Suppression Of Body Weight Gain Research Articles

Trimethylphosphate: a 30-month chronic toxicity/carcinogenicity study in Wistar rats with administration in drinking water.

Trimethylphosphate (TMPO) was administered to 50 male and 50 female Wistar rats through their drinking water at doses of 0, 1, 10, or 100 mg/kg body weight up to 30 months. The dosage of 100 mg/kg was reduced to 50 mg/kg in week 54 for reasons of tolerance, and the animals were euthanized in week 100. Additional 10 animals per dose and sex were treated for 12 months and then euthanized for interim analysis. Weakness of the hind limbs, increased incidences of sunken flanks, distended abdomen, and poor general condition were observed in both sexes of the 100/50 mg/kg group beginning with week 46. Food intake was reduced in high dose males. At 10 mg/kg body weights were up to 10% (males) and at 100/50 mg/kg up to 20% (males) or 15% (females) lower than in controls. Mortality was not affected in animals receiving up to 10 mg/kg. At 100/50 mg/kg it was markedly increased, reaching about 70% at week 100. Relatively slight hematologic changes (reduced hemoglobin, hematocrit, erythrocyte counts, increased reticulocyte numbers, and thrombocyte counts as well as a shift in the differential blood count) at 100/50 mg/kg are interpreted as changes most probably secondary to the other toxic effects. Increased cholesterol concentrations in plasma, shifts in the serum protein electrophoresis (males), increased organ weights (females), and an increased incidence of necroses and lymphocytic infiltrations point to a treatment-related effect on the liver at 100/50 mg/kg. Slightly increased protein excretion, increased relative kidney weights, and an increased incidence of chronic progressive nephropathy are considered treatment-related but rather secondary effects at 100/50 mg/kg. At 100/50 mg/kg an increased incidence and severity of bilateral tubular atrophy in the testes was diagnosed. The most important toxic effect was neurotoxicity, consisting of degeneration and loss of nerve fibers in the peripheral nerves and the spinal cord, associated with myopathic changes, and occurring at 100/50 mg/kg. The no-observed-adverse-effect-level, based on the suppression of body weight gain, is 1 mg/kg in males and 10 mg/kg in females. The incidence, time of occurrence, spectrum of types, and localizations of tumors provided no indication of a tumorigenic/carcinogenic effect of the test substance. TMPO is therefore considered not to be carcinogenic in Wistar rats.

Evidence for a Depressive-like State Induced by Repeated Saline Injections in Fischer 344 Rats

We investigated the behavioral changes induced by mild stress in animals that may be relatively susceptible to a depressive-like state, the Fischer 344 rat strain. The mild stress of repeated handling and intraperitoneal (IP) injections with saline (2 ml/kg, twice a day for 14 days) elicited a moderate suppression of body weight gain, a decrease in open field activity, and a prolonged immobility during the tail suspension test in Fischer 344 rats compared with Sprague–Dawley rats. Chronic treatment of Fischer 344 rats with imipramine (10 mg/kg IP, twice a day for 14 days) effectively suppressed open field activity and prolonged immobility. These results suggest that repeated saline injections may be a mild stressor in these rats. In the Fischer 344 strain, which may be vulnerable to the effects of mild stressors, repeated saline injections might induce a depressive-like state and could presumably represent an experimental model for depression.

Repeated dose toxicity studies of taltirelin tetrahydrate (TA-0910) with oral administration to dogs

Taltirelin tetrahydrate (TA-0910), novel thyrotropin-releasing hormone (TRH) analogue, was orally administered to dogs as dose levels 0.5, 5, and 50 mg/kg for 13 weeks and 0.15, 1.5 and 15 mg/kg for 52 weeks. Blood concentrations of test substance measured in 52-week study revealed that absorption of TA-0910 was with dose-dependent manner and not changed through the treatment period. These toxicokinetics suggested that there were no alterations on metabolism of TA-0910 with repeated treatment. The animals receiving 5 or 50 mg/kg showed decrease in body weight or suppression of body weight gain, and decrease in food intake (13-week study). As an abnormality in general conditions, vomiting and salivation (5 mg/kg or more, both in 13- and 52-week studies), increase in behavior as water intake (5 mg/kg or more, 13-week study), and hyperlocomotion (50 mg/kg) were observed. Elevating GPT values were noted temporally in the animals treated with 5 mg/kg or more (both in 13- and 52-week studies) without abnormal findings in histopathology. The thyroid weights were increased in treated animals receiving 5 or 50 mg/kg in 13-week study, but no histopathological changes were noted. Electron microscopy revealed dilatation of granular endoplasmic reticulums in follicular cells of thyroid from 50 mg/kg group in 13-week study. It was concluded that no-effect levels of 13- and 52-week studies were 0.5 mg/kg and 1.5 mg/kg, respectively.

