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PubMed2001

Severe fenitrothion poisoning complicated by rhabdomyolysis in psychiatric patient.

Non-traumatic rhabdomyolysis associated with organophosphate intoxication has not been generally reported. We report here in a severe case of fenitrothion poisoning complicated by rhabdomyolysis. A 43-year-old woman ingested approximately 100 ml of fenitrothion emulsion (50%) in an attempt to commit suicide. On day 3 after admission, her creatine phosphokinase (CPK) peaked at 47,762 IU/L. She received supportive treatment included sodium bicarbonate and fluid resuscitation. However, muscarinic symptoms including excessive miosis and salivation developed on day 5 when her CPK levels decreased. The delay in cholinergic symptoms might have been due to the trihexyphenidyl she took with the antipsychotic drugs. Fortunately, the present patient recovered from the acute cholinergic crisis, and acute renal failure was prevented by early diagnosis. This is a case of organophosphate poisoning complicated by rhabdomyolysis in a psychiatric patient. The masking of acute cholinergic symptoms should be taken into consideration in such patients.

Adult↗
PubMed1977

Studies of operant and reflexive key pecks in the pigeon.

The duration of pigeons' key pecks was studied in three experiments. Experiment I revealed that key pecks early in exposure to continuous reinforcement were of short duration, as were key pecks observed on an omission procedure in which pecks prevented food delivery. Key pecks later in exposure to continuous reinforcement, and those that occurred on positive automaintenance procedures, were of long duration. In Experiment II, pigeons were exposed to fixed-interval and fixed-ratio reinforcement schedules, and durations were recorded separately for each quarter of each interval or ratio. On fixed interval, durations were shorter in the first quarter of each interval than in subsequent quarters; on fixed ratio, durations were longer in the first quarter of the ratio than in subsequent quarters. These data parallel observations of concurrent operant responding and salivation in dogs. In Experiment III, pigeons were exposed to a discrete trial, differential-reinforcement-of-low-rate 6-sec schedule. Durations of responses in the first 2 sec of the trial were substantially shorter than those of responses that occurred later. The data from all three experiments support the view that the pigeon's "key peck" actually consists of two subclasses of peck, one reflexive and one operant.

Journal Article↗
PubMed1982

Effect of peptide extracted from skeletal muscles of the fur seal on periodontal diseases.

It has been confirmed previously that a physiologically active peptide extracted from the skeletal muscles of fur seals exhibits excellent dermal absorption and has peripheral vasodilating properties. These properties were postulated to be beneficial to inflamed periodontal tissues. To test this, a dentifrice containing the peptide was prepared and utilized in a double-blind test. Significant improvement in the gingiva conditions was observed when a 0.1% or more concentration of peptide was used. As time progressed, distinct clinical improvement in redness, swelling, drainage, bleeding and pocket depth was noted. No significant side effects were noted although there were seen increased salivation and gingival blanching. It is believed, as a result of this and other studies, that the clinical efficacy of this peptide is due to its vasodilating action on the venules, thus reducing the internal pressure in the vascular beds.

Adolescent↗
PubMed1992

Spongiform encephalopathies in Cervidae.

The known host range of naturally-occurring transmissible spongiform encephalopathies has expanded in recent years to include wild ruminants. Chronic wasting disease (CWD) occurs in mule deer (Odocoileus hemionus hemionus) and Rocky Mountain elk (Cervus elaphus nelsoni) in Colorado and Wyoming, United States of America. These species belong to the family Cervidae. Cases have occurred primarily in captive animals but a few affected free-ranging animals have been identified. Clinical disease in both species is characterised by progressive weight loss, behavioural alterations and excessive salivation. In deer polydipsia and polyuria also commonly occur. Significant lesions are confined to the central nervous system and consist of spongiform change in grey matter, intraneuronal vacuolation, astrocytosis and amyloid plaques. Inflammatory reaction is absent. The origin of this disease is not known. In contrast to the cases of spongiform encephalopathy recognised in five species of antelope (family Bovidae) in British zoological parks, which are an extension of the current bovine spongiform encephalopathy epizootic, CWD is not the result of food-borne exposure to the infectious agent. CWD appears to be maintained within captive populations by lateral and, possibly, maternal transmission. Spongiform encephalopathies in wild ruminants are currently geographically isolated and involve relatively small numbers of animals. However, these potentially transmissible diseases could be of greater importance in the future and should be viewed with concern in the light of international movements of wild ruminants and the current expansion of the game farming and ranching industry in many parts of the world.

