Development of an HPLC method using relative molar sensitivity for the measurement of blood concentrations of nine pharmaceutical compounds.

We developed a reliable high-performance liquid chromatographic analysis method using a relative molar sensitivity (RMS) technique that does not require an authentic, identical reference analyte material to quantify blood serum carbamazepine, phenytoin, voriconazole, lamotrigine, meropenem, mycophenolic acid, linezolid, vancomycin, and caffeine levels for routine blood concentration measurements. Carbamazepine and caffeine were also used as non-analyte reference materials to calculate the RMS of each analyte. The RMS was calculated from the ratio of the slope of the calibration equation (analyte/non-analyte reference material), then used to quantify analytes in control serum samples spiked with carbamazepine, phenytoin, voriconazole, meropenem, mycophenolic acid, linezolid or vancomycin. In addition, the concentrations of these six drugs in control serum samples determined by the proposed RMS method agreed well with that obtained using a conventional method. The proposed RMS method is a promising tool for the clinical determination of nine drugs, given the accuracy, precision, and efficiency of quantifying these analytes.

Effects of co-administration of lamotrigine on valproate transfer across the placenta and its brain entry in developing Genetic Absence Epilepsy Rats from Strasbourg (GAERS).

During development, embryos and foetuses may be exposed to maternally ingested antiseizure medications (ASM), valproate and lamotrigine, essential in some patients to control their epilepsy symptoms. Often, the two drugs are co-administered to reduce required doses of valproate, a known potential teratogen. This study used Genetic Absence Epilepsy Rat from Strasbourg to evaluate transfer of valproate and lamotrigine across late gestation placenta and their entry into cerebrospinal fluid (CSF) and brain of developing rats, in mono- and combination therapies. Animals at embryonic day (E) 19, postnatal day (P) 0, 4 and 21, and adults were administered valproate (30 mg/kg) or lamotrigine (6 mg/kg) with their respective [3H]-tracers, either alone or in combination. In chronic experiments, females consumed valproate-containing diet from 2 weeks prior to mating until offspring were used at E19 and P0. Drugs were injected 30 min before blood, CSF and brain samples were collected from terminally anaesthetised animals. Radioactivity in samples was measured. In acute monotherapy brain entry of valproate was higher in foetal than postnatal animals, correlating with its plasma protein binding. Brain entry of lamotrigine was not age-dependent. Combination therapy enhanced entry of lamotrigine into the adult brain but had no effects on brain and CSF entry of valproate. Following chronic valproate exposure, placental transfer of valproate decreased in combination therapy; however, foetal brain entry increased. Results suggest that during pregnancy, the use of combination therapy of valproate and lamotrigine may mitigate overall foetal exposure to valproate but potential risks to foetal brain development are less clear.

An update on pharmacotherapy for trigeminal neuralgia.

INTRODUCTION: Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and potentially treatment-limiting adverse effects. Third-generation anticonvulsants, new calcitonin gene-related peptide blockers for migraine, and older drugs such as ketamine and cannabinoids may be promising adjuvants or monotherapeutic options. AREAS COVERED: The new drugs, their presumed mechanisms of action, safety and efficacy are discussed herein. There is a paucity of robust clinical evidence in support of these drugs for trigeminal neuralgia. New migraine agents are considered as well although migraines and trigeminal neuralgia are distinct, albeit similar, conditions. No new drugs have been released to market in recent years with the specific indication of trigeminal neuralgia. EXPERT OPINION: In real-world clinical practice, about half of trigeminal neuralgia patients take more than one agent for prevention and combination therapy may be the optimal approach. Combination therapy might allow for lower doses of carbamazepine or oxcarbazepine, thus reducing the number and severity of potential adverse events but the potential for pharmacokinetic drug-drug interactions must be considered. Drug therapy for trigeminal neuralgia involves acute or abortive treatments, often administered in hospital versus long-term preventive therapy, usually involving oral agents.

