Ketamina eta esketaminaren erabilera depresioerresistentea tratatzeko: etorkizunerako erronkak

Depressive disorders have become one of the major public health problems in recent years, not only because of their impact on quality of life, but also because of the partial response or lack of response to antidepressant treatment. Therefore, the rapid and potent antidepressant effect of (R,S)-ketamine (ketamine) is considered one of the most important psychiatric discoveries of the last decades. Although, intravenous administration of ketamine has prevailed in most clinical trials conducted so far, the intranasal route has been considered a useful and safe alternative. Thus, the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) approved a esketamine nasal spray named Spravato for the use in treatment resistant depression, although clinical trials supporting its marketing are not long-term. In line with this, major long-term safety concerns, such as dependence and cognitive impairment, has not been assessed so far. Therefore, there is an urgent need to investigate the relevance ofrepeated administration protocols on the long-term antidepressant response and safety. In this regard, potential pharmacological interactions between ketamine and some antidepressant drugs and benzodiazepines may impact the antidepressant response. In fact, while in some clinical trials adjunctive antidepressant medication is allowed, in others it is specifically removed, and this pharmacological variability may alter the efficacy of the treatment. Consequently, it is undeniable that in addition to massive long-term clinical trials, post-marketing studies are necessary to ensure the safety and efficacy of long-term ketamine and esketamine use.; Nahasmendu depresiboak osasun publikoko arazo handienetako bat bilakatu dira azken urteotan, ez bakarrik bizi-kalitatean duten eraginagatik, baita tratamendu antidepresiboaren erantzun partzial edo erantzun ezagatik ere. Hori dela eta, (R,S)-ketaminaren (ketamina) efektu antidepresibo azkarra eta eraginkorra azken hamarkadetako aurkikuntza garrantzitsuenen artean dago psikiatria arloan. Orain arteko entseguetan ketaminaren zain barneko bidea gailendu den arren sudur bideko administrazioa aukera erabilgarri eta segurutzat jo da. Hori dela eta, FDAk (Food and Drug Administration) eta EMAk (European Medicines Agency) S-ketamina (esketamina) baimendu dute Spravato izen komertzialarekin merkaturatutako sudur-lainoztagailurako soluzio bezala, depresio erresistentea tratatzeko, farmako horren merkaturatze-baimena sostengatzen duten entsegu klinikoak epe luzekoak ez diren arren. Horregatik, epe luzeko segurtasun-profila ikertzea premiazkoa da, eta, testuinguru berean, baita administrazio-protokolo errepikatuen egokitasuna ere. Izan ere, ketaminak farmako antidepresibo batzuekin eta bentzodiazepinekin izan ditzakeen elkarrekintzak ebaluatzea gomendatzen da, tratamenduaren eragin antidepresiboa baldintza dezaketelako. Ildo horretan, orain arte egindako entseguen diseinuaren aldakortasuna kontuan hartzeko ezaugarria litzatekeela proposatu da. Izan ere, entsegu batzuetan, tratamendu antidepresibo gehigarria baztertzen da, eta beste batzuetan, berriz, mantendu egiten da; aldakortasun metodologiko horrek tratamendu antidepresiboaren eraginkortasuna alda dezake. Ondorioz, uka ezina da epe luzerako entsegu klinikoak egiteaz gain merkaturatze ondorengo farmakozaintza-azterlanak ere nahitaezkoak direla ketaminaren eta esketaminaren segurtasuna eta eraginkortasuna epe luzera bermatzeko

Analysis of Acetylcholinesterase Activity in Cell Membrane Microarrays of Brain Areas as a Screening Tool to Identify Tissue Specific Inhibitors

Acetylcholinesterase (AChE) is responsible for hydrolyzing the acetylcholine neurotransmitter, bringing an end point to cholinergic neurotransmission. Thus, AChE is the primary target of a wide spectrum of compounds used as pesticides, nerve agents or therapeutic drugs for neurodegenerative diseases such as Alzheimer’s disease (AD). This enzyme is heterogeneously distributed in the brain showing different activity depending on the nervous region. Therefore, the aim of this work is to report a novel technology that enables the simultaneous determination of tissue specific AChE activity, as well as the analysis and screening of specific inhibitors, by using cell membrane microarrays. These microarrays were composed of cell membranes, isolated from 41 tissues, organs and brain areas, that were immobilized over a slide, maintaining the functionality of membrane proteins. To validate this platform, demonstrating its usefulness in drug discovery as a high throughput screening tool, a colorimetric protocol to detect the membrane-bound AChE activity was optimized. Thus, rat cortical and striatal AChE activities were estimated in presence of increased concentrations of AChE inhibitors, and the donepezil effect was assessed simultaneously in 41 tissues and organs, demonstrating the major potential of this microarray’s technology.The Spanish Ministry of Economy and Competitiveness (Innpacto program: IPT-2011-1205-010000), and the Basque Government Department of Economic Development, sustainability and environment (Etorgai program: ER-2011/00015, Bikaintek program: 48-AF-W2-2019-7)

