Taiwan – 15 crianças com doença neuromuscular e que apresentavam insuficiência respiratória em UTI foram incluidas neste estudo ( uma das crianças com duas internações); elas receberam ventilação não invasiva e assistência mecanica a tosse (mechanical in-exsufflator). A causa mais freuqnete da insuficiência respiratória foi a pneumonia. O sucesso, isto é, a ausência de intubação, foi obtida em 75% dos casos, incluindo 6 (38%) que assinaram termo para não serem intubados. Os parâmetros de função pulmonar melhoraram nos pacientes. Os autores concluem que a associação entre ventilação não-invasiva e assistência mecânica a tosse é segura e eficaz melhorando os parâmetros funcionais respiratórios em pacientes com doença neuromuscular e insuficiência respiratória.

IMPORTANTE: a prevenção de infecções é fundamental em pacientes com doenças neuromusculares, especialmente coma vacinação contra a gripe e pneumonia. O uso de assistência mecânica a tosse ajuda importantemente na recuperação dos pacientes que já aprsentam infecção. O aparelho ainda não foi incluído na portaria de assistência ventilatória nas doenças neuromusculares.

Leiam mais sobre o artigo aqui.

Itália – A inflamação desempenha um papel crucial na remodelação e reparação muscular após a lesão aguda e crónica, em particular no distrofias musculares, um grupo heterogêneo de doenças genéticas que levam à degeneração muscular. Defeito da geração de óxido nítrico (NO) é um evento-chave na patogënese das distrofias musculares, portanto, doadores têm sido explorados como novas terapêuticas para esta doença. Os autores investigaram o efeito imuno-modulador de uma dessas drogas, molsidomina, capazes de retardar a progressão da distrofia muscular em camundongos com distrofia tipo cinturas A molsidomina já foi liberada para uso em seres humanos. Os animais tratados apresentaram menor processo inflamatório e reduzida fibrose muscular com o tratamento.

O resumo em inglês pode ser lido abaixo:

(European Journal of Pharmacology, 2013) The Nitric Oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy

Paola Zordan, Clara Sciorati, Lara Campana, Lucia Cottone, Emilio Clementi, Patrizia-Rovere Querini, Silvia Brunell

Inflammation plays a crucial role in muscle remodelling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair, were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most the remaining macrophages displayed characteristics of transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing of chronic muscle damage. This, alongside its already approved use in human, make of molsidomine a drug with a significant therapeutic potential in muscular dystrophies.

Reino Unido – neste artigo o Dr. V. Dubowitz faz uma análise do uso de cortícoides em Duchenne desde a primeira publicação há cerca de 39 anos. Pode-se perceber a evolução das evidências de que os corticóides podem retardar a evolução da doença e que se constituem no tratamento preconizado para todos os pacientes com esta forma de distrofia. Ele também sugere que as evidências apontam para os benefícios do uso destas drogas numa faixa etária mais jovem, dos 3 aos 5 anos e que estudos clínicos devem ser feitos para comprovar estes resultados num grupo maior de pacientes..

Leiam mais sobre o artigo aqui.

Itália – A inflamação desempenha um papel crucial na remodelação e reparação muscular após a lesão aguda e crónica, em particular no distrofias musculares, um grupo heterogêneo de doenças genéticas que levam à degeneração muscular. Defeito da geração de óxido nítrico (NO) é um evento-chave na patogënese das distrofias musculares, portanto, doadores têm sido explorados como novas terapêuticas para esta doença. Os autores investigaram o efeito imuno-modulador de uma dessas drogas, molsidomina, capazes de retardar a progressão da distrofia muscular em camundongos com distrofia tipo cinturas A molsidomina já foi liberada para uso em seres humanos. Os animais tratados apresentaram menor processo inflamatório e reduzida fibrose muscular com o tratamento.

O resumo em inglês pode ser lido abaixo:

(European Journal of Pharmacology, 2013) The Nitric Oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy

Paola Zordan, Clara Sciorati, Lara Campana, Lucia Cottone, Emilio Clementi, Patrizia-Rovere Querini, Silvia Brunell

Inflammation plays a crucial role in muscle remodelling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair, were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most the remaining macrophages displayed characteristics of transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing of chronic muscle damage. This, alongside its already approved use in human, make of molsidomine a drug with a significant therapeutic potential in muscular dystrophies.

