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1.
Fortschr Neurol Psychiatr ; 87(12): 703-710, 2019 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-31847032

RESUMEN

With Nusinersen, a first causative treatment for 5q-associated spinal muscular atrophy (SMA) has been available in Europe since 2017. Real-world data from neuromuscular clinical centers in Germany increasingly show a therapeutic benefit of nusinersen also in adult SMA patients of both sexes: in many cases, relevant improvements in or at least a stabilization of motor functions are achieved, potentially leading to enhanced autonomy in activities of daily life and to improved quality of living. Even in patients with severe spinal deformities, intrathecal application is usually feasible and safe using imaging modalities. Regular systematic evaluation of the motor status with validated instruments is crucial for adequate monitoring of the therapeutic effects. The documentation in SMA registries enables systematic development of a database for further development of this novel treatment paradigm. Relevant aspects of this novel therapeutic principle were discussed at an experts conference in Frankfurt / Main in February 2019.


Asunto(s)
Atrofia Muscular Espinal , Oligonucleótidos , Adulto , Femenino , Alemania , Humanos , Masculino , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico
2.
Buenos Aires; CONETEC; nov. 2019. tab.
No convencional en Español | BRISA/RedTESA | ID: biblio-1025032

RESUMEN

INTRODUCCIÓN: La Atrofia Muscular Espinal (AME) es una enfermedad neuromuscular hereditaria caracterizada por la afectación de las células del asta anterior de la médula espinal (neuronas motoras), que cursa con debilidad proximal simétrica y atrofia progresiva de los grupos musculares. Es una patología poco frecuente, altamente discapacitante y con elevada mortalidad en sus formas más graves. Tiene una incidencia aproximada de 1 cada 6.000/10.000 nacidos vivos, y constituye la principal causa de mortalidad infantil por una enfermedad genética. Actualmente, no existe un tratamiento curativo para la AME; sólo se dispone de tratamiento sintomático para retrasar la progresión de la enfermedad y sus efectos discapacitantes, y tratamiento de sostén nutricional, ventilatorio y neuromuscular para mitigar sus complicaciones. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y políticas de cobertura de nusinersen para el tratamiento de la atrofia muscular espinal y el impacto presupuestario de su potencial inclusión en la cobertura del sistema de salud. DESCRIPCIÓN DE LA TECNOLOGÍA: Nusinersen (ISIS-SMNRx o ISIS 396443, SPINRAZANR) es un oligonucleótido antisentido, diseñado para alterar el empalme de ARN mensajero del gen SMN2 y aumentar la síntesis de proteína SMN funcional compensando así la ausencia de proteína SMN protectora, causada por el defecto en el gen SMN1, y la consecuente atrofia muscular. Se encuentra aprobado por FDA (Food and Drug Administration) y EMA (European Medicines Agency) para el tratamiento de AME6. BÚSQUEDA BIBLIOGRÁFICA: Se llevó a cabo una búsqueda bibliográfica utilizando las siguientes palabras claves: nusinersen (all) OR spinraza (all). Se exploraron las siguientes bases de datos: PubMed, Cochrane Library, Biblioteca Virtual en Salud, Biblioteca Central de Medicina (RIMA), Epistemonikos, Tripdatabase, Lilacs, NICE, National Guidelines Clearinghouse, Scielo, Clinical Trials, Orphanet. También se realizó búsqueda manual. Se encontraron 5 estudios8­12, todos ellos financiados por el productor de la tecnología, de los cuales se seleccionaron 2 estudios de fase 3.8,9 Se consideraron además documentos de aprobación de FDA13, EMA14y NHS15.Se revisó información aportada por el fabricante, que solicitó un registro especial. RESULTADOS: Existe evidencia de que el nusinersen para AME tipo I disminuye la mortalidad y el requerimiento de asistencia ventilatoria mecánica, así como también mejora la función motora permitiendo el desarrollo y la adquisición de ciertas habilidades (por ejemplo sentarse, permanecer de pie o caminar) hasta por lo menos los 13 meses de observación. Por otro lado, si bien existe evidencia sobre el uso de nusinersen en pacientes con AME tipo II que muestra una mejora en la función motora a los 15 meses de tratamiento, no se encontró evidencia sobre efectos en la mortalidad, el requerimiento de asistencia ventilatoria mecánica o la calidad de vida. No se encontró evidencia sobre el uso de nusinersen en pacientes con AME de inicio luego de los 20 meses de edad (la mayoría de los pacientes con diagnóstico de AME tipo III y todos los tipo IV). La incidencia global de Efectos Adversos (EAs) resultó similar en los grupos nusinersen y control, al igual que los EAs moderados o graves. Sin embargo, una comunicación de julio de 2018 del productor de la tecnología revela que se han notificado casos de hidrocefalia comunicante no asociada a meningitis ni a hemorragia en pacientes tratados con nusinersen. Varios de estos pacientes fueron tratados mediante la colocación de una Válvula de Derivación Ventriculoperitoneal (VDVP). La eficacia o riesgos de nusinersen tras la implantación de una VDVP se desconocen. No hay información fehaciente más allá del seguimiento publicado y a largo plazo. CONCLUSIONES: Existe evidencia proveniente de un único ensayo clínico aleatorizado con seguimiento a 13 meses que muestra que nusinersen para pacientes con Atrofia Muscular Espinal tipo I disminuye la mortalidad y el requerimiento de asistencia ventilatoria mecánica, así como también mejora la función motora permitiendo el desarrollo y la adquisición de ciertas habilidades (sentarse, permanecer de pie, caminar). Existe evidencia proveniente de un único ensayo clínico sobre la utilización de nusinersen en pacientes con Atrofia Muscular Espinal tipo II, que muestra una mejora en la función motora a los 15 meses de tratamiento en el subgrupo de pacientes con edad de comienzo menor a los 20 meses, aunque no se encontró evidencia sobre efectos en la mortalidad, el requerimiento de asistencia ventilatoria mecánica o la calidad de vida. No se encontró evidencia sobre el uso de nusinersen en pacientes con Atrofia Muscular Espinal de inicio luego de los 20 meses de edad (la mayoría de los AME tipo III y todos los tipo IV).


