Lamotrigine Concentrations Research Articles

Risk factors of elevated blood ammonia level in epilepsy patients treated with lamotrigine.

The aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level.This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for 3 years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Total of 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils affected blood ammonia level. Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG.

Epilepsy Care in Transgender Patients.

The goal of this review is to outline the main considerations when treating transgender patients with epilepsy. Points to be addressed include the gender affirming hormone therapy regimens and how they interact with anti-seizure medications and seizure control, as well as common co-morbidities in the transgender epilepsy population. Gender affirming hormone therapy (GAHT) may affect seizure control directly, due to proconvulsant or anticonvulsant properties. GAHT may interact with anti-seizure medications; most notably, estrogen will decrease serum concentration of lamotrigine. Enzyme-inducing anti-seizure medications may decrease hormone levels, potentially interfering with goals of GAHT. Transgender epilepsy patients are at risk for co-morbidities such as decreased bone mineral density and depression. There are minimal direct studies on treatment or outcomes in the transgender epilepsy population. Providers must be knowledgeable about the bi-directional interactions between gender affirming hormone therapy and anti-seizure medications, as well as direct hormonal influences on seizure control. Future research should directly evaluate outcomes in transgender epilepsy patients with regard to seizure control, success of hormone therapy, and management of co-morbidities, to further educate providers and patients how to best manage their healthcare.

Analysis of free concentrations of lamotrigine and active oxcarbazepine metabolite in clinical patients by hollow-fiber centrifugal ultrafiltration.

Aim: To establish a simple and accurate method to explore the correlation between free and total concentrations of lamotrigine (LTG) and the active oxcarbazepinemetabolite monohydroxy derivative (MHD) (10,11-dihydro-10-hydroxycarbamazepine) in clinical patients. Materials & methods: Serum samples were prepared by hollow-fiber centrifugal ultrafiltration and then injected into UPLC for analysis. Results: Absolute recovery was as high as approximately 90.1-98.6% with excellent precision (relative standard deviation <6.7%). Analysis time was reduced to 5min. There were significant individual differences in the protein binding rates of both LTG and MHD that were probably due to the use of different clinical patients. Conclusion: Free concentrations of LTG and MHD cannot be estimated by total concentration in specific clinical patients. Free drug monitoring of LTG and MHD in clinical therapeutic drug monitoring is important and essential.

Comparison of HPLC-DAD and UPLC-MS/MS in Monitoring Serum Concentration of Lamotrigine

Background: Lamotrigine (LTG) is a broad-spectrum and first-line anti-epileptic drug. To monitor the serum levels of LTG in epileptic seizures patients, high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography-- tandem mass spectrometry (UPLC-MS/MS) methods were established and compared. Methods: Imatinib was used as the internal standard (IS) for both methods. LTG and IS were detected at 246 nm by HPLC-DAD. In UPLC-MS/MS, LTG and IS positive ion were detected by multiple reaction monitoring (MRM), with m/z of 256/210.9 and 494/394.02, respectively. A total of 37 blood samples from epileptic patients were determined and studied by these two methods. Results: There was an acceptable linearity for the two methods. The concentration range of LTG was 0.59 ~ 22.20 mg/L by HPLC, and 0.28 ~ 23.97 mg/L by UPLC-MS/MS. The Pearson regression coefficient of Deming regression was 0.9653 (95% CI: 0.9332 to 0.9821). Bland–Altman method demonstrated that the concentration of LTG determined by UPLC-MS/MS was 8.3% higher than that determined by HPLC (limits of agreement, -32.0% to +48.6%). Conclusion: There was a significant correlation between the two methods. Both HPLC and UPLC- MS/MS can be used for routine clinical monitoring of LTG.

Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period

ObjectiveTo analyse the concentrations of lamotrigine in maternal serum, colostrum, and serum of breastfed newborns, and to evaluate the effect of comedication with enzyme-inducing antiseizure medication and valproic acid. MethodsThis cohort study collected data from 158 women and 143 breastfed newborns. Maternal serum, milk (i.e., colostrum), and newborn serum samples were collected between the 2nd and 5th postnatal days, and lamotrigine concentrations were measured by high-performance liquid chromatography. ResultsThe median lamotrigine concentrations were 2.7 mg/L in maternal serum, 1.4 mg/L in milk, and 1.7 mg/L in newborn serum. The median milk/maternal serum concentration ratio was 0.60, the median newborn/maternal serum concentration ratio was also 0.60, and the median newborn serum/milk concentration ratio was 1.00. A significant correlation was observed between milk and maternal serum concentrations and between newborn serum and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight. ConclusionsExposure to lamotrigine in breastfed newborns is lower than exposure during pregnancy. However, by the same dose by the same mother, lamotrigine concentrations in both maternal serum and milk increase significantly after delivery. This finding, together with the immature function of eliminating enzymes in newborns, may be the reason for reaching concentrations in the reference range used for the general epileptic population in breastfed newborns. Therapeutic monitoring of breastfed newborns serum concentrations of lamotrigine is not mandatory; however, if signs of possible adverse events are noted, newborn serum concentrations should be analysed.

