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1.
Lancet Neurol ; 23(7): 687-699, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38782015

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.


Assuntos
Esclerose Lateral Amiotrófica , Fármacos Neuroprotetores , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Masculino , Feminino , Método Duplo-Cego , Pessoa de Meia-Idade , Idoso , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/efeitos adversos , Resultado do Tratamento , Adulto , Hidroxilaminas/uso terapêutico , Hidroxilaminas/efeitos adversos , Hidroxilaminas/farmacologia , Oxidiazóis/uso terapêutico , Oxidiazóis/efeitos adversos
2.
Neurol Clin ; 38(3): 553-564, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32703468

RESUMO

Diabetic lumbosacral radiculoplexus neuropathy, also known as diabetic amyotrophy, has a characteristic course of sudden onset of unilateral pain in the thigh and hip, which may spread to the other side in weeks to months and proceeds with progressive lower extremity weakness, often resulting in the inability to walk unassisted. The syndrome is typically monophasic, and most patients will recover at least to some degree. Less typical features include lack of pain, distal predominant weakness, absence of diabetes, and upper extremity involvement. This article provides a series of interesting cases to highlight the diagnostic challenges and discusses management decision making.


Assuntos
Diabetes Mellitus/diagnóstico por imagem , Neuropatias Diabéticas/diagnóstico por imagem , Plexo Lombossacral/diagnóstico por imagem , Debilidade Muscular/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus/fisiopatologia , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/fisiopatologia , Feminino , Humanos , Plexo Lombossacral/fisiopatologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/complicações , Debilidade Muscular/fisiopatologia , Síndrome
3.
J Clin Neuromuscul Dis ; 20(2): 49-59, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30439750

RESUMO

OBJECTIVES: To estimate the satisfactory response rate (SR%) with achieving maintenance, low-dose prednisone in acetylcholine receptor antibody-positive generalized myasthenia gravis. METHODS: In this retrospective study, we estimate the SR% as defined by (remission/minimal manifestations status for at least 6 months using 7.5 mg or less of prednisone daily, for maintenance treatment at 2, 4, and 6 years after symptoms onset) for patients who were not taking steroid-sparing immunosuppressant (SSI) as a primary outcome and for patients taking an SSI as a secondary outcome. RESULTS: Forty-five patients were not taking an SSI at 2 years, 34 patients at 4 years, and 17 patients at 6 years; SR% was 44.4%, 64.7%, and 58.8%, respectively. Thirty-six patients were taking an SSI at 2 years, 22 patients at 4 years, and 15 patients at 6 years; the SR% was 50.0%, 45.4%, and 66.7%, respectively. CONCLUSIONS: Nearly half of the generalized myasthenia gravis patients who were not taking an SSI achieved an SR.


Assuntos
Anti-Inflamatórios/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Prednisona/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptores Colinérgicos/imunologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
4.
Curr Rheumatol Rep ; 20(8): 52, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29955981

RESUMO

PURPOSE OF REVIEW: While sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease after age 50, the pathogenesis of this disease is still poorly understood. In this review, we discuss our current state of knowledge in sIBM and provide an update on our current understanding of its pathophysiology and management. RECENT FINDINGS: Lines of evidence in support of an inflammatory pathogenesis include inflammatory infiltrates in the target organ, NFκB activation, cytokine response, MHC I upregulation, and cN1A antibody. Refractoriness to immunotherapies has led to suggestion of a degenerative pathophysiology. Evidence for impaired protein homeostasis with misfolding burden is coupled with findings of endoplasmic reticulum stress, proteasome dysfunction, and mitochondrial lesion. Recent treatment trials have focused more on correcting the degenerative process or muscle growth rather than controlling the inflammation. There has been growing evidence toward degeneration as the primary process in sIBM. This is consistent with the refractory nature of this disease. Improving our understanding of this disease pathogenesis will propel efforts to find an effective therapy.


Assuntos
Imunoterapia , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/diagnóstico , Gerenciamento Clínico , Humanos , Inflamação/patologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/terapia
5.
Muscle Nerve ; 51(5): 662-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25187298

RESUMO

INTRODUCTION: We reviewed the diagnostic yield of muscle biopsy according to the presence or absence of muscle weakness, hyperCKemia, and electromyogaphic (EMG) abnormalities. METHODS: In a retrospective study, 698 muscle biopsy reports were analyzed. Logistic regression models for myopathy and specific myopathy were fit, and receiver-operating characteristic (ROC) curves were generated to assess prediction accuracy. The probability of finding specific myopathy was considered the main indication of a positive muscle biopsy. RESULTS: Isolated hyperCKemia was poorly predictive of either myopathy or specific myopathy. Combined myopathic EMG, proximal weakness, and hyperCKemia were predictive. The predictability increased proportionally to the creatine kinase (CK) level in patients with proximal weakness and myopathic EMG. Cross validation showed accuracy around 70% for a probability threshold of 50%. CONCLUSIONS: The presence of hyperCKemia, proximal weakness, and myopathic EMG together were associated with highly positive diagnostic outcome of muscle biopsy. Isolated hyperCKemia had a poor diagnostic yield.


Assuntos
Creatina Quinase/metabolismo , Debilidade Muscular/fisiopatologia , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Adulto , Idoso , Biomarcadores/metabolismo , Biópsia , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos
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