Journal articles on the topic 'Amyotrophic lateral sclerosis – Treatment – New Zealand'
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Cai, Qing, Mengya Li, and Qifang Li. "Sleep‐based therapy: A new treatment for amyotrophic lateral sclerosis." Brain Science Advances 7, no. 3 (September 2021): 155–62. http://dx.doi.org/10.26599/bsa.2021.9050010.
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Amyotrophic lateral sclerosis (ALS) is a worldwide problem with no effective treatment. Patients usually die of respiratory failure. The basic pathological process of ALS is the degeneration and necrosis of motor neurons. Neuroglial cell dysfunction is considered closely related to the development of ALS. Sleep plays an important role in repairing the nervous system, and sleep disorders can worsen ALS. Herein, we review the pathogenesis of ALS and the neuroprotective mechanism of sleep‐based therapy. Sleep‐based therapy could be a potential strategy to treat ALS.
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Wagner, Mary L., and Barbara E. Landis. "Riluzole: A New Agent for Amyotrophic Lateral Sclerosis." Annals of Pharmacotherapy 31, no. 6 (June 1997): 738–44. http://dx.doi.org/10.1177/106002809703100614.
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OBJECTIVE: To provide a comprehensive review of riluzole, including its mechanism of action, pharmacokinetics, adverse drug reactions, drug interactions, efficacy, and administration. A brief review of amyotrophic lateral sclerosis (ALS) is also included. DATA SOURCES: A computerized search of the MEDLINE database in May 1996 was used to identify publications regarding ALS, riluzole, and metabolism by CYP1A2. Manufacturer's information on riluzole was used when there was no primary literature. DATA SYNTHESIS: Riluzole is approximately 90% absorbed following an oral dose. Its bioavailability is 60%. Peak concentrations occur within 1–1.5 hours of administration. Riluzole extensively binds to lipoproteins and albumin. This agent primarily undergoes CYP1A2 hydroxylation and glucuronidation, after which it is eliminated by the kidneys. Clearance is reduced in native Japanese healthy subjects and may be reduced in patients with hepatic impairment. Two trials with a total of 1114 patients addressed the efficacy of riluzole in ALS. Riluzole extended the time to tracheostomy or death, and the effect was greatest with dosages of 100 mg/d or greater. No effect on patients' symptoms or global assessment was detected at 18 or 21 months. Several flaws in these trials have led to questions concerning the validity of these results. The most commonly reported adverse effects of riluzole have been transient elevation of liver enzyme concentrations (2–5 times the upper limit of normal), worsening of asthenia, nausea, vomiting, diarrhea, anorexia, dizziness, vertigo, somnolence, and mouth paresthesia. Not as commonly reported, but still very serious, is neutropenia, which occurred in 3 of 4000 patients. CONCLUSIONS: Although the benefits of riluzole are questionable and it is expensive, this agent may extend the time to tracheostomy or death in patients with ALS. At present, this is the only agent approved for the treatment of ALS and should be made available for these patients.
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Strong, Michael J., and Ralph M. Garruto. "Chronic Aluminum-Induced Motor Neuron Degeneration: Clinical, Neuropathological and Molecular Biological Aspects." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 18, S3 (August 1991): 428–31. http://dx.doi.org/10.1017/s0317167100032601.
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ABSTRACT:The monthly intracisternal inoculation of young adult New Zealand white rabbits with low-dose (100 Μg) aluminum chloride induces aggregates of phosphorylated neurofilament that mimics the intraneuronal inclusions of amyotrophic lateral sclerosis. The chronic progressive myelopathy and topographically-specific motor neuron degeneration that occurs in the absence of suppressions of neurofilament messenger RNA levels in this model contrasts with the acute fulminant encephalomyelopathy and nonspecific gene suppressions that occur subsequent to high-dose (1000 Μg) aluminum chloride inoculations. Further analysis of this unique model of chronic motor system degeneration can be expected to provide additional insights into the pathogenesis of amyotrophic lateral sclerosis.
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Seibold, Heidi, Achim Zeileis, and Torsten Hothorn. "Individual treatment effect prediction for amyotrophic lateral sclerosis patients." Statistical Methods in Medical Research 27, no. 10 (February 21, 2017): 3104–25. http://dx.doi.org/10.1177/0962280217693034.
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A treatment for a complicated disease might be helpful for some but not all patients, which makes predicting the treatment effect for new patients important yet challenging. Here we develop a method for predicting the treatment effect based on patient characteristics and use it for predicting the effect of the only drug (Riluzole) approved for treating amyotrophic lateral sclerosis. Our proposed method of model-based random forests detects similarities in the treatment effect among patients and on this basis computes personalised models for new patients. The entire procedure focuses on a base model, which usually contains the treatment indicator as a single covariate and takes the survival time or a health or treatment success measurement as primary outcome. This base model is used both to grow the model-based trees within the forest, in which the patient characteristics that interact with the treatment are split variables, and to compute the personalised models, in which the similarity measurements enter as weights. We applied the personalised models using data from several clinical trials for amyotrophic lateral sclerosis from the Pooled Resource Open–Access Clinical Trials database. Our results indicate that some amyotrophic lateral sclerosis patients benefit more from the drug Riluzole than others. Our method allows gradually shifting from stratified medicine to personalised medicine and can also be used in assessing the treatment effect for other diseases studied in a clinical trial.
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Štětkářová, Ivana, Radoslav Matěj, and Edvard Ehler. "New insights in the diagnosis and treatment of amyotrophic lateral sclerosis." Česká a slovenská neurologie a neurochirurgie 81/114, no. 5 (September 27, 2018): 546–54. http://dx.doi.org/10.14735/amcsnn2018546.
