ABSTRACT
The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations.
Subject(s)
Disease Models, Animal , Electroencephalography , Lacosamide , Neuroprotective Agents , Pregabalin , Topiramate , Animals , Lacosamide/pharmacology , Lacosamide/therapeutic use , Topiramate/pharmacology , Topiramate/therapeutic use , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Male , Pregabalin/pharmacology , Pregabalin/therapeutic use , Rats , Behavior, Animal/drug effects , Drug Resistant Epilepsy/drug therapy , Drug Therapy, Combination , Hippocampus/drug effects , Hippocampus/physiopathology , Hippocampus/pathology , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Status Epilepticus/drug therapy , Status Epilepticus/chemically induced , Status Epilepticus/physiopathology , Rats, Wistar , Epilepsy, Temporal Lobe/drug therapy , Epilepsy, Temporal Lobe/physiopathology , Epilepsy, Temporal Lobe/chemically inducedABSTRACT
BACKGROUND: Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures. METHODS: A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects. RESULTS: A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted. CONCLUSIONS: LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population.
Subject(s)
Anticonvulsants , Electroencephalography , Lacosamide , Seizures , Humans , Lacosamide/administration & dosage , Lacosamide/pharmacology , Retrospective Studies , Anticonvulsants/administration & dosage , Anticonvulsants/pharmacology , Infant, Newborn , Male , Seizures/drug therapy , Female , Drug Therapy, Combination , Phenobarbital/administration & dosage , Phenobarbital/therapeutic use , Levetiracetam/administration & dosage , Levetiracetam/pharmacologyABSTRACT
BACKGROUND: Few studies have investigated intravenous lacosamide use to treat cluster seizures in pediatric patients. Therefore, we aimed to investigate the efficacy and safety of intravenous lacosamide therapy in pediatric patients with cluster seizures. METHODS: We retrospectively evaluated the efficacy and safety of intravenous lacosamide therapy in 25 pediatric patients with cluster seizures at Saitama Children's Medical Center between March 2019 and June 2023. Cluster seizures were defined as a single seizure of less than five minutes duration, repeated three or more times within 12 hours, with recovery of consciousness between seizures. Response was defined as seizure freedom for at least 12 hours after lacosamide infusion. RESULTS: The median age at onset of epilepsy was 1.5 (0.0 to 9.8) years. The median seizure frequency was 5 (3 to 20) times per 12 hours. The etiologies were remote (n = 17), acute (n = 4), and progressive (n = 4). The median age at which intravenous lacosamide therapy was administered was 4.2 (0.0 to 11.3) years. The median lacosamide dose was 2.6 (1.3 to 5.2) mg/kg. In total, 12 of 25 patients (48.0%) responded. Among patients treated with intravenous lacosamide as first-line therapy, nine of 17 (52.9%) had complete seizure remission. The frequency of complete seizure remission in patients with remote etiologies was 58.8% (10 of 17); among them, seven of 12 (58.3%) patients with structural abnormalities showed complete seizure remission. No adverse events were observed. CONCLUSIONS: Intravenous lacosamide therapy is a potentially useful treatment option for cluster seizures in pediatric patients.
Subject(s)
Anticonvulsants , Lacosamide , Seizures , Humans , Lacosamide/administration & dosage , Lacosamide/pharmacology , Child , Male , Female , Child, Preschool , Anticonvulsants/administration & dosage , Retrospective Studies , Infant , Seizures/drug therapy , Administration, Intravenous , Infusions, IntravenousABSTRACT
BACKGROUND: There is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates. METHODS: A retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days. RESULTS: Among 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates. CONCLUSIONS: The results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results.
