Impact of Plant-Derived Compounds on Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by progressive motor neuron degeneration. Conventional therapies for ALS are based on treatment of symptoms, and the disease remains incurable. Molecular mechanisms are unclear, but studies have been pointing to involvement of glia, neuroinflammation, oxidative stress, and glutamate excitotoxicity as a key factor. Nowadays, we have few treatments for this disease that only delays death, but also does not stop the neurodegenerative process. These treatments are based on glutamate blockage (riluzole), tyrosine kinase inhibition (masitinib), and antioxidant activity (edaravone). In the past few years, plant-derived compounds have been studied for neurodegenerative disorder therapies based on neuroprotection and glial cell response. In this review, we describe mechanisms of action of natural compounds associated with neuroprotective effects, and the possibilities for new therapeutic strategies in ALS.

Add-on treatment with Cerebrolysin improves clinical symptoms in patients with ALS: results from a prospective, single-center, placebo-controlled, randomized, double-blind, phase II study.

Amyotrophic lateral sclerosis (ALS) is a devastating and progressive neurodegenerative disease with limited treatment options available. Cerebrolysin is a drug candidate for the treatment of ALS because of its neuroprotective and neuroregenerative effects. We initiated a pilot clinical study of a combination of Cerebrolysin and riluzole to assess the therapeutic benefit of Cerebrolysin as an add-on treatment on clinical signs and symptoms in outpatients with ALS. Twenty patients with a clinically definitive diagnosis of ALS were enrolled and randomly assigned in a 1:1 ratio to receive Cerebrolysin or placebo. All patients received 50 mg of riluzole PO twice daily as a standard treatment. Patients in the Cerebrolysin group received intravenous injections of 10 mL of Cerebrolysin once daily, five days a week for the first month and three days a week for the next two months. Analysis of the ALS Functional Rating Scale - revised at Month 1 (primary outcome measure), showed a significant treatment effect in favor of Cerebrolysin with a 2.3-point improvement from baseline to Month 1 compared to a 0.9-point decrease in patients on placebo (P=0.005). The effect was maintained over the three-month study period, and the beneficial effect of Cerebrolysin over placebo was also evident in the secondary outcome measures. The safety analysis showed that the combination of riluzole and Cerebrolyisn was well tolerated. Our results demonstrate for the first time a significant clinical effect of Cerebrolysin in improving functional outcomes in patients with ALS and suggest that Cerebrolysin has potential as a novel therapeutic option for ALS.

Impacto do tratamento medicamentoso na voz, fala e deglutição de pacientes com esclerose lateral amiotrófica: revisão sistemática / Impact of drug treatment on voice, speech, and swallowing in patients with amyotrophic lateral sclerosis: a systematic review

RESUMO Objetivos Revisar sistematicamente a literatura sobre o impacto do tratamento medicamentoso nas funções de voz, fala e deglutição de indivíduos adultos com esclerose lateral amiotrófica esporádica, mensuradas por meio de escalas e seus respectivos escores, em relação ao grupo placebo. Estratégia de pesquisa A busca foi realizada com base na estratégia PICO (problema/população/paciente; intervenção; comparação/controle; desfecho/outcome). As palavras-chave foram selecionadas a partir de consulta aos Descritores em Ciências da Saúde (DeCS) e ao Medical Subject Headings (MeSH). Dois pesquisadores independentes fizeram busca na American Speech-Language-Hearing Association (ASHA), Cochrane, LILACS, PubMed, Scopus e Web of Science, em inglês, espanhol e português. Critérios de seleção Foram incluídos ensaios clínicos randomizados, realizados em adultos, e excluídos artigos cujos desfechos estavam relacionados à autoavaliação e à qualidade de vida, teses, dissertações, apenas resumos disponíveis, estudos de caso, estudos experimentais, capítulos de livro, enciclopédias e comunicações breves. Os estudos foram avaliados por meio das ferramentas Robins II (Risk Of Bias In Non-randomized Studies II) e GRADE (Grading of Recommendations Assessment, Development and Evaluation). Resultados dos 9824 artigos encontrados, 5 realizaram a intervenção medicamentosa e foram selecionados para análise. Observou-se ausência de estudos voltados para reabilitação das funções bulbares. A qualidade de evidência gerada variou de alto a baixo risco e o nível de evidência, de baixo a muito baixo. Conclusão a maioria dos estudos demonstra que o tratamento medicamentoso atrasa a degeneração das funções bulbares, com relação ao placebo, embora tal achado não tenha sido observado nos escores de escalas que mensuram tais funções. Os estudos apresentam risco de viés de seleção e muito baixa/baixa qualidade metodológica, limitando a confiança nos achados.

