Suppression Of Body Weight Gain Research Articles

Studies on toxicity of clobetasone-17-butyrate (II)--chronic toxicity in rats (author's transl)

Chronic toxicity of clobetasone-17-butyrate, an anti-inflammatory corticosteroid, was investigated in rats. Subcutaneous administration with the drug at dose of 0.003, 0.01 and 0.03 mg/kg/day for three and six months induced no significant changes in the rats. At 0.1 and 0.3 mg/kg/day, however, some dose-dependent symptoms such as suppression of body weight gain, emaciation, regressive changes in adrenals, lymphatic and hematopoietic tissues, decrease in circulating white blood cell and lymphocyte counts, which have been known as toxic effects of synthetic corticosteroids, were induced. The results indicates that the maximum no-toxic dose of clobetasone-17 butyrate was 0.03 mg/kg/day on this experimental condition. In the recovery test for two months no significant differences in the treated rats from controls were found, suggesting that the toxic effects were reversible in the animals treated at 0.3 mg/kg/day and lower than that.

On the subacute toxicity of labetalol (AH5158): a combined alpha-and beta-adrenoceptor blocking agent (author's transl)

Subacute toxicity and recovery tests of labetalol hydrochloride, alpha- and beta-adrenoceptor blocking agent, were carried out using male and female Wistar strain rats. The drug was orally administered at 50, 150, 450 or 1000 mg/kg/day for 1 month. In all the drug-treated groups, increase in salivation was observed from immediately to 15 minutes after dosing through the treatment period. Eight of the 10 males and 9 of the 10 females in the group treated with 1000 mg/kg/day died of intoxication. Suppression of body weight gain was observed in male rats in the 450 and 1000 mg/kg/day groups and in female rats in the 1000 mg/kg/day group. In the 150 mg/kg/day and higher dose groups, water consumption showed a tendency to increase as compared with that of control group. Increase in urine volume was observed in female rats in the 450 mg/kg/day group. In the serum biochemical examination, slight elevation in potassium levels was noted in the 150 and 450 mg/kg/day groups. In histopathological findings, some abnormalities were found in the groups treated at 150 mg/kg/day and higher. Major abnormalities found in organs were; congestion and hypremia of various organs due to vasodilation, swelling of parenchymatous cells in liver and kidneys, and loose arrangement and change in the thickness of muscle fibers in cardiac and skeletal muscles. None of these abnormal findings was found in any examination in recovery tests.

Studies on toxicity of clobetasone-17-butyrate (I)--acute toxicity in mice and rats and subacute toxicity in rats (author's transl)

Acute and subacute toxicities of clobetasone-17-butyrate, a new anti-inflammatory corticosteroid, were studied in mice and rats. In the acute toxicity tests intraperitoneal LD50 values of the drug were estimated to be around 5 g/kg for both sexes of mice, 1.51 g/kg for male and 1.66 g/kg for female rats. Subcutaneous and oral administration induced no fatal cases at dose of 3.6 (mice, s.c.), 2.6 (rats, s.c.) and 6.0 g/kg (mice and rats, p.o.). As for the toxic signs in both mice and rats after the i.p. and s.c. administrations, emaciation was marked, and atrophy of thymus, spleen and adrenals were observed. No marked symptoms, however, were induced in animals administered orally. In the subacute toxicity tests male and female rats were subcutaneously administered with the drug at daily doses of 0.01, 0.03, 0.1, 1.0, 10 and 100 mg/kg for one month. Dose dependent symptoms such as suppression in body weight gain, emaciation, regressive changes in adrenal, lymphatic and hematopoietic tissues, decrease in circulating white blood cell and lymphocyte counts, and increase in total cholesterol level of serum were induced in the rats administered at 0.1 mg/kg/day and more than that, indicating that the maximum nontoxic dose in this experimental condition was 0.03 mg/kg/day. In recovery tests it was observed that the rats, which had been administered with the drug at 1.0 mg/kg/day for one month, were almost normal two months after the final administration.

Three-generation Reproduction Study on Furylfuramide in Mice

Furylfuramide (2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide) is a chemical which had been used widely in such foods as soybean caud, fish paste product and fish sausage as a food preservative in Japan from 1965 to 1974. The effects of furylfuramide on pregnant mice, fetuses and neonates were studies in ICR: JCL mice for three generations.Furylfuramide at dietary concentations of 0.1 or 0.5% was fed to both male and female weanling mice (F0). Thereafter the same dietary concentrations were administered continuously to each generation until F2 offspring were 60 days of age.Hepatic enlargement and degenerative hepatic changes were consistently found in the treated dams and their offspring. High mortality in F1 neonates and poor conception in F1 dams occurred in the group fed 0.5% furylfuramide. Suppression of body weight gain was also observed in pregnant mice and offspring at the 0.5% level. However, continuous administration of furylfuramide for three generations did not increase fetal mortality nor did it cause major malformations.

