Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.

Discovery of a novel series of pyridone amides as NaV1.8 inhibitors.

The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.

Sodium Channel ß Subunits-An Additional Element in Animal Tetrodotoxin Resistance?

Tetrodotoxin (TTX) is a neurotoxic molecule used by many animals for defense and/or predation, as well as an important biomedical tool. Its ubiquity as a defensive agent has led to repeated independent evolution of tetrodotoxin resistance in animals. TTX binds to voltage-gated sodium channels (VGSC) consisting of α and ß subunits. Virtually all studies investigating the mechanisms behind TTX resistance have focused on the α subunit of voltage-gated sodium channels, where tetrodotoxin binds. However, the possibility of ß subunits also contributing to tetrodotoxin resistance was never explored, though these subunits act in concert. In this study, we present preliminary evidence suggesting a potential role of ß subunits in the evolution of TTX resistance. We gathered mRNA sequences for all ß subunit types found in vertebrates across 12 species (three TTX-resistant and nine TTX-sensitive) and tested for signatures of positive selection with a maximum likelihood approach. Our results revealed several sites experiencing positive selection in TTX-resistant taxa, though none were exclusive to those species in subunit ß1, which forms a complex with the main physiological target of TTX (VGSC Nav1.4). While experimental data validating these findings would be necessary, this work suggests that deeper investigation into ß subunits as potential players in tetrodotoxin resistance may be worthwhile.

Analgesic potential of voltage gated sodium channel modulators for the management of pain.

Neuronal electrochemical signals involve the flux of sodium ions through voltage-gated sodium channels (NaV) located in the neurolemma. Of the nine sodium channel subtypes, NaV-1.7, 1.8, and 1.9 are predominantly located on nociceptors, making them prime targets to control pain. This review highlights some of the latest discoveries targeting NaV channel activity, including: (1) charged local anaesthetic derivatives; (2) NaV channel toxins and associated small peptide blockers; (3) regulation of NaV channel accessory proteins; and (4) genetic manipulation of NaV channel function. While the translation of preclinical findings to a viable treatment in humans has remained a challenge, a greater understanding of NaV channel physiology could lead to the development of a new stream of therapies aimed at alleviating chronic pain.

Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action.

Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (NaVs) are responsible for action potential initiation and transmission of pain signals. NaV1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective inhibition of NaV1.8 can ameliorate pain while minimizing effects on other NaV isoforms essential for cardiac, respiratory, and central nervous system physiology. Here we present the pharmacology, interaction site, and mechanism of action of LTGO-33, a novel NaV1.8 small molecule inhibitor. LTGO-33 inhibited NaV1.8 in the nM potency range and exhibited over 600-fold selectivity against human NaV1.1-NaV1.7 and NaV1.9. Unlike prior reported NaV1.8 inhibitors that preferentially interacted with an inactivated state via the pore region, LTGO-33 was state-independent with similar potencies against closed and inactivated channels. LTGO-33 displayed species specificity for primate NaV1.8 over dog and rodent NaV1.8 and inhibited action potential firing in human dorsal root ganglia neurons. Using chimeras combined with mutagenesis, the extracellular cleft of the second voltage-sensing domain was identified as the key site required for channel inhibition. Biophysical mechanism of action studies demonstrated that LTGO-33 inhibition was relieved by membrane depolarization, suggesting the molecule stabilized the deactivated state to prevent channel opening. LTGO-33 equally inhibited wild-type and multiple NaV1.8 variants associated with human pain disorders. These collective results illustrate LTGO-33 inhibition via both a novel interaction site and mechanism of action previously undescribed in NaV1.8 small molecule pharmacologic space. SIGNIFICANCE STATEMENT: NaV1.8 sodium channels primarily expressed in peripheral pain-sensing neurons represent a validated target for the development of novel analgesics. Here we present the selective small molecule NaV1.8 inhibitor LTGO-33 that interdicts a distinct site in a voltage-sensor domain to inhibit channel opening. These results inform the development of new analgesics for pain disorders.

