Investigations on the exogenous influencing of the spontaneous tumour rate in rats.

72 male and 72 female rats of the strain Can-Hoe-Wiga received standard diet in a long-term study (24 months). A group of equal size received the beta-blocker BM 51.052 administered at a dose of 900 ppm in the feed. The animals in the drug group showed a 20 to 30% delay in body weight gain in comparison with the control animals. These drug-treated animals showed, similarly to experiments with a restrictive diet, a lower death rate, fewer glomerulopathies, and lower creatinine and protein levels in the serum. In addition, there were fewer tumour bearers, the total number of tumours was less, and the malignancy and formation of metastases was reduced. This experiment shows the importance which should be attached to the course of body weight gain during a long-term study. Only if these parameters are taken into consideration, an interpretation of the experimental results is possible.

A postulated mechanism of beta-sympathomimetic induction of rib and limb anomalies in rat fetuses.

Treatment of gravid rats (days 6-15 of gestation) with the beta-sympathomimetic doxaminol resulted in wavy ribs and bent limbs in the offspring. The fetuses also exhibited defective mineralization. These anomalies were produced by pharmacologically effective doses of the drug. Prior treatment with the beta-receptor blocker carazolol prevented their formation, so that the beta-sympathomimetic action of doxaminol is evidently a causative factor. Various hypotensive agents whose activity is not mediated by beta-receptors failed to produce abnormalities. This eliminates the possibility of a non-specific etiology such as diminished placental perfusion. The cyclooxygenase inhibitor indomethacin lowered the incidence of wavy ribs. Furosemide, a loop diuretic that stimulates renal prostaglandin synthesis, increased the incidence of abnormalities when combined with doxaminol. The nature of the anomalies found suggests that 1) fetal compression by the myometrium and 2) defective mineralization are prerequisites for their development. The first condition could be produced via the complex mechanism of beta-sympathomimetic-induced stimulation of prostaglandin synthesis. Defective mineralization can result directly from cAMP-mediated activation of osteoclasts and possibly be further promoted by beta-sympathomimetic-mediated prostaglandin action on the osteoclast. The pathological findings in the fetal rat skeleton cannot be correlated with corresponding findings in human neonates whose mothers were subjected to prolonged therapeutic uterine relaxation with beta 2-sympathomimetics, for example. Since the anomalies in the rat disappear spontaneously in the post-natal period, their clinical relevance appears to be slight.

Incidence of spontaneous tumors in laboratory rats.

The Caw-Hoe-Wiga strain of the Sprague-Dawley rat was observed for a period of ten years (1974--1983). In toxicity studies, a gradual increase of food intake could be noted in 12- to 13-week-old rats. The food intake of males was 21 g in 1974 and 27 g in 1983; in females 16 g in 1974 and 19 g in 1984. Correspondingly, a gradual increase of body weight was measured. The body weight of males was 400 g in 1974 and 470 g in 1983; of females 240 g in 1974 and 285 g in 1983. The gradual increase of food intake and body weight was followed by a gradual increase in the incidence of spontaneous tumors, 1974: 5% and 1983: 13%. Our experiments support the opinion of a causal connection between food intake, body weight and incidence of spontaneous tumors. Tumors can appear in any age group, but tumors. occur more often in older animals. In our studies, the increase in the incidence of spontaneous tumors was proportional to the increase in age: At 15 months only 6%, at 32 months 86%. 32% of the tumors were located in the mammary glands, 27% in the hypophysis, 12% in skin and appendages, and 9% in other endocrine organs. The comparison of toxicity and carcinogenicity studies revealed no change in the tumor spectrum, but strain-related tumors appeared earlier in life, more frequently and more often multifocally towards the end of the 10-year observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of acute toxicity of cyclophosphamide and X-rays by the new immunomodulating compound BM 12.531.

BM 12.531, the 2-[2-cyanaziridinyl-(1)]-2-[2-carbamoylaziridinyl-(1)]-propane, (prop. INN Azimexon), reduces significantly the acute toxicity of cyclophosphamide and X-rays in rats and mice, respectively. The leucopenia induced by X-rays was partially compensated by BM 12.531 in rats.

