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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 *

BY

EDWARD W. BOLAND Los Angeles, California, U.S.A.

The discovery by Hench, Kendall, Slocumb, and diseases responsive to , the need for drugs Polley (1950) that 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 . 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 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 coupled with excessive compounds as treatment agents in a variety 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, , and chemical development, animal testing, and clinical hypertrichiasis in women, negative calcium balance, assessment of chemically modified derivatives of and ; retardation of fibrosis and delayed cortisone and . Research has been healing; elevation of ; nervous channelled in this direction with the aim of deter- ; masking of ; 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 , and peripheral agents for and other chronic neuropathy-or they may aggravate certain disease states, such as arterial , peptic ulcer, * Address delivered at the Royal Society of Medicine, London, , osteoporosis, and , 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 , iodine, or bromine-was substituted. objectionable "side-effects" and complications, while For example, 9-alpha fluorohydrocortisone, or retaining their potent anti-inflammatory action- 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 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, 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 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 , 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 of steroids. characters of the artificial compounds differed in During the past 10 years, our group has assessed, Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

178 ANNALS OF THE RHEUMATIC DISEASES on either long-term or short-term basis, the anti- out long-term treatment studies with each of them, rheumatic effects of 33 different analogues (Boland, and in this communication an attempt is made to 1961a, b). Some of these, together with their summarize in general terms their relative merits and antirheumatic potencies as determined among disadvantages. rheumatoid patients, are listed in the Table. The chemical formulae of the original cortisone and hydrocortisone and the eight therapeutic derivatives are shown in the Figure TABLE (opposite). ANTIRHEUMATIC POTENCIES OF CERTAIN CHEMICALLY MODIFIED ADRENOCORTICAL STEROID COMPOUNDS and

Potency Times that of Herzog, Nobile, Tolksdorf, Charney, Hershberg, Prednisolone (taking Perlman, and Pechet, 1955) introduced a double Prednisolone as 1 0) Compound bond at the first and second carbon position of Range (individual Average cortisone and hydrocortisone, thereby producing cases) their delta-l analogues, prednisone and prednisolone. * Prednisolone and Prednisone .. Dehydrogenation at this position was found to 6-meth/vl Analogues enhance anti-inflammatory potency and glycogen * 6 ac- (Methylprel- deposition without causing a corresponding increase nisolone)0.. I O - 2 0 6 ac-methyl, 9 a-fluoro, 21-desoxypred- in electrolyte activity (Bunim, Pechet, and Bollet, nisolone.. 0... 2S- O 5 1955). Each synthetic analogue that has been mar- 16-methyl Analogues keted since 1955 has contained this chemical altera- 16 ac-methylhydrocortisone 0 3 -- 1.0 16 a-methyl, 9 a-fluorohydrocortisone 2 5 -- 4 -2 tion. Prednisone and prednisolone possess similar 16 a-methylprednisolone I 0-- 1 7 adrenocortical 16 xc-methylprednisone. 10-- 1 3 activity. As measured by eosinopenic 16 - 1 3-methylprednisolone 10- 5 response, liver glycogen deposition, and thymuscopyright. 16 r3-methylprednisone. 10-- 1 2 * 16 ct-methyl, 9 a-fluoroprednisolone involution in adrenalectomized mice, the biological () 5 0 --10.0 * 16 fi-methyl, 9 at-fluoroprednisolone activity of prednisone and prednisolone has been () 6 0 -- 8 0 shown to be three to four times greater than that of 16 ac-methyl, 9 ac-fluoro, 21-desoxypred- nisolone.. .. 1.0-- 1 6 hydrocortisone. 16 ct-methyl, 9 a-fluoro, 6-dehydropred- nisolone. 5 -0 --10.0 An attempt will now be made to review briefly * 16 a-methyl, 6 ac-fluoroprednisolone our clinical evaluations of prednisolone and pred- () 2 5 -- 3 5 on nisone, based observations made during long-http://ard.bmj.com/ 16-hydroxy Analogues term treatment more 16 c-hydroxyprednisolone 0 25-- 0 75 studies of than 400 patients * 16 ac-hydroxy, 9 ac-fluoroprednisolone with rheumatoid arthritis treated with the com- (). 1.0-- 1 5 16 a-hydroxy, 6 ac-fluoro, 9 ac-fluoro- pounds over a 5-year period. The antirheumatic prednisolone 1 8-- 2 5 16 xc-hydroxy, 6 x-fluoroprednisolone 0 3 -- 0 6 potencies of prednisone and prednisolone per milligram are, on an average, approximately four 6-fluoro Analogues * 6 ac-fluoroprednisolone () 3 - 4 2 times greater than those of hydrocortisone-the * 6 oc-fluoro, 16 a-methylprednisolone range in our cases (Paramethasone) 2 5 -- 3 5 being from 2-4:1 to 5-3:1 6 a-fluoro, 16 ac-methyl, 9 xc-fluoropred- (Boland, 1956). Accordingly, the doses required on September 26, 2021 by guest. Protected nisolone. 5 0 --9 3 6 a-fluoro, 9 ac-fluoro, 16 x-hydroxy- are smaller than with hydrocortisone. In our prednisolone I 8-- 2 5 practice, the upper 6 a-fluoro, 16 ac-hydroxyprednisolone 0 3 - 0- 6 limits for maintenance doses have been 10 to 12 5 mg. a day for severe cases, Miscellaneous Analogues 9 a-fluoro, 21-desoxycortisone 0 2 -- 0 5 7-5 to 10 mg. for moderately severe cases, and 9 c-fluoroprednisolone. 3 0 -- 5 -0 5 to 7 5 mg. for moderate cases. Dosage com- 9 ac-fluoro, 21-methvlprednisolone 1.0-- 1 67 6 a-fluoro, 9 a-fluoro, 21-methylpred- parison studies of 22 patients revealed that pred- nisolone. I10 -- 1 75 nisone and prednisolone were approximately equal