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Zerecero-Morcksharpe, Marquelle, and Elisa García-Vences. "Clinical advances in multiple sclerosis and amyotrophic lateral sclerosis treatment: A review." Proceedings of Scientific Research Universidad Anáhuac. Multidisciplinary Journal of Healthcare 1, no. 2 (August 6, 2021): 58–69. http://dx.doi.org/10.36105/psrua.2021v1n2.06.
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Neurodegenerative diseases are clinical manifestations that depend on the anatomy and function of the affected areas. Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are some of these diseases, but they are also autoimmune and their etiology makes treatments limited and of little therapeutic efficacy. Currently, some clinical research advances can be pillars for the development of new treatments for these diseases. Therefore, the objective of this review is to describe the latest clinical advances in ALS and MS as well as their results in clinical recovery in randomized clinical trials, meta-analyzes, and full-text systematic reviews conducted in humans and rats, published in English and Spanish in the last 5 years, using PubMed, SciELO, and Cochrane. For clinical trials to be included, they had to provide a detailed breakdown of randomization methods, diagnostic criteria, intervention details, and efficacy evaluation. The results show that, so far, available medications, like riluzole and edaravone for ALS and fingolimod, dimethyl fumarate, and IFN β-1b for MS, only prolong the life of the patient. Among these drugs are also glutamate neurotransmitter antagonists, immunomodulators and even antioxidants; each of them showed significant improvement in the reviewed trials. Similarly, other non-pharmaceutical treatments, as the 600-mg dose of curcumin in the diet for ALS, showed improvement of the patients’ conditions. Regarding MS, more studies should be carried out on autotransplantation with adiposederived mesenchymal stem cells (AdMSCs) to investigate the potential therapeutic benefit of this technique in phases prior to secondary-progressive (SPMS).
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Poppe, Lindsay, Laura Rué, Wim Robberecht, and Ludo Van Den Bosch. "Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS)." Experimental Neurology 262 (December 2014): 138–51. http://dx.doi.org/10.1016/j.expneurol.2014.07.001.
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Alekseeva, T. M., T. R. Stuchevskaya, and V. S. Demeshonok. "Amyotrophic lateral sclerosis: pathogenetic mechanisms and new approaches to pharmacotherapy (literature review)." Neuromuscular Diseases 8, no. 4 (January 12, 2019): 12–18. http://dx.doi.org/10.17650/2222-8721-2018-8-4-12-18.
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Amyotrophic lateral sclerosis is a neurodegenerative disease, resulting in the loss of self-service and death of the middle-aged and elderly people. In the last 2 decades, significant progress has been made in the study of the pathogenesis of this disease. Two known drugs (riluzole and edaravone) have been approved by the Food and Drug Administration for treatment of amyotrophic lateral sclerosis. The efficacy of these drugs is extremely low, so clinical trials of new drugs are ongoing all over the world. This review discusses the current achievements and future directions of therapy of this disease.
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Filipi, Tereza, Zuzana Hermanova, Jana Tureckova, Ondrej Vanatko, and Miroslava Anderova. "Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment." Journal of Clinical Medicine 9, no. 1 (January 18, 2020): 261. http://dx.doi.org/10.3390/jcm9010261.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.
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Yang, Xiaoming, Yanan Ji, Wei Wang, Lilei Zhang, Zehao Chen, Miaomei Yu, Yuntian Shen, Fei Ding, Xiaosong Gu, and Hualin Sun. "Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies." Antioxidants 10, no. 7 (June 24, 2021): 1012. http://dx.doi.org/10.3390/antiox10071012.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. According to whether there is a family history of ALS, ALS can be roughly divided into two types: familial and sporadic. Despite decades of research, the pathogenesis of ALS is still unelucidated. To this end, we review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS, and introduce the effects of RNA binding proteins, ALS-related genes, and non-coding RNA as biomarkers on ALS. In addition, we also mention other ALS biomarkers such as serum uric acid (UA), cardiolipin (CL), chitotriosidase (CHIT1), and neurofilament light chain (NFL). Finally, we discuss the drug therapy, gene therapy, immunotherapy, and stem cell-exosomal therapy for ALS, attempting to find new therapeutic targets and strategies. A challenge is to study the various mechanisms of ALS as a syndrome. Biomarkers that have been widely explored are indispensable for the diagnosis, treatment, and prevention of ALS. Moreover, the development of new genes and targets is an urgent task in this field.
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Welty, Devin F., Gerald P. Schielke, and Jeffrey D. Rothstein. "Potential Treatment of Amyotrophic Lateral Sclerosis with Gabapentin: A Hypothesis." Annals of Pharmacotherapy 29, no. 11 (November 1995): 1164–67. http://dx.doi.org/10.1177/106002809502901118.
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Objective: To provide the biochemical rationale for the use of the new anticonvulsant agent gabapentin as a treatment for amyotrophic lateral sclerosis (ALS). Background: ALS is a neuropathologic disorder of the central nervous system characterized by a progressive loss of upper and lower motor neurons. Although the etiopathology of ALS is incompletely known, it is hypothesized that glutamatergic neurotransmission is related to neuropathology. Glutamate is an excitatory amino acid neurotransmitter that is cytotoxic when overexpressed at synaptic terminals, probably through a calcium-related mechanism. The concentration of glutamate in cerebrospinal fluid is increased in patients with ALS. The increased extracellular concentrations of glutamate may be caused by a decreased capacity of glutamate transport in brain tissue and/or abnormal glutamate metabolism. Recent success with the glutamate release inhibitor riluzole in well-controlled clinical trials supports the excitotoxic mechanism of neuropathology in patients with ALS. Potential Treatment For Als: Gabapentin has demonstrated neuroprotective properties in a model of chronic glutamate toxicity in vitro. Although the neuroprotective mechanism of action of gabapentin is currently unknown, it is hypothesized here that gabapentin decreases the rate of formation of glutamate derived from the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. The proposed decrease in formation of glutamate from BCAAs may decrease the pool of releasable glutamate and therefore compensate for diminished glutamate uptake capacity and/or abnormal glutamate metabolism in patients with ALS. Conclusions: Based on this rationale, it is proposed that gabapentin may provide a beneficial effect in the treatment of patients with ALS.