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

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

Unusual increase of lipogenesis in rat white adipose tissue after multiple cycles of starvation-refeeding

The purpose of the study was to determine the response of liver and brown (BAT) and white (WAT) adipose tissue lipogenesis and total body weight in rats subjected to multiple cycles of 3 days of fasting and 3 days of refeeding. Rats fasted for 3 days showed significant reduction in body weight. These changes were reversed on 3 days' refeeding. Body weight was much higher in rats fed ad libitum than in animals experiencing more than one cycle of 3 days of fasting followed by 3 days of refeeding. Despite the significant body weight reduction, an unusual increase of lipogenesis in WAT was found after multiple cycles of starvation-refeeding of rats on standard laboratory diet. The rate of lipogenesis in the liver and BAT was also elevated but to a much smaller extent. A parallel increase in enzymatic activities related to fatty acid synthesis, ie, fatty acid synthase, acetyl-coenzyme A carboxylase, adenosine triphosphate (ATP)-citrate lyase, NADP-linked malic enzyme, and hexose monophosphate shunt dehydrogenases, suggests that the increased rate of lipogenesis in WAT is a consequence of increased lipogenic enzyme activities. These data suggest that upregulation of WAT lipogenesis occurs after the multiple cycles of the starvation-refeeding protocol. An unusual increase of lipogenesis in rat WAT may have a survival advantage, because starved-refed rats must develop the ability to ingest large amounts of food during a refeeding period to store it in a convenient form than can be used as an oxidizable substrate during a period of starvation. Moreover, these results suggest that it is possible to develop appropriate starvation-refeeding conditions that may inhibit body weight gain.

Morphometric and immunohistochemical studies on atrophic changes in lympho-hematopoietic organs of rats treated with piperonyl butoxide or subjected to dietary restriction.

Changes observed in lympho-hematopoietic organs in rats given piperonyl butoxide may be attributable either to direct toxic effects or to undernutrition. Male F344 rats were therefore fed diet containing 2.5% piperonyl butoxide or subjected to a 64% restriction of food intake for 2 weeks. Marked inhibition of body weight gain, decreased white blood cell count, depletion of T/B lymphocytes in lymphoid tissues, hypoplasia of the bone marrow, and decreased proliferating cell nuclear antigen (PCNA) labeling indices in these tissues were seen in both dietary restriction and 2.5% piperonyl butoxide groups. The depletion of T lymphocytes in the thymus and spleen was stronger in the 2.5% piperonyl butoxide group, as indicated by PCNA labeling indices and image analysis of T lymphocyte areas of the spleen, however, the toxicological profile observed for the chemically treated group was essentially the same as for animals on the restricted diet. These results suggest that the lympho-hematopoietic findings in rats receiving 2.5% piperonyl butoxide are probably due to undernutrition resulting from a reduced food intake.

Chronic hypobaric hypoxia decreases intracellular and total body water in microswine

The effects of hypobaric hypoxia on body fluid distribution were studied in five unanesthetized immature microswine (body weight 17.1 ± 1.5 kg, mean ± SEM) at sea level and after 23 days of simulated altitude exposure (427 Torr, 4600 m, 24°C, 50% RH). Total body water (TBW), extracellular fluid volume (ECF), and plasma volume (PV) were determined with D 2O, NaBr, and indocyanine green, respectively. Intracellular fluid volume (ICF = TBW − ECF) and interstitial fluid volume (ISF = ECF − PV) were calculated. Hypoxia resulted in characteristic decreases ( P < 0.05) in arterial PO 2 and PCO 2, and an increase in hemoglobin concentration. Chronic exposure to hypobaric hypoxia elicited significant ( P < 0.05) decrements in body weight gain (− 14%), TBW (− 11%, 12.5 vs 11.3 L), ICF volume (− 13%, 8.9 vs 7.8 L) and PV (− 28%, 0.82 vs 0.57 L). Although the ECF was unaffected (3.66 vs 3.57 L), the ISF was significantly increased (+ 6%, 2.83 vs 3.22 L) ( P < 0.05). Decreased TBW accounted for 51% of the expected reduction in body mass. These results suggest that the suppression in body weight gain is partially accounted for by decreases in TBW, ICF and PV. In addition the apparent elevation of ISF occurring concurrently with decreases in ICF and PV may be related to the development of edema, which can accompany exposure to high altitude.

