[Rational combination therapy in epilepsy. III. Possible associations between antiepileptic drugs]. / Politerapia racional en epilepsia. III. Posibles asociaciones de antiepilépticos.

INTRODUCTION: As the foundation underlying rational combination therapy it is necessary to consider the mechanism of action of each antiepileptic drug, its spectrum, the safety and pharmacodynamic and pharmacokinetic interactions, and to select the association of antiepileptic drugs in accordance with these factors. DEVELOPMENT: This paper consists of three parts. In this third part we consider possible associations between antiepileptic drugs; we suggest associations that may be beneficial, others that must be kept under surveillance because their advantages can be offset by their drawbacks, and others that should be avoided because their disadvantages outweigh their possible advantages. CONCLUSIONS: Until more is known about the aetiopathogenesis of epilepsy and we have markers of the cause of epilepsy in a particular patient it will not be possible to associate antiepileptic drugs according to their mechanisms of action. The absence of clinical trials only allows us to make suggestions about possible beneficial or harmful associations depending on the pharmacodynamic and pharmacokinetic characteristics of antiepileptic drugs, which can thus enhance their effectiveness and safety.

[Rational combination therapy in epilepsy. II. Clinical and pharmacological aspects]. / Politerapia racional en epilepsia. II. Aspectos clínicos y farmacológicos.

INTRODUCTION: From an analysis of the studies published to date, the criteria used to select the antiepileptic drugs that can be associated for the treatment of a particular situation or patient need to be optimised because combination therapy offers a low level of evidence. It is also acknowledged that it is advisable to begin treatment with monotherapy (although 30% of patients do not respond and in such cases combination therapy is usually employed), but the possibility of starting with bitherapy in epilepsies that are usually resistant to treatment has also been suggested. DEVELOPMENT: This paper consists of three parts. This second part reviews the foundations underlying the rational association of antiepileptic drugs. CONCLUSIONS: For the association of antiepileptic drugs to result in increased effectiveness without raising the level of toxicity, the theoretical bases of rational combination therapy take into account the mechanism of action, the spectrum, the safety, and the pharmacodynamic and pharmacokinetic interactions of each antiepileptic drug; the number of times the drug is taken is another factor to be taken into consideration. Although it is still early to associate two antiepileptic drugs on the basis of their mechanism of action, these theoretical foundations suggest a sodium channel inhibitor should be associated with a GABAergic agent or an antiepileptic with multiple mechanisms and that we should avoid the association between antiepileptic drugs with additional (sedative and neurological) toxicity or that are likely to interact. Evaluation of the effectiveness, safety, interactions and number of doses suggests the following order, from more to less suitable for combination therapy: levetiracetam/pregabalin > gabapentin > lamotrigine > oxcarbazepine/topiramate/zonisamide > tiagabine > valproic acid > carbamazepine > phenytoin > phenobarbital/primidone > benzodiazepines.

[Rational combination therapy in epilepsy. I. Concepts and foundations]. / Politerapia racional en epilepsia. I. Concepto y fundamentos.

INTRODUCTION: It is an accepted fact that it is wise to start antiepileptic treatment 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 is commonly utilised (the appearance of ten second-generation antiepileptic drugs on the market has not changed this scenario to any significant extent). Yet, on the other hand, the use of bitherapy in epilepsies that are usually resistant to treatment has been suggested as a interesting way to begin treatment. DEVELOPMENT: This article consists of three parts. In this first part we review the concept of rational combination therapy, the concept of how and when it should be used and the studies about associations of antiepileptic drugs conducted in animals and in humans. CONCLUSIONS: Although combination therapy is frequent as treatment for epilepsy, it is not always so obvious that it offers more benefits in terms of greater effectiveness with a lower, or at least equal, degree of toxicity. Few methodologically correct clinical trials have been conducted and recent reviews continue to consider that no controlled clinical trials have been carried out that confirm the benefits of combination therapy. This does not mean, however, that rational combination therapy is totally void of any kind of usefulness, but rather it stresses the fact that it offers a low level of evidence.

[Mechanism of action of antiepileptic drugs and new antiepileptic drugs]. / Mecanismo de acción de los antiepilépticos y nuevos antiepilépticos.

