Efecto del zumo del fruto Solanum quitoense (lulo) sobre el daño cerebral y cognitivo inducido por cloruro de mercurio en ratones / Effect of Solanum quitoense (lulo) fruit juice on brain and cognitive damageinduced by mercury chloride in mice

Introducción: Las enfermedades neurodegenerativas han ido en aumento durante las últimas décadas, siendo la demencia la principal patología con mayor repercusión a nivel global. Objetivo: Evaluar el efecto neuroprotector del zumo del fruto Solanum quitoense (lulo) frente a la toxicidad del cloruro de mercurio (II) en los ratones. Materiales y métodos: Diseño experimental, con grupo control y posprueba. Se empleó 42 ratones machos. Para inducir a la toxicidad se empleó una solución de HgCl2 (10 mg/kg), vía orogástrica, por un periodo de siete días. Durante ese periodo recibieron los siguientes tratamientos: grupos I y II suero fisiológico; grupos III vitamina E (40UI/kg); grupo IV-V-VI zumo de lulo, 0,5; 2,0 y 8,0 mL/kg, respectivamente. Terminado el tratamiento los animales fueron sacrificados por decapitación, el cerebro y cerebelo fueron extraído de la cavidad craneana. El hemisferio izquierdo fue homogenizado para la determinación de la lipoperoxidación, glutatión (reducido y total), actividad de superóxido dismutasa y catalasa. El hemisferio derecho y cerebelo fueron conservados, para la evaluación histológica. Se evaluó la función cognitiva (aprendizaje y memoria), según protocolo de Deacon y Rawlis. Resultados: La administración del zumo de lulo disminuyeron los índices de cerebro en los grupos V-VI. La lipoperoxidación disminuyó (grupos IV-VI), la relación GSH/GSSG aumentaron (grupos V-VI). La actividad de la catalasa aumentó (grupos IV-VI). La relación SOD/CAT disminuyeron (grupos IV-VI). El tiempo de latencia y número de intentos fueron menores en los grupos IV-VI. Conclusiones: La administración del zumo del fruto Solanum quitoense presenta efecto neuroprotector para el modelo estudiado. Palabras clave: Neuroprotección, Solanum quitoense, cloruro de mercurio, función cognitiva, alimento funcional (Fuente: DeCS BIREME).(AU)

Introduction: Neurodegenerative diseases have beenincreasing in recent decades, with dementia being the mainpathology with the greatest impact globally. Objective: To evaluate the neuroprotective effect ofSolanum quitoense (lulo) fruit juice against the toxicity ofmercury (II) chloride in mice. Materials and methods: Experimental design, withcontrol group and post-test. 42 male mice were used. Toinduce toxicity, a solution of HgCl2 (10 mg/kg) was used viathe orogastric route for a period of seven days. During thisperiod, they received the following treatments: groups I and II physiological saline; groups III vitamin E (40IU/kg); groupIV-V-VI lulo juice, 0.5; 2.0 and 8.0 mL/kg, respectively. Oncethe treatment was completed, the animals were sacrificed bydecapitation, the brain and cerebellum were removed fromthe cranial cavity. The left hemisphere was homogenized forthe determination of lipoperoxidation, glutathione (reducedand total), superoxide dismutase and catalase activity. Theright hemisphere and cerebellum were preserved forhistological evaluation. Cognitive function (learning andmemory) was evaluated according to the Deacon and Rawlisprotocol. Results: The administration of lulo juice decreased brainindices in groups V-VI. Lipoperoxidation decreased (groupsIV-VI), the GSH/GSSG ratio increased (groups V-VI). Catalaseactivity increased (groups IV-VI). The SOD/CAT ratiodecreased (groups IV-VI). The latency time and number ofattempts were lower in groups IV-VI. Conclusions: The administration of Solanum quitoensefruit juice has a neuroprotective effect for the model studied.(AU)

Anesthetic management of a child with Loeys-Dietz syndrome undergoing complete aortic arch replacement.

Loeys-Dietz syndrome (LDS) is a connective tissue disease related to ß-transforming growth factor mutations, which causes aneurysms formation, vascular tortuosity and skeletal manifestations. The prognosis is very poor, and mortality occurs at the age of 27 in patients without surgical treatment. Despite being diagnosed in childhood, is not usual surgical aortic replacement in children. We report a case of 12 years old child with LDS and multiple aneurysms in thoracic aorta, undergoing complete aortic arch replacement and our proposal for the anesthetic management, due to surgical complexity and implications in pediatric population.

El síndrome de Loeys-Dietz (SDL) es una enfermedad del tejido conectivo debida a mutaciones del factor de crecimiento transformador beta que provocan formación de aneurismas, malformaciones vasculares y esqueléticas. Tiene mal pronóstico y el fallecimiento sobreviene de media a los 27 años sin tratamiento quirúrgico. A pesar de diagnosticarse en la infancia, es infrecuente la cirugía en niños. Presentamos el caso de una niña de 12 años con SDL y aneurisma múltiple en aorta torácica, programada para recambio completo de arco aórtico, proponiendo estrategias para el manejo anestésico, dada la complejidad y las implicaciones de esta cirugía en la población pediátrica.

EGb 761 reduces Ca2+ influx and apoptosis after pentylenetetrazole treatment in a neuroblastoma cell line.

Background: Transient receptor potential (TRP) channels have been found to have significant implications in neuronal outgrowth, survival, inflammatory neurogenic pain, and various epileptogenic processes. Moreover, there is a growing body of evidence indicating that transient receptor potential (TRP) channels have a significant impact on epilepsy and its drug-resistant subtypes. Objective: We postulated that EGb 761 would modulate TRPA1 channels, thereby exhibiting anti-inflammatory and neuroprotective effects in a neuroblastoma cell line. Our rationale was to investigate the impact of EGb 761 in a controlled model of pentylenetetrazole-induced generalized epilepsy. Methodology: We evaluated the neuroprotective, antioxidant and anti-apoptotic effects of EGb 761 both before and after the pentylenetetrazole application in a neuroblastoma cell line. Specifically, we focused on the effects of EGB 761 on the activity of Transient receptor potential (TRP) channels. Results: EGb 761 applications both before and after the pentylenetetrazole incubation period reduced Ca release and restored apoptosis, ROS changes, mitochondrial depolarization and caspase levels, suggesting a prominent prophylactic and therapeutic effect of EGb 761 in the pentylenetetrazole-induced epileptogenesis process. Conclusion: Our basic mechanistic framework for elucidating the pathophysiological significance of fundamental ion mechanisms in a pentylenetetrazole treated neuroblastoma cell line provided compelling evidence for the favorable efficacy and safety profile of Egb 761 in human-relevant in vitro model of epilepsy. To the best of our knowledge, this is the first study to investigate the combined effects of EGb 761 and pentylenetetrazole on TRP channels and measure their activation level in a relevant model of human epileptic diseases.

