[Animal studies on the tolerability of AR-L 115 BS (author's transl)]

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.