An attenuated alpha-1 potentiation of beta adrenoceptor-stimulated cyclic AMP formation after repeated saline injections in fischer 344 strain rats

We investigated the behavioral and neurochemical features of Fischer 344 strain rats in which a depressive state was induced by repeated handling and saline injections as a mild Stressor. The repeated intraperitoneal injections of saline (2 ml/kg, twice a day for 14 days) elicited a moderate suppression of body weight gain, a decrease in their open field activity and a prolonged immobility in the tail suspension test. In the stress-exposed rats, the tissue content of norepinephrine (NE) was increased in the cerebral cortex and hypothalamus, whereas that of dopamine or serotonin was not affected. Although the stress exposure did not affect the binding properties of either the alpha-1 or beta adrenoceptors, it suppressed cAMP formation stimulated by NE, but not by isoproterenol or forskolin, in the cerebral cortical slices. In the presence of prazosin or phorbol ester, the difference in NE-stimulated cAMP formation between the control and the stress groups was totally abolished. Phenylephrine enhanced isoproterenol-stimulated cAMP formation in the control but not in the stress group. From these results, it is postulated that the alpha-1 potentiation of beta adrenoceptor-stimulated cAMP formation was attenuated in the stress group. These findings suggest that the manipulation of mild Stressor with repeated handling and saline injections to Fischer 344 rats elicits a depressive state characterized by the behavioral changes and the attenuated alpha-1 potentiation in the cerebral cortex, and that this manipulation might be available for the study of the stress-induced depressive state as a generally acceptable mild stress model.

Clinical studies with mazindol.

An anoerxiant, mazindol suppresses food intake by 1) stimulating beta-adrenergic receptors, 2) inhibiting the feeding center and, 3) stimulating the satiety center in the hypothalamus. In Japan, mazindol is available for clinical use. We examined the effects of mazindol on 1) body weight, appetite, and abnormalities of obesity-related diseases in long-term use 2) maintenance of the reduced body weight after very-low-calorie diet (VLCD) therapy 3) combined use with VLCD therapy and, 4) inhibition of body weight gain in Prader-Willi syndrome. In long-term effects of mazindol, the average reduction of individual body weight was around 6.8 kg. The appetite of 59% of obese subjects was moderately suppressed. Systolic blood pressure, serum GOT, serum triglyceride, serum cholesterol, and glucose tolerance were also improved. With mazindol, 53.3% of obese subjects kept the reduced body weight after VLCD, in contrast, 20.0% of them kept it without mazindol. Combined use of mazindol with VLCD made the VLCD therapy more effective in outpatients. Two of 3 patients with Prader-Willi syndrome inhibited their body weight gain with mazindol. Thus, mazindol produced positive effects in these studies, although the effects were limited.

Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression.

The effects of long-term corticotropin-releasing hormone (CRH) infusion in the lateral ventricle of the rat on hypothalamic-pituitary-adrenocortical (HPA) axis parameters and on the immune system function were studied. Compared with infusion of vehicle, the CRH treatment produced a sustained overactivity of the HPA axis, as evidenced by elevated plasma ACTH and corticosterone levels, increased anterior pituitary POMC messenger RNA (mRNA) expression, and adrenal enlargement. Long-term CRH treatment also inhibited body weight gain and reduced thymus and spleen weight. In the CRH-treated animals, both Concanavalin A (Con A)-induced T lymphocyte proliferation and lipopolysaccharide (LPS)-induced B lymphocyte mitogenesis was largely suppressed. Surprisingly, interleukin-2 (IL-2) levels were higher in supernatants of splenocyte cultures from CRH-treated rats than in those of control animals. However, IL-2 receptor alpha chain (IL-2R alpha) mRNA expression after Con A stimulation was highly suppressed in the CRH-treated animals. In addition, Northern blot analysis of RNA from splenocytes isolated from spleens of CRH-treated rats revealed a marked expression of IL-1 beta mRNA, in contrast to the barely detectable levels of this cytokine in control animals. Moreover, incubation of total splenocytes and spleen macrophages with LPS resulted in an enhanced induction of IL-1 beta mRNA in cells of CRH-treated rats compared with that of control animals. When adrenalectomized rats were treated with CRH or vehicle, the effects of the CRH treatment on T and B cell proliferation, IL-2 production, and IL-1 beta mRNA expression were abolished. Thus, a continuously increased HPA axis drive results in disparate changes in immune system function. Whether the observed changes in cytokine expression should be regarded as physiologically adaptive adjustments in support of immune function or as potentially pathological anomalies remains to be elucidated.