Tratamientos agudos de recanalización en el ictus arterial isquémico pediátrico posnatal. Código ictus pediátrico / Acute recanalization treatments in postnatal paediatric ischaemic arterial strole. Paediatric stroke code

El ictus arterial isquémico infantil es una patología mucho menos conocida que en adultos debido a su menor frecuencia y a su diferente etiología. Sin embargo, es también una patología grave con una alta incidencia de secuelas severas y perennes, que sobrepasan el 50% de los casos. El manejo agudo del ictus arterial isquémico pediátrico posnatal (IAIPP) ha cambiado drásticamente en los últimos años, fundamentalmente en lo referente a los tratamientos de recanalización (trombólisis y terapias endovasculares). Estos tratamientos, que antes no se recomendaban en la edad infantil, se están afianzando cada vez más en la práctica diaria. Aunque los estudios realizados en niños no tienen un grado de evidencia alto por ser retrospectivos y porque el número de casos es bajo, soportan la idea de que dichos tratamientos son igual de seguros y eficaces que en los adultos siempre que se realicen con unos criterios de inclusión y exclusión determinados y dentro de un tiempo determinado desde el inicio de los síntomas (ventana terapéutica). En este artículo se revisa, a la luz de los conocimientos actuales, el manejo agudo del IAIPP. Debido a que la eficacia de estos tratamientos está íntimamente ligada al inicio precoz de los mismos, es necesaria la existencia de un código ictus infantil como ampliación del código ictus que se aplica a los adultos. Ha empezado a implantarse en España desde el año 2019 aunque todavía hay importantes zonas del país donde aún no se aplica. (AU)

In children, arterial ischemic stroke is a much less understood disease compared to in adults due to its lower frequency and different aetiology. However, it is also a serious disease, with a high incidence of severe and permanent sequelae that exceeds 50% of total cases. The acute management of postnatal arterial ischaemic stroke (MNAIS) has changed drastically in recent years, chiefly on account of recanalization treatments (thrombolysis and endovascular therapies). These treatments, which used to not be recommended in childhood, are increasingly implemented in everyday clinical practice. Although the evidence from studies carried out in children is not of high quality due to their retrospective design and the small number of reported cases, they support the hypothesis that these treatments are as safe and effective as they are in adults as long as appropriate eligibility criteria are applied and they are used within a certain time from the onset of symptoms (therapeutic window). This article reviews the MNAIS based on the current scientific evidence. Since the efficacy of these treatments is highly dependent on their early initiation, a paediatric stroke code needs to be in place as an extension of the stroke code applied to adults. It has started to be introduced in Spain since 2019, although there are still large areas of the country where it has yet to be applied. (AU)

Acute recanalization treatments in postnatal paediatric ischaemic arterial stroke. Paediatric stroke code.

In children, arterial ischemic stroke is a much less understood disease compared to in adults due to its lower frequency and different aetiology. However, it is also a serious disease, with a high incidence of severe and permanent sequelae that exceeds 50% of total cases. The acute management of postnatal arterial ischaemic stroke (MNAIS) has changed drastically in recent years, chiefly on account of recanalization treatments (thrombolysis and endovascular therapies). These treatments, which used to not be recommended in childhood, are increasingly implemented in everyday clinical practice. Although the evidence from studies carried out in children is not of high quality due to their retrospective design and the small number of reported cases, they support the hypothesis that these treatments are as safe and effective as they are in adults as long as appropriate eligibility criteria are applied and they are used within a certain time from the onset of symptoms (therapeutic window). This article reviews the MNAIS based on the current scientific evidence. Since the efficacy of these treatments is highly dependent on their early initiation, a paediatric stroke code needs to be in place as an extension of the stroke code applied to adults. It has started to be introduced in Spain since 2019, although there are still large areas of the country where it has yet to be applied.

Cuidado desenvolvimental para recém-nascidos pré-termos: revisão de escopo / Atención del desarrollo de los recién nacidos pretérmino: revisión del alcance / Developmental care for preterm newborns: a scoping review

Objetivo: mapear como o cuidado desenvolvimental prestado aos recém nascidos pré-termos tem sido desenvolvido nas unidades de terapia intensiva neonatal com a finalidade de sintetizar as evidências científicas atuais. Métodos: revisão de escopo com busca realizada em novembro de 2022 nas bases MEDLINE, Biblioteca Virtual em Saúde, CINAHL, Embase e Web of Science. Foram incluídos estudos que retratavam o cuidado desenvolvimental nas unidades neonatais, nos últimos cinco anos, sem restrição de idioma. Resultados: incluíram-se sete artigos e os principais temas foram: contato pele a pele, controle do ruído e luminosidade, participação da família e sensibilização e treinamento da equipe. Conclusão: esses cuidados contribuem para o desenvolvimento neuropsicomotor do prematuro, melhoram a assistência e reduzem a morbimortalidade e o tempo de internação.

Objective: To map the evolution of developmental care provided to preterm newborns in Neonatal Intensive Care Units to synthesize current scientific evidence. Methods: Bibliographic search for a scoping review was conducted in November 2022 on the MEDLINE, Virtual Health Library, CINAHL, Embase and Web of Science databases. Studies discussing developmental care in neonatal units in the past five years, without language restriction, were included. Results: The scoping review included articles, whose main topics were skin-to-skin contact, noise and light control, family participation, and team awareness and training. Conclusion: Developmental care practices contribute to the neuropsychomotor development of preterm infants, improve care, reduce morbidity and mortality, and the length of hospitalization.

