Neuromuscular Di.sorders, Vol. 1, No. 4. pp. 261 266, 1991 Printed in Great Britain

096~8966/91 $3.00 + 0.00 ~t" 1992 Pergamon Press plc

STEROIDS IN D U C H E N N E M U S C U L A R D Y S T R O P H Y DEFLAZACORT TRIAL L. E. MESA,A. L. DUBROVSKY,*J. CORDERI,P. MARCOand D. FLORES Seccionde EnfermedadesNeuromusculares,Centro Neurologico,Hospital Frances, BuenosAires, Argentina (Received 9 May 1991,"accepted 5 September 1991)

--We conducted a double blind controlled trial in 28 Duchenne muscular dystrophy (DMD) patients with Deftazacort (DF), an oxazoline derivative of prednisolone which reduces its side-effects. Myometric muscle strength measurements, Scott Score and timed tests showed statistically significant improvement for the treated group (P < 0.05). Side-effects after 9 months of treatment included mild cushingoid appearance in four patients (28 %) and moderate in only one (7%), increased appetite in seven (50%), increased body hair in four (28%), irritability and hyperactivity in three (21%). Increased body weight was not prominent and was controlled with dietary measures. No patient had to be withdrawn from medication. More research and longterm follow-up are needed in order to establish the mechanism of improvement and the consequences of long-term steroid administration in DMD. In this regard DF appears as an alternative to prednisone preserving its benefits but with fewer side-effects. Abstract

Key words: Steroids, deflazacort, Duchenne dystrophy, therapeutic trial.

lupus erythematosus, bronchial asthma and others [12]. We have recently reported the benefit of D F vs P in the treatment of myasthenia gravis in an open uncontrolled 1 yr therapeutic trial [13]. We conducted a double blind controlled trial in 28 D M D patients using D F as an alternative to P, in order to reduce its side-effects.

INTRODUCTION

Although major achievements have been accumulating lately regarding the genetics and pathogenesis of Duchenne muscular dystrophy (DMD) [1-3], no effective medical treatment has been found yet. In 1974 the benefits ofcorticosteroid treatment were reported in a group of 14 patients treated with prednisone (P) [4] but the efficacy of this therapy was denied by other authors shortly afterwards [5]. However, in 1987 long-term benefit from such medication was suggested on the basis of the prolonged ambulation period the previously treated patients achieved [6]. In the last 2 yr more carefully developed trials confirmed the improvement of motor function and muscle strength in P treated D M D patients [7-9]. Nevertheless, significant side-effects were reported and they establish a serious limitation for its long-term use. Deflazacort (DF) a new glucocorticoid, oxazoline derivative of prednisolone [10,11] has been shown to reduce the side-effects caused by P and its efficacy has been proved in several autoimune diseases such as rheumatoid arthritis, systemic

*Author to whom correspondenceshould be addressed.

MATERIALS AND METHODS

A total of 28 D M D patients, 5-11 yr old, were included. The criteria for the diagnosis of D M D are described elsewhere [14]. No patients still walking over 11 yr were included. No patient lost the ability to walk during the trial. Two groups of 14 patients each were formed after an initial evaluation designed to balance the scores and composition of the groups. One group receiving 1 mg kg-1 day-~ of D F and the other receiving placebo. Capletts containing 6 mg of D F or placebo were prepared by Lepetit Laboratories. Physical evaluation was carried out by two physical therapists with cross-check training and clinical evaluations including side-effects were performed by a paediatric neurologist. From our evaluating protocol the Scott Score [15], timed functional tests and myometric evaluation of 10 muscle groups in the lower extremities were selected for statistical analysis.

261

262

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PLACEBO ( n = l 4)

T

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DEFLAZACORT (n=14)

3.5# p < 0.05 ~ 5% 5-10% 11-20% > 20%

6months PL

9 m o n t h s DF

9 m o n t h s PL

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5 1 8 0

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(65) (28) (7) (0)

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(21) (63) (7) (7)

slight increase in body hair which was noted also by their parents. One patient (7%) referred what was interpreted as stomach discomfort which was transient and reversible. In the placebo group two patients presented some behavioural changes which were lately attributed to family problems. Body weight increases are shown in Table 2. The average increment from the initial weights

represented 6.7% and 4.4% at 6 months and 10.7% and 6.6% after 9 months of treatment for the drug and placebo group, respectively. Percentage weight gains over baseline in our patients are lower than those reported in the P treated series (Table 3). Stature increases for the 9 month period were 2.66 4- 1.35 cm for the treated group and 3.47 41.01 cm for the placebo group these differences

