Biomedical subjects

N Sumi

Publications and source records attributed to N Sumi.

At least 37 records · Page 2Linked to original sources

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (3). Teratogenicity study in rabbits by oral administration].

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (4). Perinatal and postnatal study in rats by oral administration].

A study of the effect of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats during the perinatal and lactational periods. Female rats(thirty-three per dose level) were given NS-21 orally at dose levels of 0 (control), 2, 25 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. At the 300 mg/kg dosage level, reduced activity, salivation and rales were observed in dams, and five dams died. Decreases in body weight gain, food consumption and water consumption were also observed in the dams at the 300 mg/kg. The number of remaining implantation sites was increased at 300 mg/kg, indicating fetal mortality. The number of live newborns, birth index and survival index at the birth were decreased at the 300 mg/kg dosage level. Reduced activity, paleness in color and/or discoloration were observed for many pups at the 300 mg/kg on lactation day 0. Body weights of male and female offspring at the birth were also decreased at the 300 mg/kg dosage group. Survival index at the 4 days was decreased at the 300 mg/kg dosage level. Body weight gains of male and female offspring were decreased at the 300 mg/kg during the lactational period and after weaning. NS-21 did not affect the postnatal development of the offspring, including physical and functional development, motor activity, emotionality, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity and reproductive function in mother rats and 25 mg/kg for developmental toxicity of their offspring.

Administration, Oral↗

PubMed1997

[Mutagenicity studies of (+/-)-4-diethylamino-1,1,-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence].

The mutagenicity of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was investigated by the reverse mutation test in bacteria, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at a dose from 31.3 to 4000 micrograms/plate, at which dose cell killing was observed, using Salmonella typhimurium TA100, TA1535, TA98, and TA1537, and Escherichia coli WP2uvrA. NS-21 did not increase revertant colonies significantly in any of the test strains with or without metabolic activation system (S9 mix). The chromosome aberration test was carried out at a dose from 3.75 to 140 micrograms/ml, at which dose more than 50% cell proliferation was inhibited, using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosome aberrations were observed with or without S9 mix. The micronucleus test was conducted in the bone marrow cells of Slc : ddY male mice. Mice were given NS-21 by a single oral administration at doses of 0, 43.8, 87.5, 175, and 350 mg/kg, the geometric mean dose between the maximum tolerated dose and the minimum lethal dose. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that NS-21 has no mutagenic activity in vitro or in vivo.

Animals↗

PubMed1997

[Mutagenicity studies of RCC-36, the active metabolite of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence].

The mutagenicity of (+/-)-4-ethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36), an active metabolite of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), was investigated by the reverse mutation test in bacteria, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at a dose range of 6.25-400 micrograms/plate using Salmonella typhimurium TA100, TA1535, TA98, and TA1537, and Escherichia coli WP2uvrA. RCC-36 did not increase revertant colonies significantly in any of the test strains with or without metabolic activation system (S9 mix). The chromosome aberration test was carried out at a dose range of 2.5-20 micrograms/ml without S9 mix and 10-80 micrograms/ml with S9 mix using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosome aberrations were observed with or without S9 mix. The micronucleus test was conducted in the bone marrow cells of Slc:ddY male mice. Mice were given RCC-36 by a single intraperitoneal administration at doses of 0, 10, 20, 40, and 80 mg/kg. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that RCC-36 has no mutagenic activity in vitro or in vivo.

Animals↗

PubMed1997

[A 13-week oral repeated dose toxicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in rats followed by a 5-week recovery test].

A 13-week oral repeated dose toxicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Sprague-Dawley rats. Male and female rats were given the drug orally for 13 weeks at doses of 0 (control), 6, 30, 150 and 750 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted at doses of 0, 30, 150 and 750 mg/kg. Nine cases of death occurred in the 750 mg/kg group. Main pathological findings in these cases were congestion and edema in lung. Mydriasis, salivation, lacrimation and a decrease in body weight or a suppression of its weight gain were seen in the 30 mg/kg group and over. Piloerection and an increase in water consumption were seen in the 150 and 750 mg/kg groups. In addition, a decrease in spontaneous locomotor activity, abdominal distention, unkempt fur, soft stool, diarrhea and decreases in feces and food consumption were seen in the 750 mg/kg group. Ophthalmologic examination confirmed mydriasis and lacrimation in the 30 mg/kg group and over. Urinalysis showed decreases in Na+ and K+ excretions in the 30 mg/kg group and over, an increase in urinary protein in the 150 and 750 mg/kg groups, and a decrease in urine volume in the 750 mg/kg group. Hematological examination showed decreases in hemoglobin and hematocrit in the 150 and 750 mg/kg groups, and a decrease in lymphocytes in the 750 mg/kg group. Blood chemical examination showed an increase in total protein in the 30 mg/kg group and over, a decrease in triglyceride in the 150 and 750 mg/kg groups, and an increase in BUN in the 750 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy caused by hyperplasia of smooth-ER in the 30 mg/kg group and over, and a decrease in number of glycogen granules in the 150 and 750 mg/kg groups. Stimulated thyroid follicles were seen in the 30 mg/kg group and over. Increases in incidence and severity of chronic progressive nephropathy were observed in the 150 and 750 mg/kg groups. Ultrastructual features of the renal lesions were swelling and foot process loss of the glomerular epithelial cells, absorption droplets in the glomerular epithelial cells, increase of lysosomes in the proximal tubular cells and hyaline casts in the tubular lumen. Adrenocortical hypertrophy was seen in the 150 and 750 mg/kg groups. In the 750 mg/kg group, a decrease of hematopoietic tissue in bone marrow and thymic and testicular tubular atrophy were observed. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. No treatment-related effects were seen in the 6 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 6 mg/kg for 13-week oral toxicity in rats.