ABSTRACT Purpose To carry out a systematic review of the literature on the impact of drug treatment on the voice, speech, and swallowing functions of adult individuals with sporadic ALS, measured through scales and their respective scores, concerning the placebo group. Research strategy The search strategy was created based on the PICO strategy. The keywords were selected from a consultation with the health sciences descriptors - DECS and the medical subject headings - MeSH. Two independent researchers searched ASHA, Cochrane, Lilacs, Pubmed, Scopus and Web of Science, in English, Spanish and Portuguese. Selection criteria Randomized clinical trials, carried out on adults, were included, and articles with outcomes related to selfassessment and quality of life, theses, dissertations, abstracts only , case studies, experimental studies, book chapters, encyclopedia and brief communication were excluded. The studies were evaluated using the Robins II and Grade tool. Results Of the 9824 articles found, 5 were selected for analysis and underwent drug intervention. It is noticed the absence of studies aimed at the rehabilitation of bulb functions. The quality of evidence generated varied from high to low risk and the level of evidence low and very low. Conclusion Most studies show a delay in the degeneration of bulbar functions in relation to placebo, although this finding has not been observed in the scores of scales that measure such functions. Studies are at risk of selection bias and very low/low methodological quality makes the findings questionable.

Riluzole inhibits Kv4.2 channels acting on the closed and closed inactivated states.

Riluzole is an anticonvulsant drug also used to treat the amyotrophic lateral sclerosis and major depressive disorder. This compound has antiglutamatergic activity and is an important multichannel blocker. However, little is known about its actions on the Kv4.2 channels, the molecular correlate of the A-type K+ current (IA) and the fast transient outward current (Itof). Here, we investigated the effects of riluzole on Kv4.2 channels transiently expressed in HEK-293 cells. Riluzole inhibited Kv4.2 channels with an IC50 of 190 ± 14 µM and the effect was voltage- and frequency-independent. The activation rate of the current (at +50 mV) was not affected by the drug, nor the voltage dependence of channel activation, but the inactivation rate was accelerated by 100 and 300 µM riluzole. When Kv4.2 channels were maintained at the closed state, riluzole incubation induced a tonic current inhibition. In addition, riluzole significantly shifted the voltage dependence of inactivation to hyperpolarized potentials without affecting the recovery from inactivation. In the presence of the drug, the closed-state inactivation was significantly accelerated, and the percentage of inactivated channels was increased. Altogether, our findings indicate that riluzole inhibits Kv4.2 channels mainly affecting the closed and closed-inactivated states.

The Effects of Riluzole on Cisplatin-induced Ototoxicity

Abstract Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of riluzole hydrochloride i.p., and 8 mg/kg of riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 (p < 0.05) and 3 (p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 (p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of riluzole hydrochloride. Conclusion We can say that riluzolemay have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of riluzole.

Does Riluzole Influence Bone Formation?: An In Vitro Study of Human Mesenchymal Stromal Cells and Osteoblast.

