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A perinatal and postnatal study was performed in female Sprague-Dawley rats treated orally with trandolapril (RU44570) at dosage levels of 3, 30 and 300 mg/kg/day from day 17 of pregnancy to postpartum day 21. In each group, 24 or 25 pregnant female rats were allowed to litter naturally for the postnatal examination of their offspring. Clinical symptoms and mortality attributable to the administration of RU44570 were not observed in the dams (P). In the 30 and 300 mg/kg group, food consumption was slightly lower than that of the control group during the lactation period, however RU44570 did not affect body weight gain. Incidence of dilatation of renal pelvis with higher value in kidney weight was increased in offspring (F1) in the 30 and 300 mg/kg dosage groups, and water consumption at the same dosage groups was higher than that of the control group. Body weight gain in offspring (F1) was depressed in each treated group and viability of offspring (F1) from postpartum day 0 to day 4 was slightly decreased in the 30 and 300 mg/kg dosage groups comparing with that of the control group. No adverse effects were observed on the other postnatal development of the offspring, such as differentiation, sexual maturation, reflex, motor activity, emotionality, learning ability and reproductive performance. No adverse effects were detected in the second generation offspring (F2). The results suggest that the non-effective dose of RU44570 is 3 mg/kg for dams (P), lower than 3 mg/kg for development in offspring and 300 mg for fetuses (F2), respectively.

1) The chronic toxicity of (-)-(2S, 3aR, 7aS)-1-[(S)-N-[(S)-1- ethoxycarbonyl-3-phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic++ + acid (trandolapril: RU44570), a novel angiotensin-converting enzyme blocking antihypertensive drug, was assessed in rats by oral administration for 12 months at dosage levels of 0.05, 0.25, 2.50 and 25.00 mg/kg/day, comparing with the control animals received 0.5% methylcellulose solution. Reversibility of the drug-induced changes was also examined by 3 months' withdrawal following the administration period. 2) There was no death or general symptom that was thought to be attributable to the administration of RU44570. 3) The body weight gain was significantly suppressed from 1st week to the end of administration period in male animals of the dosage groups of 2.50 mg/kg or more and from week 1 to 15 of administration in female animals of the 25.00 mg/kg dosage group. During the withdrawal period, the difference of the body weights between these groups and control was reduced and that was never statistically significant. 4) The food consumption generally tended to be lowered in male animals of the dosage groups of 2.50 mg/kg or more throughout the administration period. The values were significantly different from that of control group on almost all measurement points from week 2 to 34 of administration. The difference of the food consumption of these groups from control group tended to be smaller thereafter, although significant difference was seen sporadically. Male animals of the 0.05 and 0.25 mg/kg dosage groups also showed the tendency of decreased food consumption infrequently. There was no constant tendency of fluctuation in the food consumption among the each RU44570 treated group during the withdrawal period. 5) The water consumption increased significantly in male animals of the 25.00 mg/kg dosage group from 1st week to the end of administration period. Male animals of the 2.50 mg/kg dosage group showed similar high value of the water consumption but the degree was lesser than that of 25.00 mg/kg dosage group. Although female animals of the 25.00 mg/kg dosage group showed significantly increased water consumption from week 3 to 4 of administration, they began to show decreasing tendency from approximately week 10 of administration conversely. From week 26 of administration, the water consumption of this group significantly decreased frequently comparing with that of control group. Female animals of the 2.50 mg/kg dosage group showed similar decrease in water consumption from approximately week 26 of administration.(ABSTRACT TRUNCATED AT 400 WORDS)

A fertility study was performed in Sprague-Dawley rats treated orally with trandolapril (RU44570) at the dosage levels of 3, 30 and 300 mg/kg/day. The male rats were treated for 63 days before mating and during the mating period. The female rats were treated from 14 days before mating to day 7 of pregnancy. Each 24 male and female rats in the same dosage group were mated and female rats were sacrificed on day 20 of pregnancy for the examination of their fetuses. No abnormal findings were observed in symptom during the administration period, however body weight gain and food consumption in both male and female animals of treated groups were lower than control group. Any adverse effects on reproductive performance were not detected. Numbers of implantations and live fetuses were decreased slightly at 30 and 300 mg/kg dosage group comparing with those of the control group. However, RU44570 did not affect fetal mortality, growth of fetuses, or the incidence of external, visceral or skeletal malformation of the fetuses. From these results, it is suggested that non-effective dose level of RU44570 is lower than 3 mg/kg for general toxicity in parent animals, 300 mg/kg for reproductive ability in parent animals, and 3 mg/kg for development in embryos and fetuses, respectively.

