Efficacy and Safety of Remacemide versus Carbamazepine in Newly Diagnosed Epilepsy: Comparison by Sequential Analysis.

An international trial comparing remacemide hydrochloride with carbamazepine was undertaken in newly diagnosed epilepsy using a novel double-blind, parallel group, double triangular sequential design. Patients with two or more partial or generalized tonic-clonic seizures in the previous year were randomized to 600 mg daily of remacemide or carbamazepine. Subsequent dosage adjustments were allowed while maintaining the blind.

P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice.

Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls.

Acute stroke: trial by jury. The toothless tiger (role of the principal investigator).

All trials require a principal investigator to take the lead role and act as main contact amongst the various groups of participants. His role ranges from assistance in protocol design; through selection of investigators, monitoring of study conduct and responding to Safety Committee recommendations; to involvement in study reporting and in maintaining access to the data set after the conclusion of the trial. This article describes the role of the principal investigator and Steering Committee in more detail and discusses the issues that arise out of the organisational requirements of modern clinical trials and the potential tensions between the various participating groups.

Stroke: trial by jury.

Trials of pharmacological intervention for acute stroke show several points of similarity with legal trials by jury. The relationships between sponsoring organisation and regulatory authorities and the roles of the many other participants are described. Only through a partnership can the common aim of developing improved treatment for patients with stroke be realised.

Tolerability of NXY-059 at higher target concentrations in patients with acute stroke.

Background And Purpose: NXY-059 is a nitrone-based free radical-trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke.

Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure.

Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure.

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy.

Purpose: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy.

Methods: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day.

Seizure freedom with more than one antiepileptic drug.

Many people with epilepsy take antiepileptic drug (AED) polytherapy, although supportive evidence for the success of this strategy is sparse. Of 2881 treated patients registered in our database, 1617 (56%) have been seizure-free for at least the previous year, with 21% taking more than one AED (287 on two, 86%; 42 on three, 13%; 3 on four, 1%). There were 40 effective duotherapies and 28 triple therapies.

Influence of cytochrome P450 induction on the pharmacokinetics and pharmacodynamics of remacemide hydrochloride.

Remacemide hydrochloride (RMD) is a putative anticonvulsant agent with an active metabolite, desglycinyl-remacemide (DGR) and a broad spectrum of activity in experimental seizure models. In clinical trials, however, the efficacy of RMD is questionable. In the case of add-on studies, the inconclusive findings may be related to pharmacokinetic interactions between RMD and established antiepileptic drugs.

Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia.

Objective: To compare the efficacy of non-invasive testing for Helicobacter pylori with that of endoscopy (plus H pylori testing) in the management of patients referred for endoscopic investigation of upper gastrointestinal symptoms.

Design: Randomised controlled trial with follow up at 12 months.

Setting: Hospital gastroenterology unit.

Staged approach to epilepsy management.

The natural history of treated epilepsy has substantial relevance to its pharmacologic and surgical management. In our center, 525 unselected, untreated patients were given a diagnosis of epilepsy, started on antiepileptic drug (AED) therapy, and followed for a median of 5 years. Sixty-three percent of patients had been seizure-free for at least the previous year.

Topiramate in patients with learning disability and refractory epilepsy.

Purpose: Management of seizures in learning disabled people is challenging. This prospective study explored the efficacy and tolerability of adjunctive topiramate (TPM) in patients with learning disability and refractory epilepsy attending a single centre.

Methods: Sixty-four patients (36 men, 28 women, aged 16-65 years) were begun on adjunctive TPM after a 3-month prospective baseline on unchanged medication.

Na(+) channel effects of remacemide and desglycinyl-remacemide in rat cortical synaptosomes.

The effects of the novel anticonvulsant, remacemide hydrochloride and its active metabolite, desglycinyl-remacemide, on veratridine-induced Na(+) influx in rat cortical synaptosomes were investigated and compared to established Na(+) channel blocking antiepileptic drugs. Remacemide and desglycinyl-remacemide reduced veratridine-stimulated Na(+) influx to 30.7% (IC(50)=160.

Early clinical experience with the novel NMDA receptor antagonist CNS 5161.

Aims: To investigate the safety, tolerability and pharmacokinetics of the novel NMDA antagonist CNS 5161 in humans. Excessive activation of glutamate receptors, especially of the N-methyl-d-aspartate (NMDA) subtype has been associated with neuropathic pain, and brain damage caused by focal ischaemia in mature brain or hypoxia-ischaemia (HI) in neonates. CNS 5161 is a novel NMDA ion-channel antagonist that interacts with the NMDA receptor/ion channel site to produce a noncompetitive blockade of the actions of glutamate.

Differential effects of remacemide and desglycinyl-remacemide on epileptiform burst firing in the rat hippocampal slice.

Remacemide is a potential anticonvulsant drug with an active metabolite, desglycinyl-remacemide (DGR). Both moieties have been reported to block neuronal Na(+) channels and the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. The effects of remacemide and DGR on zero Mg(2+)/4-aminopyridine-induced epileptiform discharges were investigated in the rat hippocampal slice preparation and compared with carbamazepine (CBZ), a prototypic Na(+) channel blocker, and AR-R15896AR, a putative NMDA channel blocker.

Altered vascular function in young women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinemic insulin resistance, a metabolic disorder that in other circumstances is associated with increased cardiovascular risk. We compared macrovascular and microvascular function in 19 women with PCOS with 12 control subjects matched as a group for body mass index. Macrovascular function was assessed by recording pulse wave velocity (PWV) across the aorta and brachial artery.

Effectiveness of first antiepileptic drug.

Purpose: To investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug (AED) in patients with newly diagnosed epilepsy.

Methods: The 470 patients were diagnosed, treated and followed up from January 1984 at a single center. Outcome was classified as seizure freedom for at least the last year or failure of initial treatment because of inadequate seizure control, adverse events, or for other reasons.

Design of the Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial.

The Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial is a multicentre,randomised, placebo-controlled trial of magnesium sulphate (MgSO4) funded by the UK Medical Research Council. When complete, it will be the largest single neuroprotective study undertaken to date. Conscious patients presenting within 12 h of acute stroke with limb weakness are eligible.

Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy.

Purpose: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation.

Methods: Hormone profiles in men and women taking VPA (n = 40) or LTG (n = 36) monotherapy for epilepsy were compared.

Management strategies for refractory localization-related seizures.

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.