210 PTEROYLGLUTAMIC ACID 



worm infestation, and those following gastrectomy, intestinal strictures, 

 blind loops, and short-circuiting operations or fistulae. Megaloblastic ane- 

 mia sometimes occurring in cases of chronic liver disease is also probably 

 due to a "conditioned" deficiency of vitamin B12 . These anemias are dis- 

 cussed in connection with the pathology of vitamin B12 , but it is pertinent 

 at this time to consider certain disturbances of PGA metabolism which 

 may be encountered in them. Soon after PGA and certain of its conjugates 

 became available for clinical trial their effect was observed in pernicious 

 anemia. For a more detailed account of the early therapeutic experiences 

 with PGA and related compounds, with complete bibliography, reference 

 should be made to the review of Jukes and Stokstad.^^"* A reticulocyte 

 response, a rise in erythrocyte values, a conversion of marrow megaloblas- 

 tosis to normoblastosis, and symptomatic improvement occurred in essen- 

 tially every case of pernicious anemia in relapse treated with PGA. The 

 conjugates of PGA, pteroyldiglutamic and pteroyltrigiutamic acids, were 

 also found to be effective, although the number of patients receiving these 

 compounds was much smaller than that treated with PGA itself. On the 

 other hand, the "hexaglutamyl conjugate," also known as pteroylhepta- 

 glutamic acid, failed to produce responses in several patients treated by 

 two independent groups of investigators. ^^^' ^'^^ This is not invariably true, 

 since a few patients have subsequently been observed who responded in 

 some degree to the administration of this conjugate. ^^'^ The impaired utiUza- 

 tion of pteroylheptaglutamic acid by patients with pernicious anemia, 

 which appears to be a quantitative defect, gains special significance from 

 the fact that a large part of the dietary PGA is in the form of this conjugate. 

 Demonstration of the effectiveness of PGA in the treatment of pernicious 

 anemia raised the question of the relationship of the compound to the 

 active principle in liver known as the erythrocyte maturing factor (EMF). 

 It was at once apparent that the two substances could not be identical for 

 the following reasons. First, although liver is a rich source of PGA or re- 

 lated compounds, the processes of fractionation and purification yielding 

 the most active anti-pernicious anemia extracts eliminate almost all the 

 PGA originally present. Second, the weight of the total nitrogenous solids 

 present in a volume of concentrated parenteral liver extract sufficient to 

 treat a pernicious anemia patient for 15 days (15 U.S. P. units per milli- 

 liter) is far less than the quantity of PGA recjuired for the same purpose 

 (50 to 75 mg.). Third, the relative efficacy of liver extract given by intra- 



i»^ T. H. Jukes and E. L. R. Stokstud, Physiol. Revs. 28, 51 (1948). 



198 F. H. Bethell, M. C. Meyers, G. A. Andrews, M. K. Swendseid, O. D. Bird, and 



R. A. Brown, J. Lab. Clin. Med. 32, 3 (1947). 

 i9« R. W. Heinle and A. D. Welch, Ann. N. Y. Acad. Sci. 48, 343 (1946). 

 '" A. D. Welch and R. W. Heinle, Pharmacol. Revs. 3, 345 (1951). 