* in milligram potency; and our subsequent experience Compounds described in this paper. has justified the impression that in equal doses the two congeners promote about the same initial Eight of the compounds have been introduced suppression, maintenance of improvement, and commercially as therapeutic agents for rheumatoid adverse reactions. arthritis and other responsive disease states; these Among patients not previously treated with are prednisone, prednisolone, methylprednisolone, steroids, the pattern of improvement resulting from triamcinolone, dexamethasone, betamethasone, flu- suppressive doses of comparable antirheumatic prednisolone, and paramethasone. We have carried strength is much the same with prednisone and Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

THE NEWER ANTI-INFLAMMATORY CORTICOSTEROIDS COMPARED 179

CH20H C=O

OH -OH

HYDROCORTISONE CORTISONE

CH20H CH20H C=O c=O OH OH OH

0

CH3 PREDNISOLONE PREDNISONE METHYL PREDNISOLONE (A'-hydrocortisone) ( d'-cortisone) (6a-methylprednisolone) copyright. CH20H CH20H CH20H C=O C=O C=O OH H OH-O OH CH3 H3 http://ard.bmj.com/ TRIAMCINOLONE DEXAMETHASONE BETAMETHASONE <16a-hydroxy, 9a-fluoroprednisolone) (16a-methyl, 9a- fluoroprednisolone ) (16b-methyl,9a-fluoroprednisolone)

OHN on September 26, 2021 by guest. Protected

F FLUPREDNI SOLONE PARAMETHASONE (6a-fluoroprednisolone) (16a-methyl, 6a-fluoroprednisolone) Figure.-Chemical formulae of cortisone, hydrocortisone and derivatives. Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

180 ANNALS OF THE RHEUMATIC DISEASES prednisolone as with hydrocortisone and cortisone. able reactions. Observations made among 109 Statistical results of the improvement status among patients, whose was transferred directly our patients after the first few months of treatment from hydrocortisone to the analogues, allowed were similar with delta-1 analogues and hydro- comparisons to be made with respect to the incidence cortisone, but the results of long-term therapy were and character of hormonal side-effects. Four significantly better with the analogues. As with the general deductions were made: older steroids, the number of patients showing adequate response declined as treatment was con- (1) The total incidence of side-effects is not tinued over the months, and overall results varied lowered when prednisone or prednisolone inversely with disease severity and duration. After is substituted for hydrocortisone in smaller prednisone or prednisolone had been administered but equally potent antirheumatic doses; continuously for one year, 55 per cent. of the (2) The number of side-effects is increased patients retained satisfactory degrees of control. when the analogues are employed in Our observations, as well as those of others, dosages that exceed equivalently potent indicate that prednisone and prednisolone are doses of hydrocortisone; capable of maintaining satisfactory response among patients who are amenable to hydrocortisone (3) Prednisone and prednisolone differ from therapy. In one of our early studies, medication hydrocortisone in their tendency to promote was changed to one of the analogues in 39 patients certain individual side-effects; who at the time were responding well to hydro- (4) The occurrence of undesirable physiological cortisone. At the end of one year, 35 of them had effects is contingent, as with hydrocortisone, retained adequate improvement. Deterioration in on individual patient susceptibility, the size the remaining four patients, we believed, could be of the dose employed, the duration of attributed to the development of steroid resistance sex. administration, and copyright. from prolonged therapy rather than to refractoriness to prednisone or prednisolone per se. Prednisone and prednisolone differ from hydro- Among seventy patients, we attempted to deter- cortisone in their proclivity for individual unwanted mine whether prednisone and prednisolone were effects. After transfer of medication from hydro- capable of improving the status after satisfactory cortisone, the incidence of salt and water retention control with hydrocortisone had been lost. This and raised blood pressure are greatly reduced. group was a stubborn one and for the most part Conversely, digestive complaints, peptic ulcers, consisted of patients with more severe disease states vasomotor symptoms, and cutaneous ecchymoseshttp://ard.bmj.com/ whose conditions had regressed after having taken develop more frequently (Boland, 1957, 1959). hydrocortisone in relatively large amounts (average Other undesirable reactions, such as facial mooning, 46 mg. per day) for long periods (average 19 months). fat pads, nervous excitation, , acne, In most instances, the dosages for individual skin tabs, disturbances in tolerance, and patients were considered maximal with respect to osteoporosis, seem to appear with similar frequency adverse effects or prudency. Nearly one-half of when comparable antirheumatic doses are pres-