Administration, Oral↗

PubMed1997

Seventy-eight-week dietary carcinogenicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in mice.

The oncogenic potential of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was assessed when it was administered in the diet of Charles River B6C3F1 mice for 78 weeks in dosages of 0, 30, 100 and 300 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Average food consumption, food efficiency and hematologic values also were apparently unaffected. Statistically significantly low body weights were observed in the 100 and 300 mg/kg/day mice. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed midzonal hepatocellular vacuolization compatible with lipid vacuoles in both sexes at the 300 mg/kg/day dose level. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in B6C3F1 mice when NS-21 was administered in the diet in concentrations to produce an intake of up to 300 mg/kg/day for 78 weeks.

Administration, Oral↗

PubMed1997

Two-year dietary carcinogenicity study of (+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in rats.

The oncogenic potential of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was assessed when it was administered in the diet of Charles River Fischer-344 rats for 2 years in dosages of 0, 10, 30 and 100 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Food efficiency and hematologic values also were apparently unaffected. Statistically significantly low mean weekly body weights and average food consumption values were observed in the all dose groups. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed test article-related increases in the incidence of periportal hypertrophy and midzonal hepatocellular vacuolization in the livers of the 100 mg/kg/day animals. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in Fischer-344 rats when NS-21 was administered in the diet in concentrations to produce an intake of up to 100 mg/kg/day for 2 years.

Administration, Oral↗

PubMed1997

[A 26-week oral repeated dose toxicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in rats followed by a 9-week recovery test].

A 26-week oral repeated dose toxicity study of (+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Sprague-Dawley rats. Male and female rats were given the drug orally for 26 weeks at doses of 0 (control), 5, 50 and 500 mg/kg. After discontinuation of the treatment, a 9-week recovery test was also conducted. Two cases of death occurred in the 500 mg/kg group. Mydriasis, salivation and lacrimation were seen in the 50 and 500 mg/kg groups. Alopecia, a suppression of body weight gain and an increase in water consumption were seen in the 500 mg/kg group. Food consumption measurement showed no abnormalities attributable to the treatment. Ophthalmologic examination confirmed mydriasis in the 50 and 500 mg/kg groups. Urinalysis showed an increase in urine volume in the 50 and 500 mg/kg groups, and an increase in urinary protein and decreases in Na+, K+ and Cl- excretions in the 500 mg/kg group. Hematological examination showed decreases in hemoglobin, hematocrit, MCV, MCH, MCHC and lymphocytes in the 500 mg/kg group. Blood chemical examination showed increases in total cholesterol, phospholipid and total protein and decreases in glucose, triglyceride, free T3 and T4 in the 500 mg/kg group. Measurements of liver drug-metabolizing enzymes showed an increase in T4UDP-GT activity in the 50 and 500 mg/kg groups, and an increase in cytochrome P-450 in the 500 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy caused by hyperplasia of smooth-ER in the 50 and 500 mg/kg groups, and a decrease in number of glycogen granules in the 500 mg/kg group. Stimulated thyroid follicles were seen in the 50 and 500 mg/kg groups. Increases in incidence and severity of chronic progressive nephropathy were also observed in the 500 mg/kg group. In this dose group, adrenocortical hypertrophy was also observed. The recovery test showed that the above-mentioned changes were satisfactorily reversible. The serum concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. No treatment-related effects were seen in the 5 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 5 mg/kg for 26-week oral toxicity in rats.

Administration, Oral↗

PubMed1997

[Oral single-dose and 13-week repeat-dose toxicity studies of RCC-36, the active metabolite of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence, in rats].

