British Journal of Dermatology (1981) 104, 179.

Phantiacolofiv aftd Treatment

Halogenation and topical corticosteroids: a comparison between the 17-butyrate esters of hydrocortisone and clobetasone in ointment bases
C.F.ALLENBY* AND C.G.SPARKESt
*Lister Hospital, Stevenage, Herts S96 2LH and tMedical Department, Glaxo Laboratories Ltd, Greenford, Middlesex Accepted for publication 14 May 1980

SUMMARY

Clobetasone butyrate 005 (Eumovate), a halogenated topical steroid, was compared with hydrocortisone butyrate 0 1 " , , (Locoid) which does not contain any halogen atoms. In the treatment of eczema there was no difference between the preparations, but in that of psoriasis the halogencontaining steroid was significantly more etfectivc. Under normal circumstances neither preparation had any detectable effect on adrenal function, but with large doses under total-body polythene occlusion, circulating cortisol levels were reduced less by the halogenated than by the non-halogcnated preparation. Corticosteroids which contain a halogen atom are often considered to cause more adverse effects than the non-halogenated preparations with similar clinical efficacy. This study shows that this cannot be assumed for their ability to suppress cortisol levels.

During the development of corticosteroids, increased potency has often been achieved by incorporation of substituents {e.g. fluorine at the 6a or 92 position) into the natural hormone cortisol. Increases in topical potency have been associated with increases in topical lipophilic groups in the presence or absence of halogen substituents. However, there is no evidence to support the idea that fiuorination per se is directly related to either the steroids' intrinsic therapeutic activity or their abihty to produce local or systemic side effects. Hydrocortisone butyrate o i ' X does not contain a halogen atom and published work suggested that it may have similar clinical activity to clobetasone butyrate 0-05",, which does contain halogens (Munro& Wilson, 1975; Morley, Fry & Walker, 1976; Stevanovic, Wilson & Sparkes, 1977; Polano& Kaanar, 1973; Takino & Kobayashi, 1975; Yasuda, 1973). It was therefore of interest to compare the two preparations for efficacy and for the ability to affect the HPA axis following percutaneous absorption.
0007-0963/81/0200-0179S02.00 C 1981 British Association of Dermatologists

179

i8o

CFMlenhy and C.G.Sparkes

PATIENTS AND METHODS Comparison of clinical efficacy

Patients were consecutive out-patients with clinically similar bilateral lesions of eczema or psoriasis suitable for treatment with topical corticosteroids. The preparations were allocated at random to left or right side for application twice a day. The study was double-blind. Methods of assessment and analysis were exactly as described previously (Sparkes & Wilson, 1974), with the effects of treatment being recorded at, or as near as possible to, 7 days from the start of the trial. The lesions were rated as healed, improved, static or worse, and whether one side had responded better than the other. The results were analysed by a sequential design (Armitage, i960).
Comparison of effects on HPA axis in patients

Patients with psoriasis or eczema that was sufficiently widespread to need treatment in hospital were randomly allocated on admission to treatment with either hydrocortisone butyrate or clobetasone butyrate ointment. The trial was double-blind with ten patients in each group. HPA function was assessed by response to tetracosactrin at the beginning and end of the trial and also by frequent fasting early morning plasma cortisol estimations. The criteria for normality of the HPA axis were those laid down by Wood et al. (1965). The methods and assessment were as previously described by Allenby et al. (1975), in which the extent of the disease was graded from one to four.
Comparison of effects on HPA axis in volunteers

Hydrocortisone butyrate or clobetasone butyrate ointments were used by all volunteers with random allocation to first or second test week. The trial was double-blind. In each test week five male volunteers with normal skin had blood samples for cortisol estimation taken at 9 a.m. each day from Monday to Friday. Over the 12-hour periods of Tuesday and Wednesday nights they applied 60 g of ointment to their trunk, arms and legs under polythene occlusion. After a gap of at least four weeks they used the comparison ointment in the same way.
RESULTS Comparison of clinical efficacy

