Pharmacokinetics and toxicity of the oxime HGG 12 in dogs

The pharmacokinetics, pharmacodynamics, and toxicity of the oxime HGG 12 were studied in conscious and anesthetized dogs. IV administration. The mean value of the half-time for terminal elimination of HGG 12 was 47 min; plasma clearance amounted to 4.6 ml kg-1 min-1 and Vapp to 0.315 1 kg-1. At doses above 1 mumol/kg heart rate, left ventricular pressure and mean arterial pressure decreased, while central venous pressure and femoral blood flow increased. The dose-response curves were very flat. Repetitive administration of various doses of HGG 12 in 30 min intervals did not enhance the negative chronotropic effect when the preceding total dose amounted to about 1 mumol/kg. IM administration. The half-times for the absorption of HGG 12 dichloride and HGG 12 dinitrate were about 3.5 min; the corresponding value for HGG 12 dibromide was 9.4 min. In the elimination phase the half-time was comparable with that of the IV experiments. About 60% of the oxime was excreted unchanged in the urine within 24 h. The circulatory changes showed the same tendency as after IV injection. Conscious dogs tolerated well daily doses of 10 mumol/kg for 6 weeks. At 30 mumol/kg all dogs survived, displaying symptoms reminiscent of a cholinergic syndrome. Five out of eight dogs survived at 90 mumol/kg. Macroscopic and microscopic examinations and blood chemistry data showed no abnormality.