Search Results (1,088)

Gymnodinium catenatum is a paralytic shellfish toxin (PST)-producing dinoflagellate that produces classical PSTs and hydroxybenzoate analogues known as GC toxins. Toxicological evaluation of GC toxins remains limited because certified reference materials (CRMs) and toxicity data are unavailable. This study applied the Neuro-2a (N2a) cell-based assay to evaluate PST functional toxicity in a Korean G. catenatum strain. The algal extract was analyzed by dose–response curve fitting to estimate total saxitoxin (STX)-equivalent toxicity, while GC1 & 2, GC3, and GC4 & 5, isolated from large-scale culture and structurally confirmed by NMR and LC-MRM-MS/MS, were evaluated to determine toxicity equivalence factors (TEFs). A clear sigmoidal curve yielded a functional toxicity of 3.7275 pg STX eq cell⁻¹, and TEFs followed the order GC3 > GC4 & 5 > GC1 & 2, with potency gaps considerably larger than previously reported receptor-binding differences. These findings support the N2a assay as a complementary approach for PST analogues lacking CRMs and suggest that receptor-binding affinity alone does not fully predict cellular functional potency. Although the proposed TEFs, obtained from single assays per preparation, are preliminary and assay-specific, this study provides the first functional toxicity estimates for GC toxins, contributing to the toxicological characterization of novel PST analogues. Full article

For a long time, pain management has relied on relatively old opioids and broad-spectrum non-opioids, which display efficacy gaps and non-negligible safety risks. This review explores why voltage-gated sodium channels, particularly NaV1.7 and NaV1.8, emerged as prime targets for pain relief, and why early development efforts failed. NaV1.7 was initially considered a promising target due to its role in nociception and genetic evidence linking it to pain disorders. However, clinical trials of selective NaV1.7 inhibitors have repeatedly failed. We explore the reasons for these failures and discuss the clinical shortcomings of non-selective blockers and early NaV1.7 inhibitors. In contrast, NaV1.8 has emerged as a much stronger drug target, because it is mostly limited to peripheral nerves, directly drives continuous pain signaling, and shows less apparent functional redundancy in specific nociceptive axonal compartments. Nevertheless, compensatory mechanisms involving NaV1.7, NaV1.9, and other conductances remain context-, tissue-, and disease-dependent. Suzetrigine, a highly selective inhibitor of this channel, recently gained regulatory approval for acute pain, marking a major breakthrough in non-opioid options, even though its Phase 3 efficacy was comparable to hydrocodone/acetaminophen rather than superior to it. Its clinical success is built on high selectivity, excellent pharmacokinetics, and a smart trial design that focused specifically on standardized postoperative pain models. While suzetrigine shows that NaV1.8 can be successfully targeted, it represents a regulatory and mechanistic victory rather than a complete replacement for opioids in daily practice. Progress in this field will ultimately require precise targeting, better pharmacology, and trials that better match patient phenotypes. Full article