Subject(s)
Anticonvulsants , Electroencephalography , Lacosamide , Seizures , Humans , Lacosamide/adverse effects , Lacosamide/pharmacology , Lacosamide/administration & dosage , Infant, Newborn , Retrospective Studies , Male , Anticonvulsants/adverse effects , Anticonvulsants/administration & dosage , Female , Seizures/drug therapyABSTRACT
BACKGROUND: Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that primarily affects the motor system. Although there are several treatments available to alleviate PD symptoms, there is currently no cure for the disease. Lacosamide, an anti-epileptic drug, has shown promising results in preclinical studies as a potential neuroprotective agent for PD. In this study, we aimed to investigate the neuroprotective effect of lacosamide in a murine model of PD. METHODS: Twenty-one adult male rats were randomly divided into the following three groups (n = 7): 1 group received stereotaxical infusion of dimethyl sulfoxide (vehicle, group 1), and the others received stereotaxical infusion of rotenone (groups 2 and 3). The apomorphine-induced rotation test was applied to the rats after 10 days. Thereafter, group 2 was administered isotonic saline, whereas group 3 was administered lacosamide (20 mg/kg,i.p.) for 28 days. Apomorphine-induced rotation tests were performed to assess the effect of lacosamide on motor function. In addition, immunohistochemistry and biochemistry were used to assess the dopaminergic neuron loss in the substantia nigra and MDA, TNF-α and HVA levels, respectively. RESULTS: In rats with Parkinson's disease induced by rotenone, levels of malondialdehyde and TNF-α significantly increased and HVA levels decreased, whereas in mice treated with lacosamide, levels of malondialdehyde and TNF-α significantly decreased and HVA levels increased. The apomorphine-induced rotation test scores of lacosamide-treated mice were lower compared with the untreated group. Furthermore, treatment with lacosamide significantly mitigated the degeneration of dopaminergic projections within the striatum originating from the substantia nigra and increased tyrosine hydroxylase (TH) immunofluorescence, indicative of preserved dopaminergic neuronal function. CONCLUSION: In conclusion, our study provides evidence that lacosamide has a neuroprotective effect on the rat model of PD. Further studies are required to investigate the underlying mechanisms and evaluate the potential clinical use of lacosamide as a neuroprotective agent for PD.
Subject(s)
Neuroprotective Agents , Parkinson Disease , Rats , Male , Mice , Animals , Parkinson Disease/drug therapy , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Apomorphine/pharmacology , Lacosamide/pharmacology , Lacosamide/therapeutic use , Rats, Sprague-Dawley , Rotenone/pharmacology , Tumor Necrosis Factor-alpha , Substantia Nigra , Dopaminergic Neurons , Dopamine , Malondialdehyde , Disease Models, AnimalABSTRACT
The effects of lacosamide (LCS, Vimpat®), an anti-convulsant and analgesic, on voltage-gated Na+ current (INa) were investigated. LCS suppressed both the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa with the IC50 values of 78 and 34 µM found in GH3 cells and of 112 and 26 µM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent INa (INa(P)) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of INa(T) or INa(L) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the INa block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ's of recovery from the INa block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window INa (INa(W)) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of INa activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of INa in excitable cells.
Subject(s)
Sodium Channels , Sodium , Ions/metabolism , Lacosamide/pharmacology , Sodium/metabolism , VeratridineABSTRACT
Lacosamide (Vimpat®, LCS) is widely known as a functionalized amino acid with promising anti-convulsant properties; however, adverse events during its use have gradually appeared. Despite its inhibitory effect on voltage-gated Na+ current (INa), the modifications on varying types of ionic currents caused by this drug remain largely unexplored. In pituitary tumor (GH3) cells, we found that the presence of LCS concentration-dependently decreased the amplitude of A-type K+ current (IK(A)) elicited in response to membrane depolarization. The IK(A) amplitude in these cells was sensitive to attenuation by the application of 4-aminopyridine, 4-aminopyridine-3-methanol, or capsaicin but not by that of tetraethylammonium chloride. The effective IC50 value required for its reduction in peak or sustained IK(A) was calculated to be 102 or 42 µM, respectively, while the value of the dissociation constant (KD) estimated from the slow component in IK(A) inactivation at varying LCS concentrations was 52 µM. By use of two-step voltage protocol, the presence of this drug resulted in a rightward shift in the steady-state inactivation curve of IK(A) as well as in a slowing in the recovery time course of the current block; however, no change in the gating charge of the inactivation curve was detected in its presence. Moreover, the LCS addition led to an attenuation in the degree of voltage-dependent hysteresis for IK(A) elicitation by long-duration triangular ramp voltage commands. Likewise, the IK(A) identified in mouse mHippoE-14 neurons was also sensitive to block by LCS, coincident with an elevation in the current inactivation rate. Collectively, apart from its canonical action on INa inhibition, LCS was effective at altering the amplitude, gating, and hysteresis of IK(A) in excitable cells. The modulatory actions on IK(A), caused by LCS, could interfere with the functional activities of electrically excitable cells (e.g., pituitary tumor cells or hippocampal neurons).