Objetivo: mapear cómo se ha desarrollado la atención del desarrollo brindada a los recién nacidos pretérmino en las unidades de cuidados intensivos neonatales para sintetizar la evidencia científica actual. Métodos: revisión de alcance realizada en noviembre de 2022 mediante búsquedas en las bases de datos MEDLINE, Biblioteca Virtual en Salud, CINAHL, Embase y Web of Science. Se incluyeron estudios que trataron la atención del desarrollo en unidades neonatales, en los últimos cinco años, sin restricción de idioma. Resultados: se incluyeron siete artículos y los temas principales fueron contacto piel con piel, control de luz y ruido, participación familiar y sensibilización y entrenamiento del equipo. Conclusión: estos cuidados contribuyen al desarrollo neuropsicomotor de los prematuros, mejoran la asistencia y reducen la morbimortalidad y la estancia hospitalaria.

Una década después de la implantación en España de la hipotermia terapéutica en el recién nacido con encefalopatía hipóxico-isquémica perinatal / Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain

Introducción: Se cumple ahora más de una década del inicio de la hipotermia terapéutica (HT)en Espa ̃na, la única intervención neuroprotectora que ha venido a ser práctica estándar en eltratamiento de la encefalopatía hipóxico-isquémica perinatal (EHI). El objetivo de este artículoes ofrecer un panorama actual y presentar las controversias surgidas alrededor de la aplicaciónde esta terapia. Desarrollo: En esta década se ha implantado con éxito la HT en la gran mayoría de los hospitalesterciarios de Espa ̃na y más del 85% de los recién nacidos con EHI moderada-grave reciben estaterapia. Entre los aspectos que pueden mejorar la eficacia de la HT están su inicio precoz dentrode las primeras 6 h de vida y el control de factores comórbidos asociados a la asfixia perinatal. En los pacientes con EHI moderada el inicio después de las 6 h parece mantener cierta eficacianeuroprotectora. Una duración de la HT mayor de 72 horas o un enfriamiento más profundo noofrecen mayor eficacia neuroprotectora y aumentan el riesgo de efectos adversos. Aspectosno bien aclarados aún son la sedación durante la HT y la aplicación de esta intervención a losneonatos con EHI leve y en otros escenarios. La información pronóstica y su marco temporal esuno de los aspectos más desafiantes. Conclusiones: La HT es universal en países con recursos económicos, aunque existen puntos de controversia no resueltos. Si bien es un tratamiento generalizado en nuestro país, falta disponerde dispositivos para el traslado de estos pacientes y su centralización.(AU)

Introduction: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice inthe treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to providea current picture of the technique and to address the controversies surrounding its use. Development: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severeHIE currently receive the treatment. The factors that can improve the efficacy of TH includeearly treatment onset (first 6 hours of life) and the control of comorbid factors associated withperinatal asphyxia. In patients with moderate HIE, treatment onset after 6 hours seems to havesome neuroprotective efficacy. TH duration longer than 72 hours or deeper hypothermia do notoffer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infantswith mild HIE, and its application in other scenarios. Prognostic information and time frame areone of the most challenging aspects. Conclusions: TH is universal in countries with sufficient economic resources, although certainunresolved controversies remain. While the treatment is widespread in Spain, there is a needfor cooling devices for the transfer of these patients and their centralisation.(AU)

Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain.

INTRODUCTION: More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use. DEVELOPMENT: In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 h of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 h seems to have some neuroprotective efficacy. TH duration longer than 72 h or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Controversy persists around the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects. CONCLUSIONS: TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for devices for the transfer of these patients and their centralisation.

Nuevos sistemas de liberación controlada de sustancias activas de administración intraocular / Novel delivery systems of active substances for intraocular administration

Las patologías neurodegenerativas que afectan al segmento posterior del ojo como la retinopatía diabética, la degeneración macular asociada a la edad y el glaucoma se encuentran entre las principales causas de ceguera en el mundo. Se trata de enfermedades crónicas, multifactoriales y, en determinados casos, relacionadas con la edad. Su tratamiento requiere mantener concentraciones terapéuticas en el segmento posterior, acudiéndose al empleo de inyecciones intraoculares sucesivas que se asocian con efectos secundarios y son mal toleradas por los pacientes.Los sistemas de liberación controlada de sustancias activas de administración intraocular surgen como alternativa a las inyecciones repetidas ya que son capaces de liberar, de forma controlada, el agente medicamentoso en el interior del ojo con una única administración del preparado. Dependiendo del biomaterial con el que se elaboran dichos sistemas pueden ser biodegradables o no biodegradables. Atendiendo a su tamaño se clasifican en implantes (>1mm), microsistemas (1-1000μm) y nanosistemas (1-1000nm).Las microesferas biodegradables son herramientas terapéuticas de gran interés en el tratamiento de patologías neurodegenerativas ya que pueden encapsular sustancias activas de distinta naturaleza y conseguir distintos perfiles de cesión que se adapten a las necesidades clínicas. Además, se puede recurrir a la administración de diferentes cantidades de micropartículas correspondiendo a distintas dosis de las sustancias medicamentosas en una terapia personalizada. La encapsulación simultánea de varias sustancias activas en las microesferas resulta de gran interés en el tratamiento de patologías multifactoriales ya que se pueden abordar distintas dianas terapéuticas. (AU)

Neurodegenerative pathologies affecting the posterior segment of the eye such as diabetic retinopathy, age related macular degeneration and glaucoma are among the main causes of blindness in the world. They have in common that are cronic, multifactorial and in some cases related with the elderly. The treatment of these pathologies require to maintain therapeutic concentrations in the posterior segment thanks to the use of successive intraocular injections which are associated to secondary effects being poor tolerated by patients.Intraocular drug delivery systems emerged as an alternative to frequent injections as they are able to deliver the therapeutic agent in a controlled fashion into the eye after a single administration. Depending on the biomaterial these delivery systems are biodegradable or non biodegradable. Attending to their sizes, drug delivery systems are classified in implants (>1mm), microsystems (1-1000μm) y nanosystems (1-1000nm).Biodegradable microspheres emerge as therapeutic tools of great interest for the treatment of neurodegenerative pathologies as they can encapsulate active substances of distinct nature and provide release profiles tailoring with clinical needs. Furthermore, it is possible to administer different amounts of microspheres which correspond to the most adequated doses of the medicine in a personalized therapy. The simultaneous encapsulation of several active substances in the microspheres are of great interest in the treatment of multifactorial diseases covering different therapeutic targets. (AU)