To address the challenges associated with severe lost-circulation formations, including large loss-channel dimensions, rapid fluid losses, and the tendency of conventional bridging or physical-filling materials to accumulate at fracture entrances rather than penetrate deeply into fractures and form stable pressure-bearing plugs, a slag–fly ash–gypsum–sodium ethylenediamine tetramethylene phosphonate (EDTMPS) controlled-setting lost-circulation system was developed in this study. A 4 wt% bentonite base slurry was used as the dispersion medium, while a slag–fly ash blend served as the principal cementitious component. Gypsum was used to regulate the setting reaction, and EDTMPS was employed to control the slurry-thickening process, thereby coordinating slurry pumping, fracture filling, and in situ setting. The operational feasibility, consolidation capability, and short-term pressure-bearing performance of the system were evaluated through formulation screening, tests of slurry placement and hardened-material properties, water-based drilling-fluid contamination evaluation, and pressure-bearing tests in regular fractures with apertures of 1–5 mm. The results showed that, at a slag-to-fly-ash mass ratio of 6:4, the hardened material exhibited a compressive strength of 12.91 MPa. Within the investigated dosage range, the highest observed 1 d and 3 d compressive strengths were both obtained at a gypsum dosage of 2.0%. Under conditions of 150 °C and 50 MPa, the addition of 1.5 g of EDTMPS extended the slurry thickening time from 2.6 h to 7.3 h, while the compressive strength of the hardened material after 24 h of curing reached 17.18 MPa. At a water-based drilling-fluid contamination ratio of 30%, the compressive strength of the hardened material was 13.86 MPa, corresponding to a strength-retention ratio of 80.7%. In straight, constant-aperture fractures with apertures of 1.0, 2.0, 3.0, 4.0, and 5.0 mm, the maximum pressures sustained by the plugs before breakthrough were 16, 15, 14, 13, and 12 MPa, respectively, and decreased with increasing fracture aperture. These results indicate that, within the formulation range, water-based drilling-fluid contamination conditions, and short-term pressure-bearing conditions in regular fractures investigated in this study, the system can coordinate slurry-thickening control, 24 h hardened strength, contamination tolerance, and pressure-bearing performance in regular fractures. The findings provide a verifiable formulation-design approach for reconciling the placement-time window of lost-circulation materials for severe lost circulation with their post-placement pressure-bearing capacity. Full article

A 56-year-old man with a family history of myopathy developed generalized muscle weakness at age 45. At age 52, he was diagnosed with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), confirmed by muscle pathology and a pathogenic VCP mutation (c.464G>A, p.R155H). Concurrent testing identified a heterozygous SCN4A variant (c.215C>T, p.P72L), a known modifier in myotonic dystrophy type 2 (DM2). At age 56, neurological examination showed proximal muscle weakness (MMT grade 3), distal lower extremity weakness (grade 4–5), and areflexia. He ambulated independently with knee locking, though squatting was impossible. No myotonia or periodic paralysis was observed. Multimodal imaging captured classic IBMPFD hallmarks: skeletal muscle computed tomography (CT) showed advanced fatty degeneration of paraspinal and limb muscles; brain magnetic resonance imaging (MRI) revealed mild frontal lobe atrophy; and bone scintigraphy showed increased uptake in the lumbar spine and iliums. Although the SCN4A p.P72L variant exacerbates DM2, the patient’s three-year progression from independent walking to cane use remained consistent with the natural history of IBMPFD. This case suggests that in the presence of a robustly penetrant VCP phenotype, the SCN4A variant does not necessarily exert a clinical modifying effect. Full article

Solid-state sodium metal batteries are promising for large-scale energy storage owing to their high safety, abundant sodium resources, and low material cost. However, NASICON-type solid-state electrolytes, such as Na₃Zr₂Si₂PO₁₂, still suffer from limited room-temperature ionic conductivity and poor ceramic densification. Herein, a multivalent co-doping strategy using Zn²⁺, Sc³⁺, Hf⁴⁺, and Nb⁵⁺ was employed to regulate the crystal structure, sintering behavior, and Na⁺ transport properties of NASICON electrolytes. The effects of isovalent and aliovalent dopants were systematically investigated by XRD, Rietveld refinement, SEM-EDS, bond-valence-site calculations, and electrochemical impedance spectroscopy. The optimized monoclinic Na_3.167Zn_0.167Hf_0.167Zr_1.5Nb_0.167Si₂PO₁₂ electrolyte delivered a room-temperature total ionic conductivity of 1.16 mS cm⁻¹ and an activation energy of 0.35 eV, mainly due to optimized Na⁺ migration-channel geometry and enhanced ceramic densification. Na||Na symmetric cells exhibited stable cycling for 500 h with a maximum polarization voltage of 20 mV. Furthermore, solid-state Na||Na₃V₂(PO₄)₃ cells retained 95% capacity after 624 cycles at 1 C. This work provides a feasible doping strategy for advanced NASICON electrolytes and solid-state sodium metal batteries. Full article