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Grigorev, Igor P., and Dmitrii E. Korzhevskii. "Mast cells and neuroinflammation in pathogenesis of neurologic and psychiatric diseases." Medical academic journal 21, no. 2 (September 24, 2021): 7–24. http://dx.doi.org/10.17816/maj63228.
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The review summarizes current data on the role of neuroinflammation and mast cells in the pathogenesis of nervous and mental diseases, such as multiple sclerosis, Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, depression, autism, migraine, schizophrenia and some others. The contribution of neuroinflammation to the pathogenesis of many of these diseases has been demonstrated. The involvement of mast cells in the development of the neuroinflammatory process has with varying degrees of evidence been shown for multiple sclerosis, amyotrophic lateral sclerosis, Alzheimers disease and migraine. There is still no convincing evidence that mast cells contribute to neuroinflammation in Parkinsons disease, depression, schizophrenia and autism spectrum disorder, although it is possible that they play a role in the pathogenesis of these diseases. Data on the causal role of neuroinflammation and mast cells in the development of neuropsychiatric diseases may become the basis for the development of new approaches to their pharmacological treatment. The review provides data on the first clinical trials of anti-inflammatory and mast cell activity-modulating drugs for the treatment of migraine, Alzheimers disease, multiple sclerosis and amyotrophic lateral sclerosis.
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Menounos, Spiro, Philip M. Hansbro, Ashish D. Diwan, and Abhirup Das. "Pathophysiological Correlation between Cigarette Smoking and Amyotrophic Lateral Sclerosis." NeuroSci 2, no. 2 (April 20, 2021): 120–34. http://dx.doi.org/10.3390/neurosci2020008.
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Cigarette smoke (CS) has been consistently demonstrated to be an environmental risk factor for amyotrophic lateral sclerosis (ALS), although the molecular pathogenic mechanisms involved are yet to be elucidated. Here, we propose different mechanisms by which CS exposure can cause sporadic ALS pathogenesis. Oxidative stress and neuroinflammation are widely implicated in ALS pathogenesis, with blood–spinal cord barrier disruption also recognised to be involved in the disease process. In addition, immunometabolic, epigenetic and microbiome alterations have been implicated in ALS recently. Identification of the underlying pathophysiological mechanisms that underpin CS-associated ALS will drive future research to be conducted into new targets for treatment.
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Štětkářová, Ivana, and Edvard Ehler. "Diagnostics of Amyotrophic Lateral Sclerosis: Up to Date." Diagnostics 11, no. 2 (February 3, 2021): 231. http://dx.doi.org/10.3390/diagnostics11020231.
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by gradual loss of upper and lower motor neurons and their pathways, usually without affecting the extraocular and sphincter muscles. The cause of the disease is not yet known. It is a chain of subsequent events, ending in programmed cell death in selective neuronal subpopulations. The prognosis for survival is rather short with a median of 2 to 4 years. Survival may be prolonged based on prompt diagnosis, ALS subtype and proper management with supportive treatment (tracheostomy, gastrostomy, etc.). According to the clinical picture, the typical form of ALS with upper and lower motoneuron involvement and progressive bulbar paralysis with bulbar muscle involvement is observed. The ALS form with progressive muscle atrophy, where only the lower motoneuron is affected, and primary lateral sclerosis with only upper motoneuron damage are rare. Familiar forms of ALS (FALS) associated with specific genes (the most common is C9orf72) have been discovered. FALS is usually associated with dementia (frontotemporal lobar dementia, FTLD), behavioral disorders, cognitive dysfunction and impairment of executive functions. The diagnosis of ALS is determined by excluding other conditions and utilizing clinical examinations, laboratory and genetic tests and nerve conduction/needle electromyography studies (EMG). Needle EMG records abnormal activities at rest and looks for neurogenic patterns during muscle contraction. Motor evoked potentials after transcranial magnetic stimulation remain the test of choice to identify impairment of upper motor neurons. New biochemical, neurophysiological and morphological biomarkers are extensively studied as early diagnostic and prognostic factors and have implications for clinical trials, research and drug development.
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Proaño, Belén, Julia Casani-Cubel, María Benlloch, Ana Rodriguez-Mateos, Esther Navarro-Illana, Jose María Lajara-Romance, and Jose Enrique de la Rubia Ortí. "Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?" Biomedicines 10, no. 9 (August 25, 2022): 2084. http://dx.doi.org/10.3390/biomedicines10092084.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by the loss of upper and lower motor neurons (MNs) in the cerebral cortex, brainstem and spinal cord, with consequent weakness, atrophy and the progressive paralysis of all muscles. There is currently no medical cure, and riluzole and edaravone are the only two known approved drugs for treating this condition. However, they have limited efficacy, and hence there is a need to find new molecules. Dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase (5AR) enzymes, the therapeutic purposes of which, to date, are the treatment of benign prostatic hyperplasia and androgenic alopecia, shows great anti-ALS properties by the molecular-topology methodology. Based on this evidence, this review aims to assess the effects of dutasteride on testosterone (T), progesterone (PROG) and 17β-estradiol (17BE) as a therapeutic alternative for the clinical improvement of ALS, based on the hormonal, metabolic and molecular pathways related to the pathogenesis of the disease. According to the evidence found, dutasteride shows great neuroprotective, antioxidant and anti-inflammatory effects. It also appears effective against glutamate toxicity, and it is capable of restoring altered dopamine activity (DA). These effects are achieved both directly and through steroid hormones. Therefore, dutasteride seems to be a promising molecule for the treatment of ALS, although clinical studies are required for confirmation.