INTRODUCTION: Although 10 second generation new antiepileptic drugs are currently available on the market, 30% of patients are resistant to pharmacological treatment. In addition, today's antiepileptic drugs avert or suppress seizures but do not prevent the appearance of epilepsy or its progression. DEVELOPMENT: The foundations of the aetiopathogenesis of epilepsy and the main targets of antiepileptic drugs are described. Describing the important role of gamma-aminobutyric and glutamic acid in the genesis and proliferation of the seizures has allowed for the development of new antiepileptic drugs that increase the inhibitory tone of GABA or inhibit the excitatory tone of glutamate. The discovery that some epilepsies may be due to channelopathies is now making it possible to conduct research into drugs that inhibit calcium channels, activate potassium channels or inhibit abnormal AMPA/KA receptor channels. Recent reports describing a specific attachment of some antiepileptic drugs to the a2d subunits of the calcium channel and to the synaptic vesicles proteins SV2A open up new perspectives. Moreover, research is also being carried out on new drugs that are capable of preventing epileptogenesis, stemming the progression of epilepsy or overcoming the resistance to pharmacological treatment displayed by some epilepsies. CONCLUSIONS: The identification of new pharmacological targets in the aetiopathogenesis of epilepsies has made it possible to develop second generation antiepileptic drugs and it is allowing for the development of third generation antiepileptic drugs.

Mecanismo de accion de los antiepilepticos y nuevos antiepilepticos / Mechanism of action of antiepileptic drugs and new antiepileptic drugs

Introducción. A pesar de la comercialización de 10 antiepilépticosnuevos de segunda generación, hay un 30% de pacientesresistentes al tratamiento farmacológico. Además, los antiepilépticosactuales previenen o suprimen las crisis pero no evitan laaparición de epilepsia ni su progresión. Desarrollo. Se describenlos fundamentos de la etiopatogenia de la epilepsia y las principalesdianas de los antiepilépticos. La descripción del importante papeldel ácido gamma-aminobutírico y el glutámico en la génesis yla propagación de las crisis han permitido desarrollar nuevos antiepilépticosque aumenten el tono inhibidor gabérgico o inhiban eltono excitador glutamérgico. El descubrimiento de que algunasepilepsias pueden deberse a canalopatías está permitiendo investigarfármacos que inhiban canales de calcio, activen canales depotasio o inhiban canales anómalos de receptores AMPA/KA. Recientementese ha descrito una fijación específica de algunos antiepilépticosa las subunidades a2d del canal de calcio y a las proteínasde las vesículas sinápticas SV2A que abren nuevas perspectivas.Por otra parte, se investigan fármacos nuevos que puedanprevenir la epileptogénesis, evitar la progresión de la epilepsia ovencer la resistencia al tratamiento farmacológico de algunas epilepsias.Conclusión. La identificación de nuevas dianas farmacológicasen la etiopatogenia de las epilepsias ha permitido el desarrollode los antiepilépticos de segunda generación y está permitiendodesarrollar nuevos antiepilépticos de tercera generación

Introduction. Although 10 second generation new antiepileptic drugs are currently available on the market, 30% ofpatients are resistant to pharmacological treatment. In addition, today’s antiepileptic drugs avert or suppress seizures but do notprevent the appearance of epilepsy or its progression. Development. The foundations of the aetiopathogenesis of epilepsy and themain targets of antiepileptic drugs are described. Describing the important role of gamma-aminobutyric and glutamic acid in thegenesis and proliferation of the seizures has allowed for the development of new antiepileptic drugs that increase the inhibitorytone of GABA or inhibit the excitatory tone of glutamate. The discovery that some epilepsies may be due to channelopathies isnow making it possible to conduct research into drugs that inhibit calcium channels, activate potassium channels or inhibitabnormal AMPA/KA receptor channels. Recent reports describing a specific attachment of some antiepileptic drugs to the a2d subunits of the calcium channel and to the synaptic vesicles proteins SV2A open up new perspectives. Moreover, research is alsobeing carried out on new drugs that are capable of preventing epileptogenesis, stemming the progression of epilepsy orovercoming the resistance to pharmacological treatment displayed by some epilepsies. Conclusions. The identification of newpharmacological targets in the aetiopathogenesis of epilepsies has made it possible to develop second generation antiepilepticdrugs and it is allowing for the development of third generation antiepileptic drugs

[The interactions of antiepileptic drugs in oncology practice]. / Interacciones de los antiepilépticos en la práctica oncológica.