Long-term intracerebroventricular corticotropin-releasing hormone administration induces distinct changes in rat splenocyte activation and cytokine expression

The effects of long-term corticotropin-releasing hormone (CRH) infusion in the lateral ventricle of the rat on hypothalamic-pituitary-adrenocortical (HPA) axis parameters and on the immune system function were studied. Compared with infusion of vehicle, the CRH treatment produced a sustained overactivity of the HPA axis, as evidenced by elevated plasma ACTH and corticosterone levels, increased anterior pituitary POMC messenger RNA (mRNA) expression, and adrenal enlargement. Long-term CRH treatment also inhibited body weight gain and reduced thymus and spleen weight. In the CRH-treated animals, both Concanavalin A (Con A)-induced T lymphocyte proliferation and lipopolysaccharide (LPS)-induced B lymphocyte mitogenesis was largely suppressed. Surprisingly, interleukin-2 (IL-2) levels were higher in supernatants of splenocyte cultures from CRH-treated rats than in those of control animals. However, IL-2 receptor alpha chain (IL-2R alpha) mRNA expression after Con A stimulation was highly suppressed in the CRH-treated animals. In addition, Northern blot analysis of RNA from splenocytes isolated from spleens of CRH-treated rats revealed a marked expression of IL-1 beta mRNA, in contrast to the barely detectable levels of this cytokine in control animals. Moreover, incubation of total splenocytes and spleen macrophages with LPS resulted in an enhanced induction of IL-1 beta mRNA in cells of CRH-treated rats compared with that of control animals. When adrenalectomized rats were treated with CRH or vehicle, the effects of the CRH treatment on T and B cell proliferation, IL-2 production, and IL-1 beta mRNA expression were abolished. Thus, a continuously increased HPA axis drive results in disparate changes in immune system function. Whether the observed changes in cytokine expression should be regarded as physiologically adaptive adjustments in support of immune function or as potentially pathological anomalies remains to be elucidated.

Pancreatic acinar cell neoplasia in male Wistar rats following 2 years of gabapentin exposure

Gabapentin, an anticonvulsant agent designated chemically as 1-(aminomethyl)-cyclohexaneacetic acid, was evaluated in a 2-year tumor bioassay in male Wistar rats. Three groups of 50 rats were fed gabapentin at 250, 1000 and 2000 mg/kg in the diet for 104 weeks. A fourth group was fed diet without drug. All rats were subjected to full histopathological evaluation. Body weight gain suppression occurred at 1000 and 2000 mg/kg. Survival was comparable across all groups. There was a treatment-related increase in the number of pancreatic acinar cell carcinomas; 0, 4, 3 and 8 of these carcinomas were observed in the control, 250, 1000 and 2000 mg/kg groups, respectively. There were no other increases in other tumor types, and there were no tumor increases in female rats. The frequency of pancreatic acinar cell hyperplasia was similar in treated and control groups. Biologically, the pancreatic carcinomas were not invasive, did not metastasize, were of late onset and did not compromise survival. Thus, gabapentin was a carcinogen in male Wistar rats. However, the tumorigenic response was of low-grade because it constituted a late tumor response which required very high doses. We reported recently that mice treated with gabapentin had no increase in pancreatic tumors. Therefore, neoplastic development was confined to the pancreas in a single sex and species of rodent. Consequently, gabapentin at therapeutic doses poses a low carcinogenic risk to humans.

Collaborative work to determine the optimal administration period and parameters to detect drug effects on male rat fertility--study on estradiol benzoate effects.

In order to examine the optimal administration period and parameters for male fertility assessment, male rats were subcutaneously administered 0.2, 2 or 20 micrograms/kg of estradiol benzoate (E2B), a known testicular toxicant, for 4 weeks or 9 weeks before mating. After 4 weeks administration, suppression of body weight gain and food consumption, decreases in prostate and seminal vesicle weights, atrophy of Leydig cells, and mature spermatid retention at stages IX, X and XI were observed in the 2 and 20 micrograms/kg groups. In the 20, micrograms/kg group, decreases in epididymides weight and copulation index were also found but the number of sperm and sperm motility were not affected. In the 0.2 micrograms/kg group, no changes were noted in any parameters. After 9 weeks administration, decreases in testis weight and the number and motility of sperm were observed in the 20, micrograms/kg group, in addition to the changes found after 4 weeks administration. These results suggest that detailed histopathological evaluation and determination of accessory sex organ weights are sensitive for evaluating the effects of E2B on male fertility. Results with the 4-weeks treatment were comparable to those with the 9-weeks treatment in terms of these parameters.

Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits.

The developmental toxicity of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, was investigated in pregnant rats and rabbits given daily oral doses during organogenesis. Rats received 0, 10, 100, or 300 mg/kg on days 6-15 of gestation, and rabbits received 0, 10, 50, or 100 mg/kg on days 6-18 of gestation. Maternal and fetal parameters were evaluated on day 20 (rats) or 29 (rabbits) of gestation. Live fetuses were examined for external, visceral, and skeletal malformations and variations. At 300 mg/kg in rats, 1 treatment-related death occurred on day 12 of gestation, and maternal body weight gain and food consumption were decreased during treatment (43% and 23%, respectively). In addition, 1 animal at 300 mg/kg had total litter resorption. Increased postimplantation loss (not statistically significant) and slightly decreased fetal body weight (statistically significant only in males) were also observed at 300 mg/kg. There were no significant differences between treated and control groups in the incidence of fetal malformations or variations. No maternal or developmental toxicity was observed in rats at 10 or 100 mg/kg. In rabbits, marked maternal toxicity (7 deaths, body weight loss during and after treatment, and decreased food consumption) and abortion occurred at 100 mg/kg. At 50 mg/kg, maternal toxicity (2 deaths and 72% body weight gain suppression) and abortion also occurred. There were no treatment-related effects on live litter size or sex ratio. At 50 and 100 mg/kg, nonstatistically significant increases in postimplantation loss and decreases in gravid uterine weight were observed, and at 100 mg/kg, decreases in fetal body weight were observed relative to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of long-term dietary supplement of tea polyphenols on lipid peroxide levels in rats

We examined the effects of tea polyphenols (TP) on the body weight gain and contents of lipids and lipid peroxides in rat plasma, kidney and liver. The supplementation of TP (0.5% and 1.0%) in the diet was performed from weanling (3 weeks of age) to 19 months old. A significant suppression of body weight gain was observed only at 7–11 weeks of age, but there were no significant changes in liver and kidney weight between control group and TP-feeding group (TP group). Daily food intake of animals in two TP groups was almost the same as the control group.

Theobromine toxicity on sertoli cells and comparison with cocoa extract in male rats

The target cell(s) of theobromine toxicity on rat testes and reproductive toxicity induced by pure theobromine and cocoa extract are evaluated in the present studies. Theobromine (500 mg kg × 7 days) inhibited body weight gain in treated rats. Decreased cauda epididymal sperm reserve (38%), seminiferous tubule fluid (STF) volume (33%), lactate concentration in STF (22%), inhibition of binding activity of androgen binding protein (ABP, 21%) and reduced ABP content in STF were also observed in theobromine-treated animals. Cocoa extract containing an equivalent amount of theobromine did not produce significant toxicity in treated rats. Theobromine concentrations in serum and testes from pure theobromine-treated rats were 1.8- and 1.6-fold higher, respectively, than that in rats treated with cocoa extract. The results support Sertoli cells as the primary target cells of theobromine toxicity. The lower theobromine concentrations in serum and testes of cocoa extract-treated rats could account for the lower toxicity in these animals.

Acute, subchronic and chronic toxicity studies of a synthetic antioxidant, 2,2'-methylenebis(4-methyl-6-tert-butylphenol) in rats.

General toxicity studies on 2,2'-methylenebis(4-methyl-6-tert-butylphenol) (MBMBP) were conducted using male and female Wistar rats. LD50 values were greater than 5 g/kg BW by oral administration for both sexes. Diarrhea was observed until 5 days. In the subchronic test, rats were fed diet containing MBMBP at 0, 0.12, 0.6 or 3.0% for 12 weeks. Severe suppression of body weight gain was observed in both sexes of 0.6 and 3.0% groups. Death accompanied by hemorrhage from nasal cavity was observed in 0.6 and 3.0% males and 3.0% females. Dose-dependent toxicity to the liver in both sexes was observed in blood chemical analysis. Histopathologically, testicular atrophy and decrease of spermatogenesis were dose- and time-dependently observed in all treated males. Atrophy of ovaries was evident in 0.6 and 3.0% females. Thymus atrophy and bone marrow hypoplasia were observed in both sexes of 0.6 and 3.0% groups. In the chronic test, rats were fed diet containing MBMBP at 0, 0.01, 0.03 and 0.1% for 18 months. Body weight gain was only suppressed in both sexes receiving 0.1%. Histopathologically, testicular atrophy and decrease of spermatogenesis were apparent in 0.1% males. No neoplastic response by MBMBP administration was noted. NOAEL was concluded to be 0.03% in the diet (12.7 mg/kg BW/day for male rats and 15.1 mg/kg BW/day for female rats).

