RESUMEN
Hyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Oxigenoterapia Hiperbárica , Oxígeno/toxicidad , Convulsiones/inducido químicamente , Bloqueadores de los Canales de Sodio/administración & dosificación , Tiagabina/administración & dosificación , Animales , Carbamazepina/administración & dosificación , Gabapentina/administración & dosificación , Lamotrigina/administración & dosificación , Ratones Endogámicos C57BL , Convulsiones/tratamiento farmacológicoRESUMEN
The series of experiments herein evaluated prototype drugs representing different mechanisms of antiseizure, antinociceptive or antidepressant action in a battery of preclinical pain models in adult male CF#1 mice (formalin, writhing, and tail flick) and Sprague Dawley rats partial sciatic nerve ligation (PSNL). In the formalin assay, phenytoin (PHT, 6 mg/kg), sodium valproate (VPA, 300 mg/kg), amitriptyline (AMI, 7.5 and 15 mg/kg), gabapentin (GBP, 30 and 70 mg/kg), tiagabine (TGB, 5 and 15 mg/kg), and acetominophen (APAP, 250 and 500 mg/kg) reduced both phases of the formalin response to ≤ 25% of vehicle-treated mice. In the acetic acid induced writhing assay, VPA (300 mg/kg), ethosuximide (ETX, 300 mg/kg), morphine (MOR, 5 & 10 mg/kg), GBP (10, 30, and 60 mg/kg), TGB (15 mg/kg), levetiracetam (LEV, 300 mg/kg), felbamate (FBM, 80 mg/kg) and APAP (250 mg/kg) reduced writhing to ≤ 25% of vehicle-treated mice. In the tail flick test, MOR (1.25-5 mg/kg), AMI (15 mg/kg) and TGB (5 mg/kg) demonstrated significant antinociceptive effects. Finally, carbamazepine (CBZ, 20 and 50 mg/kg), VPA, MOR (2 and 4 mg/kg), AMI (12 mg/kg), TPM (100 mg/kg), lamotrigine (LTG, 40 mg/kg), GBP (60 mg/kg), TGB (15 mg/kg), FBM (35 mg/kg), and APAP (250 mg/kg) were effective in the PSNL model. Thus, TGB was the only prototype compound with significant analgesic effects in each of the four models, while AMI, GBP, APAP, and MOR each improved three of the four pain phenotypes. This study highlights the importance evaluating novel targets in a variety of pain phenotypes.
Asunto(s)
Analgésicos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Modelos Animales de Enfermedad , Neuralgia/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Analgésicos/farmacología , Animales , Anticonvulsivantes/farmacología , Antidepresivos/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Masculino , Ratones , Neuralgia/patología , Ácidos Nipecóticos/farmacología , Ácidos Nipecóticos/uso terapéutico , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Roedores , TiagabinaRESUMEN
The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation-inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15-30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta-ERD) and movement-related gamma synchronisation (MRGS) (60-90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated.
