 231-239
    Published: June 05, 1996
    Released: February 21, 2008
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    Antigenicity of prulifloxacin, a new antibacterial agent, and that of its active metabolite (NM394) were investigated using guinea pigs and mice in this study. In the study with guinea pigs, the animals were immunized with prulifloxacin by oral administration, the predetermined clinical route, and with prulifloxacin alone or emulsified with Freund's complete adjuvant (FCA) by s.c. When active systemic anaphylaxis (ASA) test and passive cutaneous anaphylaxis (PCA) test of these animals were conducted by eliciting with NM394 alone or protein conjugate (NM394-GPSA) of NM394 and guinea pig serum albumin (GPSA), no ASA and PCA reactions were observed. When guinea pigs were immunized subcutaneously with protein conjugate (NM394-BSA) of NM394 and bovine serum albumin (BSA) together with FCA, ASA and PCA reactions were positive by eliciting with NM394-GPSA or NM394-BSA, but were negative by eliciting with NM394 alone. In the study with mice, the animals were immunized orally with prulifloxacin and intraperitoneally with prulifloxacin alone or suspended with alminium hydroxide gel (alum). When rat PCA test of sera from these mice was conducted by eliciting with NM394 or NM394-GPSA, no positive PCA reaction was observed. When mice were immunized intraperitoneally with NM394-BSA together with alum, PCA reactions were positive by eliciting with NM394-GPSA or NM394-BSA, but were negative by eliciting with NM394 alone. These results show that prulifloxacin has no immunogenicity to guinea pigs and mice, and NM394 as its active form has no eliciting potential to anti-NM394-BSA antibody.
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  • Keiko IWAKURA, Hironobu TAMURA, Yasuhiro YAMASHITA, Masataka WATANABE, ...
    1996 Volume 21 Issue SupplementI Pages 241-257
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    The mutagenicity of prulifloxacin, a new antibacterial agent, was investigated by the reverse mutation test in bacteria, the chromosomal aberration test in cultured cells, and the micronucleus test in mice. In addition, NM394, an active metabolite of prulifloxacin, was examined for mutagenicity in the chromosomal aberration test in cultured cells. The reverse mutation test was performed at dose range of 0.0078-0.25 μg/plate using Salmonella typhimurium strains (TA100, TA1535, TA98, and TA1537), and Escherichia coli (WP2uvrA). Prulifloxacin did not increase revertant colonies significantly in any of the test strains with or without metabolic activation system (S9 mix). The chromosomal aberration tests were carried out in cultured Chinese hamster lung cells (CHL/IU). Prulifloxacin increased aberrant cells without S9 mix, and NM394 also induced chromosomal aberrations. In human lymphocytes, no significant increases of the frequencies of cells with chromosomal aberrations were observed at dose range of 5-320 μg/ml with or without S9 mix. The micronucleus test was conducted at doses of 625-5000 mg/kg in the bone marrow cells of Slc:ddY male mice. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes.
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  • Kouhachi KAMATA, Akihiko OGAWA, Tatsumi INOUE, Mikako ISHIHARA, Katsum ...
    1996 Volume 21 Issue SupplementI Pages 259-265
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Photoallergenicity of prulifloxacin, a new antibacterial agent, was examined using guinea pigs compared with those of the other quinolone antibacterial drugs, ofloxacin (OFLX), lomefloxacin (LFLX), ciprofloxacin (CPFX), enoxacin (ENX) and nalidixic acid (NA). Prulifloxacin and other drugs were orally administered at minimal phototoxic doses 1 hr before UVA (18 J/cm2) irradiation. This photosensitization procedure was daily repeated for 5 days. On 16 days after the final sensitization, the animals were challenged with UVA (18 J/cm2) after the administration of correspondent substances at maximal non-phototoxic doses. Photoallergic reactions were induced by OFLX (40 mg/kg), LFLX (3 mg/kg), CPFX (170 mg/kg) and ENX (80 mg/kg), but were not observed in prulifloxacin (170 mg/kg) and NA (30 mg/kg). These results show that photoallergenicity of prulifloxacin were less severe than those of the other quinolone antibacterial drugs under the conditions of this study.
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  • Akitaka KAWAMINAMI, Takeharu TAWARATANI, Seitaro ISHIBASHI, Takaaki OK ...
    1996 Volume 21 Issue SupplementI Pages 267-276
    Published: June 05, 1996
    Released: February 21, 2008
    JOURNALS FREE ACCESS
    Renal toxicity of prulifloxacin, a new antibacterial agent, was investigated in rats of both sexes. The animals were given prulifloxacin orally for 28 days at a dose of 3000 mg/kg. Tubular nephrosis in which crystalline substances appeared primarily within tubules was observed from the second day of administration, and a large number of brown circular crystals were found in the urinary sediment from the first day of administration. Electron microscopic observation revealed a close resemblance of the ultrastructural characteristics between the intratubular crystalline substance and the urinary brown circular crystal, and the tubules were occasionally occluded by the crystalline substances. Infrared spectral analysis and X-ray microanalysis indicated that the brown circular crystal consisted of NM394, an active metabolite of prulifloxacin. These results suggested that NM394, which was filtered into the primary urine, may be precipitated ad crystals on the process of water reabsorption in the tubules. And then most of the crystals would be washed out as crystalluria particles, and some of crystals retained and caused the obstructive uropathy.
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