Eficacia y seguridad de lacosamida como tratamiento complementario en pacientes pediátricos con epilepsia focal refractaria / Efficacy and safety of lacosamide as adjunctive treatment in pediatric patients with refractory focal epilepsy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD-2022, se ha elaborado el presente dictamen que expone la evaluación de la eficacia y seguridad de lacosamida para el tratamiento de pacientes pediátricos con epilepsia focal refractaria. Así, el médico Dr. Edwin Martín Lazo Rivera, especialista en neurología pediátrica del Hospital Nacional Carlos Alberto Seguín Escobedo - Red Asistencial Arequipa y la Dra. Rebeca Fiorella Valdivia Bravo, especialista en pediatría del Hospital Nacional Alberto Sabogal Sologuren de la Red Prestacional Sabogal, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, enviaron al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI sus respectivas solicitudes de autorización de uso del producto farmacéutico lacosamida no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La epilepsia es una condición del sistema nervioso central caracterizada por crisis epilépticas recurrentes y no provocadas por desencadenantes inmediatos identificables. Así, la crisis epiléptica es aquel acontecimiento transitorio de signos y/o síntomas originados por una actividad neuronal cerebral sincrónica anormal o excesiva, que puede manifestarse por fenómenos sensitivos, motores, sensoriales o autonómicos con o sin pérdida de la conciencia, ya que dependen del área cerebral donde se originan. En ese sentido, las crisis convulsivas se clasifican según tres posibilidades de origen: las de inicio focal, generalizado y desconocido. Las crisis focales, a su vez, se pueden subclasificar en aquellas que tienen pérdida o no de la consciencia, para posteriormente categorizar si los síntomas son motores o no motores. En consecuencia, los especialistas deciden el abordaje terapéutico de los pacientes con epilepsia focal teniendo en cuenta esta clasificación, adicional a la etiología y a las comorbilidades asociadas (Reséndiz-Aparicio et al.,2019, Fisher et al.,2017, INSN.,2020). En todo el mundo, la epilepsia afecta aproximadamente a 65 millones de personas, reportándose una incidencia de la epilepsia de 67,8 por 100 000 habitantes en los países en desarrollo (Mohammadzadeh et al., 2022). En el Perú, se estima que la prevalencia de epilepsia es de 11,9 a 32,1 por cada 1000 personas (Burneo et al., 2017). Asimismo, es conocido que la incidencia de la epilepsia en la población pediátrica es de aproximadamente 0,5 % a 1 % de la población general. Además, algunos estudios sugieren que hasta el 60 % de los pacientes pediátricos con epilepsia presentarán remisión de su condición, mientras que alrededor del 20 % a 30 % de los pacientes con epilepsia serán refractarios al tratamiento médico (Ortiz de la Rosa et al., 2015). METODOLOGÍA: La búsqueda bibliográfica exhaustiva se llevó a cabo con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de lacosamida para el tratamiento de pacientes pediátricos con epilepsia focal refractaria a los FAE disponibles en EsSalud. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library. Web of Science y LILACS. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) de: la National Institute for Health and Care Excellence (NICE), la American Academy of Neurology (ANN), la American Epilepsy Society (AES), la Scottish Intercollegiate Guidelines Network (SIGN), la Internacional Database of GRADE Guideline (BIGG), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Comissáo Nacional de Incorporadáo de Tecnologias no Sistema Único de Saúde (CONITEC) y el Ministerio de Salud del Perú (MINSA). Adicionalmente, se realizó una búsqueda manual en las bases el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), y el repositorio institucional de la Dirección General de Medicamentos, Insumos y Drogas (DIGEMID). Finalmente, se realizó una búsqueda en el portal ClinicalTrials.govdel National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que aún no hayan sido publicados. La metodología de tipo escalonada fue utilizada para la selección de documentos a ser incluidos en el presente dictamen. De acuerdo con los criterios de elegibilidad, se priorizaron durante la selección: GPC, ETS, RS de ensayos clínicos (EC) con o sin metaanálisis (MA), y ensayos clínicos aleatorizados (ECA) de fase III. Se elaboraron estrategias de búsqueda sensibles en bases de datos bibliográficas y sitios web para obtener la evidencia científica que permita responder a la pregunta PICO. Las estrategias de búsqueda incluyeron términos relacionados con la intervención y población de interés. Se emplearon términos MeSH4, así como términos de lenguaje libre, junto con operadores booleanos para cada una de las bases de datos elegidas para la búsqueda. Los registros obtenidos de la búsqueda bibliográfica fueron importados al aplicativo web Rayyan (http://rayyan.qcri.org/) para una revisión manual por título y resumen. La selección de los estudios se realizó en una primera fase por dos evaluadores del Equipo Técnico del IETSI de manera independiente (búsqueda par); evaluando los títulos y resúmenes en relación con la pregunta PICO y seleccionando aquellos que serían evaluados a texto completo en una segunda fase por un único evaluador. En la segunda fase, uno de los evaluadores revisó los documentos a texto completo incluidos en la primera fase y realizó la selección final de los estudios. RESULTADOS: Luego de la búsqueda bibliográfica, se incluyó una GPC elaborada por la National Institute for Health and Care Excellence (NICE 2022), y un ECA de fase III, NCT01921205 (Farkas et al., 2019). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de lacosamida para el tratamiento complementario en pacientes pediátricos con epilepsia focal refractaria, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente informe preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Phenytoin promotes the proliferation of oligodendrocytes and enhances the expression of myelin basic protein in the corpus callosum of mice demyelinated by cuprizone.