the patients recovered and maintained their previous cribed. It has been shown that the incidences of on September 26, 2021 by guest. Protected improvement after transfer to prednisone or pred- digestive complaints and of roentgenographically nisolone, although the dosages used were slightly identified ulcers are substantially reduced when larger in terms of antirheumatic strength. As non-absorbable are taken with each dose prednisone or prednisolone therapy was continued, of the drugs, and that the incidences are then no and the period of steroid administration was further greater than during hydrocortisone administration prolonged, improvement again waned in certain (Boland, 1958a; Boland and Headley, 1958). patients; but in 34 per cent. of this recalcitrant Like most investigators, we prefer prednisone or group management remained successful for more prednisolone to hydrocortisone and cortisone for than 2 years. The acquisition of higher levels of rheumatoid patients requiring steroid therapy. The improvement with the analogues could be attributed reasons for this choice are their lower tendency to in some patients, but not all, to the fact that an produce salt and water retention and potassium absence of salt and water retention permitted the loss, their ability to restore improvement in a signi- employment of more effective doses. ficant percentage of patients after improvement from An important question to which we sought an hydrocortisone has deteriorated, and the better answer is how prednisone and prednisolone differ statistical results on long-term administration. It from hydrocortisone in their proclivity for undesir- seems justified to conclude, then, that the thera- Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

THE NEWER ANTI-INFLAMMATORY CORTICOSTEROIDS COMPARED 181 peutic indices of prednisone and prednisolone are much in antirheumatic strength; on an average, higher than those ofcortisone and hydrocortisone. methylprednisolone was estimated to be about 20 per cent. more potent per milligram. The character and degree of improvement that resulted Methylprednisolone from methylprednisolone employed as initial therapy were identical with those which would be anticipated Hogg, Lincoln, Jackson and Schneider (1955) and from prednisolone given in somewhat larger milli- Spero, Thompson, Magerlein, Hanze, Murray, gram amounts. Among patients being maintained Sebek, and Hogg (1956) synthesized and tested on either drug, transfer of medication from one to biologically a number of steroids with a methyl the other did not interfere significantly with the group at the sixth carbon position. Their interest state of improvement. in compounds that contained such a modification The type, incidence, and degree of adverse reac- was prompted by knowledge that the sixth carbon tions were essentially the same as from prednisolone, position was important in the process of metabolic although its proclivity to salt retention was thought oxidation. It was thought that the presence of a to be less. Our studies did not permit true com- substituent at C-6 might slow down the enzymatic parisons of incidence of peptic ulcers and osteo- reduction which causes the inactivation of cortico- porosis resulting from the use of the two compounds steroids and thus increase the intensity and/or -and, unfortunately, such data have not been forth- duration of their action. Biological experiments coming from other sources. in animals disclosed that, in contrast to methylation From these initial observations and from a at the second carbon position, the introduction of subsequent larger clinical experience, the conclusion a methyl group at C-6 tended to potentiate the anti- was reached that methylprednisolone is a satis- inflammatory property without increasing electro- factory antirheumatic agent; but that in comparison lyte activity. The liver glycogen depositing activity with prednisolone it does not exhibit clear-cut of methylprednisolone was found to be sixteen advantages or disadvantages. Since both compounds times greater than that of hydrocortisone. As promote similar responses in previously untreated copyright. measured by the granuloma pouch technique, its patients, uphold clinical improvement equally well anti-inflammatory activity was 5 - 5 times greater on long-term administration, and provoke adverse than that of hydrocortisone and twice that of pred- effects which, for the most part, are similar in kind and nisolone. These findings suggested that methyl- frequency, it would appear that their therapeutic prednisolone might possess a partial dissociation of indices are about equal. In the United States, properties-one that might be interesting and useful methylprednisolone is, at the present time, used clinically. other steroid. This may be http://ard.bmj.com/ During 1956 and 1957, we collaborated with more widely than any Dr. Grant Liddle of Vanderbilt University in the attributed to the fact that physicians and patients study of the metabolic and antirheumatic effects of alike seem to have a penchant for new drugs, that it methylprednisolone (Boland and Liddle, 1957). has been successfully promoted by its manufacturer, Dr. Liddle's metabolic studies indicated that in and that it produces no peculiar "new bad effects" human subjects the sodium-retaining and potassium- of its own. losing activities of methylprednisolone were slightly, but not conclusively, less than those of prednisolone. Triamcinolone on September 26, 2021 by guest. Protected The compound was found to be at least as powerful as prednisolone as a nitrogen-wasting agent, and it Bernstein, Lenhard, Allen, Heller, Littell, Stolar, produced the same degree of pituitary-adrenal Feldman and Blank (1956) created several com- functional inhibition when it was given in equal pounds containing an hydroxyl radical at the C-16 milligram doses. Furthermore, the reductions in position. This substitution uniformly lessens gluco- the number of eosinophils which occurred during corticoid potency and drastically reduces mineralo- administration of the compound did not differ corticoid activity. The presence of an hydroxyl significantly from those noted with equal milligram group at C-16 practically eliminates the severe amounts of prednisolone. sodium retention which results from 9-alpha From clinical observations in 41 rheumatoid fluorination and allows compounds containing this patients we were permitted to make certain deduc- substituent to be prescribed systemically. tions. Direct comparisons of dosages required to Triamcinolone is a complex steroid which differs uphold similar degrees of clinical improvement were from prednisolone by the addition of an hydroxyl made in nineteen patients, and these revealed that radical at C-16 and a fluorine atom at the C-9 posi- methylprednisolone and prednisolone did not differ tion (Figure). Biological assays reveal that its glyco- Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

