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1.
Medicine (Baltimore) ; 99(5): e18921, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000403

RESUMO

BACKGROUND: Recent studies have suggested that the potential functional polymorphism R47H in triggering receptors expressed on myeloid cells 2 (TREM2) is associated with several neurodegenerative diseases, however, the results remain inconclusive. This meta-analysis aimed to investigate the association between TREM2 R47H and the risk for 3 typical neurodegenerative diseases: Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS: A literature review was carried out using PubMed, Medline, and Embase. Data analysis was conducted using Stata 15.0 software. The pooled odds ratio (ORs) and 95% confidence interval (CIs) were calculated. RESULTS: A total of 35 articles were identified as eligible: 22 on AD, 3 on ALS, 7 on PD, 2 on AD and ALS, and 1 on ALS and PD. The AD set included 23,092 cases and 30,920 controls, the ALS set included 7391 cases and 12,442 controls, and the PD set included 8498 patients and 9161 controls. We found that R47H was associated with an increased risk of AD in the total pooled population (P < .001, OR = 4.02, 95% CI = 3.15-5.13). However, this significant difference existed for Caucasian people (OR = 4.16, 95% CI = 3.24-5.33) but not for Asian or African people. Moreover, we did not find any significant differences in minor allele frequency distribution between the PD and control groups or between the ALS and control groups, not only for the total pooled population but also for the subgroups of different ethnicities. CONCLUSION: Our study suggested that R47H in the TREM2 gene leads to an increased risk for developing AD, but not for ALS and PD, which adds evidence to the notion that diverse pathogenesis may be involved in different neurogenerative diseases.


Assuntos
Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/genética , Glicoproteínas de Membrana/genética , Doença de Parkinson/genética , Receptores Imunológicos/genética , Predisposição Genética para Doença , Humanos , Polimorfismo Genético
2.
Brain Nerve ; 72(1): 13-22, 2020 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-31907329

RESUMO

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness. Riluzole was the sole drug available for treating ALS until 2015, when edaravone was approved as a new anti-ALS drug. Recent discoveries of the disease-causal genes and proteins, as well as the rapid advancement of induced pluripotent stem (iPS) cell manipulations, drug deliveries, and molecular modifications have provided diverse and promising drug candidates. In particular, antisense-oligonucleotide therapy appears to significantly prevent disease progression when introduced early. Moreover, the in vitro modeling of ALS using patients' own iPS cells enables effective screening of approved drugs. Drug repositioning is a robust short-cut to bedside use in patients with ALS, due to the availability of data for safety concerns. Currently, five investigator-initiated drug trials are underway in Japan. These include trials of hepatocyte growth factor, perampanel, ultra-high-dose methylcobalamin, ropinirole, and bosutinib. This is a review of new ALS drugs that are either currently available or in on-going trials. We additionally review the pathogenic pathways that these drugs target.


Assuntos
Esclerose Amiotrófica Lateral , Atrofia Muscular Espinal , Progressão da Doença , Humanos , Japão
3.
Codas ; 32(1): e20180216, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31721923

RESUMO

PURPOSE: This study aimed to compare the fiberoptic endoscopic findings of oropharyngeal swallowing of distinct food consistencies in Amyotrophic Lateral Sclerosis (ALS). METHODS: This was a retrospective clinical study of a convenience sample of 20 individuals (13 males and seven females aged 34 to 78 years old) with a diagnosis of ALS and oropharyngeal dysphagia confirmed by clinical and objective evaluation of swallowing, regardless of the bulbar or skeletal type and of the time of neurological diagnosis. The fiberoptic endoscopic evaluation of swallowing (FEES) of the liquid (N = 18), thickened liquid (N = 19) and pureed samples (N = 20) in a volume of 5 ml were analyzed. Data related to posterior oral spillage, pharyngeal residues, laryngeal penetration and/or aspiration after swallowing the three food consistencies were analyzed statistically by the Friedman ANOVA test. RESULTS: No impairment of laryngeal sensitivity was found in this population. There was no statistically significant difference in posterior oral spillage, penetration and/or aspiration between food consistencies. There was a statistically significant difference only related to pharyngeal residues of the thickened liquid and pureed consistency. CONCLUSION: Among the fiberoptic endoscopic findings of swallowing in ALS, only pharyngeal residues had a higher frequency depending on the consistency of food.


