[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

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.

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

Objetivo. El diacepam rectal plantea problemas personales y sociales que lo hacen inadecuado para su uso en lugares públicos y por personal no sanitario, en niños y especialmente en adolescentes y adultos. El midazolam intranasal (MIN) y bucal podría ser una opción al diacepam rectal. Se revisa la eficacia y seguridad de estas formas de administración del midazolam que se utilizan ya en algunos países como sedante y como anticonvulsionante, a pesar de que todavía no se han autorizado. Desarrollo. El MIN comenzó a utilizarse como sedante, especialmente en niños, para extracciones dentales, ecocardiografía, endoscopias o cirugía. Tras verificar electroencefalográficamente su eficacia en pacientes con convulsiones, empezó a utilizarse para interrumpir las convulsiones agudas. En tres ensayos aleatorizados, la eficacia del midazolam intranasal y bucal en pacientes hospitalizados fue similar e incluso superior a la del diacepam intravenoso o rectal, con similares rapidez de acción y seguridad; pero no hay estudios en el medio extrahospitalario, y su riesgo de depresión respiratoria puede ser similar al de otras benzodiacepinas. Un problema de utilizar la solución parenteral para la administración intranasal es la irritación que producen su pH ácido y el volumen relativamente alto que se ha de administrar. Estos problemas podrían reducirse con la utilización de aerosoles de una solución de midazolam en ciclodextrina, que consigue una concentración mayor con un pH menos ácido. En los pacientes con secreciones nasales o con movimientos intensos de cabeza puede preferirse la administración bucal. Conclusiones. El midazolam intranasal o bucal puede mejorar el tratamiento de las convulsiones agudas en el medio hospitalario y, especialmente, en el medio extrahospitalario, cuando los pacientes son atendidos por personal no sanitario; pero se requieren ensayos que demuestren su eficacia y seguridad en este medio (AU)

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 buccal 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 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 buccal 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. Buccal administration can be prefered in patients with nasal secretions or intense movements of the head. Conclusions. Intranasal or buccal 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 (AU)

[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.

Bases farmacológicas de la retirada de fármacos antiepilépticos / The pharmacological basis for withdrawal of antiepileptic drugs

Objetivo. Objetivo. Revisar las bases farmacológicas de la retirada de los antiepilépticos: mecanismos de reaparición de las crisis, variables del tratamiento que influyen en las recidivas y procedimientopara suprimir la medicación. Desarrollo. Los antiepilépticos no son curativos, por lo que su retirada pone de manifiesto la evolución natural de la epilepsia. La reaparición de las crisis puede deberse adesprotección y síndrome de abstinencia. Las crisis por desprotección surgen tras la supresión de cualquier antiepiléptico cuando la epilepsia no está curada; pueden tardar años en aparecer (aunquemás del 80 por ciento se presentan en el primer año) y requieren la reintroducción del tratamiento. Parecen ser menos frecuentes tras la retirada de la carbamacepina o la fenitoína que el valproato, pero sedesconoce el motivo. Las crisis por síndrome de abstinencia sólo las producen las benzodiacepinas, el fenobarbital y la primidona; se observan, tanto en pacientes con epilepsia activa como inactiva,durante la supresión y suelen ser autolimitadas, por lo que no requieren reintroducir la medicación cuando la epilepsia está curada. El felbamato y la vigabatrina producen crisis relacionadas con el cesede su administración, pero su mecanismo no está claro. No hay una pauta de supresión científicamente establecida, pero se considera importante interrumpir los antiepilépticos uno a uno, empezando por los que pueden producir síndrome de abstinencia y siguiendo por los antiepilépticos más tóxicos, menos eficaces, con más interacciones y más incómodos de tomar. Conclusión. Se necesitan estudiosmás específicos para establecer los mecanismos de las recidivas y las bases científicas de la supresión de los antiepilépticos (AU)

[The use of intravenous valproate]. / Utilización del valproato por vía intravenosa.

OBJECTIVE: To review the role of intravenous valproate (i.v. VPA) as an alternative to the oral route in the acute treatment of epileptic seizures and status epilepticus, and to establish criteria for its use. DEVELOPMENT: The bioavailability and tolerance of i.v. VPA, when administered in infusion for 60 minutes every 6 hours, are similar to those of oral VPA. Much of the data on acute administration, by injections of 3 to 5 minutes, for the treatment of seizures, are from series of cases and summaries from congresses and require confirmation. However, they suggest that i.v. VPA may be useful for the treatment of: a) convulsions due to insufficient blood drug levels or failure to take the drug, in order to rapidly raise the drug levels; b) a generalized convulsive status which is partially resistant to diazepam and phenytoin, as a non-depressant alternative to phenobarbital and other CNS depressants, and c) a non-convulsive status as an alternative to benzodiazepines when it is desired to avoid their side effects or when the treatment is going to be continued with oral VPA. The initial dose should be based on the concentration to be reached and the patient's previous VPA levels; the maintenance dose should be based on the stable level to be maintained, the age of the patient and the presence of enzyme inducers. CONCLUSION: Intravenous VPA would seem to offer new perspectives for the acute treatment of seizures, but its usefulness may be critically dependent on its correct use based on clinical and pharmacokinetic principles.

Trends in the supply and use of lipid-lowering drugs in Spain, 1983 through 1991.

Trends in the supply and use of lipid-lowering drugs in Spain were studied throughout the period of 1983-1991. Although the supply of such drugs remains excessive, a trend towards more rational standards has been apparent: 20 specialties out of 53 existing in 1983 have been withdrawn (10 fixed-dose combinations and 10 obsolete drugs). The overall use of lipid-lowering drugs rose from 2.51 DDD/1000 inhab/day in 1983 to 8.47 DDD/1000 inhab/day in 1991. The increase was mostly attributable to the subgroup of fibric acid derivatives (1.23 DDD/1000 inhab/day in 1983 and 6.14 in 1991). The bile acid sequestrants accounted for a small fraction of the overall use (0.23 DDD/inhab/day in 1991), in spite of its increasing consumption. The use of the two subgroups, nicotinic acid derivatives and fixed-dose combinations, has declined. The introduction into the market of HMG-CoA reductase inhibitors in 1991 contributed to the increase of the overall use in 1.28 DDD/1000 inhab/day but it seems not to have any negative influence on the use of other subgroups. Although the prevalence rates of hypercholesterolemia are similar, the use of lipid-lowering drugs in 1991 in Spain was 3 to 8 times higher than that of the Nordic countries. In conclusion, our data suggest that lipid-lowering drugs are highly used in Spain, at least in comparison with other western countries, and that the pattern of drug use is not in accordance with international recommendations.

Interference of digoxin-like immunoreactive substances with TDx digoxin II assay in different patients.

The TDx digoxin II immunoassay was used in controls and in patients not taking digoxin or any other cardiac glycoside. We report the frequency of interference thought to be caused by digoxin-like factors (DLFs). We found a high incidence of false-positive results in 15 patients with severe hepatic disease (60% false-positive results). In newborn infants we found false-positive results both when their blood was drawn from a peripheral vein (89% false-positive results) and, more strikingly (100% false-positive results), when it was obtained from an umbilical cord vein (p less than 0.001). Compared to a control group, no statistically significant false-positive results were found in patients with mild to moderate chronic renal failure (n = 21) or in pregnant women (n = 15). In patients with chronic renal failure undergoing hemodialysis six of 25 had false-positive results. These results suggest that digoxin levels must be interpreted carefully in patients with chronic liver disease and chronic renal failure and in newborns until new methods that eliminate the interference caused by DLFs become readily available.