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h series of 133 2 4 2-pyridyl)-1,2-diarylalkanols, or compounds closely related to them, were synthesized and assayed for their hypocholesteremic and estrogenic activities in rats. Many of these compounds were active in both tests, but there is no necessary correlation between the two effects. Compound 16 was selected for preclinical toxicologic study, followed by a study of its hypocholesteremic effect in man. The compound selected was remarkably nontoxic in all species studied, but it had no hypocholesteremic el'fect in the dog, the monkey, or in man.

Kinetics analysis of a linear model enzyme system shows that, in theory, the combined effect of two inhibitors acting by sequential blockage is necessarily synergistic. The rate equations for the system describe a theoretical dose-effect surface for the drug pair which results in a formal definition of synergism that correlates well with experimental observation over the concentration range for which the effect is demonstrable. This definition provides a rationale for the isobole technique for demonstrating synergism experimentally and a means for defining and calculating the "amount" of synergism shown by two drugs.

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