Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model.

BACKGROUND: Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. METHODS: An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p < 0.05). RESULTS: Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-ß levels versus non-induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p = 0.001) and TGF-ß (p = 0.008), and no difference in TNF-α levels versus Sham non-induced controls. CONCLUSION: Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.

Identification of Potentially Repurposable Drugs for Lewy Body Dementia Using a Network-Based Approach.

The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson's disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.

The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease.

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

Utilidad farmacoclínica de los antidepresivos ISRS en la impulsividad y la agresividad / Utility of SSRI antidepressants in the treatment of impulsivity and aggression

Introducción: Estudios preliminares sobre neurobiología de la agresividad impulsiva destacaron el papel de la serotonina para inhibir la conducta violenta que se relacionaría con la impulsividad, pero no con la agresividad. En el ámbito carcelario las conductas agresivas e impulsivas presentan una alta prevalencia y requieren su abordaje por el equipo interdisciplinario de Salud Mental. Objetivos: Determinar la utilidad farmacoclínica de antidepresivos ISRS en el tratamiento de la impulsividad y la agresividad, y sus especificidades clínicas y poblacionales. Material y Método: Estudio observacional y transversal mediante evaluación de historias clínicas de 104 masculinos con pena privativa de la libertad. Se evaluaron psicopatológicamente y se valoraron los resultados obtenidos en 4 escalas de seguimiento clínico para impulsividad y agresividad. Al subgrupo con resultado positivo en al menos 2 escalas y en la evaluación clínica (n=30) se les indicó un ISRS (paroxetina o sertralina) a su plan farmacológico y se los reevaluaron en 2 tiempos posteriores. Se aplicaron parámetros estadísticos y se cumplimentó con requisitos ético-legales. Resultados: Al analizar las subescalas de la ABS hallamos que el parámetro de agresividad y el de desinhibición fueron los que más respondieron de forma significativa (25.96%, 21.43%; p<0.01). El análisis de la escala IRS arrojó que las subescalas de tiempo para toma de decisiones y de capacidad para diferir disminuyeron significativamente (p<0.01), mientras que la de agresividad y de paciencia/impaciencia tuvieron menor significación estadística (p<0.05). Conclusiones: Los inhibidores selectivos de recaptación de serotonina tienen eficacia y utilidad clínica en el tratamiento de pacientes con comportamientos impulsivo-agresivos con particularidades asociadas a otros fármacos, diagnóstico psicopatológico y tipo de agresividad.

Introduction: Preliminary Studies on neurobiology of impulsive aggression highlighted the role of serotonin to inhibit violent behavior that would be related to impulsivity, but not aggressive. In prisons, aggressive and impulsive behaviors have a high prevalence and require interdisciplinary team approach for Mental Health. Objectives: To determine the utility of SSRI antidepressants in the treatment of impulsivity and aggression, and its clinical and population specific. Material and method: Observational and transversal study through evaluation of medical records of 104 men in prision. Psychiatrically evaluated and the results obtained in four scales for clinical follow-up were evaluated impulsivity and aggressiveness. The subgroup with a positive result in at least 2 scales and clinical evaluation (n = 30) were prescribed an SSRI (paroxetine or ser traline) to your drug plan and the re-evaluated in two later times. Statistical parameters were applied and complied with ethical and legal requirements. Results: to analyze ABS ́s subscales we found that aggressiveness and disinhibition settings were the ones that responded significantly (25.96%, 21.43%; p<0.01). The analysis of the IRS scale showed that time for decision making scale and ability to differ subscales decreased significantly (p<0.01), while aggressiveness and patience/impatience ones had less statistical significance. Conclusions: Selective serotonin reuptake inhibitors have clinical utility and effectiveness in the treatment of patients with impulsive-aggressive behavior associated with drugs other particularities, psychopathological diagnosis and aggressive type

Cardiopulmonary parameters in propofol- or thiopental-anesthetized dogs induced to pulmonary hypertension by serotonin / Parâmetros cardiopulmonares em cães anestesiados com propofol ou tiopental e induzidos à hipertensão pulmonar pela serotonina

