SEARCH · Search PubMed

Results for “SALIVATION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,531 records · Page 85Linked to original sources

PubMed1992

[A 13-week subacute oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187) in dogs.

A subacute oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187), a new protease-inhibiting agent, was carried out in beagle dogs of both sexes. FUT-187 was administered to dogs at daily oral doses of 15, 50 and 150 mg/kg. Dogs in 150 mg/kg group were given twice a day in a.m. and p.m.. The results were as follows: 1. Changes of physical sign attributed to FUT-187, consisted of vomiting, diarrhea, salivation, decrease of locomotor activity, sedation and hyperemia of eye mucosa. These changes expect vomiting vanished within about 2 hours after treatment. One male given 150 mg/kg died on day 19 and two females given 150 mg/kg were sacrificed on day 55 and 67 due to deterioration of systemic conditions. 2. Body weight gain was suppressed in males given 150 mg/kg and females given 50 mg/kg or more. 3. In hematological examinations, some changes suggesting anemia or inflammation were observed in a few animals received 50 mg/kg or more 4. In serum biochemical examinations, dogs given 50 mg/kg or more had decrease of albumin, total protein, A/G ratio and total cholesterol, increase of GPT activity. In liver function test, decrease of function was observed in a few animals in 150 mg/kg group. These changes diminished by the end of recovery period. 5. In autopsy findings, ulcer formation and desquamation of mucosa in the digestive tract were observed in dead or sacrificed animals and survived animals given more than 50 mg/kg. In sacrificed animals, liver was yellow in color and intussusception was seen. 6. Plasma levels of intact FUT-187 and metabolites on the day 37 or 83 were higher than that on the first day of administration. 7. In histopathological examinations, ulcer formation, desquamation, degeneration and/or atrophy of mucosa in the digestive tract were observed in the animals from 50 mg/kg and 150 mg/kg groups. In addition, fatty deposition in hepatocytes was observed in one dead animal and two sacrificed animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1994

[Toxicity studies of paclitaxel. (III)--Six-month intermittent intravenous toxicity in rats].

Paclitaxel, an antineoplastic agent, was intravenously given to Crj:CD (SD) rats of both sexes at 0 (saline), 0 (vehicle), 0.3 (low dose), 1.0 (intermediate dose) and 3.3 (high dose) mg/kg at seven-day interval over a six-month period (total of 27 doses) to investigate its repeated dose toxicity. The results obtained are summarized as follows: 1. No deaths occurred in this study. Vehicle-related salivation was seen for some high dose and vehicle control rats. Soiling of the perigenital region was observed for some high dose females. 2. Red blood cell count, hemoglobin, hematocrit and white blood cell count were decreased for high dose rats. Reticulocyte count was increased and relative neutrophil count was decreased for high dose males. 3. Relative erythroid and myeloid cell count were decreased for high dose rats in bone marrow smear examinations. 4. Bone marrow hypoplasia and splenic hemosiderosis were observed for high dose rats, and thymic atrophy and lymphoid depletion were seen for some high dose males. Based on the these results, the no-toxic effect dose of paclitaxel was estimated to be 1.0 mg/kg in rats under this study condition.

Animals↗

PubMed1994

[13-week oral toxicity study of lactitol (NS-4) in rats followed by 5-week recovery test].

Twenty male and 20 female Slc : SD rats were orally given lactitol, a hepatic encephalopathy drug, for 13 weeks at doses of 0, 0.625, 2.5 or 10 g/kg/day. A 5 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool and decreased food consumption were seen in the 2.5 and 10 g/kg groups. In the 10 g/kg group, there were diarrhea, soiled fur, abdominal distention, salivation, piloerection, decreased body weight gain and increased water consumption. Urinalysis showed decreased urine volume and K+ excretion in the 10 g/kg group. In this dose group, biochemical examination showed decreased ALP, total cholesterol, triglyceride, glucose, Ca, Na+, Cl- and total protein. In the pathological examination, the cecum weight was increased in all dose groups. In the 2.5 and 10 g/kg groups, cecum distention with mucosal hyperplasia was observed. The adrenal weight was increased in the 10 g/kg group and hypertrophy of zona fasciculata of adrenal gland were seen in the 2.5 and 10 g/kg groups. The thymic weight was decreased in the 10 g/kg group. Ophthalmoscopic and hematologic examinations failed to reveal any drug induced changes. The increased cecum weight in the 0.625 g/kg group was regarded as toxicologically insignificant because of the failure of the association with any clinical or morphological findings. The above mentioned changes were satisfactorily reversible except for those in the cecum. Based on the results obtained, the NOAEL of this study was suggested to be 0.625 g/kg/day.