Efectos beneficiosos de las antocianinas para la salud / Efeitos benéficos das antocianinas para a saúde / Beneficial effects of anthocyanins for health

Las antocianinas son polifenoles pertenecientes al grupo de los flavonoides que actúan como pigmentos en las flores, hojas o frutos de las plantas en las que se encuentran. Desde un punto de vista nutricional, las antocianinas son los flavonoides más abundantes en la dieta con interesantes propiedades antioxidantes. Además, la industria alimentaria y farmacéutica ha utilizado antocianinas como aditivos alimentarios o excipientes debido a sus propiedades colorantes. Sin embargo, más allá de sus efectos antioxidantes, las antocianinas también pueden actuar como agentes terapéuticos debido a sus propiedades neuroprotectoras, antidiabéticas y cardioprotectoras. A pesar del gran número de estudios in vitro y en animales en relación con la neuroprotección, la actividad antioxidante o los efectos sobre el sistema cardiovascular, el número de ensayos clínicos continúa siendo limitado. Se han realizado muy pocos estudios en humanos en áreas como SNC, cardioprotección o diabetes. Sin embargo, considerando los resultados alcanzados en los ensayos en humanos junto con las intervenciones en relación con el estrés oxidativo, así como los datos que muestran los efectos en los experimentos preclínicos, podemos sugerir que las antocianinas presentan un papel importante en la prevención y podrían contribuir al tratamiento de diversas patologías en las que el estrés oxidativo se encuentra como elemento subyacente. (AU)

As antocianinas são polifenóis pertencentes ao grupo dos flavonóides que atuam como pigmentos nas flores, folhas ou frutos das plantas em que se encontram. Do ponto de vista nutricional, são os flavonóides mais abundantes na dieta com interessantes propriedades antioxidantes. Além disso, a indústria alimentícia e farmacêutica tem utilizado antocianinas como aditivos ou excipientes alimentares devido às suas propriedades corantes. No entanto, além de seus efeitos antioxidantes, as antocianinas também podem atuar como agentes terapêuticos devido às suas propriedades neuroprotetoras, antidiabéticas e cardioprotetoras. Há evidências crescentes sugerindo o papel desses compostos em diferentes áreas. Apesar do grande número de estudos in vitro e em animais sobre neuroproteção, atividade antioxidante ou efeitos no sistema cardiovascular, o número de ensaios clínicos permanece limitado. Muito poucos estudos humanos foram realizados em áreas como SNC, cardioproteção ou diabetes. No entanto, considerando os resultados alcançados em testes em humanos juntamente com as intervenções em relação ao estresse oxidativo, bem como os dados que mostram os efeitos em experimentos pré-clínicos, podemos sugerir que as antocianinas têm um papel importante na prevenção e podem ter um papel importante na tratamento de diversas patologias em que se encontra o stress oxidativo como elemento subjacente. (AU)

Anthocyanins are polyphenols belonging to flavonoid group which act as pigments in plant flowers, fruits and leaves. From a nutritional point of view, anthocyanins arethe most common flavonoids in diet, showing interesting antioxidant properties. In addition, the food and pharma industry has used anthocyanins as food additives or excipients due to its coloring properties. However, beyond its antioxidant effects, anthocyanins may also act as therapeutic agents due to neuroprotective, antidiabetic and cardioprotective properties. Beside the great number of in vitro and animal studies related to neuroprotection, antioxidant activity or the effects on cardiovascular system, the number of clinicaltrials is still very limited. Very few human studies have been conducted in the CNS, cardioprotection or in the area of diabetes. However, considering all the results achieved in human trials together with interventions in relation to oxidative stress, as well as the data showing the effects in preclinical experiments, we can suggest that anthocyanins may play an important role in prevention and could also contribute to the treatment of various pathologies in which oxidative stress is found as an underlying element. (AU)

Citicolina: revisión farmacológica y clínica, actualización 2022 / Citicoline: pharmacological and clinical review, 2022 update

Esta revisión se basa en la publicada en 2016 –Secades JJ. Citicolina: revisión farmacológica y clínica, actualización 2016. Rev Neurol 2016; 63 (Supl 3): S1-S73–, e incorpora 176 nuevas referencias aparecidas desde entonces, con toda la información disponible para facilitar el acceso a toda la información en un único documento. La revisión se centra en las principales indicaciones del fármaco, como los accidentes cerebrovasculares agudos y sus secuelas, incluyendo el deterioro cognitivo, y los traumatismos craneoencefálicos y sus secuelas. Se recogen los principales aspectos experimentales y clínicos en estas indicaciones

This review is based on the previous one published in 2016 (Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63 (Supl 3): S1-S73), incorporating 176 new references, having all the information available in the same document to facilitate the access to the information in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications.(AU)

Effect of intranasal administration of NeuroEPO in the histological structure of the olfactory mucosa of Wistar rats / Efecto de la administración intranasal de NeuroEPO en la estructura histológica de la mucosa olfatoria de ratas Wistar

Introduction: Strokes and neurodegenerative diseases are major global health problems, not only because they cause high mortality and disability, but due to the lack of effective therapies. NeuroEPO, a variant of recombinant human erythropoietin (rHu-EPO) with a low sialic acid content, has shown encouraging results as a potential neuroprotective agent when administered intranasally. Objective: To determine the effect of intranasal administration of NeuroEPO on the histological structure of the olfactory mucosa of Wistar rats. Materials and Methods: An experimental, prospective, and longitudinal study was conducted on Wistar rats. Ten healthy animals were randomly distributed into two groups of five each. The control group received a vehicle (0.3 μl/g/day) and the treated group received NeuroEPO (300 μg/kg/day). Both treatments were administered intranasally for 28 days. The histological characteristics of the olfactory mucosa were evaluated. The medians between the study groups were compared using the Mann-Whitney U test. Results: There were no alterations in the histological characteristics of the olfactory epithelium. However, slight hypertrophy and hyperplasia of the Bowman's glands were observed at the level of the lamina propria in the group treated with NeuroEPO. Conclusions: The administration of the nasal formulation of NeuroEPO did not induce histological alterations of the olfactory mucosa of Wistar rats under the experimental conditions of this research.