Sistema serotonergikoaren eta gongoil basalen arteko elkarrekintza: inplikazio funtzionala eta terapiaren alderdia Parkinsonen gaixotasunean

Serotonina neurotransmisoreak funtzio ezberdinak betetzen ditu informazio-prozesaketaren modulazioan hainbat familiatako hartzaileen aktibazioaren bidez. Hauen artean, erreten ionikoa den hartza ile bat (5-HT3) eta G proteinei lotutako (5-HT1, 5-HT2 , 5-HT4. 7) hartzaileak daude. Neurona serotonergiko gehienak mesentzefaloan kokatuta daude, rafe nukleoetan bereziki . Gongoil basaletara (GB) iristen diren proiekzioak , batez ere dorsal raphe nucleusetik (DRN) heltzen dira. GBak oso ondo antolatuta dauden nukleo subkot1ikalez eratutako sarea da, GB-etako nukleoak striatuma, subthalamic nucleusa (STN), globus pallidusa (barrukoa, GPi eta kanpokoa, GPe) eta substantia nigra (pars compacta, SNc, eta pars reticulata , SNr) direlarik. GBek kontrol motorrean , emozioan eta funtzio kognitiboan parte hartzen dute, eta oso garrantzitsuak dira Parkinsonen Gaixotasunean (PO). Berrikuspen honek serotoninak GBen modulazioan duen funtzioa laburbiltzen du. Bestalde , elkan·ekintza honek PGaren tratamenduan eta L-DOPArebn tratamendu kronikoak eragindako asaldu ra motorretan duen garrantzia eztabaidatzen da

Efficacy of acetylcholinesterase inhibitors on cognitive function in alzheimer’s disease. Review of reviews

Alzheimer’s disease (AD) is the most common form of dementia over the age of 65. It is estimated that 115.4 million people will be affected by AD by 2050. Acetylcholinesterase inhibitors (AChEI) are the only available and approved treatment for AD. The aim of the present study was to analyse the evidence on the efficacy of the AChEI in the treatment of cognitive symptoms of Alzheimer’s disease. For that purpose, a review of review of the systematic reviews (SRs) on this topic was carried out by Web of Science, PubMed, and The Cochrane Library, among others, were searched until 24 September 2021. Thirteen of the 1773 articles evaluated the efficacy of AChEI on cognitive function and/or general condition and/or behavioural disturbances of patients with mild to moderate AD. Methodological quality and risk of bias were rated using the ROBIS scale. The quality of the identified studies was high for nine of them, unclear for two, and finally only in two of the 13 studies did we detect low quality. Overall, AChEI showed very low efficacy in improving cognition in patients with mild to moderate AD. Better results were obtained in improving global state, with donepezil being the most effective treatment. No improvements in behavioural disturbances were found. Few high-quality reviews provide clear evidence of the effects of AChEI on cognition, global change, behaviour, and mortality. The data suggest that AChEI stabilize or slow cognitive deterioration, improving global status. In addition, data indicate that the use of AChEI decreases mortality in patients with mild to moderate AD. However, there is no evidence that they improve patient behaviour. Donepezil is the best therapeutic alternative at a dose of 10 mg/day.This research received no external funding

Strategies to Improve Therapeutic Adherence in Polymedicated Patients over 65 Years: A Systematic Review and Meta-Analysis