Animals↗
PubMed1988

[Acute toxicity study of cefodizime sodium].

Acute toxicity of cefodizime sodium (THR-221) was examined in mice of both sexes, rats of both sexes (including 5-day-old young), and male dogs. The LD50 values of THR-221 (mg/kg) were as follows: (1) mice: intravenous, 7200 for males and 5000 for females; intraperitoneal, 10500 for males and 11000 for females; subcutaneous, 17500 for males and 16500 for females; and oral, 28000 for males and 29000 for females. (2) rats (adult): intravenous, 7000 for males and 8200 for females; intraperitoneal, 9500 for males and 8800 for females; subcutaneous, 17000 for males and 15500 for females; oral, more than 20000 for both sexes; and intramuscular, more than 3200 for both sexes. (3) 5-day-old rats: subcutaneous, 5278 for males and 5314 for females. (4) male dogs: intravenous, more than 5000. Major changes in general conditions observed in mice and rats were decreased spontaneous activity, lying prone, respiratory changes, staggering gait, clonic or clonic-tonic convulsions, and cyanosis, and in the animals dosed orally, diarrhea or salivation was also noted. The changes in 5-day-old rats were respiratory changes, agony, loss of reflex to an external stimulus, and congestion at the injection site, and those in dogs were vomiting, dryness of the nose, and soft or mucous stools. Autopsies on the mice and rats which died revealed hemorrhage on the brain surface. In addition, the following were seen: intraperitoneal retention of fluid and dark red spots on the abdominal wall (i.p.), subcutaneous retention of fluid or jellylike material and hemorrhage at the injection site (s.c.), and retention of fluid and dark red spots on the mucosa in the digestive tract (mice p.o.). In 5-day-old rats which died, the subcutaneous tissue at the injection site showed hemorrhage macroscopically and inflammatory changes microscopically. Hematological and blood chemical tests performed in dogs showed an increase in white blood cells and changes suggesting anemia, increases in GOT, LDH and ALP activities, and slight changes in urea nitrogen and inorganic phosphorus. In one animal given a low dose of 2500 mg/kg, an increase in GPT activity was also seen. However, these changes were all transient. Microscopic findings in dogs were slight inflammatory changes in the subcutaneous tissue around the injection site.

Administration, Oral↗
PubMed1989

[Thirteen-week oral toxicity study of propiverine hydrochloride in rats].

A subacute toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out using male and female Wistar rats. P-4 was orally administered to rats at dose levels of 2, 10, 50 and 150 mg/kg/day for 13 weeks, followed by 5 weeks recovery period. The results obtained are as follows: 1. In the general conditions, transient salivation was observed immediately after administration and blotted fur at lower abdomen was noted in rats given 50 mg/kg/day or more. There were no deaths related to P-4. 2. Body weight gain was depressed in males given 50 mg/kg/day or more and females given 150 mg/kg/day. No significant changes in food consumption were observed. Water consumption increased in the groups of 50 mg/kg/day or more. 3. Urinalysis revealed an increase of urine volume, decreases of osmotic pressure, protein and urobilinogen, and a slight increase in excretion of electrolyte in rats given 50 mg/kg/day or more. 4. Hematological examinations revealed slight changes such as an increase in erythrocyte count and a shortening of APTT in rats given 150 mg/kg/day. 5. Serum biochemical examinations showed a decrease in triglyceride and increases in gamma-GTP and AlP activities, and urea nitrogen in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Additionally, decreases in total and free cholesterol, and phospholipid for males and an increase of total cholesterol and a decrease of cholinesterase activity for females were detected. 6. At autopsy, atrophy of thymus and spleen was observed in rats given 50 mg/kg/day or more, but without histopathological correlation. Histopathological examinations revealed hypertrophy and fatty degeneration of hepatocytes, which were accompanied with increases of absolute and/or relative liver weight, in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Electron-microscopy showed proliferation of smooth endoplasmic reticulum in the same groups. In the kidney, eosinophilic and intranuclear inclusions in the tubular epithelium were detected, in which cytoplasm there were no toxic injuries, in males given 10 mg/kg/day or more and females given 50 mg/kg/day or more. 7. After 5 weeks recovery period, above-mentioned changes were generally disappeared, suggesting that these were reversible. 8. The non-effective dose levels and the toxic dose levels of P-4 were estimated to be 2 mg/kg/day for males and 10 mg/kg/day for females, and 50 mg/kg/day for males and 150 mg/kg/day for females, respectively.