Introducción: Los accidentes cerebrovasculares y las enfermedades neurodegenerativas constituyen un importante problema de salud mundial. No solo porque causan una alta mortalidad y discapacidad, sino por la falta de terapias eficaces para tratarlos. La NeuroEPO, una variante de la eritropoyetina humana recombinante (rHu-EPO) con bajo contenido en ácido siálico, ha mostrado resultados alentadores como potencial agente neuroprotector al ser administrada por vía intranasal. Objetivo: Determinar el efecto de la administración intranasal de NeuroEPO en la estructura histológica de la mucosa olfatoria de ratas Wistar. Materiales y Métodos: Se realizó un estudio experimental, prospectivo y de corte longitudinal en ratas Wistar. Se utilizaron diez animales sanos distribuidos aleatoriamente en dos grupos de cinco cada uno. El grupo control recibió vehículo (0,3 μl/g/día) y el grupo tratado recibió NeuroEPO (300 μg/kg/día). Ambos tratamientos fueron administrados por vía intranasal durante 28 días. Fueron evaluadas las características histológicas de la mucosa olfatoria. Las medianas de los grupos del estudio fueron comparadas mediante la prueba U de Mann-Whitney. Resultados: No se evidenciaron alteraciones en las características histológicas del epitelio olfatorio. Sin embargo, a nivel de la lámina propia en el grupo tratado con NeuroEPO, se observó una ligera hipertrofia e hiperplasia de las glándulas de Bowman. Conclusiones: La administración de la formulación nasal de NeuroEPO no indujo alteraciones histopatológicas de la mucosa olfatoria de ratas Wistar en las condiciones experimentales de esta investigación.

A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients.

BACKGROUND: Few treatments are currently available for amyotrophic lateral sclerosis (ALS). A combination of lithium carbonate and valproic acid (VPA-Li) was shown to inhibit motor neuron death and delay disease progression. METHODS: Outpatients with a typical ALS presentation were enrolled in a randomized, placebo-controlled trial to assess the efficacy of orally administered VPA-Li. Changes in a functional scale score (ALSFRS-R) and survival rate were chosen as primary outcome variables. Secondary outcome variables included BMI, respiratory monitoring, quality of life, and a global impression of the treatment. RESULTS: Out of 42 patients enrolled, 20 individuals receiving VPA-Li and 18 on placebo treatment were included in the final analysis. Forty-five percent of patients receiving VPA-Li completed the trial, whereas only 22.22% of patients in the placebo group attended the final visit 18 months later (P = 0.09). Major changes in the ALSFRS-R score were observed, including a decrease of 1.195 points/month in the placebo group (95% CI: 0.7869-1.6031) and of 0.5085 under VPA-Li treatment (95% CI: 0.2288-0.7882) between months 6 and 14. Adverse events included bad mouth taste, constipation, and anorexia. Survival rate, body weight, and quality of life were positive outcomes by the end of the trial despite a high sample reduction, especially in the placebo group. The inclusion of 212 subjects in each group would confirm these differences. CONCLUSIONS: Combined VPA-Li treatment associated with slower ALS progression and better secondary outcomes. This dual treatment overcame the futility threshold and merits further investigation in ALS.

Intranasal administration of NeuroEPO does not affect the structure of respiratory mucosa in Wistar rats / La administración de NeuroEPO intranasal no afecta la estructura de la mucosa respiratoria en ratas Wistar

Introduction: Diseases associated with the Central Nervous System represent a group of conditions with important social and economic repercussions. New treatment strategies with NeuroEPO offer new opportunities to prevent the onset and progression of these disorders. NeuroEPO administered intranasally can reach the Central Nervous System through various mechanisms involving the olfactory and trigeminal nerves, respiratory and olfactory mucosa, nasal vasculature, cerebrospinal fluid, and the lymphatic system. Objective: To determine the effect of intranasal administration of NeuroEPO on the histologic structure of the respiratory mucosa and its associated lymphatic tissue in Wistar rats. Material and Methods: An experimental, descriptive, longitudinal, prospective study was conducted, using the Wistar rat as a biological model. Ten healthy animals were randomly distributed in two groups of five animals each. One of the groups received intranasal NeuroEPO for 28 days at doses of 300 μg/kg. The other group was given a vehicle at a rate of 0,3μl/g. The histological characteristics of the respiratory mucosa were studied. The Mann-Whitney test was used to compare the means. Results: No alterations in the histological characteristics of the respiratory mucosa and the lymphatic tissue associated with the nasal mucosa were observed in Wistar rats after the administration of NeuroEPO. Conclusion: Intranasal administration of NeuroEPO does not cause pathological changes in the histological structure of the respiratory mucosa or the lymphatic tissue associated with the nasal mucosa of Wistar rats in our experimental conditions.

