今日の臨床サポート

進行性筋ジストロフィー

概要・推奨   

  1. 筋力低下の進行を抑制するにはステロイドが推奨される(推奨度2)
  1. 筋疾患診断にはCK値が有用であり、推奨される(推奨度1)
  1. DMDに対してはプレドニゾロン0.75mg/kg/日が第1に推奨される。副作用を注意深くモニターする必要がある(推奨度2)
  1. 筋ジストロフィーに対してβ2刺激薬は効果があり推奨される。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
石井亜紀子 : 特に申告事項無し[2021年]
監修:庄司進一 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 新規核酸医薬品について追記。 
  1. ガイドラインに基づき治療法を改定した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 筋ジストロフィーとは骨格筋の変性・壊死を主病変とし、進行性の筋力低下、筋萎縮を特徴とする遺伝子疾患群の総称である。
  1. 病型は多数存在し、人名、障害部位、遺伝子異常により分類・命名されている。
 
 
  1. Duchenne型筋ジストロフィー(DMD:発症率3,500男子出生当たり1人)/Becker型筋ジストロフィー(BMD:発症率2万男子出生当たり1人):X染色体連鎖性劣性。ジストロフィン遺伝子異常による。
  1. 筋緊張性ジストロフィー(MD:人口10万人当たり4.9~5.5人):第19番染色体長腕にあるDMPK遺伝子の3′非翻訳領域のCTGリピートの増加が原因。
  1. 筋ジストロフィーは、指定難病であり、一部(modified Rankin Scale、食事・栄養、呼吸、循環のそれぞれの評価スケールを用いて、いずれかが3以上の場合)などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。(平成27年7月施行)
  1. [難病法に基づく医療費助成制度
 
ジストロフィン染色

患者ではジストロフィンが染色されない
a:ジストロフィン染色(ジストロフィンが染色される)
b:ジストロフィン染色(DMD患者ジストロフィンが染色されない

出典

img1:  著者提供
 
 
病歴・診察のポイント  
  1. 進行性の筋力低下と筋萎縮。近位筋優位。家族歴の有無。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

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文献 

著者: A Y Manzur, T Kuntzer, M Pike, A Swan
雑誌名: Cochrane Database Syst Rev. 2004;(2):CD003725. doi: 10.1002/14651858.CD003725.pub2.
Abstract/Text BACKGROUND: Duchenne muscular dystrophy is the most common muscular dystrophy of childhood. This incurable disease is characterised by muscle wasting and loss of walking ability leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is one of the major aims of treatment.
OBJECTIVES: The aim of this review was to assess whether glucocorticoid corticosteroids stabilize or improve muscle strength and walking in boys with DMD.
SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised register (October 2003) using the term 'Duchenne muscular dystrophy'. We also searched MEDLINE (January 1966 to October 2003), EMBASE (January 1980 to October 2003), CINAHL and LILACS (January 1982 to October 2003). We wrote to authors of published studies and other experts in this disease to help identify other trials, checked the references in the identified trials and handsearched the abstracts of relevant journals.
SELECTION CRITERIA: Types of studies: randomised or quasi-randomised trials.
TYPES OF PARTICIPANTS: all patients with a definite diagnosis of Duchenne muscular dystrophy. Types of interventions: glucocorticoids such as prednisone, prednisolone, deflazacort or others, with a minimum treatment period of three months.
PRIMARY OUTCOME MEASURE: prolongation of walking (independent walking without long leg calipers).
SECONDARY OUTCOME MEASURES: strength outcome measures, manual muscle strength testing using Medical Research Council strength scores, functional outcome measures and adverse events.
DATA COLLECTION AND ANALYSIS: We identified five randomised controlled trials that met the inclusion criteria for our review. Two reviewers independently selected the trials for the review and assessed methodological quality. Data extraction and inputting were double-checked.
MAIN RESULTS:
PRIMARY OUTCOME MEASURE: data from one small study used prolongation of walking as an outcome measure and did not show significant benefit.
SECONDARY OUTCOME MEASURES: The meta-analysis of the results from three randomised controlled trials showed that glucocorticoid corticosteroids improved muscle strength and function over six months. Improvements were seen in time taken to rise from the floor (Gowers' time), nine metres walking time, four-stair climbing time, ability to lift weights, leg function grade and forced vital capacity. One randomised controlled trial showed that glucocorticoid corticosteroids stabilize muscle strength and function for up to two years. The most effective prednisolone regime appears to be 0.75 mg/kg/day. Not enough data were available to compare efficacy of prednisone with deflazacort.Adverse effects: Excessive weight gain, behavioural abnormalities, cushingoid appearance and excessive hair growth were all more common with glucocorticoid corticosteroids than placebo. Long-term adverse effects of glucocorticoid therapy could not be evaluated because of the short-term duration of the randomised studies.Non-randomised studies: a number of non-randomised studies with important efficacy and adverse effects data are tabulated and discussed.
REVIEWERS' CONCLUSIONS: There is evidence from randomised controlled studies that glucocorticoid corticosteroid therapy in Duchenne muscular dystrophy improves muscle strength and function in the short-term (six months to two years). The most effective prednisolone regime appears to be 0.75 mg/kg/day. In the short term, adverse effects were significantly more common but not clinically severe. Long-term benefits and hazards of glucocorticoid treatment cannot be evaluated from the currently published randomised studies. Non-randomised studies support the conclusions of functional benefits but also indicate clinically significant adverse effects of long-term treatment. These benefits and adverse effects have implications for future research studies and clinical practice.