Trigeminal neuralgia is a relatively rare condition that usually affects one side of the face below the eye around the cheekbone. The cause of trigeminal neuralgia is sometimes a damaged nerve or a nerve that has lost part of its outer protective sheath (myelin). However, trigeminal neuralgia may have other neurological causes as well. Pain can be triggered by touch, pressure, or chewing and it tends to occur in very painful brief attacks followed by pauses with little or no pain. There are two types of drug treatment for trigeminal neuralgia: drugs to stop an ongoing attack (which are often administered in an emergency room or hospital intravenously) and drugs that are taken orally over the long term to reduce or prevent attacks.The two most effective drugs for trigeminal neuralgia are carbamazepine and oxcarbazepine, which are actually drugs to prevent seizures. They are effective in reducing the pain intensity and number of attacks of trigeminal neuralgia but they have side effects. In fact, these side effects can be so severe that people stop taking the drugs.Many new drugs have come to market recently that may work for trigeminal neuralgia, although none was specifically developed for this use. The newest generation of anti-seizure medications including eslicarbazepine, lacosamide, levetiracetam, and retigabine, may be just as effective as the older carbamazepine and oxcarbazepine drugs with fewer side effects. Clinical studies are needed to test them in trigeminal neuralgia patients but their mechanisms of action suggest that they might work well.There are some new drugs developed for migraine headache that inhibit a substance in the body called CGRP. Migraine headaches and trigeminal neuralgia have some of the same symptoms but they are different conditions but both involve too much CGRP.Other new drugs include lasmiditan, pimozide (used for Tourette syndrome), tizanidine (muscle relaxant), lamotrigine and vixotrigine (anti-seizure drugs) may also be beneficial. It may be that people with trigeminal neuralgia will have to take combination therapy, the use of two or more drugs with different mechanisms of action. Older drugs like ketamine and cannabinoids are also being considered as possible add-on agents for therapy for trigeminal neuralgia.

Seizure control and adverse outcomes of lamotrigine use during pregnancy: A systematic review and meta-analysis.

OBJECTIVE: This review aims to summarize existing evidence on the adverse pregnancy outcomes and seizure control effects of using lamotrigine (LTG) monotherapy in pregnancy women with epilepsy (WWE) during pregnancy. METHODS: A comprehensive search was conducted in various databases including Cochrane, Web of Science, CBM, PubMed, Embase, CNKI, and Pregnancy Registration Center databases to identify relevant studies. The search was concluded up to January 2024. Studies comparing LTG with other antiseizure medications (ASMs) for treating epilepsy in pregnant women were included, with no language or regional restrictions. RESULTS: A total of 19 studies were included for analysis, with 16 studies reporting adverse pregnancy outcomes and 6 studies reporting seizure control outcomes. Meta-analysis showed that compared to monotherapy with carbamazepine (CBZ), sodium valproate (VPA), and levetiracetam (LEV), LTG monotherapy had a slightly weaker ability to control seizures during pregnancy, with ORs and 95 %CIs of 0.65 (0.57-0.75; CBZ), 0.50 (0.32-0.79; VPA), and 0.55 (0.36-0.84; LEV). Regarding adverse pregnancy outcomes, the occurrence rate of LTG monotherapy was significantly lower than that of CBZ, VPA, phenytoin (PHT), and phenobarbital (PHB), with ORs and 95 %CIs ranging from 0.30 (0.25-0.35; VPA) to 0.68 (0.56-0.81; CBZ). CONCLUSION: Based on meta-analysis, LTG and LEV appear to be preferred medications for controlling seizures during pregnancy. This review provides further support for the use of LTG monotherapy in pregnant WWE, building upon existing evidence for clinical practitioners.

Unexpected Seizure Activity in the Setting of Lamotrigine Toxicity.

Lamotrigine, a widely utilized broad-spectrum anticonvulsant, is commonly prescribed for epilepsy management and bipolar mood disorders. Despite its extensive clinical usage, instances of lamotrigine overdose are underreported. Here, we present a case involving acute encephalopathy and seizure onset following an intentional lamotrigine overdose. This case underscores the importance of recognizing the potential clinical manifestations of lamotrigine toxicity, such as encephalopathy and seizures, emphasizing the necessity for vigilant management of patients receiving this medication.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Analysis of the Russian Database of Spontaneous Reports.