The cardiopulmonary changes in propofol- or thiopental-anesthetized dogs induced to pulmonary hypertension (PH) were evaluated. Twenty adult animals were randomly assigned to two groups: propofol group (PG) and thiopental group (TG). In PG, propofol was used for induction (8(0.03mg.kg-1) and anesthesia maintenance (0.8mg.kg-1.minute-1), while, in TG, thiopental was used (22±2.92mg.kg-1; 0.5mg.kg-1.minute-1, respectively). Mechanical ventilation using time cycle was started. PH was induced by administration of serotonin (5HT) (10µg.kg-1 and 1mg.kg-1.hour-1) through a thermodilution catheter positioned in the pulmonary artery. The measurements were performed before administration of 5HT (T0), after 30 minutes (T30), then at 15-minute intervals (T45, T60, T75 and T90). No differences between groups were registered for systolic (sPAP) and mean pulmonary arterial pressure (mPAP), mean arterial pressure (MAP), total peripheral resistance index (TPRI) and pulmonary vascular resistance index (PVRI). In PG, sPAP and mPAP increased from T30. While in TG, sPAP and mPAP increased from T75. In PG, heart rate (HR) increased from T30, in which PG was higher than TG. The TPRI values decreased from T30 in PG, and in TG, at T45, T60 and T90. In PG, at T0, PVRI was lower than at other times. In PG, arterial partial pressures of oxygen (PaO2) decreased from T60 and alveolar-arterial oxygen gradient (PA-aO2) increased at T60. In TG, at T0 PaO2 was higher than at T30, T45, T60 and T90, while PA-aO2 at T0 was lower than at T90. From T30 to T90, TG showed higher PaO2 means and lower arterial partial pressures of carbon dioxide (PaCO2) values when compared to PG. In PG, from T30, PaCO2 increased, while in TG this parameter was stable. In conclusion, thiopental anesthesia attenuated the cardiopulmonary changes resulting from serotonin-induced PH, probably by attenuation of vasoconstriction and bronchoconstriction.

Avaliaram-se as alterações cardiopulmonares em cães anestesiados com propofol ou tiopental induzidos à hipertensão pulmonar (HP). Vinte animais adultos foram distribuídos aleatoriamente em dois grupos: grupo propofol (PG) e grupo tiopental (TG). No PG, o propofol foi usado para indução (8(0,03mg.kg-1) e manutenção da anestesia (0,8mg.kg-1minuto-1), enquanto no TG foi empregado o tiopental (22(2,92mg.kg-1; 0,5mg.kg-1.minute-1, respectivamente). Em seguida, a ventilação mecânica ciclada a tempo foi iniciada. A HP foi induzida pela administração de serotonina (5HT) (10µg.kg-1e 1mg.kg-1.hour-1) por meio de cateter de termodiluição posicionado na artéria pulmonar. As mensurações tiveram início antes da administração da 5HT (T0), depois de 30 minutos (T30), seguida de intervalos de 15 minutos (T45, T60, T75 e T90). Diferenças entre os grupos não foram registradas para pressões sistólica (PAPs) e média (PAPm) da artéria pulmonar, pressão arterial média (PAM), índices da resistência periférica total (IRPT) e da resistência vascular pulmonar (IRVP). A PAPs e a PAPm aumentaram a partir de T30, no PG, e a partir de T75, no TG. No PG, a frequência cardíaca (FC) aumentou a partir de T30, no qual PG foi maior que TG. O IRPT diminuiu no T45, T60 e T90, no TG, e a partir de T30 no PG. No PG, no T0, IRVP foi menor que nos outros momentos. No PG, a pressão parcial de oxigênio no sangue arterial (PaO2) diminuiu a partir de T60, e a diferença de tensão entre o oxigênio alveolar e arterial (PA-aO2) aumentou no T60. No TG, no T0, a PaO2 foi maior que no T30, T45, T60 e T90, enquanto a PA-aO2,, no T0, foi menor que no T90. Entre T30 e T90, TG apresentou maior PaO2 e menor pressão parcial de dióxido de carbono no sangue arterial (PaCO2) quando comparado ao PG. No PG, a partir de T30, a PaCO2 aumentou. A anestesia com tiopental abrandou as mudanças cardiopulmonares resultantes da indução da HP pela serotonina, provavelmente devido à atenuação da vasoconstrição e broncoconstrição.