Subject(s)
Delayed Rectifier Potassium Channels/antagonists & inhibitors , Ion Channel Gating , Lacosamide/pharmacology , Pituitary Neoplasms/drug therapy , Potassium/metabolism , Adenoma/drug therapy , Adenoma/metabolism , Adenoma/pathology , Animals , Anticonvulsants/pharmacology , Ion Transport , Pituitary Neoplasms/metabolism , Pituitary Neoplasms/pathology , Rats , Tumor Cells, CulturedABSTRACT
Epilepsy is one of the most common brain disorders, affecting more than 50 million people worldwide. Although its treatment is currently symptomatic, the last generation of anti-seizure drugs is characterized by better pharmacokinetic profiles, efficacy, tolerability and safety. Lacosamide is a third-generation anti-seizure drug that stands out due to its good efficacy and safety profile. It is used with effectiveness in the treatment of partial-onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures and off-label in status epilepticus. Despite scarcely performed until today, therapeutic drug monitoring of lacosamide is proving to be advantageous by allowing the control of inter and intra-individual variability and promoting a successful personalized therapy, particularly in special populations. Herein, the pharmacology, pharmacokinetics, and clinical data of lacosamide were reviewed, giving special emphasis to the latest molecular investigations underlying its mechanism of action and therapeutic applications in pathologies besides epilepsy. In addition, the pharmacokinetic characteristics of lacosamide were updated, as well as current literature concerning the high pharmacokinetic variability observed in special patient populations and that must be considered during treatment individualization.
Subject(s)
Anticonvulsants/pharmacology , Lacosamide/pharmacology , Animals , Anticonvulsants/adverse effects , Anticonvulsants/pharmacokinetics , Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Humans , Lacosamide/adverse effects , Lacosamide/pharmacokinetics , Lacosamide/therapeutic use , Neuralgia/drug therapyABSTRACT
BACKGROUND: Status epilepticus (SE) is a neurological disorder characterized by a prolonged epileptic activity followed by subsequent epileptogenic processes. The aim of the present study was to evaluate the early effects of topiramate (TPM) and lacosamide (LCM) treatment on oxidative stress and inflammatory damage in a model of pilocarpine-induced SE. METHODS: Male Wistar rats were randomly divided into six groups and the two antiepileptic drugs (AEDs), TPM (40 and 80 mg/kg, i.p.) and LCM (10 and 30 mg/kg, i.p.), were injected three times repeatedly after pilocarpine administration. Rats were sacrificed 24 h post-SE and several parameters of oxidative stress and inflammatory response have been explored in the hippocampus. RESULTS: The two drugs TPM and LCM, in both doses used, succeeded in attenuating the number of motor seizures compared to the SE-veh group 30 min after administration. Pilocarpine-induced SE decreased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels while increasing the catalase (CAT) activity, malondialdehyde (MDA), and IL-1ß levels compared to the control group. Groups with SE did not affect the TNF-α levels. The treatment with a higher dose of 30 mg/kg LCM restored to control level the SOD activity in the SE group. The two AEDs, in both doses applied, also normalized the CAT activity and MDA levels to control values. In conclusion, we suggest that the antioxidant effect of TPM and LCM might contribute to their anticonvulsant effect against pilocarpine-induced SE, whereas their weak anti-inflammatory effect in the hippocampus is a consequence of reduced SE severity.