182 ANNALS OF THE RHEUMATIC DISEASES gen deposition activity is thirteen times greater than to produce such objectionable reactions as mental that of hydrocortisone-and that its anti-inflamma- irritability, hirsutism, acne, striae, vasomotor tory strength, as measured by granuloma formation, symptoms, glycosuria, and dyspepsia. Although is four times greater. Sodium retention is not pro- conclusive data are not available, the same is voked by the drug; but, on the contrary, marked probably true for osteoporosis, peptic ulceration and diuresis and sodium removal are produced in its complications, and vasculitis. In our experience, adrenalectomized rats loaded with salt, and even the incidence and severity of thinning and friability in normal rats and . Balance studies in of the skin, increased fragility of the cutaneous human subjects indicate that the agent produces capillaries, and ecchymotic lesions are greater with slight losses of nitrogen, calcium, and phosphorus triamcinolone and dexamethasone-both of which with dosages in therapeutic range, and that sodium contain a 9 a-fluoro substituent-than with other often occurs during the first few days of steroids. administration. Among the unique unwanted effects of triam- From the experiences of Freyberg, Berntsen, and cinolone are anorexia, weight loss-sometimes with Hellman (1958), and as a result of our own long- notable wasting of subcutaneous and muscle tissue term observations of 62 rheumatoid subjects muscle weakness, leg cramps, nausea, cutaneous (Boland, 1960), a comparison of the effects of erythema, dryness and burning sensations, general- triamcinolone and prednisolone may be summarized ized , and dizziness. The occurrence rates as follows: for some of these have been substantial: anorexia in On a weight for weight basis, the antirheumatic 10 per cent., muscle weakness in 16 per cent., and potency of triamcinolone is somewhat greater (about pronounced weight loss in 18 per cent. These 20 per cent. on average) than prednisolone, and is peculiar effects have been troublesome enough to about equal to methylprednisolone. At dosage discourage its routine use for rheumatoid patients levels up to 12 mg. a day, the compound does not requiring steroid therapy. In our opinion, the drug cause sodium retention-in fact, it may induce may be employed to best advantage as a "specialcopyright. sodium and water diuresis. purpose" steroid. It should be reserved for selected The improvement that results from triamcinolone situations, such as when salt and water retention as initial treatment is similar to that noted from other develops from other steroids or from cardiac steroid compounds possessing powerful antirheu- decompensation, or when excessive appetite and matic activity. In our experience, however, the weight gain are problems in management. percentage of patients that are maintained satis- http://ard.bmj.com/ factorily for long periods of time is distinctly smaller Dexamethasone than with prednisolone and methylprednisolone. This is due principally to the fact that troublesome Arth, Johnston, Fried, Spooncer, Hoff, and side-effects peculiar to the drug frequently intrude Sarett (1958), Arth, Fried, Johnston, Hoff, Sarett, during the course of treatment and make the Silber, Stoerk, and Winter (1958), and Oliveto (1959) transfer of medication to another steroid necessary independently synthesized a family of analogues or prudent. Actually it was found advisable to containing, in common, a methyl grouping at C-16. discontinue triamcinolone in approximately 25 per 16-methylation, like 16-hydroxylation, markedly on September 26, 2021 by guest. Protected cent. of our patients who received the drug as initial reduces the salt-retaining property of 9-alpha treatment and in over 30 per cent. of those whose fluorinated compounds, so allowing them to be used medication was transferred from prednisolone. systemically. By contrast, however, 1 6-methylation When comparable antirheumatic dosages of does not reduce anti-inflammatory potency but prednisolone and triamcinolone are employed, there often increases it greatly (Silber, 1959). Altogether is a considerable difference in the incidence and we have studied eleven different 16-methylated degree of individual unwanted hormonal reactions: compounds. In general, antirheumatic activity Triamcinolone, as already indicated, has less has been decidedly enhanced by the presence of a tendency than any other commercially available methyl group at C-16 if the compound also contains steroid to cause salt and water retention. Oedema, a 9 a-fluoro component; but the potency has been of even a slight degree, is rarely seen-and the drug only slightly increased if the fluoro substituent is is not prone to produce or aggravate arterial absent. hypertension. It has less tendency than other Dexamethasone differs from prednisolone by the steroid preparations to appetite stimulation, and it presence of a methyl grouping at the 16 alpha frequently causes anorexia and weight loss. It seems position and of a fluorine atom at the 9 alpha to have about the same tendency as prednisolone position (Figure). Biological tests have demon- Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