Eficacia y utilidad clínica de los tratamientos para las víctimas adultas de atentados terroristas: una revisión Sistemática / Efficacy and clinical utility (effectiveness) of treatments for adult victims of terrorist attacks: a systematic review

Se presenta una revisión sobre la eficacia y utilidad clinica de los tratamientos para los trastornos mentales en victimas adultas del terrorismo. Una busqueda en PsycINFO, PILOTS y MEDLINE encontro ocho estudios, todos sobre el trastorno por estres postraumatico (TEPT): siete sobre la terapia cognitivo conductual centrada en el trauma y uno sobre la de exposicion en combinación con un inhibidor selectivo de la recaptacion de serotonina, pero ninguno sobre otros farmacos, otras terapias psicologicas no cognitivo conductuales u otros trastornos mentales. Los resultados sugieren que: (a) la terapia cognitivo conductual centrada en el trauma no solo es eficaz y util en la practica clínica para el tratamiento del TEPT en victimas adultas del terrorismo, sino actualmente la terapia de eleccion y (b) la investigacion futura deberia desarrollar, adaptar y probar tratamientos para los otros trastornos mentales que pueden sufrir las victimas del terrorismo (p. ej., trastornos depresivos y de ansiedad, duelo complicado) y para las victimas de los paises no desarrollados y no occidentales que son los que sufren en mayor medida el terrorismo

A review of the efficacy and clinical utility (effectiveness) of the treatments for mental disorders in adult victims of terrorism is presented. A search in PsycINFO, PILOTS and MEDLINE found eight studies, all of them on posttraumatic stress disorder (PTSD): seven on trauma-focused cognitive-behavioral therapy and one on exposure therapy in combination with a selective inhibitor of serotonin reuptake, but none on other medications, other non-cognitive-behavioral psychological therapies or other mental disorders. The results of this review suggest that: (a) trauma-focused cognitive behavioral therapy is not only efficacious and useful in clinical practice for the treatment of PTSD in victims of terrorism, but also currently the therapy of choice, and (b) future research should develop, adapt and test treatments for other mental disorders that victims of terrorism may suffer from (e.g., depressive and anxiety disorders, complicated grief) and for victims of non-developed, non-Western countries that are the countries that suffer most from terrorism

Fibromialgia: princípios práticos que auxiliam na indicação e no ajuste do tratamento medicamentoso / Fibromyalgia: practical principles that help in the indication and adjustment of drug treatment

A fibromialgia (FM) é uma síndrome de dor difusa crônica acompanhada de sintomas somáticos, tais como fadiga, transtornos do humor, do sono e da cognição. Em uma abordagem prática do paciente com FM, além das medidas não farmacológicas, cada sintoma pode ser tratado com medicamento específico. O objetivo deste artigo é prover revisão atualizada da literatura sobre os principais medicamentos atualmente disponíveis no Brasil para o tratamento da FM em adultos. O sucesso terapêutico da FM depende, essencialmente, do uso racional de medicamentos voltados para os sintomas refratários às medidas não farmacológicas.

Fibromyalgia (FM) is the chronic widespread pain syndrome associated with fatigue, mood, sleep and cognitive disorders. Besides non-pharmacological approach, each symptom should be treated with a specific drug. The goal of this study is to provide up-to-date literature review on main aspects of adult FM drugs available for use in Brazil. Treatment success in FM depends essentially on using drugs based on symptoms that are not responsive to non-pharmacological approach.

A potential role of the 5-HTTLPR polymorphism in self-reported executive functioning

Intense effort is directed toward searching for associations between genes and neuropsychological measures of executive functions. In contrast, the impact of genetic polymorphisms on self-rating of everyday executive functioning has not been investigated so far. This study was designed to test associations of self-reported executive functioning, measured with the Behavior Rating Inventory of Executive Function (BRIEF-A), with dopaminergic and serotoninergic genes in non-clinical population and to assess impact of neuropsychological and personality characteristics on these associations. One hundred healthy adults completed the BRIEF-A, personality inventories SPQ-74, STAI, MMPI, and neuropsychological tests for executive functions. Polymorphisms in the DRD4, COMT, DRD2, HTR2A, and SLC6A4 genes were genotyped. We revealed a significant main effect of the SLC6A4’s 5-HTTLPR polymorphism on BRIEF-A scores (F = 2.21, P = .018, η2 = .24). Among the BRIEF-A measures, the genotype effect was significant for the Plan/Organize (F = 7.34, P = .008, η2 = .07) and Task Monitor scales (F = 4.33, P = .04, η2 = .04), and the Metacognition index (F = 4.21, P = .043, η2 = .04). Carriers of the short allele reported fewer problems than homozygotes for the long allele. Correlations of the BRIEF-A measures with neuropsychological variables were weak, while those with personality characteristics were strong, with trait anxiety being the most powerful predictor of the BRIEF-A scores. However, the relationship between the 5-HTTLPR and BRIEF-A scores remained significant when trait anxiety was controlled for. The results suggest a potential role of the 5-HTTLPR in self-reported everyday task planning and monitoring (AU)