Synthesis of Molecularly Imprinted Polymers Based on a New Monomer "2-(4-Vinylphenyl) Quinoline-4-Carboxylic Acid" for the Selective Solid-Phase Extraction of Lamotrigine.

A new molecularly imprinted polymers (MIPs) have been prepared for the high selective extraction of lamotrigine (LTG), a widely used antiepileptic drug, in human serum. The MIPs were polymerized by bulk polymerization using our synthesized compound, 2-(4-vinylphenyl) quinolin-4-carboxylic acid, as functional monomer, which achieved better adsorption specificity than universal MIPs. Then, the molecularly imprinted solid phase extraction (MISPE) based on this material was coupled with high-performance liquid chromatography (HPLC) for the detection of LTG in human serum. The results of method validation showed that the developed method presented a good precision and accuracy, and the linearity was in the range of 1.50-40.00mg/mL with the limit of quantitation (LOQ) at 0.20mg/mL. The recovery ranged from 80.8% to 83.8% with RSD ranges from 5.5% to 11.1%. The validated method was successfully used to determine the concentration of LTG in human simulate serum samples.

Rare sudden unexpected death in epilepsy SCN5A variants cause changes in channel function implicating cardiac arrhythmia as a cause of death.

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multifactorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Nav 1.5sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases, but the impact of these variants on channel function is unknown. Here, we use whole-cell voltage clamp recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V, and p.R523C. Expression and biophysical properties, including activation, inactivation, and recovery from inactivation, were probed. Each SCN5A variant significantly impacted human NaV 1.5 channel function, indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human NaV 1.5 wild-type, but not p.R523C channels, implicating a gene-by-drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in individuals with epilepsy.

Quality control concerns in relation to lamotrigine and their impact.

To pursue explanations for compromised efficacy and induction of side-effects in some generic brands of lamotrigine distributed in Australia. Bioassays of the non-generic and five generic lamotrigine tablets were undertaken (also after exposure to heat and cold), as well as assays of two generic drugs generating concerning side-effects in two patients, while enquiries were made of manufacturing companies. Mass spectrometry of the six tested products showed comparable properties and no compromising when those tablets were heated and cooled, while analyses of the products taken by the two patients reporting significant side-effects showed an increase in the peak area lamotrigine concentration. We failed to identify any intrinsically compromised product in our comparison analyses of the six preparations. We consider alternate explanations for an issue leading to widespread international reporting of distinct side-effects and deaths following brand switching, with analyses of the two problematic preparations supporting a 'faulty' batch explanation.

The possible role of ursolic acid in Covid-19: A real game changer.

Ursolic acid (UA) is a pentacyclic terpenoid is usually found in the fruit peels and stem bark as secondary metabolites. UA has antiviral, antibacterial, and antiparasitic properties. UA has a wide spectrum of pharmacological activities against different infections. Because of the greatest antiviral and anti-inflammatory properties of UA, so it could be a plausible therapeutic herbal medicine in Covid-19 treatment. Covid-19 is a recent worldwide virulent disease pandemic due to severe acute respiratory coronavirus disease 2 (SARS-CoV-2). The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and exaggerated immune response by which acute lung injury (ALI) and/or acute respiratory distress syndrome might be developed in critical cases. UA may inhibit main protease of SARS-CoV-2, and inhibits the interface flanked by SARS-CoV-2 viral proteins and its entry point commonly recognized as angiotensin converting enzyme 2 (ACE2). In addition, UA attenuates SARS-CoV-2-induced inflammatory reactions and oxidative stress.Therefore, UA could avert SARS-CoV-2 infection from causing ALI. This opinion proposed that UA might be a potential candidate therapy against Covid-19 and can mitigate post-Covid-19 complications such as lung fibrosis. In this regards, forthcoming studies are reasonable to substantiate the therapeutic role of UA in Covid-19. However, taken into account that Covid-19 is yet to be investigating for further evaluations, therefore, clinical trials are recommended regarding use and dose of UA in Covid-19 treatment, as well as secondary effects.