AIMS: Antiepileptic drugs, which often have to be used in patients with cancer, can have important effects on the results offered by antineoplastic agents. Here, we review the influence of antiepileptic drugs on antineoplastic agents and the influence of antineoplastic agents on antiepileptic drugs; measures to prevent such interactions are also suggested. DEVELOPMENT: Antiepileptic drugs that induce cytochrome P450, such as carbamazepine, phenytoin and phenobarbital, can reduce the levels and effects of antineoplastics that metabolise by means of this enzyme, for example, taxanes, Vinca alkaloids, methotrexate, teniposide and camptothecin. Furthermore, enzyme-inducing antiepileptic drugs diminish the levels and effects of many other drugs that can be administered to oncology patients, such as other antiepileptic drugs used in polytherapy, narcotic analgesics, antidepressants, antipsychotics or antibiotics. In contrast, valproate can increase the toxicity of etoposide or nitrosoureas. Moreover, antineoplastic agents like cisplatin or corticoids can lower the effectiveness of phenytoin and methotrexate has a similar effect on valproate. In contrast, 5-fluorouracil can increase the toxicity of phenytoin. Pharmacodynamic interactions are also possible. CONCLUSIONS: Information about the clinical consequences of the interactions between antiepileptics and antineoplastic agents is often based on cases or series of cases, but a growing body of evidence from pharmacokinetic studies shows that enzyme-inducing antiepileptics exert an important influence on the effectiveness of the antineoplastic agents. It is therefore recommendable to avoid them and replace them with non-enzyme-inducing antiepileptics, such as gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate or zonisamide. When enzyme-inducing antiepileptics have to be used, it is likely that higher doses of antineoplastic agents or other inducible drugs will have to be utilised.

Interacciones de los antiepilépticos en la práctica oncológica / The interactions of antiepileptic drugs in oncology practice

Objetivo. Los antiepilépticos, que con frecuencia se tienenque utilizar en el paciente oncológico, pueden interferir de formaimportante con los efectos de los antineoplásicos. Se revisa lainfluencia de los antiepilépticos sobre los antineoplásicos y la delos antineoplásicos sobre los antiepilépticos, y se sugieren medidaspara evitarlas. Desarrollo. Los antiepilépticos que inducen el citocromoP450, como carbamacepina, fenitoína y fenobarbital, puedenreducir los niveles y los efectos de los antineoplásicos que semetabolizan mediante esta enzima como taxanos, alcaloides de lavinca, metotrexato, tenipósido y camptotecina. Además, los antiepilépticosinductores reducen los niveles y los efectos de muchosotros fármacos que se pueden administrar en el paciente oncológico,como otros antiepilépticos utilizados en la politerapia, analgésicosnarcóticos, antidepresivos, antipsicóticos o antibióticos. Ensentido opuesto, el valproato puede aumentar la toxicidad del etopósidoo las nitrosureas. A su vez, los antineoplásicos como el cisplatinoo los corticoides pueden reducir la eficacia de la fenitoína yel metotrexato la del valproato. En sentido opuesto, el 5-fluoruracilo puede aumentar la toxicidad de la fenitoína. También hay posibilidadde interacciones farmacodinámicas. Conclusiones. La informaciónsobre las consecuencias clínicas de las interacciones entreantiepilépticos y antineoplásicos se basan con frecuencia en casoso series de casos, pero hay cada vez más estudios farmacocinéticosque demuestran una importante influencia de los antiepilépticosinductores sobre la eficacia de los antineoplásicos que hace recomendableevitarlos y sustituirlos por antiepilépticos no inductores,como gabapentina, lamotrigina, levetiracetam, pregabalina, topiramatoo zonisamida. Cuando sea necesario utilizar antiepilépticosinductores, es probable que haya que utilizar dosis mayores delos antineoplásicos o de otros fármacos que sean inducibles