Asunto(s)
Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Evaluación de la Tecnología Biomédica , Análisis Costo-Eficiencia
4.
Muscle Nerve ; 60(4): 409-414, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31298747

RESUMEN

INTRODUCTION: Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied. METHODS: Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12. RESULTS: Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%). DISCUSSION: These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA.


Asunto(s)
Fatiga/fisiopatología , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Adolescente , Niño , Preescolar , Fatiga/etiología , Femenino , Humanos , Lactante , Masculino , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/fisiopatología , Prueba de Paso
6.
Biofactors ; 45(5): 666-689, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31185140

RESUMEN

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Curcumina/farmacología , Demencia/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiedad/fisiopatología , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Trastorno Autístico/fisiopatología , Disponibilidad Biológica , Curcuma/química , Curcumina/aislamiento & purificación , Demencia/metabolismo , Demencia/fisiopatología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/fisiopatología , Glioma/tratamiento farmacológico , Glioma/metabolismo , Glioma/fisiopatología , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/fisiopatología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/fisiopatología , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatología , Fármacos Neuroprotectores/aislamiento & purificación , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Patentes como Asunto , Enfermedades por Prión/tratamiento farmacológico , Enfermedades por Prión/metabolismo , Enfermedades por Prión/fisiopatología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología
7.
J Pediatr Orthop B ; 28(4): 393-396, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30932967

RESUMEN

This study describes a new procedure for a safer and easier access for the intrathecal injection of the recently approved nusinersen therapy in spinal muscular atrophy. This therapy changed the natural history of the disease, but, to date, scoliosis surgery was an excluding criteria for nusinersen therapy. The bone mass, due to the posterior spinal fusion of the scoliosis surgery, prevents the needle for the nusinersen administration from intervertebral access. This is a single-center, single-surgeon case series descriptive study. A laminotomy at the L3-L4 level was performed to provide safer access for the intrathecal injection. The procedure was carried out during the scoliosis surgery in patients who underwent posterior spinal fusion (PSF) after the nusinersen therapy was introduced, whereas for those who underwent PSF earlier, a second procedure was necessary to perform a laminotomy. A fat grafting was used to prevent bone overgrowth in the laminotomy. Markers were applied as radiographic references for the intrathecal injection. Five patients were enrolled, four females and one male. The mean age of the patients was 11 years. Three patients underwent PSF before the introduction of the nusinersen therapy. Two patients underwent PSF after the nusinersen therapy was available. All of them underwent a laminotomy with a fat grafting at the L3-L4 laminotomy level and received nusinersen therapy without complications. The procedure described is simple and effective in providing safe intrathecal access to make these patients eligible for such important therapy.