Forty-seven patients were included in the trial. The results are shown in Table i and Fig. i. Thirtythree patients were admitted to the eczema section of the trial until the sequential analysis showed that a statistical difference at the 5",, level between the two treatments would not occur. In the psoriasis section however, after fourteen patients had been treated, there was a significant difference in favour of clobetasone butyrate (P<oo$).
TABLK I. The number of times the clinician chose one preparation in preference to the other Clobeiasone butyrate Eczema Psoriasis 8 7 Hydrocortisone butyrate 6 O

Equal 19

Total

33 ' 1 4

Halogenation and topical corticosteroids

Non -occluded psoriasis Non-occluded eczemo to /
5

iSl

Clobetasone l7-butyrQte 15

1 5 1 0 ]5\2O
25

1 30

Number of preferences
-5

\
-10

power 1-0^0-95 ^ HydroCOrtiSOne 17- butyrate -/

-15 -

FIGURE I. Sequential analysis of efficacy for clobetasone and hydrocortisone 17-butyrate

Comparison of effects on HPA axis in patients

The results are shown in Table 2. There were about the same number of patients with eczema as with psoriasis, but there was an uneven distribution between treatments. During the trial all dermatoses improved but only one was cleared. We presume, therefore, impaired barrier function in all but the one patient throughout the trial. All patients used around 200 g of ointment in the 7 days average treatment time. Eighteen of the patients had previously been treated with local steroids before admission and eleven of these had abnormal tetracosactrin tests on admission. In sixteen of these
TABLE 2 .

Number of patients Psoriasis Eczema Total HPA Function Start Locoid Abnormal 4 End Abnormal
2

Normal 5 Abnormal I Starr Normal 4'*

Normal
2

Eumovate

10

Abnormal 7

Normal 3 End Abnormal Normal

Abnormal 2

Normal 4*

*Onc not done at end. One had one day low cortisol.

I82
500 r

C.F.Allenby and C.G.Sparkes

O X O Ciobe^osone 1 7 - b u t y o t e X Hydrocortiscone 17-butyrate

400

300

200 6/ig/IOO ml

100
12 h
Mon Tue Wea

12 h
Thur

* Differences significont p< 0-01

Fri

Doys

FIGURE 2. Plasma cortisol levels in volunteers receiving cither ctobctasone or hydrocortisone 17butyrate.

recovery occurred by the time of discharge whereas in two of those normal on entry there was some abnormality at the end. Of those patients who had normal tctracosactrln tests at the start and end of the trial only one had an abnormally low 9 a.m. plasma cortisol level during treatment. We detect from these results no difference between Eumovate and Locoid.
Comparison of effects on HPA axis of volunteers

The results are shown in Fig. 2. All volunteers had normal 9 a.m. plasma cortisol levels on day one and two of each experimental week (control days). While using hydrocortisone butyrate one volunteer remained normal throughout, one was suppressed after the first night's occlusion and the other three suppressed after the second night's occlusion. When the same volunteers used clobetasone butyrate no significant depression of cortisol levels appeared. All levels returned to normal on the fifth day following a night without application of ointment.
DISCUSSION

When comparing the therapeutic activity of local preparations, statistical differences are not found if the dermatoses chosen for treatment are either easily healed or very resistant to treatment by both preparations. In this trial eczemas were cleared by both local steroids and no differences between them were shown; psoriasis was more slowly and less completely healed and showed the fiuorinated steroid as statistically more effective. Application of the fiuorinated or the non-fiuorinated preparation to in-patients had similar effects on the HPA axis. Of the in-patients treated a number had abnormal HPA function on admission, presumably induced by out-patient local corticosteroid applications. When they were treated in hospital and the skin healed and barrier function was restored, the adrenal function of most of them either improved or returned to normal. Two patients, however, developed