Aims. Antiepileptic drugs, which often have to be used in patients with cancer, can have important effects on theresults offered by antineoplastic agents. Here, we review the influence of antiepileptic drugs on antineoplastic agents and theinfluence of antineoplastic agents on antiepileptic drugs; measures to prevent such interactions are also suggested.Development. Antiepileptic drugs that induce cytochrome P450, such as carbamazepine, phenytoin and phenobarbital, canreduce the levels and effects of antineoplastics that metabolise by means of this enzyme, for example, taxanes, Vinca alkaloids,methotrexate, teniposide and camptothecin. Furthermore, enzyme-inducing antiepileptic drugs diminish the levels and effectsof many other drugs that can be administered to oncology patients, such as other antiepileptic drugs used in polytherapy,narcotic analgesics, antidepressants, antipsychotics or antibiotics. In contrast, valproate can increase the toxicity of etoposideor nitrosoureas. Moreover, antineoplastic agents like cisplatin or corticoids can lower the effectiveness of phenytoin andmethotrexate has a similar effect on valproate. In contrast, 5-fluorouracil can increase the toxicity of phenytoin. Pharmacodynamicinteractions are also possible. Conclusions. Information about the clinical consequences of the interactions betweenantiepileptics and antineoplastic agents is often based on cases or series of cases, but a growing body of evidence frompharmacokinetic studies shows that enzyme-inducing antiepileptics exert an important influence on the effectiveness of theantineoplastic agents. It is therefore recommendable to avoid them and replace them with non-enzyme-inducing antiepileptics,such as gabapentin, lamotrigine, levetiracetam, pregabalin, topiramate or zonisamide. When enzyme-inducing antiepilepticshave to be used, it is likely that higher doses of antineoplastic agents or other inducible drugs will have to be utilised

[Use of antiepileptic drugs in bipolar disorder]. / Utilización de los antiepilépticos en el trastorno bipolar.

OBJECTIVE: Bipolar disorder is a chronic disease difficult to treat that generates a high degree of incapacity. Although lithium remains the first choice drug, some patients do not respond and others show adverse reactions. One alternative to lithium is the use of certain antiepileptic drugs. Data on the efficacy of old and new antiepileptic drugs in bipolar disorder obtained in controlled clinical trials are reviewed. DEVELOPMENT: Results in many clinical trial support the use of some old antiepileptic drugs such as carbamazepine and sodium valproate in monotherapy in the acute treatment of severe, mixed or mild manic episodes as well as in the management treatment of bipolar disorder. Overall, new antiepileptic drugs show a better profile of adverse reactions with fewer interactions than lithium, but data on their efficacy in bipolar disorder remain scarce. Oxcarbazepine efficacy in mania is similar to that of the carbamazepine. Lamotrigine is becoming the best alternative to lithium in depressive episodes. Topiramate does not appear to be effective in acute treatment of manic episodes. Levetiracetam seems to produce some benefits, but controlled, randomized and double blind clinical trials are not yet available. Data on gabapentin efficacy are controversial. CONCLUSIONS: Although lithium is still the first choice for the treatment of bipolar disorder, carbamazepine and valproate are also first choice drugs. Oxcarbazepine and lamotrigine may be a good option in some patients. Other new antiepileptic drugs may also be effective in bipolar disorder but more solid evidence of their efficacy is needed.

Ion channels and epilepsy.

The role of voltage-gated and ligand-gated ion channels in epileptogenesis of both genetic and acquired epilepsies, and as targets in the development of new antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised epilepsy with febrile seizures plus and benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of carbamazepine, phenytoin and lamotrigine, and is a probable mechanism for many other classic and novel AEDs. Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the benign neonatal epilepsy and episodic ataxia type 1; they are new targets for AEDs such as retigabine. Voltage-gated Ca2+ channels are involved in neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence seizures; their mutations are a substrate for juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in GABA(A) transmission, and mutations in these channels have been described in some families with juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awakening or juvenile absence epilepsy. Hyperpolarisation-activated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. The Cl- ionophore of the GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with juvenile myoclonic epilepsy or generalised epilepsy with febrile seizures plus; enhancement of GABA(A) inhibitory transmission is the primary mechanism of benzodiazepines and phenobarbital and is a mechanistic approach to the development of novel AEDs such as tiagabine or vigabatrin. Altered GABA(B)-receptor function is implicated in spike-wave seizures. Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans; felbamate, phenobarbital and topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the nicotinic acetylcholine receptor are the substrates for the nocturnal frontal lobe epilepsy. The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.

[Intranasal and buccal midazolam in the treatment of acute seizures]. / Midazolam intranasal y bucal en el tratamiento de las convulsiones agudas.