Oligodendrocyte loss and myelin sheet destruction are crucial characteristics of demyelinating diseases. Phenytoin promotes the proliferation of endogenous neural precursor cells in the ventricular-subventricular zone in the postnatal brain that help restore the oligodendroglial population. This study aimed to evaluate whether phenytoin promotes myelin recovery of the corpus callosum of demyelinated adult mice. CD1 male mice were exposed to a demyelinating agent (0.2% cuprizone) for 8 weeks. We assembled two groups: the phenytoin-treated group and the control-vehicle group. The treated group received oral phenytoin (10 mg/kg) for 4 weeks. We quantified the number of Olig2 + and NG2 + oligodendrocyte precursor cells (OPCs), Rip + oligodendrocytes, the expression level of myelin basic protein (MBP), and the muscle strength and motor coordination. The oligodendroglial lineage (Olig2 + cells, NG2 + cells, and RIP + cells) significantly increases by the phenytoin administration when compared to the control-vehicle group. The phenytoin-treated group also showed an increased expression of MBP in the corpus callosum and better functional scores in the horizontal bar test. These findings suggest that phenytoin stimulates the proliferation of OPCs, re-establishes the oligodendroglial population, promotes myelin recovery in the corpus callosum, and improves motor coordination and muscle strength.

Oral Use of Phenytoin to Reduce Calcification in Bovine Pericardium and Porcine Aortic Leaflets Implants in Rats.

INTRODUCTION: This study aims to test the effect of phenytoin as an inhibitor of the process of dystrophic calcification in bovine pericardium and porcine leaflets implanted in the subcutaneous tissue of rats. METHODS: Isolated segments of biomaterials were implanted subcutaneously in young rats. The study groups received 500 mg phenytoin per kilogram of diet per day. After 90 days, samples were collected and quantitative calcification assessment by optical microscopy, radiological studies with mammography, and atomic emission spectrometry were performed. RESULTS: Inflammatory reaction was a frequent finding in all groups when analyzed by optical microscopy. The calcium level assessed by atomic absorption spectrophotometry was significantly lower in the study groups using phenytoin compared to the control groups (control bovine pericardium group X=0.254±0.280 µg/mg; study bovine pericardium group X=0.063±0.025 µg/mg; control porcine aortic leaflets group X=0.640±0.226 µg/mg; study porcine aortic leaflets group X=0.056±0.021 µg/mg; P<0.05). Radiologic studies revealed a statistically significant difference between the groups treated with and without phenytoin (not only regarding the bovine pericardium but also the porcine leaflets). CONCLUSION: The results obtained suggest that phenytoin reduces the calcification process of bovine pericardium segments and porcine aortic leaflets in subdermal implants in rats; also, the incidence of calcification in bovine pericardium grafts was similar to that of porcine aortic leaflets.