Acute liver failure associated with lamotrigine in children with epilepsy: A report of two cases and thoughts on pharmacogenomics

Pediatric acute liver failure (PALF) is a rare and life-threatening clinical syndrome for which drug-induced liver injury is a cause. Lamotrigine (LTG) is generally a safe and effective antiseizure medication, and PALF related to LTG has rarely been reported. Here, we describe two cases of PALF associated with LTG in children with epilepsy. In both patients, LTG was used in combination with valproic acid at an initial dose exceeding the recommended dose, which increased the risk of adverse reactions. In addition, single nucleotide polymorphisms of genes associated with the pharmacokinetics and pharmacodynamics of LTG were selected for pharmacogenomic testing. However, the results revealed that genotypes of the patients had variable effects on the serum concentration and therapeutic responsiveness of LTG and therefore did not explain the clinical manifestations well. The findings of this case report caution clinicians to be aware of the risk of liver failure when using antiseizure medication in polytherapy, especially LTG in combination with valproic acid. When administered to children, the recommended dosage of LTG should be strictly followed. Further pharmacogenomic studies are needed to help improve the efficacy and safety of epilepsy treatment in the future.

Rapid and direct concentration range judgment of lamotrigine in plasma by the multi test lines with different detection limits on the same lateral flow strip

Continuous and interval monitoring of target drug concentration is of great importance for the effective and controllable therapy of diseases. In this research, the colloidal gold labeled lateral flow strip (LFS) is utilized for rapid and direct judgement of lamotrigine (LTG) concentration range, a specific medicine for epilepsy with the effective therapeutic concentration from 2.5 to 15 μg/mL in serum (corresponding to 25–150 ng/mL after 100-time dilution). Interestingly, two test lines of different detection limits on the same LFS can show different optical signal intensities at the same concentration of LTG in serum. Therefore, for concentration range judgment, it can be directly judged by the combination results of the two test lines on the same LFS without aid of any instruments. Typically, just with the dilution treatment of serum samples for 100 times, three concentration ranges including 0–25 ng/mL, 25–150 ng/mL, and higher than 150 ng/mL can be easily distinguished by the different test line combination results on the same LFS. The clinical serum samples at different concentrations of LTG have also been successfully measured with this multi detection limits LFS, which is 100% consistent with those of the HPLC. The simple operation and judgement standards of LFS with multi detection limits will make the home-test or self-test of therapeutic drug monitoring possible.

Lamotrigine effects on immune gene expression in larval zebrafish

PurposeDespite growing evidence that neuroinflammation and pro-inflammatory cytokines are involved in the pathogenesis of seizures and epilepsy, this knowledge has not been incorporated in the proposed mechanism of action of any of the current antiseizure medications (ASMs). Here, we tested the hypothesis by assessing inflammation markers in larval zebrafish (Danio rerio) exposed to lamotrigine (LTG). MethodsIn order to establish the most appropriate LTG concentrations for the transcriptome analysis (RNAseq), we initially assessed for teratogenic (spinal cord deformation, heart oedema, failed inflation of the swim bladder) and behavioural effects (distance moved, time spent active, and average swimming speed during a light/dark test) in zebrafish larvae exposed to 0, 50, 100, 300, 500, 750, and 1000 μM LTG continuously between 5 and 120 h post fertilisation. Subsequently, we repeated the experiment with 0, 50, 100, or 300 μM LTG for transcriptomic analyses. Two databases (Kyoto Encyclopedia of Genes and Genomes; Gene Ontology) were used to interpret changes in gene expression between groups. ResultsMajor teratogenic effects were observed at concentrations of ≥ 500 μM LTG, whereas behavioural changes were observed at ≥ 300 μM LTG. Transcriptome analysis revealed a non-linear response to LTG. From the suite of differentially expressed genes (DEG), 85% (n = 80 DEGs) were upregulated following exposure to 50 μM LTG, whereas 58% (n = 12 DEGs) and 91% (n = 210 DEGs) were downregulated in response to 100 and 300 μM LTG. The metabolic pathways affected following exposure to 50 and 300 μM LTG were associated with responses to inflammation and pathogens as well development and regulation of the immune system in both groups. Notable genes within the lists of DEGs included component complement 3 (C3.a), which was significantly upregulated in response to 50 μM LTG, whereas interleukin 1β (IL-1β) was significantly downregulated in the 300 μM LTG group. The lowest exposure of 50 μM LTG is regarded as clinically relevant to therapeutic exposure. ConclusionWe demonstrated that LTG had an impact on the immune system, with a non-monotonic response curve. This dose-dependent relation could indicate that LTG can affect inflammatory responses and also at clinically relevant concentration. Further studies are needed to establish this method as a tool for screening the effects of ASMs on the immune system.