AIMS: There are several personal and social problems involved in the administration of rectal diazepam that make it unsuitable for use in public places and by non medical workers, in children and especially in teenagers and adults. Intranasal and oral midazolam could be an alternative to rectal diazepam. We review the efficacy and safety of these ways of administering midazolam, which is already used in some countries as a sedative and as an anticonvulsive drug, despite the fact that it has not yet received authorisation. DEVELOPMENT: Intranasal midazolam (INM) was first used as a sedative in dental extractions, echocardiography, endoscopies or surgery, especially in children. After proving its efficacy electroencephalographically in patients with seizures, it started to be used to interrupt acute seizures. In three randomised trials, the efficacy of intranasal and oral midazolam in hospitalised patients was similar to, and even higher than, that of intravenous or rectal diazepam, with a similar speed of action and safety; no studies have been conducted, however, in the extra hospital milieu and its risk of respiratory depression may be like that of other benzodiazepines. One of the problems of using the parenteral solution for intranasal administration is the irritation that is produced by its acidic pH and the relatively large volume that has to be administered. These problems could be reduced by using aerosols containing a solution of midazolam in cyclodextrin, which accomplishes a greater concentration with a pH that is less acidic. Oral administration can be used in patients with nasal secretions or intense movements of the head. CONCLUSIONS: Intranasal or oral midazolam can improve the treatment of acute seizures in the hospital milieu and, more especially, in the extra hospital milieu when patients are attended by non medical staff. There is a need, however, for trials that prove its efficacy and safety in this situation.

[Evidence based treatment of epilepsy]. / Tratamiento de la epilepsia basado en la evidencia.

OBJECTIVE: Evidence based medicine is becoming popular in all fields of medicine. Through systematic reviews, critical evaluation, and statistical strategies such as meta analysis it aids to take decisions in clinical practice. We revise the information on the treatment of epilepsy found in the main sources of evidence based medicine. DEVELOPMENT: After commenting some basic concepts such as systematic review, meta analysis, odds ratio, relative risk and numbers needed to treat, we describe the main primary, secondary and tertiary drug information sources with emphasis on sources of evidence based medicine. Some representative examples are given about the information on treatment of epilepsy found in the main sources of evidence based medicine such as TRIP, DARE, Cochrane Library, clinical practice guidelines, Clinical Evidence or Bandolier. Most clinical trials analyze the efficacy and tolerability of add on new antiepileptic drugs in partial refractory epilepsy. However, we found few trials on efficacy and tolerability of these drugs in monotherapy, in newly diagnosed partial epilepsy, on other types of epilepsy or in children. There are also few trials comparing the new antiepileptic drugs between them or in relation to the old ones. CONCLUSION: Treatment of epilepsy is yet an art more than a science because clinical practice decisions depends on therapeutic habits and clinical expertise more than on the results emerging from randomized and controlled clinical trials. Large comparative trials are needed but relevant criteria of efficacy and validated procedures to evaluate quality of life, tolerability or cognitive function outcomes should be used in these trials.

[Monitoring serum levels of new antiepileptics]. / Monitorización de los niveles séricos de los nuevos antiepilépticos.

AIM: Therapeutic monitoring of old antiepileptic drugs has been useful in improving their use in clinical practice. The new antiepileptic drugs have been developed with the idea that monitoring their serum levels was going to be unnecessary. We review the characteristics of the new antiepileptic drugs that can be relevant to their being monitored and their possible uses. DEVELOPMENT: After discussion of the evolution of the therapeutic monitoring of antiepileptic drugs in general, we take a more detailed look at the requirements needed for it to be useful, such as the indications, the procedure and a correct interpretation of the results. We point out the reasons why monitoring the new antiepileptic drugs can be worthwhile and we examine the characteristics of felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide which may be relevant in their monitoring. These include the type of kinetics, the factors that have an influence on the relationship between dosage and serum levels, the concentration/dose ratio, data on the relationship between serum levels and effects, the factors that can influence this relationship, as well as the characteristics of sampling. CONCLUSION: The new antiepileptic drugs present a wide interindividual and intraindividual variability which leads us to believe that some of they may be suitable candidates for therapeutic monitoring, but at present no target ranges have been clearly defined for any of them. Therefore, routine monitoring cannot be recommended, but it may be useful to establish an individual reference level that allows control over compliance and dosage readjustment in the presence of factors that alter their pharmacokinetics. Specific prospective studies are needed to establish target ranges that allow to individualize dosage in the absence of clinical criteria and to resolve doubts about the efficacy and toxicity of these drugs. Quicker and simpler assays that make monitoring easier are also needed.