Fonte: http://distrofiamuscular.net/noticias

Holanda – Quarenta e oito pacientes com distrofia muscular de Becker foram incluídos, o que representa 11 mutações diferentes. As alterações genéticas que eles apresentam serão as mesmas que os pacientes que se submeteram ou se submeterão ao salto de exon A idade média dos pacientes foi de 43 anos (variação 6-67). Nove pacientes eram usuários de cadeiras de rodas (26-56 anos). Cardiomiopatia dilatada estava presente em 7/36 pacientes. Apenas um paciente utilizava suporte ventilatório. Três pacientes morreram com a idade de 45, 50 e 76 anos, respectivamente. Portanto a severidade da distrofia muscular será amenizada com o uso de oligonucleotideos para salto de exon.

O resumo em inglês pode ser lido abaixo:

(J Neurol Psychiatry, May 2013) Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy

J C van den Bergen, S M Schade van Westrum, L Dekker, A J van der Kooi, M de Visser, B H A Wokke, C S Straathof, M A Hulsker, A Aartsma-Rus, J J Verschuuren, and H B Ginjaar

Abstract

Objective Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD.

Methods Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD

Results Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6–67). Nine patients were wheelchair users (26–56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively

Conclusions This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a ‘skipped’ DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.

Grécia – os autores descrevem um caso de distrofia de Becker, com cardiomiopatia e que apesar da medicação correta não estava compensado do ponto de vista cardíaco. Internado, ele foi submetido a instalação de um cardioversor-desfibrilador interno com sincronização dos ventrículos, resultando no aumento da função cardíaca e controle da doença.

Leiam mais sobre o artigo aqui

USA – neste Congresso serão apresentadas 45 pesquisas relacionadas com a terapia gênica e celular relacionadas com o tratamento de várias formas de distrofia muscular. As pesquisas ainda são básicas e longe dos estudos clínicos.

Leiam mais sobre o artigo aqui.

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

USA – no Experimental Biology, maior congresso de ciências básicas dos Estados Unidos, serão apresentados três trabalhos de um mesmo grupo que reforçam o papel das alterações vasculares na distrofia muscular de Duchenne. Estudos prévios demonstraram que há uma incapacidade dos portadores de distrofia de Becker em reduzir a vasocontrição reflexa desencadeada por exercícios. Nestes três trabalhos, dois em seres humanos e um em camundongos este efeito é novamente demonstrado. Além disso com o uso de inibidores da fosfodiesterase habitualmente utilizados em disfunção erétil, como o tadalafil ou sildenafil, a resposta vasoativa se recupera ao menos parcialmente.

O resumo em inglês destes trabalhos pode ser lido aqui:

a) (Experimental Biology, 2013) Phosphodiesterase 5 inhibition rescues functional sympatholysis in Duchenne Muscular Dystrophy
Michael Nelson, Elizabeth A. Martin, Xiu Tang, Jimmy Johannes, Joshua Lewis, Swaminatha V. Gurudevan, Stanley Nelson, Carrie Miceli, Ronald G. Victor.

We recently reported that functional sympatholysis (i.e., muscle contraction-induced attenuation of reflex vasoconstriction) is impaired in Becker Muscular dystrophy and rescued by phosphodiesterase (PDE)5 inhibition with tadalafil. However, tadalafil failed to rescue sympatholysis in one BMD patient with a rapidly progressive disease resembling Duchenne Muscular Dystrophy. Thus, we tested the ability of two different phosphodiesterase inhibitors, tadalafil and sildenafil, to rescue sympatholysis in DMD. In 6 boys with DMD (ages 7-13) and 8 healthy controls, we measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] evoked by lower body negative pressure) at rest and during rhythmic handgrip exercise. First, we confirm that sympatholysis is impaired in DMD, because handgrip greatly attenuated vasoconstriction in controls (ΔHb02:-22±6 vs. -9±5 %, p<.05; rest vs. HG) but caused no attenuation in DMD (-17±2 vs. -15±3%). Then, in a randomized single dose (0.5 mg/kg) cross-over trial of tadalafil vs. sildenafil, we show that sympatholysis is rescued in DMD by either PDE5 inhibitor (tadalafil: -21±3 vs. -11±4; sildenafil, -22±4 vs. -12±3%; ΔHb02 rest vs. HG). PDE5 inhibition therefore constitutes a putative therapeutic treatment option for patients with either Becker or Duchenne Muscular Dystrophy.