Oral single-dose and 13-week repeat-dose toxicity studies of (+/-)-4-ethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36), an active metabolite of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, were conducted in male and female Sprague-Dawley rats. In the single-dose toxicity study, rats were given the drug at doses of 0 (control), 400, 600, 900, 1350 and 2030 mg/kg. In the 13-week repeat-dose toxicity study, rats were given the drug for 13 weeks at doses of 0 (control), 3, 30 and 300 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. In the single-dose toxicity study, death occurred in the 600 mg/kg group and over, and LD50 values were 735 mg/kg in both sexes. The major clinical signs observed following the administration of this drug were mydriasis, salivation, decreased spontaneous locomotor activity, ataxic gait, lacrimation and urorrhea in the 400 mg/kg group and over, hypopnea and soft feces in the 600 mg/kg group and over. In addition, prone or lateral position and tonic or clonic convulsion were observed in the dead animals. Rats showed a decrease in body weight or a suppression of its weight gain in the 400 mg/kg group and over. Macroscopic findings in the dead animals were congestion in lung and retention of foamy mucinous fluid in trachea. The animals alive showed no abnormalities attributable to the treatment. In the 13-week repeat-dose toxicity study, 13 cases of death occurred in the 300 mg/kg group. Main pathological findings in these cases were congestion and edema in lung. Mydriasis was seen in the 30 mg/kg group and over. Lacrimation, salivation, wheezing, emaciation [corrected] wasting and unkempt fur were seen in the 300 mg/kg. A suppression of body weight gain and a decrease in food consumption were observed in the 300 mg/kg group. An increase in water consumption was seen in the 30 and 300 mg/kg groups. Ophthalmologic examination confirmed the mydriasis in the 30 mg/kg group and over. Urinalysis showed an increase in urine volume and a decrease in Na+ excretion in the 30 and 300 mg/kg groups and decreases in K+ and Cl- excretions in the 300 mg/kg group. Hematological examination showed decreases in hemoglobin, hematocrit, MCV and MCH, and an increase in MCHC in the 300 mg/kg group. Blood chemical examination showed decreases in triglyceride and glucose, and an increase in total protein in the 300 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy associated with hyperplasia of smooth-ER, a decrease in number of glycogen granules and an increase in number of lipofuscin in the 300 mg/kg group. Stimulated thyroid follicles were seen in the 300 mg/kg/group. In kidney, an increase in number of hyaline droplets in the proximal tubular epithelium, in which lysosomes and dense bodies were increased, was observed in the 300 mg/kg group. Dense bodies were increased also in the glomerular epithelium. In this dose group, adrenocortical hypertrophy was also observed. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. No treatment-related effects were seen in the 3 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of RCC-36 is 3 mg/kg for 13-week oral toxicity in rats.

Administration, Oral↗

PubMed1996

[A 13-week oral toxicity study of prulifloxacin (NM441) in dogs followed by a 5-week recovery test].

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 beta- and gamma-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.

Administration, Oral↗

PubMed1996

[A 4-week intravenous toxicity study of the active metabolite (NM394) of prulifloxacin (NM441) in rats followed by a 4-week recovery test].

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 substance 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 gamma-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 substance 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 gamma-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.

Animals↗

PubMed1996

[Single and 4-week oral toxicity studies of prulifloxacin (NM441) in aged dogs].

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 were 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 electrocardio-graphic 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 was 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.

Administration, Oral↗

PubMed1996

[Reproductive and developmental toxicity studies of prulifloxacin (NM441)(1)--A fertility study in rats by oral administration].

A study of fertility and fetal development of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Male rats were given the drug orally from 63 days before mating to the end of the 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 were sacrificed 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, 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.

Administration, Oral↗

PubMed1996

[Reproductive and developmental toxicity studies of prulifloxacin (NM441)(2)--A teratogenicity study in rats by oral administration].

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.

Abnormalities, Drug-Induced↗

PubMed1996

[Reproductive and developmental toxicity studies of prulifloxacin (NM441)(3)--A teratogenicity study in rabbits by oral administration].

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), 10, 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 were 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.

Abnormalities, Drug-Induced↗

PubMed1996

[Reproductive and developmental toxicity studies of prulifloxacin (NM441)(4)--A perinatal and postnatal study in rats by oral administration].

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.

Administration, Oral↗

PubMed1996

[Antigenicity studies of prulifloxacin (NM441)].

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 aluminum 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 intraperiotneally 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.

Anaphylaxis↗

PubMed1996

[Mutagenicity studies of prulifloxacin (NM441) and the active metabolite (NM394)].

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 micrograms/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 micrograms/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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