Pilot Trial of Salbutamol in Central Core and Multi-Minicore Diseases

Abstract

Several studies have documented positive effects of β-adrenergic agonists on human skeletal muscle with regard to muscle mass and strength. The aim of this pilot study was to evaluate the effect of the β2-agonist salbutamol (albuterol) in a group of children with central core disease and multi-minicore disease. Thirteen patients, 8 with central core disease (mean age 17.5 years) and 5 with minicore disease (mean age 13.6 years) received oral salbutamol at a dose of 2 mg four times a day. Measures of efficacy were the change from baseline at 3 and 6 months in muscle strength, assessed by MRC score, myometry, functional measures and forced vital capacity. Statistical analysis was performed using repeated measures ANOVA (significance level < 0.05). Two patients with central core disease stopped the medication after one month because they did not notice any improvement and another one with minicore disease after 4 months because of increased tremors and palpitations. The remaining ten (6 with central core and 4 with minicore disease) completed the course of salbutamol without any significant adverse effects. There were significant increases in myometry, MRC scores and forced vital capacity between baseline and the six-month assessments. For both myometry and MRC the difference was already significant at 3 months and this was associated with a significant increase in functional abilities assessed with a structured functional scale. Our results suggest that salbutamol was overall well tolerated and might be beneficial in both central core and minicore patients. Larger prospective randomised, double-blind, placebo-controlled trials with salbutamol will be needed to confirm these preliminary findings.

Key words

β-agonists - skeletal muscle - central core disease - multi-minicore disease - therapeutic trial

References

• 1 Beenakker E AC, van der Hoeven J H, Fock J M, Maurits N M. Reference values of maximum isometric muscle force obtained in 270 children aged 4 - 16 years by hand-held dynamometry.  Neuromuscul Disord. 2001;  11 441-446
• 2 Beitzel F, Gregorevic P, Ryall J G, Plant D R, Sillence M N, Lynch G S. Beta2-adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury.  J Appl Physiol. 2003;  96 1385-1392
• 3 Caruso J F, Signorile J F, Perry A C. et al . The effects of albuterol and isokinetic exercise on the quadriceps muscle group.  Med Sci Sports Exerc. 1995;  27 1471-1476
• 4 Criswell D S, Powers S K, Herb R A. Clenbuterol-induced fiber type transition in the soleus of adult rats.  Eur J Appl Physiol Occup. 1996;  74 391-396
• 5 Dubowitz V. Muscle Disorders in Childhood. 2nd ed. London; WB Saunders 1997: 135-142
• 6 Dupont-Vesteegden E E, Katz M S, McCarter R J. Beneficial versus adverse affects of long-term use of clenbuterol in mdx mice.  Muscle Nerve. 1995;  18 1447-1459
• 7 Ferreiro A, Estournet B, Chateau D. et al . Multi-minicore disease-searching for boundaries: phenotype analysis of 38 cases.  Ann Neurol. 2000;  48 745-757
• 8 Ferreiro A, Monnier N, Romero N B. et al . A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene.  Ann Neurol. 2002;  51 750-757
• 9 Ferreiro A, Quijano-Roy S, Pichereau C. et al . Mutation of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, causes the classical phenotype of multi-minicore disease: reassessing the nosology of early-onset myopathies.  Am J Hum Genet. 2002;  71 739-749
• 10 Hinkle R T, Hodge K M, Cody D B, Sheldon R J, Kobilka B K, Isfort R J. Skeletal muscle hypertrophy and anti-atrophy effects of clenbuterol are mediated by the beta2-adrenergic receptor.  Muscle Nerve. 2002;  25 729-734
• 11 Jungbluth H, Sewry C, Brown S C, Manzur A Y, Mercuri E, Bushby K, Rowe P, Johnson M A, Hughes I, Lelsey A, Dubowitz V, Muntoni F. Minicore myopathy in children: a clinical and histopathological study of 19 cases.  Neuromuscul Disord. 2000;  10 264-273
• 12 Kinali M, Mercuri E, Main M, De Biasia F, Karatza A, Higgins R, Banks L, Manzur A Y, Muntoni F. Pilot trial of albuterol in spinal muscular atrophy.  Neurology. 2002;  59 609-610
• 13 Kissel J T, Mendell J R, Griggs R C, McDermott M, Tawil R. The FSH-DY group . Open-label clinical trial of albuterol in facioscapulohumeral muscular dystrophy.  Neurology. 1998;  50 1402-1406
• 14 Kissel J T, McDermott M P, Mendell J R, King W M, Pandya S, Griggs R C, Tawil R. The FSH-DY group . Randomised, double-bind, placebo-controlled trial of albuterol in facio-scapulohumeral dystrophy.  Neurology. 2001;  57 1437-1440
• 15 Lynch G S, Hayes A, Campbell S P, Williams D A. Effects of beta2-agonist administration and exercise on contractile activation of skeletal muscle fibers.  J Appl Physiol. 1996;  81 1610-1618
• 16 Maltin C A, Delday M I, Watson J S. et al . Clenbuterol, a beta-adrenoreceptor agonist, increases relative muscle strength in orthopaedic patients.  Clin Sci. 1993;  84 651-654
• 17 Martineau L, Horan M A, Rothwell N J. et al . Salbutamol, a beta-adrenoreceptor agonist, increases skeletal muscle strength in young men.  Clin Sci. 1992;  83 615-654
• 18 Monnier N, Romero N B, Lerale J. et al . An autosomal dominant congenital myopathy with central cores and nemaline rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor.  Hum Mol Genet. 2000;  9 2599-2608
• 19 Ryall J G, Plant D R, Gregorevic P, Sillence M N, Lynch G S. β2-agonist administration reverses muscle wasting and improves muscle function in aged rats.  J Physiol (Lond). 2004;  555 175-188
• 20 Scott O M, Hyde S A, Goddard C. et al . Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy.  Muscle Nerve. 1982;  5 291-301
• 21 Shy G M, Magee K R. A new congenital non-progressive myopathy.  Brain. 1956;  79 610-621
• 22 Signorile J F, Banovac K, Gomez M. et al . Increased muscle strength in paralyzed patients after spinal cord injury: effect of beta-adrenergic agonist.  Arch Phys Med Rehabil. 1995;  76 55-58
• 23 Zeman R J, Peng H, Danon M J, Etlinger J D. Clenbuterol reduces degeneration of exercised or aged dystrophic (mdx) muscle.  Muscle Nerve. 2000;  23 521-528
• 24 Zerres K, Rudnick-Schoneborn S. Natural history in proximal spinal muscular atrophy.  Arch Neurol. 1995;  52 518-523
• 25 Zhang K, Hu P, Wang S, Feher J J. et al . Salbutamol changes the molecular and mechanical properties of canine skeletal muscle.  J Physiol. 1996;  496 211-220

1 These authors contributed equally