Trigeminal Neuralgia Crisis - Intravenous Phenytoin as Acute Rescue Treatment.

OBJECTIVE: The aim of this retrospective cohort study was to analyze responses to intravenous (IV) phenytoin (PHT) for trigeminal neuralgia (TN) crisis in a group of patients treated at our institution. BACKGROUND: TN is one of the most common causes of facial pain. Its treatment relies on preventive therapy with either carbamazepine or oxcarbazepine. During severe pain episodes, patients may be unable to eat, drink, or even swallow oral medication, requiring in-hospital treatment. There is scarce evidence to support IV medication use for TN, making management of this condition difficult. METHODS: We reviewed clinical records of patients with TN crisis consulting the emergency department at a tertiary neurological referral center in Buenos Aires, Argentina, treated with IV PHT as analgesic strategy, and with at least 1-month posttreatment follow-up. Demographic features, magnetic resonance imaging findings, and therapeutic management were analyzed. RESULTS: Thirty-nine patients with TN were included, 18 (46.2%) receiving IV PHT more than once (total number of infusions administered, 65). Immediate pain relief was observed in 89.2% (58/65) and 15.4% (10/65) presented side effects. CONCLUSIONS: We recommend IV PHT as acute rescue treatment in TN crisis.

Phenytoin-loaded lipid-core nanocapsules improve the technological properties and in vivo performance of fluidised bed granules.

Lipid-core nanocapsules (LNCs) were recently reported by our group as a suitable binder system to produce fluidised bed granules. However, there is still a lack of knowledge about the influence of using these nanocarriers loaded with a drug on the properties of the granules and their in vivo performance. Therefore, this study was designed to produce innovative fluidised bed granules containing phenytoin-loaded LNCs (LNCPHT) as a strategy to evaluate the influence of the presence of the drug-loaded nanocarriers on their in vitro and in vivo properties. Granules were produced using a mixture of maltodextrin and phenytoin (1:0.004 w/w) as substrate. They were prepared by fluid bed granulation using water or LNCPHT as the liquid binder, affording good yields (73-82%) of granules with low moisture content (<5%). Granules prepared with LNCPHT had larger mean size (122 µm) compared to maltodextrin primary particles (50 µm) due to the formation of solid bridges. Moreover, the use of LNCPHT as the liquid binder improved their powder flow properties. The nanocarriers were recovered after aqueous dispersion (3.00 mg.mL-1 of PHT) with a redispersibility close to 90%. After reconstitution in water, granules containing LNCPHT showed an improved dissolution behaviour compared to those prepared without them. In addition, they showed a higher mucoadhesive effect due to a combined effect of the LNCPHT and maltodextrin in the interactions with porcine intestinal mucosa. Regarding the in vivo studies, granules containing the combination of non-encapsulated PHT and PHT-loaded lipid-core nanocapsules increased the latency to seizures compared to placebo granules, showing effective anticonvulsant effect in mice. In conclusion, the use of drug-loaded nanocapsules as binder is an encouraging approach to produce fluidised bed mucoadhesive granules with improved technological properties and in vivo performance.

Chitosan hydrogels containing nanoencapsulated phenytoin for cutaneous use: Skin permeation/penetration and efficacy in wound healing.

Although phenytoin is an antiepileptic drug used in the oral treatment of epilepsy, its off-label use as a cutaneous healing agent has been studied in recent years due to the frequent reports of gingival hyperplasia after oral administration. However, the cutaneous topical application of phenytoin should prevent percutaneous skin permeation. Therefore, the aim of this study was to evaluate the in vitro skin permeation/retention and in vivo effects of nanocapsules and nanoemulsions loaded with phenytoin and formulated as chitosan hydrogels on the healing process of cutaneous wounds in rats. The hydrogels had adequate pH values (4.9-5.6) for skin application, drug content of 0.025% (w/w), and non-Newtonian pseudoplastic rheological behaviour. Hydrogels containing nanocapsules and nanoemulsions enabled improved controlled release of phenytoin and adhesion to skin, compared with hydrogels containing non-encapsulated phenytoin. In vitro skin permeation studies showed that phenytoin permeation to the receptor compartment, and consequently the risk of systemic absorption, may be reduced by nanoencapsulation without any change in the in vivo performance of phenytoin in the wound healing process in rats.