Effects of Lamotrigine and Topiramate on Glial Properties in an Astrocyte-Microglia Co-Culture Model of Inflammation.

BackgroundAstrocytes and microglia are involved in the pathophysiology of epilepsy and bipolar disorder with a link to inflammation. We aimed to investigate the effects of the antiepileptic and mood-stabilizing drugs lamotrigine (LTG) and topiramate (TPM) on glial viability, microglial activation, cytokine release, and expression of gap-junctional protein connexin 43 (Cx43) in different set-ups of an in vitro astrocyte-microglia co-culture model of inflammation.MethodsPrimary rat co-cultures of astrocytes containing 5% (M5, representing “physiological” conditions) or 30% (M30, representing “pathological, inflammatory” conditions) of microglia were treated with different concentrations of LTG and TPM for 24 hours. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to measure the glial cell viability. The microglial activation state was analyzed by immunocytochemistry. The pro-inflammatory tumor necrosis factor-α (TNF-α) and anti-inflammatory transforming growth factor-ß1 (TGF-ß1) cytokine levels were measured by enzyme-linked immunosorbent assay. The astroglial Cx43 expression was quantified by western blot.ResultsA significant reduction of the glial cell viability after incubation with LTG or TPM was observed in a concentration-dependent manner under all conditions. LTG caused no significant alterations of the microglial phenotypes. Under pathological conditions, TPM led to a significant concentration-dependent reduction of microglial activation. This correlated with increased astroglial Cx43 expression. TNF-α levels were not affected by LTG and TPM. Treatment with higher concentrations of LTG, but not with TPM, led to a significant increase in TGF-ß1 levels in M5 and M30 co-cultures.ConclusionsDespite the possible glial toxicity of LTG and TPM, both drugs reduced inflammatory activity, suggesting potential positive effects on the neuroinflammatory components of the pathogenesis of epilepsy and bipolar disorder.

Determination of lamotrigine by fluorescence quenching of N-doped graphene quantum dots after its solid-phase extraction using magnetic graphene oxide

A sensitive fluorescent nanoprobe is reported for the determination of lamotrigine after its preconcentration by magnetic graphene oxide nanocomposite. The fluorescent nanoprobe is based on the quenching effect of lamotrigine on the nitrogen graphene quantum dots fluorescence at 440 nm, through strong hydrogen bonding. Under optimum conditions, the quenching fluorescent intensity of nitrogen graphene quantum dots shows linearity with the lamotrigine concentration in the range of 2.0–45.0 µg L−1, limits of detection (LOD), and quantification of 0.39 and 1.28 µg L−1 respectively. The parameters affecting the extraction and determination of lamotrigine were optimized via the central composite design (CCD) and one at the time method, respectively. The developed method was successfully employed for the extraction and quantification of lamotrigine in biological samples.

Association of Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders: A Systematic Review.

The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder). Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders. A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 μg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 μg/mL. Overall, LAM was well tolerated with no major significant adverse effects. Most studies showed a minimum LAM threshold level of 3 μg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question.

Redefining the age-specific therapeutic ranges of lamotrigine for patients with epilepsy: A step towards optimizing treatment and increasing cost-effectiveness