Administration, Oral↗
PubMed1989

[Reproduction study of propiverine hydrochloride (1)--fertility study in rats by oral administration].

A fertility study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0 (control), 2, 10 and 50 mg/kg/day. Male rats were treated for 9 weeks before mating and following 4 weeks including mating period. Female rats were administered the test substance from 2 weeks before mating to day 7 of pregnancy. The females were sacrificed on day 21 of pregnancy for examination of their fetuses. Toxic signs consisted of mydriasis, salivation and rale were observed in both male and female animals at the dose of 50 mg/kg group and in male animals at the dose of 10 mg/kg group. Body weight gain was supressed and food intake was decreased in the 50 mg/kg group throughout the administration period. Water intake of the 50 mg/kg group was decreased temporarily at the early stage of administration period, although increased thereafter. Autopsy revealed the enlargement of the liver with yellow-brownish coloration in one male rat at the 50 mg/kg group. Fertility and reproductive ability in both sexes were not affected by administration of P-4. There was no lethal effect and no growth-inhibiting or teratogenic effects on the embryos and the fetuses. The results suggest that the non-effective dose level of P-4 was 2 and 10 mg/kg/day for general toxicity in male and female parent animals respectively, 50 mg/kg/day for reproductive ability in parent animals and in embryos and fetuses.

Abnormalities, Drug-Induced↗
PubMed1989

[Reproduction study of propiverine hydrochloride (2)--teratological study in rats by oral administration].

A teratogenicity study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0 (control), 2, 10 and 50 mg/kg/day to dams from day 7 to day 17 of pregnancy. Twenty two or twenty three female rats in each group were sacrificed on day 21 of pregnancy for examination of their fetuses, and thirteen female rats were allowed to deliver for the postnatal examination of their offspring. In dams, the dose of 50 mg/kg caused toxic signs consisting of mydriasis, salivation and rale, body weight loss in the early stage of administration, and reduced food intake and increased water intake. The dose of 10 mg/kg caused rale, very slight suppression of body weight gain and slight reduction of food intake. Body weight of the fetuses was decreased very slightly in the 50 mg/kg group. However, embryonal or fetal mortality and incidences of external, visceral or skeletal anomalies were not increased. In offspring, P-4 had no adverse effect on the postnatal development such as viability, growth, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of P-4 is 2 mg/kg/day in maternal animals, 10 mg/kg/day in fetuses and 50 mg/kg/day in offspring.

Abnormalities, Drug-Induced↗
PubMed1989

[Reproduction study of propiverine hydrochloride (4)--perinatal and postnatal study in rats by oral administration].

A perinatal and postnatal study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0 (control), 2, 10 and 50 mg/kg/day to dams from day 17 of pregnancy to day 21 after delivery. Twenty two or twenty four dams in each group were allowed to deliver for the postnatal examination of their offspring. In dams, the dose of 50mg/kg caused toxic signs consisting of mydriasis, salivation and rale. One dam of this group showed piloerection, low body temperature, blanching of extremity and auricle, and emaciation associated with marked prolongation of delivery. Body weight gain of the dams was retarded in the 50 mg/kg group throughout the administration period. Food and water intakes were reduced in the 50mg/kg group. In gross pathology of the dam that showed prolonged delivery, the spleen and thymus were moderately or severely atrophied and the adrenal was moderately enlarged. The viability index of the offspring on day 4 was reduced in the 50mg/kg group. Body weight of pups slightly decreased in the 50mg/kg group during sucking and rearing periods. Absolute weights of some organs of the three-week aged offspring were reduced due to attributable depression of body weight gain. However, P-4 had no adverse effect on the postnatal development such as emotionality, motor activity, learning ability or reproductive performance. The results suggest that the non-effective dose level of P-4 is 10mg/kg/day in maternal animals and offspring.