Background: Drug-resistant epilepsy (DRE) affects approximately one-third of individuals with epilepsy, where seizures remain uncontrolled despite appropriate trials of at least two antiseizure medications (ASMs). Neuroinflammation, specifically chronic microglial activation, plays an important role in epileptogenesis, seizure perpetuation, and pharmacoresistance. Traditionally, antiseizure medications (ASMs) target neuronal excitability through modulation of ion channels and neurotransmitter systems; however, several ASMs, including sodium valproate and lamotrigine, have demonstrated anti-inflammatory and microglia-modulating properties beyond their conventional antiseizure mechanisms. Rational polytherapy involving combinations of ASMs with complementary mechanisms and anti-neuroinflammatory effects may provide enhanced seizure control while minimizing adverse effects. Among available combinations, sodium valproate and lamotrigine have consistently been regarded as one of the few combinations demonstrating potential pharmacodynamic synergism. Although several clinical studies have evaluated this combination in pediatric DRE, the overall evidence has not been quantitatively synthesized. Objectives: To systematically evaluate the efficacy and safety of rational polytherapy with sodium valproate plus lamotrigine in children with drug-resistant epilepsy. Methods: Electronic databases, including PubMed, Medline, Scopus, Embase, Web of Science, Google Scholar, PubMed Central, ScienceDirect, Cochrane Library, and clinicaltrials.gov, were systematically searched. Studies involving pediatric patients aged 18 years or less with DRE receiving polytherapy regimens containing sodium valproate plus lamotrigine were included. Primary outcomes were total treatment effect defined as ≥50% seizure reduction and seizure freedom. Secondary outcomes included changes in seizure frequency, adverse events, treatment discontinuation, and serious adverse events. Risk of bias was assessed using the Cochrane Risk of Bias tool and Newcastle–Ottawa Scale. Meta-analyses were performed using random-effects models. Results: A total of 7 studies met the eligibility criteria. The pooled proportion of patients achieving an overall treatment response was 65.3% (95% CI 51.8–78.8%), with high heterogeneity (I² = 63.4%, p = 0.027). Rational polytherapy with sodium valproate plus lamotrigine combination provided preliminary comparative evidence of higher responder rates in a single comparative trial, requiring confirmation in larger randomized trials. Overall, sodium valproate plus lamotrigine was well tolerated, and most reported adverse events were mild to moderate in severity. The pooled adverse event rate was 18.1% (95% CI 8.3–28.0%), with high heterogeneity (I² = 64.3%, p = 0.024). Conclusions: Rational polytherapy with sodium valproate plus lamotrigine that have both complementary antiseizure and immunomodulatory mechanisms appears to represent an effective and generally well-tolerated therapeutic strategy for pediatric drug-resistant epilepsy. However, the basis of this conclusion is derived mainly from observational studies, requiring confirmation in larger randomized trials. This systematic review provides quantitative evidence supporting its clinical use while highlighting the need for larger prospective comparative studies to strengthen the evidence base. Full article

The development of antiepileptic drugs remains a serious challenge for both academia and industry. Ionotropic glutamate receptors and voltage-gated sodium channels are among the primary targets of antiepileptic agents. Recent studies have revealed a unique property of phenytoin: unlike other sodium-channel blockers, it inhibits calcium-impermeable AMPA receptors at micromolar concentrations. In this study, we explored the structure–activity relationships of eight phenytoin derivatives. The effects of the compounds on neuronal voltage-gated Na⁺ channels and neuronal AMPA receptor channels were examined using the patch-clamp technique. For the Na⁺ channels, we analyzed tonic block, shifts of steady-state inactivation, and frequency-dependent block. For the AMPA receptors, we investigated kinetics, agonist dependence, and trapping effects. NH groups at positions 1 and 3, the carbonyl groups at positions 2 and 4, and the phenyl group at position 5 are important, since their replacement causes a decrease in activity. Replacement of oxygen with sulfur at position 2 results in a significant increase in activity on both types of channels. For the AMPA receptor, this increase is attributable to a more stable drug–channel complex. The enhanced action on sodium channels is due to an increase in tonic block, whereas the effects on inactivated and open channels remain unchanged. These results suggest a new possibility for tuning the activities of phenytoin derivatives against both primary targets to obtain anticonvulsants with novel properties. Full article