PMID 15106215  Cochrane Database Syst Rev. 2004;(2):CD003725. doi: 10.・・・
著者: R T Moxley, S Ashwal, S Pandya, A Connolly, J Florence, K Mathews, L Baumbach, C McDonald, M Sussman, C Wade, Quality Standards Subcommittee of the American Academy of Neurology, Practice Committee of the Child Neurology Society
雑誌名: Neurology. 2005 Jan 11;64(1):13-20. doi: 10.1212/01.WNL.0000148485.00049.B7.
Abstract/Text BACKGROUND: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence.
OBJECTIVE: To review available evidence on corticosteroid treatment of boys with Duchenne dystrophy.
METHODS: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification, and areas for future research are defined.
RESULTS: Seven class I studies and numerous less rigorous trials all demonstrated that corticosteroid treatment for 6 months with prednisone (0.75 or 1.5 mg/kg/day) increased muscle strength, performance, and pulmonary function and significantly slowed the progression of weakness. Two class I trials examined the effect of lower dosage of prednisone (0.30 and 0.35 mg/kg/day), demonstrated lesser but similar benefits, and showed a lower frequency of side effects (e.g., weight gain). The only significant side effects in all class I trials were weight gain and development of a cushingoid facial appearance. One longer-term trial of daily prednisone (0.3 to 0.7 mg/kg/day), a class III study, showed prolongation of functional ability and slower progression of weakness in patients during 3 years of treatment. One class IV, open trial of alternate-day prednisone (2 mg/kg for 2 months, then two-thirds dose every other day) extended ambulation by approximately 2 years in treated compared with untreated patients. Deflazacort, a corticosteroid similar in structure to prednisone, produced similar improvement in muscle strength and function with a similar side effect profile.
CONCLUSIONS: Prednisone has been demonstrated to have a beneficial effect on muscle strength and function in boys with Duchenne dystrophy and should be offered (at a dose of 0.75 mg/kg/day) as treatment. If side effects require a decrease in prednisone, tapering to dosages as low as 0.3 mg/kg/day gives less robust but significant improvement. Deflazacort (0.9 mg/kg/day) can also be used for the treatment of Duchenne dystrophy in countries in which it is available. Benefits and side effects of corticosteroid therapy need to be monitored. The offer of treatment with corticosteroids should include a balanced discussion of potential risks.