Asunto(s)
Inyecciones Espinales/métodos , Vértebras Lumbares/cirugía , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/cirugía , Escoliosis/cirugía , Fusión Vertebral/métodos , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Laminectomía/métodos , Masculino , Atrofia Muscular Espinal/complicaciones , Oligonucleótidos/uso terapéutico , Radiografía , Escoliosis/complicaciones , Escoliosis/tratamiento farmacológico
8.
Brasília; CONITEC; abr. 2019. graf, ilus, tab.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1024265

RESUMEN

INTRODUÇÃO: As Atrofias Musculares Espinhais são um grupo de doenças neuromusculares hereditárias autossômicas recessivas caracterizadas pela degeneração dos neurônios motores na medula espinhal e tronco encefálico, resultando em fraqueza muscular progressiva. Com um diagnóstico difícil e geralmente determinada por sinais clínicos, a doença é caracterizada por prejudicar os movimentos voluntários mais simples, como sustentar a cabeça, sentar ou andar. A AME é dividida em quatro tipos, sendo o primeiro de maior gravidade e o último, menos agressivo, com manifestação tardia e perda de função motora gradativa. TECNOLOGIA: Nusinersena. PERGUNTA: Nusinersena é eficaz e seguro para o tratamento de pacientes com diagnóstico de AME 5q quando comparado ao placebo? EVIDÊNCIAS CIENTÍFICAS: Dois ensaios clínicos randomizados (ECR), um estudo de extensão e seis relatos de coorte foram encontrados. Dos ECR, um avaliou o uso de nusinersena em pacientes com AME de início precoce (ou tipo 1) e o outro AME de início tardio. O ECR avaliando AME 5q tipo 1 encontrou diferenças estatisticamente significantes entre o grupo em uso do medicamento e o controle na melhora do escore HINE 2, sobrevida livre de evento, CHOP INTEND e morte. Já para os desfechos proporção de pacientes que passaram a requerer ventilação mecânica e incidência de eventos adversos (EA) não houve diferença estatisticamente significante entre os dois grupos. Pacientes com menor tempo de duração da doença tiveram melhores resultados com o uso do nusinersena em relação à mortalidade e uso de ventilação mecânica. O outro ECR, de pacientes com AME 5q de início tardio, avaliou o ganho motor pela escala HFMSE, sendo maior no grupo nusinersena quando comparado ao controle. Os desfechos secundários não apresentaram diferenças estatisticamente significantes entre os grupos, assim como a segurança. Os estudos avaliando a efetividade correspondiam a relatos de Programas de Acesso Expandido de cinco países, para AME 5q tipo 1. Observou-se maior benefício com nusinersena no escore CHOP INTEND nas crianças que iniciaram o tratamento até os sete meses de idade. Quanto ao HINE 2, os pacientes atingiram uma melhora variando de 1,26 a 1,5 após o período de uso do nusinersena. Em relação à função respiratória, 10 a 18% dos pacientes em tratamento passaram a necessitar de suporte ventilatório. AVALIAÇÃO ECONÔMICA: Uma análise de custo-utilidade foi realizada para os dois tipos considerados no relatório: AME 5q de início precoce e AME 5q de início tardio. Para AME 5q de início precoce a RCEI calculada considerando qualidade de vida (QV) de pacientes e cuidadores foi de R$749.276,00 por ano de vida ajustado a qualidade (QALY) ganho e de R$ 1.023.351,00 por QALY, computando apenas QV de pacientes. Já a de início tardio apresentou RCEI de pacientes e cuidadores de R$ 410.783,00 por QALY ganho e de R$ 841.859,00 por QALY computando apenas a QV de pacientes. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Estima-se um gasto de R$122,6 a R$217,1 milhões no primeiro ano após a incorporação de nusinersena. No quinto ano, o impacto financeiro para o SUS pode variar entre R$ 359,3 e R$ 456,8 milhões. Considerando o total acumulado em cinco anos, prevê-se uma variação de R$ 1,2 a mais de R$ 1,6 bilhão. CONSIDERAÇÕES FINAIS: O nusinersena apresenta resultados de eficácia e segurança plausíveis para o tratamento de indivíduos com AME 5q tipo I. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes em sua 75ª reunião ordinária, no dia 14 de março de 2019, indicaram que o tema seja submetido à Consulta Pública com recomendação preliminar favorável à incorporação no SUS do nusinersena para o tratamento da AME 5q tipo I com os seguintes condicionantes: para pacientes com menos de 7 meses de vida, com início de tratamento até 13 semanas após o diagnóstico e com diagnóstico genético confirmatório; atendimento em centros de referência com a disponibilização de cuidados multidisciplinares; protocolo clínico e diretrizes terapêuticas (com estabelecimento de critérios de inclusão, exclusão e interrupção); avaliação da efetividade clínica; reavaliação pela CONITEC em 3 anos; e doação pela empresa fabricante das 3 primeiras doses do tratamento de cada paciente. CONSULTA PÚBLICA: A Consulta Pública nº 12 foi realizada entre os dias 19/03/2019 e 28/03/20119. Foram recebidas 41.787 contribuições, sendo 494 pelo formulário para contribuições técnico-científicas e 41.293 pelo formulário para contribuições sobre experiência ou opinião. Das contribuições sobre experiência e opinião, 1.621 foram contrárias (800 parcialmente contrárias e 821 totalmente contrárias) e 39.672 a favor (26.767 parcialmente, 12.905 totalmente) da recomendação preliminar da CONITEC. Já em relação às contribuições técnicas, foram recebidas 40 contribuições contrárias (28 totalmente contrárias e 12 parcialmente contrárias) e 454 contribuições favoráveis (110 totalmente favoráveis e 344 parcialmente favoráveis) à recomendação preliminar da CONITEC. Apesar do grande volume de contribuições recebidas, não foram identificadas novas evidências que alterassem o sentido da recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da CONITEC presentes na 76ª reunião ordinária, no dia 04 de abril de 2019, deliberaram por unanimidade recomendar a incorporação no SUS do nusinersena para AME 5q tipo I, para pacientes com diagnóstico genético confirmatório que não estejam em ventilação mecânica invasiva permanente contínua (24 horas por dia). O atendimento dos pacientes deverá ser realizado em centros de referência com a disponibilização de cuidados multidisciplinares, mediante Protocolo Clínico e Diretrizes Terapêuticas (com estabelecimento de critérios de inclusão, exclusão e interrupção); avaliação da efetividade clínica; reavaliação pela CONITEC em 3 anos e negociação de preço com a empresa fabricante do medicamento. A CONITEC informa que caso sejam apresentadas evidências adicionais sobre eficácia, efetividade e segurança do nusinersena para tratamento dos tipos II e III de AME 5q, o tema poderá ser reavaliado. DECISÃO: Incorporar o nusinersena para atrofia muscular espinhal (AME) 5q tipo I, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 24, publicada no Diário Oficial da União nº 79, seção 1, página 52, em 25 de abril de 2019.