THE NEWER ANTI-INFLAMMATORY CORTICOSTEROIDS COMPARED 183 strated that this analogue is one of the most powerful medication to dexamethasone resulted in the recovery anti-inflammatory steroids yet devised. Its activity, and maintenance of adequate improvement by as determined by thymus involution, is 140-200 times approximately one-third of them for periods of greater than that of hydrocortisone; by granuloma 6 to 9 months. The dosages used, in terms of anti- inhibition, 200 times greater; and by glycogen rheumatic strength, were slightly larger, on average, deposition, twenty times greater. Sodium retention than the calculated equally potent doses. The in animals is not provoked even at high dosage improvement again deteriorated in many cases when levels. Its influence on carbohydrate metabolism treatment was continued for longer periods; but, at was found to be less than on anti-inflammatory the end of 2 years, one-sixth of the group was still activity-a finding that suggested a dissociation of classified as adequately controlled. properties which might be useful therapeutically, An analysis of long-term treatment results for especially in patients with co-existing diabetes 92 of our patients revealed that the increased potency mellitus. Unfortunately, however, studies of its of dexamethasone was not accompanied by a hyperglycaemic effects in man did not justify this lessening of undesirable effects. Actually, the hope. Frawley, Kistler, and Shelley (1959), and overall incidence of unwanted reactions was greater West, Johnson, Kyriakopoulos, Bahr, and Bloedow than from comparably effective doses of predniso- (1960) determined that the hyperglycaemic, as well lone. The steroid had approximately the same as the eosinopenic and adrenal suppressive, potencies proclivity to cause abnormal fat deposits in the face, of dexamethasone parallel its anti-inflammatory supraclavicular, and cervicodorsal regions as well as strength. hypertrichosis, acne, and nervous excitation. Peri- Clinical evaluations with dexamethasone were pheral oedema was noted uncommonly and, even conducted independently by Boland (1958b, c) and then, was mild; its occurrence rate was 7 per cent., by Bunim, Black, Lutwak, Peterson, and Whedon an incidence which was slightly lower than for (1958), and the results were remarkably similar in prednisolone and greater than for triamcinolone. most particulars. Our series embraced 110 patients The steroid demonstrated little or no tendency to who, during the time of analysis, had been treated elevate blood pressure or to aggravate pre-existing copyright. for periods ranging from 12 to 24 months. Direct hypertension. dosage comparison studies revealed that dexa- On the debit side of the balance sheet, however, is about seven times more potent in a number of unfavourable reactions were more antirheumatic activity than prednisolone on a weight common. Most objectionable of these were exces- for weight basis. Among individual patients there sive appetite (in 21 per cent.), excessive weight gain was a rather wide range of potency (1:5 to 1:10). (in 26 per cent.), excessive increase in abdominal However, in the majority of cases, it was 1:6 to 1:8. girth (in 20 per cent.), and abdominal and http://ard.bmj.com/ By calculation, then, dexamethasone is about distension (in 16 per cent.). The frequency and 30 to 35 times more powerful than hydrocortisone. severity of these reactions varied directly with the In our experience, the only steroid that has exhibited size of the maintenance dose; and an effort was made, greater antirheumatic strength is a congener of therefore, not to exceed daily dosages of 1 mg. for dexamethasone that contains in addition a fluorine females and 1 5 mg. for males. Even so, the atom at C-6. The compound-16 a-methyl, 9 a- symptoms were sufficiently troublesome to warrant fluoro, 6 oc-fluoroprednisolone- is about eight times change of medication to another steroid in one-third on September 26, 2021 by guest. Protected more potent than prednisolone. of the cases. Ecchymotic lesions were noted in Among patients not previously treated with 69 per cent. and thinning of the skin in 28 per cent. steroids, dexamethasone prescribed in remarkably Except for triamcinolone, these cutaneous reactions small initial doses, i.e. 0 5 to 2 mg. per day, promoted developed more commonly and more intensively an immediate response and subsequent early than from other steroids; and they worsened as improvement identical to that induced by other dosage was raised and therapy was prolonged. anti-inflammatory steroids given in much larger Digestive symptoms suggestive of peptic ulcer doses. Among our patients, the average main- were uncommon, being experienced by only 2 per tenance dose was I - 13 mg. a day. cent. of the patients. But, after 3 months of A substantial number of patients who had ulti- administration, routine gastro-intestinal x-ray studies mately become relatively refractory to prednisolone disclosed that active peptic ulcers had developed in responded favourably to dexamethasone. In a nine of 91 patients (10 per cent.). Eight of these recalcitrant group of 55 patients, who were suffering nine patients had no digestive symptoms, and in six from severe or moderately severe disease and were the lesions were gastric in location. This incidence poorly controlled by prednisolone, transfer of was almost identical with that which we had found Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