ObjectiveThe pharmacokinetics of lamotrigine exhibits age-related characteristics. Nevertheless, current evidence regarding the therapeutic range of lamotrigine has been derived almost exclusively from studies in adult patients, and the applicability of this therapeutic range to the pediatric population remains unclear. The purpose of this study was to establish the appropriate age-specific therapeutic ranges of lamotrigine corresponding to adequate clinical responses for patients with epilepsy. MethodsThis prospective cohort study of therapeutic drug monitoring included 582 Chinese epilepsy patients receiving lamotrigine monotherapy. Patients were divided into three age-related subgroups: (1) toddler and school-age group (2–12 years old, n = 168), (2) adolescent group (12–18 years old, n = 171), and (3) adult group (>18 years old, n = 243). Patients with a reduction in seizure frequency of 50 % or greater than baseline were defined as responders, and the remaining patients were non-responders. The relationship between lamotrigine serum concentrations and clinical response was assessed using multivariate logistic regression analysis. A receiver operating characteristic curve was generated to determine the representative cut-off values of lamotrigine trough levels, to distinguish responders from non-responders. The upper margin of the therapeutic range of lamotrigine was determined by developing concentration-effect curves for the three age-related subgroups. ResultsThe median trough levels of lamotrigine were significantly higher in responders than in non-responders from all three age-related groups (P < 0.0001). Results of logistic regression analysis revealed that higher serum concentrations of lamotrigine predicted a higher probability that seizure frequency would be reduced by more than 50 % compared to baseline (adjusted odds ratio: 1.228, 95 % CI: 1.137–1.327; P < 0.0001), and younger children were less likely to be responders (adjusted odds ratio: 1.027, 95 % CI: 1.012–1.043; P = 0.001). Based on a trade-off between sensitivity and specificity, the optimal cut-off values for lamotrigine trough concentrations corresponding to clinical response were 3.29 mg/L, 2.06 mg/L, and 1.61 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. By reducing interpatient variability, the results of the concentration-effect curves suggested no additional clinical benefit from a continued increase of doses for lamotrigine concentrations exceeding 9.08 mg/L, 8.43 mg/L, and 10.38 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. In conclusion, the therapeutic ranges of lamotrigine trough concentrations corresponding to adequate clinical response were 3.29–9.08 mg/L in the toddler and school-age group, 2.06–8.43 mg/L in the adolescent group, and 1.61–10.38 mg/L in the adult group. ConclusionsThe study determined age-specific therapeutic ranges corresponding to optimal clinical efficacy for lamotrigine. Our findings lay the foundation for catalyzing novel opportunities to optimize treatment and reduce therapeutic costs. Based on the age-specific therapeutic ranges identified in this study, individualized and cost-effective algorithms for lamotrigine treatment of epilepsy patients may be developed and validated in larger cohort studies of therapeutic drug monitoring.

Chicken embryo as animal model to study drug distribution to the developing brain

IntroductionRodent models are routinely used to assess the safety and developmental toxicity of pharmaceuticals, along with analysis of their distribution. These models require sacrifice of parent females, have challenges in the estimation of the number of embryos and stage of development, and are expensive and time-consuming. In this study, we used fertilized chicken eggs as an alternative model to address drug distribution to the developing brain of two antiepileptic drugs, valproic acid (VPA) and lamotrigine (LTG) at two developmental stages. MethodsVPA or LTG was injected into the allantois of the egg on embryonic day 13 (E13) or E16. Whole chicken brains were harvested at time-points of 5 min to 24 h and the concentrations of the drugs determined using GC/MS and LC-MS/MS, for VPA and LTG, respectively. ResultsVPA and LTG had distinct absorption and elimination phases and were found in the brain as early as 5–15 min after injection. Both drugs reached the brain in clinically relevant concentrations, with Cmax 10–30% of the calculated concentration assuming uniform distribution throughout the egg. LTG concentrations were higher when injected at E13 compared to E16. ConclusionThe chicken embryo model may be a suitable alternative animal model for preclinical drug distribution studies. It enables to easily approach antenatal development on an individual level, with a precise number of experimental animals, high reproducibility and low time and cost. Knowledge of the concentrations reaching the brain at different developmental stages with different drugs is important for the planning and interpretation of neurodevelopmental toxicity studies.

The pharmacogenomics of lamotrigine (a literature review)