Asunto(s)
Humanos , Placebos/uso terapéutico , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
9.
Neuroradiology ; 61(5): 565-574, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30868184

RESUMEN

PURPOSE: To examine diagnostic reference levels (DRL) and achievable doses (AD) of image-guided and size-specific dose estimates (SSDE) and organ and effective doses of CT-guided intrathecal nusinersen administration to adult patients with spinal muscular atrophy (SMA). METHODS: This study involved a total of 60 image-guided intrathecal nusinersen treatments between August 2017 and June 2018. Patient cohort comprised 14 adult patients with the following SMA types: type 2 (n = 9) and type 3 (n = 5) with a mean age of 33.6 years (age range 25-57 years). DRL, AD, SSDE, organ, and effective doses were assessed with a dose-monitoring program based on the Monte Carlo simulation techniques. RESULTS: DRL and AD for computed tomography are summarised as follows: in terms of CT-dose index (CTDIvol), DRL 56.4 mGy and AD 36.7 mGy; in terms of dose-length product (DLP), DRL 233.1 mGy cm and AD 120.1 mGy cm. DRL and AD for fluoroscopic guidance were distributed as follows: in terms of dose-area product (DAP), DRL 239.1 µGy m2 and AD 135.2 mGy cm2. Mean SSDE was 9.2 mGy. Mean effective dose of the CT-guided injections was 2.5 mSv (median 2.0 mSv, IQR 1.3-3.2 mSv). Highest organ doses in the primary beam of radiation were the small intestine 12.9 mSv, large intestine 9.5 mSv, and ovaries 3.6 mSv. CONCLUSION: Radiation exposure of SMA patients measured as DRLs is generally not higher compared with patients without SMA despite severe anatomical hazards. Dose monitoring data may allow clinicians to stratify radiation risk, identify organs at risk, and adopt measures for specific radiation dose reduction.