Monitorización de los niveles séricos de los nuevos antiepilépticos / Monitoring serum levels of new antiepileptics

Objetivo. La monitorización de los niveles séricos de los antiepilépticos clásicos ha sido útil para mejorar su uso en la práctica clínica. Los nuevos antiepilépticos se han desarrollado considerando que la monitorización de sus niveles séricos no iba a ser necesaria. Se revisan las características de los nuevos antiepilépticos que pueden ser relevantes para su monitorización y su posible utilidad. Desarrollo. Tras comentar la evolución de la monitorización de los niveles séricos de antiepilépticos en general, se abordan con más detalle los requisitos para que sea útil, como las indicaciones, el procedimiento y una correcta interpretación del resultado. Se indican los motivos por los que se considera que la monitorización de los nuevos antiepilépticos puede ser beneficiosa y se revisan las características del felbamato, gabapentina, lamotrigina, oxcarbacepina, tiagabina, topiramato, vigabatrina y zonisamida, que pueden ser relevantes en su monitorización, tales como el tipo de cinética, factores que influyen en la relación entre la dosis y el nivel, índices nivel/dosis, datos sobre la relación entre niveles y efectos, factores que pueden alterar esta relación y dificultar la monitorización así como las características de la obtención de las muestras. Conclusiones. Los nuevos antiepilépticos presentan una amplia variabilidad inter e intraindividual que hacen prever que la monitorización de sus niveles puede ser útil, pero en la actualidad no hay intervalos óptimos claramente definidos para ninguno de ellos. Su monitorización rutinaria no está justificada, pero puede ser provechosa para establecer un nivel de referencia individual que permita controlar el cumplimiento y reajustar la dosis en presencia de factores que alteren su farmacocinética. Se necesitan estudios prospectivos específicos para establecer intervalos óptimos que permitan ajustar la dosis en ausencia de criterios clínicos y resolver dudas sobre la eficacia y toxicidad. También hacen falta métodos analíticos más rápidos y sencillos que faciliten la monitorización (AU)

[Advances in the physiopathology of epileptogenesis: molecular aspects]. / Avances en la fisiopatología de la epileptogénesis: aspectos moleculares.

OBJECTIVE: We review the molecular basis of epileptogenesis and the new perspectives in the treatment of epilepsy. DEVELOPMENT: Epileptogenesis are the molecular and cellular events producing the disordered firing of a subpopulation of neurons resulting in periodic seizures. Epilepsies may be due to genetic and acquired factors. Some idiopathic epilepsies are due to mutant genes coding voltage gated sodium and potassium channels, GABAA receptor chloride channels and nicotinic acetylcholine receptor sodium channels. Genetic defects also produce epilepsy secondary to either neuronal developmental or metabolic abnormalities, and may contribute to acquired epilepsy. Events observed in both animal and human acquired epilepsies are an increase in glutamate levels and NMDA receptor sensitivity, selective lost of pyramidal neurons, mossy fibre sprouting and neosinaptogenesis. There is also a reduction in inhibitory control due to lost of GABAergic interneurons, and a decrease in GABA levels and GABAA receptor sensitivity. Hyperexcitability may be also due to reduction in glial ATPasa activity, increase in astrocytes gap junctions, and decrease in extracellular calcium. Chandelier GABAergic interneuron microlesions and an hyperexcitable thalamus are key in spread of partial seizures. Absences may be caused by cortex hyperexcitability and genetic abnormalities in thalamic voltage gated T calcium channels. Brain stem is key in convulsive seizures. The role of voltage gated potassium, sodium and calcium channels, and GABAergic and glutamatergic neurotransmission in epileptogenesis and treatment of epilepsies are revised. The role of other neurotransmitters and neuromodulators, second messengers, and immediate early genes and neurotrophins are also commented. CONCLUSION: Understanding the molecular basis of epileptogenesis should lead to the rational design of drugs both to prevent the development of epilepsy, and minimize hyperexcitability which may be the result of a genetic or acquired disorder.

[Ion channels and epilepsy]. / Canales iónicos y epilepsia.