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Shah, Fahad Hassan, and Song Ja Kim. "Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis." Natural Product Communications 16, no. 10 (October 2021): 1934578X2110308. http://dx.doi.org/10.1177/1934578x211030815.
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Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.
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Lastres-Becker, Isabel, Eva de Lago, Ana Martínez, and Javier Fernández-Ruiz. "New Statement about NRF2 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia." Biomolecules 12, no. 9 (August 29, 2022): 1200. http://dx.doi.org/10.3390/biom12091200.
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders displaying substantial overlay, although there are substantial differences at the molecular level. Currently, there is no effective treatment for these diseases. The transcription factor NRF2 has been postulated as a promising therapeutic target as it is capable of modulating key pathogenic events affecting cellular homeostasis. However, there is little experimental evidence on the status of this pathway in both ALS and FTD. Therefore, in this work, we wanted to carry out an exhaustive analysis of this signaling pathway in both transgenic mouse models (ALS and FTD) and human samples from patients with sporadic ALS (sALS) versus controls. In samples from patients with sALS and in the transgenic model with overexpression of TDP-43A315T, we observed a significant increase in the NRF2/ARE pathway in the motor cortex and the spinal cord, indicating that NRF2 antioxidant signaling was being induced, but it was not enough to reach cellular homeostasis. On the other hand, in the transgenic FTD model with overexpression of the TDP-43WT protein in forebrain neurons, a significantly decreased expression of NQO1 in the prefrontal cortex was seen, which cannot be attributed to alterations in the NRF2 pathway. Our results show that NRF2 signature is differently affected for ALS and FTD.
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Pinto, Susana, and Mamede de Carvalho. "Breathing new life into treatment advances for respiratory failure in amyotrophic lateral sclerosis patients." Neurodegenerative Disease Management 4, no. 1 (February 2014): 83–102. http://dx.doi.org/10.2217/nmt.13.74.
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Handy, Chalonda R., Christina Krudy, Nicholas Boulis, and Thais Federici. "Pain in Amyotrophic Lateral Sclerosis: A Neglected Aspect of Disease." Neurology Research International 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/403808.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons, muscle wasting, and respiratory dysfunction. With disease progression, secondary symptoms arise creating new problematic conditions for ALS patients. Amongst these is pain. Although not a primary consequence of disease, pain occurs in a substantial number of individuals. Yet, studies investigating its pathomechanistic properties in the ALS patient are lacking. Therefore, more exploratory efforts into its scope, severity, impact, and treatment should be initiated. Several studies investigating the use of Clostridial neurotoxins for the reduction of pain in ALS patients suggest the potential for a neural specific approach involving focal drug delivery. Gene therapy represents a way to accomplish this. Therefore, the use of viral vectors to express transgenes that modulate the nociceptive cascade could prove to be an effective way to achieve meaningful benefit in conditions of pain in ALS.
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Zheng, Xuanlu, Joana Schröder, Dandan Sima, Mingzhe Wang, Qiudong Wang, and Weidong Pan. "Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatments (ALS-SSIT) for Evaluating Therapeutic Effect of Traditional Chinese Medicine: A Prospective Study." Computational and Mathematical Methods in Medicine 2022 (April 16, 2022): 1–5. http://dx.doi.org/10.1155/2022/7594481.
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Objective. To evaluate the reliability, validity, sensitivity, and clinical applicability of a new scale—the amyotrophic lateral sclerosis symptom score in integrative treatments (ALS-SSIT)—for measuring the effect of traditional Chinese medicine (TCM) in patients with amyotrophic lateral sclerosis (ALS). Methods. A total of 160 patients with ALS were enrolled and followed up for 6 months. All patients received TCM. Patients were evaluated at enrollment and at the end of 6 months with a new scale, the ALS-SSIT, developed after extensive consultations with TCM experts with several years of experience in the treatment of ALS. The 36-item Medical Outcomes Study Short Form (SF-36) scale and the amyotrophic lateral sclerosis functional rating scale (ALSFRS) were used as the reference standards. Results. The acceptance rate and completion rate of the ALS-SSIT scale were high, and the content validity was confirmed by experts. Test-retest performed at enrollment and at 6 months showed good reliability of the ALS-SSIT scale (Cronbach α , 0.9172 and 0.9181, respectively). The ALS-SSIT scale score showed significant change at 6 months, indicating the ability to reflect the change in disease severity. Conclusion. The ALS-SSIT appears to be a feasible, reliable, and sensitive tool for the evaluation of the effect of TCM in patients with ALS.
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Pikatza-Menoio, Oihane, Amaia Elicegui, Xabier Bengoetxea, Neia Naldaiz-Gastesi, Adolfo López de Munain, Gorka Gerenu, Francisco Javier Gil-Bea, and Sonia Alonso-Martín. "The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis." Journal of Personalized Medicine 11, no. 7 (July 16, 2021): 671. http://dx.doi.org/10.3390/jpm11070671.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.
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Novak, Valentina, Boris Rogelj, and Vera Župunski. "Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia." Antioxidants 10, no. 8 (August 23, 2021): 1328. http://dx.doi.org/10.3390/antiox10081328.
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.
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Kiaei, Mahmoud. "Peroxisome Proliferator-Activated Receptor-γin Amyotrophic Lateral Sclerosis and Huntington’s Disease." PPAR Research 2008 (2008): 1–8. http://dx.doi.org/10.1155/2008/418765.