Anti-hypertensive action of DL-alpha-tocopharyl esters in rats.

1. Oral administration of DL-alpha-tocopheryl nicotinate (EN) (0-04 or 0-2 mmol day-1 kg-1) or DL-alpha-tocopharyl acetate (EA) (0-2 mmol day-1 kh-1) delayed the progress of hypertension in unilaterally nephrectomized rats, which were treated with deoxycorticosterone and salt, and in genetically hypertensive rats (SHR) which were given sodium chloride solution. Suppression of body weight gain, incidence of pneumonia and mortality were reduced by treatment with EN or EA. 2. Severe hypertension in old SHR (9 months) further progressed, when drinking water was replaced by sodium chloride solution, and four out of ten of these animals died of cerebral haemorrhage during 4 weeks. The administration of EN or EA prevented the increase in blood pressure and incidence of stroke.

Studies on the Relationship between the Nutritive Value and the Structure of Polymerized Oils. XI.

In a previous paper, we reported that linseed oil heated in an inert gas showed toxicity to mice and the skeletal structures of toxic compounds were methyl 9-(2′-n-propylcyclohexyl) nonanoate and/or methyl 8-(2′-n-butylcyclohexyl) octanoate and contained two double bonds. Moreover, the authors noticed the presence of four positional isomers of the double bonds. To know toxic effects of cyclic fatty acids, feeding experiments were carried out. Rats were given a diet containing 2.24.9% cyclic fatty acids for three weeks and the inhibition of body weight gain, hypertrophy and/or hyperplasy of liver, and a little decrease of digestibility were observed. Analyses of liver lipids revealed the symptom of fatty liver accompanied by the increase of neutral lipids and phospholipids. Histopathological changes were also observed in nuclei, cytoplasms and intercellular substances of liver cells by histological examination. To investigate the absorption of cyclic fatty acids which caused pathological changes, component fatty acids of plasma and liver lipids were determined by gas chromatography-mass spectrometry (GC-MS). The presence of these cyclic fatty acids was observed in both plasma and liver. This result indicated the possibility of the absorption of these cyclic fatty acids through small intestine. Furthermore, cyclic fatty acids were also found in neutral lipids, phospholipids and cholesteryl esters fractions of liver lipids. To know the relationship between the skeletal structure of cyclic fatty acids and toxicity, cyclic fatty acids were reduced and administered orally to mice. The hydrogenated cyclic fatty acids showed less toxicity than the original acids. From these results, we concluded that cyclic fatty acids are absorbed through small intestine and cause fatty liver and the other histopathological changes. Thus one of the reasons for the toxic effect of cyclic fatty acids is attributable to the metabolic injury in liver.

Oral toxicity of tebuthiuron (1-(5-tert-butyl-1,3,4-thiadiazol-2-yl-2-y)-1,3-dimethylurea) in experimental animals

The toxicity of tebuthiuron (1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-1,3-dimethylurea) has been studied in several animal species. The acute oral LD50s in mice, rats and rabbits were 579, 644 and 286 mg/kg, respectively. In cats, oral doses of 200 mg/kg were not lethal, while 500 mg/kg given orally did not kill dogs, quail, ducks or chickens. The acute TL50 in fish was > 160ppm.A 3-month study in rats fed diets containing 0, 400, 1000 or 2500 ppm tebuthiuron resulted in moderate growth retardation and a reduction in the efficiency of food utilization in the highest dose group. These changes were evident by wk 1 of the study. In the same group, a non-inflammatory diffuse vacuolization of the pancreatic acinar cell was found. No other important evidence of toxicity occurred. A 3-month study in dogs given daily oral doses of 0, 12·5, 25 or 50 mg tebuthiuron/kg resulted in slight anorexia in all the treated dogs, and a slight body-weight loss in dogs of the highest dose group. There were no other treatment-related signs of toxicity. A 1-month study in chickens fed rations containing 0, 400, 1000 or 2500 ppm tebuthiuron produced, in the highest treatment group, a reduction in food intake and suppression of body-weight gain but no other signs of toxicity. A teratology study produced no significant effects in the offspring of rats fed diets containing 0, 600, 1200 or 1800 ppm tebuthiuron.Skin and eye irritation studies in rabbits and a contact sensitization study in guinea-pigs revealed no remarkable evidence of toxicity.These studies indicate that tebuthiuron has a low order of toxicity in animals.

