THE FOLIC ACID COMPLEX 



Folic acid gives perfectly satisfactory results in the treatment of 

 nutritional anaemias, including pernicious anaemia of pregnancy, 

 nutritional macrocytic anaemia, and the sprue syndromes, because in 

 these conditions there is no danger of spinal cord disease. ^^ The 

 variable results obtained in sprue may be due to the fact that the 

 disease assumes different forms in different places ; thus contrasting 

 results were obtained with Asiatic and non-tropical sprue. 



Etiology of Pernicious Anaemia 



Although the use of liver and liver extracts in the treatment of 

 pernicious anaemia has long been known, the treatment is quite 

 empirical and until recently nothing was known about the way in 

 which liver extracts worked or, indeed, what was the nature of the 

 physiological or biochemical lesion responsible for pernicious anaemia. 

 The theory most generally favoured was that of W. B. Castle, ^^ who 

 suggested that " the haemopoietic factor effective in Addisonian 

 pernicious anaemia is normally formed by the interaction of a gastric 

 (intrinsic) and a food (extrinsic) factor. ... In Addisonian pernicious 

 anaemia, the intrinsic factor is usually absent. ... In other types of 

 macrocytic anaemia also the specific factor in liver extract is lacking 

 as a result of absence of food (extrinsic) or of gastric (intrinsic) factor ; 

 of defective absorption of their reaction products from the gastro- 

 intestinal tract ; or of some combination of these pathogenic factors, "^s 



Castle's theory was re-examined by several workers after the effect 

 of folic acid in haemopoiesis had been discovered. According to 

 Welch et al.,^^ pteroylheptaglutamic acid was ineffective in the treat- 

 ment of pernicious anaemia when given orally and did not become 

 effective when administered simultaneously with or after normal 

 human gastric juice so that it appears unlikely that the conjugated 

 form of folic acid can be Castle's extrinsic factor. The heptaglutamate 

 was likewise ineffective when given intramuscularly, and the amount 

 of folic acid excreted in the urine was not increased, as it was when 

 pteroylglutamic acid, liver extract, or conjugate incubated with con- 

 jugase was injected.^*^ On the other hand, normal subjects exhibited 

 an increased urinary excretion of folic acid following injection of the 

 conjugate, whence it was concluded that normal subjects but not 

 pernicious anaemia patients can utilise the conjugate. Since purified 

 liver extracts added to bone-marrow extracts appeared to bring about 

 the formation of pteroylglutamic acid from the heptaglutamate, it 

 was suggested that liver extract may contain either a component of a 

 conjugase system or a substance capable of counteracting inhibitors 

 of conjugase activity. Similar observations were made and similar 

 conclusions were reached by L. S. P. Davidson and R. H. Girdwood,^^ 



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