A study of some of the toxic reactions of 4-aminofolic acid together with the modifications of these reactions induced by giving varying amounts of folic acid daily to white rats is reported.

Seven groups of young male rats ranging in weight from 110 to 130 Gm. were arranged. Aminopterin (4-aminofolic acid) was given intraperitoneally, in amounts equivalent to 50 micrograms daily, to all rats of six of these seven groups. Folic acid was given by mouth to these animals in such amounts as to provide 5, 10, 20, 30 or 50 mg. daily to each animal respectively of five of the six groups receiving aminopterin. One group received the analogue without the vitamin. One group of 8 animals received neither the vitamin nor its analogue.

Observations continued for six days, when all surviving animals were killed and necropsy was performed. Data were assembled on the appetite, body weights, the weights of adrenals, thymus and spleen, the distribution of leukocytes in the peripheral blood and the changes in the bone marrow. The following conclusions seem warranted:

1. Aminopterin is extremely toxic and incites within six days anorexia, extreme diarrhea with atony of the entire gastro-intestinal tract, adrenal hyperplasia, atrophy of the thymus and spleen, and an inhibition to development of myeloid cells in the bone marrow.

2. Small amounts of folic acid are essentially without effect on the toxicity of that amount of the analogue we chose to administer.

3. Larger amounts of folic acid daily (30 mg.) proved effective in essentially inhibiting the development of the severe toxic reactions for the six-day period.

4. The severe toxicity of aminopterin does not manifest itself until the third or or fourth day of its daily administration. The onset of these symptoms is thereafter extremely rapid.

5. Thirty milligrams of folic acid daily will not indefinitely counteract the toxic symptoms induced by 50 micrograms of aminopterin. In our experience, within twelve to fourteen days, the characteristic syndrome will appear in spite of the continuous administration of the vitamin.

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