Assuntos
Esclerose Amiotrófica Lateral/complicações , Transtornos de Deglutição/diagnóstico por imagem , Transtornos de Deglutição/etiologia , Laringoscopia/métodos , Adulto , Idoso , Deglutição , Endoscopia do Sistema Digestório , Feminino , Alimentos/classificação , Humanos , Laringe , Masculino , Pessoa de Meia-Idade , Orofaringe , Estudos Retrospectivos
4.
Nat Neurosci ; 22(12): 1966-1974, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768050

RESUMO

To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Exoma/genética , Predisposição Genética para Doença/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Estudos de Casos e Controles , Feminino , Variação Genética/genética , Humanos , Masculino
5.
Adv Exp Med Biol ; 1189: 233-265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758537

RESUMO

Inflammation plays an important role in the onset and progression of many neurological diseases. As the central nervous system (CNS) constitutes a highly specialized environment where immune activation can be detrimental, it is crucial to understand mechanisms by which the immune system is regulated during neurological diseases. The system of co-signaling pathways provides the immune system with the means to fine-tune immune responses by turning on and off immune cell activation. Studies of co-signaling molecules in neurological diseases and their animal models have highlighted the complexities of immune regulation within the CNS and the intricacies of the interplay between the different cells of the immune system and how they interact with the resident cells of the CNS. This complexity poses challenges when targeting co-signaling pathway to treat neurological diseases and may explain why no drugs targeting these pathways have been successfully developed this far. Here, we will review the current literature on some important co-signaling pathways in multiple sclerosis (MS), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and ischemic stroke to understand these pathways in mediating and controlling neuroinflammation.


Assuntos
Doenças do Sistema Nervoso , Transdução de Sinais , Doença de Alzheimer , Esclerose Amiotrófica Lateral , Animais , Isquemia Encefálica , Esclerose Múltipla , Doença de Parkinson
6.
Zhonghua Yi Xue Za Zhi ; 99(43): 3413-3416, 2019 Nov 19.
Artigo em Chinês | MEDLINE | ID: mdl-31752469

RESUMO

Objective: To investigate the application value of motor unit number index (MUNIX) for diagnosis and assessment progress in patients with amyotrophic lateral sclerosis (ALS). Method: Sixty healthy controls and 60 ALS patients in the clinic were enrolled from May 2017 to December 2018. The bilateral deltoid, abductor digiti minimi, quadriceps femoris and tibialis anterior muscles of the subjects were detected by MUNIX method, and the negative peak amplitude of compound muscle action potential (CMAP) of ulnar nerve, femoral nerve, peroneal nerve, axillary nerve in bilateral was collected. MUNIX and motor unit size index (MUSIX) of muscles were compared between ALS group and control group. The difference between the MUNIX abnormal rate of muscles and abnormal rate of the corresponding CMAP negative peak amplitude in ALS patients was further compared. Meanwhile, the correlation between the disease course of ALS patients and MUNIX and MUSIX was analyzed. Results: Compared with the control group, the MUNIX values of the deltoid, abductor digiti minimi, quadriceps femoris and tibialis anterior decreased significantly (97±24 vs 183±38, 48±17 vs 191±39, 54±15 vs 159±22, 49±16 vs 147±25, all P<0.05). MUSIX values increased ((175±32) µV vs (47±15) µV, (189±34) µV vs (54±16) µV, (170±30) µV vs (49±13) µV, (190± 36) µV vs (48± 14) µV, all P<0.05)). In ALS patients, the abnormal rate of MUNIX was respectively 81%, 87%, 75% and 89%. The negative peak amplitude abnormal rate of corresponding neuralCMAP was 35%, 40%, 31% and 36%, respectively, with a significant difference (P<0.05). There was a negative correlation between MUNIX value and the course of disease in ALS patients (P<0.05), and a positive correlation between MUSIX value and the course of disease (P<0.05). Conclusion: The MUNIX technique exhibits the features of quantifying the proximal upper and lower limb muscles and assessing the loss of motor units in motor neuron degeneration.


Assuntos
Esclerose Amiotrófica Lateral , Potenciais de Ação , Eletromiografia , Humanos , Neurônios Motores , Músculo Esquelético , Nervo Fibular
7.
Brain Nerve ; 71(11): 1129-1137, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722299

RESUMO

This brief review of recent epidemiologic literature and risk factors of sporadic ALS found that the incidence and prevalence of the condition is higher among Caucasians and lower in East Asians, with the Japanese in the middle. The review also found that worldwide, the prevalence increases with age and the condition is 1.3 to 1.6 times higher in males than in females. The number of patients with ALS was calculated based on official diagnostic certificates from fiscal 1997 to 2015 obtained from a registry managed by Japan's Ministry of Health, Labor and Welfare. The data matched with those reported in the guidelines of the Japanese Society of Neurology (2013), with an incidence of 1.1-2.5, and prevalence 7.0-8.5/100,000 people. Smoking has been considered an established risk factor for sporadic ALS. The following possible risk factors have been speculated but are to be confirmed: excessive physical activity, head trauma, farming, environmental pollutants, pesticides, exposure to certain metals/heavy metals, electromagnetic fields, alcohol, low BMI, and low-density lipoprotein. Bandres-Ciga et al. applied linkage disequilibrium score regression and Mendelian randomization to a large data set and concluded that elevated low-density lipoprotein cholesterol is a causal risk factor for ALS.


