Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 61
Filtrar
1.
Epilepsy Res ; 117: 97-103, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26432930

RESUMO

Huperzine A (HupA) is a naturally occurring compound found in the firmoss Huperzia serrata. While HupA is a potent acetylcholinesterase inhibitor, its full pharmacologic profile is incompletely described. Since previous works suggested a capacity for HupA to prophylax against seizures, we tested the HupA antiepileptic potential in pentylenetetrazole (PTZ) rat epilepsy model and explored its mechanism of action by spectral EEG analysis and by paired-pulse transcranial magnetic stimulation (ppTMS), a measure of GABA-mediated intracortical inhibition. We tested whether HupA suppresses seizures in the rat PTZ acute seizure model, and quantified latency to first myoclonus and to generalized tonic-clonic seizure, and spike frequency on EEG. Additionally, we measured power in the EEG gamma frequency band which is associated with GABAergic cortical interneuron activation. Then, as a step toward further examining the HupA antiepileptic mechanism of action, we tested long-interval intracortical inhibition (LICI) using ppTMS coupled with electromyography to assess whether HupA augments GABA-mediated paired-pulse inhibition of the motor evoked potential. We also tested whether the HupA effect on paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA or the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic or GABAA receptors by co-administration of HupA and atropine or PTZ, respectively. In tests of antiepileptic potential, HupA suppressed seizures and epileptic spikes on EEG. Spectral EEG analysis also revealed enhanced gamma frequency band power with HupA treatment. By ppTMS we found that HupA increases intracortical inhibition and blocks PTZ-induced cortical excitation. Atropine co-administration with HupA did not alter HupA-induced intracortical inhibition suggesting independent of muscarinic acetylcholine receptors mechanism in this model. Last, pyridostigmine did not affect the ppTMS-measured cortical inhibition suggesting that HupA-induced effect is centrally-mediated. Our data support antiepileptic HupA applications, and suggest that such activity may be via enhancement of GABAergic intracortical inhibition.


Assuntos
Alcaloides/uso terapêutico , Anticonvulsivantes/uso terapêutico , Córtex Cerebral/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Convulsões/prevenção & controle , Sesquiterpenos/uso terapêutico , Alcaloides/farmacologia , Animais , Anticonvulsivantes/farmacologia , Córtex Cerebral/fisiopatologia , Masculino , Inibição Neural/fisiologia , Pentilenotetrazol , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Sesquiterpenos/farmacologia
2.
Neuroscience ; 150(2): 386-95, 2007 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-17945434

RESUMO

Alpha-secretase (alpha-secretase), cleaves the amyloid precursor protein (APP) within the amyloid-beta (Abeta) sequence, resulting in the release of a secreted fragment of APP (alphaAPPs) and precluding Abeta generation. We investigated the effects of the acetylcholinesterase inhibitor, huperzine A (Hup A), on APP processing and Abeta generation in human neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. Hup A dose-dependently (0-10 microM) increased alphaAPPs release. Therefore, we evaluated two alpha-secretase candidates, a disintegrin and metalloprotease (ADAM) 10 and ADAM17 in Hup A-induced non-amyloidogenic APP metabolism. Hup A enhanced the level of ADAM10, and the inhibitor of tumor necrosis factor-alpha converting enzyme (TACE)/ADAM17 inhibited the Hup A-induced rise in alphaAPPs levels, further suggesting Hup A directed APP metabolism toward the non-amyloidogenic alpha-secretase pathway. Hup A had no effect on Abeta generation in this cell line. The steady-state levels of full-length APP and cell viability were unaffected by Hup A. Alpha-APPs release induced by Hup A treatment was significantly reduced by muscarinic acetylcholine receptor antagonists (particularly by an M1 antagonist), protein kinase C (PKC) inhibitors, GF109203X and calphostin C, and the mitogen-activated kinase kinase (MEK) inhibitors, U0126 and PD98059. Furthermore, Hup A markedly increased the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, which was blocked by treatment with U0126 and PD98059. In addition, Hup A inhibited acetylcholinesterase activity by 20% in neuroblastoma cells. Our results indicate that the activation of muscarinic acetylcholine receptors, PKC and MAP kinase may be involved in Hup A-induced alphaAPPs secretion in neuroblastoma cells and suggest multiple pharmacological mechanisms of Hup A regarding the treatment of Alzheimer's disease (AD).


Assuntos
Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sesquiterpenos/farmacologia , Proteínas ADAM/efeitos dos fármacos , Proteínas ADAM/metabolismo , Proteína ADAM10 , Proteína ADAM17 , Alcaloides , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Antagonistas Muscarínicos/farmacologia , Neuroblastoma , Neurônios/metabolismo , Fragmentos de Peptídeos/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C/metabolismo , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo
3.
Neurology ; 62(8): 1252-60, 2004 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-15111659

RESUMO

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.


