RESUMEN
OBJECTIVES: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. METHODS: Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. RESULTS: Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. CONCLUSIONS: Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.
Asunto(s)
Anticonvulsivantes/farmacocinética , Dibenzazepinas/farmacocinética , Adulto , Anciano , Anticonvulsivantes/efectos adversos , Dibenzazepinas/efectos adversos , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Convulsiones/tratamiento farmacológicoRESUMEN
In neurological malignancies, antiepileptic drugs (AEDs) are frequently used to control the seizure activity that accompanies the disorder. There is a growing body of evidence on the importance of AED selection for reasons other than pharmacokinetics (PK) properties. Epigenetic modifications may occur in glioblastomas, such as changes in gene methylation and histone acetylation states. Secondary mechanisms of AED drug action which impact these epigenetic modifications could play a significant role in patient survival outcomes. Both valproic acid (VPA) and carbamazepine have histone deacetylase (HDAC) inhibitory activities, and levetiracetam and VPA reduce the activity of O6-methylguanine-DNA methyltransferase (MGMT), a DNA-repair molecule implicated in resistance to alkylating agents used for chemotherapy. The use of AEDs for purposes other than seizure prophylaxis and their selection based on non-PK properties present a potential paradigm shift in the field of neuro-oncology.
Asunto(s)
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Animales , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/metabolismo , Carbamazepina/farmacocinética , Carbamazepina/uso terapéutico , Humanos , Levetiracetam , Piracetam/análogos & derivados , Piracetam/farmacocinética , Piracetam/uso terapéutico , Convulsiones/etiología , Convulsiones/metabolismo , Ácido Valproico/farmacocinética , Ácido Valproico/uso terapéuticoRESUMEN
Vigabatrin (VGB), an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase, is approved as adjunct treatment of refractory partial seizures as well as infantile spasms. Although VGB has been proven to be effective, its use is limited by the risk of retinopathy and associated peripheral visual field defects. This review describes and analyzes current literature related to potential pathophysiologic mechanisms underlying VGB-mediated cellular toxicity. Animal data suggest that GABA mediates neural excitotoxicity. The amino acid taurine is concentrated in retinal cells, and deficiency of this amino acid may be involved in VGB-mediated retinal degeneration and possible phototoxicity.
Asunto(s)
Anticonvulsivantes/efectos adversos , Enfermedades de la Retina/inducido químicamente , Enfermedades de la Retina/metabolismo , Taurina/metabolismo , Vigabatrin/efectos adversos , Animales , Epilepsia/tratamiento farmacológico , HumanosRESUMEN
This document summarizes the proceedings of an expert panel consensus process addressing the nonemergency use of parenteral phenytoin products for management of seizures in pediatric and adult patients. The algorithm and consensus statements developed by the expert panel emphasize strategies for lowering the probability of adverse events associated with the use of parenteral phenytoin products. Specific patient characteristics are defined to guide administration and monitoring of parenteral phenytoin therapy. The algorithm provides a decision pathway for the selection of the product and the route of administration of phenytoin sodium or fosphenytoin sodium after it has been determined that a parenteral phenytoin product is appropriate. Key factors covered in the algorithm include a list of patient characteristics and considerations necessary to prevent parenteral phenytoin adverse effects during selection of administration route and recommendations for monitoring of parenteral phenytoin therapy once it has been initiated. Situations requiring rapid attainment of high phenytoin concentrations, such as in the management of acute seizures, are not addressed in these guidelines.
Asunto(s)
Algoritmos , Anticonvulsivantes/administración & dosificación , Fenitoína/análogos & derivados , Fenitoína/administración & dosificación , Convulsiones/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Niño , Costos y Análisis de Costo , Humanos , Infusiones Intravenosas , Inyecciones Intramusculares , Persona de Mediana Edad , Fenitoína/efectos adversos , Fenitoína/uso terapéutico , SeguridadRESUMEN
OBJECTIVE: To evaluate the steady-state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady-state therapeutic doses of valproate. METHODS: This was an open-label, randomized, three-way crossover study of 18 normal male volunteers. Subjects received oral valproate (500 mg Depakote twice a day) throughout the study. Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) for 1 week each, with a 2-week washout period between lamotrigine treatment periods. Valproate and lamotrigine trough plasma samples were determined by a capillary gas chromatography method and immunofluorometric assay, respectively. Urine samples were assayed for 11 valproate metabolites by gas chromatography/mass spectrometry. RESULTS: When compared to other studies in which lamotrigine was administered with no concurrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug. The addition of lamotrigine was associated with a small but significant 25% decrease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pentenoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E),4-diene-valproate], was unaffected by lamotrigine administration. CONCLUSIONS: As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.