Asunto(s)
Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/administración & dosificación , Radiografía Intervencional/métodos , Tomografía Computarizada por Rayos X/métodos , Adulto , Femenino , Humanos , Inyecciones Espinales , Masculino , Persona de Mediana Edad , Método de Montecarlo , Exposición a la Radiación
10.
Prog Med Chem ; 58: 119-156, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30879473

RESUMEN

Targeting RNA drastically expands our target space to therapeutically modulate numerous cellular processes implicated in human diseases. Of particular interest, drugging pre-mRNA splicing appears a very viable strategy; to control levels of splicing product by promoting the inclusion or exclusion of exons. After describing the concept of "splicing modulation", this chapter will cover the outstanding progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of spinal muscular atrophy using two therapeutic modalities: splice switching oligonucleotides and small molecules. This review discusses the vital but feasible requirement for such drugs to deliver selectivity, and critical safety aspects are highlighted. Transformational medicines such as those developed to treat SMA are likely just the beginning of this story.


Asunto(s)
Atrofia Muscular Espinal/patología , Compuestos Azo/química , Compuestos Azo/uso terapéutico , Descubrimiento de Drogas , Fluorobencenos/química , Fluorobencenos/uso terapéutico , Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Oligonucleótidos/metabolismo , Oligonucleótidos/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Empalme del ARN , Proteínas del Complejo SMN/genética , Proteínas del Complejo SMN/metabolismo
11.
Life Sci Alliance ; 2(2)2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30910806

RESUMEN

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by reduced levels of functional survival motor neuron (SMN) protein. To identify therapeutic agents for SMA, we established a versatile SMN2-GFP reporter line by targeting the human SMN2 gene. We then screened a compound library and identified Z-FA-FMK as a potent candidate. Z-FA-FMK, a cysteine protease inhibitor, increased functional SMN through inhibiting the protease-mediated degradation of both full-length and exon 7-deleted forms of SMN. Further studies reveal that CAPN1, CAPN7, CTSB, and CTSL mediate the degradation of SMN proteins, providing novel targets for SMA. Notably, Z-FA-FMK mitigated mitochondriopathy and neuropathy in SMA patient-derived motor neurons and showed protective effects in SMA animal model after intracerebroventricular injection. E64d, another cysteine protease inhibitor which can pass through the blood-brain barrier, showed even more potent therapeutic effects after subcutaneous delivery to SMA mice. Taken together, we have successfully established a human SMN2 reporter for future drug discovery and identified the potential therapeutic value of cysteine protease inhibitors in treating SMA via stabilizing SMN proteins.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Genes Reporteros/genética , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Estabilidad Proteica/efectos de los fármacos , Animales , Barrera Hematoencefálica/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , Dipéptidos/farmacología , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Cetonas/farmacología , Leucina/análogos & derivados , Leucina/farmacología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Sustancias Protectoras/farmacología , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Transfección , Resultado del Tratamiento
12.
NeuroRehabilitation ; 44(1): 79-84, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30741700

