Folic acid

Editorial Folic Acid

I

N a

recent

groups

joint

announcement,

of investigators1

made

the results of their successful

tion of the structural

formula

two

of

public

megaloblastic

investiga-

sprue factor

of liver Lacto-

associates.

amino}

Its efficacy

has been

by

as an anti-

well established

by

Within

a few days of institution

improved appetite and sense of well being. Relief of glossitis and regeneration of lingual papillae soon follow, along with cessation of

benzoyl]

glutamic acid. As a convenient and appropriate abbreviation for this compound the designation pteroylglutamic acid was

diarrhea which occurs without any significant change in the fat content of the stools. There is a considerable weight gain beginning on the fifth to seventh day, at first largely due to retention of water. The

proposed. The authors also clarified the relationship of liver L. casei factor to fermentation L. casei factor and to Streptococcus faecalis factor, all of which have been included

arrest.

characterized

of therapy there is a marked subjective change characterized by alertness, vigor,

material. The formula established for liver L. casei factor was N-[4-([(2-amino-4-hymethyl]

anemias

the work of Spies2v3 and of Darby4 and their

bacillus casei factor, together with methods of synthesis of crystalline, biologically active

droxy-6-pteridyl)

macrocytic

hemopoietic response is initiated by an increase in reticulocytes on the third to sixth day of treatment, the peak rise usually

R at

times under the general term “folic acid.” It was shown that anaerobic alkaline

acid, subsequently identified. A compound which was active for Str. ,faecaZis R (but not for L. casei or normal growth and hemo-

occurring on the sixth to eighth day and reaching levels similar to those obtained with liver extract. The red blood cell count increases correspondingly, together with a marked rise in platelets and some increase in white blood cells. Bone marrow studies show decrease of megaloblasts with normo-

globin tained

blastic predominance. It is of interest that the response in “non-tropical” sprue is the

hydrolysis converted fermentation L. casei factor -into liver L. casei factor with the liberation of two moles of an alpha-amino

formation in by substituting

the chick) was obp-aminobenzoic acid

for the p-aminobenzoylglutamic in the synthesis

acid

same as in “tropical”

used

of L. casei factor.

sprue, further evidence

that there is no essential difference between these disorders and that both are deficiency states caused by inadequate gastrointestinal absorption of folic acid and probably of other

The chemical identification and synthesis of these compounds marks an important step forward in the study of a new class of substances of exceptional interest. It is already clear that synthetic liver L. casei factor is an effective agent in the treatment 1ANGIER, ROBERT B., BOOTHE, JAMES H., HUTCHINGS,

factors. 2 SPIES, TOM D., VILTER, CARL F., KOCH: MARY B. and CALDWELL, MARGARET H. Observations of the antianemic properties of synthetic folic acid. South. M. J.,

BRIAN L., MOWAT; JOHN H., SEMB, JOSEPH, STOKSTAD, E. L. R., SUBBAROW, Y. and WALLER, COY W. COSULICH, DONNA B., FARHRENBACH. M. 1.. HULTQUIST, M. E., KUH, ERWIN, NORTHEY, .E. H:,~ SEEOER: DORIS R.; SICKLES,J. P. and SMITH, JAMES M., JR. The structure and synthesis of the liver L. casei factor. Science, 103: 667, 1946.

38:707, 1945. 3 SPIES, TOM D. Effect of folic acid on persons with macrocytic anemia in relapse. 3. A. M. A., 130: 474, 1946. 4 DARBY, WILLIAM J., JONES, EDGAR and JOHNSON, HOWARD C. Effect of synthetic Lactobacillus casei factor in treatment of sprue. 3. A. M. A., 130: 780, 1946.

210

AMERICAN

JOURNAL

OF

MEDICINE

Editorial Striking

responses

to synthetic

folic acid

211

cious anemia,

has aroused much speculation

are obtained also in nutritional macrocytic anemia, addisonian pernicious anemia,

as to the relation

pernicious

between

anemia of pregnancy

blastic anemia order, recently

of infancy. This last disdescribed by Zuelzer and

Ogden, jv6 appears infants

under

to be common

in white

the age of eighteen

months.

It is characterized anemia,

and megalo-

by severe normochromic

antianemia

of liver;

particularly

the chemical

structure

of folic acid,

now clarified, and that of liver antianemia principle, as yet unknown. That

the two substances

by a tendency to leukopenia and neutropenia, a decrease in platelets and a megaloblastic bone marrow pattern or one intermediate between the megaloblastic and normoblastic types. The response to treat-

are not identical

as to therapeutic

effects

amount

liver antianemia

of purified

ple which

usually but not always macrocytic;

between folic acid and the

principle

sonian

will produce

pernicious

is evident. remission

anemia

The princi-

in addi-

is much less than

the requisite dosage of pure synthetic folic acid which, moreover, has proven disappointing thus far in the treatment of com-

ment with folic acid is so striking as to indicate that megaloblastic anemia of infants, like sprue and nutritional macrocytic anemia in adults, is essentially a folic acid

bined system disease; consequently synthetic folic acid therapy does not appear to be indicated in addisonian pernicious anemia except in subjects sensitive to liver extract. On the other hand, the efficacy of

deficiency syndrome. Aplastic anemias, iron deficiency

crude liver extracts in sprue and nutritional macrocytic anemia probably derives in large

anemia

accompanying

leukemia,

anemia, anemia

of

prematurity and certain other forms of anemia have proven refractory to folic acid therapy. Satisfactory hemopoietic responses are obtained, apparently, only in macrocytic anemias accompanied marrow. The evidence indicates

by hyperplastic that

pteroyl-

part from their folic acid content. Liver therapy in these disorders is being displaced by synthetic folic acid orally administered. There is one point of similarity in the chemical composition of the two substances: folic acid is a glutamic acid derivative and liver antianemia principle contains a relatively

high proportion

glutamic acid is an important maturation factor, performing some specific function in

The significance,

the maturation

tionship

of erythrocytes

bly also of other

formed

and proba-

elements

of the

blood. This property, together with the remission produced in addisonian perniWOLF W. and OGDEN, FAITH N. Megaloblastic anemia in infancy: a common syndrome responding specifically to folic acid therapy. Am. 3. Dir. Child., 71: 211, 1946. 6 ZUELZER, WOLF W. Folic acid therapy in the anemias of infancy and childhood. 3. A. M. A., 131: 7, 1946. 5Z~~~~~~,

AMERICANJOURNAL

OFMEDICINE

of this amino

is not clear nor is any other chemical between

ent at this time. success achieved of folic may the

acid

the two substances Nevergheless, in elucidating

would

suggest

be ripe for a concerted obscurities

antianemia

acid.

if any, of this circumstance

of the

principle

relaappar-

the striking the structure that

the time

attack

constitution

upon of the

of liver. A. B. G.