Ketamine has pharmacological actions beyond N-methyl-D-aspartate receptor antagonism, whereas sodium selenite modulates redox-dependent signaling. Transient receptor potential vanilloid 1 (TRPV1) channels regulate Ca²⁺ influx and may contribute to oxidative stress-associated apoptosis. We investigated whether ketamine and sodium selenite, alone and combined, promote apoptosis through TRPV1-associated mechanisms in SH-SY5Y neuroblastoma cells. Cells were assigned to control, ketamine+sodium selenite (Ket+Sel), Ket+Sel+capsazepine (CPZ), ketamine, ketamine+CPZ, sodium selenite, and sodium selenite+CPZ groups. Ketamine (10 µM) and/or sodium selenite (500 nM) were applied for 48 h; CPZ (0.1 mM, 30 min) was used for pharmacological antagonism, and capsaicin (0.1 mM) for stimulation. Intracellular Ca²⁺ responses were assessed using Fura-2-AM, whereas apoptosis, reactive oxygen species production, mitochondrial depolarization, and caspase-3/9 activities were measured spectrophotometrically or fluorometrically. Under capsaicin-stimulated assay conditions, ketamine and sodium selenite increased all endpoints relative to control, and the combined treatment produced the greatest responses for most endpoints. CPZ attenuated Ca²⁺ responses and several downstream oxidative and apoptotic markers. These findings indicate that ketamine and sodium selenite, particularly in combination, enhance apoptosis through a CPZ-sensitive pathway compatible with TRPV1-associated Ca²⁺-ROS-mitochondrial signaling, while not establishing exclusive TRPV1 mediation. Full article

Background: Despite more than 30 licenced antiseizure medications (ASMs), approximately one third of people with epilepsy remain drug-resistant, and developmental and epileptic encephalopathies represent one of the greatest unmet needs in epilepsy therapeutics. The past decade has produced a substantial reorientation of ASM discovery, driven by epilepsy genetics, new disease models, advances in drug screening, and innovative therapeutic modalities. Objective: The objective of this study was to review the contemporary clinical-stage pipeline of ASMs with novel or differentiated mechanisms of action, organized by molecular target, while placing recent regulatory successes and instructive failures within the broader transition toward mechanism-based, precision, and potentially disease-modifying therapies. Findings: A 2024 pipeline analysis identified more than 200 epilepsy therapies in preclinical or clinical development; at the cutoff of the present literature search (30 June 2026), over 40 compounds had reached phase II or III, with the majority directed at DEEs. Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial. Several of the efficacy figures summarized here derive from congress presentations, interim analyses, or open-label extensions and await full peer-reviewed publication. Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABA_A modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen). Pre-symptomatic intervention in tuberous sclerosis complex provides an early, single-trial clinical proof of principle for delaying and reducing the incidence of epilepsy in a genetically defined population; this should not yet be equated with established disease prevention. Conclusions: The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent translational gap between early signals and randomized-trial confirmation, and by the preliminary status of much of the supporting evidence. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, and effective biomarkers for prognosis and therapeutic guidance are still lacking. TRPM4, a sodium-related ion channel, has been implicated in tumor progression; however, its role in LUAD, particularly at the single-cell level, remains unclear. Methods: Single-cell RNA sequencing data were used to analyze the cellular distribution of TRPM4 in LUAD. TRPM4-related genes were identified through correlation analysis in the TCGA cohort, followed by construction of a prognostic model using Cox and LASSO regression analyses. The model was validated in an independent GEO dataset. Functional enrichment and drug sensitivity analyses were performed to explore the underlying mechanisms and therapeutic implications. Random forest analysis was applied to identify key genes, and in vitro experiments were conducted to validate their biological functions. Results: A TRPM4-related prognostic signature was established, demonstrating robust predictive performance in both training and validation cohorts. High-risk patients were characterized by activation of cell cycle and DNA replication pathways, showing differences in computationally predicted sensitivity to multiple chemotherapeutic and targeted agents. Furthermore, RNPEPL1 was identified as a key gene and experimentally validated to promote LUAD cell proliferation, migration, and invasion. Conclusions: The TRPM4-related signature and RNPEPL1 may provide novel insights for risk stratification and personalized therapeutic strategies. Full article