Effects of Linear Alkylbenzene Sulfonate Applied Dermally to Pregnant Mice on the Development of Their Fetuses

Linear alkylbenzene sulfonate (LAS) was applied dermally to pregnant mice in order to examine the embryotoxic and teratogenic effects. In ICR-JCL strain mice, LAS was given once daily at 0.5ml per mouse as 0.85, 1.7, 2.55, and 3.4% solutions from day 1 to 13 of gestation, and in ddY strain mice as 0.017, 0.17, and 1.7% solutions from day 2 to 14 of gestation. The results obtained were summarized as follows:1. Neither suppression of body weight gain nor visceral defects of the dams were observed in all the groups tested. However, the reduced rate of pregnancy was observed in 3.4% group, in which considerable skin irritation was seen at the applied site.2. Slight growth suppression of live fetuses in ICR-JCL mice were observed in 0.85, 2.55, and 3.4% groups. No significant difference between the applied and the control groups was found in external and internal abnormalities of the fetuses.3. The retarded ossification of sternebrae in ICR-JCL mouse fetuses were observed more frequently in both groups of 2.55 and 3.4% compared with the control. No skeletal abnormalities, assumed to be caused by the application of LAS, were observed in all groups.The results of this study would suggest that there was no conclusive evidence of teratogenic effects, assumed to be originated from LAS application, even at high concentrations.

Studies on the Teratogenicity of Food Additives (2)

The teratogenic effects of cyelohexylamine (CHA) and cyclohexylamine sulfate (CHA-sulfate) were examined in rats. The results obtained were as follows:Adult Wistar strain female and male rats and Wistar-lmamichi strain non-pregnant and pregnant female rats were orally given aqueous solution of CHA. Acute toxic symptoms caused by CHA were staggering gait, salivation, lacrymation and convulsion. In postmortem examination, remarkable hemorrhage in lung, marked edematous change in the mucous membrane of fore-stomach and congestion in glandural-stomach and duodenum were observed.Median lethal doses calculated following oral administration of CHA were 236.6mg/kg, 278.2mg/kg for Wistar strain female and male rats, 155.7mg/kg for Wistar-Imamichi strain female rats and 180.1mg/kg for pregnant Wistar-Imamichi rats, respectively.Pregnant Wistar-Imamichi strain rats were orally given once daily for 7 days from day 7 to 13 of gestation at the doses of 1.8, 3.6, 18 and 36mg/kg of CHA and its sulfate of 71.6mg/kg.In the highest dose of CHA, a suppression in body weight gain and reduction in food and water consumptions were ebserved and 2 of 17 dams died following the administration. No significant difference between the treated and control groups was found in maintenance of pregnancy and in fetal development, and no abnormal ities of the fetuses such as resorption and malformation were observed in all groups.

Studies on the Teratogenicity of Food Additives (3)

The teratogenic effects of cyelohexylamine (CHA) and cyclohexylamine sulfate (CHA-sulfate) were examined in rats. The results obtained were as follows:Adult Wistar strain female and male rats and Wistar-lmamichi strain non-pregnant and pregnant female rats were orally given aqueous solution of CHA. Acute toxic symptoms caused by CHA were staggering gait, salivation, lacrymation and convulsion. In postmortem examination, remarkable hemorrhage in lung, marked edematous change in the mucous membrane of fore-stomach and congestion in glandural-stomach and duodenum were observed.Median lethal doses calculated following oral administration of CHA were 236.6mg/kg, 278.2mg/kg for Wistar strain female and male rats, 155.7mg/kg for Wistar-Imamichi strain female rats and 180.1mg/kg for pregnant Wistar-Imamichi rats, respectively.Pregnant Wistar-Imamichi strain rats were orally given once daily for 7 days from day 7 to 13 of gestation at the doses of 1.8, 3.6, 18 and 36mg/kg of CHA and its sulfate of 71.6mg/kg.In the highest dose of CHA, a suppression in body weight gain and reduction in food and water consumptions were ebserved and 2 of 17 dams died following the administration. No significant difference between the treated and control groups was found in maintenance of pregnancy and in fetal development, and no abnormal ities of the fetuses such as resorption and malformation were observed in all groups.

