Monotherapy For Partial-onset Seizures Research Articles

Direct Chiral HPLC-MS/MS Method for Determination of R-Lacosamide in Human Plasma

R-Lacosamide (RLC) is a new approved antiepileptic drug for adjunctive use and monotherapy for partial-onset seizures in some countries. RLC use in other epilepsies and diseases is under study. Research is also going on the activities exhibited by the S-enantiomer (SLC). Taking into consideration further perspectives, the development of direct chiral method that can selectively estimate R-isomer in the presence of S-isomer from human plasma is needed. Plasma samples were spiked with RLC, deuterated internal standard, and SLC. Deuterated RLC as the internal standard enabled us to precisely measure the concentration of RLC by minimizing variations associated with the extraction, ionization, and separation. Target compounds were recovered by liquid-liquid extraction from human plasma using methyl tert-butyl ether. The percentage recovery was found to be 68%.The isomers were resolved completely using DIACEL-IC3 column in the reverse phase mode. The retention times of R- and S-isomers were found to be 6.20 ± 0.5 and 8.00 ± 0.5 min, respectively. The proposed method was found to be linear in a concentration range from 1.00 × 102 to 1.50 × 104 ng/mL. Direct chiral HPLC tandem mass spectrometric method that can quantify R-lacosamide in the presence of S-isomer from human plasma without any carry-over and matrix effects was successfully developed. This method is very simple, fast, economic, sensitive, and validated as per EMA guidelines.

Effectiveness of eslicarbazepine acetate in dependency of baseline anticonvulsant therapy: Results from a German prospective multicenter clinical practice study

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug (AED) approved as monotherapy for partial-onset seizures in adults and as adjunctive therapy in patients aged above 6 years in the European Union (EU). The prospective observational Zebinix Effects in DEpendency of BAseline Conditions (ZEDEBAC) study aimed at investigating the effectiveness of ESL in clinical practice, with ESL being administered as monotherapy (mono group), as only add-on to a current monotherapy (1+ group), or as add-on to ≥2 baseline AEDs (≥2+ group). In total, 237 patients were included, 35 in the mono group, 114 in the 1+, and 88 in the ≥2+ group. Six-month retention rates were 93.9%, 78.0%, and 75.3% in the mono, 1+, and ≥2+ group. There were 90.5%, 77.6%, and 48.3% of patients in the mono, 1+, and ≥2+ groups who were responders (patients with a ≥50% reduction in seizure frequency at follow-up vs. baseline). Seizure freedom rates were 81.5%, 47.9%, and 23.4%, respectively. Adverse drug reactions (ADRs) occurred in 11.4% of patients of the mono, 19.3% of the 1+, and 28.4% of patients of the ≥2+ group. Hyponatremia was reported as ADR in 3.4% of all patients. Although baseline variables differed considerably, with most elderly patients with tumor-related and vascular etiologies in the mono group and most patients with refractory epilepsies with pronounced use of concomitant sodium channel blockers (SCBs) in the ≥2+ group, retention as a measure of real-life effectiveness turned out not to be substantially different and favorable in all groups.

Eslicarbazepine Acetate Monotherapy: A Review in Partial-Onset Seizures.

Eslicarbazepine acetate (Aptiom(®)) is a once-daily, orally administered antiepileptic drug (AED) approved previously in the EU, USA and several other countries for use as adjunctive therapy for the treatment of partial-onset seizures. Based on the findings of two randomized, dose-blinded, conversion-to-monotherapy phase III trials in patients with uncontrolled partial epilepsy, the US license for eslicarbazepine acetate has recently been expanded to include use as monotherapy for partial-onset seizures. The pivotal trials demonstrated that seizure control following conversion from other AEDs was superior for eslicarbazepine acetate monotherapy (1200 or 1600mg once daily) compared with a pseudo-placebo historical control. Other efficacy outcomes appeared to support the benefit of treatment, with up to 10% of patients remaining seizure free and up to 46% of patients experiencing a ≥50% reduction from baseline in standardized seizure frequency during the monotherapy periods of the trials. Eslicarbazepine acetate monotherapy was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity. Its tolerability profile was generally consistent with the established profile of the drug based on its use as adjunctive therapy. Thus, once-daily eslicarbazepine acetate, either as monotherapy or adjunctive therapy, represents a useful option for the treatment of patients with partial-onset seizures. The recent licensing of the drug in the USA as monotherapy expands the range of treatment options for patients with partial-onset seizures and increases the opportunity to tailor therapy to the individual patient.

Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4h after intake. Oral bioavailability is high (100%) for a dose up to 800mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all<20%). The pharmacokinetic profile of lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13h in young subjects and 14-16h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15% and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

Development of lacosamide for the treatment of partial-onset seizures.

Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long-term channel availability without affecting physiological function. Lacosamide has a well-characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P-450 izoenzymes, and a low potential for drug–drug interactions. Lacosamide clinical development included three placebo-controlled, double-blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic–clonic seizures in those with idiopathic generalized epilepsy.

Clinical pharmacology of levetiracetam for the treatment of epilepsy

Levetiracetam is an antiepileptic drug that is mainly indicated for the adjunctive treatment of partial-onset seizures in adults and children and of myoclonic and primary generalized tonic–clonic seizures in patients with idiopathic generalized epilepsy. In Europe, levetiracetam is also indicated as monotherapy for partial-onset seizures in patients with newly diagnosed epilepsy. Synaptic vesicle protein 2A is the primary molecular target for its anticonvulsive effect but additional mechanisms may also contribute. Recent clinical and pharmacokinetic developments for levetiracetam are reviewed in specific populations, including the effects of age, pregnancy, birth and lactation, pediatric development, and ethnic origin. The population pharmacokinetics of levetiracetam and drug–drug interactions have been explored across large adult and pediatric populations. The exposure–response relationship has also been characterized in adults and children through nonlinear mixed-effects modeling. Finally, new formulations including intravenous infusion and extended-release once-daily tablets have been compared with immediate-release tablets and oral solution, and can be used interchangeably.

Clinical studies of topiramate.

Topiramate had well-documented efficacy as an adjunctive agent for partial-onset seizures in 5 double-blind, parallel trials, reducing seizure frequency by 35-47% at 400 mg/day, the optimal dose for most patients. It can also be used as monotherapy for partial-onset seizures. A broad spectrum of action is suggested by studies showing efficacy against a variety of generalized-onset seizure types, including primary generalized tonic-clonic seizures and the component seizures of Lennox-Gastaut syndrome. The major adverse effects of topiramate are of CNS origin. Psychomotor slowing is most common, but disappears in most patients with time or dosage adjustments; 11-28% of patients discontinue the drug because of side effects. No serious skin, liver or blood toxicity has been identified. Efficacy and adverse effect profiles are similar for children and adults. Introduction at rates not exceeding 25-50 mg increases per week will minimize adverse effects and be satisfactory for most adults.