Triamcinolone therapy in rheumatoid arthritis.

The introduction of cortisone as an anti-inflammatory agent stimulated the search for newer steroids with greater anti-rheumatic effect, but with fewer associated side-reactions. Shortly afterwards, hydrocortisone became available, and, although its anti-rheumatic effect was slightly greater, undesirable physiological responses were more or less similar. Fried and Sabo (1953) synthesized a corticosteroid analogue with a halogen atom at the 9 carbon position of the steroid nucleus called 9-alpha-fluoro-hydrocortisone. It was very much more potent than hydrocortisone, about ten times greater in anti-inflammatory effect, and with approximately 125 times the mineralocorticoid action (Liddle, Richard, and Tomkins, 1956; Boland, 1955). Marked sodium retention with this halogenated derivative precluded its application for practical use as an antiphlogistic agent in the treatment of rheumatoid arthritis, but it was of some value for patients with Addison's disease where the exaggerated mineralocorticoid effect was desirable. In 1955, a very important chemical structural change resulted in the formulation of prednisone and prednisolone (Herzog, Nobile, Tolksdorf, Charney, Hershberg, Perlman, and Pechet, 1955) when a double bond was inserted between carbon atoms 1 and 2 of cortisone and hydrocortisone, respectively. These newer compounds were equally potent; they were approximately four times as great as their predecessors in glucocorticoid effect, whereas the mineralocorticoid action was diminished. In the usual maintenance dosages for treatment of rheumatoid arthritis, for example, electrolyte changes induced by these delta-1 analogues of cortisone and hydrocortisone proved no problem in clinical management of patients. However, other undesirable physiological reactions still occurred. In the hands of some investigators (Bunim, Pechet, and Bollet, 1955; Bollet, Black, and Bunim, 1955; Boland, 1956), complications with these latter steroids, such as peptic ulceration, have been reported with even greater frequency. In 1955 and 1956 a series of methylated corticosteroids were synthesized. Boland and Liddle (1957) reported that one of these, 6-methyl-prednisolone (Medrol), differed in no essential way from prednisolone itself. The sodium-retaining and potassium-losing activities of this compound were thought to be slightly less than those of prednisolone, but this was not definitely established. The hormone appeared to be at least as powerful as prednisolone in producing nitrogen-wasting; 41 patients with rheumatoid arthritis who received the drug as initial therapy showed no significant difference in degree or character of improvement from that anticipated with prednisone or prednisolone. Dosages were alike. Although the authors stated that their study was not sufficiently extensive properly to evaluate the complications of this new compound, they thought that most of the adverse reactions seen with the older preparations were also observed with 6-methyl-prednisolone. Bernstein, Lenhard, Allen, Heller, Littell, Stolar, Feldman, and Blank (1956) synthesized a new preparation, by adding a 16-alpha-hydroxyl group to the 9-alpha-fluoro-prednisolone structure, and triamcinolone (16-alpha-hydroxyl-9-alpha-fluoroprednisolone) was formulated. This compound eliminated the marked sodium-retaining potency of the previous analogue without diminution of glucocorticoid activity. Animal investigations (Perrine, Bell, Bortle, Heyder, Ross, and Ringler. In the press) revealed that triamcinolone was ten to forty times more active than hydrocortisone and three to twelve times more active than prednisolone in inducing glycogen deposition in fasted adrenalectomized rats. Diuretic and natriuretic potency exceeding that of prednisolone or hydrocortisone was also demonstrated in both adrenalectomized and normal animals. No hypertensive effect was observed in