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Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-γ(PPAR-γ) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-γagonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-γagonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-γmay be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-γin HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-γcoactivator-1α(PGC-1α) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-γin the regulation of mitochondrial biogenesis. Therefore, PPAR-γis a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1α. In this review, the role of PPAR-γin ALS and HD is discussed based on the current literature and hypotheses.
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Gröger, Victoria, Alexander Emmer, Martin Staege, and Holger Cynis. "Endogenous Retroviruses in Nervous System Disorders." Pharmaceuticals 14, no. 1 (January 16, 2021): 70. http://dx.doi.org/10.3390/ph14010070.
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Human endogenous retroviruses (HERV) have been implicated in the pathogenesis of several nervous system disorders including multiple sclerosis and amyotrophic lateral sclerosis. The toxicity of HERV-derived RNAs and proteins for neuronal cells has been demonstrated. The involvement of HERV in the pathogenesis of currently incurable diseases might offer new treatment strategies based on the inhibition of HERV activities by small molecules or therapeutic antibodies.
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Gugliandolo, Agnese, Placido Bramanti, and Emanuela Mazzon. "Mesenchymal Stem Cells: A Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis?" Stem Cells International 2019 (March 10, 2019): 1–16. http://dx.doi.org/10.1155/2019/3675627.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Patients show both motor and extra-motor symptoms. A cure is not available at this time, and the disease leads to death within 3–5 years, mainly due to respiratory failure. Stem cell therapy is arising as a new promising approach for the treatment of neurodegenerative disorders. In particular, mesenchymal stem cells (MSCs) seem the most suitable type of stem cells, thanks to their demonstrated beneficial effects in different experimental models, to the easy availability, and to the lack of ethical problems. In this review, we focused on the studies involving ALS rodent models and clinical trials in order to understand the potential beneficial effects of MSC transplantation. In different ALS rodent models, the administration of MSCs induced a delay in disease progression and at least a partial recovery of the motor function. In addition, clinical trials evidenced the feasibility and safety of MSC transplantation in ALS patients, given that no major adverse events were recorded. However, only partial improvements were shown. For this reason, more studies and trials are needed to clarify the real effectiveness of MSC-based therapy in ALS.
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Martín-Cámara, Olmo, Marina Arribas, Geoffrey Wells, Marcos Morales-Tenorio, Ángeles Martín-Requero, Gracia Porras, Ana Martínez, et al. "Multitarget Hybrid Fasudil Derivatives as a New Approach to the Potential Treatment of Amyotrophic Lateral Sclerosis." Journal of Medicinal Chemistry 65, no. 3 (January 5, 2022): 1867–82. http://dx.doi.org/10.1021/acs.jmedchem.1c01255.
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Sever, Belgin, Halilibrahim Ciftci, Hasan DeMirci, Hilal Sever, Firdevs Ocak, Burak Yulug, Hiroshi Tateishi, et al. "Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 23, no. 5 (February 22, 2022): 2400. http://dx.doi.org/10.3390/ijms23052400.
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Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.
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Tarantino, Nancy, Ileana Canfora, Giulia Maria Camerino, and Sabata Pierno. "Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle." Cells 11, no. 3 (January 25, 2022): 415. http://dx.doi.org/10.3390/cells11030415.
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Amyotrophic Lateral Sclerosis is a neurodegenerative disease caused by progressive loss of motor neurons, which severely compromises skeletal muscle function. Evidence shows that muscle may act as a molecular powerhouse, whose final signals generate in patients a progressive loss of voluntary muscle function and weakness leading to paralysis. This pathology is the result of a complex cascade of events that involves a crosstalk among motor neurons, glia, and muscles, and evolves through the action of converging toxic mechanisms. In fact, mitochondrial dysfunction, which leads to oxidative stress, is one of the mechanisms causing cell death. It is a common denominator for the two existing forms of the disease: sporadic and familial. Other factors include excitotoxicity, inflammation, and protein aggregation. Currently, there are limited cures. The only approved drug for therapy is riluzole, that modestly prolongs survival, with edaravone now waiting for new clinical trial aimed to clarify its efficacy. Thus, there is a need of effective treatments to reverse the damage in this devastating pathology. Many drugs have been already tested in clinical trials and are currently under investigation. This review summarizes the already tested drugs aimed at restoring muscle-nerve cross-talk and on new treatment options targeting this tissue.
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Lembke, Kayly M., and David B. Morton. "Exploring the Interaction of Drosophila TDP-43 and the Type II Voltage-Gated Calcium Channel, Cacophony, in Regulating Motor Function and Behavior." Journal of Experimental Neuroscience 11 (January 1, 2017): 117906951774089. http://dx.doi.org/10.1177/1179069517740892.
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Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neurodegenerative disease. The cause of the disease remains obscure, and as such there is no effective treatment or cure. Amyotrophic lateral sclerosis and other neurodegenerative diseases are frequently characterized by dysfunction of the RNA-binding protein, TDP-43. Using model systems to understand the mechanisms underlying TDP-43 dysfunction should accelerate identification of therapeutic targets. A recent report has shown that motor defects caused by the deletion of the Drosophila TDP-43 ortholog, tbph, are not driven by changes in the physiology at the neuromuscular junction. Rather, defective motor burst rhythmicity and coordination, displayed by tbph mutants, are rescued by genetically restoring a voltage-gated calcium channel to either motor neurons or just a single pair of neurons in the brain. If these effects are mirrored in human TDP-43 proteinopathies, these observations could open new avenues to investigate alternative therapeutic targets for these neurodegenerative diseases.
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Maestro, Ines, Laura R. de la Ballina, Gracia Porras, Silvia Corrochano, Eva De Lago, Anne Simonsen, Patricia Boya, and Ana Martinez. "Discovery of Mitophagy Inhibitors with Therapeutic Potential in Different Familial Amyotrophic Lateral Sclerosis Mutations." International Journal of Molecular Sciences 23, no. 20 (October 21, 2022): 12676. http://dx.doi.org/10.3390/ijms232012676.