Effects of cyclosporin, nifedipine and phenytoin on gingival myofibroblast transdifferentiation in monkeys

Abstract Objective: Myofibroblasts have been associated with the development of several pathologic fibrotic conditions. This longitudinal study aims to assess the proliferative and antiapoptotic effects of cyclosporin, nifedipine and phenytoin on gingival connective tissue cells of nonhuman primate, as well as to analyze a possible role of myofibroblasts in gingival overgrowth. Materials and Methods: Gingival samples from the right superior canine area were obtained from 12 male monkeys ( Sapajus spp ) to comprise the control group. After one week, the animals were randomly assigned to three groups, which received daily oral doses of cyclosporin, nifedipine or phenytoin for 120 days. Gingival samples were collected from the left superior canine area of two animals of each group at 52 and 120 days. Histological sections were stained with hematoxylin and eosin, and immunoreacted against α-SMA, Ki- 67 and bcl-2. Results: α-SMA immunoreaction was negative in the control and experimental groups. Similarly, no difference between groups concerning immunostaining against Ki-67 and bcl-2 was observed in connective tissue cells. Conclusion: Based on this methodology, it may be concluded that gingival overgrowths induced by cyclosporin, nifedipine and phenytoin are not associated with neither myofibroblast transdifferentiation, proliferation nor apoptosis of gingival connective cells in monkeys.

Effects of cyclosporin, nifedipine and phenytoin on gingival myofibroblast transdifferentiation in monkeys.

OBJECTIVE: Myofibroblasts have been associated with the development of several pathologic fibrotic conditions. This longitudinal study aims to assess the proliferative and antiapoptotic effects of cyclosporin, nifedipine and phenytoin on gingival connective tissue cells of nonhuman primate, as well as to analyze a possible role of myofibroblasts in gingival overgrowth. MATERIALS AND METHODS: Gingival samples from the right superior canine area were obtained from 12 male monkeys ( Sapajus spp ) to comprise the control group. After one week, the animals were randomly assigned to three groups, which received daily oral doses of cyclosporin, nifedipine or phenytoin for 120 days. Gingival samples were collected from the left superior canine area of two animals of each group at 52 and 120 days. Histological sections were stained with hematoxylin and eosin, and immunoreacted against α-SMA, Ki- 67 and bcl-2. RESULTS: α-SMA immunoreaction was negative in the control and experimental groups. Similarly, no difference between groups concerning immunostaining against Ki-67 and bcl-2 was observed in connective tissue cells. CONCLUSION: Based on this methodology, it may be concluded that gingival overgrowths induced by cyclosporin, nifedipine and phenytoin are not associated with neither myofibroblast transdifferentiation, proliferation nor apoptosis of gingival connective cells in monkeys.

Cunaniol-elicited seizures: Behavior characterization and electroencephalographic analyses.

This study aimed at describing the characteristics and properties of seizures induced by cunaniol, a polyacetylenic alcohol isolated from the Clibadium genus, which is ubiquitous in the Amazon biodiversity and its potential use as a convulsant model. Wistar rat behavior was assessed upon cunaniol administration and animals were evaluated for neural activity through electroencephalographic records whereby epidural electrodes were positioned over the motor cortex under cunaniol-elicited seizures and seizure's control using three anticonvulsant agents, namely phenytoin, phenobarbital and diazepam. Cunaniol-induced seizures displayed a cyclic development of electrocorticographic seizures, presenting interictal-like spike and ictal period, which correlates to the behavioral observations and is in line with acute seizures induced by pentylenetetrazole. Cunaniol-elicited seizures were intractable by phenytoin treatment and controlled under the GABAergic activities of phenobarbital and diazepam. The results indicate that the cunaniol-induced changes show characteristics of seizure activity, making this plant compound a suitable animal convulsant model for seizure-related studies that could be used to assist in the development of novel anticonvulsant agents.

