The mode of action of cortisone as an antipyretic has been studied in rabbits challenged with intravenous injections of bacterial pyrogens. The fever induced by pyromen or dextran was found to be markedly suppressed when cortisone was administered in liberal amounts (25 mg. twice daily) for 3 days prior to the challenge. Although the cortisone effectively blocked the febrile response to both pyrogens, it failed to influence the transient but marked leucopenia which characteristically precedes the onset of fever.
The antipyretic action of the drug also was shown to bear no relation to the activity of the serum factor recently demonstrated by Farr, Grant, and others to be involved in the production of pyrogen-induced fever. In preliminary experiments with typhoid vaccine as the inciting pyrogen, the presence of serum factor activity in normal blood and its absence in the blood of pyrogen-tolerant rabbits was confirmed. Subsequently the blood of rabbits treated with antipyretically effective doses of cortisone was shown to contain just as much serum factor activity as that of normal rabbits. In addition, previous incubation of the pyrogen with serum factor failed to influence the antipyretic effect of the drug.
It is concluded from these findings that in suppressing pyrogen fever, cortisone acts neither upon the leucopenic reaction nor upon the fever-accelerating factor of the serum. By exclusion it would appear that the drug must influence some later stage of the fever-producing process. The mechanisms involved in the later stages of the response to exogenous pyrogen remain undefined, and the need for determining whether they are related to the prefebrile leucopenia is emphasized.