Administration, Oral↗
PubMed1990

[Fifty-two-week oral chronic toxicity study of propiverine hydrochloride in rats].

An oral chronic toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out at dose levels of 0 (control), 0.5, 5 and 50 mg/kg/day using male and female rats. They were treated for 52 weeks, followed by 5 weeks recovery period. The results obtained from the present study were as follows. 1. There were no deaths related to P-4. Mydriasis, transitory salivation were observed in both sexes receiving 50 mg/kg/day, and soil of the abdomen was also noted in females receiving 50 mg/kg/day. 2. Body weight gain was suppressed from initiation of administration in both sexes receiving 50 mg/kg/day. 3. There were no significant or remarkable changes in food consumption, hematology and ophthalmology. 4. Urinary findings in animals receiving 50 mg/kg/day showed increases of urine and potassium excretion volumes and decrease of urine osmotic pressure in both sexes, negativity of urine protein and decrease of urobilinogen value in females. 5. Biochemical findings in animals receiving 50 mg/kg/day showed increase of urea-nitrogen (Urea N) in both sexes and decrease of triglyceride (TG), total cholesterol (T. cho), free cholesterol (F. cho), non-esterified fatty acids (NEFA) and phospholipid (PL) in males. 6. The absolute and/or relative weights of the liver increased in animals receiving 50 mg/kg/day. Histopathological examination in animals receiving 50 mg/kg/day revealed intranuclear eosinophilic inclusions and cytoplasmic eosinophilic substance in renal proximal tubular epithelium and midzonal lipid droplets in liver. Histochemical examination in animals receiving 50 mg/kg/day revealed the slight increase of gamma-GTP positive area in peripheral zone of liver. Electron-microscopic examination in animals receiving 50 mg/kg/day revealed intranuclear and intracellular large and homogeneous spherical-like structure with low electron density in renal proximal tubular epithelium, and slight hyperplasia of smooth endoplasmic reticulum with dilatation of cisternae and deposition of large lipid droplets in hepatocytes, but there was no difference of VLDL and its distributions in hepatocytes among groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1992

[Reproductive and developmental toxicity study of suplatast tosilate (IPD-1151T) (2)--Teratological study in rats by oral administration].

A teratological study of suplatast tosilate (IPD-1151T), a new anti-allergic agent which has a suppressive action on IgE antibody formation, was conducted with pregnant Wistar rats. Dosage levels of IPD-1151T 0, 300, 900 and 2700 mg/kg/day were administered to dams orally by gavage on days 7 through 17 of gestation. Two-thirds of dams per group was caesarean-sectioned on day 20 of gestation and their fetuses were removed for examination of external, visceral and skeletal anomalies. The remaining one-third was allowed to deliver naturally. F1 neonates were examined developmental, functional and behavioral parameters and reproductive abilities. The results were as follows: 1. Toxicities on F0 dams in the 2700 mg/kg/day group were salivation, piloerection, and decreases in body weight and food consumption. Seven animals (19.4%) showed severe toxicity and were dead. Toxicity in the 900 mg/kg/day group was a slight decrease in food consumption. The dosage level of 300 mg/kg/day was non-toxic. 2. Toxicities on F1 fetuses in the 2700 mg/kg/day group were a decrease in body weight and an increase in visceral anomalies (main one was ventricular septal defect that might be related to developmental retardation). No toxicities were seen in the 300 and 900 mg/kg/day. 3. In F1 neonates, suppressions of body weight were observed clearly in the male and female 2700 mg/kg/day and slightly in the male 900 mg/kg/day groups. But no changes in parameters of development, function, behavior or reproductive ability were seen in any dosed groups. It was suggested that no effective dose levels of IPD-1151T were 300 mg/kg/day for F0 dams and F1 neonates, and 900 mg/kg/day for F1 fetuses.