Asunto(s)
Anticonvulsivantes/farmacocinética , Triazinas/farmacocinética , Ácido Valproico/farmacocinética , Análisis de Varianza , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacología , Esquema de Medicación , Interacciones Farmacológicas , Semivida , Humanos , Lamotrigina , Masculino , Valores de Referencia , Factores de Tiempo , Triazinas/administración & dosificación , Triazinas/efectos adversos , Triazinas/farmacología , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversos , Ácido Valproico/farmacologíaRESUMEN
Long-term treatment with the anticonvulsant valproate (VPA) leads to well-documented weight gain and obesity in humans. In an attempt to develop an animal model of this condition, adult rats were given VPA 20 g/kg (high-dose) or 2 g/kg (low-dose) in their daily feeding or orally 120 mg/kg body weight/day in two divided doses, and food intake and body weight were assessed. Valproate resulted in lower body weights in all protocols. Food intake was lower (p<0.001) for rats receiving high-dose VPA than for controls. Feed efficiency (change in weight divided by cumulative food intake for that period) was lower than that of controls for both high (p<0.0001) and low doses (NS). Metabolic rate and physical activity were not different between control and VPA animals, although decreased food intake would be expected to decrease metabolic rate. Valproate failed to produce obesity in rats in any treatment period. For reasons that are unclear, rats do not appear to be suitable as a model to study this adverse side effect of VPA in humans with epilepsy.
Asunto(s)
Anticonvulsivantes/toxicidad , Obesidad/inducido químicamente , Ácido Valproico/toxicidad , Animales , Anticonvulsivantes/sangre , Peso Corporal/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ácido Valproico/sangreRESUMEN
PURPOSE: To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. METHODS: Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). RESULTS: Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. CONCLUSIONS: Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.
Asunto(s)
Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacocinética , Piracetam/análogos & derivados , Piracetam/farmacocinética , Adulto , Anciano , Algoritmos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Levetiracetam , Masculino , Persona de Mediana Edad , Caracteres SexualesRESUMEN
PURPOSE: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. METHOD: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). RESULTS: sixty-two patients (33.6+/-11.3 years, 47+/-9.9 kg) receiving LTG monotherapy (n=19) or polytherapy with VPA (n=15), inducer(s) (n=32) or both (n=5) were evaluated. LTG dose of 369+/-236 mg per day (8.1+/-5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8+/-3.3 microg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/F) were 0. 69+/-0.2, 1.60+/-0.65 and 0.2+/-0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/F. CONCLUSION: LTG Cl/F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.
Asunto(s)
Anticonvulsivantes/farmacocinética , Discapacidades del Desarrollo/metabolismo , Epilepsia/metabolismo , Triazinas/farmacocinética , Ácido Valproico/farmacocinética , Adolescente , Adulto , Algoritmos , Anticonvulsivantes/sangre , Niño , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Discapacidades del Desarrollo/complicaciones , Interacciones Farmacológicas , Epilepsia/complicaciones , Femenino , Humanos , Lamotrigina , Masculino , Persona de Mediana Edad , Modelos Biológicos , Población , Triazinas/sangre , Ácido Valproico/sangreRESUMEN
Drug interactions can significantly complicate the management of patients receiving multiple medications. It is essential therefore that potential pharmcokinetic interactions be evaluated as new antiepileptic medications are introduced. Lamotrigine (LTG) is a recently marketed medication whose pharmacokinetics are significantly influenced by concomitant drugs. Felbamate (FBM), another relatively new antiepileptic agent has been associated with multiple interactions including both enzyme induction and inhibition. The purpose of the present pilot study was to evaluate potential differences in lamotrigine kinetics in six patients concomitantly receiving FBM compared to five patients receiving lamotrigine as monotherapy. There was no statistically significant differences in either apparent LTG oral clearance (0.026 +/- 0.005 vs. 0.024 +/- 0.01 l/kg per h, respectively), or in mean elimination half-life (33.7 +/- 7.5 vs. 40.2 +/- 15.05 h, respectively). Oral clearance values in our patients are also consistent with data reported previously in the literature. Data from this pilot study suggest that a marked effect of FBM upon lamotrigine pharmacokinetics is unlikely.
