VOL. 4 {1950) GLYCOLYSIS IN PHARMACOLOGY I41 



shown that doses of the diamidines which were active against trypanosomes did not 

 produce a fall in blood sugar of the host. Therefore, attention was given to the sugar 

 metabolism and oxygen utilization of these organisms. Lourie and Yorke" have 

 stated that the diamidines may block the aerobic glucose metabolism in the diamidine- 

 sensitive species. The diamidine-insensitive species would be capable of obtaining their 

 energy from the anerobic glycolysis in the presence of the drug. 



Some attention has been paid to the possible enzymatic site of the action of these 

 compounds. Blaschko and Duthie^^ have found an inhibitory action of the various 

 amidine derivatives on the amine oxidase activity of the rabbits' liver. Bernheim^^ 

 has shown that the oxidation of proline and alanine by E. coli is inhibited by prop- 

 amidine. However, the oxidation of glucose, pyruvate and succinate is not affected by 

 this drug. Dickens^" has demonstrated that guanidine carbonate increases the aerobic 

 glycolysis of the rat brain cortex. These facts led to a study of the effects of diamidines 

 and related compounds on anerobic glycolysis of glycogen to lactate in muscle extract 

 (Gemmill^i). The various compounds in this series which inhibited glycolysis are given 

 in Table II. In the same paper is given a list of styryl and cyanine compounds which 

 are active inhibitors. 



TABLE II 



AMIDINES AND REL.\TED COMPOUNDS WHICH INHIBITED 

 GLYCOLYSIS IN CONCENTRATIONS OF I • lO"^ MOLAR OR LESS 



Diamidines : Diguanidines : 



Ci2-2 HCl Diguanidine HCl 



C13.2HCI C12 HCl 



Monoguanidines: Diisothioureas: 

 Guanidine HCl C^^ HBr 



Methylguanidine sulfate C^g HBr 



Arginine HCl Stilbamidine 



Cg HCl Pentamidine 



Cjo HCl Chlorguanidine 



Alloxan: Since the discovery that alloxan may produce diabetes by destroying 

 the cells in the islets of Langerhans, there has been a renewed interest in the effect of 

 alloxan on enzyme systems. Purr^^ has demonstrated that alloxan has the abihty to 

 inhibit papain and cathepsin and Hopkins, Morgan, and Lutwak-Mann^^ have shown 

 the same effect on the succinic dehydrogenase. Alloxan may act as a hydrogen acceptor 

 in enzyme solutions^*' ^^. Gemmill^^ has demonstrated that alloxan may inhibit gly- 

 colysis. The degree of inhibition was proportional to the concentration of alloxan and 

 the inhibition was partially reversed by cysteine. Therefore alloxan may be added to 

 the group of oxidizing agents which can reversibly inactivate glycolysis. It would be of 

 interest to show that the cells in the islets of Langerhans have a glycolytic system 

 which was very sensitive to this reagent. 



Caffeine: Considerable work has been done on the effect of caffeine on glycolysis 

 in the intact muscle. Meyerhof^^ demonstrated that caffeine increased lactate formation. 

 Matsuoka^ continued and reported in detail this demonstration. David^^ has shoNvn 

 a large increase in lactate formation in caffeine contracture. Gemmill*", in cell free 

 extracts, was able to demonstrate that caffeine and some theobromine derivatives 

 caused an increase in the rate of glycolysis which was followed by an inhibition. 

 References p. 142 j 143. 