Administration, Oral↗

PubMed1995

[Reproductive and developmental toxicity studies of montirelin hydrate (3)--Teratogenicity study in rabbits by intravenous administration].

A study of the effect of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, during the period of organogenesis was conducted in New Zealand white rabbits. Female rabbits were given the drug intravenously at dose levels of 0 (control), 0.01, 0.1 and 1 mg/kg from day 6 to day 18 of pregnancy. Female rabbits were sacrificed on day 29 of pregnancy for examination of their fetuses. In the 0.1 mg/kg group, food consumption decreased slightly. In the 1 mg/kg group, tachypnea, salivation and rhinorrhea were observed, and body weight and food consumption decreased and water consumption increased. The drug had no effect on the number of corpora lutea and implantations, or on fetal mortality, on fetal body weights, on placental weight, on sex ratio, or on external, visceral and skeletal development of the fetuses. These results show that the NOAEL of montirelin hydrate are 0.1 mg/kg for general toxicity in mother animals, and 1 mg/kg for pregnancy of mother animals and for development of fetuses.

Animals↗

PubMed1996

Acute oral toxicity of capsaicin in mice and rats.

The oral toxicity of capsaicin was investigated in mice and rats. Oral LD50 values were 118.8 mg/kg for male and 97.4 mg/kg for female mice, and 161.2 mg/kg for male and 148.1 mg/kg for female rats. Major toxic symptoms in mice were salivation, erythema of skin, staggering gait, bradypnea and cyanosis. Some animals showed tremor, clonic convulsion, dyspnea and lateral or prone position and then died 4 to 26 min after dosing. Survivors recovered within 6 hr in mice and 24 hr in rats. Toxic symptoms of rats were almost the same as mice, but rats showing higher incidence of cyanosis, clonic or tonic convulsion, dyspnea and lateral position, and the recovery was later than mice. The cause of death by capsaicin may be due to hypotension and respiratory paralysis in both animals, although the pathophysiology of death is not clearly understood. At pathological examination, erosion and ulcer of gastric fundus were seen in dead animals, while no pathological change was seen in surviving ones.

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

[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

[A 4-week oral toxicity study of prulifloxacin (NM441) in dogs followed by a 4-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 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 alpha 2-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 dose-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.

Administration, Oral↗

PubMed1996

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

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 substance 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 1000 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.

Administration, Oral↗

PubMed1996

[Single dose toxicity studies of calcipotriol (MC903) in rats and dogs].