Synergistic effect of honey and Nigella sativa on wound healing in rats.

PURPOSE: To investigate the therapeutic potential of honey, Nigella sativa (N. sativa) and their combination in rat model of excisional wound healing. METHODS: A circular excision wound was established in the back region of 50 Wistar rats. Subsequently, they were divided into 5 groups and daily topical administration of lanolin in the control group, honey in the honey group, cold-pressed N. sativa seed oil in the N. sativa groups, mix of 1:1 ratio of honey and N. sativa seed oil in the mix group, and phenytoin cream in the phenytoin group were used. Then, wound surface areas were evaluated using digital camera immediately after the injury and at post excision days 5, 10, 15 and 20. RESULTS: Significant reduction in wound surface area was observed within and between the groups (P < 0.001). In the post excision days 5, 10, 15 and 20 the wound surface areas in the mix group were significantly lower than the other groups followed by the phenytoin, honey, N. sativa, and control groups. CONCLUSION: The wound healing may be improved and accelerated by using topical solutions of honey, N. sativa seed oil and especially their mixture.

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice.

The induction of cytochrome P450 (P450) enzymes in response to drug treatment is a significant contributing factor to drug-drug interactions, which may reduce therapeutic efficacy and/or cause toxicity. Since most studies on P450 induction are performed in adults, enzyme induction at neonatal, infant, and adolescent ages is not well understood. Previous work defined the postnatal ontogeny of drug-metabolizing P450s in human and mouse livers; however, there are limited data on the ontogeny of the induction potential of each enzyme in response to drug treatment. Induction of P450s at the neonatal age may also cause permanent alterations in P450 expression in adults. The goal of this study was to investigate the short- and long-term effects of phenytoin treatment on mRNA and protein expressions and enzyme activities of CYP2B10, 2C29, 3A11, and 3A16 at different ages during postnatal liver maturation in mice. Induction of mRNA immediately following phenytoin treatment appeared to depend on basal expression of the enzyme at a specific age. While neonatal mice showed the greatest fold changes in CYP2B10, 2C29, and 3A11 mRNA expression following treatment, the levels of induced protein expression and enzymatic activity were much lower than that of induced levels in adults. The expression of fetal CYP3A16 was repressed by phenytoin treatment. Neonatal treatment with phenytoin did not permanently induce enzyme expression in adulthood. Taken together, our data suggest that inducibility of drug-metabolizing P450s is much lower in neonatal mice than it is in adults and neonatal induction by phenytoin is not permanent.

Synergistic effect of honey and Nigella sativa on wound healing in rats

Abstract Purpose: To investigate the therapeutic potential of honey, Nigella sativa (N. sativa) and their combination in rat model of excisional wound healing. Methods: A circular excision wound was established in the back region of 50 Wistar rats. Subsequently, they were divided into 5 groups and daily topical administration of lanolin in the control group, honey in the honey group, cold-pressed N. sativa seed oil in the N. sativa groups, mix of 1:1 ratio of honey and N. sativa seed oil in the mix group, and phenytoin cream in the phenytoin group were used. Then, wound surface areas were evaluated using digital camera immediately after the injury and at post excision days 5, 10, 15 and 20. Results: Significant reduction in wound surface area was observed within and between the groups (P < 0.001). In the post excision days 5, 10, 15 and 20 the wound surface areas in the mix group were significantly lower than the other groups followed by the phenytoin, honey, N. sativa, and control groups. Conclusion: The wound healing may be improved and accelerated by using topical solutions of honey, N. sativa seed oil and especially their mixture.

Mutations in SCN3A cause early infantile epileptic encephalopathy.

OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit ß1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala). METHODS: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria. RESULTS: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels. INTERPRETATION: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703-717.

Chronic administration of phenytoin induces efflux transporter overexpression in rats.