Investigations in mice on the potentiation of resistance to infections by a new immunostimulant compound.

BM 12.531, 2-[2-cyranaziridinyl-(1)]-2-[2-carbamoylaziridinyl-(1)]-propane, a new immunostimulant compound, increased the resistance of mice to infection with Candida albicans. Because BM 12.531 had no fungistatic activity in vitro, it is proposed that the therapeutic effect of BM 12.531 is caused by the stimulation of cell-mediated immunity. Administration of cyclophosphamide alone increased the mortality among mice infected with C. albicans and Pseudomonas aeruginosa, but when BM 12.531 was then administered to these animals, the mortality was reduced. Among mice with acute Escherichia coli infection, a synergistic effect of chloramphenicol and BM 12.531 was demonstrated.

Animal experiments on the compensation of the immunosuppressive action of cyclophosphamide by 2-[-2-cyanaziridinyl-(1)-]-2-[-2-carbamoylaziridinyl-(1)]-propane BM 12 531.

BM U2 531, the 2-[2-Cyanaziridinyl-(1)-]-2-[-2-carbamoylaziridinyl-(1)-]-propane, the further development of BM 06 002 is able to compensate the immunosuppressive action of Cyclophosphamide and to increase the carcinostatic action of Cyclophosphamide. These properties are demonstrated 1. by a leucocytosis induced after application of BM 12 531 in rats 2. by a quick restauration of leucocyte depression induced by Cyclophosphamide in rats and dogs 3. by an increase of resistance against an infection (candida albicans) in mice 4. by an increase of antitumour effect of Cyclophosphamide against a DS-carcinosarcoma in rats.

Experimental investigations on increased resistance to infections with Candida albicans and Staphylococcus aureus Smith by 4-imino-1,4-diazobicyclo-(3.1.0)-hexane-2-on BM 06.002 (prop. INN imexon) in mice.

BM 06.002 increases the resistance of mice to experimentally induced chronic infection with Candida albicans. Furthermore, BM 06.002 leads to increased resistance in the case of experimentally induced infection with Staphylococcus aureus Smith, when a subtherapeutic dose of sulfadiazine is applied. In mice immunosuppressively pretreated with hydrocortisone, BM 06.002 effectuates immunorestauration.

[Examination of pyrogens in vitro by means of the limulus test/2. Results (author's transl)]. / In-vitro-Pyrogenprüfung mittels des Limulus-Tests. 2. Mitteilung der Ergebnisse

Rabbit and Limulus test were studied comparatively in regard to applicability of water for injections. The examinations included the auxiliary material water and water bacteria, which have to be considered potential pyrogens. With freshly distilled water conformity of 95%, with water germs of 80% was reached.

[Pyrogen testing in vitro using the Limulus test]. / Ein Beitrag zur in-vitro-Pyrogenprüfung mittels des Limulus-Tests

The applicability of the Limulus test for the pyrogen test was checked in comparison to the pyrogen test in rabbits. In 6 out of 24 lots of raw materials and drugs pyrogens could be detected by means of the pyrogen test in rabbits. 2 of these 6 lots showed positive reaction in the Limulus test, there were no false positive results. Testing 7 bacterial strains in modified quantity of germs the Limulus test turned out to be more sensitive than the pyrogen test in rabbits. The application of this in vitro test as a complement to the pyrogen test in rabbits for a certain kind of problems is discussed.

Investigations into the effect of castration on the blood glucose profile of male and female rats treated with glibenclamide (HB 319).

In SPF-bred male and female Sprague-Dawley rats the effect of castration on the hypoglycaemic action of a single dose of glibenclamide (HB 419) was investigated. The results of castration showed no unambiguous influence on the normal blood glucose values. The effect of this sulphonyl urea, however, was considerably stimulated by castration and was prolonged in male animals. Obviously the absence of testosterone has an inhibitory effect on the activity of liver ribosomes thus causing a delay in the metabolism. Furthermore the metabolic rate depends on the testosterone value in the organism as evidenced by the differences between male and female animals. The results were ascertained statistically.