STUDY DESIGN: A post-test design biological experiment. OBJECTIVE: The aim of this study was to evaluate the osteogenic effects of riluzole on human mesenchymal stromal cells and osteoblasts. SUMMARY OF BACKGROUND DATA: Riluzole may benefit patients with spinal cord injury (SCI) from a neurologic perspective, but little is known about riluzole's effect on bone formation, fracture healing, or osteogenesis. METHODS: Human mesenchymal stromal cells (hMSCs) and human osteoblasts (hOB) were obtained and isolated from healthy donors and cultured. The cells were treated with riluzole of different concentrations (50, 150, 450 ng/mL) for 1, 2, 3, and 4 weeks. Cytotoxicity was evaluated as was the induction of osteogenic differentiation of hMSCs. Differentiation was evaluated by measuring alkaline phosphatase (ALP) activity and with Alizarin red staining. Osteogenic gene expression of type I collagen (Col1), ALP, osteocalcin (Ocn), Runx2, Sox9, Runx2/Sox9 ratio were measured by qRT-PCR. RESULTS: No cytotoxicity or increased proliferation was observed in bone marrow derived hMSCs and primary hOBs cultured with riluzole over 7 days. ALP activity was slightly increased in hMSCs after treatment for 2 weeks with riluzole 150 ng/mL and slightly upregulated by 150% (150 ng/mL) and 90% (450 ng/mL) in hMSCs at 3 weeks. In hOBs, ALP activity almost doubled after 2 weeks of culture with riluzole 150 ng/mL (P < 0.05). More pronounced 2.6-fold upregulation was noticed after 3 weeks of culture with riluzole at both 150 ng/mL (P = 0.05) and 450 ng/mL (P = 0.05). No significant influence of riluzole on the mRNA expression of osteocalcin (OCN) was observed. CONCLUSION: The effect of riluzole on bone formation is mixed; low-dose riluzole has no effect on the viability or function of either hMSCs or hOBs. The activity of ALP in both cell types is upregulated by high-dose riluzole, which may indicate that high-dose riluzole can increase osteogenic metabolism and subsequently accelerate bone healing process. However, at high concentrations, riluzole leads to a decrease in osteogenic gene expression, including Runx2 and type 1 collagen. LEVEL OF EVIDENCE: N/A.

Mechanism of Neuroprotection Against Experimental Spinal Cord Injury by Riluzole or Methylprednisolone.

Any spinal cord injury carries the potential for persistent disability affecting motor, sensory and autonomic functions. To prevent this outcome, it is highly desirable to block a chain of deleterious reactions developing in the spinal areas immediately around the primary lesion. Thus, early timing of pharmacological neuroprotection should be one major strategy whose impact may be first studied with preclinical models. Using a simple in vitro model of the rat spinal cord it is possible to mimic pathological processes like excitotoxicity that damages neurons because of excessive glutamate receptor activation due to injury, or hypoxic/dysmetabolic insult that preferentially affects glia following vascular dysfunction. While ongoing research is exploring the various components of pathways leading to cell death, current treatment principally relies on the off-label use of riluzole (RLZ) or methylprednisolone sodium succinate (MPSS). The mechanism of action of these drugs is diverse as RLZ targets mainly neurons and MPSS targets glia. Even when applied after a transient excitotoxic stimulus, RLZ can provide effective prevention of secondary excitotoxic damage to premotoneurons, although not to motoneurons that remain very vulnerable. This observation indicates persistent inability to express locomotor activity despite pharmacological treatment conferring some histological protection. MPSS can protect glia from dysmetabolic insult, yet it remains poorly effective to prevent neuronal death. In summary, it appears that these pharmacological agents can produce delayed protection for certain cell types only, and that their combined administration does not provide additional benefit. The search should continue for better, mechanism-based neuroprotective agents.

Pharmacokinetics of Riluzole in Beagle Dogs.

BACKGROUND: Riluzole is a benzothiazole anticonvulsant used in the treatment of patients with amyotrophic lateral sclerosis and it is being investigated for clinical use in patients with spinal cord injury. The present study evaluated the pharmacokinetics of riluzole in beagle dogs after oral dose administration. METHODS: The oral doses (1.5, 5, 15 and 50 mg/kg) of riluzole were administered to beagle dogs and blood samples were collected from 0 h to 24 h post drug administration. Riluzole was quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). RESULTS: The method was sensitive, precise, accurate and selective to riluzole quantification in plasma of beagle dogs. The pharmacokinetics following oral administration was linear from 1.5 to 15 mg/kg and the t1/2 was 2.16, 1.5, 1.8 and 3.0 h after oral administration of 1.5, 5.0, 15 and 50 mg/kg riluzole. CONCLUSION: The riluzole pharmacokinetics was linear up to 15 mg/kg and had a significantlyshorter t1/2 in beagle dogs than in humans.

Epidemiological and clinical factors impact on the benefit of riluzole in the survival rates of patients with ALS.

OBJECTIVE: To investigate the impact of epidemiological and clinical factors on the benefit of riluzole in patients with amyotrophic lateral sclerosis (ALS). METHODS: The survival rate of 578 patients with ALS (1999-2011) was analyzed by descriptive statistics and Kaplan-Meier curves. Considering the median of the sample survival time (19 months), patients were divided in two groups: below (B19) and above the median (A19). Kaplan-Meier curves compared the survival rates of patients treated with riluzole and with patients who did not take the medication. RESULTS: Riluzole increased the survival rates of patients with lower limb onset who were diagnosed after the first appointment in B19. Patients with bulbar onset and diagnosed on the first, or after the first appointment showed higher survival rates in A19. Males lived longer than females in both groups. CONCLUSION: Epidemiological and clinical factors influenced the benefit of riluzole in the survival rates of patients with ALS.