PMID 15642897  Neurology. 2005 Jan 11;64(1):13-20. doi: 10.1212/01.WNL・・・
著者: D M Escolar, L P Hache, P R Clemens, A Cnaan, C M McDonald, V Viswanathan, A J Kornberg, T E Bertorini, Y Nevo, T Lotze, A Pestronk, M M Ryan, E Monasterio, J W Day, A Zimmerman, A Arrieta, E Henricson, J Mayhew, J Florence, F Hu, A M Connolly
雑誌名: Neurology. 2011 Aug 2;77(5):444-52. doi: 10.1212/WNL.0b013e318227b164. Epub 2011 Jul 13.
Abstract/Text OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).
METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.
RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone.
CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

PMID 21753160  Neurology. 2011 Aug 2;77(5):444-52. doi: 10.1212/WNL.0b・・・
著者: Christopher F Spurney, Carolina Tesi Rocha, Erik Henricson, Julaine Florence, Jill Mayhew, Ksenija Gorni, Livia Pasquali, Alan Pestronk, Gerard R Martin, Fengming Hu, Lei Nie, Anne M Connolly, Diana M Escolar, Cooperative International Neuromuscular Research Group Investigators
雑誌名: Muscle Nerve. 2011 Aug;44(2):174-8. doi: 10.1002/mus.22047. Epub 2011 Jun 22.
Abstract/Text INTRODUCTION: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle.
METHODS: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score.
RESULTS: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03).
CONCLUSIONS: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.

Copyright © 2011 Wiley Periodicals, Inc.
PMID 21698649  Muscle Nerve. 2011 Aug;44(2):174-8. doi: 10.1002/mus.22・・・
著者: Fumi Takeuchi, Naohiro Yonemoto, Harumasa Nakamura, Reiko Shimizu, Hirofumi Komaki, Madoka Mori-Yoshimura, Yukiko K Hayashi, Ichizo Nishino, Mitsuru Kawai, En Kimura, Shin'ichi Takeda
雑誌名: J Neurol. 2013 Dec;260(12):3023-9. doi: 10.1007/s00415-013-7104-y. Epub 2013 Sep 22.
Abstract/Text We evaluated the long-term efficacy of prednisolone (PSL) therapy for prolonging ambulation in Japanese patients with genetically confirmed Duchenne muscular dystrophy (DMD). There were clinical trials have shown a short-term positive effect of high-dose and daily PSL on ambulation, whereas a few study showed a long-term effect. Especially in Japan, "real-life" observation was lacking. We utilized the national registry of muscular dystrophy in Japan for our retrospective study. We compared the age at loss of ambulation (LOA) between patients in PSL group and those in without-PSL group. Out of 791 patients' in the Remudy DMD/BMD registry from July 2009 to June 2012, 560 were matched with inclusion criteria. Of the 560, all were genetically confirmed DMD patients, 245 (43.8 %) of whom were treated with PSL and 315 (56.2 %) without PSL. There was no difference between the two groups regarding their mutational profile. The age at LOA was significantly greater (11 month on average) in the PSL group than in the without-PSL group (median, 132 vs. 121 months; p = 0.0002). Although strictly controlled clinical trials have shown that corticosteroid therapies achieved a marked improvement in ambulation, discontinuation of the drug due to intolerable side effects led to exclusion of clinical trial participants, which is considered as unavoidable. In our study, patients were not excluded from the PSL group, even if they discontinued the medication shortly after starting it. The results of our study may provide evidence to formulate recommendations and provide a basis for realistic expectations for PSL treatment of DMD patients in Japan, even there are certain limitations due to the retrospectively captured data in the registry.