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Mitophagy is the selective degradation of mitochondria by autophagy. It promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria, which can lead to cellular degeneration. Mitophagy is known to be altered in several pathological conditions, especially in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We recently demonstrated an increase in autophagy flux in lymphoblasts from ALS patients bearing a mutation in SOD1. Thus, the identification of mitophagy inhibitors may be a therapeutic option to recover mitochondrial homeostasis. Here, using a phenotypic mitophagy assay, we identified a new mitophagy inhibitor, the small molecule named IGS2.7 from the MBC library. Interestingly, the treatment of different cellular and in vivo models of ALS with mutations on SOD1 and TARDBP with this inhibitor restores autophagy to control levels. These results point mitophagy inhibitors, especially IGS2.7, to a new therapeutic approach for familial ALS patients.
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Madruga, Enrique, Inés Maestro, and Ana Martínez. "Mitophagy Modulation, a New Player in the Race against ALS." International Journal of Molecular Sciences 22, no. 2 (January 13, 2021): 740. http://dx.doi.org/10.3390/ijms22020740.
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Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.
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Westley, Michelle, Dean Sutherland, and H. Timothy Bunnell. "Voice Banking to Support People Who Use Speech-Generating Devices: New Zealand Voice Donors' Perspectives." Perspectives of the ASHA Special Interest Groups 4, no. 4 (August 15, 2019): 593–600. http://dx.doi.org/10.1044/2019_pers-sig2-2018-0011.
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Purpose Voice banking is the process of recording an individual's speech to create a personalized synthetic voice to use on speech-generating augmentative and alternative communication devices. This study set out to examine the experience of healthy voice donors during the ModelTalker voice banking process and to identify specific issues related to voice banking in the New Zealand context. Method Eight healthy adults and 2 children completed the ModelTalker voice banking protocol. All participants completed a questionnaire about their voice banking experience, including the length of time required as well as the ease and the technical aspects of the process. Results The median time taken to complete the voice banking process was 5 hr 30 min (range: 3 hr 10 min to 11 hr). Questionnaire responses included themes related to the voice banking process, such as increased awareness of voice banking and its benefits, positive features and challenges of the ModelTalker process, and potential adaptations for the New Zealand context. Conclusions The findings support the use of ModelTalker with New Zealand speakers and inform development of voice banking protocols. The voices created as part of this study are available for people using speech-generating devices who want to use New Zealand–accented voices. Future research is needed to investigate the voice banking experiences of clinical populations, such as people with amyotrophic lateral sclerosis.
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Liu, Jinmeng, Fenghua Zhou, Yingjun Guan, Fandi Meng, Zhenhan Zhao, Qi Su, Weiwei Bao, et al. "The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis." Cells 11, no. 3 (February 7, 2022): 572. http://dx.doi.org/10.3390/cells11030572.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.
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Imamura, Keiko, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, et al. "The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis." Science Translational Medicine 9, no. 391 (May 24, 2017): eaaf3962. http://dx.doi.org/10.1126/scitranslmed.aaf3962.
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Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.
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Mignani, Serge, Jean-Pierre Majoral, Jean-François Desaphy, and Giovanni Lentini. "From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies." Molecules 25, no. 15 (July 22, 2020): 3320. http://dx.doi.org/10.3390/molecules25153320.
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The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.
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Yamashita, Toru, Yoshihiro Kushida, Koji Abe, and Mari Dezawa. "Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases." Cells 10, no. 4 (April 20, 2021): 961. http://dx.doi.org/10.3390/cells10040961.
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Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.
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Silva, Jamire M., Michelangela S. C. Nobre, Sonaly L. Albino, Lucas L. Lócio, Agnis P. S. Nascimento, Luciana Scotti, Marcus T. Scotti, et al. "Secondary Metabolites with Antioxidant Activities for the Putative Treatment of Amyotrophic Lateral Sclerosis (ALS): “Experimental Evidences”." Oxidative Medicine and Cellular Longevity 2020 (November 24, 2020): 1–22. http://dx.doi.org/10.1155/2020/5642029.
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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder that is characterized by progressive loss of the upper and lower motor neurons at the spinal or bulbar level. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain are factors that contribute to neurodegeneration and perform a potential role in the pathogenesis of ALS. Natural antioxidant molecules have been proposed as an alternative form of treatment for the prevention of age-related neurological diseases, in which ALS is included. Researches support that regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in this disease, and antioxidant drugs are aimed at a promising pathway to treatment. Among the strategies used for obtaining new drugs, we can highlight the isolation of secondary metabolite compounds from natural sources that, along with semisynthetic derivatives, correspond to approximately 40% of the drugs found on the market. Among these compounds, we emphasize oxygenated and nitrogenous compounds, such as flavonoids, coumarins, and alkaloids, in addition to the fatty acids, that already stand out in the literature for their antioxidant properties, consisting in a part of the diets of millions of people worldwide. Therefore, this review is aimed at presenting and summarizing the main articles published within the last years, which represent the therapeutic potential of antioxidant compounds of natural origin for the treatment of ALS.
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Garbuzova-Davis, Svitlana, Robert Shell, Hilmi Mustafa, Surafuale Hailu, Alison E. Willing, Paul R. Sanberg, and Cesario V. Borlongan. "Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis." Cell Transplantation 29 (January 1, 2020): 096368972091349. http://dx.doi.org/10.1177/0963689720913494.
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Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.