(1) Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are extremely severe cutaneous adverse drug reactions which are relatively rare in routine clinical practice. An analysis of a national pharmacovigilance database may be the most effective method of obtaining information on SJS and TEN. (2) Methods: Design-a retrospective descriptive pharmacoepidemiologic study of spontaneous reports (SRs) with data on SJS and TEN retrieved from the Russian National Pharmacovigilance database for the period from 1 April 2019 to 31 December 2023. Descriptive statistics was used to assess the demographic data of patients and the structure of suspected drugs. (3) Results: A total of 170 SRs on SJS and TEN were identified, of which 32.9% were SJS and 67.1%-TEN. In total, 30% were pediatric SRs, 21.2%-SRs of the elderly. There were 12 lethal cases, and all cases were TEN. The leading culprit drugs were anti-infectives for systemic use and nervous system agents. The top 10 involved drugs are as follows: lamotrigine (23.5%), ibuprofen (12.9%), ceftriaxone (8.8%), amoxicillin and amoxicillin with beta-lactam inhibitors (8.8%), paracetamol (7.6%), carbamazepine (5.9%), azithromycin (4.1%), valproic acid (4.1%), omeprazole (3.5%), and levetiracetam (3.5%). (4) Conclusions: Our study was the first study in Russia aimed at the assessment of the structure of the drugs involved in SJS and TEN on the national level.

Antiseizure medication and SUDEP - a need for unifying methodology in research.

The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic-clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have been suggested to increase the risk. However, the prevailing viewpoint is that the choice of antiseizure medication (ASM) does not influence the occurrence. We have explored the approach to addressing this question in relevant studies to evaluate the validity of the conclusions reached. A systematic search was performed in PubMed to identify all controlled studies on SUDEP risk in individuals on CBZ or LTG. Studies were categorized according to whether idiopathic generalized epilepsy (IGE) or females were considered separately, and whether data were adjusted for seizure frequency. Eight studies on CBZ and six studies on LTG were identified. For CBZ, one study showed a significantly increased risk of SUDEP without adjustment for seizure frequency. Another study found significantly increased risk after statistical adjustment for seizure frequency and one study found increased risk with high blood levels. Five other studies found no increase in risk. For LTG, one study showed a significantly increased risk in patients with IGE as opposed to focal epilepsy, and another study showed a significantly increased risk in females. None of the subsequent studies on LTG and none of the studies on CBZ considered females with IGE separately. Taken together the available studies suggest that LTG, and possibly CBZ, may increase occurrence of SUDEP when used in females with IGE. Additional studies with sub-group analysis of females with IGE are needed.

Molecularly Imprinted Drug Carrier for Lamotrigine-Design, Synthesis, and Characterization of Physicochemical Parameters.

This study presents the initial attempt at introducing a magnetic molecularly imprinted polymer (MIP) designed specifically for lamotrigine with the purpose of functioning as a drug carrier. First, the composition of the magnetic polymer underwent optimization based on bulk polymer adsorption studies and theoretical analyses. The magnetic MIP was synthesized from itaconic acid and ethylene glycol dimethacrylate exhibiting a drug loading capacity of 3.4 ± 0.9 µg g-1. Structural characterization was performed using powder X-ray diffraction analysis, vibrating sample magnetometry, and Fourier transform infrared spectroscopy. The resulting MIP demonstrated controlled drug released characteristics without a burst effect in the phospahe buffer saline at pH 5 and 8. These findings hold promise for the potential nasal administration of lamotrigine in future applications.

The efficacy of lamotrigine in bipolar disorder: A systematic review and meta-analysis.

OBJECTIVE: To provide up-to-date clinical guidance on the efficacy of lamotrigine in bipolar disorder (BD). METHODS: Eligible studies were identified during a systematic literature search according to PRISMA-guidelines. We included randomized controlled trials (RCTs) and cohort studies that quantitatively assessed lamotrigine's efficacy in BD. We divided the included studies into three groups: 1. acute treatment of depression, 2. acute treatment of mania and hypomania, and 3. maintenance treatment. Analyses were stratified by control group (placebo vs active comparator) and treatment strategy (monotherapy vs add-on treatment). RESULTS: We included 20 RCTs (n = 1166 lamotrigine users) and 20 cohort studies (n = 11,141 lamotrigine users). Twenty-four of these studies were included in meta-analyses. During depressive episodes, greater decreases in depressive symptomatology were associated with initiation of lamotrigine as add-on treatment than with placebo (SMD -0.30 [95% CI = -0.51, -0.10], df = 3, p = 0.004). Decreases in depressive symptomatology did not differ significantly between lamotrigine and the active comparator (SMD -0.28 [95% CI = -1.06, 0.50], df = 3, p = 0.488). As a maintenance treatment, lamotrigine was associated with a significantly lower relapse/recurrence rate than placebo (risk ratio (RR) 0.84 [95% CI = 0.71, 0.99], df = 2, p = 0.037). Relapse/recurrence rates did not differ significantly between lamotrigine and lithium (RR 1.06 [95% CI = 0.89, 1.25], df = 2, p = 0.513). A qualitative assessment of high-quality register-based studies found that lamotrigine was associated with lower hospital admission rates than other commonly used treatment regimes. CONCLUSIONS: There is substantial evidence for the efficacy of lamotrigine in BD, specifically as add-on treatment during acute depressive episodes and as maintenance treatment for preventing relapse and recurrence.