Favorable combinations of antiseizure medication with vagus nerve stimulation to improve health-related quality of life in patients with epilepsy.

BACKGROUND: Vagus nerve stimulation (VNS) is a non-pharmacological treatment of refractory epilepsy, which also has an antidepressive effect. The favorable combinations of VNS with specific mechanisms of action of antiseizure medication (ASM) on mood and health-related quality of life (HrQol) have not yet been studied. The objective was to identify favourable combinations of specific ASMs with VNS for the HrQoL and depression in refractory epilepsy. METHODS: We performed an observational study including patients with refractory epilepsy and an implanted VNS (N = 151). In the first 24 months after VNS implantation, all patients were on stable ASM therapy. We used the standardized questionnaires QOLIE10, EQVAS and EQ5D to evaluate HrQoL as well as the Beck Depression Inventory (BDI). Multiple regression analysis was performed to evaluate the synergistic combinations of ASM with VNS for HrQoL. RESULTS: At the year-two follow-up (N = 151, age 45.2 ± 17.0 years), significant improvement (p < 0.05) in BDI scores was found for combination of VNS with SV2A modulators (58.4 %) or AMPA antagonists (44.4 %). A significant increase of HrQoL by at least 30 % (p < 0.05) was measured for a combination of VNS with SV2A modulators (brivaracetam, levetiracetam) or slow sodium channel inhibitors (eslicarbazepine, lacosamide). CONCLUSION: The results of our study suggests a favorable effect of the combination of SV2A modulators or slow sodium channel inhibitors with VNS on the HrQoL in comparison to other ASMs. Besides the possible synergistic effects on the seizure frequency, the amelioration of behavioral side effects of SV2A modulators by VNS is an important factor of HrQoL-improvement in these combinations.

The effect of lacosamide in peripheral neuropathic pain: A randomized, double-blind, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is common and difficult to treat. The sodium channel blocker lacosamide is efficacious in animal models of pain, but its effect on neuropathic pain in humans is inconclusive. METHODS: In a multicentre, randomized, double-blinded placebo-controlled phenotype stratified trial, we examined if lacosamide produced better pain relief in patients with the irritable nociceptor phenotype compared to those without. The primary outcome was the change in daily average pain from baseline to last week of 12 weeks of treatment. Secondary and tertiary outcomes included pain relief, patient global impression of change and presence of 30% and 50% pain reduction. RESULTS: The study was prematurely closed with 93 patients included and 63 randomized to lacosamide or placebo in a 2:1 ratio, of which 49 fulfilled the per protocol criteria and was used for the primary objective. We did not find a better effect of lacosamide in patients with the irritable nociceptor phenotype, the 95% CI for the primary objective was 0.41 (-1.2 to 2.0). For all patients randomized, lacosamide had no effect on the primary outcome, but significantly more patients were responders to lacosamide than during placebo, with an NNT of 4.0 (95% CI 2.3-16.1) and 5.0 (95% CI 2.8-24.5) for 30% and 50% pain reduction respectively. We did not identify any predictors for response. Lacosamide was generally well tolerated. CONCLUSION: We could not confirm that lacosamide was more efficacious in patients with the irritable nociceptor type, but the study was prematurely closed, so we cannot exclude a small difference. SIGNIFICANCE: Treatment of neuropathic pain is often a trial and error process. Little is known about which patient benefit from which kind of medication. The sodium channel blocker lacosamide shows variable effect on neuropathic pain. Pain sensory phenotype, as defined by quantitative sensory testing, did not predict response to treatment with lacosamide.

Discovery and development of BI 1265162, an ENaC inhibitor for the treatment of cystic fibrosis.

Lung selective inhibition of the endothelial sodium channel (ENaC) is a potential mutation agnostic treatment of Cystic Fibrosis (CF). We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. The design of BI 1265162 focused on its suitability for inhalation via the Respimat® Soft Mist™ Inhaler and a long duration of action. A convergent and scalable route for the synthesis of BI 1265162 as dihydrogen phosphate salt is presented, that was applied to support clinical trials. A phase 2 study with BI 1265162 did not provide a clear sign of clinical benefit. Whether ENaC inhibition will be able to hold its promise for CF patients remains an open question.

