Clinical Comparison of the Newer Anti-Inflammatory Corticosteroids*
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Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from Ann. rheum. Dis. (1962), 21, 176. CLINICAL COMPARISON OF THE NEWER ANTI-INFLAMMATORY CORTICOSTEROIDS* BY EDWARD W. BOLAND Los Angeles, California, U.S.A. The discovery by Hench, Kendall, Slocumb, and diseases responsive to steroids, the need for drugs Polley (1950) that cortisone has the capacity to with higher therapeutic indices has long been reverse the inflammatory reactions of rheumatoid evident. Among the deficiencies inherent in the arthritis stimulated great research activity in many natural hormones are their suppressive rather than disciplines of medicine. Biochemists, physiologists, curative effect, the ephemeral nature of their benefits, and physicians, gifted with imagination and skilled their failure to halt the natural progression of rheu- in basic research, have contributed a vast body of matoid arthritis even while adequate degrees of knowledge about the mechanisms of adrenocortical improvement and functional rehabilitation are secretion. The rates, cycles, and pathways of their being maintained, and their inhibiting effect copyright. on biosynthesis have been explored; and their dis- endogenous adrenocortical function. position and metabolic fates are now known. Moreover, their usefulness, even as suppressive Much valuable information has also been acquired agents, is severely limited by their multiple physio- about the influence of adrenocortical steroids on logical properties. In addition to their anti- carbohydrate, protein, and electrolyte metabolism, inflammatory effect, they have many other actions, their effects on the processes of inflammation and some of which produce unwanted signs of hormonal immune reactions, their influence on the response of excess. The intrusion of these often prohibits thehttp://ard.bmj.com/ mesenchymal tissues, and their interrelation with administration of doses of sufficient strength to the function of other endocrine glands. Simul- maintain satisfactory improvement. The common taneously, resourceful physicians of many lands undesirable reactions are now well known. They have been making practical application of cortico- include heightened appetite coupled with excessive steroid compounds as treatment agents in a variety weight gain and abnormal deposits of adipose of disease states, including several rheumatic tissue; disturbances of electrolyte metabolism- disorders, and have been critically appraising their particularly sodium and water retention and potas- on September 26, 2021 by guest. Protected merits, deficiencies, and hazards. sium loss, increased capillary fragility, cutaneous Investigators have been especially active in the ecchymoses, thinning of the skin, striae, acne, and chemical development, animal testing, and clinical hypertrichiasis in women, negative calcium balance, assessment of chemically modified derivatives of and osteoporosis; retardation of fibrosis and delayed cortisone and hydrocortisone. Research has been healing; elevation of blood pressure; nervous channelled in this direction with the aim of deter- irritability; masking of infections; and other effects. mining how alterations in formulae influence bio- And, in the course of treatment, unwanted physio- logical function, and, if possible, of devising com- logical actions may promote such complications as pounds with greater therapeutic efficiency than the peptic ulcer, pathological fractures, phlebitis, natural hormones. Since cortisone and hydro- thrombo-embolic phenomena, emotional psychotic cortisone have serious limitations as treatment disturbances, necrotizing vasculitis, and peripheral agents for rheumatoid arthritis and other chronic neuropathy-or they may aggravate certain disease states, such as arterial hypertension, peptic ulcer, * Address delivered at the Royal Society of Medicine, London, diabetes, osteoporosis, and tuberculosis, that may on September 12, 1961. From the Department of Medicine of the co-exist with rheumatoid arthritis. University of Southern California School of Medicine and of St. Vincent's Hospital, Los Angeles, California, U.S.A. Were it possible to modify the chemical structures 176 Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from THE NEWER ANTI-INFLAMMATORY CORTICOSTEROIDS COMPARED 177 of the basic steroids in such a way as to eliminate or accordance with which halogen-i.e. chlorine, attenuate those biological functions that promote fluorine, iodine, or bromine-was substituted. objectionable "side-effects" and complications, while For example, 9-alpha fluorohydrocortisone, or retaining their potent anti-inflammatory action- fludrocortisone as it was later named, proved to be that is to split