Asunto(s)
Anticonvulsivantes/farmacocinética , Glicoles de Propileno/farmacocinética , Triazinas/farmacocinética , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Niño , Interacciones Farmacológicas , Felbamato , Femenino , Semivida , Humanos , Lamotrigina , Masculino , Persona de Mediana Edad , Fenilcarbamatos , Proyectos Piloto , Glicoles de Propileno/administración & dosificación , Triazinas/administración & dosificaciónRESUMEN
Although lamotrigine (LTG) appears to have a low propensity to cause pharmacokinetic interactions with other medications, it has been suggested that LTG may interfere with the elimination of carbamazepine 10,11-epoxide (CBZE), the active metabolite of carbamazepine (CBZ). Evidence for this pharmacokinetic interaction is inconclusive and conflicting, however. We evaluated CBZ apparent oral clearance and the steady-state CBZE/CBZ serum concentration ratios in nine patients (30.8 +/- 7.7 years) with epilepsy prior to and following the initiation of adjunctive treatment with LTG. Overall, CBZ oral clearance was unchanged following the introduction of LTG (5.58 +/- 1.60 vs. 5.81 +/- 1.74 1/h, P = 0.630). Likewise, CBZE to CBZ serum concentration ratios were not significantly different (0.241 +/- 0.082 vs. 0.232 +/- 0.082, P = 0.782). These observations suggest that the addition of LTG did not result in a significant pharmacokinetic interaction involving either CBZ or CBZE.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Carbamazepina/análogos & derivados , Carbamazepina/sangre , Epilepsia/tratamiento farmacológico , Triazinas/uso terapéutico , Administración Oral , Adulto , Epilepsia/sangre , Femenino , Humanos , Lamotrigina , Masculino , Tasa de Depuración MetabólicaRESUMEN
UNLABELLED: Gabapentin (GBP) is a non-metabolized, non-plasma protein bound, renally excreted antiepileptic drug that is actively absorbed via the system L amino acid transporter. Previous studies have demonstrated that gabapentin displays dose-dependent absorption. OBJECTIVES: These studies were conducted to determine inter- and intra-subject variability of gabapentin absorption. Two prospective clinical studies in healthy adult volunteers were conducted. Coefficient of variation (CV) was used to express variability of gabapentin absorption. METHODS: Study A: 400-mg single dose, randomized, cross-over study to assess bioavailability of four different gabapentin formulations (n=20, 9 males, 11 females; mean age and weight 41 years, 75.1 kg). Plasma was serially collected up to 48 h and bioavailability (F) calculated post-dose to determine concentration-time curves (AUC). All four formulations were bioequivalent, thus repeated measures analysis was performed to assess inter-and intra-subject variability. Study B: 600-mg single dose study (n=50, 15 males, 35 females; mean age and weight 31.1 years, 72.7 kg) was conducted to determine inter-subject variability in gabapentin F. Urine was collected over 48 h and bioavailability (F) calculated. Urine and plasma gabapentin concentrations were measured by HPLC-UV. RESULTS: Study A: Overall mean (CV) of GBP AUC values was 34.1+/-24 ug/h per ml. Inter-subject CV for AUC was 22.5% and intra-subject CV was 12.1%. Study B: Overall mean (SD) GBP F was 49.3+/-13.6%. Inter-subject CV of F was 27.6%. DISCUSSION: The inter-subject variability in gabapentin absorption is substantially less than that of the inter-subject variability. This indicates that one would expect a wide range in gabapentin absorption between subjects; however, a much smaller variability within a subject. The within subject variability of gabapentin is small enough that plasma drug monitoring may be used to assess gabapentin absorption for a given subject and the benefit of dose individualization.
Asunto(s)
Acetatos/farmacocinética , Aminas , Anticonvulsivantes/farmacocinética , Ácidos Ciclohexanocarboxílicos , Ácido gamma-Aminobutírico , Acetatos/sangre , Acetatos/orina , Adulto , Análisis de Varianza , Anticonvulsivantes/sangre , Anticonvulsivantes/orina , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Gabapentina , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The anticonvulsant gabapentin is transported across biological membranes via the L-amino acid transport system (System-L). Absorption of gabapentin is saturable, and in-vitro data have previously demonstrated that both L-leucine and L-phenylalanine may compete with the intestinal transport of gabapentin. The purpose of this study therefore was to determine whether a high-protein meal would interfere with gabapentin absorption. Ten healthy volunteers received in a randomized, cross-over design, a single 600-mg dose of gabapentin in the fasting state and after a high-protein meal consisting of 80 gm total protein (4.1 g phenylalanine, 8.2 g leucine and 4.2 g isoleucine), 52 g carbohydrate, and 9 g fat. Plasma gabapentin concentrations were measured by HPLC at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 30 h. Calculated pharmacokinetic parameters included Cmax' Tmax' AUC and T1/2. In addition, a pharmacodynamic assessment (using visual analog scales) of gabapentin-related adverse effects was performed at 2 h post drug ingestion and was compared between study phases. Statistical analysis included Student's t-test for paired data, with significance assigned at P < 0.05. Cmax was significantly increased by 36% (3.87 +/- 1.15 vs 5.28 +/- .97 micrograms/ml, P = 0.002), and Tmax tended to be shorter (3.9 +/- 1.8 vs 2.8 +/- .35 h, P = 0.10), after the high-protein meal. Although AUC was increased by 11%, this did not achieve statistical significance. Despite significantly higher plasma concentrations at 2 h, subjects reported significantly fewer adverse effects after the high-protein meal. Potential mechanisms to explain these unexpected findings may be that the large amino acid load delivered with the high-protein meal enhanced gabapentin absorption via trans-stimulation, the process by which acutely increased intestinal luminal amino acid concentrations result in an acute up regulation in System-L activity. Conversely, the decrease in perceived adverse CNS effects of gabapentin following the high-protein meal may reflect CNS competition for System-L transport.
Asunto(s)
Acetatos/farmacocinética , Aminas , Anticonvulsivantes/farmacocinética , Ácidos Ciclohexanocarboxílicos , Proteínas en la Dieta , Ácido gamma-Aminobutírico , Adulto , Ingestión de Alimentos , Femenino , Gabapentina , Humanos , MasculinoRESUMEN
UNLABELLED: Gabapentin (GBP) is a non-metabolized antiepileptic drug that is eliminated by renal excretion and displays saturable, dose dependent absorption. The recommended dosing schedule for GBP is t.i.d. At large daily doses, oral bioavailability (F) may be improved by giving the daily dose more frequently. OBJECTIVE: To evaluate whether switching GBP dosage regimen from t.i.d. to q.i.d. results in increased oral bioavailability. METHODS: This study consisted of two parts; a computer simulated pharmacokinetic model and a clinical pharmacokinetic study in nine adult epileptic patients receiving 3600 mg/day and 11 receiving 4800 mg/day. All patients were evaluated during both t.i.d. and q.i.d. regimens. F were determined by calculation of percent of dose excreted unchanged using steady-state 24-h urine collections and were compared using a paired t-test. RESULTS: At 3600 mg/day, mean F following t.i.d. and q.i.d. dosing were 38.7+/-22.1% and 40.0+/-18.9%, respectively (P=0.738). At 4800 mg/day, mean F following t.i.d. and q.i.d. dosing were 29.2+/-16.2% and 35.6+/-17.6%, respectively (P=0.006). DISCUSSION: Good agreement was observed between values from this study and predicted values based on the pharmacokinetic model. Improved GBP F at doses of 3600 mg/day was not achieved with more frequent drug administration, and thus is not warranted. At 4800 mg/day, a 22% increase in F was observed with more frequent drug dosing. CONCLUSION: GBP F may be significantly increased by q.i.d. versus t.i.d. dosing, depending upon dose level. This increase in F however must be balanced against the inconvenience of more frequent dosing. Therapeutic drug level monitoring may aid in the evaluation of such pharmacokinetic maneuvers.
Asunto(s)
Acetatos/farmacocinética , Aminas , Anticonvulsivantes/farmacocinética , Ácidos Ciclohexanocarboxílicos , Epilepsia/tratamiento farmacológico , Ácido gamma-Aminobutírico , Acetatos/sangre , Acetatos/uso terapéutico , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Disponibilidad Biológica , Epilepsia/metabolismo , Femenino , Gabapentina , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A physician's choice of an antiepileptic drug (AED) usually depends upon the patient's seizure type. But the pharmacokinetic characteristics of AEDs can further help determine the best drug for a particular patient. These characteristics, including absorption, elimination pathway, and potential for drug interactions, are of critical importance for patients who take other medication for comorbid conditions and for patients with impaired renal or hepatic function. The ideal AED would have a rapid, linear, consistent absorption rate with complete clearance, low plasma protein binding, and rapid central nervous system penetration. It would be eliminated predominantly by the kidneys. The new AEDs do not prompt the same concerns about interactions because they have much better pharmacokinetic profiles than the older drugs and as a result require less monitoring for potential interactions.
Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/clasificación , Anticonvulsivantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Monitoreo de Drogas , Epilepsia/clasificación , Humanos , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Estados UnidosRESUMEN
A 13-year-old boy with Lennox-Gastaut syndrome characterized by absence, myoclonic, complex-partial, and secondarily generalized tonic-clonic seizures, presents with progressive obtundation and loss of motor and verbal skills over a 2-day period. Initial evaluation revealed therapeutic phenytoin serum concentrations. This article discusses the differential diagnosis and management approach used in this setting, as well as the appropriate interpretation of antiepileptic drug serum concentrations.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Trastornos de la Conciencia/etiología , Fenitoína/efectos adversos , Estado Epiléptico , Enfermedad Aguda , Adolescente , Hormona Adrenocorticotrópica/uso terapéutico , Anticonvulsivantes/sangre , Trastornos de la Conciencia/diagnóstico , Diagnóstico Diferencial , Relación Dosis-Respuesta a Droga , Electroencefalografía , Humanos , Masculino , Fenitoína/sangre , Estado Epiléptico/complicaciones , Estado Epiléptico/diagnóstico , Estado Epiléptico/tratamiento farmacológico , SíndromeRESUMEN
Neuroimaging and the neuropsychological evaluation are important components of the presurgical evaluation for epilepsy surgery. Advances in neuroimaging over the last decade, to a large part, underlie improvements in pediatric epilepsy surgery outcomes. The neuropsychological evaluation plays an important role in the evaluation of the older child and adolescent, particularly in the evaluation of mesial temporal sclerosis. However, its role in the young child being considered for surgery remains to be defined. This section reviews the definition of medical intractability, issues related to medication withdrawal during video-EEG monitoring, recent neuroimaging advances, and the neuropsychological evaluation.
Asunto(s)
Encéfalo/patología , Epilepsia/diagnóstico , Epilepsia/cirugía , Pruebas Neuropsicológicas , Adolescente , Anticonvulsivantes , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/cirugía , Niño , Preescolar , Diagnóstico Diferencial , Dominancia Cerebral , Electroencefalografía/métodos , Epilepsia/patología , Epilepsia/psicología , Humanos , Cuidados Preoperatorios , Pronóstico , Cintigrafía/métodos , Convulsiones/inducido químicamente , Resultado del TratamientoRESUMEN
Hyperammonemia is an adverse effect of valproate (VPA) treatment. In particular, transient hyperammonemia has been reported to occur in VPA-treated patients after protein-rich meals. This phenomenon may occur secondary to a VPA-mediated carnitine insufficiency. We sought to confirm that protein ingestion would result in transient hyperammonemia and to determine whether supplementation with L-carnitine would prevent this effect. We studied the effect of consumption of a standardized protein-rich meal (45 g protein) before (phase I) and after (phase II) administration of L-carnitine 50 mg/kg/day for 7 days in 11 epileptic children (13.3 +/- 2.3 years of age) receiving VPA. Venous blood was obtained during fasting (baseline) and at 2 and 4 hours after the protein-rich meal for analysis of ammonia (NH3), and VPA concentrations. Mean VPA trough concentrations did not differ significantly at any time. After protein ingestion, 2-hour NH3 concentration increased by 86% (P < .05) from baseline in phase I as compared with a 38% increase in phase II. In both phases I and II, 4-hour NH3 concentrations decreased toward baseline values. We conclude that (1) modest protein ingestion can result in significant transient increases in NH3 in VPA-treated children, (2) significant increases may occur in patients with normal fasting NH3 concentrations, (3) these increases can be significantly attenuated by L-carnitine supplementation, and (4) these changes do not appear to be related to changes in VPA concentration.
Asunto(s)
Amoníaco/sangre , Anticonvulsivantes/efectos adversos , Carnitina/uso terapéutico , Dieta , Epilepsia/tratamiento farmacológico , Ácido Valproico/efectos adversos , Administración Oral , Adolescente , Niño , Epilepsia/sangre , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits.
Asunto(s)
Inmunosupresores/uso terapéutico , Inmunoterapia , Esclerosis Múltiple/terapia , Adulto , Azatioprina/uso terapéutico , Cladribina/uso terapéutico , Ensayos Clínicos como Asunto , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Ciclosporinas/uso terapéutico , Acetato de Glatiramer , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Interferones/uso terapéutico , Péptidos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de TiempoRESUMEN
The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits.
Asunto(s)
Inmunoterapia/métodos , Esclerosis Múltiple/terapia , Corticoesteroides/uso terapéutico , Hormona Adrenocorticotrópica/uso terapéutico , Adulto , Azatioprina/uso terapéutico , Ensayos Clínicos como Asunto , Antígenos HLA-D/inmunología , Humanos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/inmunología , RecurrenciaRESUMEN
The paper evaluates the efficacy of the newer anticonvulsant lamotrigine in a developmentally disabled patient population. A retrospective evaluation was done at two institutional centres to assess adjunctive lamotrigine (Lamictal) efficacy in a developmentally disabled population. Mean seizure frequency was compared between a 2-month pre-lamotrigine baseline period and a 2-month treatment period. A 3-month lamotrigine titration phase occurred between baseline and treatment periods. Seizure frequency data was obtained from standardized, daily seizure records. Adverse effect data was obtained from medical and nursing notes. An intent to treat analysis was performed. Data were analysed using Student's t-test for paired data. We evaluated 44 centre residents (25 male, 19 female, average age 33 +/- 11 years). Mean lamotrigine dose was 272 +/- 133 mg per day. A significant reduction in seizure frequency was noted. Seizure frequency (all seizures) was 10.1 +/- 11.2 during the baseline period vs. 5.8 +/- 7.9 seizures per month during the treatment period (P = 0.002). Thirty-two percent of patients (n = 14) had greater than a 75% reduction in seizure frequency. Twenty-three percent of patients (n = 10) had a 50-74% seizure reduction. Twenty-five percent of patients (n = 11) had less than a 50% reduction in seizures, while 20% (n = 9) had an increase in seizures. A significant reduction of 48% in generalized seizures (9.5 +/- 11.6 vs. 4.9 +/- 6.5 seizures per month, P = 0.013) was noted. Reductions in partial seizure frequency of 48% (7.9 +/- 10 vs. 4 +/- 6.6 seizures per month, P = 0.16) as well as in mixed-type seizures (19.9 +/- 9.3 was vs. 15 +/- 12.1 seizures per month, P = 0.11) were also seen; however, these changes did not reach significance. Overall, lamotrigine was well tolerated by the subject population. Adjunctive treatment with lamotrigine appears to be an efficacious and well-tolerated treatment for seizures in a significant percentage of developmentally disabled patients with epilepsy.