OBJECTIVE: We review the role of ligand-gated ion channels and voltage-gated ion channels as a substrate for the epileptogenesis and as targets in the development of new antiepileptic drugs. DEVELOPMENT: Voltage-gated calcium channels are involved in the release of neurotransmitters, in the sustained depolarization-phase of paroxysmal depolarisation shifts (PDS), and in the generation of absences; they are also the genetic substrate of generalized tonic-clonic convulsions and absence-like pattern seen in some mice. The voltage-gated potassium channel has been implicated in the hyperpolarization-phase of PDS, it is the genetic substrate of the long QT syndrome, benign neonatal epilepsy, and episodic ataxia/myokymia syndrome, and it is the target of some antiepileptic drugs which activate this channel. The voltage-gated sodium channel is the target of most of the classical and newer antiepileptic drugs; it is also the substrate for generalized epilepsy with febrile seizures plus. The sodium channel of the nicotinic acetylcholine receptor is the substrate for nocturnal frontal lobe epilepsy. The sodium channels of the AMPA and KA glutamate receptors have been proposed as substrate for juvenile absence epilepsy and are a target for new antiepileptic drugs which inhibit it. The calcium channel of the NMDA glutamate receptor has been implicated in the sustained depolarization-phase of PDS and in epileptogenesis after kindling and is a main target for new antiglutamate drugs. The chloride channel of the GABAA receptor is responsible for the rapid hyperpolarization of PDS, it has been involved in epileptogenesis after kindling, it may be the substrate of the Angelman syndrome, and it is activated by many classical and new antiepileptic drugs. CONCLUSION: The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.

[Antiepileptic drugs and the liver]. / Antiepilépticos e hígado.

OBJECTIVES: We review the metabolism of antiepileptic drugs with particular emphasis on the formation of active metabolites and toxic intermediate metabolites, together with the factors altering this and the possibility of interactions between the antiepileptic drugs themselves and with other drugs. DEVELOPMENT: Most antiepileptic drugs undergo complex metabolic processes in the liver which determine the time course of their concentration in the organism and therefore their therapeutic and toxic effects. Also, the processes by which drugs are metabolised may be influenced by many physiological and pathological factors, as well as the presence of other drugs which cause clinically relevant interactions. We analyze the function of the liver in the metabolism of these drugs with special reference to the microsome oxidation mediated by cytochrome P-450 and the glucuronidation catalysed by glucuronosyltransferase and the processes of enzyme induction and inhibition. Subsequently, we describe the metabolism of the antiepileptic drugs, their main routes of elimination, factors affecting this, role of the active and intermediate metabolites and the involvement of the enzyme induction and inhibition underlying the interactions of these drugs. Finally, we describe the metabolism of the most important classical and new antiepileptic drugs, the isoforms of cytochrome P-450 involved, the factors altering this and the most relevant interactions with other antiepileptic and non-antiepileptic drugs. CONCLUSION: Knowledge of the paths by which the antiepileptic drugs are metabolised, particularly the isoforms of cytochrome P-450 involved facilitates understanding of the influence of various factors on the metabolism of drugs, and also of their complex interactions.

Antiepilépticos e hígado / Antiepileptic drugs and the liver

Objetivo. Estudiar los efectos de las epilepsias, de las crisis y de las descargas electroencefalográficas sobre las funciones cognitivas en el niño, específicamente, el lenguaje. Se considera la relación entre disfasia del desarrollo y epilepsia, teniendo en cuenta que esta asociación puede producirse fortuitamente, como consecuencia de una misma causa o teniendo a la epilepsia como responsable del trastorno del lenguaje, bien de forma crítica o de manera constante (afasia-epiléptica). Desarrollo. Se valora la relación entre disfasia del desarrollo y afasia crítica con las epilepsias, especialmente, el síndrome de afasia-epiléptica adquirida de Landau-Kleffner (SLK). Sobre la base de los hallazgos de la literatura y de una serie personal de nueve casos, se estudian sus características generales, heterogeneidad clínica, signos clínicos asociados, alteraciones electroencefalográficas (presentes en el 100 por ciento de los pacientes); coexistencia de crisis convulsivas (67-90 por ciento); hechos etiopatogénicos invocados pero actualmente no concluyentes; negatividad de los estudios de neuroimagen salvo algunos datos de SPECT y PET; diagnóstico diferencial; evolución clínica y pronóstico difíciles de precisar de antemano. El tratamiento farmacológico y/o quirúrgico, complementado con logopedia y psicopedagogía (buenos resultados en £50 por ciento de los casos), se evalúa en la prudencia que la evolución imprevisible del SLK conlleva. Conclusiones. No puede afirmarse una relación directa entre epilepsia y trastornos del lenguaje, si bien en algunos casos se encuentra esta relación. Se acepta la hipótesis de que el SLK, la epilepsia con punta-onda continua durante el sueño lento y la epilepsia parcial benigna atípica son las formas grave, moderada y ligera, respectivamente, de un mismo síndrome epiléptico; éste aparece en una etapa de maduración en la que el cerebro es especialmente vulnerable, y que se caracteriza por cursar con complejos puntaonda continuos durante el sueño lento, que condicionan trastornos cognitivos y conductuales (AU)