PMID 24057148  J Neurol. 2013 Dec;260(12):3023-9. doi: 10.1007/s00415-・・・
著者: Nathalie M Goemans, Mar Tulinius, Johanna T van den Akker, Brigitte E Burm, Peter F Ekhart, Niki Heuvelmans, Tjadine Holling, Anneke A Janson, Gerard J Platenburg, Jessica A Sipkens, J M Ad Sitsen, Annemieke Aartsma-Rus, Gert-Jan B van Ommen, Gunnar Buyse, Niklas Darin, Jan J Verschuuren, Giles V Campion, Sjef J de Kimpe, Judith C van Deutekom
雑誌名: N Engl J Med. 2011 Apr 21;364(16):1513-22. doi: 10.1056/NEJMoa1011367. Epub 2011 Mar 23.
Abstract/Text BACKGROUND: Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051.
METHODS: We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients, with each of four possible doses (0.5, 2.0, 4.0, and 6.0 mg per kilogram of body weight) given to 3 patients. Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points. All patients subsequently entered a 12-week open-label extension phase, during which they all received PRO051 at a dose of 6.0 mg per kilogram per week. Safety, pharmacokinetics, serum creatine kinase levels, and muscle strength and function were assessed.
RESULTS: The most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary α(1)-microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (±SD) improvement of 35.2±28.7 m (from the baseline of 384±121 m) on the 6-minute walk test.
CONCLUSIONS: Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).

PMID 21428760  N Engl J Med. 2011 Apr 21;364(16):1513-22. doi: 10.1056・・・
著者: J T Kissel, M P McDermott, R Natarajan, J R Mendell, S Pandya, W M King, R C Griggs, R Tawil
雑誌名: Neurology. 1998 May;50(5):1402-6.
Abstract/Text BACKGROUND/OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is currently untreatable, and there have been few therapeutic trials of any agent in the disease. Animal studies have demonstrated that beta2-adrenergic agonists induce muscle hypertrophy and prevent atrophy after a variety of physical and biochemical insults, and two human studies have shown that these agents increase certain measures of strength in healthy volunteers. We conducted an open-label pilot trial of a beta2-agonist (albuterol) in patients with FSHD.
METHODS: Fifteen FSHD patients were given sustained-release albuterol (16.0 mg/day) for 3 months. The primary outcome measure was lean body mass, which was assessed through dual energy X-ray absorptiometry (DEXA). Strength was evaluated through maximal voluntary isometric contraction testing (MVICT) and manual muscle testing.
RESULTS: Albuterol significantly increased DEXA lean body mass (the skeletal muscle compartment) by 1.29 +/- 1.18 kg (mean +/- SD, p = 0.001). Strength assessed through composite MVICT scores also increased by an average of 0.33 +/- 0.60 (p = 0.05), representing an overall 12% improvement in strength.
CONCLUSIONS: These encouraging results suggest that beta2-agonists may have a role in treating FSHD and possibly other neuromuscular diseases. The effects of albuterol in FSHD are currently being evaluated in a larger, randomized, double-blind, placebo-controlled trial lasting 1 year.

PMID 9595995  Neurology. 1998 May;50(5):1402-6.
著者: Tsuyoshi Matsumura, Takuhisa Tamura, Satoshi Kuru, Yasuki Kikuchi, Mitsuru Kawai
雑誌名: Intern Med. 2010;49(14):1357-63. Epub 2010 Jul 15.
Abstract/Text OBJECTIVE: Heart failure is one of the most serious complications in Duchenne muscular dystrophy (DMD). Beta-blocker medication is known to improve the prognosis of chronic heart failure of adults, but its efficacy and safety for DMD patients has not been fully assessed. Thus we conducted a multicenter open trial.
METHODS: Fifty-four DMD patients participated; 41 received carvedilol (BB group) and 13 did not (non BB group). All patients with an ejection fraction of less than 50% received angiotensin-converting enzyme inhibitor. Then, patients in BB group were started on carvedilol. The mean maintenance dose of carvedilol in BB group was 7.85+/-2.80 mg/day. Clinical signs and cardiac function were monitored regularly and statistical analysis was done.
RESULTS: The survival rate free from primary endpoints (death, deterioration of heart failure and severe arrhythmia) was higher in the BB group. The survival rate free from all-cause death was also higher in the BB group, although not significantly higher. Patients with primary endpoints received lower maintenance doses of carvedilol and presented higher mean heart rates (HR) during the observation period. In the BB group, mean HR at enrollment and the reduction of mean HR were correlated with the change of ejection fraction. Although serious adverse events were rare during the introduction of carvedilol, patients with advanced cardiac dysfunction required a longer period for up-titration and frequently presented with minor complaints.
CONCLUSION: The present study suggests that carvedilol is relatively safe and can prevent cardiac events even in patients with DMD.