Halogenation and topical corticosteroids

183

abnormal adrenal function during treatment thougb without total suppression. One of these was being treated with hydrocortisone butyrate, the other with clobetasone butyrate. Under occlusivc experimental conditions in normal subjects adrenal function suppression occurred with the non-fiuorinated hydrocortisone butyrate but not with the clobetasone butyrate wbich is fiuorinated. It has been shown that the number of halogen atoms is unrelated to a product's ability to produce side effects; clobetasol propionate contains the same number of halogen atoms as clobetasone butyrate but the former suppresses adrenal function (Allenby et ai, 1975; Staughton & August, 1975) and thins skin to a much greater extent than the latter (Munro & Wilson, 1975; Morley et al.y 1976; Sparkcs, 1976; Winter & Wilson, 1976; Stevanovic et al., 1977; Dykes & Marks, 1977); tbe degree of atrophy caused by steroids is not necessarily directly related to their anti-inflammatory potency (Smith, Wchr & Chalkcr, 1976); fluorination is not necessary for potent anti-inflammatory effect (Stewart et aL, 1973; Young, Yoxall & Wagner, 1977); and we now show that fJuorination is not related to the ability to depress adrenal function. We feel therefore that the word 'fiuorination' associated with steroids should be discontinued as it tends, incorrectly, to be associated with efficacy and the ability to produce side effects.

REFERENCES
ALLENBY, C.F., MAIN, R.A., MABSDEN, R . A . & SP.^RKES, C . G . (I97S) Effect on adrenal function of topically

applied clobeiasol propionate (Dermovatc). British Medical Journal, 4, 619. ARMITAGH, P. (i960) Sequential Medical Trials. Blackwcll Scientific Publications, Oxford. DYKES, P.J. & MARKS, R, (1977) The atrophogcnicity of i",, hydrocortisone plus 10"^ urea (AJphaderm)a comparison with other corlicosteroids. Clinical Trials Journal, 14, 139. MuNHO, I),D. & WILSON, I. (1975) Clobetasone buiyrate, a new topical corticosteroidclinical activity and effects on pituitary adrenal axis function and model of atrophy. British Medical Journal, 2, 626, MORLEY, N . , FRY, L . & WALKHK, S.R. (1976) Clinical evaluation of clobetasone butyrate in the treatment of children with atopic eczema, and its effect on plasma corticosteroid levels. Current Medical Research and Opinion, 4, 233. PoLANO, M.K. & KAANAR, P . (1973) A clinical trial with hydrocortisone butyrate cream in eczema. British Journal of Dermatology, 88, 83. SMITH, J.G., WEHR, R . F . & CHALKER, D . K . (1976) Corticosteroid-induced cutaneous atrophy and telanglectasia. Archives of Dermal ology, II2, I115. SPARKES, C.G, & WILSON, L . (1974) The clinical evaluation of a new topical corticosteroid, clobetasol propionate. British Journal of Dermatology, 90, 197. SPARKES, C.G. (1976) Measuring adrenal function in out-patients using topical corticosteroids. British Journal of Dermatology, 94, suppl. 12, 77. STAUGHTON, R . C . D . & AUGUST, P.J. {1975) Cushing's syndrome and pituitary-adrenal suppression due to clobetasol propionate. British Medical Journal, 2, 419. STEVANOVIC, D.V., WILSON, L . & SPARKES, C.G. (1977) A separation of clinical from epidermal thinning effect in the topical glucocorticoid clobetasone butyrate. British Journal of Dermatology, 96, 67.
STEWART, W.D., RUNIKIS, J.O., VEKMA, S.C. & WALLACE, S. (1973) Problems of selection of topical anti-inflam-

matory corticosteroids. Canadian Medical Association Joimml, 108, 33. TAKINO, C. & KOBAYASHI, S. (1975) Experience with topical hydrocorrisone 17-butyrate (Locoid) with special reference to long term application of topical fiuorinated steroids. Nishikon Journal of Dermatology, 37, 452. WINTER, G . D . & WILSON, L . (1976) Corticosteroid induced atrophy in the skin of the domestic pig. In: Mechanisms of 'Topical Coriicosteroid Activity. Churchill Livingstone, London.
WOOD, J.B., FRANKL.'VND, A.W., J.\MES, V . H . T . & LANDON, J. (1965) A rapid test of Adrenocortical function.

Lancei, t, 243. YASUDA, T . (1973) A controlled double-blind trial on clinical effects of a topical preparation of hydrocortisone 17-butyrate. Progress of Aledicine, 85, 151.
YOUNG, J.M., YOXALL, B.E. & WAGNER, B . S . C977) Corticosteroid-induced dermal atrophy in the rat. Journal

of Invesligative Dermarology, 69, 458.