Asunto(s)
Ritmo beta/fisiología , Sincronización Cortical/fisiología , Corteza Motora/fisiología , Movimiento/fisiología , Ácido gamma-Aminobutírico/metabolismo , Adulto , Ritmo beta/efectos de los fármacos , Sincronización Cortical/efectos de los fármacos , Estudios Cruzados , Femenino , Agonistas del GABA/farmacología , Humanos , Magnetoencefalografía , Masculino , Corteza Motora/efectos de los fármacos , Ácidos Nipecóticos/farmacología , Procesamiento de Señales Asistido por Computador , Tiagabina , Adulto JovenRESUMEN
We analyzed the effect of combination therapy on seizure frequency in all adult patients (N=193) with focal epilepsy followed at a single institution in a cross-sectional study. One hundred and thirty-five patients were on two AEDs, of them, 37 (27%) were seizure-free, 50 patients were on three AEDs including 5 (10%) seizure-free patients (p<0.01 for seizure-freedom with two AEDs versus three AEDs). Thirty-five different combinations were used in patients on two AEDs and 40 combinations on patients on three drugs emphasizing the difficulties involved in evaluation of the efficacy and tolerability of specific combinations. The significant proportion of seizure-free cases (27%) on duotherapy is suggesting the usefulness of combination therapy in achieving seizure-freedom in epilepsies refractory to single drug treatment. The material in the study was not from a randomized trial and therefore the comparability of patients on different AEDs is uncertain, but on the other hand the clinical practice followed provides a natural experiment suitable for comparative, non-randomized assessment of treatment outcomes.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Encéfalo/anatomía & histología , Encéfalo/fisiopatología , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatología , Adulto , Carbamazepina/análogos & derivados , Carbamazepina/uso terapéutico , Quimioterapia Combinada , Femenino , Lóbulo Frontal/fisiopatología , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Humanos , Lamotrigina , Levetiracetam , Masculino , Ácidos Nipecóticos/uso terapéutico , Lóbulo Occipital/fisiopatología , Oxcarbazepina , Lóbulo Parietal/fisiopatología , Piracetam/análogos & derivados , Piracetam/uso terapéutico , Convulsiones/diagnóstico , Lóbulo Temporal/fisiopatología , Tiagabina , Topiramato , Resultado del Tratamiento , Triazinas/uso terapéutico , Ácido Valproico/uso terapéuticoRESUMEN
New generation antiepileptic drugs, including gabapentin and tiagabine, are used in monotherapy or in combination with other drugs for specific seizure types. The multidirectional mechanism of activity and varied pharmacological properties of these drugs suggest that they could also be used in the therapy of other diseases. A possible limitation of new generation antiepileptic drugs is the incidence of CNS-related adverse effects. Few studies have assessed the effect of new antiepileptic drugs on electroencephalogram (EEG) recordings in subjects using these drugs for diseases other than epilepsy. The aim of this study was to determine the effects of tiagabine and gabapentin on EEG recordings from the midbrain reticular formation, dorsal hippocampus and frontal cortex in rabbits. Tiagabine was administered orally at a single dose of 5 and 20 mg kg(-1), or repeatedly at a dose of 5 mg kg(-1) (twice a day) for 14 days. Gabapentin was administered orally at a single dose of 25 and 100 mg kg(-1), or repeatedly at a dose of 25 mg kg(-1) (twice a day) for 14 days. Both tiagabine and gabapentin caused changes indicative of CNS inhibitory properties, which may be associated with the adverse effects of the drugs. After repeated doses of the drugs, the changes in EEG recordings were less pronounced than after single doses, which may indicate adaptive changes. The hippocampus was found to be the least sensitive to the effect of gabapentin.
Asunto(s)
Aminas/farmacología , Anticonvulsivantes/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Electroencefalografía/efectos de los fármacos , Ácidos Nipecóticos/farmacología , Ácido gamma-Aminobutírico/farmacología , Aminas/administración & dosificación , Animales , Anticonvulsivantes/administración & dosificación , Ácidos Ciclohexanocarboxílicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Lóbulo Frontal/efectos de los fármacos , Gabapentina , Hipocampo/efectos de los fármacos , Masculino , Metencéfalo/efectos de los fármacos , Ácidos Nipecóticos/administración & dosificación , Conejos , Tiagabina , Ácido gamma-Aminobutírico/administración & dosificaciónRESUMEN
PURPOSE: To explore acute effects of pregabalin (PGB) on human motor cortex excitability with transcranial magnetic stimulation (TMS). METHODS: PGB, 600 mg/day, was orally administered in 19 healthy subjects twice daily in a randomized, double-blind, placebo-controlled crossover design. Several measures of motor cortex excitability were tested with single- and paired-pulse TMS. RESULTS: Mean short-interval intracortical inhibition (SICI) was reduced after PGB (74 +/- 7% of unconditioned response) compared with placebo (60 +/- 6% of unconditioned response). In contrast, mean long-interval intracortical inhibition (LICI) was increased by PGB (26 +/- 4% of unconditioned response) compared with placebo (45 +/- 8% of unconditioned response), and mean cortical silent period (CSP) showed an increase from 139 +/- 8 ms or 145 +/- 8 ms after placebo to 162 +/- 7 ms or 161 +/- 10 ms after PGB. Motor thresholds, intracortical facilitation, and corticospinal excitability were unaffected. CONCLUSIONS: The observed excitability changes with oppositional effects on SICI and LICI or CSP suggest gamma-aminobutyric acid (GABA)B-receptor activation. They are markedly distinct from those induced by gabapentin, although both PGB and gabapentin are thought to mediate their function by binding to the alpha2-delta subunit of voltage-gated calcium channels. Conversely, the TMS profile of PGB shows striking similarities with the pattern evoked by the GABA-reuptake inhibitor tiagabine.
Asunto(s)
Anticonvulsivantes/farmacología , Corteza Motora/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Estimulación Magnética Transcraneal/estadística & datos numéricos , Ácido gamma-Aminobutírico/análogos & derivados , Adulto , Aminas/farmacología , Canales de Calcio/efectos de los fármacos , Canales de Calcio/fisiología , Ácidos Ciclohexanocarboxílicos/farmacología , Método Doble Ciego , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Gabapentina , Humanos , Masculino , Corteza Motora/fisiología , Inhibición Neural/fisiología , Inhibidores de la Captación de Neurotransmisores/farmacología , Ácidos Nipecóticos/farmacología , Placebos , Pregabalina , Receptores de GABA-B/efectos de los fármacos , Receptores de GABA-B/fisiología , Reclutamiento Neurofisiológico/efectos de los fármacos , Reclutamiento Neurofisiológico/fisiología , Tiagabina , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Cocaine addiction continues to be an important public health problem worldwide. At present, there are no proven pharmacotherapies for cocaine addiction. The studies reviewed here revealed a number of emerging targets for cocaine pharmacotherapy. First, disulfiram, a medication with dopaminergic effects, reduced cocaine use in a number of clinical trials. Second, GABA medications, tiagabine and topiramate, were found promising in clinical trials. Third, a beta-adrenergic blocker, propranolol, may be effective especially among cocaine-addicted individuals with high withdrawal severity. Fourth, treatment with a stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine that slows entry of cocaine into the brain holds promise. These promising findings need to be further tested in controlled clinical trials.
Asunto(s)
Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Compuestos de Bencidrilo/uso terapéutico , Encéfalo/enzimología , Estimulantes del Sistema Nervioso Central/uso terapéutico , Cocaína/inmunología , Disulfiram/farmacología , Disulfiram/uso terapéutico , Dopamina/metabolismo , Dopaminérgicos/farmacología , Dopaminérgicos/uso terapéutico , Dopamina beta-Hidroxilasa/antagonistas & inhibidores , Dopamina beta-Hidroxilasa/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Agonistas del GABA/uso terapéutico , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Inhibidores de Recaptación de GABA , Humanos , Modafinilo , Ácidos Nipecóticos/uso terapéutico , Propranolol/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiagabina , Vacunas/uso terapéutico , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Twenty novel N-diarylalkenyl-piperidinecarboxylic acid derivatives were synthesized and evaluated as gamma-aminobutyric acid uptake inhibitors. The biological assay showed that (R)-1-[4,4-bis(3-phenoxymethyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic hydrochloride possessed almost as strong GAT1 inhibitory activity as tiagabine. The synthesis and structure-activity relationships are discussed.
Asunto(s)
Ácidos Carboxílicos/química , Agonistas del GABA/farmacología , Ácidos Pipecólicos/química , Ácido gamma-Aminobutírico/metabolismo , Animales , Transporte Biológico , Ácidos Carboxílicos/síntesis química , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Agonistas del GABA/química , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Neuronas/metabolismo , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacología , Ácidos Pipecólicos/síntesis química , Relación Estructura-Actividad , Tiagabina , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
The aim of this study was to characterise the types of interactions between gabapentin (GBP), tiagabine (TGB) and three second-generation antiepileptic drugs (AEDs) with different mechanisms of action (felbamate [FBM], loreclezole [LCZ], and oxcarbazepine [OXC]) by isobolographic analysis. Anticonvulsant and acute neurotoxic adverse effect profiles of combinations of GBP and TGB with other AEDs at fixed ratios of 1:3, 1:1 and 3:1 were investigated in pentylenetetrazole (PTZ)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated for each combination in order to properly classify the investigated interactions. Isobolographic analysis revealed that only the combination of GBP with OXC at the fixed ratio of 1:1 exerted supra-additive (synergistic) interaction (P<0.05) against PTZ-induced seizures. The other combinations tested between GBP and OXC (1:3 and 3:1), as well as all combinations of GBP with FBM or LCZ (1:3, 1:1 and 3:1) were additive in the PTZ test. Similarly, all combinations of TGB with FBM LCZ, and OXC (at the fixed ratios of 1:3, 1:1 and 3:1) were associated with additive interactions against PTZ-induced seizures in mice. In the chimney test, the isobolographic analysis revealed that the combinations of GBP and OXC (at the fixed ratios of 1:3 and 1:1), GBP and LCZ (at 1:1), as well as TGB and OXC (at 1:3 and 1:1) were sub-additive (antagonistic; P<0.05 and P<0.01). In contrast, only one combination tested (TGB and LCZ at the fixed ratio of 1:1) was supra-additive (synergistic; P<0.05) in the chimney test, whereas the other combinations of GBP and TGB with OXC, FBM, and LCZ displayed barely additivity. Based upon the current preclinical data, GBP and OXC appear to be a particularly favourable combination. Also, the combinations of GBP with FBM, GBP with LCZ, and TGB with OXC are beneficial. In contrast, during the combining of TGB with FBM, or TGB with LCZ, the utmost caution is advised because of their unfavourable profiles in this preclinical study.
Asunto(s)
Anticonvulsivantes/farmacología , Convulsiones/prevención & control , Aminas/farmacología , Animales , Carbamazepina/análogos & derivados , Carbamazepina/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Quimioterapia Combinada , Gabapentina , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ácidos Nipecóticos/farmacología , Oxcarbazepina , Pentilenotetrazol , Convulsiones/inducido químicamente , Tiagabina , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Changes in gene expression were examined in the brain of mice treated with a drug of abuse, 3,4-methylenedioxymethamphetamine (MDMA, also called Ecstasy). Frontal cortex and midbrain mRNA, analyzed by differential display polymerase chain reaction (DD-PCR) method, showed an altered expression of several cDNAs, 11 of which were isolated, cloned and sequenced. The sequence of one MDMA-induced mRNA corresponds (99.3%) to the mouse gamma-amino butyric acid (GABA) transporter 1 (mGAT1). The established involvement of GABA neurotransmission in the activity of several abused drugs prompted us to focus herein on MDMA effect on the GABA transporter gene family. Semi-quantitative PCR analysis with primers selective to the reported mGAT1 sequence confirmed that MDMA treatment increased mGAT1 expression. Time-course study of the expression of the three GABA transporter subtypes showed that MDMA induced a differential temporal activation of mGAT1 and mGAT4, but had no effect on mGAT2. Quantitative real-time PCR further proved the increased expression of mGAT1 and mGAT4 upon MDMA treatment. Western immunoblotting with anti-GAT1 antibodies showed that MDMA also increased GAT1 protein levels, suggesting that neurotransmission of GABA was altered. MDMA effect was also verified in serotonin transporter knockout (-/-) mice that are insensitive behaviorally to MDMA; the drug did not increase GAT1 protein level in these mutants. In mice, tiagabine and NO-711, inhibitors of GABA transporters, restrained MDMA-induced acute toxicity and death. These results should facilitate novel approaches to prevent deleterious effects, including fatality, induced by MDMA and similar abused psychostimulants.
Asunto(s)
Proteínas Portadoras/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de la Membrana/efectos de los fármacos , Proteínas de Transporte de Membrana , Mesencéfalo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Transportadores de Anión Orgánico , Animales , Proteínas Portadoras/clasificación , Proteínas Portadoras/genética , Clonación Molecular , Proteínas Transportadoras de GABA en la Membrana Plasmática , Masculino , Proteínas de la Membrana/clasificación , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados/metabolismo , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Proteínas del Tejido Nervioso/efectos de los fármacos , Ácidos Nipecóticos/farmacología , Oximas/farmacología , Isoformas de Proteínas/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serotonina/genética , Serotonina/metabolismo , Tiagabina , Ácido gamma-Aminobutírico/efectos de los fármacosRESUMEN
Localization-related epilepsy, the most common type of seizure disorder, often provides major management problems. Five new antiepileptic drugs (AEDs) with different mechanisms of action have been licensed in the United Kingdom in the 1990s for adjunctive use in the management of poorly controlled partial seizures. These were, in chronologic order, vigabatrin, lamotrigine, gabapentin, topiramate, and tiagabine. Their practical deployment is explored here. Mention also is made of clobazam and acetazolamide. Combination therapy with two or even three AEDs having complementary pharmacologic effects can provide an essential contribution to the management of partial seizures. This article discusses some of the pharmacologic strategies used in treating patients with refractory localization-related epilepsy.
Asunto(s)
Aminas , Anticonvulsivantes/uso terapéutico , Ácidos Ciclohexanocarboxílicos , Epilepsias Parciales/tratamiento farmacológico , Ácido gamma-Aminobutírico , Acetatos/administración & dosificación , Acetatos/uso terapéutico , Anticonvulsivantes/administración & dosificación , Esquema de Medicación , Quimioterapia Combinada , Fructosa/administración & dosificación , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Gabapentina , Humanos , Lamotrigina , Ácidos Nipecóticos/administración & dosificación , Ácidos Nipecóticos/uso terapéutico , Pautas de la Práctica en Medicina , Tiagabina , Topiramato , Resultado del Tratamiento , Triazinas/administración & dosificación , Triazinas/uso terapéutico , Vigabatrin/administración & dosificación , Vigabatrin/uso terapéuticoRESUMEN
The present study examines the effect of tiagabine (a selective inhibitor of GABA transporter 1, GAT-1), SNAP-5114 (a semi-selective inhibitor of rat GAT-3/mouse GAT4) and NNC 05-2045 (a non-selective GABA uptake inhibitor) in modulating GABA levels in the hippocampus and thalamus. Anticonvulsant effects of the same compounds were assessed (after intranigral administration) after maximal electroshock (MES) in juvenile rats. Anticonvulsant effects were also tested after intraperitoneal (i.p.) administration against audiogenic seizures in DBA/2 mice and against pentylentetrazole (PTZ)-induced tonic convulsions or MES in NMRI mice. Tiagabine (30 microM, perfused through the microdialysis probe in halothane anaesthetized rats) increased GABA levels to (% basal+/-SEM) 645+/-69 in the hippocampus and 409+/-61 in the thalamus. SNAP-5114 (100 microM) increased GABA levels in the thalamus (% basal+/-SEM) to 247+/-27 but had no effect on hippocampal GABA-levels. NNC 05-2045 (100 microM) increased GABA levels both in the hippocampus (% basal+/-SEM, 251+/-51) and in the thalamus (298+/-27). All compounds protected against tonic hindlimb extension (THE) in juvenile male rats after intranigral administration. Sound induced convulsions in DBA/2 mice were dose-dependently inhibited by all compounds (administered intraperitoneal, i.p.) with ED(50) values of 1, 6 and 110 micromol/kg, for tiagabine, NNC 05-2045 and SNAP-5114, respectively. Tiagabine and NNC 05-2045 but not SNAP-5114 protected against PTZ-induced tonic convulsions whereas only NNC 05-2045 protected against MES-induced tonic convulsions in NMRI mice. However, tiagabine and NNC 05-2045 exerted a synergistic effect in the MES model. These findings substantiate and extend previous findings of different effects of selective versus non-selective GABA uptake inhibitors in animal models of epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Ácido gamma-Aminobutírico/metabolismo , Estimulación Acústica , Anestesia , Animales , Anisoles/farmacología , Carbazoles/farmacología , Cromatografía Líquida de Alta Presión , Convulsivantes/farmacología , Electrochoque , Femenino , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Microdiálisis , Ácidos Nipecóticos/farmacología , Pentilenotetrazol/antagonistas & inhibidores , Pentilenotetrazol/farmacología , Piperidinas/farmacología , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Sustancia Negra/fisiología , Tálamo/efectos de los fármacos , Tálamo/metabolismo , TiagabinaRESUMEN
Evidence based health care uses systematic literature reviews with statistical strategies like meta-analysis to aid decision-making. This information can help clinicians by organizing data and providing up-to-date quantitative summaries of efficacy and adverse effects of treatments. Limitations of meta-analysis include problems inherent in combining data from trials of somewhat different design, choice of appropriate dosages, and summarizing complex questions as a single odds ratios. I summarize the results of a meta-analysis of the following antiepileptic treatments for partial seizures in adults: gabapentin, lamotrigine, topiramate, tiagabine, valproate and the vagal nerve stimulator. Each treatment was significantly more efficacious than placebo, and there were nonsignificant trends toward differences among the treatments in efficacy and tolerability. Quantitative analysis of adverse effects is presented. Absent the availability of a comprehensive randomized controlled trial for comparison, a rigorously conducted meta-analysis provides some useful information.
Asunto(s)
Aminas , Anticonvulsivantes/uso terapéutico , Ácidos Ciclohexanocarboxílicos , Epilepsias Parciales/tratamiento farmacológico , Medicina Basada en la Evidencia , Ácido gamma-Aminobutírico , Acetatos/efectos adversos , Acetatos/uso terapéutico , Adulto , Anticonvulsivantes/efectos adversos , Intervalos de Confianza , Esquema de Medicación , Terapia por Estimulación Eléctrica/efectos adversos , Epilepsias Parciales/terapia , Medicina Basada en la Evidencia/estadística & datos numéricos , Fructosa/efectos adversos , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Gabapentina , Humanos , Lamotrigina , Ácidos Nipecóticos/efectos adversos , Ácidos Nipecóticos/uso terapéutico , Oportunidad Relativa , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiagabina , Topiramato , Triazinas/efectos adversos , Triazinas/uso terapéutico , Nervio Vago/fisiologíaRESUMEN
GABA release and uptake were examined in Genetic Absence Epilepsy Rats from Strasbourg and in non-epileptic control animals, using crude synaptosomes prepared from the cerebral cortex and thalamus. Uptake of [3H]GABA over time was reduced in thalamic synaptosomes from epileptic rats, compared to controls. The affinity of the uptake process in thalamic synaptosomes was lower in epileptic animals. NNC-711, a ligand for the GAT-1 uptake protein, reduced synaptosomal uptake by more than 95%; beta-alanine, an inhibitor selective for the uptake proteins GAT-2 and -3, did not significantly reduce synaptosomal uptake. Autoradiography studies using [3H]tiagabine, a ligand selective for GAT-1, revealed no differences between the strains in either affinity or levels of binding. Ethanolamine O-sulphate (100 microM), a selective inhibitor of GABA-transaminase, did not affect uptake levels. Aminooxyacetic acid (10-100 microM), an inhibitor of GABA-transaminase and, to a lesser extent, glutamate decarboxylase, caused an increase in measured uptake in both thalamic and cortical synaptosomes, in both strains. We found no difference in in vitro basal or KCl-stimulated endogenous GABA release between epileptic and control rats. These results indicate that GABA uptake in the thalamus of Genetic Absence Epilepsy Rats from Strasbourg was reduced, compared to control animals. The lower uptake affinity in the epileptic animals probably contributed to the reduction in uptake over time. Uptake appeared to be mediated primarily by the 'neuronal' transporter GAT-1. Autoradiography studies revealed no differences in the number or affinity of this uptake protein. It is therefore possible that altered functional modulation of GAT-1 caused the decrease in uptake shown in the epileptic animals. Inhibition of GABA-transaminase activity had no effect on measured GABA uptake, whereas a reduction in glutamate decarboxylase activity may have affected measured uptake levels.
Asunto(s)
Epilepsia/metabolismo , Sinaptosomas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ácido Aminooxiacético/farmacología , Animales , Autorradiografía , Corteza Cerebral/ultraestructura , Epilepsia/genética , GABAérgicos/farmacología , Agonistas del GABA/metabolismo , Antagonistas del GABA/farmacología , Cinética , Ácidos Nipecóticos/metabolismo , Ácidos Nipecóticos/farmacología , Oximas/farmacología , Ratas , Ratas Mutantes , Tálamo/ultraestructura , Tiagabina , Tritio , beta-Alanina/farmacologíaRESUMEN
The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/farmacología , Ácidos Nipecóticos/farmacología , Nociceptores/efectos de los fármacos , Receptores de GABA-B/metabolismo , Abdomen/fisiopatología , Animales , Baclofeno/farmacología , Constricción Patológica/inducido químicamente , Constricción Patológica/prevención & control , Relación Dosis-Respuesta a Droga , Reacción de Fuga/efectos de los fármacos , Espacio Extracelular/metabolismo , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Masculino , Ratones , Microdiálisis , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Compuestos Organofosforados/farmacología , Dolor/prevención & control , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Tálamo/efectos de los fármacos , Tálamo/metabolismo , Tálamo/fisiopatología , Tiagabina , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
A case of complex partial status epilepticus (CPSE) with high dose treatment of tiagabine (TGB) is reported. Seizure aggravation and CPSE developed after stepwise increase of TGB to a dose of 60 mg per day as add-on treatment to carbamazepine (CBZ) 1200 mg/day and vigabatrine (VGB) 1000 mg/day. The EEG during CPSE showed bilateral rhythmic slow activity. Clinical symptoms of CPSE and the EEG normalized after i.v. treatment with clonazepam. The literature and the possible mechanism of this paradoxical phenomenon are discussed.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Electroencefalografía/efectos de los fármacos , Epilepsia Parcial Compleja/diagnóstico , Epilepsia Parcial Compleja/tratamiento farmacológico , Ácidos Nipecóticos/uso terapéutico , Adulto , Carbamazepina/uso terapéutico , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Tiagabina , Vigabatrin , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
The presynaptically located gamma-aminobutyric acid (GABA) transporter (GAT-1) was studied in a group of patients with Alzheimer's disease (AD) and in a control group using the GAT-1 selective radioligand [3H]tiagabine. Post mortem brain tissue from frontal cortex, temporal cortex, and caudate nucleus from 18 AD patients and 23 age-matched controls were studied. The binding was saturable (Kd 26 nM) and region specific. There were no significant differences between the groups with respect to the binding capacity (Bmax) and binding affinity (Kd). The unaltered [3H]tiagabine binding to GAT-1 protein indicates that intrinsic GABA neurons are spared in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Química Encefálica , Proteínas Portadoras/análisis , Proteínas de la Membrana/análisis , Proteínas de Transporte de Membrana , Transportadores de Anión Orgánico , Anciano , Anciano de 80 o más Años , Núcleo Caudado/química , Femenino , Lóbulo Frontal/química , Agonistas del GABA/metabolismo , Agonistas del GABA/farmacología , Proteínas Transportadoras de GABA en la Membrana Plasmática , Humanos , Masculino , Neuritas/química , Ácidos Nipecóticos/metabolismo , Ácidos Nipecóticos/farmacología , Lóbulo Temporal/química , Tiagabina , Tritio , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.
