Metabolic and antirheumatic activities of 6-methylprednisolone (medrol).

During the past few years a concerted effort has been made to develop synthetic derivatives of hydrocortisone and cortisone which would retain their anti-inflammatory activity but would be devoid of certain of their unwanted physiologic effects. Hope that analogues with enhanced therapeutic indices could be synthesized has stemmed from the knowledge that several properties of the naturally occurring hormones may be modified, sometimes selectively, by making changes in their chemical structures. Since 1953 a number of significant innovations have been made in the synthesis of corticosteroid analogues. The first was the introduction, by Fried and Sabo (1953) and Fried (1955), of halogen atoms at the 9th carbon position of the steroid nucleus. The resulting 9-alpha-halogen corticosteroids were in most respects very much more potent than cortisone and hydrocortisone. For example, the potency of 9-alpha-fluorohydrocortisone was found to be ten times that of hydrocortisone with respect to anti-inflammatory, glycogenic, eosinopenic, ACTH-suppressing, and nitrogenwasting activities (Boland, 1955; Liddle, Richard, and Tomkins, 1956). But the electrolyte activity (sodium retention, potassium loss) of the fluoro compound has been found to be at least 125 times that of hydrocortisone, a feature which has precluded its application systemically as an antiphlogistic agent. Another important chemical transformation in the steroid nucleus was the introduction, by Herzog, Nobile, Tolksdorf, Charney, Hershberg, Perlman, and Pechet (1955), of a double bond between carbon atoms 1 and 2 of cortisone and hydrocortisone. The compounds so derived, prednisone and prednisolone, have been found to be approximately four times as potent as their predecessors in anti-inflammatory, glycogenic, ACTH-suppressing, nitrogen-losing, and related properties. However, the 1-dehydro-analogues have exhibited no such increase in electrolyte activity and the partial dissociation of this effect has made them useful therapeutically. Clinical experience with prednisone and prednisolone has demonstrated, however, that they share most of the other shortcomings of the older steroids and, according to some investigators, they have seemed to promote such complications as peptic ulcers and ecchymotic skin lesions with greater frequency (Bunim, Pechet, and Bollet, 1955; Bollet, Black, and Bunim, 1955; Boland, 1956). Hence the quest for more suitable anti-inflammatory steroids has continued. Hogg, Lincoln, Jackson, and Schneider (1955) and Spero, Thompson, Magerlein, Hanze, Murray, Sebek, and Hogg (1956) synthesized a series of methylated corticosteroids. Biologic experiments with these compounds indicated that when a methyl radical was substituted for a hydrogen atom at the second carbon position of the steroid nucleus, the sodium-retaining and potassium-losing effects of 11-hydroxy-corticosteroids were enhanced (Spero and others, 1956; Byrnes, Barnes, Bowman, Dulin, Morley, and Stafford, 1956). But if the methyl grouping were introduced at the 6th carbon position instead, no such increase in electrolyte activity resulted. Preliminary studies in animals with one of the methyl derivatives (6-alpha-methyl-prednisolone) suggested that this compound might have therapeutic promise. Lyster, Barnes, Lund, Meinzinger, and Byrnes (1956) and Glenn, Stafford, Lyster, and Bowman (1957) found the rat-liverglycogen depositing activity of the compound to be sixteen times that of hydrocortisone on oral administration and ten times that of hydrocortisone on subcutaneous administration; the potency ratio of 6-methyl prednisolone to prednisolone was calculated as 3: 1. The anti-inflammatory potency of