Nusinersena: eficácia, segurança e custo-efetividade para o tratamento da atrofia muscular espinhal / Nusinersena: efficacy, safety and cost-effectiveness for the treatment of spinal muscular atrophy

As Atrofias Musculares Espinhais (AME) são um grupo de doenças neuromusculares hereditárias raras (incidência de cerca de 1 para cada 11.000 nascidos vivos).Caracterizam-se pela degeneração dos neurônios motores na medula espinhal e tronco encefálico, resultando em fraqueza muscular progressiva. As AME são categorizadas em subtipos clínicos (tipo I, II, III e IV) com base na idade de início dos sintomas e sua gravidade. O medicamento Nusinersena é eficaz, seguro e custo efetivo para o tratamento de pessoas com Atrofia Muscular Espinhal?

A gestão municipal de saúde de Campo Grande-MS recebeu solicitação de acesso ao medicamento de alto custo Nusinersena (Spinraza®) para crianças diagnosticadas com AME. Diante da necessidade de aprofundamento dos conhecimentos acerca da doença e possibilidades de tratamento, a Secretaria Municipal de Saúde encomendou este estudo para elucidar melhor a tomada de decisão da gestão. Estudos evidenciam que o Nusinersena prolonga a sobrevida livre de ventilação para portadores de AME tipo I e melhora a função motora para portadores de AME tipo I e II. Estas revisões indicam que a maior potencialidade da terapia ocorre nos estágios iniciais da doença pois existe uma janela de oportunidade para ação do medicamento com vistas a resgatar ou estabilizar a função do neurônio motor. Ou seja, melhores respostas ocorreram em crianças mais novas. No entanto, não há cura completa da doença, apenas melhora da sintomatologia5. Em abril de 2019, o Ministério da Saúde incorporou o medicamento Nusinersena para portadores de AME tipo I, ficando em aberto a cobertura dos tipos II,III e IV. O perfil de segurança e tolerabilidade do Nusinersena são aceitáveis, mas há escassez de dados sobre sua eficácia e desdobramentos a longo prazo. Devido aos custos extremamente elevados deste medicamento (análise baseada em preços oficiais) ele se tornou não custo-efetivo. Em agosto de 2018, a CONITEC recomendou a não incorporação do medicamento ao SUS, porém a Advocacia Geral da União recomendou uma nova submissão, feita pela empresa produtora onde foi aprovada em março de 2019 (para portadores de AME tipo I). Não houve acréscimo de novas evidências ou redução de preço que justificassem a mudança de decisão.

Effects of high EPA and high DHA fish oils on changes in signaling associated with protein metabolism induced by hindlimb suspension in rats.

The effects of either eicosapentaenoic (EPA)- or docosahexaenoic (DHA)-rich fish oils on hindlimb suspension (HS)-induced muscle disuse atrophy were compared. Daily oral supplementations (0.3 mL/100 g b.w.) with mineral oil (MO) or high EPA or high DHA fish oils were performed in adult rats. After 2 weeks, the animals were subjected to HS for further 2 weeks. The treatments were maintained alongside HS At the end of 4 weeks, we evaluated: body weight gain, muscle mass and fat depots, composition of fatty acids, cross-sectional areas (CSA) of the soleus muscle and soleus muscle fibers, activities of cathepsin L and 26S proteasome, and content of carbonylated proteins in the soleus muscle. Signaling pathway activities associated with protein synthesis (Akt, p70S6K, S6, 4EBP1, and GSK3-beta) and protein degradation (atrogin-1/MAFbx, and MuRF1) were evaluated. HS decreased muscle mass, CSA of soleus muscle and soleus muscle fibers, and altered signaling associated with protein synthesis (decreased) and protein degradation (increased). The treatment with either fish oil decreased the ratio of omega-6/omega-3 fatty acids and changed protein synthesis-associated signaling. EPA-rich fish oil attenuated the changes induced by HS on 26S proteasome activity, CSA of soleus muscle fibers, and levels of p-Akt, total p70S6K, p-p70S6K/total p70S6K, p-4EBP1, p-GSK3-beta, p-ERK2, and total ERK 1/2 proteins. DHA-rich fish oil attenuated the changes induced by HS on p-4EBP1 and total ERK1 levels. The effects of EPA-rich fish oil on protein synthesis signaling were more pronounced. Both EPA- and DHA-rich fish oils did not impact skeletal muscle mass loss induced by non-inflammatory HS.

Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas.

Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS) causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7) [Ang-(1-7)], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7) in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7) and the Mas receptor in disuse muscle atrophyin vivousing unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT) and Mas-knockout (Mas KO) mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7) immobilization-induced muscle atrophy. Our results found that Ang-(1-7) prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7) increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7) were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7) via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy.

Sleep and muscle recovery: endocrinological and molecular basis for a new and promising hypothesis.

Sleep is essential for the cellular, organic and systemic functions of an organism, with its absence being potentially harmful to health and changing feeding behavior, glucose regulation, blood pressure, cognitive processes and some hormonal axes. Among the hormonal changes, there is an increase in cortisol (humans) and corticosterone (rats) secretion, and a reduction in testosterone and Insulin-like Growth Factor 1, favoring the establishment of a highly proteolytic environment. Consequently, we hypothesized that sleep debt decreases the activity of protein synthesis pathways and increases the activity of degradation pathways, favoring the loss of muscle mass and thus hindering muscle recovery after damage induced by exercise, injuries and certain conditions associated with muscle atrophy, such as sarcopenia and cachexia.

Doenças neuromusculares e instrumentos úteis na avaliação motora em crianças e adolescentes / Neuromuscular diseases and usefull instruments in the motor evaluation of children and adolescents

As doenças neuromusculares acometem a unidade motora, podendo comprometer os neurônios do corno anterior da medula, as raízes nervosas e os nervos periféricos, a junção neuromuscular ou o músculo. Podem ser de origem genética ou adquirida. Na infância predominam as de origem genética, sendo as mais frequentes a distrofia muscular tipo Duchenne e a amiotrofia espinhal progressiva. Vários métodos e escalas foram propostos para a avaliação e acompanhamento aos pacientes com doenças neuromusculares, tais como a escala de força manual, conhecida como medical research counsil (MRC), a goniometria e escalas funcionais. Entre as escalas funcionais, destaca-se a escala medida da função motora (MFM), uma vez que ela pode ser utilizada em qualquer doença neuromuscular,é de fácil aplicação e de baixo custo. O presente estudo é uma revisão bibliográfica não sistemática sobre as doenças neuromusculares mais comuns na infância e os instrumentos de medida úteis na avaliação dos pacientes portadores dessas doenças...

The neuromuscular diseases affect the motor unit, and may compromise the neurons of the anterior horn of the spinal cord, the nerves’ roots and the peripheral nerves, the neuro muscular junction or the muscle. They can have genetic or acquired origin. The genetic origin diseases predominate in childhood, and the most frequent are the Duchenne muscular dystrophy and the spinal muscular atrophy. Several methods and scales were proposed for the assessment and monitoring of patients with neuromuscular diseases, such as the manual strength know as medical research council (MRC), the goniometry and the functional scales. Among the functional scales the motor function measure (MFM) is noteworthy, asit can be used in any neuromuscular disease, is easily applicable and has low cost. This study is a bibliographic review on the most common neuromuscular diseases in childhood and the useful measuring instruments for the assessment of patients with these diseases...