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Morello, Maria, Massimo Pieri, Rossella Zenobi, Alessandra Talamo, Delphine Stephan, Verena Landel, François Féron, and Pascal Millet. "The Influence of Vitamin D on Neurodegeneration and Neurological Disorders: A Rationale for its Physio-pathological Actions." Current Pharmaceutical Design 26, no. 21 (June 24, 2020): 2475–91. http://dx.doi.org/10.2174/1381612826666200316145725.
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Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this “neuroactive” steroid can help to optimize the prevention and treatment of several neurological diseases.
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Khamaysa, Mohammed, and Pierre-François Pradat. "Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas." Journal of Personalized Medicine 12, no. 10 (September 28, 2022): 1601. http://dx.doi.org/10.3390/jpm12101601.
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Amyotrophic lateral sclerosis (ALS) is an extremely heterogeneous disease of motor neurons that eventually leads to death. Despite impressive advances in understanding the genetic, molecular, and pathological mechanisms of the disease, the only drug approved to date by both the FDA and EMA is riluzole, with a modest effect on survival. In this opinion view paper, we will discuss how to address some challenges for drug development in ALS at the conceptual, technological, and methodological levels. In addition, socioeconomic and ethical issues related to the legitimate need of patients to benefit quickly from new treatments will also be addressed. In conclusion, this brief review takes a more optimistic view, given the recent approval of two new drugs in some countries and the development of targeted gene therapies.
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Beydoun, Said R., and Jeffrey Rosenfeld. "Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design." US Neurology 14, no. 1 (2018): 47. http://dx.doi.org/10.17925/usn.2018.14.1.47.
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Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.
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McDermott, Christopher J., Mike J. Bradburn, Chin Maguire, Cindy L. Cooper, Wendy O. Baird, Susan K. Baxter, Judith Cohen, et al. "DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis – a randomised controlled trial." Health Technology Assessment 20, no. 45 (June 2016): 1–186. http://dx.doi.org/10.3310/hta20450.
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BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2–3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4®diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure.ObjectiveThe Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure.DesignThe DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy.ParticipantsEligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation.InterventionsParticipants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS.Main outcome measuresThe primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost–utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy.ResultsIn total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25;p = 0.01).ConclusionsDiaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.Future workIt may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further.Trial registrationCurrent Controlled Trials ISRCTN53817913.FundingThis project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.
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Chen, Si, Qiao Liao, Ke Lu, Jinxia Zhou, Cao Huang, and Fangfang Bi. "Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis." Current Neurovascular Research 17, no. 3 (September 29, 2020): 275–85. http://dx.doi.org/10.2174/1567202617666200409125227.
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Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.
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Bushara, K. O. "Sialorrhea in amyotrophic lateral sclerosis: a hypothesis of a new treatment - botulinum toxin A injections of the parotid glands." Medical Hypotheses 48, no. 4 (April 1997): 337–39. http://dx.doi.org/10.1016/s0306-9877(97)90103-1.
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Scotter, Emma L., Leon Smyth, James W. T. Bailey, Chun-Hao Wong, Martina de Majo, Caroline A. Vance, Beth J. Synek, et al. "C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue." Neurobiology of Aging 49 (January 2017): 214.e1–214.e5. http://dx.doi.org/10.1016/j.neurobiolaging.2016.06.019.
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Wang, Wenyue, Sandeep Gopal, Roger Pocock, and Zhicheng Xiao. "Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease." Molecules 24, no. 24 (December 16, 2019): 4604. http://dx.doi.org/10.3390/molecules24244604.
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Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.
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Schoenfeld, David Alan, Dianne M. Finkelstein, Eric Macklin, Neta Zach, David L. Ennist, Albert A. Taylor, and Nazem Atassi. "Design and analysis of a clinical trial using previous trials as historical control." Clinical Trials 16, no. 5 (July 1, 2019): 531–38. http://dx.doi.org/10.1177/1740774519858914.
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Background/AimsFor single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation.MethodsWe fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials.ResultsWe find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial.ConclusionThis article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.
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Lee, Jui-Hao, Jen-Wei Liu, Shinn-Zong Lin, Horng-Jyh Harn, and Tzyy-Wen Chiou. "Advances in Patient-Specific Induced Pluripotent Stem Cells Shed Light on Drug Discovery for Amyotrophic Lateral Sclerosis." Cell Transplantation 27, no. 9 (July 23, 2018): 1301–12. http://dx.doi.org/10.1177/0963689718785154.
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Induced pluripotent stem cells (iPSCs), which are generated through reprogramming adult somatic cells by expressing specific transcription factors, can differentiate into derivatives of the three embryonic germ layers and accelerate rapid advances in stem cell research. Neurological diseases such as amyotrophic lateral sclerosis (ALS) have benefited enormously from iPSC technology. This approach can be particularly important for creating iPSCs from patients with familial or sporadic forms of ALS. Motor neurons differentiated from the ALS-patient-derived iPSC can help to determine the relationship between cellular phenotype and genotype. Patient-derived iPSCs facilitate the development of new drugs and/or drug screening for ALS treatment and allow the exploration of the possible mechanism of ALS disease. In this article, we reviewed ALS-patient-specific iPSCs with various genetic mutations, progress in drug development for ALS disease, functional assays showing the differentiation of iPSCs into mature motor neurons, and promising biomarkers in ALS patients for the evaluation of drug candidates.
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Bertazzi, Renan Nogueira, Fernanda Resernde Martins, Samir Zacarias Zica Saade, and Virgílio Ribeiro Guedes. "Esclerose lateral amiotrófica." Revista de Patologia do Tocantins 4, no. 3 (September 26, 2017): 54. http://dx.doi.org/10.20873/uft.2446-6492.2017v4n3p54.