Subject(s)
Anticonvulsants/therapeutic use , Inflammation/pathology , Lacosamide/therapeutic use , Reactive Oxygen Species/metabolism , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , Topiramate/therapeutic use , Animals , Anticonvulsants/pharmacology , Biomarkers/metabolism , Hippocampus/drug effects , Hippocampus/pathology , Hippocampus/physiopathology , Interleukin-1beta/metabolism , Lacosamide/pharmacology , Male , Motor Activity/drug effects , Oxidative Stress/drug effects , Pilocarpine , Rats, Wistar , Seizures/physiopathology , Status Epilepticus/physiopathology , Topiramate/pharmacology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real-world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling with a 1-compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age-associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71- and 1.46-fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age-associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight-based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age.
Subject(s)
Anticonvulsants/pharmacokinetics , Lacosamide/pharmacokinetics , Adolescent , Age Factors , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Body Weight , Child , Child, Preschool , Drug Interactions , Drug Therapy, Combination , Electronic Health Records , Humans , Infant , Lacosamide/pharmacology , Lacosamide/therapeutic use , Metabolic Clearance Rate , Models, Biological , Racial Groups , Retrospective Studies , Seizures/drug therapy , Sex FactorsABSTRACT
This study evaluated the effect of lacosamide (LCM) on biochemical and mitochondrial parameters after PTZ kindling in mice. Male mice were treated on alternative days for a period of 11 days with LCM (20, 30, or 40 mg/kg), saline, or diazepam (2 mg/kg), before PTZ administration (50 mg/kg). The hippocampi were collected to evaluate free radicals, the activities of superoxide dismutase (SOD), catalase (CAT), and the mitochondrial complexes I-III, II, and II-III, as well as Bcl-2 and cyclo-oxygenase-2 (COX-2) expressions. Hippocampi, blood, and bone marrow were collected for genotoxic and mutagenic evaluations. LCM 40 mg/kg increased latency and decreased percentage of seizures, only on the 3rd day of observation. The dose of 30 mg/kg only showed positive effects on the percentage of seizures on the 2nd day of observation. LCM decreased free radicals and SOD activity and the dose of 40 mg/kg were able to increase CAT activity. LCM 30 and 40 mg/kg improved the enzymatic mitochondrial activity of the complex I-III and LCM 30 mg/kg improved the activity of the complex II. In the comet assay, the damage induced by PTZ administration was reduced by LCM 20 and 30 mg/kg. The dose of 20 mg/kg increased COX-2 expression while the highest dose used, 40 mg/kg, was able to reduce this expression when compared to the group treated with LCM 20 mg/kg. Although LCM did not produce the antiepileptogenic effect in vivo, it showed the neuroprotective effect against oxidative stress, bioenergetic dysfunction, and DNA damage induced by the repeated PTZ administration.
Subject(s)
Kindling, Neurologic/drug effects , Lacosamide/pharmacology , Neuroprotective Agents/pharmacology , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred Strains , PentylenetetrazoleABSTRACT
The lithium-pilocarpine model in rats is commonly used to study the characteristic events of acute status epilepticus (SE), epileptogenesis and temporal lobe epilepsy (TLE). Here we investigated the impact of lacosamide alone and in combination with other drugs (pregabalin, piracetam and scopolamine) on spontaneous recurrent seizures (SRSs) and behavioral parameters during the time frame of 6 weeks after SE. In addition, the level of oxidative stress in the hippocampus was accessed by real-time microdialysis study (8-isoprostanes) and antioxidants enzymes in the homogenate. Results revealed severe behavioral deficits with the control epileptic group and animals displayed hyperexcitability, aggression apprehension and memory insufficiency. Pharmacological manipulation for 6 weeks with lacosamide (L) - 80 mg/kg; in polypharmacy with pregabalin (L/P) - 50/50 mg/kg and piracetam (L/Pi) - 50/140 mg/kg significantly (P < 0.05) ameliorated the anxiety-related behavior (open filed, elevated plus maze, light/dark tests), depression (forced swim test) and improved spatial/reference memory (Morris water maze). There were low incidences of seizures in L, L/P and L/Pi groups revealing disease-modifying effects of employed drugs. Furthermore, the chronic use of scopolamine (L/P/S; 50/50/2 mg/kg) as polypharmacy with the concept of antagonizing the cholinergic inputs in the epileptogenic phase aberrated the behavioral situation further worse. Treatments with L/P and L/Pi significantly attenuated (P < 0.05) the oxidative stress by reducing 8-isoprostanes and malondialdehyde (MDA) levels. Furthermore, superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels in the L/P group were significantly (P < 0.05) improved. Overall, our findings support the use of a combination of drugs (L/P and L/Pi) in lithium-pilocarpine model which remarkably ameliorated SRSs, reduced anxiety-related behaviors, retention of spatial/reference memory and lowered oxidative stress in a time-course evaluation 6 weeks post- SE insult.
