RESUMEN

The German Chemicals Act requires that chemicals are tested for behavioral toxicity at stage 2 of the testing procedure, i.e. if more than 1000 annual tons are produced. For this purpose a guideline was developed according to which data on behavioral toxicity are to be collected, which are based on cageside observations during longterm exposure. The protocol covers outer appearance, as well as motor, sensory, autonomic and central nervous system functions. Data are to be reported in tabular form and should be evaluated by taking all aspects of the toxicological profile into account.

Asunto(s)

RESUMEN

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno [3,2-f]-1,2,4-triazolo[4,3-a]-1,4-diazepine, We 941, Lendormin), a new hypnotic, was submitted to a comprehensive range of safety assessment tests. Acute (single dose) toxicity was very low, while in subacute and chronic studies in rodents, signs of toxicity were first seen at doses of 400 mg/kg or more. Histopathological changes were only seen in the 1 1/2-year study. Ataxia, salivation, and diarrhea were observed in a 4-week intravenous study in dogs, and ataxia, increased feed intake, muscular spasms, increased liver weight, and lipid depletion of the adrenal cortex in two oral studies in monkeys. Reproductive studies in the rat and the rabbit revealed no disturbances in fertility, nor were any embryotoxic or teratogenic effects detected in doses of up to 30 mg/kg. Only at 400 mg/kg was litter mortality increased. Local tolerance tests in rabbits indicated good compatibility of brotizolam when administered intramuscularly, intra-arterially, or intravenously. No signs of any genotoxic action could be detected. A carcinogenicity study in mice showed no evidence of any oncogenic effect, while in rats, although the incidence of certain tumors appeared somewhat higher in the high-dose group, this could be explained by the range of biological variation within the strain, a possible modulating effect on the immune system due to the stress of a very high dose, and a functional effect on the thyroid. These studies thus demonstrate that brotizolam has a remarkably wide therapeutic range.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

RESUMEN

In four subchronic and three chronic toxicity studies in rats, in which the application of pharmacologically active substances led to a reduction in body weight development, the lengths of the animals were also measured. It could be shown that a lower body weight gain was always accompanied by a reduction in body length increase. With increasing doses or higher toxicity the within-group variations of individual values were smaller and the correlation between body weight and length of the rats was generally greater.

Asunto(s)

RESUMEN

Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents greater than 10,000 and greater than 900 mg/kg, respectively). Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams wer treated with 400 mg/kg, litter mortality was markedly increased. Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

The aim of the animal experiments was to investigate the question of the age dependence of the morphokinetic reactions of the thyroid gland under standardised conditions. Through the administration of pharmaceutical substances, it was possible to produce defined functional states of the thyroid in the various age groups. Materials and Methods 700 Albino rats of the Chbb: Thom (SPF) strain, age 0 days (newborn) to 110 weeks, were used in the investigations. The animals were divided into 4 groups each with 12 subgroups according to age. One group received 300 mug/kg/day triiodothyronine (T3) for 10 days for the suppression of thyroid gland function, one group received methylthiouracil (MTU) for 10 days to block hormone synthesis, and one group received 10 IU/kg/day thyrotrophic hormone (TSH) for 5 days to stimulate the gland. The control group received distilled water. Investigations carried out: Protein-bound iodine (PBI) and total thyroxine (T4) in the serum; enzyme histochemical demonstration in the thyroid of alkaline phosphatase (a. Ph.), acid phsophatase (s. Ph.), cytochrome oxidase (Cyt. ox.), succinic dehydrogenase (SDH), iso-citric acid dehydrogenase (ICDH), ATP-ase and nonspecific esterase. The height of the follicular epithelium and the nuclear diameters of the follicular epithelial cells were estimated in embedded material. Light-microscopical investigations were performed using Paraplast and Epon embedded material. Staining methods: H. and E., Azan, PAS-alcian blue, Elastica-van Gieson, Perl's method for iron, Gomori's reticulin stain and von Kossa's calcium method (in aged animals). Staining of semithin sections with toluidine blue, Movat's stain and Morgenroth's stain. Biometric analysis of results: Simple and two factor analysis of variance, Scheffé test, graphic demonstration after polynomial fitting of third to fifth degree. Results a. Histochemical findings In the thyroid gland, all the above mentioned enzyme histochemical reactions studied show a mostly distinct age dependent relationship in the intensity of enzyme activity. Age dependent changes in the histo-topochemical behaviour of individual reactions are also demonstrable on light-microscopical examination. In control animals at the time of birth, alkaline phosphatase and cytochrome oxidase react moderately, the others weakly. With hydrolases the activity of alkaline phosphatassr remains at a moderate level throughout the life span, while acid phosphatase and ATP-ase show a marked increase up to puberty, and the reaction is still mnd I.C.D.H. an increase during the growth period, a marked response in middle life, and a lessening of activity in ageing animals can be demonstrated. Cytochrome oxidase increases up to the seventeenth week of life, and then decreases in older animals. The activity of nonspecific esterase increases up to the eleventh week, remains at a high level up to the forty fourth week and then lessen after one year of life...

Asunto(s)

RESUMEN

400 albin rats (200 male, 200 female) of the strain Chbb: THOM (SPF) were investigated for the occurrence of spontaneous tumours over a period of almost three years. On day 750 of the study 78% of the male and 84% of the female animals were still alive. In 295 tumour hosts (73.8%) we discovered a total of 419 tumours. Several primary tumours were observed in 97 animals. The examinations revealed 240 tumours in the male and 179 tumours in the female rats. The highest tumour rate of 34.5% was established for adenomas of the interestial cells of Leydig in the testes. In female animals mammary tumours were the most frequent type of tumour, accounting for 31%. Talking into account the life expectation of the rats as well as the type and frequency of the tumours these results prove the suitability of this strain for carcinogenicity studies.

Asunto(s)

RESUMEN

The acute, subacute and chronic toxicity of (8r)-3alpha-hydroxy-8-isopropyl-1alphaH,5alphaH-tropaniumbromide (ipratropiumbromide, Sch 1000, Atrovent) was studied on mice, rats, dogs and monkeys following oral, s.c., i.v. administration and inhalation. With toxic doses all typical symptoms of atropine or atropine derivatives were present, like mydriasis, dryness of the mucosa and meteorism with coprostasis. It was not possible to determine the LC50 of the substance due to its low toxicity.

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)