Evaluation of Anticonvulsant-Induced Leukocytosis: A Review of Evidence for Carbamazepine, Lamotrigine, and Phenobarbital.

Objective: The objective was to determine the incidence of leukocytosis associated with carbamazepine, lamotrigine, and phenobarbital. Data sources: A comprehensive literature review was conducted with the assistance of a medical reference librarian on PubMed, MEDLINE, Embase, and Google Scholar through June 2023 using the following search terminology: "leukocytosis/chemically induced"[MeSH Terms] AND ("Anticonvulsants"[MeSH Terms] OR ("Anticonvulsants"[Pharmacological Action] OR "Anticonvulsants"[MeSH Terms] OR "Anticonvulsants"[All Fields] OR "anticonvulsant"[All Fields] OR "anticonvulsion"[All Fields] OR "anticonvulsive"[All Fields] OR "anticonvulsives"[All Fields]) OR ("Anticonvulsants"[Pharmacological Action] OR "Anticonvulsants"[MeSH Terms] OR "Anticonvulsants"[All Fields] OR "antiepileptic"[All Fields] OR "antiepileptics"[All Fields])). Study selection and data extraction: Thirteen reports were included from 64 potential results of our literature review following the application of inclusion and exclusion criteria: 7 of the reports involved carbamazepine, 4 of the reports involved lamotrigine, and 2 of the reports involved phenobarbital. Data synthesis: Drug-induced leukocytosis is commonly a diagnosis of exclusion and is a phenomenon that has numerous ramifications to patients and clinicians at the bedside, including mandating a full infectious evaluation, the identification of confounding variables, and the eventual discontinuation of the offending agent. Despite several medications and medication classes possessing this adverse drug effect, an evaluation of the specific clinical presentation and management strategies for drug-induced leukocytosis associated with anticonvulsant medications has not been elucidated in the literature. Conclusions: Clinicians should be judicious when evaluating leukocytosis in patients on potentially precipitating medications, including carbamazepine, lamotrigine, and phenobarbital.

Acute kidney injury in lamotrigine-induced DRESS syndrome.

We present a case of lamotrigine-triggered DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome with acute kidney injury stage 3. A 17-year-old girl with known epilepsy treated with lamotrigine presented with acute kidney injury as well as skin eruption, fever, and apathy. Extended diagnostics, considering infectious and autoimmune diseases, remained unremarkable. Lamotrigine blood levels were within the target range. Kidney biopsy showed acute interstitial nephritis with tubular necrosis. Methylprednisolone pulse therapy led to an improvement in kidney function; skin eruption and neurological symptoms resolved. During the hospital stay, the girl admitted to inconsistent and variable intake of lamotrigine, occasionally resulting in notable overdosing. This report demonstrates that acute kidney injury in lamotrigine-induced DRESS syndrome is an acute interstitial nephritis with tubular necrosis, an aspect that has not been deeply characterized so far. Additionally, we aim to elevate awareness towards non-adherence as cause of disease, especially among the adolescent population.

Supramolecular synthons in hydrates and solvates of lamotrigine: a tool for cocrystal design.

