Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

Lamotrigine联合钙通道阻滞剂Nimodipine治疗局灶性脑缺血的实验研究

目的:观察同时应用钠通道阻滞剂和钙通道阻滞剂对鼠局灶性脑缺血的保护作用。方法:采用单尼龙线线栓法制备鼠大脑中动脉缺血3小时再灌流21小时模型,分别观察lamotrigine(20mg/kg ip),nimodipine(1μg/kg/min iv)以及两者联合应用对在鼠神经功能缺损的恢复、梗塞体积、突触体内游离钙浓度的影响。结果:联合应用lamotrigine和nimodipine缩小大鼠梗塞体积,恢复神经功能缺损较单独应用lamotrigine或nimodipine效果更明显(P<0.05)。结论:联合使用钠通道阻滞阻滞剂和钙通道阻滞剂优于单用其中一种药。

Solubility and thermodynamics of lamotrigine in ternary mixtures of ionic liquids([OMIm][Br]+[HMIm][Br]+water)at different temperatures

Experimental mole fraction solubility of lamotrigine(LTG)in ternary aqueous mixtures of two ionic liquids(ILs),1-hexyl and 1-octyl-3-methylimidazolium bromide,[HMIm][Br]and[OMIm][Br]were reported at several temperatures T=(293.15 to 313.15)K.The van’t Hoff and(Jouyban-Acree-van’t Hoff,E-Jouyban-Acree-van’t Hoff,e-NRTL,UNIQUAC and Wilson)models were used to correlate the solubility data.The comparison of the models with temperature and solvent composition dependencies shows that the Wilson model has the minimum ARD which are relatively close to those obtained from Jouyban-Acree-van’t Hoff and E-Jouyban-Acree-van’t Hoff models and maximum ARD belonged to the UNIQUAC model.The order of ARDs for these models is:Wilson b Jouyban-Acree-van’t Hoff,E-Jouyban-Acree-van’t Hoff b e-NRTL b UNIQUAC.Moreover,the apparent thermodynamic functions,Gibbs free energy,enthalpy and entropy of dissolution and mixing were calculated based on the van’t Hoff and Gibbs free energy equations.The strong LTG-ILs interactions and enthalpic contribution of the dissolution process resulted from the calculated thermodynamic functions.

Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine-pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug-resistant epilepsy

Background:Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs.The presence of lamotrigine,at a very low dose,does not hamper kindling in mice;rather it modifies this epileptogenesis process into drug-resistant epilepsy.The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine,phenytoin,and carbamazepine.It may also be possible that other licensed antiseizure drugs,like the mentioned drugs,remain ineffective in this model;therefore,this was the subject of this study.Methods:Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine(subtherapeutic dose,ie,5 mg/kg).Vehicle vs lamotrigine-kindled mice were compared in terms of(a)resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations;(b)lamotrigine bioavailability in blood and brain;(c)blood-brain barrier integrity;and(d)amino acids and monoamines in the cerebral cortex and hippocampus.Results:Lamotrigine vs vehicle-kindled mice are similar(or not significantly different P>.05 from each other)in terms of(a)response toward drug combinations;(b)lamotrigine bioavailability;and(c)blood-brain barrier integrity except for,significantly(P<.05)reduced taurine and increased glutamate in the cerebral cortex and hippocampus.Aside from these,lamotrigine-kindled mice show significant(P<.05)resistant to lamotrigine(15 mg/kg),levetiracetam(40 mg/kg);carbamazepine(40 mg/kg),zonisamide(100 mg/kg),gabapentin(224 mg/kg),pregabalin(30 mg/kg),phenytoin(35 mg/kg),and topiramate(300 mg/kg).Conclusion:Lamotrigine-pentylenetetrazole kindling takes longer to develop(~5 weeks)in comparison to lamotrigine-amygdale(~4 weeks)and lamotriginecorneal(~2 weeks)kindling models.However,drug screening through this model may yield superior drugs with novel antiseizure mechanisms.