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A Esclerose Lateral Amiotrófica (ELA) é uma desordem neurodegenerativa dos neurônios motores, invariavelmente progressiva e incapacitante. Sua complexidade e multifatorialidade são determinantes para a dificuldade de tratamentos específicos, embora este cenário tenha mudado nos últimos anos. OBJETIVOS: realizar uma revisão de literatura acerca da ELA, utilizando os agregadores de conteúdo PubMed, BVS e ScieLo. EPIDEMIOLOGIA: A ELA é rara, com predominância de 2:1 em gênero masculino e possui incidência estimada em 1 para 105 habitantes, com prevalência constante. ETIOPATOGÊNESE: Verificadas alterações genéticas em SOD1, FUS, ANG, proteínopatia em TDP-43, dentre outras, que associadas a fatores como exotocicidade, fatores quimiotáxicos de neutrófilos, estresse oxidativo, distúrbios intracelulares do metabolismo do cálcio, lesão mitocondrial, fatores ambientais, infecções e autoimunidade parecem estar implicadas na lesão neuronal. SINTOMATOLOGIA: A entidade progride para perda dos movimentos refinados de prensa, deglutição e fala, acompanhados de miastenia, fasciculações e cãimbras, alentecimento motor, e efeitos pseudobulbares com perda do controle do riso/choro, poupando as funções sensitivas, mantendo a propriocepção do doente. TRATAMENTO: somente o riluzol é aprovado para uso específico, porém outras drogas podem ser usadas: anti-inflamatórios, antiapoptose, anticititóxicos, antioxidantes e mais os inibidores da SOD1. Intervenções cirúrgicas vêm sendo experimentadas, algumas com resultados promissores. O tratamento de suporte deve permear o cuidado com a sialorréia, efeitos pseudobulbares, distúrbios do sono, insuficiência respiratória, fadiga, dor, espasticidade e o laringoespasmo. CONCLUSÃO: Nas últimas décadas, em especial, vimos avanços na determinação dos diferentes elementos da patologia, contudo a terapêutica específica continua restrita. A visibilidade midiática foi importante na implementação de novos estudos. Palavras-chave: Esclerose Amiotrófica Lateral, Doença do Neurônio Motor.
ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder of motor neurons, invariably progressive and incapacitating. Your complexity and multifactoriality are determinant for the difficulty of specific treatments, although this scenario has changed in recent years. OBJECTIVES: Make a literature review on ALS using the PubMed, BVS and ScieLo. EPIDEMIOLOGY: ALS is a rare condition, with a predominance of 2:1 in men and has an estimated incidence of 1 to 105 habitants, with a constant prevalence. ETHIOPATHOGENESIS: The presence of genetic alterations in SOD1, FUS, ANG, TDP-43, and others, have been verified, such as exotocicity, neutrophil quimiotaxic factors, oxidative stress, intracellular disorders of calcium metabolism, mitochondrial damage, environmental factors, infections and autoimmunity appear to be implicated in neuronal injury. SYMPTOMATOLOGY: The entity progresses to loss of refined movements of the press, swallowing and speech, accompanied by myasthenia, fasciculations and cramps, motor eningement, and pseudobulbar effects with loss of control of laughter/crying, sparing the sensory functions, preserving the proprioception of the patient. TREATMENT: Only riluzoleis approved for specific use, but other drugs may be used: anti-inflammatories, anti-apoptosis, anti-cytotoxic agents, antioxidants, and SOD1 inhibitors. Surgical interventions have been tried, some with promissory results. The supportive treatment should permeate the care with sialorrhea, pseudobulbar effects, sleep disturbers, respiratory failure, fatigue, pain, spasticity and laryngospasm. CONCLUSION: In the last decades, in particular, we have seen some advances in the determination of the different elements of the pathology, however the specific therapy remains restricted. The media visibility was important in the implementation of new studies. Keywords: Lateral Amyotrophic Sclerosis. Motor Neuron Disease.
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Syková, Eva, Petr Rychmach, Ivana Drahorádová, ŠImona Konrádová, Kateřina Růžičková, Ivan Voříšek, Serhiy Forostyak, Aleš Homola, and Martin Bojar. "Transplantation of Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: Results of Phase I/IIa Clinical Trial." Cell Transplantation 26, no. 4 (April 2017): 647–58. http://dx.doi.org/10.3727/096368916x693716.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a progressive untreatable neurodegenerative disorder, leading to the death of the cortical and spinal motoneurons (MNs). Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) may represent a new approach to slowing down the progression of ALS by providing neurotrophic support to host MNs and by having an anti-inflammatory effect. We have designed a prospective, nonrandomized, open-label clinical trial (phase I/IIa, EudraCT No. 2011-000362-35) to assess the safety and efficacy of autologous multipotent BM-MSCs in ALS treatment. Autologous BM-MSCs were isolated and expanded under GMP conditions. Patients received 15 ± 4.5 × 106 of BM-MSCs via lumbar puncture into the cerebrospinal fluid. Patients were monitored for 6 months before treatment and then for an 18-month follow-up period. Potential adverse reactions were assessed, and the clinical outcome was evaluated by the ALS functional rating scale (ALSFRS), forced vital capacity (FVC), and weakness scales (WSs) to assess muscle strength on the lower and upper extremities. In total, 26 patients were enrolled in the study and were assessed for safety; 23 patients were suitable for efficacy evaluation. After intrathecal BM-MSC application, about 30% of the patients experienced a mild to moderate headache, resembling the headaches after a standard lumbar puncture. No suspected serious adverse reactions (SUSAR) were observed. We found a reduction in ALSFRS decline at 3 months after application ( p < 0.02) that, in some cases, persisted for 6 months ( p < 0.05). In about 80% of the patients, FVC values remained stable or above 70% for a time period of 9 months. Values of WS were stable in 75% of patients at 3 months after application. Our results demonstrate that the intrathecal application of BM-MSCs in ALS patients is a safe procedure and that it can slow down progression of the disease.