PMID 20647648  Intern Med. 2010;49(14):1357-63. Epub 2010 Jul 15.
著者: Y Ishikawa, J R Bach, Y Ishikawa, R Minami
雑誌名: Am J Phys Med Rehabil. 1995 Sep-Oct;74(5):345-50.
Abstract/Text The physiatrist can now be instrumental in prolonging the survival of individuals with neuromuscular disease by using respiratory muscle aids. As a result, morbidity and mortality from cardiomyopathy are likely to increase for patients with generalized myopathies. One hundred consecutive patients with dystrophin-deficient muscular dystrophy and a mean age of 17.2 yr (range, 5-41) satisfied criteria for having dilated cardiomyopathy (DCM) and received digitalis and diuretics. Nine of the 14 patients were symptom-free, despite left ventricular ejection fractions (LVEFs) of 25-40%. The five patients with symptomatic heart failure had severe ventricular dilatation, with LVEFs < 25%. Two of the five patients died of heart failure within 1 yr. For the remaining three patients, we evaluated the addition of the angiotensin-converting enzyme (ACE) inhibitor enalapril and, subsequently, the use of beta-blockers to the therapeutic regimen. Addition of these medications, never before attempted in the management of cardiomyopathy associated with generalized myopathic disease, complemented each other in relieving symptoms and reversing signs of congestive heart failure and DCM. We conclude that the combination of ACE inhibitor and beta-blocker deserves further exploration for inclusion in any management regimen for the treatment of muscular dystrophy-associated cardiomyopathy.

PMID 7576410  Am J Phys Med Rehabil. 1995 Sep-Oct;74(5):345-50.
著者: Daniel P Judge, David A Kass, W Reid Thompson, Kathryn R Wagner
雑誌名: Am J Cardiovasc Drugs. 2011 Oct 1;11(5):287-94. doi: 10.2165/11594070-000000000-00000.
Abstract/Text Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD.

PMID 21812510  Am J Cardiovasc Drugs. 2011 Oct 1;11(5):287-94. doi: 10・・・
著者: Denis Duboc, Christophe Meune, Guy Lerebours, Jean-Yves Devaux, Guy Vaksmann, Henri-Marc Bécane
雑誌名: J Am Coll Cardiol. 2005 Mar 15;45(6):855-7. doi: 10.1016/j.jacc.2004.09.078.
Abstract/Text OBJECTIVES: The aim of this research was to examine the effects of perindopril on cardiac function in patients with Duchenne muscular dystrophy (DMD).
BACKGROUND: Duchenne muscular dystrophy, an inherited X-linked disease, is characterized by progressive muscle weakness and myocardial involvement.
METHODS: In phase I, 57 children with DMD and a left ventricular ejection fraction (LVEF) >55% (mean 65.0 +/- 5.4%), 9.5 to 13 years of age (mean 10.7 +/- 1.2 years), were enrolled in a three-year multicenter, randomized, double-blind trial of perindopril, 2 to 4 mg/day (group 1), versus placebo (group 2). In phase II, all patients received open-label perindopril for 24 more months; LVEF was measured at 0, 36, and 60 months.
RESULTS: Phase I was completed by 56 (27 in group 1 and 29 in group 2) and phase II by 51 patients (24 in group 1 and 27 in group 2). There was no difference in baseline characteristics between the treatment groups. At the end of phase I, mean LVEF was 60.7 +/- 7.6% in group 1 versus 64.4 +/- 9.8% in group 2, and was <45% in a single patient in each group (p = NS). At 60 months, LVEF was 58.6 +/- 8.1% in group 1 versus 56.0 +/- 15.5% in group 2 (p = NS). A single patient had an LVEF <45% in group 1 versus eight patients in group 2 (p = 0.02).
CONCLUSIONS: Early treatment with perindopril delayed the onset and progression of prominent left ventricle dysfunction in children with DMD.