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La esencia del temblor esencial: bases neuroquímicas / The essence of essential tremor: neurochemical bases

Introducción. El temblor esencial es el trastorno del movimiento más frecuente en el adulto. Se ha considerado una enfermedad benigna, pero puede ocasionar una importante discapacidad física y psicosocial. El tratamiento farmacológico sigue siendo poco satisfactorio. Su etiología, fisiopatología y anatomía siguen sin conocerse del todo. Objetivo. El conocimiento de las bases neuroquímicas es fundamental para el desarrollo de terapias más eficaces. Se revisan los conocimientos actuales en este campo a fin de incentivar nuevas investigaciones e ideas que permitan mejorar la comprensión de la enfermedad y que fomenten el desarrollo de nuevas terapias farmacológicas. Desarrollo. Se revisan los trabajos realizados hasta la fecha en humanos y en modelos animales de neurotransmisores (ácido gamma-aminobutírico, glutamato, noradrenalina, serotonina, adenosina), proteínas y otros fenómenos neuroquí- micos, como los canales de calcio de tipo T en el temblor esencial. Conclusiones. Se han descrito cuatro disfunciones neuroquímicas que acontecerían básicamente en el cerebelo y el núcleo olivar inferior: alteración del sistema gabérgico, aumento del rebote postinhibitorio mediante corrientes de calcio de tipo T, disminución de los mecanismos de inhibición neuronal y aumento de la actividad de los neurotransmisores excitatorios. Estas disfunciones neuroquímicas comportarían un aumento de la actividad de las neuronas profundas cerebelosas con actividad oscilatoria, que se trasladaría al núcleo del tálamo y a la corteza motora, y comportarían la aparición del temblor. Son necesarios nuevos estudios para poder confirmar estas hipótesis y seguir avanzando para conseguir tratamientos farmacológicos más eficaces para los pacientes con temblor esencial (AU)

Introduction. Essential tremor is the most frequent movement disorder in adults. It has been considered a benign disease, but can result in significant physical and psychosocial disability. Pharmacological treatment is still not very satisfactory. Its causation, pathophysiology and anatomy remain only partially understood. Aims. An understanding of its neurochemical basis is essential to be able to develop more efficient therapies. We review what is currently known in this field in order to motivate further research and ideas that allow an enhanced understanding of the disease and which foster the development of new pharmacological therapies. Development. We review the studies conducted to date in humans and in animal models of neurotransmitters (gammaaminobutyric acid, glutamate, noradrenalin, serotonin, adenosine), proteins and other neurochemical phenomena, such as T-type calcium channels, in essential tremor. Conclusions. Four neurochemical dysfunctions have been described that basically occur in the cerebellum and the inferior olivary nucleus: alteration of the GABAergic system, increased post-inhibitory rebound via T-type calcium currents, decreased neuronal inhibition mechanisms and an increase in excitatory neurotransmitter activity. These neurochemical dysfunctions would involve an increase in the activity of the deep neurons of the cerebellum with an oscillatory activity that would shift to the thalamic nucleus and the motor cortex, which in turn would lead to the appearance of tremor. Further research is needed to be able to confirm these hypotheses and to continue to advance towards achieving more efficient pharmacological treatments for patients with essential tremor (AU)

Interacción de los receptores NMDA - 5-HT6 en la investigación preclínica de las alteraciones cognitivas relacionadas con la esquizofrenia / Interaction of nmda AND 5-HT6 receptors in the preclinical investigation of schizophrenia-related cognitive changes

