EXPERIENCES WITH 9‐ALPHA‐FLUOROHYDROCORTISONE ACETATE IN RHEUMATOID ARTHRITIS

Although hydrocortisone and cortisone have earned import ant roles in the treatment of rheumatoid arthritis, the results from their long-term administration are less than satisfactory in a large proportion of patients. Widened experience with the hormones has led to refinements in methods for their practical application and has increased their utility-but i t has also emphasized their inherent limitations. Chief among the latter, has been a proclivity to produce unwanted physiologic side effects in addition to the wanted antirheumatic action. The intrusion of undesirable reactions during the course of treatment has too often created a barrier to successful management, especially in patients with marked rheumatoid activity who require large daily doses for adequate control of the disease. Thus, clinicians have continued to search for an agent which would provide a specialized anti-inflammatory action and would be devoid of annoying or deleterious effects. Hope that such a substance might be found in the steroid field has been fostered by the knowledge that it is possible to modify several properties of the hormones by substituting various chemical radicals or groupings at one or another carbon position in the steroid nucleus. Indeed, this fact has so excited the imagination of chemists that literally hundreds of synthetic analogs of hydrocortisone and cortisone have been prepared, and a t a rate more rapid than they can be tested therapeutically or experimentally in animals. Like others, we have screened a number of esterified preparations of hydrocortisone and have made clinical comparisons of their antirheumatic activity. I n the spring of 1954, our attention was attracted to a halogen derivative-9alpha-fluorohydrocortisone acetate-which, though not destined as a practical agent for systemic therapy in rheumatoid arthritis, was of interest because it exhibited far greater antirheumatic potency, milligram for milligram, than any steroid we had thus far tested. Interest in the halogen derivatives of hydrocortisone was stimulated by results of animal studies which indicated that they possess unusually high glycogenic activity as measured by rat liver glycogen assays for 11-oxygenated corticoids. demonstrated that the 9-alpha-halo derivatives (chloro, Huoro, iodo, and bromo) manifest both glucocorticoid and mineralocort icoid properties, each in differing degrees. The glycogen deposition activity of the fluoro compound was found to be twice as great and its sodium-retaining effect to be only one-fifth that of the chloro derivative. Compared with cortisone acetate, fluorohydrocort isone acetate was much more potent in glycogenic activity (about 10 times), in producing thymus involution (four times), and in its sodium-retaining effect. Data derived from clinical trials with 9-alphafluorohydrocortisone acetate Fried and Sabo'z '? and Borman, Singer, and Numerof3