Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial

Fernández-Rhodes, Lindsay; Kokkinis, Angela; White, Michelle J.; Watts, Charlotte A.; Auh, Sungyoung; Jeffries, Neal; Shrader, Joseph A.; Lehky, Tanya; Li, Li; Ryder, Jennifer E; Levy, Ellen W.; Solomon, Beth; Harris‐Love, Michael O.; Pean, Alison La; Schindler, Alice B.; Chen, Cheun Ju; Prospero, Nicholas A. Di; Fischbeck, Kenneth H.

doi:10.1016/s1474-4422(10)70321-5

Cited by 138 publications

(131 citation statements)

References 26 publications

(28 reference statements)

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“…There was no significant difference in age between the two groups ( P = 0.16). The characteristics of this study population, including age, CAG repeat length, disease duration, and ALSFRS‐R scores, were similar to those of previous studies 11, 23, 24. Fifty‐three of the 111 SBMA patients reported having subjective dysphagia (Table 1).…”

Section: Resultssupporting

confidence: 72%

Swallowing markers in spinal and bulbar muscular atrophy

Banno

Katsuno

Suzuki

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWe examined the characteristics of dysphagia in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease causing weakness of limb, facial, and oropharyngeal muscles via a videofluoroscopic swallowing study, and investigated the plausibility of using these outcome measures for quantitative analysis.MethodsA videofluoroscopic swallowing study was performed on 111 consecutive patients with genetically confirmed spinal and bulbar muscular atrophy and 53 age‐ and sex‐matched healthy controls. Swallowing of 3‐mL liquid barium was analyzed by the Logemann's Videofluorographic Examination of Swallowing worksheet.ResultsOf more than 40 radiographic findings, the most pertinent abnormal findings in patients with spinal and bulbar muscular atrophy, included vallecular residue after swallow (residue just behind the tongue base), nasal penetration, and insufficient tongue movement (P < 0.001 for each) compared with healthy controls. Quantitative analyses showed that pharyngeal residue after initial swallowing, oral residue after initial swallowing, multiple swallowing sessions, and the penetration–aspiration scale were significantly worse in these patients (P ≤ 0.005 for each) than in controls. In patients with spinal and bulbar muscular atrophy, laryngeal penetration was observed more frequently in those without subjective dysphagia.InterpretationDysphagia of spinal and bulbar muscular atrophy was characterized by impaired tongue movement in the oral phase and nasal penetration followed by pharyngeal residues, which resulted in multiple swallowing sessions and laryngeal penetration. Although major limitations of reproducibility and radiation exposure still exist with videofluoroscopy, pharyngeal residue after initial swallowing and the penetration–aspiration scale might serve as potential outcome measures in clinical studies.

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Section: Resultssupporting

confidence: 72%

Swallowing markers in spinal and bulbar muscular atrophy

Banno

Katsuno

Suzuki

et al. 2017

Ann Clin Transl Neurol

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“…Clinical assessment was performed at the same time in all siblings. Neurological assessment was performed using two established scales: bulbar rating scale (BRS) and in adult myopathy assessment tool (MATG) [Fernández-Rhodes et al 2011]. These scales provide a quantitative measure of clinical affectation.…”

Section: Methodsmentioning

confidence: 99%

“…At the physical exam, tongue with fasciculations, abolished gag reflex, fasciculations and intention tremor in extremities, bilateral gynecomastia, absence of facial hair, and diminished axillar hair were noted. Neurological assessment was performed according to previously described scales [Fernández-Rhodes et al 2011]. His bulbar rating scale (BRS) total score was 27/32 and adult myopathy assessment tool (AMAT) score was 15/45.…”

Section: Individual IImentioning

confidence: 99%

A rapidly progressive defective spermatogenesis in a Mexican family affected by spino-bulbar muscular atrophy

Piña-Aguilar

Regalado-Hernández

Moreno-García

et al. 2016

Systems Biology in Reproductive Medicine

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Spino-bulbar muscular atrophy (SBMA) is an X-linked recessive adult progressive disorder affecting motor neurons. It is caused by a poly-glutamine tract expansion in the androgen receptor (AR) which generates protein aggregates that cannot be processed by proteasomes. A secondary mild androgen resistance is developed by AR dysfunction and patients present endocrine abnormalities including gynecomastia and poor function of testosterone in tissues; however, normally they are fertile. In this report we describe a Mexican family with three affected brothers with primary infertility caused by a progressive impairment of spermatogenesis leading to azoospermia before 40 years of age. They presented common features associated to patients affected by SMBA, such as gynecomastia, high level of CPK, muscle cramps, fasciculations, muscle wastage, and impaired swallowing. Two intracytoplasmic sperm injection (ICSI) cycles were performed in one of the patients resulting in fertilization failure. Molecular analysis of AR gene exon 1 revealed 54 CAG repeats in DNA extracted from leukocytes in affected patients and 22 repeats in the fertile non-affected brother. Severe impaired spermatogenesis of rapid progression has not been associated before to SBMA. This is the first report of assisted reproduction techniques indicated by male infertility in patients with this rare disorder. Further studies are required to confirm the unusual result of intracytoplasmic sperm injection cycles. We discuss the implications and possible pathogenesis of these unique features of SBMA in this family. ARTICLE HISTORY

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“…25 Also, a phase 2 clinical trial of dutasteride, a 5-a-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone, did not demonstrate effectiveness. 26 Although the results of these studies are inconclusive, their findings do not exclude the possibility that ligand-targeted therapies slow the progression of SBMA. Given the strong evidence shown in basic studies, this hypothesis needs to be further verified in clinical trials with a rigorous and efficient design.…”

Section: Development Of Therapies Targeting Abnormal Protein Accumulamentioning

confidence: 97%

Translational research on disease‐modifying therapies for neurodegenerative diseases

Katsuno

Watanabe

Tanaka

et al. 2013

Neurology & Clinical Neurosc

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Neurodegenerative diseases are a group of disorders that affect a certain population of neurons, and are characterized by progressive impairment of cognitive and/ or motor function. Although most current therapies aim at symptomatic relief, recent studies using cellular and animal models have given insight into the molecular pathogenesis of neurodegenerative diseases and the development of diseasemodifying therapies that slow neurodegeneration. However, few clinical trials have confirmed the efficacy of disease-modifying therapy for neurological deficits. For successful translational research on neurodegenerative disorders, several challenges in basic and clinical studies should be overcome. Elucidation of the molecular basis for neurodegeneration and creation of animal models that faithfully replicate human pathology are fundamental to basic studies, while the efficiency of clinical trials needs to be improved by establishing sensitive outcome measures, enrichment of trial designs by identifying the target individuals who are expected to show a high response, and innovative study designs. Initiation of therapy at the presymptomatic stage is another key to the successful development of disease-modifying therapy for neurodegenerative diseases. Although accumulation of abnormal proteins is thought to be the pivotal molecular trigger of neurodegeneration, it has also been revealed that disease progression is influenced by various factors, including the neuron-glia interaction and the propagation of causative proteins. The entire mechanism of neurodegeneration appears to be more complicated than hitherto expected, and thus therapies that target multiple molecular pathways also need to be developed.

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Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial

Abstract: SummaryBackground-Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment.

Cited by 138 publications

References 26 publications

Swallowing markers in spinal and bulbar muscular atrophy

Swallowing markers in spinal and bulbar muscular atrophy

A rapidly progressive defective spermatogenesis in a Mexican family affected by spino-bulbar muscular atrophy

Translational research on disease‐modifying therapies for neurodegenerative diseases

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