RESUMEN
OBJECTIVE: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. BACKGROUND: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. METHODS: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. RESULTS: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. CONCLUSIONS: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsias Parciales/tratamiento farmacológico , Triazinas/administración & dosificación , Adolescente , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Infecciones/inducido químicamente , Lamotrigina , Placebos , Fases del Sueño , Triazinas/efectos adversos , Triazinas/uso terapéutico , Vómitos/inducido químicamenteRESUMEN
PURPOSE: To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3-15 years, n = 45). METHODS: A "responder-enriched" study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG. RESULTS: During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason. CONCLUSIONS: LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia Tipo Ausencia/tratamiento farmacológico , Triazinas/uso terapéutico , Adolescente , Factores de Edad , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Estatura , Peso Corporal , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Electroencefalografía/métodos , Femenino , Humanos , Lamotrigina , Masculino , Monitoreo Ambulatorio , Placebos , Resultado del Tratamiento , Triazinas/administración & dosificación , Triazinas/sangreRESUMEN
Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Triazinas/uso terapéutico , Adolescente , Adulto , Anticonvulsivantes/farmacocinética , Carbamazepina/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Epilepsia/sangre , Femenino , Humanos , Lamotrigina , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Fenobarbital/uso terapéutico , Fenitoína/uso terapéutico , Primidona/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Triazinas/sangre , Triazinas/farmacocinéticaRESUMEN
The primary structure of gamma-bungarotoxin, a new toxin from Bungarus multicinctus venom, was determined using mass spectrometry and Edman degradation. The toxin has a mass of 7524.7 D and consists of 68 residues having the following sequence: MQCKTCSFYT CPNSETCPDG KNICVKRSWT AVRGDGPKRE IRRECAATCP PSKLGLTVFC CTTDNCNH. Gamma-bungarotoxin is structurally similar to both kappa-bungarotoxin and elapid long postsynaptic neurotoxins. Its C-terminal nine residues are identical to those of the kappa-toxins. Its disulfide bond locations appear identical to those of several elapid toxins of unknown pharmacology and its hydrophobicity profile is also strikingly similar. However, with an LD50 of 0.15 microg/g i.v. in mice, gamma-bungarotoxin is 30-150-fold more toxic than other members of this latter class. Its toxicity is comparable to those of alpha-nicotinic acetylcholine receptor antagonists.
Asunto(s)
Bungarotoxinas/química , Bungarotoxinas/toxicidad , Bungarus/metabolismo , Neurotoxinas/química , Receptores de Neurotransmisores/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Cromatografía , Cromatografía Líquida de Alta Presión , Inyecciones Intraventriculares , Masculino , Espectrometría de Masas , Ratones , Datos de Secuencia Molecular , Neurotoxinas/toxicidad , SolubilidadRESUMEN
The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mg/day. Seizure frequency with LTG decreased by > or = 50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2:1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEDs. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.