Anetodermia inducida por fármacos. informe de un caso / Anetodermia induced by drugs: case report

Se muestran los resultados de un estudio de caso diagnosticado como anetodermia inducida por fármacos (acetónido de triamcinolona bb) en paciente de 18 meses. Se diagnostica la enfermedad a través de interrogatorio y resultados del examen físico de piel. Se sigue a la paciente por consulta con evolución estable, sin lesiones nuevas (AU)

Sarcopenia in rheumatoid cachexia: definition, mechanisms, clinical consequences and potential therapies / Sarcopenia da caquexia reumatoide: conceituação, mecanismos, consequências clínicas e tratamentos possíveis

A caquexia relacionada à artrite reumatoide é conceituada como perda involuntária de massa magra, predominantemente de músculo esquelético, que também ocorre em vísceras e sistema imune, com massa gorda estável ou um pouco elevada e com pequena ou nenhuma perda de peso. A causa é multifatorial, incluindo a produção acentuada de citocinas, principalmente TNF± e IL-1², diminuição da ação periférica da insulina e pouca atividade física. A caquexia se faz presente em doentes com AR ativa ou mesmo inativa. Neste artigo discutem-se aspectos relacionados à patogenia, implicações clínicas e possíveis opções terapêuticas.

Rheumatoid cachexia can be defined as an involuntary loss of body cell mass, which predominates in skeletal muscle, but is also observed in the viscera and immune system. It occurs with little or no weight loss in the presence of stable or increased fat mass. The etiology is likely multifactorial, and involves excessive inflammatory cytokine production, namely excess tumor necrosis factor-± and interleukin-1² production, reduced peripheral insulin action, and low habitual physical activity. Cachexia occurs in active rheumatoid arthritis and even in the presence of disease control. In this article, we discuss the pathogenesis of rheumatoid cachexia, its clinical implications and potential therapies.

Sarcopenia en la pérdida funcional: rol del ejercicio / Sarcopenia in functional lost: excercise role

Sarcopenia is refers to the gradual decline in muscle mass and quality noted with advancing age, but is not only present in that’s condition. In the last time appear new names proposal how myoestheatosis of the aging in reference at changes in the fat composition of the mass muscle. Factors implicated in the etiology of sarcopenia include decreased physical activity, malnutrition, increase inflammatory activity, oxidative stress and abnormalities in the hormonal and the vitamin axes and others. There is growing evidence linking sarcopenia to the frailty and functional disability, falls, decreased bone density, glucose intolerance contributes significantly to the morbidity, decrease in quality of life, and health care cost in the elderly. Exercise has been shown to increase strength, aerobic capacity, and muscle protein synthesis, in both young and older people, however, exercise does not reverse all age – related changes, but is a strong tool for maintain the autonomy. In special of the strength and resistence together with adequate nutritional state.

A new model for the immobilization of the rat hind limb.

An alternative device for the immobilization of the hind limb of the rat was developed to study the effects of chronic disuse on the soleus and tibialis anterior muscles, maintained for 3 weeks in the shortening and the stretching positions, respectively. The proposed device is made of steel mesh and cotton materials, and has some advantages when compared to cast or plaster cast: it is cheaper, lighter (12 g or 4% of the body weight of the rat) and the same unit can be easily adjusted and used several times in the same animal or in animals of similar size. Immobilization is also useful to restrain the movements of the hip, knee, and ankle joints. Male rats (291 +/- 35 g and aged 14 +/- 2 weeks) were used to develop and test the model. The soleus muscle of 18 rats was maintained in a shortened position for 21 consecutive days and lost 19 +/- 7% of its length (P = 0.008) and 44 +/- 6% of its weight (P = 0.002) compared to the contralateral intact muscle. No difference (P = 0.67) was found in the stretched tibialis anterior of the same hind limb when compared to the contralateral muscle. No ulcer, sore or foot swelling was observed in the animals. Immobilization was effective in producing chronic muscle disuse in the hind limbs of rats and is an acceptable alternative to the traditional methods of immobilization such as cast or plaster cast.

Enfermedad de Charcot-Marie-Tooth o Atrofia muscular de peronea / Charcot-Marie-Tooth disease or peroneal muscular a trophy

Se reporta un caso de enfermedad de Charcot-Marie-Tooth en un paciente de 74 años, resaltándose las características clínicas, anatomopatológicas y electromiográficas, correspondientes a esta enfermedad(AU)