Pharmacogenomics aims to optimize drug therapy with respect to genetic variations in various human genes, whose products affect drug pharmacokinetics and pharmacodynamics. Among neurological diseases, selecting effective drug therapy is especially important in epilepsy since recurrent epileptic seizures can lead to persistent epileptic brain activity and patient traumatization. Lamotrigine is a new generation broad-spectrum antiepileptic drug and is recommended as the drug of choice in focal and generalized epilepsy. By genotyping single-nucleotide polymorphisms (SNPs) associated with decreased or increased lamotrigine blood concentration, predicting the drug dose that will achieve the therapeutic serum concentration is possible. Selecting an appropriate individual drug dose avoids the development of dose-dependent side effects, which occur when the serum drug concentration is exceeded and drug discontinuation due to a lack of the expected effect because of insufficient blood levels. This review presents the results of studies of the polymorphism in genes that directly or indirectly alter lamotrigine serum levels. These include genes that encode the UGT enzymes, responsible for the conjugation and elimination of lamotrigine from the body; genes that encode transport proteins (P-glycoprotein, organic cation transporter, multidrug resistance protein, and breast cancer resistance protein); genes that encode the transcription factors HNF4α and pregnane X receptor, which regulate the expression of several liver transport proteins and enzymes. The reviewed data demonstrate the relationship between polymorphisms in these genes and changes in lamotrigine concentration. For citation: Azhigova A.M., Broutian A.G., Vlasov P.N. [The pharmacogenomics of lamotrigine (a literature review)]. Annals of clinical and experimental neurology 2021; 15(2): 59–72. (In Russ.) DOI: http://dx.doi.org/10.25692/ACEN.2021.2.8

Randomized, single-dose, two-period, two-sequence crossover bioequivalence study evaluating two oral formulations of lamotrigine in healthy volunteers

Background: Lamotrigine is an anti-epileptic medicine used to treat epilepsy and bipolar disorder. The mechanism of action is to block voltage activated sodium channels. The aim of this study was to evaluate the bioequivalence of 2 oral formulations of lamotrigine 25 mg in healthy volunteers.Methods: A single-dose, two-period, randomized crossover study design in - healthy Indian adult volunteers was conducted at Amaris Clinical, a division of Caplin Point Laboratories Ltd., Chennai. A validated high performance liquid chromatography in conjunction with mass spectrometry was used. Lamotrigine concentration in plasma. Adverse events were determined by measuring vital functions after dosing. A total of 24 subjects were included.Results: The mean and 90% confidence intervals of the test / reference ratios for these parameters were as follows: The mean Cmax and Tmax of the test were 758.606 (157.453) ng / ml and 1.17 (0.50-5.00) hours, respectively. The mean Cmax and Tmax of the reference were 775.993 (151.654) ng / ml or 0.88 (0.25-4.00) hours. The mean AUC0-72 was 24142. 031±3641.691 (ng.hr/mL) for the test formulation and 24202.099±3742.957 (ng. h / ml) for the reference formulation. The mean test / reference ratios for Cmax and AUC0-72 were 97.92 and 99.82 respectively. The 90% parametric CIs for Cmax and AUC0-72 were 90.17-105.68% or 97.87-101.81%.Conclusions: The 90% confidence intervals ranged from 80-125% and it was concluded that the test product was bioequivalent to the reference product in these healthy adult male volunteers.

Effects of antiseizure medications on placental cells: Focus on heterodimeric placental carriers

ObjectiveAppropriate placental nutrient transfer is essential for optimal fetal development. We have previously shown that antiseizure medications (ASMs) can alter the expression of placental carriers for folate and thyroid hormones. Here we extended our analysis to heterodimeric carriers that mediate the placental uptake of amino acids and antioxidant precursors. We focused on the L-type amino acid transporter (LAT)2/SLC7A8, the cystine/glutamate antiporter xCT/SLC7A11, and their chaperone 4F2hc/SLC3A2. MethodsBeWo cells were exposed for two or five days to therapeutic concentrations of valproate, levetiracetam, carbamazepine, lamotrigine, or lacosamide. Transcript levels were measured by quantitative PCR. Levetiracetam effects on placental carriers were further explored using a tailored gene array. ResultsAt five days, 30 μg/mL levetiracetam (high therapeutic concentrations) significantly reduced the expression of all studied genes (p < 0.05). Carbamazepine treatment was associated with lower SLC7A8 (LAT2) expression (p < 0.05), whereas valproate increased the transcript levels of this transporter by up to 2.0-fold (p < 0.01). Some of these effects were already observed after two incubation days. Lamotrigine did not alter gene expression, and lacosamide slightly elevated SLC3A2 levels (p < 0.05). The array analysis confirmed the trends observed for levetiracetam and identified additional affected genes. SignificanceAltered expression of placental heterodimeric transporters may represent a mechanism by which ASM affect fetal development. The placental effects are differential, with valproate, carbamazepine and levetiracetam as the more active compounds. The concentration-dependence of those ASM effects are in line with established dose-dependent teratogenicity implying that ASM doses should be adjusted during pregnancy with caution.