Liquid chromatography tandem mass spectrometry method for the estimation of lamotrigine in human plasma:Application to a pharmacokinetic study

A reliable,selective and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of lamotrigine in human plasma using lamotrigine13C3,d3 as an internal standard.Analyte and internal standard were extracted from human plasma by solid-phase extraction and detected in positive ion mode by tandem mass spectrometry with electrospray ionization（ESI） interface.Chromatographic separation was performed on a Chromolith s SpeedROD;RP-18e column（50-4.6 mm i.d.） using acetonitrile：570.1 mM ammonium formate solution（90：10,v/v） as the mobile phase at a flow rate of 0.500 mL/min.The calibration curves were linear over the range of 5.02-1226.47 ng/mL with the lower limit of quantitation validated at 5.02 ng/mL.The analytes were found stable in human plasma through three freeze（-20℃）-thaw（ice-cold water bath） cycles and under storage on bench-top in ice-cold water bath for at least 6.8 h,and also in the mobile phase at 10℃ for at least 57h.The method has shown good reproducibility,as the intra-and inter-day precisions were within 3.0%,while the accuracies were within 76.0% of nominal values.The validated LC-MS/MS method was applied for the evaluation of pharmacokinetic and bioequivalence parameters of lamotrigine after an oral administration of 50mg lamotrigine tablet to thirty-two healthy adult male volunteers.

The efficacy and tolerability of lamotrigine adjunctive/monotherapy in patients with partial seizures refractory to poly-AEDs

Objective： This study was designed as an open-label trial to assess the effects of changing the antiepileptic drugs （AEDs） regimen to lamotrigine （LTG） as adjunctive/monotherapy in patients with partial seizures who were dissatisfied with their drug regimen because of intractable seizures. Methods： The patients were recruited from mulficenters using the following criteria： age≥ 18 years; at least 3 seizures per month during the last 16 weeks; previous use of at least 3 AEDs. The study involved a baseline phase and 2 experimental phases： LTG was first added to the regimen, and then patients could gradually change to LTG monotherapy if their seizures were reduced by at least 50 percent/month. Tolerability, the primary end point, was assessed using the Liverpool Adverse Experience Profile （LAEP）. Secondary end points included quality of life, as measured with the Quality of Life in Epilepsy-31 inventory. Reductions in seizures from baseline throughout each phase were also analyzed. Results： One hundred and fourteen patients aged between 18 and 52 years （age 27.8___ 13.2 years; 71 men and 43 women） were enrolled. After adding LTG, 105 patients （92.11%） Completed adjunctive therapy. Upon completion of the adjunctive phase, mean improvement from baseline was 2.6 points on the LAEP （p=0.037）. The overall score on the QOLIE-31 improved by 8.49 points from baseline （p=0.023）. At the end of the trial, 26 （22.81%） of patients completed LTG monotherapy, and 65 patients （57.02%） experienced at least 50% reduction in seizure frequency compared to baseline, The mean improvement from baseline was 5.1 points on the LAEP （p=0.0059）, and the overall score on the QOLIE-31 score improved by 12,72 points from baseline（p=0,0071）. Twenty-two （19.30%） patients reported adverse effects and 9 patients discontinued participation in the trial because of adverse effects. Conclusion： For patients with partial seizures who were dissatisfied with their AED regimen because of intractable seizures, adding LTG to the drug regimen was well tolerated and effective in improving the quality of life and controlling seizures. Furthermore, switching to LTG monotherapy was associated with further improvement.

Flunarizine and lamotrigine prophylaxis effects on neuron-specific enolase, S-100, and brain-specific creatine kinase in a fetal rat model of hypoxic-ischemic brain damage