PMID 15766818  J Am Coll Cardiol. 2005 Mar 15;45(6):855-7. doi: 10.101・・・
著者: Vinod Malik, Louise R Rodino-Klapac, Laurence Viollet, Cheryl Wall, Wendy King, Roula Al-Dahhak, Sarah Lewis, Christopher J Shilling, Janaiah Kota, Carmen Serrano-Munuera, John Hayes, John D Mahan, Katherine J Campbell, Brenda Banwell, Majed Dasouki, Victoria Watts, Kumaraswamy Sivakumar, Ricardo Bien-Willner, Kevin M Flanigan, Zarife Sahenk, Richard J Barohn, Christopher M Walker, Jerry R Mendell
雑誌名: Ann Neurol. 2010 Jun;67(6):771-80. doi: 10.1002/ana.22024.
Abstract/Text OBJECTIVE: The objective of this study was to establish the feasibility of long-term gentamicin dosing to achieve stop codon readthrough and produce full-length dystrophin. Mutation suppression of stop codons, successfully achieved in the mdx mouse using gentamicin, represents an important evolving treatment strategy in Duchenne muscular dystrophy (DMD).
METHODS: Two DMD cohorts received 14-day gentamicin (7.5mg/kg/day): Cohort 1 (n = 10) stop codon patients and Cohort 2 (n = 8) frameshift controls. Two additional stop codon DMD cohorts were gentamicin treated (7.5mg/kg) for 6 months: Cohort 3 (n = 12) dosed weekly and Cohort 4 (n = 4) dosed twice weekly. Pre- and post-treatment biopsies were assessed for dystrophin levels, as were clinical outcomes.
RESULTS: In the 14-day study, serum creatine kinase (CK) dropped by 50%, which was not seen in frameshift DMD controls. After 6 months of gentamicin, dystrophin levels significantly increased (p = 0.027); the highest levels reached 13 to 15% of normal (1 in Cohort 3, and 2 in Cohort 4), accompanied by reduced serum CK favoring drug-induced readthrough of stop codons. This was supported by stabilization of strength and a slight increase in forced vital capacity. Pretreatment stable transcripts predicted an increase of dystrophin after gentamicin. Readthrough efficiency was not affected by the stop codon or its surrounding fourth nucleotide. In 1 subject, antigen-specific interferon-gamma enzyme-linked immunospot assay detected an immunogenic dystrophin epitope.
INTERPRETATION: The results support efforts to achieve drug-induced mutation suppression of stop codons. The immunogenic epitope resulting from readthrough emphasizes the importance of monitoring T-cell immunity during clinical studies that suppress stop codons. Similar principles apply to other molecular strategies, including exon skipping and gene therapy.