Background/Objectives: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory approach with potential therapeutic value for cognitive impairment in Alzheimer’s disease (AD). Ferroptosis-related oxidative injury has been implicated in AD-associated neuronal dysfunction, but whether rTMS-induced functional improvement is accompanied by changes in ferroptosis-related oxidative injury remains unclear. This study evaluated the effects of high-frequency rTMS on cognitive function, hippocampal neuronal excitability, and ferroptosis-related oxidative injury in amyloid precursor protein/presenilin-1 (APP/PS1) mice, using Ferrostatin-1 (Fer-1) as a pharmacological comparator. Methods: Six-month-old female mice were used, including age-matched C57BL/6J controls and APP/PS1 mice assigned to the AD + Sham, AD + rTMS, and AD + Fer-1 groups (n = 6 per group). After 14 days of intervention, cognitive performance was assessed using behavioral tests. Whole-cell patch-clamp recordings were performed in hippocampal dentate gyrus granule neurons to evaluate neuronal excitability and voltage-gated sodium (Na⁺) and potassium (K⁺) channel properties. Biochemical assays and transmission electron microscopy were used to assess oxidative, iron-related, and mitochondrial changes, and mitochondrial ultrastructure was examined in an independent cohort (n = 3 per group) using transmission electron microscopy. Results: Compared with AD + Sham mice, high-frequency rTMS improved cognitive performance, increased evoked action potential firing, lowered the elevated action potential threshold, partially restored voltage-gated Na⁺ and K⁺ current amplitudes, and accelerated recovery of Na⁺ currents from inactivation. Fer-1 produced partially overlapping, but not identical, effects across behavioral, electrophysiological, biochemical, and ultrastructural outcomes. Both interventions increased hippocampal glutathione (GSH) levels, reduced malondialdehyde (MDA) and total iron levels, partially restored superoxide dismutase (SOD) activity, and improved mitochondrial ultrastructure and reduced the prevalence of mitochondrial profiles with small cross-sectional areas. Conclusions: High-frequency rTMS improved cognitive and hippocampal neuronal outcomes in female APP/PS1 mice. These improvements were accompanied by biochemical and mitochondrial changes compatible with attenuation of ferroptosis-related injury. However, the findings do not establish ferroptosis inhibition as either necessary or sufficient for the effects of rTMS. Full article

Background: The Six Sigma metric benchmarks analytical performance, but most reports assess one platform at one time point, merging trueness with imprecision. Using routine peer-group internal quality control (IQC), we profiled two clinical chemistry platforms over five months. Because peer-group IQC compares imprecision directly but positions trueness only against same-method peers, we characterise rather than rank cross-platform trueness. Methods: Bio-Rad Unity peer-group IQC (January–May 2026) spanned two Siemens Dimension EXL analysers and two Roche cobas pro channels, two QC levels, and 30 analytes. TEa followed the CLIA 2024 Final Rule (25 analytes; provisional EFLM goals for five non-CLIA analytes). The Standard Deviation Index (SDI) referenced trueness to same-method peers, the CV ratio (CVR) imprecision, Sigma = (TEa − |bias|)/CV. Analyte-level comparison used Wilcoxon signed-rank testing, a confirmatory mixed-effects model, and Westgard SQC mapping. Results: Across 25 CLIA-regulated analytes, median Sigma was 5.9 (IQR 4.8–8.2) for cobas pro versus 4.0 (2.3–6.1) for Dimension EXL: a Hodges–Lehmann difference of 2.4 (95% CI 1.7–3.2; p < 0.001), confirmed by CLIA-only (2.51) and mixed-effects (2.7) analyses. Both aligned with their peers (SDI near zero); the gap reflected imprecision (median CV 1.7% vs. 2.5%; CVR 0.83 vs. 1.02), stable across months and instruments. The ranking reversed for iron, GGT and amylase; sodium, chloride, urea and creatinine were TEa-limited. The SQC redesign averaged N = 6 versus N = 3 controls/run (Dimension vs. cobas pro). Conclusions: A precision-driven difference separated the platforms as implemented here. Cross-platform trueness could not be ranked, yet decomposing Sigma localised precision limits, isolated calibration outliers, and produced analyte-specific SQC strategies needing prospective validation. Full article