[Taxine, in A Pocket Full of Rye: Calcium Channel and Sodium Channel Inhibitor].

A Pocket Full of Rye is a full-length novel featured in Agatha Christie's series, "Miss Marple." Taxine, used for murder in this novel, is an alkaloid compound isolated from parts of the yew tree other than the pulp and is based on a diterpene, with a nitrogen element incorporated as a side chain in one of its many skeletal structures. Taxine binds to sodium channels, resulting in unregulated muscle contraction and arrhythmias.

Ibuprofen modulates tetrodotoxin-resistant persistent Na+ currents at acidic pH in rat trigeminal ganglion neurons.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve various symptoms such as headache, arthralgia, and dental pain. While the primary mechanism of NSAID-based pain relief is the inhibition of cyclooxygenase-2, several NSAIDs also modulate other molecular targets related to nociceptive transmission such as voltage-gated Na+ channels. In the present study, we examined the effects of NSAIDs on persistent Na+ current (INaP) mediated by tetrodotoxin-resistant (TTX-R) Na+ channels in small-to medium-sized trigeminal ganglion neurons using a whole-cell patch-clamp technique. At clinically relevant concentrations, all propionic acid derivatives tested (ibuprofen, naproxen, fenoprofen, and flurbiprofen) preferentially inhibited the TTX-R INaP. The inhibition was more potent at acidic extracellular pH (pH 6.5) than at normal pH (pH 7.4). Other NSAIDs, such as ketorolac, piroxicam, and aspirin, had a negligible effect on the TTX-R INaP. Ibuprofen both accelerated the onset of inactivation and retarded the recovery from inactivation of TTX-R Na+ channels at acidic extracellular pH. However, all NSAIDs tested in this study had minor effects on voltage-gated K+ currents, as well as hyperpolarization-activated and cyclic nucleotide-gated cation currents, at both acidic and normal extracellular pH. Under current-clamp conditions, ibuprofen decreased the number of action potentials elicited by depolarizing current stimuli at acidic (pH 6.5) extracellular pH. Considering that extracellular pH falls as low as 5.5 in inflamed tissues, TTX-R INaP inhibition could be a mechanism by which ibuprofen and propionic acid derivative NSAIDs modulate inflammatory pain.

[Analysis of the efficacy and influencing factors of sodium channel blockers in the treatment of focal epilepsy in infants under 6 months of age].

Objective: To analyze the efficacy and safety of the sodium channel blockers (SCB) antiseizure medication in the treatment of focal epilepsy in infants under 6 months of age. Methods: This was a case series study. Infants with focal epilepsy with onset within 6 months of age and treated with SCB attending the Department of Neurology of Beijing Children's Hospital from June 2016 to April 2022 were collected. The clinical data, auxiliary examinations, SCB application, efficacy, adverse reactions, and prognosis were analyzed retrospectively. Patients were grouped according to type of seizure and epileptic syndrome, age of onset and etiology. Chi square test and Fisher exact test were used to analyze the differences between groups statistically. Results: A total of 118 infants were enrolled, 65 males and 53 females, with an age of epilepsy onset of 56 (4, 114) days. Developmental and epileptic encephalopathy was diagnosed in 60 infants, 39 had self-limited neonatal and (or) infantile epilepsy, and 19 had non-syndromic focal epilepsy. Application of SCB: 106 used oxcarbazepine, 2 used lacosamide, 9 switched from oxcarbazepine to lacosamide or a combination of 2 SCB, and 1 used oxcarbazepine, lacosamide, and lamotrigine successively; oxcarbazepine was the first choice in 46 cases. The age at which SCB was applied was 103 (53, 144) days. The children were followed up for 6 months to 6 years. SCB was effective in 89 cases (75.4%), including 70 cases (59.3%) who achieved seizure freedom. The seizure-free rate was higher in the focal epilepsy only group than in the group with other seizure types (64.4% (65/101) vs. 4/17, χ²=9.99, P<0.05). The responder and seizure-free rates were all higher in the group with the onset age of >3-6 months than the group >1-3 months (84.4% (38/45) vs. 62.5% (20/32), 73.3% (33/45) vs. 46.9% (15/32), χ²=4.85 and 5.58, both P<0.05). With the exception of variants in the PRRT2 gene, those with variants in sodium or potassium channels had higher responder and seizure-free rates than those with variants in other genes(86.2% (25/29) vs. 45.5% (10/22), 62.1% (18/29) vs. 22.7% (5/22), χ²=9.65 and 7.82,both P<0.05). The most common adverse event was transient hyponatremia, which happened in 66 cases (55.9%). There were 9 cases of rash, which subsided in 6 cases after discontinuing oxcarbazepine and switching to lacosamide, and 7 cases of electrocardiogram abnormalities, which improved after withdrawing oxcarbazepine and changing to lacosamide in 1 case. Conclusion: SCB are effective and tolerable in the treatment of focal epilepsy in infants under 6 months of age, with better efficacy in patients with genetic variants of the sodium or potassium channel, focal seizures only, and seizure onset >3-6 months of age.