Assuntos
Esclerose Amiotrófica Lateral/epidemiologia , Humanos , Incidência , Japão , Prevalência , Fatores de Risco
8.
Brain Nerve ; 71(11): 1138-1144, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722300

RESUMO

Among the proposed ALS diagnostic criteria, the revised El Escorial diagnostic criteria was the most frequently utilized in clinical trials and clinical practice. However, its low sensitivity in early stage ALS prompted development of the Awaji electrodiagnostic criteria that incorporated fasciculation potentials and resulted in greater diagnostic sensitivity than the revised El Escorial criteria. Further improvements could include the updated Awaji criteria that is concordant between clinically- and electrodiagnostically-diagnosed cases, as well as the inclusion of ultrasound-detected fasciculations.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Fasciculação/patologia , Eletromiografia , Humanos
9.
Brain Nerve ; 71(11): 1145-1151, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722301

RESUMO

'Split hand' is dissociated hand muscle atrophy, characterized by preferential atrophies in the thenar and first dorsal interosseous muscles, with relative sparing of the hypothenar muscle. This symptom has been recognized as specific to amyotrophic lateral sclerosis (ALS), and distinct pathomechanisms are assumed to underlie this phenomenon. Recently, characteristic distributions of weakness and symptoms in ALS have been reported. Here, we describe characteristic symptoms of ALS, including split hand, split-hand plus sign, split elbow, split leg, relative preservation of finger flexion. Moreover, through these phenomena, potent mechanisms of motor neuron death in ALS are considered. Revealing the underlying pathophysiology of these symptoms may lead to the development of therapies for ALS.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Atrofia Muscular/fisiopatologia , Esclerose Amiotrófica Lateral/fisiopatologia , Mãos/fisiopatologia , Humanos , Neurônios Motores , Músculo Esquelético/fisiopatologia
10.
Brain Nerve ; 71(11): 1152-1168, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722302

RESUMO

The basic neuropathology of amyotrophic lateral sclerosis (ALS) is defined as the involvement of the upper motor neurons system (UMN) and the lower motor neuron system (LMN), with variable degree and combination. The characteristic pathological feature of sporadic ALS is cytoplasmic mislocalization of nuclear TDP-43 and aggregation of abnormally phosphorylated TDP-43 inclusions in cytoplasm in LMN, UMN and glial cells. TDP-43 inclusions correlate with cell loss and distribute beyond the UMN and LMN system. It has been proposed that phosphorylated TDP-43 (pTDP-43) disseminates in a sequential pattern along the motor pathways, as suggested by the hypothesis of corticofugal ('prion-like') propagation of misfolded proteins in ALS.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/patologia , Neurônios Motores/patologia , Humanos , Dobramento de Proteína
11.
Brain Nerve ; 71(11): 1169-1181, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722303

RESUMO

Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. Riluzole and edaravone are the only approved drugs available in Japan to date. Approximately 10% of ALS cases are familial in rature, defined as the existence of disease-causing mutation. SOD1 is the most frequent causative gene for ALS among Japanese individuals, while C9orf72 mutation is more prevalent in Western countries. Genotype-phenotype correlation described in the literature of familial ALS enables to establish models of the disease. This review article describes the clinical characteristics of familial ALS based on each disease-causing mutation. The pathomechanism of ALS including proteostasis, RNA metabolism, and axonal pathology are discussed in detail. We also reviewed the status of development of therapeutic strategies for familial ALS based on analysis of animal models and induced pluripotent stem cells.