BACKGROUND: Efflux transporters overexpression has been proposed as one of the responsible mechanism for refractory epilepsy by preventing access of the antiepileptic drug to the brain. In this work we investigated whether phenytoin (PHT), could induce efflux transporters overexpression, at different biological barriers and to evaluate the implication it could have on its pharmacokinetics and therapeutic/toxic response. METHODS: Forty-two adult females Sprague Dawley divided in five groups were treated with oral doses of 25, 50 and 75mg/kg/6h of PHT for 3 days and two additionally groups were treated with intraperitoneal (ip) doses of 25mg/kg/6h or 100mg/kg/24h. At day 4 PHT plasma concentrations were measured and, obtained several organs, brain, parotid gland, liver and duodenum in which were analyzed for the Pgp expression. At day 4 PHT plasma concentrations were measured and several tissues: brain, parotid gland, liver and duodenum were obtained in order to analyze Pgp expression. In order to evaluate the oral bioavailability of PHT, two groups were administered with oral or intraperitoneal doses of 100mg/kg and plasma level were measured. RESULTS: An induction of the expression of efflux transporter mediated by phenytoin in a concentration-and-time dependent manner was found when increasing oral and ip doses of phenytoin, One week after the interruption of ip treatment a basal expression of transporters was recovered. CONCLUSIONS: Overexpression of efflux transporters can be mediated by inducer agents like PHT in a local-concentration dependent manner, and it is reversible once the substance is removed from the body. The recovery of basal Pgp expression could allow the design of dosing schedules that optimize anticonvulsant therapy.

The antimanic-like effect of phenytoin and carbamazepine on methylphenidate-induced hyperlocomotion: role of voltage-gated sodium channels.

The objective of this study was to verify whether phenytoin modifies methylphenidate-induced hyperlocomotion, an animal model for screening antimanic-like drugs, and also evaluate the effect of veratrine, a voltage-gated sodium channel opener, pretreatment on the effect of phenytoin in this model. Carbamazepine was used as a positive control. Methylphenidate (5 mg/kg, s.c.) increased open-field locomotion, and phenytoin (5-10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.) blocked this effect. Veratrine (0.4 mg/kg, s.c.) pretreatment reversed the effects of phenytoin (10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.). Phenytoin (1-50 mg/kg, i.p.) and carbamazepine (10-20 mg/kg i.p.) alone did not change spontaneous locomotor activity. These results indicate that voltage-gated sodium channels play an important role in antimanic-like effects of phenytoin and carbamazepine on psychostimulant-induced hyperlocomotion model.

Antiepileptic drugs prevent changes in adenosine deamination during acute seizure episodes in adult zebrafish.

Adenosine is an endogenous modulator of brain functions, which presents anticonvulsant properties. In addition, its levels can be increased during neural injury. The modulation of extracellular adenosine levels by ectonucleotidase and adenosine deaminase (ADA) activities may represent a key mechanism in the control of epileptogenesis. In the present study, we investigated the effects of acute seizure episodes and antiepileptic drug (AED) treatments on ectonucleotidases and ADA activities in adult zebrafish brain. Our data have demonstrated that pentylenetetrazole (PTZ)-induced seizures did not alter ATP, ADP, and AMP hydrolysis in brain membrane fractions. However, there was a significant increase on ecto-ADA and soluble ADA activities in PTZ-treated animals immediately after a clonus-like convulsion and loss of posture, which are typical behavioral changes observed in Stage 3. Furthermore, our results have demonstrated that AED pretreatments prevented the stimulatory effect promoted by PTZ exposure on ADA activities. The PTZ and AED treatments did not promote alterations on ADA gene expression. Interestingly, when exposed to PTZ, animals pretreated with AEDs showed longer latency to reach the clonus-like seizure status, which is an effect that matches the suppression of the increase of ADA activity promoted by the AEDs. These data suggest that the adenosine deamination could be involved in the control of seizure development in zebrafish and may be modulated by AED treatments.

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.

4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability.

Effects of high frequency electrical stimulation and R-verapamil on seizure susceptibility and glutamate and GABA release in a model of phenytoin-resistant seizures.