Epidemiological and clinical factors impact on the benefit of riluzole in the survival rates of patients with ALS / Impacto de fatores epidemiológicos e clínicos sobre o benefício do riluzol nas taxas de sobrevida de pacientes com ELA

ABSTRACT Objective To investigate the impact of epidemiological and clinical factors on the benefit of riluzole in patients with amyotrophic lateral sclerosis (ALS). Methods The survival rate of 578 patients with ALS (1999-2011) was analyzed by descriptive statistics and Kaplan-Meier curves. Considering the median of the sample survival time (19 months), patients were divided in two groups: below (B19) and above the median (A19). Kaplan-Meier curves compared the survival rates of patients treated with riluzole and with patients who did not take the medication. Results Riluzole increased the survival rates of patients with lower limb onset who were diagnosed after the first appointment in B19. Patients with bulbar onset and diagnosed on the first, or after the first appointment showed higher survival rates in A19. Males lived longer than females in both groups. Conclusion Epidemiological and clinical factors influenced the benefit of riluzole in the survival rates of patients with ALS.

RESUMO Objetivo Investigar o impacto de fatores epidemiológicos e clínicos sobre o benefício do riluzole em pacientes com esclerose lateral amiotrófica (ELA). Métodos A sobrevida de 578 pacientes com ELA (1999-2011) foi analisada por estatística descritiva e curvas de Kaplan-Meier. Considerando a mediana do tempo de sobrevida (19 meses), a amostra foi subdividida em dois grupos: sobrevida abaixo (B19) e acima de 19 meses (A19). As curvas de Kaplan-Meier compararam a sobrevida de pacientes tratados com riluzole e com pacientes que não receberam tratamento. Resultados O riluzole aumentou a sobrevida de pacientes com início nos membros inferiores e diagnosticados após a primeira consulta no grupo B19. Pacientes com início bulbar e diagnosticados na primeira/ após a primeira consulta apresentaram maior sobrevida em A19. Os homens apresentaram sobrevida maior do que as mulheres. Conclusão Foram encontradas diferenças epidemiológicas e clínicas no benefício do riluzole em pacientes com ELA.

Propylparaben reduces the excitability of hippocampal neurons by blocking sodium channels.

Propylparaben (PPB) is an antimicrobial preservative widely used in food, cosmetics, and pharmaceutics. Virtual screening methodologies predicted anticonvulsant activity of PPB that was confirmed in vivo. Thus, we explored the effects of PPB on the excitability of hippocampal neurons by using standard patch clamp techniques. Bath perfusion of PPB reduced the fast-inactivating sodium current (INa) amplitude, causing a hyperpolarizing shift in the inactivation curve of the INa, and markedly delayed the sodium channel recovery from the inactivation state. Also, PPB effectively suppressed the riluzole-sensitive, persistent sodium current (INaP). PPB perfusion also modified the action potential kinetics, and higher concentrations of PPB suppressed the spike activity. Nevertheless, the modulatory effects of PPB did not occur when PPB was internally applied by whole-cell dialysis. These results indicate that PPB reduces the excitability of CA1 pyramidal neurons by modulating voltage-dependent sodium channels. The mechanistic basis of this effect is a marked delay in the recovery from inactivation state of the voltage-sensitive sodium channels. Our results indicate that similar to local anesthetics and anticonvulsant drugs that act on sodium channels, PPB acts in a use-dependent manner.

Efectos del riluzol en la evolución clínica y sobrevida de los pacientes con esclerosis lateral amiotrófica en Costa Rica / Effects of riluzole on clinical evolution and survival of patients with amyotrophic lateral sclerosis in Costa Rica