Asunto(s)
Aminas , Anticonvulsivantes/uso terapéutico , Ácidos Ciclohexanocarboxílicos , Epilepsia/tratamiento farmacológico , Acetatos/efectos adversos , Acetatos/uso terapéutico , Anticonvulsivantes/clasificación , Carbamazepina/administración & dosificación , Carbamazepina/uso terapéutico , Diazepam/administración & dosificación , Diazepam/uso terapéutico , Aprobación de Drogas , Diseño de Fármacos , Interacciones Farmacológicas , Resistencia a Medicamentos , Epilepsia/dietoterapia , Epilepsia/etiología , Epilepsia/genética , Epilepsia/patología , Felbamato , Fructosa/efectos adversos , Fructosa/análogos & derivados , Fructosa/uso terapéutico , Gabapentina , Humanos , Inyecciones Intravenosas , Cetonas , Lamotrigina , Inhibidores de la Captación de Neurotransmisores/efectos adversos , Inhibidores de la Captación de Neurotransmisores/uso terapéutico , Ácidos Nipecóticos/efectos adversos , Ácidos Nipecóticos/uso terapéutico , Fenilcarbamatos , Fenitoína/administración & dosificación , Fenitoína/análogos & derivados , Fenitoína/uso terapéutico , Profármacos/uso terapéutico , Glicoles de Propileno/efectos adversos , Glicoles de Propileno/uso terapéutico , Tiagabina , Topiramato , Triazinas/efectos adversos , Triazinas/uso terapéutico , Estados Unidos , Ácido Valproico/administración & dosificación , Ácido Valproico/uso terapéutico , Vigabatrin , Ácido gamma-Aminobutírico/efectos adversos , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
PURPOSE: Traditional methods of preclinical screening have predicted the effects of a putative antiepileptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pentylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: nonefficacy); (b) lamotrigine (LTG) (PTZ: nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ: efficacy; human: possible proabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ: efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lh/lh model for LTG, VGB, TGB, GBP, and TPM. METHODS: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8-week-old male lh/lh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding 15-min epochs of the 150-min period after administration. RESULTS: LTG (4.8-144 micromol/kg) significantly (p < 0.04) reduced seizure frequency (by 65%) compared with vehicle. In contrast, VGB (0.35-11 mmol/kg) and TGB (0.27-27 micromol/kg) significantly increased seizure frequency (300-700%) and seizure duration (1,700-1,800%; p < 0.001). GBP (18 micromol/kg to 1.8 mmol/kg) and TPM (8.9-295 micromol/kg) had no significant effect on seizure frequency. CONCLUSIONS: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lh/lh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.
Asunto(s)
Aminas , Anticonvulsivantes/uso terapéutico , Ácidos Ciclohexanocarboxílicos , Epilepsia Tipo Ausencia/tratamiento farmacológico , Acetatos/farmacología , Acetatos/uso terapéutico , Animales , Anticonvulsivantes/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Electroencefalografía/efectos de los fármacos , Epilepsia Tipo Ausencia/genética , Fructosa/análogos & derivados , Fructosa/farmacología , Fructosa/uso terapéutico , Gabapentina , Humanos , Lamotrigina , Masculino , Ratones , Ácidos Nipecóticos/farmacología , Ácidos Nipecóticos/uso terapéutico , Tiagabina , Topiramato , Triazinas/farmacología , Triazinas/uso terapéutico , Vigabatrin , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
The Third Eilat Conference on New Antiepileptic Drugs was held at the Royal Beach Hotel from May 27 to May 30, 1996. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss critical issues in drug development, new antiepileptic drugs (AEDs) in development, progress reports and recent findings of newly marketed AEDs, the use of AEDs in special populations and their utilization in non-epileptic disorders. Over the last seven years, six new AEDs have been introduced worldwide and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate and vigabatrin. Drugs in development include those at an advanced stage, such as remacemide and tiagabine, as well as those just entering clinical trials, such as rufinamide (CGP 331010) and levetiracetam (ucb LO59). The following is a summary of the presentations for drugs in development and recent findings on newly marketed drugs.