The present study was focused to characterize the effects of intrahippocampal application of R-verapamil, a P-glycoprotein blocker, and High Frequency Electrical Stimulation (HFS) at 130 Hz, on seizure susceptibility and extracellular concentrations of glutamate and γ-aminobutyric acid (GABA) in hippocampus of kindled rats with drug-resistant seizures. Fully kindled rats classified in responsive and non-responsive to phenytoin were used for this purpose. In contrast with responsive animals, non-responsive rats showed lower afterdischarge threshold (ADT) values in pre-kindling conditions and required less number of kindling trials to achieve the kindled state. Once the animals attained the kindled state, both epileptic groups presented high glutamate and low GABA interictal release, effect more evident in non-responsive rats. In hippocampus of responsive animals, GABA levels demonstrated two increases at 120 and 240 min after the ictal event, a situation no detected for non-responsive rats. Kindled animals receiving hippocampal HFS showed augmented ADT, an effect associated with enhanced GABA release in responsive rats. Intrahippocampal perfusion of R-verapamil (5 mM) decreased the seizure susceptibility (high ADT values), enhanced the interictal GABA release and the postictal levels of glutamate and GABA in responsive and non-responsive rats. It is conclude that alterations of glutamate and GABA release in the epileptic hippocampus of non-responsive animals resemble those found in hippocampus of patients with refractory TLE. In addition, intrahippocampal application of HFS and R-verapamil modifies the amino acid release and reduces the seizure susceptibility of both, responsive and non-responsive rats.

Antiepileptic drugs combined with high-frequency electrical stimulation in the ventral hippocampus modify pilocarpine-induced status epilepticus in rats.

PURPOSE: To evaluate the effects of high-frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium-pilocarpine (LP). METHODS: Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 mus width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. RESULTS: HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. DISCUSSION: Subeffective doses of antiepileptic drugs that increase the gamma-aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS-induced anticonvulsant effects.

Comportamiento del estatus convulsivo en niños atendidos en la UCI-P del Hospital Fernando Vélez Paiz de enero 2008-diciembre 2009 / Convulsive status behavior in children treated at the ICU-P Fernando Velez Paiz Hospital January 2008-December 2009

El estudio realizado en niños con Estatus Convulsivo ingresados en la UCIP del HFVP de Enero 2008- Diciembre 2009 la muestra fue de 16 pacientes.En relación a la edad y el sexo, el grupo etareo más afectado fue de 1- 5 años con 58%(9), siendo 6(38%) masculino y 19%(3) femeninas, seguido del 6-10 años con el 19%, de estos13%(2) masculino y 6%(1) femenino.Al revisar los antecedentes patológicos personales el 38%(6) tenía antecedentes de convulsión febril, Epilepsia 25%(5) y el 13%(2) asfixia perinatal. La principal etiología del EC fue la Epilepsia en 44%(7), seguida de la supresión del tratamiento anticonvulsivante y la fiebre en un 25% respectivamente. En el tratamiento se utilizó la Difenilhidantoina en 15 pacientes, la dosis de impregnación fue 18-20 mg/kg en el 80%(12), el Fenobarbital se utilizó en 3 pacientes, con dosis de impregnación de 10mg/kg/d en el 60% de los pacientes que se uso. En el tratamiento de mantenimiento el fármaco más utilizado fue la Difenilhidantoina en 12 pacientes, a dosis 5mg/kg/día en el 75%, seguido del Acido Valproico en 7 pacientes a dosis de 15 mg/kg/día y Fenobarbital en 4 pacientes a dosis 5mg/kg/día .La ventilación mecánica se utilizó en 5 pacientes, de estos el 40% estuvo 4-6 días con soporte ventilatorios.Dentro de los estudios complementarios realizados en los pacientescon estatus convulsivo: al 75% se les realizó Ionograma encontrando Hipocalcemia en el 44%(7), e Hiponatremia e hipernatremia en el 13%(2) de los casos respectivamente.Se presentaron complicaciones en 7 pacientes, y la complicación que se presento con mayor frecuencia fue las alteraciones electrolíticas en el 50%(7), seguida del edema cerebral 35%(5), la hemorragia intracraneal y el infarto isquémico en el 7% respectivamente.La condición de egreso el 100% de los pacientes estudiados fue dado de alta y de estos el 88%(14) no presento ninguna secuela, solo el 13%(2) presentó secuelas dentro de ellas hemiparesias e hipotonía.