Justificación y objetivo:en la actualidad no se ha publicado un estudio que permita conocer el uso del riluzol en pacientes con esclerosis lateral amiotrófica en Costa Rica. El objetivo de este estudio fue evaluar el impacto del riluzol en la evolución clínica y sobrevida de los pacientes con esclerosis lateral amiotrófica atendidos en el Centro Nacional de Control del Dolor y Cuidados Paliativos.Materiales y métodos:estudio analítico, observacional y retrospectivo basado en los registros de los pacientes con esclerosis lateral amiotrófi atendidos en el Centro Nacional de Control del Dolor y Cuidados Paliativos en un período comprendido entre enero del 2009 y mayo del 2014. El análisis estadístico fue realizado en Microsoft Excel y SPSS versión 18. Para el análisis de sobrevida se utilizó estimaciones de Kaplan - Meier y se efectuó un análisis de sobrevida multivariado empleando una regresión de Cox.Resultados:se analizó 235 expedientes clínicos con el diagnóstico de esclerosis lateral amiotrófi que se encontraban en control en el Centro Nacional de Control del Dolor y Cuidados Paliativos, de los cuales 142 (60%) estaban en tratamiento con riluzol y 93 (40%) sin tratamiento con este medicamento, para una relación de 1,5 pacientes con riluzol por uno sin riluzol. Un 66% correspondía a hombres y un 34% a mujeres. Los pacientes en tratamiento con riluzol presentaron una mediana de sobrevida de 25,0 meses (IC95% 19,8 - 30,5 meses) y los pacientes que no recibieron tratamiento de 18,0 meses (IC95% 7,8 - 28,2 meses), con un valor de p para la comparación de las distribuciones de sobrevida de 0,17. Adicionalmente se encontró una diferencia estadísticamente signifi en el tiempo entre el inicio del tratamiento con riluzol y la colocación del PEG (p < =0,001). Los pacientes que recibieron el riluzol presentaron un promedio de tiempo mayor antes de requerir la colocación del PEG...

Background and aim:There is no study on the use of riluzol in patients with amyotrophic lateral sclerosis in Costa Rica. The objective of this study was to assess the impact of riluzole on clinical evolution and survival of patients with amyotrophic lateral sclerosis treated at the National Pain Control and Palliative Care Center.Materials and methods:An analytical, observational and retrospective study based on the records of patients with amyotrophic lateral sclerosis treated at the National Pain Control and Palliative Care Center between January 2009 and May 2014. The statistical analysis was performed using Microsoft Excel and SPSS version 18. Kaplan - Meier estimates were used for the analysis of survival estimates and a survival analysis was performed using a multivariate Cox regression.Results:We analyzed 235 medical records of patients diagnosed with ALS being controlled at the National Pain Control and Palliative Care Center, of which 142 (60%) were treated with riluzole and 93 (40%) did not take this drug, for a ratio of 1.5; 66% were men and 34% women. Patients treated with riluzole showed a median survival of 25.0 months (95% CI 19.8 to 30.5 months) and patients which didn´t receive treatment with riluzole showed a median survival of 18.0 months (95% CI 7.8 to 28.2 months), with a p-value of 0.17 for the comparison of survival distributions. In addition, a statistically significant difference in the time between the beginning of treatment with riluzole and placement of PEG (p-value 0.001) was found. Patients that received riluzole showed an increased average time before requiring the placement of PEG...

Prognostic Factors in Amyotrophic Lateral Sclerosis: A Population-Based Study.

OBJECTIVE: To determine the prognostic factors associated with survival in amyotrophic lateral sclerosis at diagnosis. METHODS: This retrospective population-based study evaluated 218 patients treated with riluzole between 2005 and 2014 and described their clinical and demographic profiles after the analysis of clinical data and records from the mortality information system in the Federal District, Brazil. Cox multivariate regression analysis was conducted for the parameters found. RESULTS: The study sample consisted of 132 men and 86 women with a mean age at disease onset of 57.2±12.3 years; 77.6% of them were Caucasian. The mean periods between disease onset and diagnosis were 22.7 months among men and 23.5 months among women, and the mean survival periods were 45.7±47.0 months among men and 39.3±29.8 months among women. In addition, 80.3% patients presented non-bulbar-onset amyotrophic lateral sclerosis, and 19.7% presented bulbar-onset. Cox regression analysis indicated worse prognosis for body mass index (BMI) <25 kg/m2 (relative risk [RR]: 3.56, 95% confidence interval [CI]: 1.44-8.86), age >75 years (RR: 12.47, 95% CI: 3.51-44.26), and bulbar-onset (RR: 4.56, 95% CI: 2.06-10.12). Electromyography did not confirm the diagnosis in 55.6% of the suspected cases and in 27.9% of the bulbar-onset cases. CONCLUSIONS: The factors associated with lower survival in amyotrophic lateral sclerosis were age >75 years, BMI <25 kg/m2, and bulbar-onset.