BACKGROUND： Calcium antagonists may act as neuroprotectants, diminishing the influx of calcium ions through voltage-sensitive calcium channels. When administered prophylactically, they display neuroprotective effects against hypoxic-ischemic brain damage in newborn rats. OBJECTIVE： To investigate the neuroprotective effects of flunarizine （FNZ）, lamotrigine （LTG） and the combination of both drugs, on hypoxic-ischemic brain damage in fetal rats. DESIGN AND SETTING： This randomized, complete block design was performed at the Department of Pediatrics, Shenzhen Fourth People＇s Hospital, Guangdong Medical College. MATERIALS： Forty pregnant Wistar rats, at gestational day 20, were selected for the experiment and were randomly divided into FNZ, LTG, FNZ ＋ LTG, and model groups, with 10 rats in each group. METHODS： Rats in the FNZ, LTG, and FNZ ＋ LTG groups received intragastric injections of FNZ （0.5 mg/kg/d）, LTG （10 mg/kg/d）, and FNZ （0.5 mg/kg/d） ＋ LTG （10 mg/kg/d）, respectively. Drugs were administered once a day for 3 days prior to induction of hypoxia-ischemia. Rats in the model group were not administered any drugs. Three hours after the final administration, eight pregnant rats from each group underwent model establishment hypoxia-ischemia brain damage to the fetal rats. Cesareans were performed at 6, 12, 24, and 48 hours later; and 5 fetal rats were removed from each mother and kept warm. Two fetuses without model establishment were removed by planned cesarean at the same time and served as controls. A total of 0.3 mL serum was collected from fetal rats at 6, 12, 24, and 48 hours, respectively, following birth. MAIN OUTCOME MEASURES： Serum protein concentrations of neuron-specific enolase and S-100 were measured by ELISA. Serum concentrations of brain-specific creatine kinase were measured using an electrogenerated chemiluminescence method. RESULTS： Serum concentrations of neuron-specific enolase, S-100, and brain-specific creatine kinase were significantly higher in the hypoxic-ischemic fetal rats, compared with the non-hypoxic-ischemic group. Serum concentrations of neuron-specific enolase, S-100, and brain-specific creatine kinase were significantly less in the FNZ, LTG, and FNZ ＋ LTG groups following ischemia, compared with the model group （P 〈 0.01）. However, these values were significantly greater in the FNZ and LTG groups, compared with the FNZ ＋ LTG group, following ischemia （P 〈 0.01）. CONCLUSION： Preventive antenatal use of oral FNZ and LTG has positive neuroprotective effects on intrauterine hypoxic-ischemic brain damage. The combined effect of these two drugs is superior.

新结构的抗癫痫药Lamotrigine

近年,抗癫痫药物研究的目标是要洞悉神经元的非正常活性的发生及其如何纠正,从而得到“真正的”抗癫痫药,而不仅是控制发作的药物。Lamotrigine是一种化学结构与常用抗癫痫药不同的新型抗癫痫药。动物药理试验表明,本品类似苯妥因钠和卡马西平。

Effects of lamotrigine + sodium valproate therapy on the nerve cell nutrition and apoptosis status as well as inflammatory response in patients with intractable epilepsy

Objective: To investigate the effects of lamotrigine + sodium valproate therapy on the nerve cell nutrition and apoptosis as well as inflammatory response in patients with intractable epilepsy. Methods: A total of 70 patients with intractable epilepsy who were treated in our hospital between August 2013 and October 2016 were divided into routine group (n=35) and study group (n=35) by random number table method, routine group received sodium valproate therapy and study group received lamotrigine combined with sodium valproate therapy. The differences in serum levels of neurotrophy indexes, nerve apoptosis indexes and inflammatory factors were compared between the two groups before and after treatment. Results: Before treatment, there was no statistically significant difference in serum levels of neurotrophy indexes, nerve apoptosis indexes and inflammatory factors between the two groups. After treatment, serum BDNF and NGF levels of study group were higher than those of routine group;serum Bcl-2, Fas and FasL levels of study group were lower than those of routine group whereas Bax level was higher than that of routine group;serum IL-1β, IL-6 and PGE2 levels of study group were lower than those of routine group. Conclusion: Lamotrigine combined with sodium valproate therapy can effectively increase the neurotrophy, inhibit the nerve apoptosis and reduce the systemic inflammatory response in patients with intractable epilepsy.

Lamotrigine overdose cause skin rash and angioedema

A 23 years old female presented to Lincoln Medical and Mental Health center with skin rash and angioedema after she received 20 pills of lamotrigine 25 mg, and the patient used to take this medication before two tables a day for many months, after she received the appropriate management she improved. After reviewing MEDLINE we found a few cases reported life threatening complications related to lamotrigine intoxication and sudden increase the dose, so we should be aware about these complications before prescribing this medication.

Lamotrigine为治疗中枢性疼痛带来希望

据丹麦的研究人员报道,抗癫痫药物lamotrigine能缓解中枢性卒中后的疼痛(Central PostStroke Pain,CPSP)。该项研究的主要研究人员、丹麦奥系胡斯大学附属医院的Troles

Development of a simple and rapid method to measure the free fraction of lamotrigine in plasma using HPLC:applications for therapeutic drug monitoring

Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset, as well as refractory epilepsy. Due to the narrow treatment window and large individual variability in the pharmacokinetics and pharmacodynamics of LTG, therapeutic drug monitoring (TDM) is necessary in clinical practice to guide dose adjustments. Individual differences and drug combinations can also affect protein binding rate, which further affects the unbound concentration of LTG. The unbound fraction is more closely related to adverse reactions and therapeutic efficacy than total concentration. Therefore, it may be more meaningful to determine the unbound LTG concentration in plasma than the total concentration.Unbound LTG in plasma was extracted by ultrafiltration. High-performance liquid chromatography (HPLC) was used to measure unbound LTG concentration. This method was validated by studies of its selectivity, linearity, lower limit of quantification (LLOQ), accuracy, precision, recovery, and stability.The method was validated over a linear range of 0.2 to 10.0 μg·mL–1, and its LLOQ was 0.2 μg·mL–1. The method’s relative standard deviations (RSDs) for intra-day and inter-day precision were less than 15%, and its accuracy (RE) was ±4.69%. The recoveries of unbound LTG at three different concentrations satisfied the requirements for the analysis of biological samples, and no significant degradation of LTG was observed under different storage conditions.A simple HPLC method showed good performance when used to measure unbound LTG concentration. This method might be used to study the relationship between unboundLTG concentrations and its effectiveness according to TDM.

Glial Cell-Targeted Treatments for Bipolar Disorder: A Systematic Review of Available Data and Clinical Perspectives

This paper is a systematic review of the treatment of bipolar disorder: a systematic Google Scholar search aimed at treatment guidelines and clinical trials. The search for treatment guidelines returned 375 papers and was last performed from June 1, 2022 to August 30, 2022. The literature suggests that lithium helps control and alleviate severe mood episodes, and olanzapine is effective for acute manic or mixed episodes of bipolar I disorder. Achieving effectiveness or remission is better with Cariprazine. Lurasidone improves cognitive performance. Quetiapine improves sleep quality and co-morbid anxiety. Lamotrigine helps delay depression, mania, and mild manic episodes. Antidepressants are best used in conjunction with mood stabilizers. For co-morbid treatment, carbamazepine and lithium in combination are more effective in the treatment of psychotic mania. Co-morbid anxiety treatment considers adjunctive olanzapine or lamotrigine. Co-morbid bulimia treatment considers a mood stabilizer. Co-morbid fatigue treatment considers a dawn simulator. For diet, pay attention to a healthy diet, patients can ingest probiotics and pay attention to the balance of fatty acids.

抗癫痫药物相互作用

英国MARION Merrell Dow药物研究所制定了一张“抗癫痫药物相互作用表”。该表如下,显示当某一药物从合用方案中撤除可引起的血药浓度变化情况。

抗癫痫新药

根据保守估计,全世界约有5000万癫痫病人,每年发病率为20～70/10万,最高点达0.4％～0.8％,儿童期发病率最高。

Patch testing and cross sensitivity study of adverse cutaneous drug reactions due to anticonvulsants: A preliminary report

AIM To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions(ACDR) from common anticonvulsants. METHODS Twenty-four(M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. RESULTS Clinical patterns were exanthematous drug rash with or without systemic involvement(DRESS) in 18(75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis(SJS/TEN) overlap and TEN in 2(8.3%) patients each, SJS and lichenoid drug eruption in 1(4.2%) patient each, respectively. The implicated drugs were phenytoin in 14(58.3%), carbamazepine in 9(37.5%), phenobarbitone in 2(8.3%), and lamotrigine in 1(4.7%) patients,respectively. Twelve(50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6(50%), phenytoin alone in 4(33.3%), phenobarbitone alone in 1(8.3%), and both phenytoin and phenobarbitone in 1(8.33%) patients, respectively. Cross-reactions occurred in 11(92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three(75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. CONCLUSION Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically.

拉莫三嗪片说明书

[药品名称]33 通用名：拉莫三嗪片；商品名：利必通：Lamictal。英文名：Lamotrigine Tablets；汉语拼音：Lamosanclin Pian；本品主要成分及其化学名称为3，5二氨基-6-(2，3-二氯苯基)

拉莫三嗪片说明书

[药品名称]通用名：拉莫三嗪片 商品名：利必通：Lamictal 英文名：Lamotrigine Tablets汉语拼音：Lamosanqin Pian本品主要成分及其化学名称为3，5二氨基-6-(2，3-二氯苯基)

拉莫三嗪片说明书

[药品名称]通用名：拉莫三嗪片；商品名：利必通：Lamictal；英文名：Lamotrigine Tablets；汉语拼音：Lamosanqin Pian本品主要成分及其化学名称为3，5-二氨基-6-(23-二氯苯基)-as-三吖嗪；其结构式为：