Article

Pentoxifylline as a rescue treatment for DMD: A randomized double-blind clinical trial

Children’s National Medical Center, Washington, DC, USA.
Neurology (Impact Factor: 8.29). 03/2012; 78(12):904-13. DOI: 10.1212/WNL.0b013e31824c46be
Source: PubMed

ABSTRACT

To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).
This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.
A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs.
The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.
This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

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    • "DMD is caused by the complete absence of the dystrophin protein, which leads to extensive muscle degeneration and regeneration followed by substitution of muscle with fibrotic and adipose tissues 1,2. No cure is yet available, but several therapeutic approaches aiming at reversal of the ongoing degeneration have been investigated in preclinical and clinical settings with disappointing results 3,4,5. Currently, drugs intended to induce skeletal muscle hypertrophy via Akt-mediated protein synthesis are in preclinical (e.g. "
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    ABSTRACT: Background Duchenne muscular dystrophy is a lethal, progressive, muscle-wasting disease caused by mutations in the DMD gene. Structural remodelling processes are responsible for muscle atrophy and replacement of myofibers by fibrotic and adipose tissues. Molecular interventions modulating catabolic pathways, such as the ubiquitin-proteasome and the autophagy-lysosome systems, are under development for Duchenne and other muscular dystrophies. The Akt signaling cascade is one of the main pathways involved in protein synthesis and autophagy repression and is known to be up-regulated in dystrophin null mdx mice. Results We report that autophagy is triggered by fasting in the tibialis anterior muscle of control mice but not in mdx mice. Mdx mice show persistent Akt activation upon fasting and failure to increase the expression of FoxO3 regulated autophagy and atrophy genes, such as Bnip3 and Atrogin1. We also provide evidence that autophagy is differentially regulated in mdx tibialis anterior and diaphragm muscles. Conclusions Our data support the concept that autophagy is impaired in the tibialis anterior muscle of mdx mice and that the regulation of autophagy is muscle type dependent. Differences between muscle groups should be considered during the pre-clinical development of therapeutic strategies addressing muscle metabolism.
    Full-text · Article · Nov 2013 · PLoS Currents
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    ABSTRACT: Introduction: Evidence-based therapeutics in Duchenne muscular dystrophy (DMD) has been limited to corticosteroids for the past 30 years. There have been a host of other therapeutic interventions studied in mice, canines and more recently humans, but they are yet to show effectiveness in clinical trials. Newer genetic approaches are in early stages of clinical trials. Areas covered: In this paper, the authors review evidence-based studies for corticosteroids as well as other Phase II and Phase III clinical trials involving potential pharmacologic treatments: myostatin and phosphodiesterase inhibitors, insulin-like growth factor 1 and replenishment of nutritional deficiencies. Finally, the authors briefly review the current status of treatments specific for genetic mutations and gene therapy. Expert opinion: Since the identification of corticosteroids as an effective treatment for DMD, there has not yet been another pharmacologic intervention that has shown as much benefit, although further investigation is needed for some of the mentioned therapeutics. New therapies will need to show a significantly greater sustained benefit for our DMD patients with cost effectiveness, in order for them to supplant or reduce the use of long-term corticosteroid treatment. While studying new therapeutics, further study and trials in corticosteroids should not be lost.
    Preview · Article · Dec 2012 · Expert Opinion on Orphan Drugs
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    ABSTRACT: Background: Duchenne muscular dystrophy is recognized as a fatal X-linked recessive inheritance. It is caused by the dystrophin gene mutation, resulting in the deficiency of dystrophin and consequent degeneration and necrosis of muscle fibers gradually. Becker muscular dystrophy is also caused by the mutation of the same gene, but presented with less severe clinical symptoms compared with Duchenne muscular dystrophy. Frameshift mutation destroys the reading frames, and thus the translation cannot proceed smoothly to transcript functional proteins. In-frame mutation cannot destroy the reading frames and hence the translation can proceed smoothly. But in-frame mutation involves the whole hydrophobic regions. The three-dimensional structure of these regions and their functionality are not interpreted clearly. The effects of these regions on disease development need to be clarified in detail from the point of structure and function. Objective: By analyzing Kate and Dolittle scale mean hydrophobicity profile, to investigate the dystrophin hydrophobic regions using Swiss-model so as to provide the supplement explanation on the reading frame rule. Methods: Form 2002 to 2013, 1 038 cases diagnosed as Duchenne muscular dystrophy or Becker muscular dystrophy were collected in the First Hospital of Sun Yat-sen University in China and Leiden DMD information database was searched with deletion of codon mutation information available. The correlation between clinical types and genotypes was analyzed upon resources collected above. The mean hydrophobicity profile of dystrophin was analyzed by Bioedit as well as the reconstruction of hydrophobic domains using Swiss-model. Thus, the important functional domain of dystrophin was confirmed by analysis and the correlation between clinical types and genotypes. Results and Conclusion: Four hydrophobic regions were confirmed: Calponin homology domain CH2 on actin-binding domain, repeat 16 domain, Hinge III domain and EF Hand domain. Duchenne muscular dystrophy was developed as a result of the destruction of the 1st, 2nd and 4th hydrophobic regions which were the conjunction of dystrophin and associated protein in dystrophin-glycoprotein complex. When the 3rd hydrophobic was deleted, the repeat domain located on central rob domain remained its continuity so that the clinical symptoms were less severe. These findings indicate that the dystrophin hydrophobic regions act as an important role on the pathogenesis of Duchenne muscular dystrophy.
    No preview · Article · Jan 2013
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