USA – O uso de corticóides é considerado como único tratamento da distrofia muscular de Duchenne. No entanto seu uso tem sido muito avaliado sobre a função muscular e poucas vezes sobre a função cardíaca. Nesta pesquisa os autores avaliaram a função cardíaca em Duchenne através da ressonância nuclear magnética. Os resultados demonstraram que o grau de fibrose aumenta com a idade e com o uso de corticóides e reflete diretamente com a função cardíaca. Nesta mesma publicação há um editorial que reforça a necessidade de tratamento com corticóides visto que é a única opção de tratamento e discute todas as resalvas com relação a estes resultados.

O resumo em inglês e o editorial na íntegra podem ser lidos abaixo:

(Journal of American Heart Association, 2015) Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and Is Associated With Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy

Animesh Tandon, Chet R. Villa, Kan N. Hor, John L. Jefferies, Zhiqian Gao, Jeffrey A. Towbin, Brenda L. Wong, Wojciech Mazur, Robert J. Fleck, Joshua J. Sticka, D. Woodrow Benson, and Michael D. Taylor – USA

Background Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort.

Methods and Results We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with ≥4 cardiac magnetic resonance studies) for left ventricular ejection fraction (LVEF) and presence of late gadolinium enhancement (LGE), a marker for myocardial fibrosis. LVEF was modeled by examining LGE status, myocardial fibrosis burden (as assessed by the number of LGE‐positive left ventricular segments), patient age, and steroid treatment duration. An age‐only model demonstrated that LVEF declined 0.58±0.10% per year. In patients with both LGE‐negative and LGE‐positive studies (n=51), LVEF did not decline significantly over time if LGE was absent but declined 2.2±0.31% per year when LGE was present. Univariate modeling showed significant associations between LVEF and steroid treatment duration, presence of LGE, and number of LGE‐positive left ventricular segments; multivariate modeling showed that LVEF declined by 0.93±0.09% for each LGE‐positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of LGE‐positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age‐related increases

Conclusion Progressive myocardial fibrosis, as detected by LGE, was strongly correlated with the LVEF decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age‐related increase in myocardial fibrosis burden.

Glucocorticoid Therapy for Duchenne Cardiomyopathy: A Hobson’s Choice?
Subha V. Raman and Linda H. Cripe

Fonte: http://distrofiamuscular.net/principal.htm

USA – a insuficiência respiratória e cardíaca são as principais causas de óbito na distrofia muscular de Duchenne. Estudos prévios demonstraram que o debenone causa efeitos benéficos na distrofia muscular de Duchenne por melhorar as condições energéticas dos músculos. Neste estudo controlado fase 3 os pacientes foram tratados com idebenone (31 pacientes) (300mg, trës vezes ao dia) ou placebo (33 pacientes) por 52 semanas. A avaliação da função respiratória mostrou que a queda da função pulmonar foi menor nos tratados com idebenone, ficando a função pulmonar intermediária entre os tratados com corticóides e os que não tomaram nem corticóides e nem idebenone. Efeitos colaterais foram raros e a droga foi bem tolerada. O Idebenone reduziu a perda da função respiratória e representa uma nova opção de tratamento para pacientes com distrofia muscular de Duchenne.

O resumo em inglês pode ser lido abaixo:

(The Lancet, 2015) Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial

Gunnar M Buyse, Thomas Voit, Ulrike Schara, Chiara S M Straathof, M Grazia D’Angelo, Günther Bernert, Jean-Marie Cuisset, Richard S Finkel, Nathalie Goemans, Craig M McDonald, Christian Rummey, Thomas Meier, for the DELOS Study Group

Background

Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids.

Methods

In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10–18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884.

Findings

31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (−3·05%p [95% CI −7·08 to 0·97], p=0·134, vs placebo −9·01%p [–13·18 to −4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (−2·57%p [–6·68 to 1·54], p=0·215, vs −8·84%p [–12·73 to −4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients).

Interpretation

Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy.

Fonte: http://distrofiamuscular.net/principal.htm

USA – neste congresso são apresentadas diferentes pesquisas em diversas doenças como as distrofias musculares: Duchenne, miotônica,facio escapulo umeral, disferlina, etc. Tem pesquisas com exon skipping, como o primeiro caso de tratamento com salto do exon 53, terapia gênica, células tronco, cromosso artificial, etc.

Leia mais sobre o trabalho aqui.

Fonte: http://distrofiamuscular.net/principal.htm

Japão – embora pacientes com Duchenne têm várias predisposições subjacentes para tromboembolismo venoso (TEV), pouco se sabe sobre sua prevalência e impacto prognóstico. De julho de 2007 a dezembro de 2008, um total de 102 pacientes do sexo masculino com Duchenne em longo prazo (mais de um ano) hospitalização foram inscritos e prospectivamente acompanhados até o final de outubro de 2014. No início do estudo, 24 de 102 pacientes tiveram trombose venosa profunda subclínica. Dois pacientes tinham história anterior de TEV e 1 paciente tinha recebido terapia anticoagulante. Pacientes com trombose venosa profunda tinham significativamente menor peso corporal. Uma tendência para um risco aumentado de trombose venosa profunda foi observada no uso de ventilador e por maior imobilidade.