184 ANNALS OF THE RHEUMATIC DISEASES with prednisone or prednisolone among patients of compounds containing 6-fluoro substitutions was subjected to routine x ray examinations (Boland, synthesized (Hogg, Spero, Thompson, Magerlein, 1956). Schneider, Peterson, Sebek, Murray, Babcock, Observations made during the past 3 years have Pederson, and Campbell, 1958). In general, this led us to the conclusion that the general therapeutic modification intensifies anti-inflammatory, glycogen- efficiency of dexamethasone is distinctly less than depositing, and eosinopenic activities, but not to that of prednisolone and methylprednisolone. We such a degree as fluorination at C-9. In contrast do not employ it as a general purpose steroid, but, to the effects of 9 a-fluorination, however, the instead, restrict its use to a very few special situa- addition of fluorine at C-6 does not disturb electro- tions; as when refractoriness may prompt a change lyte metabolism. of medication to another steroid or when appetite The structure of fluprednisolone differs from stimulation and weight gain are desired and cannot prednisolone only by the addition of a fluorine atom be obtained with other compounds. at C-6. In animals its anti-inflammatory strength, as gauged by granuloma inhibition, is approximately eight times greater and its glycogen-depositing Betamethasone activity eighty times greater than that of hydro- cortisone. Results of nitrogen balance assays, Among the various 16-methylated steroids, syn- ACTH suppression, eosinopenic, and hypergly- thesized in 1957 by Arth and others (1958a, b) and caemic studies in man indicated that the compound by Oliveto (1959), several contained the substitution was ten to twelve times more potent than hydro- at the beta rather than the alpha position. These cortisone, or about three times more potent than analogues were of interest because they were the prednisolone (Bowers and Ringold, 1958; Bowers, first ones with a beta-modification that demon- 1959). strated adrenocortical activity. During 1957 and During the past 3 years we have given the drug to 1958, we studied three 16 beta-methyl compounds, 68 rheumatoid patients, 55 of whom have receivedcopyright. including 16 n-methyl, 9 oc-fluoroprednisolone, later continuous administration for one year or longer. named betamethasone. Direct comparisons of dosage requirements in Data made available by the Merck Institute in thirteen patients established that the antirheumatic 1957 and subsequent metabolic studies in man potency of fluprednisolone is approximately 2 5 indicated that the biological characteristics of beta- times greater than that of prednisolone (Boland, methasone paralleled those of dexamethasone. Its 1961a, b). Eleven patients not previously treated average antirheumatic potency, as determined in with steroids were given fluprednisolone in daily nine of our patients, proved to be 6-8 times greater doses of 3 to 6 mg., depending upon disease activity.http://ard.bmj.com/ than that of prednisolone, a figure which was com- The immediate response was the same as for patients parable to that determined for dexamethasone. In given other anti-inflammatory steroids in doses of 1957, and again more recently, we transferred corresponding antirheumatic strength. patients from dexamethasone to betamethasone and The medication of 44 patients was transferred back again, using identical milligram amounts. In from prednisolone to fluprednisolone. Control general, the two congeners have proved to be inter- of rheumatoid manifestations was still adequate on changeable. From our observations of 32 rheuma- prednisolone in twenty patients, but the conditions of on September 26, 2021 by guest. Protected toid patients given betamethasone for periods longer the remaining 24 had declined to inadequate levels. than 6 months, and from the larger experience of In ten ofthese 24resistant cases, satisfactory improve- Kammerer (1961), it would appear that the com- ment was regained after exchange of medication and pound possesses all of the deficiencies of dexa- was maintained thereafter for more than one year. methasone and that its therapeutic index is about This indicated to us that there is a useful place for the same. the drug in the management of patients who initially responded well to prednisolone, but later respond poorly to dosages within prudent therapeutic range. Fluprednisolone Prednisolone and fluprednisolone promote adverse effects which are similar in most particulars. How- Since the addition of a fluorine atom at C-9 caused ever, our observations indicate that fluprednisolone striking changes in steroid activity and since modi- is less inclined to cause excessive weight gain and fications at C-6 were known to interfere with enzy- abnormal deposition of fat. This was evident in matic reduction, it was logical for chemists to the group of 44 patients in whom therapy was introduce fluorine atoms at C-6. In 1958, a series exchanged. After transfer to fluprednisolone, nine Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

THE NEWER ANTI-INFLAMMATORY CORTICOSTEROIDS COMPARED 185 of sixteen patients with excessive weight gains sus- in 24. In twenty of the prednisolone-treated tained losses of from 5 to 16 lb.; and facial mooning patients, the improvement had been graded as and supraclavicular and/or cervicodorsal fat pads inadequate, but with paramethasone six of them decreased or disappeared in ten of 24 patients recovered their previous status. Thus, as with other presenting these changes. Several patients noted compounds, a change of medication to parametha- that appetite lessened following transfer. With sone will sometimes better the condition of patients maintenance doses ranging from 2 - 25 to 7 mg. a day whose rheumatic manifestations have escaped (average 3-5 mg.), salt and water retention was not control. a problem. Our experience suggests that the An analysis of results after 9 months of continuous therapeutic index of fluprednisolone is at least as therapy indicates that the therapeutic efficiency of great as, and probably greater than, that of pred- paramethasone does not differ greatly from that nisolone (Boland, 1960). of fluprednisolone. Direct comparative studies suggest that paramethasone may have a somewhat greater tendency than fluprednisolone to cause such Paramethasone unwanted reactions as weight gain, abdominal A recent product of chemical manipulation is girth, and distension; since the two drugs differ paramethasone (Edwards, Ringold, and Djerassi, chemically in only one respect, the development of 1960), which differs from fluprednisolone by the these side-effects must be influenced by 16-methyla- presence of a methyl grouping at C-16. Biological tion. assays in animals suggested that paramethasone had an interesting skewing of properties. By the cotton-pellet granuloma test its anti-inflammatory Summary strength was approximately fifty times that of hydrocortisone, and figures for its thymolytic Our experience with eight antirheumatic cortico- activity were similar. Its glycogen deposition steroid compounds has shown that none of them copyright. activity was found to be 150 times greater than that approximates to our ideal of a suppressive agent for of hydrocortisone, and mineral assays in adrenal- rheumatoid arthritis and other steroid-responsive ectomized rats without sodium chloride loading conditions. Some of the analogues exhibit quali- revealed that sodium was excreted rather than tative differences in one or another physiological retained (Syntex Laboratories, personal communica- action, but the major deterrent features of cortico- tion). In man, paramethasone caused slight loss of steroids are shared by each of them. Prednisone,