Abnormalities, Drug-Induced↗
PubMed1992

[A fifty-two week oral chronic toxicity study of suplatast tosilate (IPD-1151T) in rats].

A 52-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 50, 300 and 1800 mg/kg/day using male and female rats. The results were as follows: 1. In general conditions, transient salivation after each administration and excretions with peculiar smells were noted in both sexes given 1800 mg/kg/day. Since one male and six female rats given 1800 mg/kg/day showed bradypnea, clonic/tonic convulsions, lying on the belly and/or side, subnormal temperature, abnormal gait, paralysis of extremities, they were sacrificed in moribund. 2. The body weight was lowered from the early stage of administration period in both sexes given 1800 mg/kg/day. 3. There were no remarkable changes in food consumption, urinalysis, fecal examination, hematology and ophthalmology. 4. Biochemical examination revealed a decrease in triglyceride in males given 300 mg/kg/day or more. 5. In pathological examination, the animals sacrificed in moribund showed necrosis and degeneration of neurons and/or sponge-like change of neuropile in nucleus caudatus of the cerebrum, necrosis and partial disappearance of granular cells and Purkinje's cells, and swelling of Bergmann's cells in the cerebellum. In survived animals, the relative organ weight in the liver increased in males given 300 mg/kg/day or more and females given 1800 mg/kg/day, and histopathological examination revealed slight vacuolization, hypertrophy of centrilobular hepatocytes in males given 1800 mg/kg/day. Furthermore, in some females, similar changes of the cerebrum and the cerebellum, as mentioned above, were slightly observed. In electron microscopic examination, slight proliferation of smooth endoplasmic reticulum in hepatocytic cytoplasm was observed in males given 1800 mg/kg/day. The necrobiotic changes, such as condensation of nuclear chromatin, increased electron density of cytoplasm and nuclei, mitochondrial accumulation and vacuolization, in the cells possibly derived from small granular cells in the cerebellum were observed in females given 1800 mg/kg/day. The mitochondrial swelling, decreased and dilated rough endoplasmic reticulum, and increased electron density of cytoplasm and nuclei with formation of cytoplasmic vacuole and membranous degenerated structure in neurons of cerebral temporal lobe cortex were observed in females given 1800 mg/kg/day. 6. In a recovery study, electron microscopic examination revealed a slight degeneration of myelinated nerve fibers in the cerebellum in males given 1800 mg/kg/day. On the contrary, there were no remarkable changes in general condition, body weight and various clinical parameters. It was noted that these changes induced by IPD-1151T seemed to be reversible changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1992

[A 52-week chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in dogs].

A chronic 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 using male and female beagle dogs. FUT-187 was orally administered to the dogs at dose levels of 7.5, 15, 30 and 60 mg/kg/day for 52 weeks, followed by 5 weeks' recovery period. Results are summarized as follows: 1. In general conditions, vomiting, salivation and the passage of mucousy stools were observed in dogs given 15 mg/kg/day or more, and diarrhea was observed at 30 mg/kg/day or more. One male given 15 mg/kg/day showed transient pallidity of the oral mucosa, and another male in the same group showed apnea and abdominal breathing. In addition, one male given 30 mg/kg/day was euthanatized due to extreme weakness, as weight loss and pallid oral mucosa, and another male in the same group died after showing acute toxic symptoms such as hyperpnea, tonic convulsion and ataxic gait. 2. Weight gain was slightly suppressed in females given 60 mg/kg/day. No significant changes in food consumption were observed. 3. Hematological examination revealed no statistically significant changes. Decreases in RBC counts, Ht values and Hb concentrations, and increased reticulocyte counts were observed in one male of 15 mg/kg/day group, which also showed pallid oral mucosa, and in one male of the 30 mg/kg/day group, which was euthanatized in a moribund state. 4. Blood biochemistry revealed increased GPT activity in males given 15 and 30 mg/kg/day and females given 60 mg/kg/day, which was accompanied by sporadic increases in GOT, A1P and/or gamma-GTP activities. Males given 30 mg/kg/day or more showed decreased total protein. 5. Hepatic function testing (ICG test) showed no statistically significant changes. One female given 60 mg/kg/day showed increased accumulating concentration of ICG. 6. There were no toxicological changes in urinalysis, fecal occult blood, renal function (PSP clearance), ophthalmological and electro-cardiographic examinations. 7. In pathological examination, inflammatory cell infiltration and microgranuloma formation in liver were noted periportally or perivenularly in both sexes given 15 mg/kg/day or more (except for 30 mg/kg/day males). In the some cases, atrophy, degeneration and necrosis of hepatocytes and/or fibrosis around inflammatory cells and microgranuloma were observed. In the spleen, one male given 15 mg/kg/day and one female given 60 mg/kg/day showed increased plasma cells in the red pulp. In the case sacrificed in a moribund condition, findings in the liver and spleen similar to those in surviving cases were detected, but were more severe, and the liver showed diffuse fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
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 rats].