Effect of Oral Administration of Methallibure (I.C.I. 33, 828) in Growing Cockerels

Effect of oral administration of Methallibure (I.C.I. 33, 828) upon body weight, feed intake, comb growth and testicular development in 4-18 weeks old cockerels were examined at the two dosages, 0.0015% (E1) and 0.003% (E2).(1) Body weight was suppressed by the administration of this drug. This suppression in body weight gain should be ascribed to reduced appetite in the treated birds, since firstly no difference was observed between E2 and an appropriate control group (C2) which was not treated but received the same amount of feed consumed one day before by E2 group, and secondly there was no difference between two treated groups with difference levels of administration. Appetite was strongly suppressed in the first week after the normal ration was changed to the experimental one, and thenafter, it returned to the normal level proportionally to their body weight gain.(2) Testicular weight in the treated group was smaller than in the control. This was more evident at the 10th week of age than at the 19th week. Spermatogenesis was somewhat inhibited by the drug but almost normal in sperm formation by the age of 19 weeks. It was suggested that the levels of administration used in this study were not sufficient to inhibit their gonadal activity as the cockerels approached to their full maturation.(3) Comb weight in 0, 003% methallibure administred cockerels was significantly smaller than the controls, which suggests that androgen secretion was inhibited markedly in the treated group. The activity of thyroid was accelerated in the treated group. Other organs such as liver, spleen, pancreas and kidney were not affected much but adrenal was smaller in the treated groups.(4) Water content in feces of treated groups was 6 to 12% higher than in the control.(5) Both fertility and hatchability by the use of those treated cockerels after 22 weeks were not affected at all. This suggests that the effect of the drug may not persist for a long period after withdrawal of the agent.

Effect of cyproterone acetate on 3H-testosterone uptake and enzyme synthesis by the ventral prostate of the rat.

Significant decreases in the concentration of radioactivity following the injection of l,2-3H-testosterone to male adult rats treated from 8–21 days with cyproterone acetate have been noted. No significant changes, however, following the drug were noted in the content of radioactivity in either liver, muscle or plasma. In addition, cyproterone acetate inhibited body weight gain and resulted in significant decreases in ventral prostate weight, decrease in RNA/DNA ratio in the ventral prostate and decreased content of acid phosphatase as compared to control rats. Results in pair feeding studies confirmed earlier random feeding experiments. These data suggest that the inhibitory effect of cyproterone acetate on the accumulation of testosterone by rat ventral prostate but not other tissues studied may represent an important mechanism to explain the selective inhibitory effect of anti-androgens on metabolic activity of secondary sex tissues. (Endocrinology84: 1330, 1969)

Pharmacological Studies on Alkylbenzene Sulfonate (2)

Administration of ABS to rats during pregnancy caused diarrhea and suppression of body weight gain in groups given 1.0% and 2.0% diet. No remarkable effect was observed in groups given 0.5%, 0.1% and 0.025% diet. Although pregnancy was maintained even in 2.0% group the increase of fetal death and the decrease in fetal development was observed in the group. No macroscopic malformation, assumed to be caused by the administration of ABS, was observed. No deleterious effect on delivery and lactation as well as on development of new-born until 5 weeks after parturition was observed.Oral administration of aqueous ABS to pregnant mice between 7 and 13 day of pregnancy caused slight effect on maternal weight gain, but no effect was observed in fetus from dams given 24mg/kg ABS. Administration of 240mg/kg caused increase of fetal development suppression and death on 18th day of pregnancy. Occurrence of congenital malformation, assumed to be originated from ABS administration, was not observed.

Changes in body weight of normal and castrated rats by different doses of testosterone propionate.

SummaryAdministration of testosterone propionate above physiological levels inhibits body weight gain of normal and castrated young adult rats. Inhibition in the normal rat appears in doses above 25 μg/day and in castrated rats at above 100 μg/day. In the castrated rat inhibition is preceded by increase in rate of body weight gain. Food consumption of both normal and castrated rats varied with changes in body weight.

Enhancement by thyroxine of the adrenal-stimulating effect of somatotrophic hormone.

SUMMARY Experiments on intact Sprague-Dawley rats indicate that the adrenal enlargement produced by somatotrophic hormone (STH) can be greatly augmented by simultaneous treatment with comparatively small doses of thyroxine. Within a certain dosage range, the corticotrophic effect of STH is even proportionate to the dose of thyroxine given. The adrenal enlargement produced by adrenocorticotrophic hormone (ACTH), on the other hand, is not enhanced by concurrent treatment with thyroxine. Attention is called to the fact that, in rats in which adrenocortical hypertrophy is produced, either by STH plus thyroxine or by ACTH plus thyroxine, many of the changes in the extra-adrenal organs, which are generally considered to be indicative of increased glucocorticoid production (inhibition of body weight gain, splenic atrophy, involution of the thymus and lymph nodes, inhibition of inflammatory exudate formation), do not parallel the increase in adrenal weight.