Diversos antagonistas del receptor N-metil-D-aspartato (RNMDA) como la fenciclidina o la ketamina estudiados en roedores han permitido inducir alteraciones cognitivas similares a las observadas en la esquizofrenia. Casualmente, uno de los receptores a serotonina, el 5-HT6, ha cobrado interés en la búsqueda de nuevos fármacos con propiedades procognitivas. Con la finalidad de comprender mejor la interacción de ambos receptores (NMDA y 5-HT6) en la regulación cognitiva se realizó una revisión exhaustiva en la literatura. Varios estudios con esquemas agudos o subcrónicos de los antagonistas NMDA en roedores fueron evaluados en distintas pruebas, en donde se encontró deterioro cognitivo. Fue común que el esquema agudo de diversos fármacos serotoninérgicos 5-HT6 revirtiera el deterioro cognitivo inducido por la administración previa de los antagonistas del RNMDA. Por el contrario y sorprendentemente, la inyección aguda y combinada tanto de los antagonistas NMDA como de los fármacos serotoninérgicos 5-HT6 lograron fortalecer la memoria. El esquema subcrónico de los antagonistas NMDA representa el modelo más integrador para el estudio de las alteraciones cognitivas asociadas a la esquizofrenia. Aunque el deterioro y el efecto procognitivo mediados por estos receptores pudieran ser explicados mediante la regulación conjunta que ejercen ambos receptores sobre la liberación de distintos neurotransmisores como el glutamato, es una situación compleja que se requiere continuar investigando para fundamentar mejor estas ideas (AU)

Diverse antagonists of the NMDA receptor studied in rodents, such as phencyclidine or ketamine, have enabled researchers to induce cognitive changes similar to those found in schizophrenia. Interestingly, one of the serotonin receptors, 5-HT6, has attracted much attention for the development of new drugs with pro-cognitive properties. With the aim of better understanding the interaction of both NMDA and 5-HT6 in cognitive regulation, an exhaustive review of the literature was carried out. Various studies have found cognitive impairment, evaluated in rodents using different tests, after applying acute or sub-chronic schemes of NMDA antagonists. An acute scheme of applying different serotogenic 5-HT6 receptors has often reversed the cognitive impairment induced by the previous administration of NMDA antagonists. Surprisingly, an acute injection of a combination of suboptimal doses of NMDA and 5-HT6 antagonists resulted in strengthening memory. The sub-chronic scheme of NMDA antagonists represents the most reliable model for the study of cognitive changes associated with schizophrenia. Cognitive impairment, as well as a pro-cognitive effect mediated by NMDA and 5-HT6, may be explained by a joint regulation of these receptors to modulate the release of distinct neurotransmitters, such as glutamate. This represents a complex interaction that requires ongoing research to clarify the mechanisms at play (AU)

Estimulación cerebral para el trastorno obsesivo-compulsivo resistente a tratamiento médico / Deep brain stimulation for drug-resistant obsessive-compulsive disorder

Aproximadamente un 10% de los pacientes con trastorno obsesivo-compulsivo tienen formas crónicas muy incapacitantes de la enfermedad, resistentes a las terapias conservadoras actuales, lo que conlleva un deterioro significativo para su calidad de vida y altas tasas de suicidio. Para estos pacientes se dispone de nuevas terapias efectivas mediante tratamiento neuroquirúrgico. A continuación revisamos de forma exhaustiva las técnicas neuroquirúrgicas actuales y las tasas de remisión y efectos adversos, con sus aspectos metodológicos fundamentales. La realización de pequeñas lesiones en dianas específicas del circuito límbico, como la cingulotomía, la capsulotomía, la tractotomía subcaudada o la leucotomía límbica, está siendo sustituida por la estimulación cerebral profunda mediante electrodos en estas dianas, lo que permite efectuar una terapia reversible y adaptable a las necesidades del paciente. Además, el desarrollo de la neuroimagen y el mejor conocimiento de los circuitos cerebrales han permitido la identificación de nuevas dianas para la neuroestimulación en este trastorno, con buenos resultados. La investigación debe continuar progresando para mejorar el tratamiento de los pacientes con trastorno obsesivo-compulsivo resistente (AU)