sodium and chloride and little or no loss ofpotassium prednisolone, methylprednisolone, fluprednisolone, http://ard.bmj.com/ when doses of 6 to 15 mg. were given (Irwin and and paramethasone seem to have similar therapeutic Ridolfo, in the press). At a daily dosage level of indices; and there appears to be little to choose 6 mg., the compound promoted little or no increase between them for the ordinary patient who requires in urinary excretion of nitrogen, phosphorus, and steroid therapy. Conversely, because they produce calcium; but at higher doses, such as 15 mg., it unique reactions of their own and because they have exerted definite catabolic effects. greater proclivity to certain troublesome side- In December, 1959, we undertook a clinical effects, the therapeutic indices of dexamethasone, appraisal of paramethasone. From direct com- betamethasone, and triamcinolone are lower than on September 26, 2021 by guest. Protected parison studies in twelve patients, its antirheumatic that of prednisolone; they are less desirable for strength was estimated as 2 8 times greater than that routine use and are best employed for selected of prednisolone, indicating that 1 6-methylation cases as "special purpose" steroids. increased the potency of fluprednisolone only slightly. Our long-term treatment studies with paramethasone are still in progress. They embrace This study was supported, in part, by a grant from a total of 82 rheumatoid patients, 64 of whom have the Ahmanson Foundation. now been observed for longer than 10 months. Ten Grateful acknowledgement is made to the following patients who had never before received steroid pharmaceutical companies for supply of steroids: to initial doses of 4 to 7 a Merck Sharp and Dohme Inc., West Point, Pa., for therapy were given mg. day. prednisone, prednisolone, dexamethasone, and beta- The pattern of their early response followed that methasone; to the Upjohn Co., Kalamazoo, Mich., for produced by other active anti-inflammatory ana- methylprednisolone and fluprednisolone; to Lederle logues. In 62 patients, therapy was transferred Laboratories, Pearl River, N.Y., for triamcinolone; from another steroid-from prednisolone in 32, and to the Eli Lilly Co., Indianapolis, Ind., for para- from dexamethasone in six, and from fluprednisolone methasone. 7 Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

186 ANNALS OF THE RHEUMATIC DISEASES REFERENCES Herzog, H. L., Nobile, A. Tolksdorf, S, Charney, W., Hershberg, E. B., Perlman, P. L., and Pechet, Arth, G. E., Fried, J., Johnston, D. B. R., Hoff, D. R., M. M. (1955). Science, 121, 176. Sarett, L. H.. Silber, R. H., Stoerk, H. C., and Winter, C. A. (1958). J. Amer. Soc., Hogg, J. A., Lincoln, F. H., Jackson, R. W., and chem. Schneider, W. P. (1955). J. Amer. chem. Soc., 80, 3161. 77, 6401. Johnston, D. B. R., Fried, J., Spooncer, W. W., Spero, G. B., Thompson, J. L., Magerlein, B. J., Hoff, D. R., and Sarett, L. H. (1958). Ibid., Schneider, W. P., Peterson, D. H., Sebek, 0. K., 80, 3160. Murray, H. C., Babcock, J. C., Pederson, R. L., Bernstein, S., Lenhard, R. H., Allen. W. S., Heller, M., and Campbell, J. A. (1958). Chem. and Ind. Litteil, R., Stolar, S. M., Feldman, L. I., and (Lond.), 77, 1002. Blank, R. H. (1956). Ibid., 78, 5693. Ingle, D. J.,and Kuizenga, M. H. (1945). Endocrinology, Boland, E. W. (1952). Brit. med. J., 1, 559. 36, 218. --(1955). Anni. N.Y. Acad. Sci., 61, 591. Irwin, G. W., and Ridolfo, A. S. (Data to be published.) --(1956). J. Amer. med. Ass., 160, 613. Kammerer, W. H. (1961). In "Proc. I Conf. Clin. (1957). Med. Clin. N. Amer., 41, 553. Apple. Betamethasone"'. Schering. ---(1958a). In "Progress in Arthritis", ed. J. H. Oliveto, E. P. (1959). Ann. N. Y. Acad. Sci., 82, 809. Talbott and L. M. Lockie, pp. 130-53. Grune Pabst, M. L., Sheppard, R.. and Kuizenga, M. H. (1947). and Stratton, New York. Endocrinology, 41, 55. (1958b). Calif. Med., 88, 417. Silber. R. H. (1959). Ann. N. Y. Acad. Sci., 82, 821. (1958c). Ann. rheum. Dis., 17, 376. Spero, G. B., Thompson, J. L., Magerlein, B. J., Hanze, -(1959). Ann. N. Y. Acad. AMel., 82, 887. A. R., Murray, H. C., Sebek, 0. K., and Hogg, (1960). J. Amer. med. Ass., 174, 835. J. A. (1956). J. Amer. chem. Soc., 79, 6213. -(1961a). Amer. J. Med., 31, 581. Thorn, G. W. (1950). In "Proc. I Clin. ACTH Conf.", ed. J. R. Mote. p. 176. Blakiston, Philadelphia. --(1961b). "Proc. X Int. Congr. Rheum. Dis.", vol. 1, p. 355. Rome. West, K. M., Johnson, P. C., Kyriakopoulos, A. A.,