RESUMEN

BACKGROUND: Trunk alignment is thought to contribute to neck function. However, this common assumption is not clear in patients with Parkinson's disease (PwPD) suffering from different postural deformities such as: Pisa syndrome (PS), Camptocormia & Antecollis (C&A). OBJECTIVES: to investigate the effect of different postural deformities including PS and C&A on neck function and pain in patient (PwPD). METHODS: Forty-five participants belonging to three groups: 15 PD patients without postural disorders (PD), 15 with PS, and 15 with C&A. The function, disability and pain were assessed by Neck Disability Index (NDI), and Brief Pain Inventory (BPI) which used to assess the pain severity (BPI-PS) and Pain Interference (BPI-PI). All groups completed clinical assessments by the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoenh & Yahr (mH&Y) staging and the Levodopa Equivalent Daily Dose (LEDD). RESULTS: PD group compared with PS and C&A groups showed differences in NDI, BPI-PS, BPI-PI, LEDD and mH&Y staging (P < 0.001), but no differences found in PD duration, UPDRS-II and III in the same groups. Moreover, no differences were observed between PS and C&A groups in the mentioned scales. DISCUSSION AND CONCLUSION: These results demonstrated that PS and C&A are associated with severe impairment of neck functions, and pain in PwPD.


Asunto(s)
Dolor de Cuello/fisiopatología , Enfermedad de Parkinson/fisiopatología , Balance Postural/fisiología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Personas con Discapacidad , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/fisiopatología , Dolor de Cuello/diagnóstico , Dolor de Cuello/epidemiología , Dolor/tratamiento farmacológico , Dolor/epidemiología , Dolor/fisiopatología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Proyectos Piloto , Curvaturas de la Columna Vertebral/tratamiento farmacológico , Curvaturas de la Columna Vertebral/epidemiología , Curvaturas de la Columna Vertebral/fisiopatología
13.
Artículo en Inglés | MEDLINE | ID: mdl-30783552

RESUMEN

Background: Camptocormia is defined as forward flexion of the spine that manifests during walking and standing and disappears in recumbent position. The various etiologies include idiopathic Parkinson's disease, multiple system atrophy, myopathies, degenerative joint disease, and drugs. Case Report: A 67-year-old diabetic female presented with bradykinesia and camptocormia that started 1 year prior to presentation. Evaluation revealed levosulpiride, a dopamine receptor blocker commonly used for dyspepsia, to be the culprit. Discussion: It is well known that dopamine receptor blockers cause parkinsonism and tardive syndromes. We report a rare and unusual presentation of camptocormia attributed to this commonly used gastrointestinal drug in the Asian population.


Asunto(s)
Antagonistas de Dopamina/efectos adversos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/etiología , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/etiología , Curvaturas de la Columna Vertebral/diagnóstico , Curvaturas de la Columna Vertebral/etiología , Sulpirida/análogos & derivados , Anciano , Encéfalo/diagnóstico por imagen , Complicaciones de la Diabetes , Diagnóstico Diferencial , Dispepsia/tratamiento farmacológico , Femenino , Humanos , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/tratamiento farmacológico , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/tratamiento farmacológico , Curvaturas de la Columna Vertebral/diagnóstico por imagen , Curvaturas de la Columna Vertebral/tratamiento farmacológico , Sulpirida/efectos adversos
14.
Ann Pharmacother ; 53(1): 61-69, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30008228

RESUMEN

OBJECTIVE: To review the efficacy and safety of nusinersen (Spinraza) in the treatment of spinal muscular atrophy (SMA). DATA SOURCES: An English-language literature search of PubMed and MEDLINE (1946 to June 2018) was performed using the terms nusinersen, ISIS-SMN (Rx), and spinal muscular atrophy. Manufacturer prescribing information, abstracts, article bibliographies, and clinicaltrials.gov data were incorporated for additional materials. STUDY SELECTION/DATA EXTRACTION: All clinical trials of nusinersen were identified and analyzed in the review. DATA SYNTHESIS: Nusinersen is the first drug therapy approved for the treatment of SMA. It is a novel modified antisense oligonucleotide designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron protein deficiency. Nusinersen has been studied for safety, pharmacokinetics, and efficacy in both open-label and randomized controlled trials. The studies show improvement in motor function across SMA of all types. The most common adverse effects were respiratory tract infections, headache, back pain, constipation, and post-lumbar puncture syndrome. Relevance to Patient Care and Clinical Practice: Based on phase III trial data, nusinersen produced positive changes in the clinical course of patients with SMA. The acquisition and administration of nusinersen present a number of challenges in clinical practice. Its intrathecal delivery and costly price tag must be recognized. CONCLUSION: Nusinersen is safe and effective in patients with SMA. It was well tolerated across all studied age groups.


