Modulation of TNF-α, interleukin-6, and interleukin-10 by nebivolol-valsartan and nebivolol-lisinopril polytherapy in SHR rats.

Antihypertensive drug therapies have demonstrated their capacity to modulate the inflammatory processes associated with hypertension, leading to improvements in disease progression. Given the prevalent use of polytherapy in treating most hypertensive patients, comprehending the time-dependent effects of combination treatments on inflammation becomes imperative. In this study, spontaneously hypertensive rats (SHR) were divided into seven groups (n = 6): (i) SHR + vehicle, (ii) SHR + nebivolol, (iii) SHR + valsartan, (iv) SHR + lisinopril, (v) SHR + nebivolol-valsartan, (vi) SHR + nebivolol-lisinopril, and (vii) WKY + vehicle. Blood pressure was measured using the tail-cuff method. Temporal alterations in inflammatory cytokines TNF-α, IL-6, and IL-10 were assessed in serum through ELISA and mRNA expression in aortic tissue via qPCR after 1, 2, and 4 weeks of treatment with nebivolol, lisinopril, valsartan, and their respective combinations. Histological alterations in the aorta were assessed. The findings indicated that combined treatments reduced systolic and diastolic blood pressure in SHR. The nebivolol and lisinopril combination demonstrated a significant decrease in IL-6 serum and mRNA expression at both 1 week and 4 weeks into the treatment. Additionally, TNF-α mRNA expression also showed a reduction with this combination at the same time points. Particularly, nebivolol-valsartan significantly decreased TNF-α serum and mRNA expression after one and four weeks of treatment. Furthermore, an elevation in serum IL-10 levels was observed with both combination treatments starting from the second week onwards. This study provides compelling evidence that concurrent administration of nebivolol with lisinopril or valsartan exerts time-dependent effects, reducing proinflammatory cytokines TNF-α and IL-6 while modifying IL-10 levels in an experimental hypertensive model.

Febrile infection-related epilepsy syndrome (fires), a possible cause of super-refractory status epilepticus. case report

ABSTRACT Introduction: Super-refractory status epilepticus (SRSE) is a pathology that affects the neuronal environment depending on the types of seizure and their duration. Case presentation. This paper presents the case of a 7-year old child presenting with super-refractory status epilepticus and multifocal seizures. Metabolic, structural, infectious, toxicological and autoimmune causes were discarded, while different anticonvulsive agents were administered without any clinical improvement; seizures were controlled 6 weeks after admission to ICU. A 12-year follow-up was performed, during which time the patient presented recurrent status epilepticus with autonomic seizures and progressive cognitive decline. Discussion: This type of status epilepticus is part of the syndrome known as Febrile Infection-Related Epilepsy Syndrome (FIRES), a possibly autoimmune form of epileptic encephalopathy that is refractory to acute and chronic management. There is no report in the literature that includes long term follow-up, therefore, there is no actual consensus about the appropriate management of the chronic phase of the disease. Conclusion: FIRES must be considered as one of the possible etiologies of super-refractory status epilepticus, so early management strategies (like ketogenic diet) can be used in order to achieve control of the critically ill patient, control long term seizures and improve cognitive outcomes, having as the final result a positive impact on the quality of life of the patient.

RESUMEN Introducción: El estado epiléptico superrefractario (EES) es una patología con importante morbimortalidad que afecta el ambiente neuronal según el tipo y duración de las crisis. Presentación del caso: Se presenta el caso de un escolar con estado epiléptico superrefractario y crisis multifocales. Se descartaron causas metabólicas, estructurales, infecciosas, toxicológicas y autoinmunes y se utilizaron diferentes manejos anticonvulsivantes sin respuesta, lográndose control de las crisis 6 semanas después del ingreso a UCI. Se realizó un seguimiento de 12 años, periodo en el que el paciente presentó múltiples recaídas del estado epiléptico asociadas a la presencia de epilepsia refractaria con múltiples tipos de crisis, en su mayoría vegetativas; además se dio involución cognitiva. Discusión: Esta forma de estado epiléptico corresponde al síndrome de estado epiléptico facilitado por fiebre (FIRES), entidad de posible origen inmunológico conocida por ser refractaria al tratamiento agudo y al manejo crónico de la epilepsia y que se presenta como secuela. Su evolución no se ha descrito a largo plazo y por tanto no hay consenso sobre el manejo en la fase crónica. Conclusión: Es importante considerar esta etiología en estado epiléptico superrefractario para utilizar de forma temprana diferentes estrategias terapéuticas, como la dieta cetogénica, que permitan, por un lado, controlar su condición crítica y las crisis epilépticas a largo plazo y, por el otro, mejorar el pronóstico cognitivo, logrando así un impacto en la calidad de vida.