Bahr, W. J., and Bloedow, C. E. (1960). Arthr.copyright. -and Headley, N. E. (1952). J. Amer. meed. Ass., and Rheum., 3, 129. 148, 981. - (1954). Ann. rheum. Dis., 13, 291. (1958). CaliJf Med., 89, 262. Comparaison clinique des corticosteroides anti-inflam- - and Liddle, G. W. (1957). Anni. rheum. Dis., matoires recents 16, 279. REsuME Borman, A.. and Singer, F. M. (1954). Fed. Proc., Notre experience avec huit composes corticosteroides 13, 185. antirhumatismaux a montre qu'aucun d'entre eux nehttp://ard.bmj.com/ and Numerof, P. (1954). Proc. Soc. Exp. s'approche de notre ideal comme agent de suppression Biol. (N. Y.), 86, 570. dans t'arthrite rhumatismale ou dans d'autres affections sensibles aux steroides. Certains analogues de la Bowers, A. (1959). J. Amer. chem. Soc., 81, 4107. cortisone manifestent des differences qualitatives dans -- and Ringold, H. J. (1958). Ibid., 80, 4423. ses actions psychologiques, mais la plupart des traits Bunim, J. J., Black, R. L., Lutwak, L., Peterson, R. E., decourageants sont communs a tous. La prednisone, and Whedon, G. D. (1958). Arthr. and Rheum., prednisolone, methylprednisolone, fluorprednisolone et 1, 313. paramethasone semblent avoir des indices therapeutiques similaires et pour le malade ordinaire ayant besoin d'un on September 26, 2021 by guest. Protected Pechet, M. M., and Bollet, A. J. (1955). J. Amer. treatement steroide le choix importe peu. Par contre, med. Ass., 157, 311. en raison de leurs reactions specifiques et de certains Edwards, J. A., Ringold, H. J., and Djerassi, C. (1960). effets secondaires nuisibles, les indices therapeutiques J. Amer. chem. Soc., 82, 2318. de la dexamethasone, betamethasone et triamcinolone sont inferieurs a ceux de la prednisolone; pour cette Frawley, T. F., Kistler, H., and Shelley, T. (1959). raison leur emploi courant est peu desirable et it est N. Y. Acad. Sci., 82, 868. preferable de les reserver pour des cas particuliers comme Freyberg, R. H., Berntsen, C. A., Jr., and Hellman, L. "steroides pour usage special". (1958). Arthr. and Rheum., 1, 215. Fried, J., and Sabo, E. F. (1953). J. Amer. chem. Soc., Comparacion clinica de los modernos corticosteroides 75. 2273. anti-inflamatorios -- 1455. (1954). Ibid., 76, SUMARIO Hench, P. S., Kendall, F. C., Slocumb, C. H., and Polley, H. F. (1950). Arch. intern. Med., 85, 545. Nuestra experiencia con ocho compuestos cortico- steroides antirreumrnticos ha mostrado que ninguno de -- and Ward, L. E. (1954). In "Medical Uses of ellos se aproxima a nuestro ideal de un agente supresivo Cortisone", pp. 177, ed. F. D. W. Lukens. para la artritis reumatoide y otras condiciones sensibles Blakiston New York. a esteroides. Algunos andlogos de la cortisone muestran Ann Rheum Dis: first published as 10.1136/ard.21.2.176 on 1 June 1962. Downloaded from

THE YEWER ANTI-INFLAMMATORY CORTICOSTEROIDS COMPARED 187 diferencias cualitativas en una u otra acci6n psicol6gica, porque producen reacciones especificas y porque tienen pero los mayores rasgos repulsivos son compartidos por una mayor tendencia a ciertos molestos efectos secun- cada uno de ellos. Prednisona, prednisolona, metil- darios, los indicios terapduticos de la dexametasona, prednisolona, fluorprednisolona y parametasona aparen- betametasona y triamcinolona son menores que los de la tan tener indicios terapeuticos similares y para el paciente prednisolona; por esta raz6n son menos deseables para ordinario que requiere terapeutica esteroide poco el uso corriente, prefiriendose su empleo para casos importa el cual de ellos se escoge. Contrariamente, seleccionados como "esteroides de efecto especial". copyright. http://ard.bmj.com/ on September 26, 2021 by guest. Protected