Assuntos
Esclerose Amiotrófica Lateral/genética , Adulto , Esclerose Amiotrófica Lateral/terapia , Animais , Axônios/patologia , Proteína C9orf72/genética , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas , Japão , Neurônios Motores/patologia , Mutação , Superóxido Dismutase-1/genética
12.
Brain Nerve ; 71(11): 1183-1189, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722304

RESUMO

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) has been studied through analysis of the function of the protein produced by the causative genes of familial ALS. The products of these genes are classified as RNA binding proteins, or proteins related to proteolytic systems. However, most case of familial ALS, and sporadic ALS show TAR DNA binding protein-43 (TDP-43) immune-positive cytoplasmic inclusions. Therefore, the molecular mechanism of formation of TDP-43 inclusions and dysfunction caused by TDP-43 inclusions has been studied. As for the mechanism of inclusion formation, non-membrane organelle formation by liquid-liquid phase separation (LLPS) is important. The ubiquitin-proteasome and autophagy systems are important for the degradation of these inclusions. Several genes associated with these systems have been identified as causative genes for ALS. The formation of cytoplasmic inclusions results in the loss of TDP-43 from the nucleus, resulting in abnormalities in RNA metabolism, through the alteration of spliceosomes and Gemini of coiled bodies. Furthermore, in ALS, the regulation of TDP-43 mRNA/protein expression levels has failed. Failure of the autoregulation system facilitates TDP-43 inclusion formation. Development of treatments for ALS based on these elucidated molecular mechanisms is desirable.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/patologia , Núcleo Celular , Humanos
13.
Brain Nerve ; 71(11): 1190-1208, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722305

RESUMO

In 2011, C9orf72 hexanucleotide (GGGGCC) repeat expansion (HRE) in intron 1 was reported as the most common cause of sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population. In the Japanese population, the C9orf72 repeat expansion was found to account for 0.2% cases of sporadic ALS and 2.6% of familial ALS. Notably, among individuals in the Kii peninsula which has recorded high incidence of ALS or ALS/PDC (parkinsonism-dementia complex), the frequency of C9orf72 repeat expansion was 20% (3/15) indicating high prevalence. It is important to obtain detailed family history of ALS and FTD to understand the cause of the diseases including the C9orf72 mutation.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Expansão das Repetições de DNA , Humanos , Japão , Proteínas
14.
Brain Nerve ; 71(11): 1209-1214, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722306

RESUMO

The most common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are known to be protein-misfolding diseases, and characterized by the presence of disease-specific protein aggregates in neuronal and glial cells. Recently, the propagation hypothesis of prion-like protein inclusions in neurodegenerative diseases has been proposed. Many studies have shown that aggregation-prone proteins such as tau, alpha-synuclein and TDP-43 can form aggregates in a seed-dependent and self-templating prion-like manner, and these aggregates can be transferred intercellularly to neighboring cells and seeded for further aggregation. Propagation of aggregated proteins in these diseases may therefore occur through mechanisms similar to those that underlie prion pathogenesis. If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block the propagation of aggregated proteins throughout the brain.


Assuntos
Doenças Neurodegenerativas/patologia , Doenças Priônicas/patologia , Príons , Doença de Alzheimer , Esclerose Amiotrófica Lateral , Proteínas de Ligação a DNA , Humanos , Doença de Parkinson , alfa-Sinucleína , Proteínas tau
15.
Brain Nerve ; 71(11): 1215-1225, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722307

RESUMO

Amyotrophic lateral sclerosis (ALS) patient registries can assist in the provision of appropriate care to patients and promote therapeutic developments related to ALS. In Japan, a multicenter registration and follow-up system called the Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS) was built in 2006. Genomic DNA samples and B-cell lines of patients with ALS were stored and linked to clinical information. Information obtained from JaCALS shows the natural histories of Japanese patients with ALS, including their genetic backgrounds and clinical and genetic factors associated with disease progression and prognosis. Research efforts that focus on pathophysiology, identification of biomarkers related to progression and prognosis, and drug discoveries for patients with ALS are advanced using data obtained from JaCALS. In the future, we expect that JaCALS will be a source of real-world evidence, combining data from a large number of cases.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Sistema de Registros , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/terapia , Progressão da Doença , Humanos , Japão , Prognóstico
16.
Brain Nerve ; 71(11): 1227-1235, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722308

RESUMO

Amyotrophic lateral sclerosis (ALS) is often comorbid with frontotemporal dementia (FTD). Patients may exhibit language deficits as seen in progressive non-fluent aphasia (PNFA) or semantic dementia (SD). In behavioral variant FTD (bvFTD), cognitive impairments such as executive function, verbal fluency and language abnormalities are frequently seen, while apathy and disinhibition are major behavioral changes. Further, there are many ALS patients who do not fulfill the criteria for FTD but have mild cognitive and/or behavioral impairments. Appropriate evaluation of these conditions is necessary for non-pharmacological and pharmacological interventions.