Steroids in Duchenne--Deflazacort

265

groups. No information was exchanged between the physical therapist who performed the physical evaluation and the paediatric neurologist. The new glucocorticoid DF has been proved to reduce the side-effects caused by P and yet preserve its action as an anti- inflammatory agent DISCUSSION as well as an immunosuppressive drug [12]. Although the benefits of P are evident in DMD The usefulness of steroid therapy in DMD was patients, side-effects appear as a serious impairtested previously in 1974 [4]. Different results ment for its widespread use. were reported and the controversy for its use has The side-effects observed in our population been settled [5,16]. were of much lower importance than those More recently a long-term follow-up study of reported in the P treated series. those patients who received steroids suggested a Of particular interest is the weight gain. long-term benefit of the medication [6]. In recent Weight control is of great importance in DMD years an improvement has been reported in and moreover it has been demonstrated that its DMD patients after P administration [7-9]. reduction in these patients is possible [18]. This double blind clinical trial confirmed the When steroids are used extra dietary measures benefits of corticosteroid therapy on muscle are needed such as avoiding sugars, lowering strength as well as functional ability in DMD. In sodium intake, inclusion of proteins of high our study hand held myometry of 10 muscle biological value among others. groups of the lower extremities showed sigIn our patients, although all values (drug or nificant improvement in strength in each placebo groups) are above ideal weight--acmeasurement as compared with the control cording to the new charts for weight control in group. Measurements of the lower extremities DMD [19]--total weight gain is not significantly were used because they are more sensitive to different between the drug and placebo group changes than the upper extremities when fol- although values are slightly higher in the DF lowed for shorter periods of time. group. Nevertheless, weight gain is reduced Functional abilities, as demonstrated by the overall when compared with that reported in the Scott Score and timed Gowers manoeuvre, also P treated patients. The use of DF and a careful showed improvement. The improvement in the dietary management can prevent exaggerated functional score correlates with the generalized weight gain. impression of the benefit shared by the parents. The mechanism by which steroids could imAlso, the time required to walk 10 m showed a prove muscle strength and functional abilities in decline in the treated group although no dif- DMD is still puzzling. ferences were found with the placebo group due An increase in muscle mass through a decrease to high data dispersion. in the rate of muscle breakdown has been The stimulatory or placebo effect of steroids suggested [8]. should be considered when analysing the results. Also, a possible explanation is the hypoIt must be kept in mind that no improvement is thetical activation of an alternative protein to achieved when other dystrophic conditions are dystrophin which could exert a complementary treated with the same medication. action over membrane structure and/or function. We have only seen mild transient improveAnti-inflammatory action must also be conment in some functional abilities with Mazindol sidered and improvement could also result from but after a short period of time the patients rapid action on focal inflammatory changes, returned to the baseline condition. We have necrosis and degenerating fibres that can be seen never seen improvement in myometric evalua- in DMD. tion or in any other parameter (unpublished An effect mediated through an immunosupobservation) resulting in a negative trial coin- pressive action is unlikely since improvement cidently with other recent reports [17]. can be detected as early as 15 days after treatAn observer bias should not be disregarded ment in some patients (unpublished observabut only the physician who performed the clinical tions), too early to be produced through such a and laboratory evaluations could have the ne- mechanism. cessary skills and training to recognize clinical Monitoring the response latency, looking at side-effects of steroids and then identify the two the dose effectiveness relationship, studying the being not significant between the groups (P = 0.12) although there is a tendency for a reduced growth rate in the treated group, this could be expected owing to the steroid administration.

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rate of i m p r o v e m e n t at different points o f the disease e v o l u t i o n is some of the i n f o r m a t i o n still needed to adjust the medication. This could also answer some of the questions regarding the possible m e c h a n i s m s of action o f the drug. Nevertheless, steroids a p p e a r to be the only alternative at this m o m e n t to cut d o w n the effects of this disease a n d they deserve special attention. C u r r e n t studies with reduced doses are in progress. If considerable slowing o f the disease can be achieved with few side-effects, then corticosteroids could be possibly considered as a s t a n d a r d therapy in D M D , b u t more research a n d longterm follow-up are needed. C o n s i d e r i n g this, the use of D F at least appears to reduce considerably the risks of p r o l o n g e d steroid a d m i n i s t r a t i o n .

6. 7.

8.

9.

10.

11.

Acknowledgements--This work was presented at the AAN

Meeting, Boston, April 1991 and was supported in part by the Muscular Dystrophy Association of Argentina. The authors thank Mrs Maria Elena Beresan for assistancein the manuscript preparation and Mr Marcelo Villegas for computer aid. REFERENCES

1. Hoffman E P, Brown R H, Kunkel L M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51: 919-928. 2. Koenig M, Hoffman E P, Bertleson C J, Monaco A P, Feener C, Kunkel L M. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987;50:509-517. 3. Zubrzycka-Gaarn E E, Bulman D E, Karpati G, et al. The Duchenne muscular dystrophy gene product is localized in the sarcolemma of human skeletal muscle fibers. Nature 1988; 333: 466-469. 4. Drachman D B, Toyka R V, Myer E. Prednisone in Duchenne muscular dystrophy. Lancet 1974; 2: 14091412. 5. Siegel I M, Miller J E, Ray R D. Failure of corticosteroid in the treatment of Duchenne (pseudo hypertrophic) muscular dystrophy: report of a clinically

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13. De Rosa E, Cammarota A, Dubrovsky A L, Flores D. Deflazacort in myastenia gravis. J Neurol Sci 1990; 98(Suppl): 417. 14. BrookeM H, Griggs R C, Mendell J R, Fenichel G M, Shumate J B, Pellegrino R J. Clinical trial in Duchenne dystrophy. I The design of the protocol. Muscle Nerve 1981; 4: 186-197. 15. Scott O M, Hyde S A, Goddard C, Dubowitz V. Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy. Muscle Nerve 1982; 5: 291- 301. 16. Rowland L P. Prednisone in Duchenne dystrophy. Lancet 1975; 1: 277. 17. Griggs R C, Moxley R T, Mendell J R, et al. Randomized,double blind trial ofmazindol in Duchenne dystrophy. Muscle Nerve 1990; 13:1169-1173. 18. EdwardsR H T, Round J M, Grifliths R D, Lilburn M F. Weight reduction in boys with muscular dystrophy. Dev Med Child Neuro11984; 26: 384-390. 19. Griffiths R D, Edwards R H T. A new chart for weight control in Duchenne muscular dystrophy. Arch Dis Child 1988; 63: 1256-1258.

Steroids in Duchenne muscular dystrophy--deflazacort trial.

We conducted a double blind controlled trial in 28 Duchenne muscular dystrophy (DMD) patients with Deflazacort (DF), an oxazoline derivative of predni...
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