Antinociceptive Agents as General Anesthetic Adjuncts: Supra-additive and Infra-additive Interactions.

The hypothesis "General anesthesia consists of producing both loss of consciousness and the inhibition of noxious stimuli reaching the brain and causing arousal" was used as a basis for the review of published data on general anesthetic interactions with antinociceptive agents: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. This review is focused on a specific type of anesthetic interaction-the transformation of antinociceptive agents into general anesthetic adjuncts. The primary aim is to answer 2 questions. First, how does an antinociceptive agent transform the effect of an anesthetic in providing a certain component of anesthesia-hypnosis, immobility, or hemodynamic response to noxious stimulation? Second, does a combination of an anesthetic with an adjunct result in a simple summation of their respective effects or in a supra-additive or infra-additive interaction? The Medline database was searched for data describing the interactions of antinociceptive agents and general anesthetics. The following classes of antinociceptive agents were considered: opioids, α 2 adrenergic agonists, and systemic sodium channel blockers. Drugs used in combination with antinociceptive agents were general anesthetics and benzodiazepines. The following terms related to drug interactions were used: anesthetic interactions, synergy, antagonism, isobolographic analysis, response surface analysis, and fractional analysis. The interactions of antinociceptive agents with general anesthetics result in a decrease of general anesthetic requirements, which differ for each of the components of general anesthesia: hypnosis, immobility, and hemodynamic response to noxious stimulation. Most studies of the nature of anesthetic interactions are related to opioid-general anesthetic combinations, and their conclusions usually confirm supra-additivity.

Rate-dependent effects of state-specific sodium channel blockers in cardiac tissue: Insights from idealized models.

A common side effect of pharmaceutical drugs is an increased propensity for cardiac arrhythmias. Many drugs bind to cardiac ion-channels in a state-specific manner, which alters the ionic conductances in complicated ways, making it difficult to identify the mechanisms underlying pro-arrhythmic drug effects. To better understand the fundamental mechanisms underlying the diverse effects of state-dependent sodium (Na+) channel blockers on cellular excitability, we consider two canonical motifs of drug-ion-channel interactions and compare the effects of Na+ channel blockers on the rate-dependence of peak upstroke velocity, conduction velocity, and vulnerable window size. In the literature, both motifs are referred to as "guarded receptor," but here we distinguish between state-specific binding that does not alter channel gating (referred to here as "guarded receptor") and state-specific binding that blocks certain gating transitions ("gate immobilization"). For each drug binding motif, we consider drugs that bind to the inactivated state and drugs that bind to the non-inactivated state of the Na+ channel. Exploiting the idealized nature of the canonical binding motifs, we identify the fundamental mechanisms underlying the effects on excitability of the various binding interactions. Specifically, we derive the voltage-dependence of the drug binding time constants and the equilibrium fractions of channels bound to drug, and we then derive a formula that incorporates these time constants and equilibrium fractions to elucidate the fundamental mechanisms. In the case of charged drug, we find that drugs that bind to inactivated channels exhibit greater rate-dependence than drugs that bind to non-inactivated channels. For neutral drugs, the effects of guarded receptor interactions are rate-independent, and we describe a novel mechanism for reverse rate-dependence resulting from neutral drug binding to non-inactivated channels via the gate immobilization motif.