off the desired from the undesired ten to fifteen times more powerful than the parent properties then suppressive drugs with greater hormone in promoting glycogen deposition and therapeutic efficiency could be created. suppressing anti-inflammatory responses in the rat; and it was fifty times more potent in retaining salt DEVELOPMENT OF CHEMICALLY-MODIFIED (Borman and Singer, 1954; Borman, Singer, and CORTICOSTEROID COMPOUNDS Numerof, 1954). That seemingly minor variations in the molecular Among rheumatoid patients, the antirheumatic composition of adrenocortical steroids might be strength of fludrocortisone was found to be ten reflected by quantitative differences in their bio- times greater than that of hydrocortisone; and it logical properties was suggested by studies which was also ten times more potent in eosinopenic, compared the effects of cortisone and hydrocortisone ACTH suppressing, and nitrogen wasting effects in laboratory animals. In 1945, four years before (Boland and Headley, 1954). Our own clinical the anti-inflammatory effect of cortisone was experiences with the compound in 1954 led to discovered, hydrocortisone, which differs from considerable early enthusiasm, but this was soon cortisone in only one structural detail-namely, the dampened when it became obvious that the sodium- presence of a hydroxyl radical rather than a ketone retaining and potassium-losing properties of the group at the eleventh carbon position of the phen- compound were enhanced to a much greater degree anthrene ring-was found to have greater physio- than its anti-inflammatory activity (Boland, 1955). logical activity. Results of muscle-work tests, liver After a few days of administration, pronounced glycogen assays, and observations of the regressive oedema developed in most of the patients; and this precluded its practical application systemically as changes produced in the thymus and adrenal glands an copyright. indicated that hydrocortisone has twice the potency anti-inflammatory drug. Nonetheless, observations of cortisone (Ingle and Kuizenga, 1945; Pabst, with 9-alpha fluorohydrocortisone led to the inescap- Sheppard, and Kuizenga, 1947). Moreover, twice able conclusion that the mineralocorticoid, gluco- as much cortisone as hydrocortisone was required corticoid, nitrogen anti-anabolic, and antiphlogistic to promote equivalent eosinopenic responses (Thorn, activities of steroids could be altered profoundly 1950). Subsequently hydrocortisone was shown by and perhaps selectively by modifying their formulae. Since 1953, a multitude of synthetic compounds us (Boland, 1952; Boland and Headley, 1952), and http://ard.bmj.com/ by Hench and Ward (1954) to have greater anti- have been devised by chemists, many of which are rheumatic activity than cortisone. Studies that yet untested, even in animals. Of those that have compared the milligram doses required for the received trial, many have demonstrated differences maintenance of equivalent control of rheumatoid in anti-inflammatory potency and some have manifestations revealed that hydrocortisone was exhibited amplification or attenuation of one or about 30 per cent. more potent. As long as 10 years another biological property. Steroids of therapeutic ago, clinical investigators reported that, with equally interest have resulted from the following chemical effective doses, hydrocortisone is less likely than changes in formulae ofhydrocortisone and cortisone: on September 26, 2021 by guest. Protected cortisone to produce mental excitation and oedema. fluorination at C-9 and at C-6; dehydrogenation at This observation suggested to researchers that subtle C-1-C-2 and at C-6-C-7; methylation at C-2, at changes in chemical composition might selectively C-6, at C-16, and at C-21; hydroxylation at C-16; influence biological properties other than the and desoxygenation at C-21. When introduced anti-inflammatory. singly, each of these modifications alters one or The first indisputable evidence that the functions several biological functions of the parent compound. of the natural corticoids could be altered selectively When introduced in combination, of two, three, or was supplied by Fried and Sabo (1953, 1954). These even more, extremely complex analogues are pro- investigators observed that the addition of halogen duced, some of which exhibit unique, and even atoms at the ninth carbon position of hydrocortisone bizarre, properties. Laboratory and clinical studies caused enhancement of several of its biological conducted with such compounds during the past properties. Most significant was the fact that the 7 years have yielded useful, though still fragmentary, potentiation did not apply with equal intensity to information regarding the structure-function rela- all metabolic functions and that the biological tionship