Subject(s)
Anticonvulsants/pharmacology , Behavior, Animal/drug effects , Brain/drug effects , Lacosamide/pharmacology , Oxidative Stress/drug effects , Status Epilepticus/prevention & control , Animals , Biomarkers/metabolism , Brain/metabolism , Brain/physiopathology , Disease Models, Animal , Drug Therapy, Combination , Male , Maze Learning/drug effects , Motor Activity/drug effects , Open Field Test/drug effects , Pilocarpine , Rats, Sprague-Dawley , Status Epilepticus/chemically induced , Status Epilepticus/metabolism , Status Epilepticus/psychology , Swimming , Time FactorsABSTRACT
BACKGROUND: Cognitive and psychiatric problems are common in people with epilepsy. They can have multiple causes, including structural brain lesions, the active epilepsy, and the effect of anti-epileptic therapy. Since patients' treatment compliance and quality of life are affected by cognitive and emotional status, it is crucial for clinicians to understand how anti-seizure medications (ASMs) affect cognition and mood, and to choose the proper ASM. OBJECTIVE: To conduct a literature review of the impact on cognition and mood status of lacosamide (LCM) in people with epilepsy. METHODS: Wesearched PubMed, the Cochrane Database of Systematic Reviews and reference lists of articles for all types of articles with no limitations on publication date. RESULTS: A total of 251 records were obtained, including 247 articles in PubMed and 4 articles from reference lists. We included 2 meta-analyses, one randomized controlled trials and 14 observational studies after the screening process. Most studies agree LCM has low risk of treatment-emergent adverse events (TEAEs) on cognition. Comparisons with other ASMs, LCM may be preferable to carbamazepine, topiramate and perampanel, and not inferior to lamotrigine. In spite of low incident rate, depression is the most common psychiatric change of LCM. There are no consistent positive or negative psychiatric effects of LCM. CONCLUSION: Lacosamide has limited impact on cognitive and mood status in this review. Several factors including mechanism of co-administration of ASMs and personal history of psychiatric disorder should be considered as important in the development of cognitive and psychiatric side effects. However, the heterogeneity between studies make the quality of evidence weaker and further trials are needed.