Politerapia racional en epilepsia infantil / Rational polytherapy in infantile epilepsy

Se acepta globalmente que el tratamiento inicial de la epilepsia debe realizarse en monoterapia. Sin embargo, dado que hasta un 30% de los pacientes son refractarios a una o varias monoterapias, es común asociar pautas combinadas de dos o más fármacos antiepilépticos (FAE). En estos supuestos de politerapia, hay que considerar el mecanismo de acción de cada FAE, su espectro, su seguridad, y sus interacciones farmacocinéticas y farmacodinámicas. La politerapia racional es un concepto terapéutico basado en la combinación de FAE con mecanismos de acción complementarios que actúan sinérgicamente para maximizar su e cacia y minimizar los potenciales efectos adversos. Para diseñar una buena politerapia racional en epilepsia es básico conocer los distintos mecanismos de acción de cada FAE y analizar la evidencia empírica existente para con cada una de las posibles combinaciones de FAE. Se sugiere que puede ser útil combinar FAE inhibidores de canales de sodio con FAE gabaérgicos, o con FAE con múltiples mecanismos de acción, y evitar aquellas combinaciones que potencien la toxicidad. Sin embargo, existe muy escasa evidencia empírica y clínica respecto a la politerapia racional y sólo está demostrado el sinergismo entre valproato y lamotrigina. La politerapia racional supone una estrategia diseñada para mejorar el balance entre e cacia y tolerabilidad de las distintas combinaciones de FAE. Sin embargo, dada la ausencia de ensayos clínicos en politerapia racional, sólo podemos hacer sugerencias sobre asociaciones de FAE potencialmente útiles o perjudiciales en base a las características farmacocinéticas y farmacodinámicas de los diversos FAE implicados.

Abstract It is an accepted fact that antiepileptic treatment must be started with monotherapy, but 30% of patients do not respond to it or to several monotherapies; in that moment an association of two or more antiepileptic drugs (AEDs) is commonly utilized. It is necessary to consider the mechanism of action of each AED, its spectrum, the safety and pharmacodynamic and pharmacokinetic interactions, and to select the association of AEDs in accordance with these factors. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the mechanisms of action subclasses among available AEDs and an appreciation of the empirical evidence that supports the use of specific combinations. These theoretical foundations suggest a sodium channel inhibitor should be associated with a GABAergic agent or with an AED with multiple mechanisms and that we should avoid the association between AEDs with additional toxicity or that are likely to interact. However, the experimental and clinical evidence in support of rational polytherapy is sparse, with only the combination of sodium valproate and lamotrigine demonstrating synergism. Rational polytherapy is a theoretical approach designed for improving the balance between efficacy and tolerability of several AEDs combinations. However, the absence of clinical trials only allows us to make suggestions about possible bene cial or harmful associations depending on the pharmacodynamic and pharmacokinetic characteristics of AEDs.

Drug utilization profile in adult patients with refractory epilepsy at a tertiary referral center / Perfil de utilizacao de farmacos por pacientes adultos com epilepsia refrataria em um centro terciario de referencia

Objective To evaluate the utilization profile of antiepileptic drugs in a population of adult patients with refractory epilepsy attending a tertiary center. Method Descriptive analyses of data were obtained from the medical records of 112 patients. Other clinical and demographic characteristics were also registered. Results Polytherapies with ≥3 antiepileptic drugs were prescribed to 60.7% of patients. Of the old agents, carbamazepine and clobazam were the most commonly prescribed (72.3% and 58.9% of the patients, respectively). Among the new agents, lamotrigine was the most commonly prescribed (36.6% of the patients). At least one old agent was identified in 103 out of the 104 polytherapies, while at least one new agent was prescribed to 70.5% of the population. The most prevalent combination was carbamazepine + clobazam + lamotrigine. The mean AED load found was 3.3 (range 0.4–7.7). Conclusion The pattern of use of individual drugs, although consistent with current treatment guidelines, is strongly influenced by the public health system. .

Objetivo Avaliar o perfil de utilização de fármacos antiepilépticos em uma população de pacientes adultos com epilepsia refratária atendidos em um centro terciário. Método Análises descritivas dos dados obtidos dos registros médicos de 112 pacientes. Também foram consideradas as características clínicas e demográficas. Resultados Foram prescritas politerapias com ≥3 antiepilépticos a 60,7% dos pacientes. Em relação aos fármacos de primeira geração, carbamazepina e clobazam foram os mais frequentemente prescritos (a 72,3% e 58,9% dos pacientes, respectivamente). Dentre os novos antiepilépticos, a lamotrigina foi o mais prescrito (36,6% dos pacientes). Ao menos um antiepiléptico de primeira geração foi encontrado em 103 das 104 politerapias; ao menos um novo antiepiléptico foi prescrito a 70,5% da população. A combinação mais prevalente foi carbamazepina+clobazan+lamotrigina. A carga média de antiepilépticos foi 3.3 (0.4 a 7.7). Conclusão O padrão de utilização de antiepilépticos, embora concordante com guias atuais, é fortemente influenciado pelo sistema público de saúde. .

Normalización de trastornos de sueño y su efecto en pacientes con epilepsia refractaria / Effects of sleep disorders normalization in patients during the use of antiepileptic drugs

Los trastornos del sueño son un problema frecuente y subdiagnosticado en niños con cuadros neurológicos y en particular con epilepsias refractarias. Evaluamos los efectos de normalización rápida de los patrones de sueño sobre la refractariedad de la epilepsia. Pacientes y Método: Se ingresaron al estudio todos los pacientes pediátricos con alteración severa del ciclo sueño-vigilia y epilepsia refractaria en control en el Servicio de Neuropsiquiatría Infantil del Hospital Clínico San Borja-Arriarán y Liga contra la Epilepsia, Santiago, Chile, entre Marzo 2004 y Marzo 2008. Cada paciente fue su propio control. Durante el primer mes se solicitó a los padres completar un registro diario de frecuencia y tipo de crisis epiléptica y del ciclo sueño-vigilia de su hijo (a). A contar del segundo mes se implementó un tratamiento para normalizar el ciclo sueño-vigilia utilizando luminoterapia, hábitos estrictos de sueño y melatonina, 30 min antes de la hora de dormir. La terapia antiepiléptica no se modificó durante los primeros seis meses de tratamiento. Resultados: Los once pacientes ingresados normalizaron el ciclo sueño-vigilia durante el primer mes de tratamiento. Diez de 11 casos mostraron una reducción dramática de la frecuencia de crisis por día, mayor a un 85 por ciento, durante los primeros tres meses de intervención, independientemente del tipo de crisis, que se mantuvo por más de un año de seguimiento (13-43 meses). En cinco pacientes se discontinuó la melatonina después de un año de tratamiento, sin que hubiese deterioro del patrón de sueño o aumento en la frecuencia de crisis. Conclusión: Es frecuente el subdiagnóstico de trastorno de sueño en niños con epilepsias refractarias. La normalización del patrón de ciclo sueño-vigilia puede disminuir dramáticamente la frecuencia de crisis y por lo tanto mejorar la calidad de vida de los pacientes y sus familias...

Sleep disorders are a frequent and underdiagnosed problem in children with neurological problems, specially in children with refractory epilepsies. We evaluated the effects of fast normalization of sleep pattern on epilepsy refractoriness. Patients and methods: We enrolled all pediatric patients from March 2004 to March 2008, with severe alterations of the sleep-wake pattern and refractory epilepsy, attending to the Neuropsychiatry Service, Hospital Clínico San Borja-Arriarán and League against Epilepsy from Santiago, Chile. Each patient was his own control. Parents were asked to complete a diary during the first month after enrollment with frequency, type of seizures and sleep-wake cycle of each patient. After the month, sleep-wake cycle was normalized using morning luminotherapy, strict sleep habits and melatonin, 30 minutes before bedtime. Antiepileptic therapy was not modified during the first six months. Results: All patients normalized the sleep-wake cycle during the first month treatment. Ten of 11 patients showed a dramatic reduction of seizure frequency (over 85 percent of total day seizures) during the first three months of intervention, independently from the seizure type that has maintained for more than a year (13–43 months) follow-up. Melatonin was discontinued in five patients after a year of treatment, with no deterioration of sleep pattern or seizures frequency. Conclusions: Sleep disorders in children with refractory epilepsies are frequently underestimated. The normalization of the sleep-wake pattern can diminish seizures dramatically, improving patients and family quality of life. This point must be always taken into account before considering a patient refractory to antiepileptic drugs and adding new drugs to polytherapy.

Gender differences, polypharmacy, and potential pharmacological interactions in the elderly

OBJECTIVE: This study aims to analyze pharmacological interactions among drugs taken by elderly patients and their age and gender differences in a population from Porto Alegre, Brazil. METHODS: We retrospectively analyzed the database provided by the Institute of Geriatric and Gerontology, Porto Alegre, Brazil. The database was composed of 438 elderly and includes information about the patients' disease, therapy regimens, utilized drugs. All drugs reported by the elderly patients were classified using the Anatomical Therapeutic and Chemical Classification System. The drug-drug interactions and their severity were assessed using the Micromedex® Healthcare Series. RESULTS: Of the 438 elderly patients in the data base, 376 (85.8 percent) used pharmacotherapy, 274 were female, and 90.4 percent of females used drugs. The average number of drugs used by each individual younger than 80 years was 3.2±2.6. Women younger than 80 years old used more drugs than men in the same age group whereas men older than 80 years increased their use of drugs in relation to other age groups. Therefore, 32.6 percent of men and 49.2 percent of women described at least one interaction, and 8.1 percent of men and 10.6 percent of women described four or more potential drug-drug interactions. Two-thirds of drug-drug interactions were moderate in both genders, and most of them involved angiotensin-converting enzyme inhibitor, non-steroidal anti-inflammatory, loop and thiazide diuretics, and β-blockers. CONCLUSION: Elderly patients should be closely monitored, based on drug class, gender, age group and nutritional status.

Tratamento das epilepsias parciais / Partial epilepsies treatment

As epilepsias parciais constituem a forma mais comum de epilepsia nos indivíduos adultos. As drogas antiepilépticas (DAEs) permanecem como a principal forma de tratamento para os pacientes com epilepsia. Apesar da importância da medicação um número elevado de pacientes permanece sob um regime terapêutico inapropriado ou até mesmo sem qualquer medicação. Existem várias medicações disponíveis para o tratamento das epilepsias. A escolha de uma medicação específica ou a associação entre DAEs deve ser particularizada o máximo possível. Neste artigo revisamos alguns aspectos como classificação, início das crises, idade, sexo, comorbidades, custo e posologia das DAEs e história medicamentosa com a perspectiva de auxiliar nesta individualização do tratamento. Algumas características das principais DAEs disponíveis também são discutidas. Estes aspectos podem auxiliar na criação de um perfil ajudando assim na escolha do regime terapêutico mais apropriado para cada indivíduo. Aspectos práticos como o manuseio dos efeitos adversos, monoterapia e politerapia também são abordados.

Partial epilepsies are the most common form of epilepsy in adult individuals. Antiepileptic drugs (AEDs) continue as the main form of treatment for patients with epilepsy. Regardless of the importance of the medication a high number of patients are under inappropriate or not receiving AEDs. There are several medications available for the treatment of epilepsy. The choice of a particular medication or association among AEDs may be individualized as much as possible. In this article some aspects such as classification, onset of the seizures, age, sex, associated medical conditions, cost and posology of AEDs and medical drug history are reviewed. Details of the available AEDs are also discussed. These points may help to create a profile helping the decision for the appropriate AED. Some practical issues like adverse reaction management, monotherapy and politherapy are also discussed.