Biological Effects of Fluorinated Derivatives of Hydrocortisone and Progesterone in Man

The biological effects of halogenated steroids in animals have been reviewed in this monograph by Doctor Fried and his collaborator^.^-^The high degree of potency which these compounds demonstrated in the animal assays clearly indicated the desirability of a clinical evaluation of their biological activity in It has been possible to test a number of these derivatives of hydrocortisone and to compare their metabolic effects with those of the nonfluorinated parent compounds.Among them, 9-alpha-fluorohydrocortisone appeared to be the most promising from a clinical point of view and was made available in amounts sufficient for adequate clinical testing.The results obtained with other derivatives are to be considered, at present, as preliminary.These studies have been carried out on the Metabolic Ward of the Peter Bent Brigham Hospital, Boston, Mass.The high degree of activity of 9-alpha-fluorohydrocortisone acetate is illustrated in FIGURE 1.The effects of 100 mg. of hydrocortisone acetate and of 5 mg. of fluorohydrocortisone acetate on urinary electrolyte excretion were compared in an Addisonian patient maintained on a constant diet.The two compounds were administered as a single dose by mouth.It is apparent that both sodium retention and potassium diuresis were considerably more marked with the fluorinated compound, indicating at least a twentyfold increase in sodium-retaining activity.Furthermore, when the urinary sodium-to-potassium ratio was followed (FIGURE 2), it appeared that both hydrocortisone and fluorohydrocortisone produced a marked and rapid decrease in this ratio, but that the effects of 5 mg. of fluorohydrocortisone were considerably prolonged as compared to those of 100 mg. of hydrocortisone.The marked effects of 9-alpha-fluorohydrocortisone on organic metabolism are illustrated in FIGURE 3. A patient with Addison's disease maintained on a constant diet was given 25 mg. of the compound as an eight-hour intravenous infusion.The steroid was dissolved in 10 ml. of absolute ethanol and diluted in 500 ml. of saline containing 5 grams of albumin.The metabolic effects obtained were compared with those of a control infusion of saline with alcohol and albumin.A maximal and prolonged eosinopenia, a marked increase in urinary glucose excretion, and a definite rise in the urinary excretion of nitrogen, uric acid, and potassium were observed with fluorohydrocortisone. Urinary glucose was measured by a specific, enzymatic method based on the oxidation of glucose by glucose oxidase.6Employing this method with a patient main-* These studies were supported by funds from the National Institutes of Health United States Public Health Service, Bethesda.Md.