Background: Part of the population over 65 years of age suffer from several pathologies and are therefore polymedicated. In this systematic review and metanalysis, we aimed to determine the efficacy of several strategies developed to improve adherence to pharmacological treatment in polymedicated elderly people. Design: Web Of Science, PubMed and the Cochrane Library were searched until 2 January 2024. In total, 17 of the 1508 articles found evaluated the efficacy of interventions to improve adherence to medication in polymedicated elderly patients. Methodological quality and the risk of bias were rated using the Cochrane risk of bias tool. Open Meta Analyst® software was used to create forest plots of the meta-analysis. Results: In 11 of the 17 studies, an improvement in adherence was observed through the use of different measurement tools and sometimes in combination. The most frequently used strategy was using instructions and counselling, always in combination, in a single strategy used to improve adherence; one involved the use of medication packs and the other patient follow-up. In both cases, the results in improving adherence were positive. Five studies using follow-up interventions via visits and phone calls showed improved adherence on the Morisky Green scale compared to those where usual care was received [OR = 1.900; 95% CI = 1.104–3.270] (p = 0.021). Discussion: There is a high degree of heterogeneity in the studies analyzed, both in the interventions used and in the measurement tools for improving adherence to treatment. Therefore, we cannot make conclusions about the most efficacious strategy to improve medication adherence in polymedicated elderly patients until more evidence of single-intervention strategies is available

Papel de los receptores mu-opioides del locus coeruleus en el síndrome de abstinencia de morfina en un modelo animal de dolor neuropático

Resumen del trabajo presentado al XIII Congreso de la Sociedad Española del Dolor, celebrado en Pamplona del 2 al 4 de junio de 2016.[Introducción]: El uso de opioides para el tratamiento del dolor crónico está limitado debido a las altas dosis requeridas que llevan a estados de dependencia y tolerancia mediados por los receptores mu-opioides (MOP). Un área implicada en la regulación del dolor y la dependencia física a opioides con una alta expresión de MOP es el locus coeruleus (LC). El presente trabajo plantea que el dolor crónico produciría alteraciones funcionales de los MOP en el LC que tendrían como consecuencia una mejoría en los síntomas adversos del tratamiento crónico de morfina. [Objetivos]: Evaluar el papel de los MOP del LC antes y después del tratamiento crónico de morfina, así como los síntomas físicos del síndrome de abstinencia en un modelo animal de dolor neuropático. [Material y método]: La constricción del nervio ciático de ratas se usó como modelo de dolor neuropático, 7 y 30 días tras la cirugía. Estudios comportamentales, electrofisiológicos, actividad AMPc-Adenilato ciclasa, inmunohistoquímicos y western blot fueron realizados antes y después del tratamiento crónico de morfina. Se usó el análisis de la varianza (ANOVA) de uno o dos factores ó t-Student (± EEM,p<0.05). [Resultados]: Los animales CCI30d mostraron un aumento significativo en los niveles de cFOS (14.33±2.35,p<0.05), pCREB (122.9±6.35,p<0.05) y MOP (9.60±1.38,p<0.01) del LC. Además, una mayor sensibilidad de los MOP en las curvas dosis-respuesta de morfina (ED50: 0.58±0.12,p<0.05), una rápida desensibilización en presencia de Met-encefalina (54.61%±5.88,p<0.05) y una pérdida de actividad adenilato ciclasa inducida por forskolina en presencia de DAMGO (94.60%±4.10,p<0.05) fue observada. Tras la precipitación del síndrome de abstinencia, una mayor incidencia de la actividad en burst fue observada en los animales sham (87.50%,p0.05). Además, en presencia de Met-encefalina el porcentaje de desensibilización fue aumentado en los animales sham (50.55%±4.05,p>0.05) pero no hubo cambios en los animales CCI30d (54.96%±2.40,p>0.05). Adicionalmente, síntomas físicos típicos del síndrome de abstinencia fueron menos evidente en los animales CCI30d, que se correlacionaron con una menor expresión de cFOS (11.96±3.30,p<0.01) en el LC. [Conclusiones]: El dolor neuropático a largo plazo induce cambios en la expresión de los MOP y proteínas de la vía de señalización opioide-AMPc-CREB del LC, dando lugar un menor síndrome de abstinencia tras el tratamiento crónico de morfina.Instituto de Salud Carlos III, FEDER, CIBERSAM (G18), PI12/00915, CTS-510, CTS- 7748, Ministerio de Economía y Competitividad (SAF2015-68647-R), 2015 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, Cátedra Externa del Dolor-Grünenthal-Universidad de Cádiz, Fundación Española del Dolor (PI2015-FED-007).Peer Reviewe