Approximately 10% of patients with obsessive-compulsive disorder have very disabling chronic forms of the disease, which are resistant to all current conservative therapies. These patients experience a significant deterioration in their quality of life and high rates of suicide. The development of new effective neurosurgical treatments has led to an improvement in a significant percentage of patients that would otherwise have remained severely disabled. We comprehensively review remission rates, adverse effects and fundamental methodological aspects of the current neurosurgical techniques for medication resistant obsessive-compulsive disorder. The making of small lesions in specific targets of the limbic circuit, such as cingulotomy, capsulotomy, limbic leucotomy and subcaudate tractotomy, is being replaced by deep brain stimulation through electrodes located in these targets, which is reversible and adaptable to every patient's need. Furthermore, the development of neuroimaging techniques and a better understanding of brain circuits in the last decades, have allowed the identification of new targets for neurostimulation in this disorder, with good results. Research must continue in order to help in the treatment of medication-resistant obsessive-compulsive disorder (AU)

Análisis de las intoxicaciones por litio ingresadas en un servicio de medicina interna / Analysis of the poisoning by lithium in a department of internal medicine

Introducción: El litio, utilizado principalmente en el tratamiento de los trastornos bipolares, presenta un estrecho margen terapéutico, que junto a sus múltiples interacciones y farmacocinética obliga a una monitorización estrecha de concentraciones plasmáticas para evitar intoxicaciones. Objetivo: Describir características clínicas y toxicológicas de los pacientes ingresados en la Unidad Toxicología Clínica (2003-2006). Material y métodos: Estudio descriptivo y retrospectivo de 16 intoxicaciones por litio, de 150 pacientes ingresados entre los años 2003-2006. Se han utilizado dos escalas: según la clínica y los valores séricos de litio. Resultados: Dieciséis pacientes incluidos (58,3 mujeres y 43,8% hombres, 49,19 ± 18,49 años). Trastorno psiquiátrico más frecuente asociado bipolar (87,5%). Causa más frecuente de intoxicación, intento autolisis (56,3%). Según escala neurológica, 50% intoxicación moderada, 25% leve y grave o muy grave el 25% restante. En relación a los niveles de litemia, 31,35% muy grave, 25% graves, 43.7 % leve-moderado.Tratamiento más utilizado en un 50% conservador, hemodiálisis 37,5%, estancia media 4,8 días en intoxicaciones aguda, y 11,2 días en crónicas. Secuelas sólo en dos pacientes (ataxia), sin ninguna muerte. Conclusiones: Las intoxicaciones por litio conllevan gravedad clínica, complicaciones y graves secuelas, incluso la muerte. Se recomienda vigilancia estrecha en pacientes polimedicados, edad avanzada o en tratamiento concomitante de antidepresivos y neurolépticos

Introduction: Lithium salts have been mainly used in the treatment of bipolar disorder. Because of its narrow therapeutic range, and several well characterised adverse effects, serum lithium levels must be monitored regularly in patients given lithium treatment in order to prevent intoxication. Objetive: To describe the clinic and toxic characteristics in inpatients at our Clinic Toxicologic Unit. Material and methods: Descriptive and retrospective study of lithium intoxications in 150 inpatients between 2003 and 2006. Patients were classified based on their neuropsychiathric symptom profile and serum lithium levels. Results: Sixteen of 150 inpatients had lithium intoxication: 58.3% women and 43.8% men; 49.19% ± 18.49% years old. Lithium was used as treatment of bipolar disorder in 87.5% of cases. The most frequent cause of intoxication was attempted suicide. Using neuropsychiatric parametres, intoxication was moderate in 50% of cases, and mild in 25% and severe or very severe in 25%. Using serum lithium levels, intoxication was very severe in 31.35%, severe in 25%, and slight-moderate in 43.7%. Conservative measures were used as the most frequent treatment (50%), and haemodial filtration was needed in 37.5%. Mean stay was 4,8 days in acute intoxication, and 11.2 days in chronic. Sequelaes were found in two patients (ataxia). Death was not present. Conclusions: Lithium intoxications can involve severe complications, even death. Narrow control is encouraged in polymedicated and elderly patients, and in concommitant treatment with antidepressant and neuroleptics