A single dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, administered subcutaneously (s.c.) and percutaneously (p.c.) was studied in Slc:SD rats (s.c. and p.c.) and beagle dogs (s.c.). The LD50 values of MC903 were as follows: rats, 2.19 mg/kg in males and 2.51 mg/kg in females by s.c., and more than 15 mg/kg in both sexes by p.c.; dogs, more than 1.5 mg/kg in males by p.c. No sexual difference was noted in LD50 values of rats. Death of rats was observed from 1 to 3 days after administration by both routes. Dead animals showed decreases in body weight and locomotor activity, reddish tear, abnormal gait and dirty hair by both routes. Furthermore, dead animals administered by s.c. showed salivation, nasal discharge, piloerection, ptosis, diarrhea, urorrhea, nasal and vaginal bleeding, subnormal temperature, loose stool, cyanosis, irregular and deep respirations, clonic and tonic convulsions. Survival of rats showed similar signs to those of dead animals except for nasal discharge, nasal and vaginal bleeding, cyanosis, agonal respiration and convulsion. Discoloration of the kidney, white patch of the heart and a dilatation of the stomach wall were observed on macroscopic examinations. No mortalities were observed in dogs which showed vomiting, conjunctival congestion, circumoral and auricular reddenings, periblepharal purplish reddening, decreases in locomotor activity and defecation, emaciation, eye discharge, skin desquamation of treated area and an increase in respiration. On macroscopic examination, desquamation of the skin, reddening of the circumoral mucosa, pale gray yellow striations in renal tubules of the cortex and discoloration of the thyroid were observed. Histopathological findings revealed epidermal thickening with parakeratosis, fibrocytes, hypertrophy and hypersecretion of the sebaceous and sweat glands, formation of epitheloid glanulomas and infiltration of neutrophils in the subcutaneous tissues. Furthermore, moderate calcium deposits in the renal tubules, fatty cells and slight calcium deposits in interstitial tissues of the thyroid, and a cystic nest of an ectopic intestinal epithelium between muscle layers of the duodenum were observed at the highest dose. On the basis of results obtained in the present study, rats administered MC903 by s.c. or p.c. died probably due to the circulatory and renal disturbance resulted from effects of this drug on the heart and kidney.

Administration, Cutaneous↗

PubMed1996

[An oral repeated dose toxicity study of a new antineoplastic agent S-1 in dogs. I. A 13-week repeated dose toxicity study. II. An ophthalmologic toxicity recovery study].

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that producted by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, a 13-week repeated dose toxicity study and a recovery study of opthalmologic effects were conducted in dogs. The following results were obtained. All S-1 doses are expressed in terms of their FT content. 1. Concerning the general condition, dark brown pigment was deposited on the sclera of the eye in all S-1 treated groups starting at the second week of treatment, and clouding of the cornea was noted in the 3 mg/kg/day group starting after 3-4 weeks of treatment. In the 3 and 6 mg/kg/day groups, general signs such as salivation, reduction in spontaneous movements, and sedation appeared, and 1 male and 2 females of the 3 mg/kg/day group died or were moribund 4-5 weeks after treatment began. All animals of the 6 mg/kg/day died or were sacrificed within 2 weeks of the start of the study. 2. Food consumption and body weight were reduced in the groups administered 1 mg/kg/day or more S-1. 3. No apparent drug-induced changes were observed on electrocardiography, urinalysis, fecal occult blood test, hematological examination, liver and kidney function tests, or ocular mucosa infection tests. 4. Blood biochemical examinations showed decreases in creatinine and chloride levels in males, an increase in LDH activity, and decreases in the albumin level and A/G ratio in females of the 3 mg/kg/day group. 5. Organ weighing showed that the relative weight of the kidney was increased in males and females of the 3 mg/kg/day group. 6. Histopathological examination revealed melanin deposition in the conjunctiva or cornea and atrophy inflammation, neutrophil infiltration, and neovascularization in the corneal epithelium. Atrophy of lymphatic tissues, such as the thymus, spleen and various lymph nodes, and changes in the reproductive system such as aspermatogenesis and uterine atrophy, which are commonly observed side effects of anticancer drugs, were also noted. 7. In the group administered FT, vacuolation of the cerebral fornix and commissura anterior was observed in 1 animal, but no changes were observed in other examinations. 8. The toxic effects of S-1 appeared primarily in the eyes, lymphatic tissues, and reproductive organs, and deaths were ascribed to weakening due to exacerbation of the general effects accompanied by disorders of immunological function. The NOAEL of S-1 in this study was estimated to be the dose that delivered less than 0.5 mg/kg/day in both males and females. 9. Changes in the eye observed after S-1 administration are such as pigmentation of the sclera and white turbidity of the cornea. Though it may be produced vision decreased, these changes are considered to be unaccompanied by functional disorders and to be reversible.