A teratogenicity study was performed in Sprague-Dawley rats treated orally with trandolapril (RU44570) at the dosage levels of 3, 30 and 300 mg/kg/day from day 7 to day 17 of pregnancy. In each group, 24 or 25 female rats were sacrificed on day 20 of pregnancy for the examination of their fetuses, and 14 or 15 female rats were allowed to litter naturally for the postnatal examination of their offspring. Clinical symptoms and mortality attributable to administration of RU44570 were not observed in the dams (P). Body weight gain and food consumption were slightly depressed in the 300 mg/kg dosage group comparing with those of control group. However, RU44570 showed no adverse effect on the fetal mortality, prenatal development or teratogenicity of the fetuses. Incidence of dilatation of renal pelvis was slightly increased in fetuses in the 300 mg/kg dosage group comparing with that of the control group. However, the offspring in each treated group showed similar incidence of this abnormality to that of the control group in more advanced age. Therefore, these changes were considered to be reversible. No adverse effects on the postnatal development of the offspring containing reproductive ability were detected. The results suggest that non-effective dose level of RU44570 is 30 mg/kg for dams, 30 mg/kg for fetuses and 300 mg/kg for development in offspring, respectively.

The effects of sex hormone on diabetic conditions were investigated in WBN/Kob strain rats, i.e., castrated or spayed, hormone-treated, and non-treated rats. The effects of sex hormone on glycosuria, body-weight change, glucose tolerance and histopathology of the pancreas were compared among these animals. There were no abnormal changes in these parameters in the non-treated females and estrogen-treated males. The glycosuria began to be observed from the age of about 30 weeks in the non-treated group and from the age of 52 weeks in the castrated group. In the female animals, this symptom began to appear from the age of 55 weeks in the testosterone-treated group and from the age of 72 weeks in the spayed group. Before the onset of the diabetic symptoms, glucose tolerance was impaired in these animals. Body weights of the castrated and estrogen-treated males were lower than that of the non-treated males, especially in the estrogen-treated males. Those of the spayed and testosterone-treated females were much heavier than that of the non-treated females. Testosterone treatment accelerated body-weight gain in the spayed female animals. Histopathological examination of the pancreas revealed atrophy of the aciner tissue and atrophy and disappearance of the islet cells similar to those of the non-treated WBN/Kob male rats in the castrated males, spayed females and testosterone-treated females. However, these changes were not observed in the non-treated females or estrogen-treated males. These findings suggest that female hormone suppressed the onset of hyperglycemia along with glycosuria and male hormone accelerates the onset of hyperglycemia in the WBN/Kob rats.

Bilateral occlusion of the carotid arteries (BCAO) killed 52% of the male ddY mice (N = 86) and 77% of the ICR mice (N = 96) within 10 min, and the mean survival time of the ddY strain recorded for the 10 min was significantly longer than the time of the ICR strain. Among animals that survived longer than 1 hr after BCAO, some (5 of ddY and 3 of ICR) were able to survive for more than 24 hr. All of the neurobehavioral and histopathological signs developed by BCAO and in most cases followed by death were found to be also inducible by unilateral occlusion alone, although this was in a small fraction of mice. The brain levels of ATP, glucose and acetylcholine significantly decreased in mice that died within 10 min after BCAO, while none of these changes were detectable in mice surviving BCAO for 1 hr, just as in mice that died by carbon monoxide or ether inhalation. The results obtained herein indicate that mice may not be homogeneous in the functional level of the collateral route of blood supply to the brain tissue and/or in the sensitivity toward the ischemia-inducible lethality.