Estresse, depressäo e hipocampo / Stress, depression and the hippocampus

A exposiçäo a fatores estressantes tem papel importante no desenvolvimento de transtornos depressivos. Os mecanismos envolvidos nesta relaçäo, no entanto, ainda säo pouco conhecidos, mas algumas evidências sugerem a participaçäo da formaçäo hipocampal: 1. o estresse pode causar alteraçöes plásticas no hipocampo, que incluem remodelaçäo dendrítica e inibiçäo de neurogênese. Drogas antidepressivas impendem estes efeitos, possivelmente por aumentarem a expressäo de fatores neurotróficos; 2. a facilitaçäo da neurotransmissäo serotoninérgica no hipocampo atenua conseqüências comportamentais do estresse e produz efeitos antidepressivos em modelos animais; 3. o antagonismo do principal neurotransmissor excitatório no hipocampo, o glutamato, produz efeitos semelhantes; 4. o hipocampo parece estar "hiperativo" em animais mais sensíveis em modelos de depressäo e em humanos resistentes à antidepressivos; 5. o hipocampo, em conjunto com o complexo amigdalar, parece ter papel fundamental na consolidaçäo e evocaçäo de memórias aversivas. Näo obstante estas evidências, o desafio futuro será o de tentar integrar os resultados destes diferentes campos (farmacológico, molecular, eletrofisiológico, clínico) em uma teoria unificadora sobre o papel do hipocampo na regulaçäo do humor e seus transtornos bem como nos efeitos de tratamentos antidepressivos

Que pena, há algo além da serotonina? / What a pity, is there something beyond serotonin?

O autor faz uma introdução focalizando a importância dos movimentos de influência psicológica e biológica, assim como da psiquiatria dinâmica nos últimos cem anos. A seguir, discorre sobre alguns novos conhecimentos, suas vantagens, desvantagens e conseqüências, acrescentando como a psicoterapia de orientação analítica pode modificar a conexão dos neurônios e assim alterar a constituição da mente. Alguns percalços são citados, como o da existência dos pacientes e de suas idiossincrasias. São feitas algumas considerações sobre o vínculo, a transferência e a contratransferência, concluindo que a verdade não é parcial, mas está na integração e nas diferentes perspectivas possíveis, seja da pessoa doente, seja do ser no mundo (AU)

Resposta neuroendócrina aguda ao citalopram e resposta terapêutica no transtorno obsessivo-complusivo / Acute neuroendocrine response to citalopram and therapeutic response in obsessive-compulsive disorder

Testes provocativos com drogas serotonérgicas mostraram resultados conflitantes no TOC. O objetivo deste estudo foi comparar a atividade serotonérgica em pacientes com TOC resistente e respondedor ao tratamento com inibidores de recaptura de serotonina e voluntários saudáveis. Foram estudados 30 sujeitos em cada grupo. Cada um recebeu 20 mg de citalopram intravenoso. Foram dosados: prolactina, cortisol, hormônio de crescimento e serotonina periféricos a cada 20 minutos por 180 minutos. Não houve diferenças nas concentrações de serotonina e de hormônio de crescimento. A droga induziu um pico maior de prolactina no grupo Controle do que nos grupos Resistentes e Respondedores (p<0,05). A secreção de cortisol mostrou-se atenuada apenas no grupo Resistentes (p<0,05), sugerindo maior disfunção serotonérgica neste grupo...

Serotonergic pharmacological challenge tests have conflictant results in OCD. The aim of this study was to compare the serotonergic activity in serotonin reuptake inhibitors treatment resistant and responsive OCD patients and healthy volunteers. Thirty subjects were included in each group. Each one has received 20 mg of intravenous citalopram. Prolactin, cortisol, growth hormone and serotonin were determined peripherically at 20 minutes intervals for 180 minutes. No changes were observed either in serotonin or growth hormone concentration. Citalopram has induced an increase in prolactin secretion in the Control group, not observed in Resistant and Responsive groups (p<0.05). The cortisol response to citalopram was attenuated only in the Resistants (p<0.05), suggesting a more disrupted serotonergic transmission in this group...