A previous investigation on limonene (LM), perillyl alcohol (POH), and carveol (CV), focused on the structure–activity relationship and hydroxyl group, documented that the presence of the hydroxyl group influences the pharmacodynamic potency of these agents, inhibiting smooth muscle contraction with the order of potency: POH > CV > LM. That investigation also suggested a mechanism of action, which importantly included activity on the voltage-dependent calcium channel. Here, we investigated whether this structure–activity relationship also applies to nerve excitability (an activity greatly dependent on sodium channels) using compound action potential (CAP) recordings from mouse sciatic nerves and in silico simulations. POH, CV, and LM inhibited both the positive amplitudes and conduction velocities of the two CAP components in a concentration-dependent manner, with IC₅₀ values of 0.8, 1.0, and 4.3 mM (1st component) and 0.6, 0.6, and 3.0 mM (2nd component) for amplitude, and 2.4, 2.4, and 7.1 mM (1st component) and 1.0, 2.6, and 4.3 mM (2nd component) for conduction velocity. The order of pharmacodynamic potency, thus, was POH = CV > LM. In silico simulation demonstrated that POH and CV penetrate the Nav 1.6 and accommodate in the channel at the interface between the selectivity filter and the central cavity, a position very favorable to block the channel pore. In contrast, LM exhibited a markedly different docking profile, suggesting that LM binding is less likely to directly obstruct sodium permeation. In conclusion, the three substances investigated inhibited nerve excitability, but those with a hydroxyl group demonstrated greater pharmacodynamic potency. Full article

Chronic synovial inflammation is a hallmark of osteoarthritis progression and is tightly regulated by synovial macrophages. Recently, voltage-gated sodium channels (NaV) have emerged as potent modulators of macrophage-driven inflammation, positioning them as novel therapeutic targets. Among selective NaV channel blockers, neosaxitoxin exerts remarkable anesthetic and immunomodulatory effects; however, its effects on joint inflammation upon intra-articular delivery remain unexplored. Using an equine model of bilateral carpal osteoarthritis, this study evaluated the immunomodulatory and tissue-preserving effects of intra-articular neosaxitoxin. Sixteen horses were randomized into two experimental groups (n = 8/each): Neosaxitoxin in one joint and triamcinolone (+control) in the contralateral joint; or neosaxitoxin in one joint and saline (−control) in the contralateral joint. Clinical parameters, synovial fluid cytology and cytokine profiles, and histological changes in synovium and cartilage were assessed over 30 days. Neosaxitoxin reduced synovial inflammation, evidenced by decreased synovial effusion and surface temperature, along with improved joint flexion. Furthermore, synovial fluid from neosaxitoxin-treated joints exhibited lower counts of erythrocytes, neutrophils, total protein, and key pro-inflammatory mediators (IL-1β and IL-6) compared to saline-treated controls. Histologically, neosaxitoxin-treated joints exhibited modest synovial inflammatory cell infiltration and minor cartilage abnormalities. In contrast, control joints exhibited synovial hyperplasia, fibrovascular proliferation, and cartilage degeneration. Our data suggests that intra-articular neosaxitoxin better preserved joint homeostasis by limiting synovial inflammation and cartilage damage. These results warrant further investigation on Neosaxitoxin as a candidate treatment for inflammatory arthropathies. Full article

The cardiac sodium channel Na_V1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of Na_V1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine “rescued” expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms. Full article