Depression of one or more parameters of cellular and/or humoral immune responses was found in 60% of general hospital patients treated with
phenytoin and 47% of patients treated with
carbamazepine.
Phenytoin-treated patients failed to manifest
delayed hypersensitivity (DHS) reactions to common
antigens, and to make antibody to Salmonella typhi and
tetanus toxoid. Serum levels of
IgA and
IgM,
DNA synthesis in circulating leucocytes, and phytohaemagglutinin (PHA) induced
deoxyribonucleic acid synthesis were also low. Depression of
IgA, DHS reactivity and antibody responsiveness to S. typhi were shown to develop after the commencement of
phenytoin therapy in a study of eleven patients. The presence of immunological defects was independent of the dosage of
drug, its serum concentration, the
duration of therapy and the sex of the subject. Studies in vitro provided evidence that immunosuppression was the result of a direct effect of
phenytoin on the metabolism of lymphoid cells.
Carbamazepine was shown to have a similar but less potent direct effect. Pharmacological concentrations of
phenytoin caused a significant depression of
DNA synthesis in PHA-stimulated and non-stimulated blood cell cultures in vitro. High concentrations in addition caused depression of cell counts, lymphocyte blastogenesis,
ribonucleic acid and
protein synthesis.
Phenytoin was not cytocidal at concentrations of up to 125 mug/ml. Depression of
DNA synthesis by
phenytoin was maximal when
phenytoin was added within 4-8 hr of the addition of PHA. PHA-induced
DNA synthesis was not significantly affected by pre-incubation with
phenytoin. In vivo, the presence of immunological defects was not related to
phenytoin-induced
folic acid deficiency. High concentrations of
carbamazepine, but not
phenobarbitone or
diazepam caused a significant depression of PHA-stimulated
DNA synthesis in blood cell cultures. The data show that immunosuppression is a common side-effect of
phenytoin therapy, and that
lymphoma is rare. They suggest that in the presence of
phenytoin-induced immunosuppression another factor, or factors are required to induce the formation of
lymphoma.