The toxicity of FUT-187, a synthetic protease inhibitor, was investigated in Sprague-Dawley rats. FUT-187 was given orally to the rats at doses of 2, 10, 50, 250 and 1250 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks for recovery. The results are summarized as follows: In the 1250 mg/kg/day group, 9 out of 20 males died with decreased body weight and exhaustion. Histopathological examination revealed renal papillary necrosis, ulcer in the urinary bladder, hemostatic lesions in the lungs and liver, ulcer or erosion in the stomach, duodenum and jejunum. The surviving animals in this group showed swelling of the limbs due to synovitis, transient salivation immediately after administration, suppression of growth with decreased food consumption. Urinalysis revealed a low pH, increased ketones and bilirubin excretion, dark yellowish change in color, the appearance of "leaflet-shaped" crystals and increased red blood cells and epithelial cells in the urinary sediment, increased water intake, decreased specific gravity and decreased sodium, potassium and chloride in the urine. Hematologically, there was an increase in the white blood cell count. A biochemical analysis of the blood revealed decreased amylase activity, glucose and total protein levels and increased GOT activity and inorganic phosphorus levels. Pathological changes were observed in the pancreas, kidney, digestive tract, urinary bladder and liver. The pancreas showed macroscopical enlargement and increased organ weight. Histopathologically, there were several alterations in the acinar cells, such as vacuolization due to increased fat droplets, nuclear irregularity, prominent nucleoli, irregular arrangement and vesiculation of rough endoplasmic reticulum (rER), dilatation of developed Golgi apparatus and increased free ribosomes. In the kidney, increased weight and pigmentation in the proximal tubular epithelium were noted. Electron microscopically, these pigments were recognized as secondary lysosomes containing filamentous material and electron dense granules within a lucent matrix. In the digestive tract, ulcer or erosion in the stomach and duodenum, and villous proliferation in the small intestine were observed. Furthermore, hyperplasia and vacuolization were noted in the mucosal epithelium of the urinary bladder. In addition, loss of perilobular fat droplets in the liver and increased adrenal weight without histological change were observed. After a 5-week recovery period, these changes disappeared almost completely. In the 250 mg/kg/day group, slight suppression of growth the appearance of "leaflet-shaped" crystals in the urinary , sediment, increased water intake and decreased sodium in the urine were observed. The pancreas showed enlargement, increased weight, acinar cell hypertrophy with increased zymogen granules, fine vacuolization, slight derangement and vesicular of rER, and dilatation of Golgi apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1992

[Reproductive and developmental toxicity studies of FUT-187. (I)--Fertility study in rats with oral administration of FUT-187].