Asunto(s)
Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Femenino , Humanos , Masculino , Oligonucleótidos/farmacología
15.
Pediatr Radiol ; 49(1): 136-140, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30167764

RESUMEN

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal-recessive disease affecting motor neurons and is the most common genetic cause of death in infants. Intrathecal nusinersen is the only therapy approved by the U.S. Food and Drug Administration for SMA. Deformities and spinal instrumentation from orthopedic surgeries are common in children with SMA, complicating traditional intrathecal access for nusinersen delivery. Cervical punctures are routinely performed in adults for cervical myelograms and should be considered for children with SMA as a viable form of intrathecal access. OBJECTIVE: This retrospective study assessed technical feasibility and complications of ultrasound-guided cervical puncture for nusinersen administration. MATERIALS AND METHODS: We reviewed 14 consecutive ultrasound-guided cervical punctures for nusinersen administration with local anesthesia. We reviewed technical success and complications. RESULTS: All procedures were technically successful. There were no major complications. Two minor complications included headaches that resolved by observation within 24 h after the procedure. CONCLUSION: Our series describes a successful novel method of ultrasound-guided cervical spine access for intrathecal administration of nusinersen, adding to the armamentarium of procedures for delivering nusinersen to adolescents with challenging lumbar spine access caused by scoliosis and spinal instrumentation. This technique has the advantages of real-time ultrasound guidance and potential avoidance of general anesthesia in children.


Asunto(s)
Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/administración & dosificación , Ultrasonografía Intervencional , Adolescente , Niño , Femenino , Humanos , Masculino , Atrofia Muscular Espinal/diagnóstico por imagen , Punciones , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
16.
Dev Med Child Neurol ; 61(1): 19-24, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30221755

RESUMEN

Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.


Asunto(s)
Fármacos del Sistema Nervioso Central/uso terapéutico , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Animales , Fármacos del Sistema Nervioso Central/economía , Aprobación de Drogas , Humanos , Atrofia Muscular Espinal/economía , Oligonucleótidos/economía
17.
Br J Clin Pharmacol ; 85(1): 181-193, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30302786

RESUMEN

AIMS: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry-into-human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers. METHODS: Part 1 had a randomized, double-blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6-18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two-period cross-over design (n = 8). RESULTS: Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi-phasic decline with a mean terminal half-life of 40-69 h. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27-55%) of the estimated maximum increase in SMN2 mRNA. CONCLUSIONS: Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full-length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing.


Asunto(s)
Compuestos Azo/administración & dosificación , Fármacos Neuromusculares/administración & dosificación , Pirimidinas/administración & dosificación , Empalme del ARN/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Compuestos Azo/efectos adversos , Compuestos Azo/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Método Doble Ciego , Interacciones de Drogas , Voluntarios Sanos , Humanos , Itraconazol/farmacocinética , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Fármacos Neuromusculares/efectos adversos , Fármacos Neuromusculares/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , ARN Mensajero/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Adulto Joven
18.
Neurol Sci ; 40(2): 327-332, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30430317

RESUMEN

Nusinsersen is now available in Italy for all SMA types. We describe the experience with intrathecal treatment with nusinersen in 50 patients with SMA at the NEMO Center (NEuroMuscular Omniservice Clinical Center) in Milan, a neuromuscular patient-centered clinic hosted within Niguarda Hospital, a National Public General Hospital. Our results indicate that the pathway of care described outweighs the burden due to the repeated intrathecal injections. Irrespective of age and severity, the treatment is feasible, accessible, and replicable provided that there is a multidisciplinary team having experience and training in SMA.


Asunto(s)
Prestación Integrada de Atención de Salud , Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Oligonucleótidos/administración & dosificación , Adolescente , Niño , Preescolar , Prestación Integrada de Atención de Salud/métodos , Familia , Geografía Médica , Humanos , Lactante , Inyecciones Espinales , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/diagnóstico , Fármacos Neuroprotectores/efectos adversos , Oligonucleótidos/efectos adversos , Grupo de Atención al Paciente , Pacientes Desistentes del Tratamiento , Escoliosis/complicaciones , Escoliosis/diagnóstico por imagen , Punción Espinal , Columna Vertebral/diagnóstico por imagen
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