Canales iónicos y epilepsia / Ion channels and epilepsy

Objetivo. Revisar el papel de los canales iónicos dependientes de voltaje y ligados a receptores en la fisiopatología de las epilepsias y en el desarrollo de nuevos antiepilépticos. Desarrollo. Los canales de calcio dependientes de voltaje intervienen en la liberación de neurotransmisores, en la despolarización sostenida de los cambios paroxísticos de despolarización y en la génesis de las ausencias, y son el sustrato de las convulsiones tonicoclónicas generalizadas y ausencias presentes en algunos ratones. El canal de potasio dependiente de voltaje participa en la hiperpolarización que sigue a los cambios paroxísticos de despolarización, es causante del síndrome del QT largo, la epilepsia benigna neonatal, la ataxia episódica con mioquimia y es el lugar de acción de algunos antiepilépticos que activan este canal. El canal de sodio dependiente de voltaje es el lugar de acción de la mayor parte de los antiepilépticos clásicos y nuevos, así como el sustrato de la epilepsia generalizada y las convulsiones febriles plus. El canal de sodio del receptor nicotínico es el sustrato de la epilepsia nocturna del lóbulo frontal. Los canales de sodio de los receptores AMPA y KA son sustrato de la epileptogénesis y los lugares de acción de nuevos antiepilépticos anti-AMPA y anti-KA. El canal de calcio del receptor NMDA es responsable de la despolarización lenta de los cambios paroxísticos de despolarización, es sustrato de la epileptogénesis y desempeña un papel relevante en el desarrollo de nuevos antiepilépticos. El canal de cloro del receptor GABAA es responsable de la fase rápida de hiperpolarización que sigue a los cambios paroxísticos de despolarización, es sustrato de la epileptogénesis, puede serlo del síndrome de Angelman y es el lugar de acción de algunos antiepilépticos clásicos y nuevos. Conclusión. El descubrimiento del papel de los canales iónicos en las epilepsias permite diseñar nuevas estrategias terapéuticas más específicas (AU)

[Pharmacological basis for withdrawal of antiepileptic drugs]. / Bases farmacológicas de la retirada de fármacos antiepilépticos.

OBJECTIVE: To review the pharmacological basis for withdrawal of antiepileptic drugs: the mechanisms by which seizures reappear, aspects of treatment which affect relapses and procedures for withdrawal of medication. DEVELOPMENT: Antiepileptic drugs are not curative, so when they are withdrawn the natural course of the condition becomes evident. Reappearance of seizures may be due to lack of protection and/or an abstinence syndrome. Seizures due to lack of protection occur following withdrawal of any antiepileptic drug when the epilepsy is not cured; they may not reappear for years (although over 80% occur within a year) and treatment then has to be restarted. They seem to be less frequent after withdrawal of carbamazepine or phenytoin than after withdrawing valproate, although the reason for this is not understood. Seizures due to an abstinence syndrome only occur after withdrawing benzodiazepines, phenobarbitone and primidone; they are seen in patients with both active and inactive epilepsy whilst the drug is being withdrawn and tend to be self-limiting. It is not necessary to reintroduce the drug when epilepsy is cured. Felbamate and vigabatrin cause seizures related to their withdrawal, but the mechanism of this is not clear. There is no scientifically established guideline for withdrawing antiepileptic drugs, but it is considered important to stop one at a time, starting with those which may cause abstinence syndromes, followed by the more toxic, less effective antiepileptic drugs, which cause more drug interactions and are more awkward to take. CONCLUSION: Further specific studies are necessary to establish the mechanisms of relapses and the scientific basis for withdrawal of antiepileptic drugs.