Subject(s)
Anticonvulsants/pharmacology , Cognition/drug effects , Epilepsy/drug therapy , Lacosamide/pharmacology , Adult , Affect/drug effects , Anticonvulsants/therapeutic use , Carbamazepine/pharmacology , Carbamazepine/therapeutic use , Epilepsy/psychology , Humans , Lacosamide/therapeutic use , Lamotrigine/pharmacology , Lamotrigine/therapeutic use , Nitriles , Pyridones , Quality of Life , Topiramate/pharmacology , Topiramate/therapeutic useABSTRACT
Jeavons syndrome is a childhood genetic generalized epilepsy characterized by eyelid myoclonia with or without absences, eyelid closure-induced epileptiform discharges and/or seizures and photoparoxysmal response. This syndrome accounts for up to 12.9% of generalized epilepsies, however, it is frequently under-reported. The utility of lacosamide in genetic generalized epilepsy and Jeavons syndrome is unclear. We present a case of a 15-year-old female with medically refractory Jeavons syndrome with seizure resolution in response to lacosamide monotherapy at standard daily doses. She had failed treatment with adequate trials of ethosuximide, valproic acid, lamotrigine, topiramate and the ketogenic diet, either as monotherapy or in combination. The frequency of seizures was confirmed in the epilepsy monitoring unit. She was treated with a loading dose of 200 mg of intravenous lacosamide and started at a maintenance dose of 100 mg, twice daily. The EEG showed a dramatic response with resolution of seizures and dramatic improvement in interictal discharges. She remained seizure-free for 11 months on lacosamide monotherapy after which seizures recurred in the setting of medication non-compliance. This highlights the potential role of lacosamide as an option in this syndrome if other drugs are ineffective or not tolerated.
Subject(s)
Anticonvulsants/pharmacology , Epilepsies, Myoclonic/drug therapy , Eyelids , Lacosamide/pharmacology , Adolescent , Anticonvulsants/administration & dosage , Epilepsies, Myoclonic/physiopathology , Eyelids/physiopathology , Female , Humans , Lacosamide/administration & dosageABSTRACT
Lacosamide is a new-generation anticonvulsant acting on Na+ channels. Compared to the classic anticonvulsants targeting Na+ channels, lacosamide is unique in structure and in its molecular action requiring longer membrane depolarization. Selective binding to the slow inactivated state of Na+ channels was then advocated for lacosamide, although slow binding to the fast inactivated state was alternatively proposed recently. In addition, quantitative characterization of lacosamide action has been deficient. We investigated the interactions between lacosamide and Na+ channels in native mammalian neurons, and found that the apparent dissociation constant (~13.7 µM) of lacosamide to the slow inactivated state is well within the therapeutic concentration range and is much (>15-fold) lower than the dissociation constant of lacosamide to the fast inactivated state. Besides, lacosamide has extremely slow binding rates (<400 M-1sec-1) to the fast but much faster binding rates (>3000 M-1sec-1) to the slow inactivated Na+ channels. Consistent with these biophysical characters, we further demonstrated that lacosamide is much more effective against the repetitive burst discharges with interburst intervals at -60 mV than -80 mV. With preponderant binding to the slow inactivation state in therapeutic concentrations and thus less propensity to affect normal discharges, lacosamide could be a drug of choice for seizure discharges characterized by relatively depolarized interburst intervals, during which more slow inactivated states could be generated and more binding of lacosamide would ensue.
Subject(s)
Lacosamide/metabolism , Lacosamide/pharmacology , Neurons/drug effects , Neurons/metabolism , Sodium Channels/metabolism , Voltage-Gated Sodium Channel Blockers/metabolism , Voltage-Gated Sodium Channel Blockers/pharmacology , Animals , Binding Sites/drug effects , Binding Sites/physiology , Dose-Response Relationship, Drug , Female , Hippocampus/drug effects , Hippocampus/metabolism , Kinetics , Lacosamide/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Voltage-Gated Sodium Channel Blockers/pharmacokineticsABSTRACT
Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures, and currently available drugs may fail to provide a thorough treatment of the patients. The present study demonstrates the utility of glucose-coated gold nanoparticles (GNPs) as selective carriers of an antiepileptic drug, lacosamide (LCM), in developing a strategy to cross the blood-brain barrier to overcome drug resistance. Intravenous administration of LCM-loaded GNPs to epileptic animals yielded significantly higher nanoparticle levels in the hippocampus compared to the nanoparticle administration to intact animals. The amplitude and frequency of EEG-waves in both ictal and interictal stages decreased significantly after LCM-GNP administration to animals with TLE, while a decrease in the number of seizures was also observed though statistically insignificant. In these animals, malondialdehyde was unaffected, and glutathione levels were lower in the hippocampus compared to sham. Ultrastructurally, LCM-GNPs were observed in the brain parenchyma after intravenous injection to animals with TLE. We conclude that glucose-coated GNPs can be efficient in transferring effective doses of LCM into the brain enabling elimination of the need to administer high doses of the drug, and hence, may represent a new approach in the treatment of drug-resistant TLE.