Introducción: Las enfermedades asociadas al Sistema Nervioso Central representan un grupo de padecimientos con importante repercusión social y económica. Las nuevas estrategias de tratamiento con NeuroEPO ofrecen nuevas oportunidades para prevenir la aparición y la progresión de estos desórdenes. La NeuroEPO administrada por vía intranasal puede alcanzar al Sistema Nervioso Central a través de varios mecanismos que involucran los nervios olfatorios y trigéminos, mucosa respiratoria y olfatoria, vasculatura nasal, fluido cerebroespinal y el sistema linfático. Objetivo: Determinar el efecto de la administración intranasal de NeuroEPO sobre la estructura histológica de la mucosa respiratoria y de su tejido linfático asociado en ratas Wistar. Material y métodos: Se realizó un estudio experimental, descriptivo, longitudinal, prospectivo, utilizando la rata Wistar como modelo biológico. Se utilizaron diez animales sanos distribuidos aleatoriamente en dos grupos de cinco cada uno. Uno de los grupos recibió NeuroEPO intranasal durante 28 días a dosis de 300 µg/ kg. Al otro grupo se le administró vehículo a una razón de 0,3µl /g. Se estudiaron las características histológicas de la mucosa respiratoria. Las medianas de los grupos fueron comparadas mediante la prueba U de Mann-Whitney. Resultados: No se observaron alteraciones en las características histológicas de la mucosa respiratoria, ni del tejido linfático asociado a la mucosa nasal en ratas Wistar, tras la administración de la NeuroEPO. Conclusión: La administración intranasal de NeuroEPO no provoca cambios patológicos sobre la estructura histológica de la mucosa respiratoria ni del tejido linfático asociado a la mucosa nasal de ratas Wistar en nuestras condiciones experimentales.

Reporte de seis casos de eclampsia en un hospital rural de la selva de Chiapas / Six Cases of Reports of Eclampsia in a Rural Hospital from the Chiapas Jungle

Resumen La eclampsia es un síndrome relativamente raro e impredecible de la enfermedad hipertensiva inducida por el embarazo, caracterizado por un estado convulsivo tónico-clónico que puede o no cursar con hipertensión previa o daño orgánico. Complica aproximadamente 3 de cada 1,000 embarazos, con alta incidencia en pacientes de zonas rurales y bajo nivel socioeconómico, mujeres con preeclampsia, primigestas adolescentes y multíparas mayores de 35 años de edad. Presentamos el reporte de 6 casos de eclampsia que sucedieron en un hospital rural del estado de Chiapas, ubicado en el corazón de la Selva Lacandona. La mayoría fueron primigestas adolescentes en trabajo de parto, quienes rebasaban las 40 semanas de gestación. Todas fueron manejadas con medidas de soporte y neuroprotección con sulfato de magnesio, 5 de ellas fueron referidas a segundo nivel a la unidad de cuidados intensivos para recibir una atención integral, con un tiempo promedio de estancia de 2 días. Ninguna presentó un nuevo cuadro convulsivo. No se registraron resultados perinatales adversos ni muerte materna. El síndrome preeclampsia-eclampsia es un problema de alto impacto en el embarazo y un reto para los 3 niveles de atención, pero sobre todo para la atención en el medio rural y zonas indígenas de todo México, ya que, debido a costumbres arraigadas, las pacientes omiten el control prenatal, además de habitar en lugares con difícil acceso a hospitales o clínicas.

Abstract Eclampsia is a relatively rare and unpredictable syndrome of pregnancy-induced hypertensive disease, characterized by a tonic-clonic seizure state which may or may not present hypertension or end-organ damage. It complicates approximately 3 out of 1000 pregnancies, with a high incidence in patients of low socioeconomic status and rural areas, women with pre-eclampsia, primiparous teen or multiparous women over 35 years old. We present the report of 6 cases of eclampsia that occurred in a first level rural hospital of attention in the state of Chiapas, located in the heart of the Lacandon Jungle. Most of them occurred in primiparous teen patients during labor, which exceeded 40 weeks of gestation. All were promptly managed with support measures and magnesium sulfate neuroprotection, 5 of them referred to the second level of the intensive care unit for more comprehensive care, the average length of stay was 2 days. No one presented a new seizure. No adverse perinatal outcomes or maternal death were recorded. The pre-eclampsia-eclampsia syndrome is a problem with a high impact on pregnancy and a challenge for all three levels of care, but especially for care in rural areas and indigenous areas throughout Mexico, since, due to entrenched customs, patients omit prenatal control, in addition to living in places with difficult access to hospitals or clinics.

Niveles plasmáticos de midkina en pacientes con trastorno por uso de cocaína en abstinencia / Plasma midkine levels in patients with cocaine use disorder during abstinence

Diversos estudios preclínicos han sugerido que la midkina endógenapodría jugar un papel modulador clave sobre los efectos neurotóxicosy adictivos de distintas drogas, incluidos los psicoestimulantes. Estahipótesis no ha sido aún explorada en humanos. Como primer pasoen esta dirección, en el presente trabajo hemos medido los nivelesplasmáticos de midkina en 75 pacientes con trastorno por uso decocaína en abstinencia y 26 controles apareados con los anteriorespor sexo, edad e índice de masa corporal. Los pacientes fueronademás divididos en un grupo de abstinencia temprana (menos deun mes, n = 30) y otro de abstinencia tardía (más de un mes, n =45). Se cuantificaron los niveles plasmáticos de midkina de todoslos participantes mediante un ensayo por inmunoabsorción ligadoa enzimas. Los pacientes en abstinencia temprana mostraron unincremento del 60% en su concentración plasmática de midkina conrespecto a los controles que tendió a desaparecer en los pacientes conperiodos de abstinencia más prolongados. Los resultados demuestranque los niveles periféricos de midkina están estrechamenterelacionados con el uso de cocaína y apoyan la idea de que dichacitoquina podría jugar un papel protector limitando la actividadbiológica de los psicoestimulantes. (AU)

Preclinical evidence suggests that endogenous midkine couldplay a key modulatory role on the neurotoxic and addictive effectsof different kinds of drugs of abuse, including psychostimulants.However, this hypothesis has not yet been explored in humans. As afirst approach to progress in this knowledge, we have comparativelystudied plasma midkine levels in 75 patients with cocaine use disorderunder abstinence and 26 control subjects matched for sex, ageand body mass index. Patients were further segmented into earlyabstinent (up to one month of abstinence, n = 30) and late-abstinent(more than one month of abstinence, n = 45). Midkine levels werequantified in plasma samples of all the participants by enzyme-linkedimmunosorbent assays. Early-abstinent patients exhibited a 60%increase of midkine plasma concentration in comparison with thecontrols. This elevation tended to normalize upon the progressionof abstinence. The results obtained demonstrate that peripheralmidkine levels are closely related to cocaine use and are consistentwith the idea that this cytokine could play a protective role by limitingthe biological activity of psychostimulants. (AU)