Riluzole stimulates BDNF release from human platelets.

Brain-derived neurotrophic factor (BDNF) has several functions in the central nervous system, where it contributes to brain development and its functionality through affecting neuronal survival and activity and also modulating neurotransmitter levels. This neurotrophin is also found in the serum, but its origin and peripheral function remain unknown. Although the source of circulating BDNF is uncertain, it is stored in platelets and can be released through pharmacological treatment. Decreased levels of BDNF in the serum have been related to the pathophysiology of depression, and this relationship is reinforced by the reversal of this condition by treatment with antidepressants. Recently, riluzole has been proposed for the treatment of depression because it has the ability to lower extracellular glutamate levels and increase BDNF expression; and both mechanisms could be associated with its antidepressant action. Considering that riluzole enhances BDNF levels in the serum of patients, we investigated if treatment with this drug could stimulate the release of this neurotrophin from human platelets obtained from healthy subjects. When platelets were incubated with riluzole for 4 h, the basal value of BDNF (92.9 ± 11.1 pg 10(-6) platelets) was significantly increased (P < 0.05, n = 27). This stimulatory effect was achieved at low concentrations of riluzole (from 10 µM) and was not observed when platelets were incubated with the drug for 24 h. The direct action of riluzole evoking BDNF release from human platelets at therapeutic concentrations is important and may contribute to the understanding of its mechanisms of action in the treatment of depression.

Anestesia peridural em paciente portadora de esclerose lateral amiotrófica - relato de caso / Epidural anesthesia in patient with amyotrophic lateral sclerosis - case report

Justificativa e objetivos: a esclerose lateral amiotrófica (ELA) é uma doença degenerativa progressiva do neurônio motor, de causa desconhecida, com padrão genético frequente. Quando os músculos responsáveis pela ventilação são acometidos, o paciente evolui para o óbito em alguns anos em decorrência da insuficiência respiratória. O objetivo deste trabalho é relatar o caso de uma paciente com ELA que foi submetida à gastrostomia e colostomia no Hospital Belo Horizonte sob anestesia peridural contínua e sedação consciente. Conclusão: as evidências têm demonstrado que a administração do bloqueio no neuroeixo associado à dexamedetomidina parece ser segura em pacientes com ELA, pois evita a manipulação das vias aéreas e as complicações respiratórias.

Justification and objectives: Amyotrophic Lateral Sclerosis (ALS) is a progressive degenerative disease of the motor neuron, of unknown cause, with a frequent genetic pattern. When the muscles responsible for ventilation are affected, the patient progresses to death in a few years as a result of respiratory failure. The aim of this study is to report the case of a patient with ALS who underwent gastrostomy and colostomy in Belo Horizonte Hospital under continuous epidural anesthesia and conscious sedation. Conclusion: Evidence has shown that the neuraxial block administration associated with dexmedetomidine seems to be safe in patients with ALS, since it avoids manipulation of the respiratory airways and complications

Evaluación de efectividad y seguridad de riluzol como tratamiento para prolongar el tiempo libre de traqueostomia en pacientes con esclerosis lateral / Evaluation of effectiveness and safety of riluzole as a treatment to prolong tracheostomy time in patients with lateral sclerosis