Leia mais sobre o trabalho aqui.
Fonte: http://distrofiamuscular.net/principal.htm

Alemanha – doenças neuromusculares hereditárias podem causar insuficiência respiratórias com complicações, inclusive fatais. Neste estudo 21 pacientes com doenças neuromusculares com capacidade vital reduzida foram submetidos a exercícios com o cough assist, 10 minutos, duas vezes ao dia. Antes do tratamento os pacientes apresentaram redução da capacidade vital que aumento 28% após os exercícios.

Leia mais sobre o assunto aqui.

Fonte: http://distrofiamuscular.net/principal.htm

Canada – pacientes com distrfoia muscular podem apresentar osteoporose e a causa não está totalemnte esclarecida. Nesta pesquisa os autores identificaram uma proteína, a osteoprotegerina, sendo produzida pelo músculo. Ela é responsável pela diferenciação de osteoclastos e remodelamento ósseo. A administração de osteoprotegerina de origem muscular promoveu aumento de força e redução das alterações patológicas dos músculos de camundongos com distrofia muscular.

O resumo em inglês pode ser lido abaixo:

(American Journal of Pathology, 2015) Osteoprotegerin Protects against Muscular Dystrophy

Sébastien S. Dufresne, Nicolas A. Dumont, Patrice Bouchard, Éliane Lavergne, Josef M. Penninger, Jérôme Frenette – Canada

Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis.

Fonte: http://distrofiamuscular.net/principal.htm

USA – A cardiomiopatia é uma das principais causas de morte em pacientes com distrofia muscular de Duchenne e dano miocárdico precede declínio da função sistólica do ventrículo esquerdo. O estudo foi feito duplo-cego, ou seja, os pacientes e os médicos não sabiam quem estava tomando a droga eplerenone, 25 mg. Os pacientes faziam uso de outras drogas para proteção cardíaca com inibidores da ECA ou bloqueadores dos receptores da angiotensina 2. Vinte meninos receberam a droga e 20 receberam placebo. Os efeitos colaterais nos meninos tratados foram mínimos. Os pacientes que receberam eplerenone tiveram aignificativa menor redução da função cardíaca em comparação com os que não receberam, demonstrando a importância da cardioproteção e a importância desta nova droga no tratamento. O número de meninos tratados foi pequeno e novos estudos deverão ser feitos para estabelecer o melhor esquema de cardioproteção na distrofia muscular de Duchenne.

O resumo em inglês pode ser lido abaixo:

(Lancet Neurology, 2014) Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

Subha V Raman, Kan N Hor, Wojciech Mazur, Nancy J Halnon, John T Kissel, Xin He, Tam Tran, Suzanne Smart, Beth McCarthy, Michae l D Taylor, ohn L Jeff eries, Jill A Rafael-Fortney, Jeovanna Lowe, Sharon L Roble, Linda H Cripe – USA
Background

Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease.
Methods

In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546.
Findings

Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1·0 [IQR 0·3–2·2] vs 2·2 [1·3–3·1]; p=0·020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo.
Interpretation

In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy.


Fonte: http://distrofiamuscular.net/principal.htm

Alemanha – Imunoglobulina G é utilizada em algumas doenças auto-imunes ou inflamatórias. Neste estudo em camundongos com distrofia muscular foram tratados mensalmente com imunogloblina injetável mensalmente, Os animais tratados apresentaram aumento da força muscular, redução da enzima CK, melhora da função cardíaca e melhora das alterações patológicas dos músculos esqueléticos.

O resumo em inglês pode ser lido abaixo:

(Clinical & Experimental Immunology, 2014) Human immunoglobulin G for experimental treatment of Duchenne muscular dystrophy

J. Zschüntzsch, P. Jouvenal, Y. Zhang, F. Klinker, M. Tiburcy, D. Malzahn, D. Liebetanz, H. Brinkmeier and J. Schmidt – Germany