Opioid Activity in the Locus Coeruleus Is Modulated by Chronic Neuropathic Pain

Pain affects both sensory and emotional aversive responses, often provoking depression and anxiety-related conditions when it becomes chronic. As the opioid receptors in the locus coeruleus (LC) have been implicated in pain, stress responses, and opioid drug effects, we explored the modifications to LC opioid neurotransmission in a chronic constriction injury (CCI) model of short- and long-term neuropathic pain (7 and 30 days after nerve injury). No significant changes were found after short-term CCI, yet after 30 days, CCI provoked an up-regulation of cAMP (cyclic 5′-adenosine monophosphate), pCREB (phosphorylated cAMP response element binding protein), protein kinase A, tyrosine hydroxylase, and electrical activity in the LC, as well as enhanced c-Fos expression. Acute mu opioid receptor desensitization was more intense in these animals, measured as the decline of the peak current caused by [Met5]-enkephalin and the reduction of forskolin-stimulated cAMP produced in response to DAMGO. Sustained morphine treatment did not markedly modify certain LC parameters in CCI-30d animals, such as [Met5]-enkephalin-induced potassium outward currents or burst activity and c-Fos rebound after naloxone precipitation, which may limit the development of some typical opioid drug-related adaptations. However, other phenomena were impaired by long-term CCI, including the reduction in forskolin-stimulated cAMP accumulation by DAMGO after naloxone precipitation in morphine dependent animals. Overall, this study suggests that long-term CCI leads to changes at the LC level that may contribute to the anxiodepressive phenotype that develops in these animals. Furthermore, opioid drugs produce complex adaptations in the LC in this model of chronic neuropathic pain.This work was supported by Spain’s Ministerio de Economía y Competitividad, co-financed by “Fondo Europeo de Desarrollo Regional” FEDER “A way to build Europe” (SAF2015-68647-R, SAF2011-25020); the “Centro de Investigación Biomédica en Red de Salud Mental-CIBERSAM” (Spain, G18); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510, CTS-7748); the Basque Government (IT 747-13); “Fundación Progreso y Salud de la Junta de Andalucía (PI-0080-2017); Fundación Española del Dolor (PI2015-FED-007); and a 2015 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (NARSAD 23982)

Multidisciplinary approach and social diffusion of a health problem

La universidad debe ser capaz de formar profesionales preparados para afrontar desafíos que requieran un abordaje multidisciplinar, así como para transmitir de forma clara y comprensible problemas sanitarios de interés para la sociedad, por ejemplo, mediante el uso de redes sociales. Este trabajo planteó un escenario complejo dentro del ámbito sanitario, como es el uso racional de los antibióticos, para que equipos multidisciplinares de alumnado de distintos grados reflexionaran de manera conjunta sobre diversas cuestiones. Como resultado, el alumnado desarrolló un blog que reflejaba las soluciones a los escenarios planteados relacionados con el tema, utilizando un lenguaje divulgativo para conseguir la concienciación de la ciudadanía sobre este problema no solo sanitario sino también ambiental. La evaluación de esta actividad fue altamente satisfactoria tanto en lo relativo a la propia elaboración del blog (máxima puntuación en 7 de los 9 ítems evaluados) así como en la pregunta de respuesta individual incluida en el examen final (96% del alumnado consiguió la máxima calificación) o en la defensa oral de su trabajo (100% del alumnado consiguió la máxima calificación). De esta manera, el alumnado tomó conciencia de la importancia del trabajo multidisciplinar, así como de la difusión del conocimiento adquirido. Además, se consiguió trabajar y evaluar competencias tanto específicas como transversales adquiridas en los diferentes Grados.The university must be able to train professionals prepared to face challenges that require a multidisciplinary approach, as well as to transmit health problems of interest to society in a clear and understandable way, for example, through the use of social networks. This work posed a complex scenario within the health field, such as the rational use of antibiotics, for multidisciplinary teams of students from different degrees to reflect together on various issues. As a result, the students developed a blog that reflected the solutions to the scenarios raised related to the topic, using an informative language to raise public awareness of this problem, not only health but also environmental. The evaluation of this activity was highly satisfactory both in terms of the development of the blog itself (maximum score in 7 of the 9 items evaluated) as well as in the individual response question included in the final exam (96% of the students obtained the maximum score) or in the oral defense of their work (100% of the students obtained the maximum score). In this way, students became aware of the importance of multidisciplinary work, as well as of the dissemination of the knowledge acquired. In addition, it was possible to work and evaluate both specific and transversal competencies acquired in the different Degrees