The molecule of anti-epileptic drug lamotrigine [LAM; 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine] is capable of the formation of multicomponent solids. Such an enhanced tendency is related to the diverse functionalities of the LAM chemical groups able to form hydrogen bonds. Two robust synthons are recognized in the supramolecular structure of LAM itself formed via N-H...N hydrogen bond: homosynthon, so-called aminopyridine dimer or synthon 1 [R22(8)] and larger homosynthon 2 [R32(8)]. The synthetic procedures for a new hydrate and 11 solvates of LAM (in the series: with acetone, ethanol: two polymorphs: form I and form II, 2-propanol, n-butanol, tert-butanol, n-pentanol, benzonitrile, acetonitrile, DMSO and dioxane) were performed. The comparative solid state structural analysis of a new hydrate and 11 solvates of LAM has been undertaken in order to establish robustness of the supramolecular synthons 1 and 2 found in the crystal structure of LAM itself as well as LAM susceptibility to build methodical solid state supramolecular architecture in the given competitive surrounding of potential hydrogen bonds. The aminopyridine dimer homosynthon 1 [R22(8)] has been switched from para-para (P-P) topology to ortho-ortho (O-O) topology in all crystal structures, except in LAM:n-pentanol:water solvate where it remains P-P. Homosynthon 2 [R32(8)] of the LAM crystal structure imitates in the LAM solvates as a heterosynthon by replacing the triazine nitrogen proton acceptor atoms of LAM with the proton acceptors of solvates molecules.

The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies.

OBJECTIVE: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics. METHODS: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines. RESULTS: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10-3, 95%CI = -16.08 to -8.58 × 10-3 (µg/mL)/(mg/day), p < 0.001, MD = -7.16 (µg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (µg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10-3 (µg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10-3, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5. CONCLUSIONS: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.

Recurrent Painful Ophthalmoplegic Neuropathy Responding to Lamotrigine: A Case Report.

Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare neurological disorder characterized by recurring ipsilateral headache and paresis of one or more ocular motor nerves. We report the case of a 56-year-old woman with systemic lupus erythematosus (SLE) and hypertension, who presented with severe recurring headaches, nausea, and vomiting. Initially misdiagnosed with cerebral venous sinus thrombosis, her symptoms persisted despite anticoagulant therapy. Further evaluation led to the diagnosis of RPON. Management included intravenous analgesia, hydration, and indomethacin for pain relief. Persistent headache episodes necessitated the introduction of lamotrigine, resulting in significant symptom improvement. However, discontinuation of lamotrigine led to a recurrence of symptoms, which resolved upon resuming the medication. This case contributes to the limited RPON literature, providing insights into its diagnosis and management, with the goal of enhancing awareness and improving patient care.

Determination of lamotrigine in human plasma by HPLC-PDA. Application to forensic samples.

PURPOSE: Therapeutic drug monitoring of plasma lamotrigine (LTG) has customarily been carried out in order to prevent some its adverse effects. For forensic purposes, determination of LTG in plasma is an useful tool in cases of accidental overdose or suicidal attempts. Currently, there are several analytical methods available including some based on LC tandem mass spectrometry techniques, but simple and accessible LC-UV methods still can be useful for the purpose. Here we report on a new high-performance liquid chromatography method for the determination of lamotrigine in human plasma which has been developed and validated including selectivity, sensitivity, accuracy, precision and recovery studies. METHODS: Lamotrigine and the internal standard chloramphenicol were extracted from plasma using liquid-liquid extraction using small volumes of buffer and ethylacetate. Detection was monitored at 305.7 and 276.0 nm for lamotrigine and chloramphenicol, respectively. RESULTS: The method was linear concentration dependence within the range of 0.1-10 µg/ml, with a mean coefficient of correlation r = 0.993. The limit of detection (LOD) was 0.04 µg/ml and the limit of quantification (LOQ) was 0.1 µg/ml. Intra and interday precision values were lower than 9.0% at all concentrations studied. The intra and interday accuracy values ranged from - 7.6 to 10.1%. Recovery was found to be 98.9% or higher. The method here described was successfully applied to 11 postmortem blood samples received at the Forensic Sciences Institute of Santiago de Compostela (Spain). CONCLUSION: A new HPLC method for the determination of lamotrigine in human plasma was developed and validated. A liquid-liquid extraction using small volumes of buffer and ethylacetate was optimized. The proposed method is suitable for forensic toxicological analysis.

Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma.

BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

An LC-MS/MS Method for Quantification of Lamotrigine and Its Main Metabolite in Dried Blood Spots.

BACKGROUND: The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response. RESULTS: The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients. CONCLUSIONS: The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.