Duchenne muscular dystrophy is the most common inherited disorder of the skeletal muscle. It is caused by a mutation in the dystrophin gene on the X chromosome. Subsequent lack of the dystrophin protein leads to impaired stability of the myocytoskeleton and reduced contraction functionality of skeletal muscle fibres [1, 2]. This devastating myopathy leads to an enormous burden of disease and often death before 30 years of age. Despite a tremendous effort with numerous clinical trials that aimed to correct the gene defect, so far no effective therapy is available [3]. Current standard treatment includes the use of glucocorticosteroids, which aims to reduce the profound bystander inflammation in the skeletal muscle [4]. However, treatment with glucocorticosteroids is hampered by severe long-term side effects.In search for a more effective and tolerable treatment we used the mdx mouse, an established model of the disease, which harbours a homologue mutation of the dystrophin gene. Mice received 2 g/kg human immunoglobulin (Ig)G once per month compared to sham treatment of equal volume, administered by intraperitoneal injection. Each mouse was housed in a separate plastic cage equipped with a computerized running wheel, which continuously recorded the running behaviour and provided parameters such as number of runs, daily and total distance and distance per run [5]. Clinical parameters included body weight, grip-strength assessment and running-wheel performance. The cardiac function was monitored by ultrasound and at the end of the experiment mice were killed for ex vivo contraction analysis. Muscle pathology and expression profile of inflammatory mediators was assessed by immunohistochemistry and quantitative polymerase chain reaction (qPCR). During the early phase of the disease, IgG led to an improved running-wheel performance and ex vivo contraction analysis displayed an elevated endurance. In line with this, myopathic changes in the skeletal muscle were ameliorated and cellular infiltration was reduced. At the same time, release of the muscle enzyme creatine kinase was diminished. In the late phase of the disease, running-wheel performance and grip strength were improved upon treatment with IgG. This was accompanied by a superior cardiac function, as evidenced by ultrasound. In tissue sections of skeletal muscle and diaphragm, myopathic alterations and infiltration by inflammatory cells were reduced. Collectively, the results demonstrate a beneficial effect of human IgG in the treatment of mdx mice. This suggests that IgG may be a promising option for the future treatment of Duchenne muscular dystrophy. Apart from a monotherapeutic approach, IgG could potentially be of value in combination with gene therapy. A clinical proof-of-concept trial is warranted to study the effect of IgG in Duchenne muscular dystrophy.


Fonte: http://distrofiamuscular.net/principal.htm

Dinamarca – alterações endócrinas são frequentes na distrofia miotônica tipo 1. Neste estudo evolutivo 30 pacientes dos 68 estudados apresentavam alguma doença endócrina. Após 8 anos 57 de 68 pacientes apresentavam alteração endócrina – diabetes, alteração do paratohormonio, alterações dos hormônios sexuais, entre outras. Portanto o avaliação hormonal deve ser feito periodicamente no acompanhamento da distrofia miotônica tipo 1.

Leia mais sobre o assunto aqui.

Fonte: http://distrofiamuscular.net/principal.htm

Itália – Na distrofia muscular de Duchenne ocorrem manifestações cardíacas, sendo a miocardiopatia dilatada um achado freqüente. Pacientes com Duchenne raramente são candidatos ao transplante cardíaco. Recentemente, o uso de dispositivos de assistência ventricular surgiram como uma terapia alternativa ao transplante cardíaco em pacientes com Duchenne. Planeamento pré-operatório e seleção dos pacientes desempenha um papel significativo no curso pós-operatório com sucesso destes pacientes. Neste artigo são descritos o pré, intra e pós-operatório da implantação do Jarvik 2000 em 4 com Duchenne na faixa etária de 12 a 17 anos. As complicações mais frequentes foram sangramento e dificuldade de desmame da ventilação mecânica. O protocolo padrão incluiu: 1) avaliação multidisciplinar pré-operatória e seleção, 2) ventilação não invasiva e cough assist em ciclos pré e pós operatórios , 3) uso intra-operatório de espectroscopia infravermelho próximo e ecocardiograma transesofágico, 4) a atenção sobre a perda de sangue cirúrgico, uso de ácido tranexamico e fatores de coagulação 5) extubação precoce e 6), evitando o uso de tubos de alimentação por sonda nasogástrica e sondas de temperatura nasal.Os autores consideram o uso da assistência ventricular esquerda como uma nova opção terapêutica em distrofia muscular de Duchenne.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by progressive skeletal muscle weakness, loss of ambulation, and death secondary to cardiac or respiratory failure. End-stage dilated cardiomyopathy (DCM) is a frequent finding in DMD patients, they are rarely candidates for cardiac transplantation. Recently, the use of ventricular assist devices as a destination therapy (DT) as an alternative to cardiac transplantation in DMD patients has been described. Preoperative planning and patient selection play a significant role in the successful postoperative course of these patients. We describe the preoperative, intraoperative and postoperative management of Jarvik 2000 implantation in 4 DMD pediatric (age range 12–17 years) patients. We also describe the complications that may occur. The most frequent were bleeding and difficulty in weaning from mechanical ventilation. Our standard protocol includes: 1) preoperative multidisciplinary evaluation and selection, 2) preoperative and postoperative non-invasive ventilation and cough machine cycles, 3) intraoperative use of near infrared spectroscopy (NIRS) and transesophageal echocardiography, 4) attention on surgical blood loss, use of tranexamic acid and prothrombin complexes, 5) early extubation and 6) avoiding the use of nasogastric feeding tubes and nasal temperature probes. Our case reports describe the use of Jarvik 2000 as a destination therapy in young patients emphasizing the use of ventricular assist devices as a new therapeutic option in DMD.


Fonte: http://distrofiamuscular.net/principal.htm