Support: Parent Project Muscular Dystrophy

b) (Experimental Biology, 2013) Tadalafil-sensitive impairment in muscle blood flow during exercise in Duchenne Muscular Dystrophy
Michael Nelson, Elizabeth A. Martin, Xiu Tang, Jimmy Johannes, Joshua Lewis, Swaminatha V. Gurudevan, Ronald G.Victor

Out-of-frame mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD)—a devastating X-linked muscle wasting disease for which there is no treatment other than corticosteroids. In DMD, loss of the cytoskeletal protein dystrophin impairs sarcoelmmal targeting of nNOS, which is the main source of skeletal muscle-derived nitric oxide (NO). We previously showed that loss of nNOS impairs the normal exercise-induced attenuation of reflex vasoconstriction in dystrophic skeletal muscle, thus implicating a putative vascular component to the pathogenesis of DMD. Here we present data on a second phenotype, that muscle blood flow (BF, measured by Doppler ultrasound of the brachial artery) fails to increase normally during mild rhythmic handgrip exercise in 6 boys with DMD (7-13 years of age) compared with 8 age-matched male controls (Ctrls): ΔBF:+13±5% vs. +81±10%, respectively (p<.05). Moreover, we show that the phosphodiesterase 5 inhibitor Tadalafil, restores active hyperemia in boys with DMD in a dose-dependent manner: 0.5 mg/kg, +56±13%; 1.0 mg/kg, +72+18% These data significantly advance the vascular hypothesis of DMD and implicate PDE5 inhibition as a putative therapeutic treatment option. Support: Parent Project Muscular Dystrophy, Heart and Stroke Foundation of Canada (MN)

c) (Experimental Biology, 2013) Chronic tadalafil treatment ameliorates functional muscle ischemia and exercise-induced muscle injury in dystrophin- deficient mdx mice

Liang Li, Nancy Zepeda, Ronald G Victor, Gail D Thomas. The
Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA

The dystrophin-deficient muscles of patients with Duchenne or Becker muscular dystrophy and mdx mice are susceptible to ischemia during exercise due to loss of sarcolemmal neuronal nitric oxide synthase (nNOS). We showed that functional muscle ischemia is alleviated in patients and mice by acute treatment with the phosphodiesterase 5A (PDE5A) inhibitor tadalafil to boost NO-cGMP signaling in the diseased muscles. We now asked if this anti-ischemic effect is sustained during chronic PDE5A inhibition. We fed mdx mice control or medicated diets (tadalafil, 4 mg/kg) for 3 months and then evaluated norepinephrine (NE)-induced hindlimb vasoconstriction. NE evoked similar decreases in femoral vascular conductance (FVC) in resting and contracting hindlimbs of untreated mdx mice, indicating functional muscle ischemia (ΔFVC contraction/rest, 1.07 ± 0.13; n=10). NE-induced ischemia was attenuated in tadalafil-treated mice (ΔFVC contraction/rest, 0.61 ± 0.06; n=9; P<0.05 vs untreated) and was similar to C57BL10 controls (ΔFVC contraction/rest, 0.50 ± 0.08; n=10).
Serum creatine kinase activity was elevated 6-fold post-exercise in untreated mice, but only 2.5-fold in treated mice (P<0.05). These findings indicate that chronic PDE5A inhibition counteracts functional muscle ischemia in mdx mice, which may reduce injury of the vulnerable dystrophin-deficient muscles during exercise. Supported by MDA, 158944.

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