FUT-187 was given orally at 20, 120 and 720 mg/kg during the pre-pairing period (63 days prior to pairing in males and 14 days prior to pairing in females) and the pairing period to male and female rats and in the early stage of pregnancy (days 0 through 7 of gestation) to female rats, and the effects of the test compound on male and female reproductive performance and fetal development were evaluated. One male of the 720 mg/kg group died due to treatment. Temporary salivation was observed in males and females in the 20 mg/kg or more groups. In males, increases in the weight of the pancreas in the 120 mg/kg or more groups and the adrenals in the 720 mg/kg group, a depression of body weight gain and decreases in food intake and weight of the carcass in the 720 mg/kg group were statistically significant in comparison with controls. In females, an increase in the weight of the pancreas in the 120 mg/kg or more groups, a slight depression of body weight gain during the early stage of pregnancy and a decrease in the food intake, and a decrease in the weight of the carcass in the 720 mg/kg group were statistically significant in comparison with controls. No dose-related changes were found in the estrus, copulation, insemination and fertility indices. In fetuses, decreased numbers of corpora lutea, implantation and live fetuses were observed in the 720 mg/kg group. There were no treatment-related abnormalities in fetal mortality, sex ratio, weights of fetuses and placenta, and external and visceral examinations. Based on these results, it is concluded that the no-effect-dose levels of FUT-187 are less than 20 mg/kg for the parents, 720 mg/kg for reproductive performance and 120 mg/kg for fetal development.

Administration, Oral↗
PubMed1992

[Reproductive and developmental toxicity study of 6-amidino-2-naphthyl 4(-)[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187). (II)--Oral administration to rats during the period of fetal organogenesis (prenatal examination)

6-Amidino-2-naphthyl 4(-)[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187) was given orally to pregnant Crj : CD (Sprague-Dawley) rats from days 7 through 17 of gestation at dose levels of 50, 200 and 800 mg/kg/day. In the 800 mg/kg/day group, salivation just after dosing, suppression in body weight gain and decreased food consumption were observed. No external, visceral and skeletal anomalies attributable to FUT-187 were observed in fetuses. From the present result, it is considered that the no-effect dose level of FUT-187 for dams and fetuses are 200 mg/kg/day and 800 mg/kg/day respectively.

Administration, Oral↗
PubMed1992

[Reproductive and developmental toxicity studies of FUT-187. (III)--Postnatal study in rat F1 offspring from dams treated orally with FUT-187 during the period of fetal organogenesis].

A postnatal study of F1 offspring exposed to FUT-187 during fetal organogenesis was carried out using Crj : CD rat. FUT-187 was dosed by gavage at 0, 50, 200 and 800 mg/kg/day from day 7 to 17 of gestation. All pregnant rats were allowed to deliver newborns, and F1 offspring were examined for development indices and reproduction and learning ability. Effects at 800 mg/kg included temporary salivation, body weight depression and decreased food intake. There were no adverse effects on delivery and lactation and no significant changes on neonatal development, growth, reproduction and learning ability in the F1 offspring. These results indicate that the no effect dose level of FUT-187 is 200 mg/kg/day in dams, and 800 mg/kg/day in offspring.

Abnormalities, Drug-Induced↗
PubMed1992

[Reproductive and developmental toxicity studies of FUT-187. (V)--Perinatal and postnatal study in rats with oral administration of FUT-187].

FUT-187 was given orally at 20, 120 and 720 mg/kg to female rats during the perinatal and postnatal periods and the effect on dams and offspring were evaluated. One dam during the terminal period of gestation and 3 dams after delivery in the 720 mg/kg group died due to FUT-187. In dams, an increased pancreas weight in the 20 mg/kg or more groups, temporary salivation after dosing in the 120 mg/kg or more groups, and a depression of body weight gain and decreased food intake and weight of the carcass in the 720 mg/kg group were statistically significant in comparison with controls. In offspring, postnatal death rate in the 720 mg/kg group tended to increased. Decreased body weight gain and delayed appearance of abdominal hair and descent of testis in the 720 mg/kg group were statistically significant in comparison with controls. There were no treatment-related abnormalities in visceral examination, organ weight, skeletal examination, sensory function, behavioral function, learning ability or reproductive function. Based on these results, it is concluded that the no-effect-dose levels of FUT-187 are less than 20 mg/kg for dams, and 120 mg/kg for reproductive performance of dams and offspring development.

Abnormalities, Drug-Induced↗