Glucocorticoid corticosteroids for Duchenne muscular dystrophy (Cochrane Review)

Hammersmith Hospital, Dubowitz Neuromuscular Centre, Department of Paediatrics, DuCane Road, London, UK, W12 OHS.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 02/2008; 1(1):CD003725. DOI: 10.1002/14651858.CD003725.pub3
Source: PubMed


Glucocorticoid corticosteroid therapy in Duchenne dystrophy improves muscle strength and function for six months to two years Duchenne muscular dystrophy is an incurable disease of childhood. Muscle wasting and loss of ability to walk lead to wheelchair dependence and eventually death. The precise way that glucocorticoids increase strength is unknown. Randomised controlled trials showed that glucocorticoid corticosteroids improved muscle strength and function for six months to two years. Short-term side effects were significant but not severe and could be managed. The long-term benefit remains unclear and has to be weighed against the long-term side effects of these drugs. Whether long-term trials to address this uncertainty are desirable should be addressed from ethical and parental perspectives.

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    • "Recent studies have, however, demonstrated that there is a 'new natural history' of the disease [1] [2] [3], mainly related to improvements in standards of care [1] [4] [5], and glucocorticoid (GC) treatment. The effect of GC has also been confirmed by Cochrane reviews concluding that GC treatment should be considered the gold standard as demonstrated by placebo controlled studies that are not available for any other treatment [6]. Recent longitudinal studies have clearly shown a delay in loss of ambulation in boys treated with GC compared to untreated boys [1]. "
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    ABSTRACT: The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    Neuromuscular Disorders 07/2015; DOI:10.1016/j.nmd.2015.07.009 · 2.64 Impact Factor
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    • "Although the genetic defect responsible for DMD was identified decades ago [4], currently there is no effective treatment available for this devastating disease. Administration of corticosteroids and related drugs to diminish inflammation in DMD [14] have limited efficacy along with significant side effects, such as respiratory muscle weakness, hypoxemia, fatigue, and hypoventilation during sleep [15]–[17]. The need for new treatments have led investigators to focus on multiple therapeutic strategies such as gene and cell based therapies designed to bypass the mutation (exon skipping) or to replace the missing gene and/or dystrophin protein, which have achieved varying degrees of success [18], [19]. "
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca2+ and Na+ overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca2+ and Na+ overload, diminished abnormal sarcolemmal Ca2+ entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway.
    PLoS ONE 09/2014; 9(9):e106590. DOI:10.1371/journal.pone.0106590 · 3.23 Impact Factor
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    • "Duchenne muscular dystrophy (DMD) is an incurable disease that manifests in children and is caused by mutations in the dystrophin gene [1]. Currently, glucocorticoids are the only available treatment that has been approved for clinical trials to improve muscle strength and function in affected children [2]. However, the harsh side effects of long-term glucocorticoid treatment, such as skeletal muscle atrophy and bone loss, limit their therapeutic application in clinical practice. "
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    ABSTRACT: Glucocorticoids are the only therapy that has been demonstrated to alter the progress of Duchenne muscular dystrophy (DMD), the most common muscular dystrophy in children. However, glucocorticoids disturb skeletal muscle metabolism and hamper myogenesis and muscle regeneration. The mechanisms involved in the glucocorticoid-mediated suppression of myogenic differentiation are not fully understood. Glycogen synthase kinase-3β (GSK-3β) is considered to play a central role as a negative regulator in myogenic differentiation. Here, we showed that glucocorticoid treatment during the first 48 h in differentiation medium decreased the level of phosphorylated Ser9-GSK-3β, an inactive form of GSK-3β, suggesting that glucocorticoids affect GSK-3β activity. We then investigated whether GSK-3β inhibition could regulate glucocorticoid-mediated suppression of myogenic differentiation in vitro. Two methods were employed to inhibit GSK-3β: pharmacological inhibition with LiCl and GSK-3β gene knockdown. We found that both methods resulted in enhanced myotube formation and increased levels of muscle regulatory factors and muscle-specific protein expression. Importantly, GSK-3β inhibition attenuated glucocorticoid-induced suppression of myogenic differentiation. Collectively, these data suggest the involvement of GSK-3β in the glucocorticoid-mediated impairment of myogenic differentiation. Therefore, the inhibition of GSK-3β may be a strategy for preventing glucocorticoid-induced muscle degeneration.
    PLoS ONE 08/2014; 9(8):e105528. DOI:10.1371/journal.pone.0105528 · 3.23 Impact Factor
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