PMID 20517938  Ann Neurol. 2010 Jun;67(6):771-80. doi: 10.1002/ana.220・・・
著者: Bidisha Banerjee, Uma Sharma, Krithika Balasubramanian, M Kalaivani, Veena Kalra, Naranamangalam R Jagannathan
雑誌名: Magn Reson Imaging. 2010 Jun;28(5):698-707. doi: 10.1016/j.mri.2010.03.008. Epub 2010 Apr 15.
Abstract/Text Randomized, placebo-controlled single blinded study was carried out to evaluate the effect of oral creatine supplementation on cellular energetics, manual muscle test (MMT) score and functional status in steroid-naive, ambulatory boys suffering with Duchenne muscular dystrophy (DMD; n=33). Eighteen patients received creatine monohydrate (Cr; 5 g/day for 8 weeks), while 15 received placebo (500 mg of vitamin C). Phosphorus metabolite ratios were determined from the right calf muscle of patients using phosphorus magnetic resonance spectroscopy ((31)P MRS) both prior to (baseline) and after supplementation of Cr or placebo. In addition, metabolite ratios were determined in normal calf muscle of age and sex matched controls (n=8). Significant differences in several metabolite ratios were observed between controls and DMD patients indicating a lower energy state in these patients. Analysis using analysis of covariance adjusted for age and stature showed that the mean phosphocreatine (PCr)/inorganic phosphate (Pi) ratio in patients treated with Cr (4.7; 95% CI; 3.9-5.6) was significantly higher (P=.03) compared to the placebo group (3.3; 95% CI; 2.5-4.2). The mean percentage increase in PCr/Pi ratio was also more in patients <7 years of age compared to older patients after Cr supplementation indicating variation in therapeutic effect with the age. In the placebo group, significant reduction in PCr/Pi (P=.0009), PCr/t-ATP (P=.05) and an increase in phosphodiester (PDE)/PCr ratios was observed after supplementation. Further, in the placebo group, patients <7 years showed reduction of PCr/t-ATP and Pi/t-ATP compared to older patients (>7 years), after supplementation. These results imply that the significant difference observed in PCr/Pi ratio between the Cr and the placebo groups after supplementation may be attributed to a decrease of PCr in the placebo group and an increase in PCr in the Cr group. Changes in MMT score between the two groups was significant (P=.04); however, no change in functional scale (P=.19) was observed. Parents reported subjective improvement on Cr supplementation versus worsening in placebo (P=.02). Our results indicated that Cr was well tolerated and oral Cr significantly improved the muscle PCr/Pi ratio and preserved the muscle strength in short term. However, this study provides no evidence that creatine will prove beneficial after long-term treatment, or have any positive effect on patient lifespan.

Copyright 2010 Elsevier Inc. All rights reserved.
PMID 20395096  Magn Reson Imaging. 2010 Jun;28(5):698-707. doi: 10.101・・・
著者: Antonio Cittadini, Lucia Ines Comi, Salvatore Longobardi, Vito Rocco Petretta, Cosma Casaburi, Luigia Passamano, Bartolomeo Merola, Emanuele Durante-Mangoni, Luigi Saccà, Luisa Politano
雑誌名: Eur Heart J. 2003 Apr;24(7):664-72.
Abstract/Text AIM: Since growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement.
METHODS AND RESULTS: Patients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alpha circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period.
CONCLUSIONS: The 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.

PMID 12657225  Eur Heart J. 2003 Apr;24(7):664-72.
著者: Daniel Skuk, Marlyne Goulet, Brigitte Roy, Pierre Chapdelaine, Jean-Pierre Bouchard, Raynald Roy, Francine J Dugré, Michel Sylvain, Jean-Guy Lachance, Louise Deschênes, Hélène Senay, Jacques P Tremblay
雑誌名: J Neuropathol Exp Neurol. 2006 Apr;65(4):371-86. doi: 10.1097/01.jnen.0000218443.45782.81.
Abstract/Text A clinical trial was conducted to test a new protocol of normal muscle precursor cell (MPC) allotransplantation in skeletal muscles of patients with Duchenne muscular dystrophy (DMD). Cultured MPCs obtained from one of the patient's parents were implanted in 0.25 or 1 cm of a Tibialis anterior in 9 patients with DMD. MPC injections were placed 1 to 2 mm from each other, and a similar pattern of saline injections was done in the contralateral muscle. The patients were immunosuppressed with tacrolimus. Muscle biopsies were performed at the injected sites 4 weeks later. In the biopsies of the cell-grafted sites, there were myofibers expressing donor's dystrophin in 8 patients. The percentage of myofibers expressing donor's dystrophin varied from 3.5% to 26%. Evidence of small myofiber neoformation was observed in some patients. Donor-derived dystrophin transcripts were detected by reverse transcriptase-polymerase chain reaction in the cell-grafted sites in all patients. The protocol of immunosuppression was sufficient to obtain these results, although it is not certain whether acute rejection was efficiently controlled in all the cases. In conclusion, intramuscular allotransplantation of normal MPCs can induce the expression of donor-derived dystrophin in skeletal muscles of patients with DMD, although this expression is restricted to the sites of MPC injection.

PMID 16691118  J Neuropathol Exp Neurol. 2006 Apr;65(4):371-86. doi: 1・・・

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