Salvia miltiorrhiza: una revisión de sus posibilidades terapéuticas / Salvia miltiorrhiza: uma revisão das suas possibilidades terapêuticas / Salvia miltiorrhiza: a review of its therapeutic possibilities

La salvia roja o salvia china, Salvia miltiorrhiza Bunge (Lamiáceas), es una planta perenne originaria de China, conocida como danshen (inglés) o dānshēn (chino). Su raíz, ampliamente utilizada en la medicina oriental, contiene componentes lipofílicos diterpénicos como las tanshinonas, e hidrofílicos, de tipo fenólico, como los ácidos salvianólicos, salviánico A (danshensu), litospérmico y otros. Sus propiedades farmacológicas han sido evaluadas in vivo, in vitro, y en ensayos clínicos, principalmente con extractos, aunque también se ha estudiado el efecto de constituyentes o mezclas concretas de ellos, como el “salvianolato”, que contiene diferentes principios hidrosolubles de la raíz. Uno de los principales problemas en la evaluación del potencial terapéutico de la salvia china es que la mayor parte de estudios clínicos se han realizado con combinaciones de sus preparados o constituyentes con preparados de otros drogas vegetales o incluso fármacos sintéticos. Un elevado número de estudios arrojan resultados prometedores, destacando sus efectos beneficiosos en la enfermedad cardiovascular, infarto de miocardio, angina y aterosclerosis. Además, cabe señalar sus propiedades antiosteoporóticas, antidiabéticas, neuroprotectoras y antitumorales, aunque algunas de ellas solo tienen evidencias preclínicas. Sería deseable incrementar los estudios clínicos con protocolos más acordes con la medicina occidental: el empleo de una única especie botánica, ensayos aleatorizados, doble ciego y controlados con placebo, multicéntricos, y con un mayor número de pacientes. De esta forma, la salvia china podría alcanzar para la fitoterapia europea una consideración similar a la que posee para medicina oriental. (AU)

A salva vermelha ou salva chinesa, Salvia miltiorrhiza Bunge (Lamiáceas), é uma planta perene originária da China, conhecida como dānshēn (inglês) ou dānshēn (chinês). A sua raiz, amplamente utilizada na medicina oriental, contém componentes diterpénicos lipofílicos, como as tanshinonas, e hidrofílicos, do tipo fenólico, como os ácidos salvianólicos, salviánico A (danshensu), litospérmico e outros. As suas propriedades farmacológicas foram avaliadas in vivo, in vitro e em ensaios clínicos, principalmente com extratos, embora também tenha sido estudado o efeito de constituintes específicos ou misturas deles, como o "salvianolato", que contem diferentes princípios hidrossolúveis da raiz. Um dos principais problemas na avaliação do potencial terapêutico da salva chinesa é que a maioria dos estudos clínicos tem sido realizada com associações de preparações ou constituintes de salva com preparações de outros fármacos vegetais ou mesmo fármacos sintéticos. Um grande número de estudos mostra resultados promissores, destacando os seus efeitos benéficos em doenças cardiovasculares, enfarte do miocárdio, angina e aterosclerose. Além disso, destacam-se também propriedades antiosteoporóticas, antidiabéticas, neuroprotectoras e antitumorais, embora algumas delas tenham apenas evidências pré-clínicas. Seria desejável aumentar os estudos com protocolos mais condizentes com a medicina ocidental: o uso de uma única espécie botânica, ensaios randomizados, duplamente-cegos, controlados por placebo, multicêntricos e com maior número de pacientes. Desse modo, a salva chinesa poderia alcançar na fitoterapia europeia uma reputação semelhante à que tem na medicina oriental. (AU)

Danshen, Salvia miltiorrhiza Bunge (Lamiaceae), is a perennial plant native to China, also known as dānshēn in Chinese. Its root, widely used in oriental medicine, contains lipophilic diterpenic constituents such as tanshinones, and hydrophilic constituents, of phenolic type, such as salvianolic acids, as well as salvianic A (danshensu), lithospermic acids and others. Its pharmacological properties have been evaluated in vivo, in vitro, and in clinical trials, mainly with extracts, although the effect of specific constituents or mixtures of them, such as "salvianolate", containing different watersoluble principles of the root, has also been studied. One of the main problems in evaluating the therapeutic potential of danshen is that most clinical studies were carried out with combinations of its preparations or constituents with preparations of other herbal drugs or even synthetic drugs. A large number of studies display promising results, showing beneficial effects in cardiovascular disease, myocardial infarction, angina and atherosclerosis. In addition, it should be noted anti-osteoporotic, antidiabetic, neuroprotective and antitumor properties, although some of them have only preclinical evidence. It would be desirable to perform additional clinical trials with protocols more aligned with Western medicine: using a single botanical species, randomized, double-blinded, placebo-controlled, multicenter, and with a larger number of patients. In this way, danshen could achieve a similar consideration for European herbal medicine as it has for oriental medicine. (AU)

Nuevos sistemas de liberación controlada de sustancias activas de administración intraocular / Novel delivery systems of active substances for intraocular administration

Las patologías neurodegenerativas que afectan al segmento posterior del ojo como la retinopatía diabética, la degeneración macular asociada a la edad y el glaucoma se encuentran entre las principales causas de ceguera en el mundo. Se trata de enfermedades crónicas, multifactoriales y, en determinados casos, relacionadas con la edad. Su tratamiento requiere mantener concentraciones terapéuticas en el segmento posterior, acudiéndose al empleo de inyecciones intraoculares sucesivas que se asocian con efectos secundarios y son mal toleradas por los pacientes. Los sistemas de liberación controlada de sustancias activas de administración intraocular surgen como alternativa a las inyecciones repetidas ya que son capaces de liberar, de forma controlada, el agente medicamentoso en el interior del ojo con una única administración del preparado. Dependiendo del biomaterial con el que se elaboran dichos sistemas pueden ser biodegradables o no biodegradables. Atendiendo a su tamaño se clasifican en implantes (>1mm), microsistemas (1-1000μm) y nanosistemas (1-1000nm). Las microesferas biodegradables son herramientas terapéuticas de gran interés en el tratamiento de patologías neurodegenerativas ya que pueden encapsular sustancias activas de distinta naturaleza y conseguir distintos perfiles de cesión que se adapten a las necesidades clínicas. Además, se puede recurrir a la administración de diferentes cantidades de micropartículas correspondiendo a distintas dosis de las sustancias medicamentosas en una terapia personalizada. La encapsulación simultánea de varias sustancias activas en las microesferas resulta de gran interés en el tratamiento de patologías multifactoriales ya que se pueden abordar distintas dianas terapéuticas.(AU)