Genistein inhibits contractile force, intracellular Ca2+ increase and Ca2+ oscillations induced by serotonin in rat aortic smooth muscle

The soy-derived isoflavones genistein and daidzein affect the contractile state ofdifferent kinds of smooth muscle. We describe acute effects of genistein and daidzeinon contractile force and intracellular Ca2+ concentration ([Ca2+]i) in in situ smoothmuscle of rat aorta. Serotonin (5-HT) (2 ìM) or a depolarizing high K+ solution producedthe contraction of aortic rings, which were immediately relaxed by 20 ìMgenistein and by 20 ìM daidzein. Accordingly, both 5-HT and a high K+ solutionincreased the [Ca2+]i in in situ smooth muscle cells. Genistein strongly inhibited the[Ca2+]i increase evoked by 5-HT (74.0 ± 7.3%, n=11, p<0.05), and had a smallereffect on high K+ induced [Ca2+]i increase (19.9 ± 4.0%, n=7, p<0.05). The K+ channelsblocker tetraethylammonium (TEA) (0.5 mM) diminished genistein effects on 5-HT-induced [Ca2+]i increase. Interestingly, during prolonged application of 5-HT,the [Ca2+]i oscillated and a short (90 s) preincubation with genistein (20 ìM) significantlydiminished the frequency of the oscillations. This effect was totally abolishedby TEA. In conclusion, in rat aortic smooth muscle, genistein is capable of diminishingthe increase in [Ca2+]i and in force evoked by 5-HT and high K+ solution, andof decreasing the frequency of [Ca2+]i oscillations induced by 5-HT. The short timerequired by genistein, and the relaxing effect of daidzein suggest that tyrosine kinasesinhibition is not involved. The small inhibiting effect of genistein on the [Ca2+]iincrease evoked by high K+ and the effect of TEA point to the activation by genisteinof calcium-activated K+ channels (AU)

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Parasomnías: fenómenos episódicos del sueño / Parasomnias: episodic phenomena during sleep

Las parasomnias consisten en fenómenos episódicos del sueño caracterizados por una activación del SNC que involucra al soma a través de las vías motoras y /o al sistema nerviosos vegetativo o a las funciones psíquicas. La prevalencia de las parasomnias es mayor en edad pediátrica, lo que sugiere que factores madurativos y del desarrollo son importantes en su etiología. El diagnóstico se basa en la historia clínica y de sueño; en la exploración neurológica y neuropsicología; y en el registro vídeo EEG- polisomnográfico. Las parasomnias se dividen en cuatro grupo atendiendo al periodo de sueño en el que aparecen; transición vigilia-sueño, sueño NREM, sueño REM y despertar. El registro EEG de las parasomnias muestra una combinación de frecuencias alfa, theta y delta, sin un patrón típico de vigilia. El registro vídeo- EEG-PSG demuestra en muchos casos el factor desencadenante de la parasomnia: apnea obstructiva, reflujo gastro-esofágico, movimientos periódicos de las piernas, etc. El diagnóstico diferencial con las crisis epilépticas se basa en: a) presencia de crisis diurnas y nocturnas en la epilepsia; b) la semiología electroclínica; c) la aparición de anomalías paroxísticas intercríticas o críticas en el EEG; y d) la respuesta al tratamiento anticomicial. Las parasomnias provocan fragmentación y escasa eficiencia del sueño. Durante el día aparecen síntomas de somnolencia y trastornos del aprendizaje. La monitorización vídeo-PSG posibilita un diagnóstico de certeza y un tratamiento adecuado (AU)

Parasomnias are episodic phenomena characterized by an activation of the CNS involving the motor and/or autonomic systems, and the psychological functions. The prevalence of parasomnias is high in children suggesting that maturational and developmental factors are of major importance in their etiology. The diagnosis is based on the child´s clinical and sleep history, family history, physical, neurological and neuropsychological examinations and a period during the night; wakefulness-sleep transition, non-REM sleep, REM sleep or arousal. The EEG shows a combination of alpha, theta and delta frequencies without evidence of clear wakefulness. The video-PSG may reveal a trigger: obstructive sleep apnea, gastroesophageal reflux, or periodic leg movements of sleep. The differential diagnosis with an epileptic seizure is based on: <) the presence of nocturnal and diurnal episodes in epilepsy; b) the electroclinical semiology; c) the appearance of interictal and/or ictal discharges on the EEG, d) the response to antiepileptic therapy. Parasomnias provoke a fragmentation of nocturnal sleep and decrease its efficiency. The child will suffer from daytime hypersomnolence and learning difficulties. Video-PSG monitoring will provide and accurate diagnosis and allow adequate therapy (AU)