Administration, Oral↗

PubMed1997

[Single-dose 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, in mice, rats and dogs].

Comparative single-dose toxicity studies 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 ddY mice and Sprague-Dawley rats after oral(p.o.),intraperitoneal(i.p.) and subcutaneous(s.c.) administration, and in Beagle dogs after p.o. administration. The p.o. LD50 values of NS-21 were 852 and 1167 mg/kg for male and female mice, 2839 and 1739 mg/kg for male and female rats, respectively. The i.p. LD50 values were 324 and 390 mg/kg for male and female mice, and 423 and 359 mg/kg for male and female rats, respectively. No death occurred in mice and rats at doses up to s.c. 5000 mg/kg. Minimum lethal dose for dogs could not be determined because of vomiting. Mydriasis was noted in all three species tested without regard to administration route. In addition, decreased spontaneous locomotor activity, prone or lateral position, hypopnea, hypothemia, ataxic gait, twitch and clonic convulsion were observed in mice and rats after p.o. and i.p. administration. In rats, salivation was observed after p.o. administration and lacrimation was observed after p.o. and i.p. administration. After s.c. administration, scab formation at the site of injection was observed in mice and rats. In dogs, vomiting, hyperemia of both conjunctiva and oral mucosa, prone position, tremor and clonic convulsion were observed after p.o. administration. Body weight was decreased or its gain was suppressed in mice and rats without regard to administration route. Body weight and food consumption were decreased in dogs after p.o. administration. Pathological examination showed congestion of lung in dead mice and rats after p.o. and i.p. administration. Distention of small intestine was observed in dead mice and rats after p.o. administration and in sacrificed rats after p.o. administration. Adhesion between the abdominal organs was observed in sacrificed mice and rats after i.p. administration. Thymic atrophy associated with a decrease in its organ weight was observed in dogs after p.o. administration.

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 dogs followed by a 5-week recovery test].

Administration, Oral↗

PubMed1997

[A 12-month 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 dogs followed by a 2-month recovery test].

A 12-month 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 beagle dogs. Male and female dogs were given the drug orally for 12 months at doses of 0 (control), 3, 17.5 and 100 mg/kg. After discontinuation of the treatment, a 2-month recovery test was also conducted. No effects related to the treatment were observed on survival and water consumption. Mydriasis, vomiting and a decrease in body weight or a suppression of its weight gain were seen in the 17.5 and 100 mg/kg groups. Salivation and a decrease in food consumption were seen in the 100 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 17.5 and 100 mg/kg groups. Electrocardiographic and hematological examinations and urinalysis showed no abnormalities attributable to the treatment. Blood chemical examination revealed increases in GPT and ALP in the 17.5 and 100 mg/kg groups, increases in GOT and triglyceride and a decrease in total protein in the 100 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy and concentric lamellar bodies derived from the smooth-ER in the 100 mg/kg group, and hyperplasia of smooth-ER, an increase in number of lysosomes and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 17.5 and 100 mg/kg groups. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. 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 3 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 3 mg/kg for 12-month oral toxicity in dogs.

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 (1). Fertility study in rats by oral administration].

Fertility and developmental 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 Crl:CD rats. Male rats were given NS-21 orally from 60 days before mating to the day of necropsy, and female rats were given NS-21 orally from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 2, 30 and 500 mg/kg. On day 20 of pregnancy, the females were sacrificed and their fetuses examined. At the 500 mg/kg dosage level, one male and one female died. Salivation and dilated pupils occurred at the 30 and 500 mg/kg dosage levels, and rales occurred at 500 mg/kg. Body weights and food consumption were decreased, and water consumption was increased in both males and females at the 500 mg/kg dosage level. Decreases in the numbers of corpora lutea and implantations per litter and a lower number of live fetuses per litter were found at the 500 mg/kg dosage level. However, the incidence and number of postimplantation loss per litter were comparable among the treatment and control groups. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 2 mg/kg for general toxicity in parental animals, and 30 mg/kg for reproductive function of the parent animals and for embryo-fetal development.

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

[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

[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↗