Subject(s)
Anticonvulsants/administration & dosage , Drug Delivery Systems , Epilepsy, Temporal Lobe/drug therapy , Lacosamide/administration & dosage , Metal Nanoparticles , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/pharmacology , Brain/metabolism , Disease Models, Animal , Electroencephalography , Gold/chemistry , Hippocampus/metabolism , Injections, Intravenous , Lacosamide/pharmacokinetics , Lacosamide/pharmacology , Male , Rats , Rats, Wistar , Tissue DistributionABSTRACT
BACKGROUND: Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians' experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug-drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice. MATERIALS AND METHODS: The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1. RESULTS: The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography. CONCLUSION: The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.
Subject(s)
Anticonvulsants/pharmacology , Lacosamide/pharmacology , Lamotrigine/pharmacology , Seizures/drug therapy , Seizures/therapy , Valproic Acid/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Interactions/physiology , Drug Synergism , Drug Therapy, Combination/methods , Electroshock/methods , Epilepsy/drug therapy , Epilepsy/therapy , Male , MiceABSTRACT
PURPOSE: The aim of this study was to evaluate the tolerability and efficacy of lacosamide (LCM) in Lebanese children with focal-onset seizures and to determine if specific variables are predictive of better effectiveness. METHODS: This is a retrospective analysis from three medical centers on consecutive children diagnosed with focal onset seizures and initiated on LCM. The seizure frequencies following the introduction of LCM were recorded and compared to the baseline monthly frequency at 3, 6, 12, 18, and 24 months. The primary efficacy variables were the 50% responder and seizure-free rates. The secondary outcome variables included the terminal 6-month seizure remission and percentages of discontinuation due to lack of efficacy or tolerability. RESULTS: 58 patients with a mean age of 10 years experiencing a mean of 36.2 seizures per month during baseline were included. The seizure-free rates were 32.8%, 29.7%, and 12.5% at 6, 12 and 24 months follow up, respectively. Patients concomitantly treated with a sodium channel blocker were less likely to achieve a terminal 6-month seizure remission while the early introduction of LCM resulted in a significantly higher likelihood of attaining such a remission. 74.1% of patients were still maintained on LCM at the last follow-up. The most common adverse events consisted of dizziness, somnolence, nausea, vomiting, and rarely double vision. CONCLUSIONS: LCM is efficacious and overall well tolerated in children with focal-onset seizures and exhibits higher efficacy with early introduction and when added to a non-sodium channel blocker.
Subject(s)
Anticonvulsants/pharmacology , Epilepsies, Partial/drug therapy , Lacosamide/pharmacology , Outcome Assessment, Health Care , Anticonvulsants/adverse effects , Child , Female , Follow-Up Studies , Humans , Lacosamide/adverse effects , Lebanon , Male , Product Surveillance, Postmarketing , Retrospective StudiesABSTRACT
We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN.
Subject(s)
Antineoplastic Agents/toxicity , Colorectal Neoplasms/drug therapy , Lacosamide/pharmacology , Neuralgia/drug therapy , Neurotoxicity Syndromes/drug therapy , Oxaliplatin/toxicity , Peripheral Nervous System Diseases/drug therapy , Voltage-Gated Sodium Channel Blockers/pharmacology , Acute Disease , Aged , Antineoplastic Agents/administration & dosage , Female , Humans , Lacosamide/administration & dosage , Male , Middle Aged , Neuralgia/chemically induced , Neurotoxicity Syndromes/etiology , Outcome Assessment, Health Care , Oxaliplatin/administration & dosage , Peripheral Nervous System Diseases/chemically induced , Pilot Projects , Prospective Studies , Voltage-Gated Sodium Channel Blockers/administration & dosageABSTRACT
Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 µM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants.