lacosamide and rufinamide

There is a need for newer anti-epileptic drugs (AEDs) with improved efficacy and tolerability. This article reviews AEDs introduced since 2007 and investigational compounds in clinical development.. Two recently introduced AEDs, stiripentol and rufinamide, have been licensed exclusively for orphan indications, that is severe myoclonic epilepsy of infancy (stiripentol, Europe) and Lennox-Gastaut syndrome (rufinamide, Europe and the USA). This signals a welcome new trend to explore novel treatments in specific pediatric syndromes for which there are high therapeutic needs. Two additional AEDs, lacosamide and eslicarbazepine acetate, have been licensed recently for a more traditional indication, refractory partial-onset seizures. Although newly introduced agents given as adjunctive therapy have been found to be superior to placebo in reducing seizure frequency, the ultimate goal of sustained seizure freedom is rarely achieved. Therefore, the search for better agents should continue. Several investigational compounds are currently in various stages of clinical development.. The recent introduction of newer AEDs has enlarged the armamentarium against epilepsy. However, newer agents had only a modest impact on the probability of achieving long-term remission. Novel strategies for the discovery and development of truly innovative AEDs are sorely needed.

Topics: Acetamides; Anticonvulsants; Clinical Trials as Topic; Dioxolanes; Drug Approval; Drug Discovery; Epilepsy; Humans; Lacosamide; Remission Induction; Triazoles

Topics: Acetamides; Amines; Animals; Anticonvulsants; Benzodiazepines; Carbamates; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Design; Gabapentin; gamma-Aminobutyric Acid; Humans; Lacosamide; Levetiracetam; Phenylenediamines; Piracetam; Pregabalin; Pregnanolone; Pyrrolidinones; Triazoles

Antiepileptic drugs (AEDs) have been used to control epilepsy. More than 17 new AEDs, including gabapentin (GPN), lacosamide (LCM), perampanel (PER), pregabalin (PRG), rufinamide (RFM), and vigabatrin (VGB) have been approved and marketed since 1989. Accurate measurement of serum concentration of the antiepileptic drugs is crucial to achieve optimal efficacy and avoid adverse events. We describe an accurate and precise liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of GPN, LCM, PER, PRG, RFM, and VGB in serum. The method requires a small volume of sample (10 μL) and has a total chromatographic run time of 4 min for simultaneous measurement of these drugs. The method showed good accuracy with a bias of -0.2-5%. The intra- and inter-day imprecision were less than 5.0% for all the analytes. The linear assay ranges were 0.3-26 μg/mL for GPN, 0.15-24 μg/mL for LCM, 7.4-1881 ng/mL for PER, 0.03-13 μg/mL for PRG, 0.78-90 μg/mL for RFM, and 0.3-43 μg/mL for VGB.

Topics: Anticonvulsants; Chromatography, Liquid; Gabapentin; Lacosamide; Pregabalin; Tandem Mass Spectrometry; Vigabatrin

We aimed to determine the morphological and histological effects of zonisamide, sultiam, lacosamide, clobazam, and rufinamide on ovarian folliculogenesis in rats. Sixty female Wistar rats were divided into six experimental groups as control, zonisamide, sultiam, lacosamide, clobazam, and rufinamide groups; control solution and drugs were administered by gavage for 90 days. The number of healthy follicles in the control group was significantly higher than in the anti-medication groups (p < 0.001), and the number of corpus luteum was significantly lower (p < 0.001). There was a significant difference in the number of TUNEL positive apoptotic follicles between the control and drug groups (p < 0.001). With EGF, IGF-1, and GDF-9 staining, a very strong immunoreaction was observed in the ovarian multilaminar primary follicle granulosa cells and oocytes in the control group compared to the drug group (p < 0.001). Long-term anti-seizure medication with zonisamide, sultiam, lacosamide, clobazam, and rufinamide from prepubertal to adulthood causes apoptosis and disruption of folliculogenesis in the ovarian follicles of nonepileptic rats.

Topics: Animals; Clobazam; Female; Lacosamide; Rats; Rats, Wistar; Thiazines; Triazoles; Zonisamide

In myotonia congenita, loss of ClC-1 Cl. Dissected muscles were rendered myotonic by ClC-1 channel inhibition. The ability of the drugs to suppress myotonia was then assessed from subclinical to maximal clinical concentrations. Drug synergy was determined using isobole plots.. All drugs were capable of abolishing myotonia in both rat and human muscles. Lamotrigine and rufinamide completely suppressed myotonia at submaximal clinical concentrations, whereas lacosamide had to be raised above the maximal clinical concentration to suppress myotonia completely. A synergistic effect of lamotrigine and rufinamide was observed.. These findings suggest that lamotrigine and rufinamide could be considered for anti-myotonic treatment in myotonia congenita. Muscle Nerve 56: 136-142, 2017.

Topics: Acetamides; Animals; Anthracenes; Anticonvulsants; Area Under Curve; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Female; Humans; In Vitro Techniques; Isometric Contraction; Lacosamide; Lamotrigine; Male; Muscle, Skeletal; Myotonia; Rats; Rats, Wistar; Triazines; Triazoles

Quantification of rufinamide in plasma was achieved using a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. The chromatographic separation was achieved on a reversed phase column (Zorbax SB-C18 100mm×3mm, 3.5μm) under isocratic conditions. The mobile phase consisted of a mixture of water containing 0.1% formic acid and methanol (50:50, v/v). The mass spectrometric detection of the analyte was in multiple reaction monitoring mode (MRM) using an electrospray positive ionization (ESI positive). The monitored ions were 127m/z derived from 239m/z rufinamide and 108m/z derived from 251m/z the internal standard (lacosamide). Protein precipitation with methanol was applied for sample preparation using only 50μl aliquots. The concentration range was 40-2000ng/ml for rufinamide in plasma. The limit of detection was 1.25ng/ml and the lower limit of quantification was established at 5ng/ml rufinamide concentration. Selectivity and matrix effect was verified using individual human, rat and rabbit plasma samples. Short-term, post-preparative and freeze-thaw stability was also investigated. The proposed method provides accuracy, precision and high-throughput (short runtime 4.5min) for quantitative determination of rufinamide in plasma. This is the first reported liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for analysis of rufinamide from low volume plasma samples. The LC-MS/MS method was validated according to the current official guidelines and can be applied to accurately measure rufinamide level of large number of plasma samples from clinical studies or therapeutic drug monitoring.

Topics: Acetamides; Animals; Chromatography, High Pressure Liquid; Humans; Lacosamide; Limit of Detection; Rabbits; Rats; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Triazoles

Topics: Acetamides; Amino Acid Sequence; Amyloid beta-Peptides; Anticonvulsants; Humans; Lacosamide; Molecular Sequence Data; Peptide Fragments; Protein Binding; Spectrometry, Mass, Electrospray Ionization; Triazoles

Topics: Acetamides; Antibodies, Monoclonal; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Azepines; Benzazepines; Benzhydryl Compounds; Benzyl Alcohol; Benzylamines; Cyclams; Cyclopropanes; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Everolimus; Febuxostat; Fluorenes; Fluoroquinolones; Gout Suppressants; Heterocyclic Compounds; Humans; Immunosuppressive Agents; Indoles; Lacosamide; Milnacipran; Oligopeptides; Phenols; Selective Serotonin Reuptake Inhibitors; Sirolimus; Tapentadol; Thiazoles; Tolvaptan; Triazoles