Assuntos
Aminas , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Ácidos Cicloexanocarboxílicos , Epilepsia/tratamento farmacológico , Frutose/análogos & derivados , Ácido gama-Aminobutírico , Acetatos/efeitos adversos , Acetatos/farmacocinética , Acetatos/uso terapêutico , Doença Aguda , Adolescente , Adulto , Anticonvulsivantes/farmacocinética , Carbamazepina/efeitos adversos , Carbamazepina/análogos & derivados , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Criança , Ensaios Clínicos Controlados como Assunto/estatística & dados numéricos , Interações Medicamentosas , Medicina Baseada em Evidências/estatística & dados numéricos , Frutose/efeitos adversos , Frutose/farmacocinética , Frutose/uso terapêutico , Gabapentina , Humanos , Lamotrigina , Oxcarbazepina , Topiramato , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética , Triazinas/uso terapêutico
4.
Neurology ; 62(8): 1261-73, 2004 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-15111660

RESUMO

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.


Assuntos
Aminas , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Ácidos Cicloexanocarboxílicos , Epilepsias Parciais/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Frutose/análogos & derivados , Ácido gama-Aminobutírico , Acetatos/efeitos adversos , Acetatos/uso terapêutico , Adulto , Carbamazepina/efeitos adversos , Carbamazepina/análogos & derivados , Carbamazepina/uso terapêutico , Criança , Ensaios Clínicos como Assunto/estatística & dados numéricos , Resistência a Medicamentos , Medicina Baseada em Evidências/estatística & dados numéricos , Frutose/efeitos adversos , Frutose/uso terapêutico , Gabapentina , Humanos , Isoxazóis/efeitos adversos , Isoxazóis/uso terapêutico , Lamotrigina , Levetiracetam , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/uso terapêutico , Oxcarbazepina , Piracetam/efeitos adversos , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Tiagabina , Topiramato , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/uso terapêutico , Zonisamida
5.
Neurology ; 62(7): 1127-33, 2004 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-15079012

RESUMO

OBJECTIVE: To classify the Lennox twin pairs according to modern epilepsy classifications, use the classic twin model to identify which epilepsy syndromes have an inherited component, search for evidence of syndrome-specific genes, and compare concordances from Lennox's series with a contemporary Australian series. METHODS: Following review of Lennox's original files describing twins with seizures from 1934 through 1958, the International League Against Epilepsy classifications of seizures and epileptic syndromes were applied to 169 pairs. Monozygous (MZ) and dizygous (DZ) pairs were subdivided into epilepsy syndromes and casewise concordances estimated. RESULTS: The authors excluded 26 pairs, with 71 MZ and 72 DZ pairs remaining. Seizure analysis demonstrated strong parallels between contemporary seizure classification and Lennox's terminology. Epilepsy syndrome diagnoses were made in 75%. The MZ and DZ casewise concordance estimates gave strong evidence for a major genetic influence in idiopathic generalized epilepsies (0.80 versus 0.00; n = 23). High MZ casewise concordances also supported a genetic etiology in symptomatic generalized epilepsies and febrile seizures. The pairs who were concordant for seizures usually had the same syndromic diagnoses in both twins (86% in MZ, 60% in DZ), suggesting syndrome-specific genes. Apart from partial epilepsies, the MZ casewise concordances were similar to those derived from Australian twin data. CONCLUSIONS: The authors were able to apply contemporary classifications to Lennox's twins. The data confirm genetic bases for common generalized epilepsies as well as febrile seizures and provide further support for syndrome-specific genes. Finally, comparable results to our Australian series were obtained, verifying the value of twin studies.


Assuntos
Doenças em Gêmeos/genética , Epilepsia/genética , Adolescente , Adulto , Idade de Início , América , Austrália , Criança , Pré-Escolar , Doenças em Gêmeos/classificação , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/história , Eletroencefalografia , Epilepsia/classificação , Epilepsia/diagnóstico , Epilepsia/história , Feminino , História do Século XX , Humanos , Lactente , Masculino , Modelos Estatísticos , Sistema de Registros , Reprodutibilidade dos Testes , Estudos Retrospectivos , Terminologia como Assunto , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética
6.
Hum Mol Genet ; 10(17): 1775-83, 2001 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-11532987

RESUMO

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.


Assuntos
Anormalidades Múltiplas/genética , Córtex Cerebral/anormalidades , Ventrículos Cerebrais/anormalidades , Proteínas Contráteis/genética , Proteínas dos Microfilamentos/genética , Aberrações dos Cromossomos Sexuais , Cromossomo X , Envelhecimento , Córtex Cerebral/patologia , Ventrículos Cerebrais/patologia , Análise Mutacional de DNA , Primers do DNA , Feminino , Filaminas , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurônios/patologia , Fenótipo , Polimorfismo Conformacional de Fita Simples , Caracteres Sexuais
7.
Respir Physiol ; 127(2-3): 125-33, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11504585

RESUMO

UNLABELLED: Vagus nerve stimulation is used to reduce the frequency and intensity of seizures in patients with epilepsy. In the present study four such patients were studied while awake. We analyzed the physiological responses to vagus nerve stimulation over a broad range of tolerable stimulus parameters to identify vagal A-fiber threshold and to induce respiratory responses typical of C-fiber activation. A-fiber threshold was determined by increasing stimulation current until laryngeal motor A-fibers were excited (frequency=30 Hz). With A-fiber threshold established, C-fiber excitation was attempted with physiologically appropriate stimulus parameters (low frequency and high amplitude). RESULTS: A-fiber thresholds were established in all patients, threshold currents ranged between 0.5 and 1.5 mA. Stimulation at lower frequency (2-10 Hz) and higher amplitudes (2.75-3.75 mA) did not produce cardiorespiratory effects consistent with C-fiber activation. It is possible that such effects were not observed because vagal C-fibers were not excited, because C-fiber effects were masked by the 'wakeful drive' to breathe, or because epilepsy or the associated therapy had altered central processing of the vagal afferent inputs.


Assuntos
Terapia por Estimulação Elétrica , Epilepsia/terapia , Respiração , Nervo Vago/fisiologia , Adulto , Conscientização , Pressão Sanguínea , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Limiar Sensorial/fisiologia , Nervo Vago/citologia
9.
Expert Opin Pharmacother ; 2(1): 179-87, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11336578

RESUMO

Tiagabine (TGB), a recently approved anti-epileptic drug (AED), has a specific and unique mechanism of action involving the inhibition of gamma-aminobutyric acid (GABA) re-uptake into neurones and glia. TGB is potent and has linear and predictable pharmacokinetics. It does not induce or inhibit hepatic metabolism and has no clinically significant effects on the serum concentrations of other AEDs or commonly used non-AEDs. Double-blind, placebo-controlled studies in primarily hepatic enzyme-induced patients showed that TGB 30 - 56 mg/day is an effective add-on treatment for all subtypes of partial seizures. The most common adverse effects in the trials were dizziness, asthenia (weakness), somnolence, accidental injury, infection, headache, nausea and nervousness. These side effects were usually mild to moderate in severity and generally did not require medical intervention. Long-term safety studies show continued efficacy of TGB over time and no evidence of tolerance for efficacy. Open studies confirm that patients with medically refractory partial epilepsy can be successfully converted to TGB monotherapy and that TGB may be effective for other seizure types, such as infantile spasms.


Assuntos
Epilepsia/tratamento farmacológico , Agonistas GABAérgicos/uso terapêutico , Ácidos Nipecóticos/uso terapêutico , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Agonistas GABAérgicos/efeitos adversos , Agonistas GABAérgicos/farmacocinética , Humanos , Estudos Multicêntricos como Assunto , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiagabina
10.
Expert Opin Investig Drugs ; 9(4): 871-83, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11060716

RESUMO

Remacemide (RMC) is a non-competitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist that does not cause the behavioural and neuropathological side effects seen with other NMDA receptor antagonists. RMC and its active metabolite, AR-R 12495 AR, which has moderate affinity for the NMDA receptor, also interact with voltage-dependent neuronal sodium channels. Both agents show efficacy in a variety of animal models of epilepsy, parkinsonism and cerebral ischaemia. There is no evidence for teratogenicity or genotoxicity. RMC delays the absorption of L-dopa and elevates the concentrations of drugs metabolised by the hepatic cytochrome P450 3A4 isoform. RMC and AR-R 12495 AR have moderate protein binding and linear pharmacokinetics. Controlled studies show evidence of efficacy in treating epilepsy and Parkinson's disease. Post-surgical outcomes in RMC-treated patients at risk for intra-operative cerebral ischaemia are also encouraging. Adverse effects are related to the gastrointestinal and central nervous systems. RMC is a promising drug with numerous potential applications for both acute or chronic conditions associated with glutamate-mediated neurotoxicity.


Assuntos
Acetamidas/uso terapêutico , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Acetamidas/farmacocinética , Acetamidas/farmacologia , Animais , Isquemia Encefálica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Doença de Huntington/tratamento farmacológico , Complicações Intraoperatórias , Fenetilaminas/farmacocinética , Fenetilaminas/farmacologia , Fenetilaminas/uso terapêutico , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos
11.
Epilepsia ; 41(9): 1195-200, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10999559

RESUMO

PURPOSE: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.


Assuntos
Terapia por Estimulação Elétrica , Epilepsia/terapia , Nervo Vago/fisiologia , Humanos , Estudos Longitudinais , Estudos Prospectivos , Resultado do Tratamento
12.
Brain Res ; 878(1-2): 223-7, 2000 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-10996157

RESUMO

We investigated whether basal forebrain cholinergic neurons influence the expression of generalized seizures. Animals received intracerebroventricular injections of saporin (lesioned) or saline (controls) and were tested for susceptibility to flurothyl- or pentylenetetrazole-induced seizures. Lesioned rats had significantly shorter latencies to onset of generalized tonic-clonic seizures than controls. Our findings suggest that basal forebrain cholinergic neurons may participate in the modulation of generalized seizures.


Assuntos
Acetilcolinesterase/metabolismo , Convulsivantes , Epilepsia Generalizada/induzido quimicamente , Imunotoxinas/farmacologia , N-Glicosil Hidrolases , Neurônios/efeitos dos fármacos , Proteínas de Plantas/farmacologia , Prosencéfalo/efeitos dos fármacos , Animais , Denervação , Suscetibilidade a Doenças , Flurotila , Masculino , Neurônios/enzimologia , Neurônios/patologia , Pentilenotetrazol , Prosencéfalo/enzimologia , Prosencéfalo/patologia , Ratos , Ratos Sprague-Dawley , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas
13.
Epilepsy Res ; 39(1): 1-12, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10690748

RESUMO

Autonomic changes accompany seizures in both animals and humans. While ictal autonomic dysfunction can be life-threatening, the participating neural networks involved are poorly understood. In this study we examined the activation of Fos following generalized seizures in brainstem structures known to mediate autonomic function. Adult female rats were sacrificed 2 h after flurothyl-induced seizures. Double-immunostaining for c-Fos and dopamine-beta-hydroxylase (DBH), and c-Fos and phenylethanol-N-methyl-transferase (PNMT) were performed in brainstem slices. Numbers of DBH-labeled neurons expressing Fos-like immunoreactivity (FLI) (DBH/Fos) and PNMT labeled neurons expressing FLI (PNMT/Fos) were counted in the noradrenergic (A1, A2, A5, A7) and adrenergic (C1, C2) cell groups localized in pons and medulla oblongata. Among the experimental animals, the highest degree of co-localization of DBH/Fos neurons was observed in the locus coeruleus (A6; 87.7%), and in the A1(72.8%) cell group located in the caudal ventrolateral medulla (VLM). No co-localization of DBH/Fos neurons was observed in control animals. The highest degree of co-localization of PNMT/Fos neurons was observed in the C1 adrenergic cell group (84.2%) located in the rostral VLM. Control animals showed very few (5.5%) PNMT/Fos co-localized neurons in the C1 adrenergic cell group. Our results indicate that flurothyl-induced generalized seizures in rats activate catecholaminergic neurons in the pons and medulla oblongata. Further studies are necessary to determine whether activation of brainstem catecholaminergic neurons contribute to the autonomic manifestations that frequently accompany epileptic seizures.


Assuntos
Bulbo/metabolismo , Neurônios/metabolismo , Ponte/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Convulsões/metabolismo , Animais , Convulsivantes , Dopamina beta-Hidroxilase/metabolismo , Feminino , Flurotila , Feniletanolamina N-Metiltransferase/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Catecolaminas/metabolismo , Convulsões/induzido quimicamente
14.
Epilepsy Behav ; 1(1): 1, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12609120
15.
Epilepsy Behav ; 1(1): 52-9, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12609127

RESUMO

Some of the disability deriving from epilepsy derives from the postictal state (PS). The PS may be complicated by impaired cognition, headache, injuries, or secondary medical conditions. Postictal depression is common, postictal psychosis relatively rare, but both add to the morbidity of seizures. The mechanisms of the PS are poorly understood. Alteration of cerebral blood flow both results from and contributes to the PS. Many neurotransmitters or neuromodulators are involved in the physiology of the PS. Response to glutamate may partially desensitize after a seizure. Endogenous opiates and adenosine serve as natural antiepileptic medications in some circumstances. Nitric oxide has numerous effects on brain excitability, and may be particularly important in regulating postictal cerebral blood flow. Just as the pathophysiology of seizures is complicated, so is that of the PS multifactorial. As a practical issue, it would be very useful to have medications that reduce the morbidity of the PS.

16.
Epilepsia ; 40 Suppl 9: S20-5, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10612358

RESUMO

Over the past 10 years, the goal of treating epilepsy has evolved from attaining complete control of seizures, regardless of medication-related side effects or psychosocial problems, to enabling the patient to lead a lifestyle consistent with his or her capabilities. The recent introduction of new medications has brought hope to patients who have previously been unable to function optimally because of refractory seizures or side effects. A rational approach to selecting antiepileptic drug (AED) therapy for a particular patient would require a detailed understanding of the underlying cause(s) of seizures in that patient. Unfortunately, this is often not possible. Furthermore, currently available AEDs have been tested on the basis of seizure type rather than etiology. Nevertheless, an individualized empirical approach based on an open dialog with the patient and perseverance is often successful. There have also been significant advances in the understanding of seizures at the cellular level, notably in the role of gamma-aminobutyric acid. Medical, social, and psychosocial issues relevant to particular patient populations (such as women of childbearing age and elderly patients) also must be considered when treatment plans are formulated. The recent addition of new AEDs, with unique mechanisms of action and favorable pharmacokinetic and tolerability profiles, has greatly widened the range of therapeutic options for patients.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Animais , Anticonvulsivantes/administração & dosagem , Prescrições de Medicamentos , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Relações Médico-Paciente , Padrões de Prática Médica , Gravidez , Complicações na Gravidez/tratamento farmacológico , Fatores Sexuais
18.
Epilepsia ; 40 Suppl 5: S17-22, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10530690

RESUMO

Tiagabine (TGB) is a recently approved antiepileptic drug (AED) that inhibits y-aminobutyric acid (GABA) reuptake into neurons and glia, a mechanism of action that is specific and unique among the AEDs. TGB is potent and has linear and predictable pharmacokinetics. It has no clinically relevant effects on hepatic metabolism or serum concentrations of other AEDs, effects on laboratory values, or interactions with common non-AEDs. TGB is effective as add-on therapy for partial seizures in patients with medically refractory epilepsy in doses ranging from 30 to 56 mg daily. Conversion to TGB monotherapy can be achieved in patients with medically refractory epilepsy, although additional controlled studies are needed to confirm the efficacy of TGB as monotherapy and to establish the effective dosage range. In controlled studies, the most common adverse events of TGB are dizziness, asthenia, somnolence, accidental injury, infection, headache, nausea, and nervousness. These are usually mild to moderate in severity and almost always resolve without medical intervention.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Ácidos Nipecóticos/uso terapêutico , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Ensaios Clínicos como Assunto , Esquema de Medicação , Quimioterapia Combinada , Epilepsias Parciais/tratamento farmacológico , Humanos , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/farmacologia , Tiagabina , Resultado do Tratamento , Ácido gama-Aminobutírico/metabolismo
20.
Epilepsy Res ; 35(1): 1-11, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10232789

RESUMO

We studied physiological and sensory effects of left cervical vagal stimulation in six adult patients receiving this stimulation as adjunctive therapy for intractable epilepsy. Stimulus strength varied among subjects from 0.1 to 2.1 microCoulomb (microC) per pulse, delivered in trains of 30-45 s at frequencies from 20 to 30 Hz; these stimulation parameters were standard in a North American study. The stimulation produced no systematic changes in ECG, arterial pressure, breathing frequency tidal volume or end-expiratory volume. Five subjects experienced hoarseness during stimulation. Three subjects with high stimulus strength (0.9-2.1 microC) recalled shortness of breath during stimulation when exercising; these sensations were seldom present during stimulation at rest. No subjects reported the thoracic burning sensation or cough previously reported with chemical stimulation of pulmonary C fibers. Four of six subjects (all those receiving stimuli at or above 0.6 microC) experienced a substantial reduction in monthly seizure occurrence at the settings used in our studies. Although animal models of epilepsy suggest that C fibers are the most important fibers mediating the anti-seizure effect of vagal stimulation, our present findings suggest that the therapeutic stimulus activated A fibers (evidenced by laryngeal effects) but was not strong enough to activate B or C fibers.


Assuntos
Terapia por Estimulação Elétrica , Epilepsias Parciais/terapia , Hemodinâmica , Mecânica Respiratória , Sensação , Nervo Vago , Adulto , Pressão Sanguínea , Terapia Combinada , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/fisiopatologia , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Reflexo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA