flunarizine and Epilepsies--Partial

In a recent NIH-sponsored parallel-group placebo-controlled blinded study of flunarizine for the treatment of partial-onset seizures, the flunarizine serum concentration was controlled to a constant level among patients in order to reduce response variability. Flunarizine was found to exhibit modest anti-epileptic efficacy. A potential criticism of this study is that the chosen controlled concentration was too low to determine optimal efficacy. As a participating center in this study we investigated the effect of higher doses of open-label flunarizine on seizure frequency in 16 patients with refractory partial seizures. Following the completion of the blinded placebo/flunarizine phase, all patients were initiated at the flunarizine dose calculated to result in a serum concentration of 60 ng.ml-1. The dose was subsequently increased each 8-12 weeks to a maximum of 2.7 times the initial dose. On the initial maintenance flunarizine dose, seizure control was improved, with an average seizure reduction of 47% compared to pre-blinded-phase baseline. When higher doses were administered, adverse reactions were more common yet improved seizure control did not occur in most patients. These findings complement those of the concentration-controlled NIH study and suggest that appropriate flunarizine doses were utilized in that study.

Topics: Adult; Anticonvulsants; Epilepsies, Partial; Female; Flunarizine; Humans; Male; Middle Aged

Flunarizine (FLN) is a potential antiepileptic drug whose pharmacokinetic properties include a long half-life (2-7 weeks) and high interpatient variability in volume of distribution and clearance. The National Institutes of Health (NIH) is sponsoring a randomized, double-masked, multicenter, parallel-group, placebo-controlled clinical trial to demonstrate the antiepileptic activity of FLN. The design is based on the premise that plasma concentrations are more strongly related to drug response than are doses. For each patient, an estimate of the concentration-time curve following a single dose of FLN is used to determine a loading dose and maintenance dosage targeted at a specified plasma FLN concentration. After an inpatient, drug-loading period, the fixed maintenance dosage (of FLN or placebo) is prescribed for the entire 24-week outpatient treatment period unless a change is required for medical reasons. If the target concentration is well chosen and approximately achieved, this design has several potential advantages: (a) A fixed-dose design is simpler and less subject to bias than a design involving dosage adjustments; (b) the drug-loading period reduces from several weeks or months to 1 week the time required to achieve the target plasma FLN concentration; (c) compared with a design in which each patient receives the same dose, the decreased variability in FLN concentrations should result in fewer patients receiving subtherapeutic doses and fewer patients requiring dose reductions, as well as increased power to detect treatment effects in a population where such effects are generally small.

Topics: Data Interpretation, Statistical; Dose-Response Relationship, Drug; Double-Blind Method; Electroencephalography; Epilepsies, Partial; Flunarizine; Humans

Flunarizine was compared to placebo in a double-blind cross-over trial of 2 16-week treatment periods separated by a 4-week wash-out period. The patients had epilepsy with complex partial seizures with or without secondary generalised seizures. Twenty-nine patients entered the trial, but 7 dropped out. Of the 22 patients completing the trial, 13 were women; the median was 39 years (range 15-58) and the median duration of epilepsy 23 years (range 4-55). There was no statistically significant difference between flunarizine 15 mg daily and placebo as adjunct therapy in total seizure frequency, neuropsychological tests, and patient's preferences. No interactions with concomitant antiepileptic drugs and no laboratory abnormalities were registered.

Topics: Adolescent; Adult; Double-Blind Method; Epilepsies, Partial; Female; Flunarizine; Humans; Male; Middle Aged; Placebos

Topics: Adult; Electroencephalography; Epilepsies, Partial; Epilepsy; Female; Flunarizine; Humans; Migraine Disorders