A. D. WELCH AND E. BUEDING 



In a recent study of the effect of quinacrine (atabrine) on re- 

 spiratory enzymes, Haas (12) found that the drug inhibits the respira- 

 tion of Plasmodium knowlesi to a greater extent than that of mammahan 

 tissues. Furthermore, at relatively low concentrations the drug in- 

 hibits cytochrome reductase and glucose-6-phosphate dehydrogenase 

 {^wischenferment), while it has little or no effect on cytochrome oxidase, 

 cytochrome C, or triphosphopyndine nucleotide. The concentration 

 of atabrine required to inhibit the respiration of malaria parasites in 

 vitro is considerably higher than those concentrations of the drug in 

 plasma which exert an antimalarial effect in vivo; conceivably, how- 

 ever, the concentration of atabrine in the parasites may be considerably 

 higher than the concentration in the plasma. Quinine was less 

 active than atabrine in inhibiting both cytochrome reductase and the 

 respiration of malaria parasites, a difference which is in agreement with 

 the fact that the antimalarial activity of atabrine is now recognized as 

 definitely greater than that of quinine. In order to test the hypothesis 

 that the antimalarial activity of these two drugs is in part due to an 

 inhibition of the activity of cytochrome reductase, it might be helpful 

 to study the enzyme-inhibiting effect of a group of compounds closely 

 related structurally to atabrine, but among which varying degrees of 

 antimalarial activity are found. The work of Haas would take on 

 added significance if a close parallelism between the relative activities 

 in vitro and in vivo were found in such a series, and if the discrepancy 

 between the concentration causing enzymic inhibition and that which 

 is therapeutically active were satisfactorily explained. A closer corre- 

 lation between the effective concentration in vitro and in vivo was found 

 by Silverman et al. (34), who showed that quinine in concentrations 

 only slightly above those therapeutically active in vivo inhibits the 

 oxidation of glucose by Plasmodium gallinaceum, without affecting 

 glycolysis. 



Earlier, but less striking, attempts have been made to correlate 

 the inhibition of enzyme systems with the action of drugs chemo- 

 therapeutically effective in vivo. In this connection there might be 

 mentioned the action of atoxyi and of quinine on certain lipases, 

 the antifumarase-activity of certain trypanocidal compounds (25), 

 and the inhibition with acriflavine of a cyanide-insensitive hydrogen- 

 transporting system in trypanosomes (30). 



Thus, various investigations have been conducted in which the 



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