[Animal studies on the tolerability of AR-L 115 BS (author's transl)]. / Tierexperimentelle Untersuchung zur Verträglichkeit von AR-L 115 BS.

Acute and subacute toxicity studies as well as reproduction-toxicologic investigations were carried out on the positive-inotropic substance 2[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) in various species. No undesirable side-effects or organ damage were observed in baboons after oral application of 2.5, 10 and 30 mg/kg AR-L 115 BS for 13 weeks. Beagle dogs, female miniature pigs and rats had brown-coloured urine after the substance. In miniature pigs and rats this was only observed at high dosage (mini-pig: 10 and 30 mg/kg; rat: 200 mg/kg). Changes in the ECG could be seen in the dose range of 20--40 mg/kg (dog i.v.), 30 mg/kg (dog p.o) and 200 mg/kg (rat p.o). Non-inflammatory mitral valve alterations (i.v. and p.o) as well as spot- and ring-shaped endocardial scleroses underneath the aortic valves in the region of the left cardiac outflow tract (30 mg/kg, p.o.) were found especially in female beagle dogs in the same dose range. The alterations are regarded as being of haemodynamic origin in view of the increased myocardial contractility caused by AR-L 115 BS. Phonocardiographic findings support this view. Besides, several dogs (30 mg/kg) and rats (200 mg/kg) showed myocardial scars. All male miniature pigs which had received 30 mg/kg AR-L 115 BS demonstrated an increase in heart and mitral valve weights. The results of the reproduction-toxicologic investigations gave no indication of an embryotoxic or mutagenic effect for the substance AR-L 115 BS. After comparing the results it can be concluded that the dog is the most sensitive of the species under investigation and that the results obtained in this species should not be generalised. Biochemical tests showed very similar metabolic patterns for AR-L 115 BS in baboons and man. From this it can be deduced that the results obtained in baboons are most likely to be transferable to man.

Detection of the carcinogenic nitrofuran derivative VR-6 as a mutagen in the Salmonella/microsome test.

The carcinogenic nitrofuran, VR-6, was evaluated for mutagenicity in Salmonella typhimurium TA 100 using the plate assay (Ames test). The dose-response curve indicated that S. typhimurium TA 100 is a very sensitive genetic indicator for this chemical class and that basepair substitution appears to be the molecular mechanism with VR-6. The results reported here provide evidence, that VR-6 is a directly acting mutagen for S. typhimurium TA 100 and that the chemical is partially deactivated in the presence of rat liver homogenates. Comparison of the results obtained with this agent in the Ames test with data from a subacute animal study, showed a good agreement in predicting the carcinogenic risk.

The spontaneous rate of tumours in the laboratory rat: strain Chbb: THOM (SPF).

The aim of this investigation was to examine the time relationship of the rate of development of spontaneous tumours in the rat, strain CHBB: THOM (SPF). The rats were divided into 6 groups, each of which consisted of 100 male and 100 female animals. The first group was killed at the age of 15 months, and the last group when aged 2 1/2 years. Thus the time interval between sacrificing the individual groups was 3 months. Spontaneous tumours seldom appear in animals up to 15 months of age except in the testes, pituitary and mammary glands. Apart from these organs tumours develop mainly in the lung, lymph nodes, thymus, adrenal cortex, thyroid, ovary, uterus, skin and in the brain. Benign tumours predominate. Malignant tumours with metastases are rare. The incidence of tumour formation increases after the age 21 months. Statistically significant increases can only be shown in a few organs.

Hormonal activity of testes in aged rats with leydig cell hyperplasia: histochemical investigation of some hydroxysteroid dehydrogenases.

The following enzymes were employed in order to investigate the hormonal activity of the testes in aged rats: 3-beta hydroxysteroid-DH, 11-beta-hydroxysteroid-DH, and 17-beta-hydroxysteroid-DH. Our investigations show that in the non-altered testis of the aged rat the same enzyme activities can be observed as in young and sexually mature animals. A proliferation of the Leydig cells (L.c.), occurring in the aging rat, brings about an increased activity of the above-mentioned steroid-DHs. An augmented production of testosterone is quite probable.

Ectopical kidney tissue in the left auricle of a rat.

A case of a 3 months old rat with ectopic renal tissue within the heart was described. The renal tissue consisted of well developed parts of the kidney cortex like glomerula and tubuli contorti. All parts of the kidney medulla such as excretory tubules and kidney pelvis were missing. It is believed that the ectopic kidney tissue developed from scattering of metanephric tissue. A physiological function of the intracardial renal tissue can be excluded.