Almost all the male animals of WBN/Kob rat strain show the diabetic syndrome whereas none of the female animals develop such diseased conditions even at elder age. We investigated the effect of sex hormones on the onset of diabetic syndrome of this rat strain by comparing the results of body weight gain and various clinical tests such as glucose tolerance, serum biochemistry and histopathology of spayed female rats with those of non-treated and sham-operated female animals kept until 88-week-old. Non-treated and sham-operated female animals had shown no abnormal result even at 88-week-old. Spayed female animals began to reveal glucosuria associated with polydipsia and polyuria from 72-week-old, and gradually developed emaciation and cataract. Increased body weight gain, impaired glucose tolerance and lasting hyperglycemia were observed prior to the onset of the symptoms. Pancreatic changes consisted of atrophy of acinar tissue and atrophy or disappearance of islet tissue attributable to clinical data also were detected in spayed female animals. These diabetic syndrome and pancreatic change were analogous to those of aged male WBN/Kob rats but the onset of spayed females was delayed and less severe. Present results suggest that female sex hormones are protective from the onset of diabetic syndrome of WBN/Kob rats.

The chronic oral toxicity of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was studied in beagle dogs. Groups of 6 males and 6 females were treated with P-4 at doses of 0, 0.3, 1, 3, 9 mg/kg/day for one year and thereafter 2 animals of both sexes in each group were placed on withdrawal for one month. During administration and recovery period, no death occurred in any dosed animals. As a toxic sign, only the frequency of vomiting was increased in animals of 1, 3 and 9 mg/kg/day groups. Body weight, food and water consumption were not affected by the P-4 administration. In serum chemical examinations, gamma-GTP activity was increased in both sexes of 9 mg/kg/day group at 6 month of administration. Further decrease in total and free cholesterol, triglyceride and phospholipid, increase in GPT activity were detected in some animals of 9 mg/kg/day group at 12 month of administration. In addition decreasing tendency in levels of albumin was noted in males of 9 mg/kg/day group at 9 and 12 month of administration. And also, a gradual increase in total protein level and a gradual decrease in alkaline phosphatase activity were seen in control group, but in females or males of 9 mg/kg/day group, those changes were mild. Urine pH rised slightly in females of 3 mg/kg/day group and in both sexes of 9 mg/kg/day group. No specific findings attributable to P-4 treatment were detected in ECG, heart rate, funduscopy, hematology, fecal occult blood test and necropsy. The absolute and/or relative liver weight in males of 3 and 9 mg/kg/day groups were significantly increased. Light-microscopically, the hypertrophy of hepatocytes characterized by homogenization and enlargement of cytoplasmic space, and concentric inclusions in hepatocytic cytoplasm were detected in both sexes of 3 and 9 mg/kg/day groups. Corresponding to these microscopical findings, the following changes were observed electron-microscopically, the proliferation of smooth surfaced endoplasmic reticulum in hepatocytes in both sexes of 1, 3 and 9 mg/kg/day groups, lamellar bodies in hepatocytes in females of 3 mg/kg/day group, and in both sexes of 9 mg/kg/day group, and annulate lamellae in hepatocytes were detected in one female of 9 mg/kg/day group. After the recovery period, the above mentioned abnormalities were markedly attenuated or disappeared except the changes in hepatocytes. From these results, it seemed that 9 mg/kg/day of P-4 might be safety dose.(ABSTRACT TRUNCATED AT 400 WORDS)

A teratogenicity study was performed in New Zealand white rabbits by oral administration of propiverine hydrochloride (P-4) at dose levels of 0 (control), 2.4, 12 and 60 mg/kg/day to dams from day 6 to day 18 of pregnancy. Thirteen or fifteen pregnant rabbits in each group were sacrificed on day 29 of pregnancy for examination of their fetuses. In dams, the dose of 60 mg/kg caused mydriasis, body weight loss or decreased body weight gain and reduced food and water intakes. Autopsy and weighing of organ weight revealed no evidence due to drug administration in any group. There were no significant differences in embryo-fetal mortality, fetal body weight, or incidences of external, visceral or skeletal anomalies and skeletal variation between treated and control animals. The compound had no lethal effects on the embryos and no growth-inhibiting or teratogenic effects on the fetuses. The results suggest that the non-effective dose level of P-4 is 12 mg/kg/day in maternal animals and 60 mg/kg/day in fetuses.

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.

Spontaneous, retinal degeneration in the WBN/Kob rat, a new diabetic strain, was examined by behavior pattern, electroretinogram (ERG) and histopathology. Histopathological evidence of retinal degeneration was first detected at about 30 weeks of age in male and female rats. The earliest change in the retina was loss of rads and cones, and the inner layer was gradually involved. The retina showed marked atrophy in the thinned inner plexiform layer and a decreased number of ganglionic cells by 90 weeks. Severe retinal change was observed in almost all rats over 90 weeks old. Prior to the onset of histological change, the ERG showed prominent change. Amplitude of a- and b-waves began to be reduced at 17 weeks and was non-recordable at 32 weeks. This retinal abnormality was thought to be hereditary, but further investigation is needed to clarify the relationship between the genetic background of this change and diabetes.

A Y-shaped test box was designed for the screening of visual abnormality using negative phototaxis in normal rats. Its availability was determined by examination of 100 animals belonging to non-treated, eyelids-sutured, and eyeballs-enucleated groups. Two kinds of examination were undertaken, the first being observation of the general behavior of the animals in the box for one minute. The second was 4 trials at selection of the dark area of the box given to each animal. In each examination many animals could be tested in a short time. The behavioral pattern of the eyelids-sutured and the eyeballs-enucleated groups was significantly different from that of the non-treated group. The selection rate for darkness by non-treated, eyelids-sutured and enucleated groups in the second examination was 97.5%, 84.5, and 50.0 percent, respectively. Therefore successful estimation could be possible by both procedures and it was possible to numerize the gained value and analyze statistically in the second examination. It was concluded that this simplified method for testing visual function should prove very useful as a behavioral teratology screening test in routine reproduction studies.

The chronic intravenous toxicity of cefodizime sodium (THR-221) was studied in beagle dogs. Groups of 6 males and 6 females were treated with THR-221 at doses of 0 (saline), 200, 400, 800 and 1600 mg/kg/day for 6 months. The THR-221 related symptoms were vomiting, excessive drinking behavior and salivation. The paleness of the visible mucosa and discoloration of vascular color by funduscopy due to systemic anemia were observed in one animal each of 800 and 1600 mg/kg/day groups. Body weight was depressed transiently or continuously in a few animals of 400-1600 mg/kg/day groups. The hematological, serum chemical and urinalysis findings in a few animals of 400-1600 mg/kg/day groups revealed decreases in RBC count, PCV and hemoglobin, an increase in reticulocyte count, a decrease in WBC count, a decrease in platelet count, slight increase in TP, and albumin, a decrease in AlP, and an increase in urinary Na. Light microscopically, deposition of hemosiderin and increased extramedullary hematopoiesis in the liver and spleen, and deposition of fibroid substance in the white pulp of the spleen and diffuse fibrosis in the bone marrows were detected in a few animals of 800 and 1600 mg/kg/day groups. Electron microscopically, no significant toxic changes were observed. The maximum nontoxic doses of THR-221 are estimated as 200 mg/kg/day in male and less than 200 mg/kg/day in female.

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.

A newly designed Y-shaped box was previously reported by authors to be useful for a screening test of visual abnormality in rats because of easy numerization and statistical analysis of the results. In the present paper, the relationship between the intensity of illumination and the negative phototaxic response were examined. The total selection rate for the dark area (total time of selecting dark area/total trials) of non-treated rats under 30 lux illumination was 98% and identical wit the result of those under 1600 lux. The selecting rates of non-treated rats under the illumination of 15, 10, 7.5, 5 and 1.25 lux were 95, 93, 89, 82 and 67%, respectively. On the other hand those of dark-adapted rats one hour under 15, 7.5 and 5 lux showed 98, 95 and 92%, respectively. From these results, the critical intensities of illumination-unaffected selection rate for darkness in non-treated and dark-adapted rats were estimated at 30 and 15 lux, respectively. There was an obvious effect of dark-adaptation on the visual ability of rats. The selection rate of eyelid-sutured rats under 30 lux was 52%, an approximate theoretical value of true blindness, but it was 85% under 1600 lux. It is suggested that a more exact detection of visual abnormality would be possible under the critical intensity of illumination-unaffected selection rate for darkness.

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.