Receptor kinetics and concentration-effect relation of cardiac glycosides.

Therapeutic and toxic actions of cardiac glycosides are attributed to an inhibition of Na, K-ATPase. The therapeutically relevant range is between 25% and 50% inhibition. There is a good correlation between the average steady state serum concentration of glycosides and their therapeutic action. However, therapeutic and toxic effects set in with a latency and therefore do not follow the daily variations in glycoside concentration. Although the effect follows the average serum concentrations, only the minimal concentration is measured. In principle this is only adequate if the ratio of average/minimal concentration is constant. A model calculation showed that with a constant average steady state concentration an increase in the distribution volume or a decrease in total body clearance with corresponding reduction of the daily dose lead to an increase of the minimal concentrations of 5-7%. This means a corresponding underestimation of the average concentration from the minimum concentration. However, the deviations are too small to be of clinical relevance.

Antiallergic activity of picumast dihydrochloride in several animal species.

Picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) was compared with cromoglycate, ketotifen and mepyramine as an inhibitor of allergic and anaphylactoid reactions. 1. In guinea-pigs, pretreatment with picumast dihydrochloride given intravenously, orally or by inhalation prevented bronchospasm induced by antigen or histamine. The fraction of the bronchospasm remaining after mepyramine pretreatment was further reduced by picumast dihydrochloride. 2. Systemic administration of picumast dihydrochloride inhibited antigen-induced conjunctivitis, whereas mepyramine and ketotifen were inactive. 3. Intravenous and oral pretreatment with picumast dihydrochloride inhibited the antigen-induced mast cell degranulation in rat mesentery. The effective doses of cromoglycate given intravenously were twice as high as those of picumast dihydrochloride. Picumast dihydrochloride did not inhibit antigen-induced bronchoconstriction in rats. 4. The cutaneous reaction induced with Ascaris antigen in atopic monkeys was insensitive to the antihistaminic action of ketotifen, whereas it was inhibited by low doses of picumast dihydrochloride. Both compounds suppressed skin reactions induced by histamine. 5. Picumast dihydrochloride decreased IgE production in atopic high responder mice. It did not prevent autoimmune nephritis in NZB/W mice. 6. In rats, picumast dihydrochloride did not reduce cotton pellet granuloma, nor adjuvant arthritis. The inhibition of carrageenin oedema is presumably due to its anti-oedematous properties rather than to an antiproliferative activity. In conclusion, the inhibition of allergic and anaphylactoid reactions by picumast dihydrochloride can be attributed to a combined inhibition of liberation and action of histamine and other mediators.

Animal experiments for estimating the radiation exposure of human subjects by radioactive drugs.

The radiation exposure of human subjects is extrapolated from the elimination rate of radioactivity from the plasma and a single determination of the tissue distribution of radioactivity in rats. With an interval of 3-4 half-lives between administration and determination, the radiation exposure of an organ is underestimated only if the elimination rate from the organ is 5.5-12.9 times lower than from the plasma. Determining the elimination rate from the relevant organs is recommendable only if the radiation exposure calculated for the commonly used dose of 100 microCi per volunteer approaches the official yearly limit.