Reproductive and developmental toxicity studies of lactitol (NS-4) (1)--Fertility study in rats by oral administration

A study of fertility and fetal development was conducted in Sprague-Dawley rats. Male rats were given lactitol, a hepatic encephalopathy drug, orally from 63 days before mating to the end of mating period. Female rats were given from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 0.7, 2.65 and 10 g/kg. The females were sacrificed on day 20 of pregnancy for examination of their fetuses. The decrease in food consumption in either male or female was observed in the intermediate and high dose groups. The high dose caused soft stool, diarrhea and increase in water consumption in either male or female. Moreover, the high dose caused salivation and suppression of body weight gain in male. In the pathological examination, the enlargement of cecum were observed in male of the intermediate and high dose groups. The increase in cecum weight were observed in male in all lactitol groups, and in female of the high dose group. Lactitol did not affect on copulation and fertility indexes in either male or female rats. Lactitol failed to affect on estrous cycle in female rats, and number of corpora lutea, implantations and preimplantation egg losses. In the fetal examination, lactitol did not affect on the development of live fetuses. The results show that no-effect dose levels of lactitol are less than 0.7 g/kg in male rats and 0.7 g/kg in female rats for general toxicity, and 10 g/kg for reproductive function in parent animals and fetuses.

Effects of sustained low-level muscarinic agonism in rats

Sustained, low level muscarinic activity was induced in rats by feeding the muscarinic agonist, experimental drug candidate CI-969 at 50, 100 and 200 mg/kg body weight/day for 4 wk. Except for urine staining, clinical signs typical of acute high-dose exposure to muscarinic agonists were not observed. A dose-related suppression of body weight gain approached 60% at the high dose, but no significant effects on haematology or clinical chemical parameters were observed after 4wk of exposure. Corneal opacities with histopathological features including neovascularization, acanthosis, stromal proliferation were observed in a dose-related fashion in both sexes at 100 and 200 mg/kg/day. Hypertrophy of the Harderian and lacrimal glands also occurred, probably as an adaptive response to sustained muscarinic activity. Lacrimal gland concentrations of the muscarinic agonist were in the range of pmol/mg tissue and therefore significant direct exposure of cornea to the compound through the tears was discounted. The presence of corneal muscarinic receptors was investigated to determine whether opacities could be related to direct, receptor-mediated events in the cornea; however, no specific binding of the muscarinic receptor radioligand [ 3H]quinuclidylbenzilate was detected. Because muscarinic agonist-induced opacities can be inhibited by scopolamine, the apparent lack of muscarinic receptors in the cornea indicates that the opacities are not a direct effect, but are instead secondary to muscarinic events at another site. To our knowledge, this is the first report of corneal opacities induced by a muscarinic agonist.

Effects of bevantolol HCl on immobilization stress-induced hypertension and central β-adrenoceptors in rats

Effects of chronic treatment with bevantolol, a β-adrenoceptor blocker, and of repeated immobilization stress on blood pressure, body weight, and [ 3H]dihydroalprenolol ([ 3H]DHA) binding to the cerebral cortex were examined in rats. Systolic blood pressure increased to approximately 150 mmHg when stress was applied for 14 days (2 h day −1). This increase was inhibited by chronic treatment with bevantolol (250 mg kg −1 daily). However, bevantolol did not suppress the inhibition of body weight gain by stress. The maximum number of [ 3H]DHA binding sites ( B max) in the cerebral cortex was decreased by stress without changing the affinity, and the decrease in B max mainly reflected the reduction of β 1-adrenoceptors. Bevantolol treatment (250 mg kg −1 increased the B max to 137% and completely inhibited the downregulation of β-adrenoceptors by stress. These results show that bevantolol can inhibit both the hypertension and downregulation of the central β 1-adrenoceptors induced by stress.