Antecedentes: Descripción de la condición de salud de interés: La esclerosis lateral amiotrófica (ELA), es una enfermedad neurodegenerativa, incurable, de rápida evolución, como resultado de un processo de degeneración de las neuronas motoras corticales, bulbares y medulares. Se ha destrito que la ELA tiene una incidencia de 1-5 caso por cada 100.000 habitantes, iniciando entre los 50-59 años de edad, teniendo su pico máximo a los 75 años, y disminuyendo a partir de los 80 años o máes. Afecta coon una frecuencia ligeramente superior a los varones en comparación con las mujeres de 1.2:1 a 2.6:1. Descripción de la tecnología: El nizulol es considerado como el único fármaco para el tratamiento de la esclerosis lateral amiotrófica (ELA), enfermedad neurológica degenerativa, cuya etiología no se conoce por completo. Atrasa la aparición de la traqueotomía o la dependencia de ventilación asistida en pacientes selecionados y puede incrementar la sobrevivencia por unos 3 a 5 meses. Evaluación de efetividad y seguridad: Pregunta de investigación: ¿Cuál es la efectividad y seguridad de del riluzol comparado con ninguna terapia farmacológica o placebo, como tratamiento para prolongar el tiempo libre de traqueostomía en los pacientes con diagnóstico de Esclerosis Lateral Amiotrófica? La pregunta de investigación fue refinada y validada con base en: autorización de mercadeo de la tecnología para la indicación de interés (registro sanitario INVIMA), listado de medicamentos vitales no disponibles, cobertura de las tecnologías en el Plan Obligatorio de Salud. (POS) (Acuerdo 029 de 2011), revisión de grupos terapéuticos (código ATC: Anatomical, Therapeutic Chemical classification system), recomendaciones de guías de práctica clínica actualizadas, disponibilidad de evidencia sobre efectividad y seguridad (reportes de evaluación de tecnologías, revisiones sistemáticas de la literatura), uso de las tecnologías (listas nacionales de recobro, estadística de prescripción, etc), estudios de prevalencia/incidencia y carga de enfermedad y consulta con expertos temáticos (especialistas clínicos), sociedades científicas y otros actores clave. No se identificaron otros comparadores relevantes para la evaluación. Población: Personas con diagnostico de Esclerosis Lateral Amiotrófica. Conclusiones: -Efectividad: En los pacientes con diagnóstico de esclerosis lateral amniotrófica, riluzol comparado con placebo incrementa el tiempo libre de traquesotomia y sobrevida en 3 meses; -Seguridad: las nauseas son más frecuentes con el uso de rilusol en comparación con placebo; Evaluación económica: no se identificaron estudios de costo-efectividad para Colombia.

In silico docking reveals possible Riluzole binding sites on Nav1.6 sodium channel: implications for amyotrophic lateral sclerosis therapy.

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder characterized mainly by a progressive loss of motor neurons. Glutamate excitotoxicity is likely the main cause of neuronal death, and Riluzole interferes with glutamate-mediated transmission. Thus, in such independent pathway, these effects may be partly due to inactivation of voltage-dependent sodium channels. Here we predict the structural model of the interaction and report the possible binding sites of Riluzole on Nav1.6 channel. The docked complexes were subjected to minimization and we further investigated the key interacting residues, binding free energies, pairing bridge determination, folding pattern, hydrogen bounding formation, hydrophobic contacts and flexibilities. Our results demonstrate that Riluzole interacts with the Nav1.6 channel, more specifically in the key residues TYR 1787, LEU 1843 and GLN 1799, suggesting possible cellular implications driven by these amino acids on Riluzole-Nav1.6 interaction, which may serve as an important output for a more specific and experimental drug design therapy against ALS.

Nuevas estrategias en el tratamiento del trauma raquimedular: actualización bibliográfica / New strategies in treatment of spinal cord injury: literature update

Better understanding of spinal cord injury pathophysiology has allowed the development of new areas of investigation, focused in reducing the injury and stimulating cord regeneration. The preliminary results of these investigations have generated great expectation in the scientific world, together with ambiguous information for patients with these injuries. In this article, we present a review of the available literature in this area, describing several non-pharmacological interventions, together with new drugs, immune therapies to block processes that inhibit cord regeneration and the renowned cell therapy. After evaluating the available articles included in this review, we observed a progress towards an increased efficacy of these treatments, but with limitations due to methodological flaws in the study protocols, which do not allow us to make applicability recommendations of them in humans.

Los recientes avances en el entendimiento de la fisiopatología del traumatismo raquimedular, han permitido el desarrollo de investigación enfocada en intervenciones orientadas a disminuir la lesión y estimular la regeneración medular. El entusiasmo por este nuevo conocimiento ha generado expectativa en el mundo científico co e información ambigua en los pacientes con este tipo de lesiones. En este trabajo revisamos la literatura reciente y la que se está llevando a cabo a este respecto, encontrando la descripción de algunas intervenciones no farmacológicas diferentes a la cirugía, nuevos medicamentos, terapias de bloqueo inmunológico de procesos que inhiben la regeneración medular y la reconocida terapia celular. Al evaluar los trabajos incluidos en esta revisión, observamos un avance hacia el aumento de la efectividad de los tratamientos pero con la limitación debida a las falencias metodológicas en la investigación que impiden hacer recomendaciones de aplicabilidad de los mismos en humanos.