ANTAGONISM, SUMMATION, AND SYNERGISM 507 



p-aminosalicylic acid prevents to some extent the development of resistance 

 to streptomycin by the mycobacteria. It is likely that such techniques will 

 have to be used in the chemotherapy of cancer inasmuch as resistance to 

 single agents appears so readily. 



ANTAGONISM, SUMMATION, AND SYNERGISM 



The terms antagonism, summation, and synergism have been applied 

 for many years in pharmacology with a variety of meanings. They have 

 been occasionally used in inhibition studies with equal vagueness. If these 

 expressions are to be used, they should have accepted and quantitative 

 meanings; otherwise it is better to state the results and omit the terms. 

 Antagonism is commonly assumed to occur when two agents produce an 

 effect that is less than expected on the basis of their individual actions; 

 likewise, synergism is deduced when the combined effect is greater than 

 expected. The question may be raised as to just what one expects and to 

 the validity of such expectation. For example, if I^ depresses respiration 

 30% and Ig depresses it 45%, what inhibition would be expected when 

 both Ii and l^ are present? How would multiple inhibitions of 50, 60, 70, 

 or 80% be classified ? In the examples previously discussed of two inhibi- 

 tors acting on various types of simple enzyme systems, it was evident that 

 different effects may be expected depending on the particular situation. 

 Before antagonism and synergism (or potentiation) can be defined, some 

 reasonable method of determining the expected result of summation in gen- 

 eral cases must be worked out. Actually, it is usually not convenient to 

 approach the subject by comparing the effect of two inhibitors with the 

 effects of each inhibitor separately; it is more profitable to look at the ef- 

 fect of a single inhibitor both alone and in the presence of the other inhi- 

 bitor. 



Let us consider the two inhibitors mentioned above. If the normal respir- 

 atory rate is designated as 100, I^ alone would depress it to 70; if Ig were 

 now added, the respiration would be reduced further to 38.5 if the first 

 inhibitor had no effect on the response to the second. Likewise, if L, were 

 used alone, the respiration would drop to 55 and the addition of I^ would, 

 of course, bring it to 38.5 again. Thus on the basis of independence of 

 action, the expected inhibition by the two inhibitors acting simultaneously 

 would be 6L5%. Such a situation may be called summation. A combined 

 effect of less than 61.5% inhibition may be called antagonism and an effect 

 greater than this synergism. This may be easily expressed in mathematical 

 form. The fractional respiratory rate in the presence of I^ alone is a^ = 

 1 — iy and the addition of Ij will reduce the activity to a^a, = (1 — ^i) 

 (1 — i^). The inhibition produced by both inhibitors will thus be 



h 2 = 1 — ^'if'2 = 1 - (1 — ^'i)(l — i-i) = ?i + H — HH 