Neurodegenerative pathologies affecting the posterior segment of the eye such as diabetic retinopathy, age related macular degeneration and glaucoma are among the main causes of blindness in the world. They have in common that are cronic, multifactorial and in some cases related with the elderly. The treatment of these pathologies require to maintain therapeutic concentrations in the posterior segment thanks to the use of successive intraocular injections which are associated to secondary effects being poor tolerated by patients. Intraocular drug delivery systems emerged as an alternative to frequent injections as they are able to deliver the therapeutic agent in a controlled fashion into the eye after a single administration. Depending on the biomaterial these delivery systems are biodegradable or non biodegradable. Attending to their sizes, drug delivery systems are classified in implants (>1mm), microsystems (1-1000μm) y nanosystems (1-1000nm). Biodegradable microspheres emerge as therapeutic tools of great interest for the treatment of neurodegenerative pathologies as they can encapsulate active substances of distinct nature and provide release profiles tailoring with clinical needs. Furthermore, it is possible to administer different amounts of microspheres which correspond to the most adequated doses of the medicine in a personalized therapy. The simultaneous encapsulation of several active substances in the microspheres are of great interest in the treatment of multifactorial diseases covering different therapeutic targets.(AU)

Ten physiological commandments for severe head injury.

Advances in multiparametric brain monitoring have allowed us to deepen our knowledge of the physiopathology of head injury and how it can be treated using the therapies available today. It is essential to understand and interpret a series of basic physiological and physiopathological principles that, on the one hand, provide an adequate metabolic environment to prevent worsening of the primary brain injury and favour its recovery, and on the other hand, allow therapeutic resources to be individually adapted to the specific needs of the patient. Based on these notions, this article presents a decalogue of the physiological objectives to be achieved in brain injury, together with a series of diagnostic and therapeutic recommendations for achieving these goals. We emphasise the importance of considering and analysing the physiological variables involved in the transport of oxygen to the brain, such as cardiac output and arterial oxygen content, together with their conditioning factors and possible alterations. Special attention is paid to the basic elements of physiological neuroprotection, and we describe the multiple causes of cerebral hypoxia, how to approach them, and how to correct them. We also examine the increase in intracranial pressure as a physiopathological element, focussing on the significance of thoracic and abdominal pressure in the interpretation of intracranial pressure. Treatment of intracranial pressure should be based on a step-wise model, the first stage of which should be based on a physiopathological reflection combined with information on the tomographic lesions rather than on rigid numerical values.

Diez mandamientos fisiológicos a lograr durante el traumatismo craneoencefálico grave / Ten physiological commandments for severe head injury

Los avances en la monitorización cerebral multiparamétrica han permitido ahondar en el conocimiento de la fisiopatología del traumatismo craneoencefálico, y en cómo la terapéutica disponible puede modularla. Para ello, se antoja imprescindible conocer e interpretar una serie de principios fisiológicos y fisiopatológicos básicos que propician, por un lado, un entorno metabólico cerebral adecuado para prevenir un incremento de la lesión cerebral primaria y favorecer su recuperación, y por otro lado, permiten adaptar de forma individualizada los recursos terapéuticos a la situación concreta del paciente. En el presente artículo se exponen, en forma de decálogo, sustentados en dichas nociones, los objetivos fisiológicos a conseguir, junto con una serie de recomendaciones diagnósticas y terapéuticas que posibiliten su logro. Se hace énfasis en la consideración y análisis de las variables fisiológicas implicadas en el transporte de oxígeno al cerebro, como el gasto cardiaco y el contenido arterial de oxígeno, junto con sus condicionantes y las posibles alteraciones de cada uno de ellos. Cobran especial atención los elementos básicos que constituyen la neuroprotección fisiológica. Asimismo, se razonan las múltiples causas que provocan hipoxia cerebral y el modo de abordarlas y corregirlas. El aumento de la presión intracraneal, como elemento fisiopatológico, se examina, subrayándose para interpretarla la interconexión e influencia de la presión torácica y abdominal sobre la intracraneal. El tratamiento de la presión intracraneal debe efectuarse sobre un modelo de acciones escalonadas, cuyo inicio debería cimentarse más que en valores numéricos rígidos, en una reflexión fisiopatológica unida a la información de las lesiones tomográficas.(AU)

Advances in multiparametric brain monitoring have allowed us to deepen our knowledge of the physiopathology of head injury and how it can be treated using the therapies available today. It is essential to understand and interpret a series of basic physiological and physiopathological principles that, on the one hand, provide an adequate metabolic environment to prevent worsening of the primary brain injury and favour its recovery, and on the other hand, allow therapeutic resources to be individually adapted to the specific needs of the patient. Based on these notions, this article presents a decalogue of the physiological objectives to be achieved in brain injury, together with a series of diagnostic and therapeutic recommendations for achieving these goals. We emphasise the importance of considering and analysing the physiological variables involved in the transport of oxygen to the brain, such as cardiac output and arterial oxygen content, together with their conditioning factors and possible alterations. Special attention is paid to the basic elements of physiological neuroprotection, and we describe the multiple causes of cerebral hypoxia, how to approach them, and how to correct them. We also examine the increase in intracranial pressure as a physiopathological element, focussing on the significance of thoracic and abdominal pressure in the interpretation of intracranial pressure. Treatment of intracranial pressure should be based on a step-wise model, the first stage of which should be based on a physiopathological reflection combined with information on the tomographic lesions rather than on rigid numerical values.(AU)