Assuntos
Esclerose Amiotrófica Lateral/complicações , Demência Frontotemporal/complicações , Humanos , Testes Neuropsicológicos
17.
Brain Nerve ; 71(11): 1236-1244, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722309

RESUMO

Recent papers of amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula, Japan (Kii ALS/PDC), published since 2015, were reviewed The studies included transition element of scalp hair analysis, dopaminergic PET study, review of life style changes in the high incident area, neurotoxic BMAA analysis, a clinical report of a migration case, comprehensive neuropathological study, cerebellar tau pathology, nitrative stress in the central nervous system study, optinurin pathology in the spinal cord, and tau PET study. Tau PET was advocated to be a new useful tool for diagnosis, even in the early stage of ALS/PDC with tauopathy. The etiology of Kii ALS/PDC remainds unknown. There are patients and healthy residents within the same environment in the high incidence foci, therefore it is difficult to explain this result by exposure to environmental factors alone. From the genetic viewpoint, rare-disease and rare-variant model may be applied to Kii ALS/PDC. Because there was an immigrant who was diagnosed neuropathologically, and a drastic decrease of the prevalence in the past several decades in the high incident area, it is feasible that Kii ALS/PDC is a multifactorial disease caused by both risk genes and environmental factors. Identifying risk genes and environmental factors for Kii ALS/PDC may contribute to the prevention of neurodegenerative diseases.


Assuntos
Esclerose Amiotrófica Lateral/epidemiologia , Demência/epidemiologia , Transtornos Parkinsonianos/epidemiologia , Humanos , Japão/epidemiologia
18.
Brain Nerve ; 71(11): 1245-1251, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722310

RESUMO

In 1993, a mutation in the superoxyde dismutase gene, SOD1, was found causative for familial ALS, suggesting that free radical-related injury may be involved in ALS pathogenesis. Therefore, clinical trials were conducted with ALS patients using a free radical scavenger, edaravone, which was already approved for acute phase treatment of cerebral infarction in Japan. Because edaravone showed a therapeutic effect in suppressing the progression of ALS symptoms, it was approved as a new therapeutic agent in Japan, in June, 2015. In this article, we discuss the recent progress of basic and clinical research for the development of new ALS treatments.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Edaravone/uso terapêutico , Humanos
19.
Brain Nerve ; 71(11): 1253-1260, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722311

RESUMO

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by the death of upper and lower motor neurons. About 10% of all ALS cases are familial, and we have identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan (Nishiyama A, 2017). From studies of the TDP43, FUS, and C9orf72 genes, perturbations of RNA processing can be highly adverse in motor neurons. Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to transgenic rats at onset of paralysis for 4 weeks. Intrathecal administration of hrHGF attenuated motor neuron degeneration and prolonged the duration of the disease by 63% (Ishigaki A, 2007). To translate this strategy to human treatment, we induced a contusive cervical spinal cord injury in the common marmoset, a primate, and then administered hrHGF intrathecally. We conducted a first-in-human phase I trial of intrathecal hrHGF in 15 Japanese patients with ALS (Warita H, 2019). Based on the results, we are conducting a phase II trial of intrathecal hrHGF for patients with ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Fator de Crescimento de Hepatócito/farmacologia , Animais , Ensaios Clínicos Fase I como Assunto , Modelos Animais de Doenças , Humanos , Injeções Espinhais , Japão , Neurônios Motores/patologia , Ratos , Ratos Transgênicos , Proteínas Recombinantes/farmacologia
20.
Brain Nerve ; 71(11): 1261-1269, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722312

RESUMO

High-dose methylcobalamin was found to be a therapeutic candidate for amyotrophic lateral sclerosis (ALS) through clinical experience. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in, exploratory analyses. Therefore, we plan to conduct an investigator-initiated trial "The Japan Early-stage Trial of high dose methylcobalamin for ALS (JETALS)" to evaluate the efficacy and safety of E0302 for ALS patients within 12 months from onset. JETALS is a prospective, multicenter, placebo-controlled, double-blind, randomized Phase III study, conducted at 25 tertiary neurology centers, and is funded by the Japan Agency for Medical Research and Development. A total of 128 patients were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo, twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale (ALSFRS-R) total score at 16 weeks. The patient enrollment period is from November 2017 to September 2019, and the follow-up is scheduled to end in March 2020. If the results are positive, we intend to apply for E0302 approval for methylcobalamin as a new drug for treating ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Vitamina B 12/análogos & derivados , Método Duplo-Cego , Humanos , Japão , Estudos Prospectivos , Vitamina B 12/uso terapêutico
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