The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells.

AIMS: Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Nav1.5 current. METHODS AND RESULTS: Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Nav1.5 channels (holding potential -120 mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33.2 µm. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast inactivation (close-to-physiological holding potential -90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 µm, while it was 16 ± 4.8 µm during partial slow inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. CONCLUSION: Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

Licochalcone Mediates the Pain Relief by Targeting the Voltage-Gated Sodium Channel.

Licorice is a traditional Chinese medicine and recorded to have pain relief effects in national pharmacopoeia, but the mechanisms behind these effects have not been fully explored. Among the hundreds of compounds in licorice, licochalcone A (LCA) and licochalcone B (LCB) are two important components belonging to the chalcone family. In this study, we compared the analgesic effects of these two licochalcones and the molecular mechanisms. LCA and LCB were applied in cultured dorsal root ganglion (DRG) neurons, and the voltage-gated sodium (NaV) currents and action potentials were recorded. The electrophysiological experiments showed that LCA can inhibit NaV currents and dampen excitabilities of DRG neurons, whereas LCB did not show inhibition effect on NaV currents. Because the NaV1.7 channel can modulate Subthreshold membrane potential oscillations in DRG neuron, which can palliate neuropathic pain, HEK293T cells were transfected with NaV1.7 channel and recorded with whole-cell patch clamp. LCA can also inhibit NaV1.7 channels exogenously expressed in HEK293T cells. We further explored the analgesic effects of LCA and LCB on formalin-induced pain animal models. The animal behavior tests revealed that LCA can inhibit the pain responses during phase 1 and phase 2 of formalin test, and LCB can inhibit the pain responses during phase 2. The differences of the effects on NaV currents between LCA and LCB provide us with the basis for developing NaV channel inhibitors, and the novel findings of analgesic effects indicate that licochalcones can be developed into effective analgesic medicines. SIGNIFICANCE STATEMENT: This study found that licochalcone A (LCA) can inhibit voltage-gated sodium (NaV) currents, dampen excitabilities of dorsal root ganglion neurons, and inhibit the NaV1.7 channels exogenously expressed in HEK293T cells. Animal behavior tests showed that LCA can inhibit the pain responses during phase 1 and phase 2 of formalin test, whereas licochalcone B can inhibit the pain responses during phase 2. These findings indicate that licochalcones could be the leading compounds for developing NaV channel inhibitors and effective analgesic medicines.

Use of Sodium Channel Blockers in the Thr226Met Pathologic Variant of SCN1A: A Case Report.

The Thr226Met pathologic variant of the SCN1A gene has been associated with the clinical development of an early infantile developmental and epileptic encephalopathy (EIDEE) different from Dravet's syndrome. The electrophysiological mechanisms of the mutated channel lead to a paradoxical gain and loss of function. The use of sodium channel blockers (SCB) that counteract this gain of function has been described in previous studies and they can be safely administered to patients carrying mutations in other sodium channel subtypes without causing a worsening of seizures. We report the use of SCB in a child harboring the Thr226Met pathologic variant of SCN1A with early-onset pharmaco-resistant migrating seizures, as well as developmental delay. Lacosamide led to a dramatic reduction in seizure frequency; however, only a mild improvement in the epileptic activity depicted by electroencephalography (EEG) was achieved. The introduction of carbamazepine as an add-on therapy led to a notable reduction in epileptic activity via EEG and to an improvement in sensorimotor development. Despite the overall clinical improvement, the patient developed febrile seizures and a nonepileptic jerking of the right hand. In this case of EIDEE with the Thr226Met variant, we demonstrate a beneficial pharmacological intervention of SCB in contrast to findings described in current literature. Our report encourages the cautious use of SCB at early stages of the disease in patients carrying this pathologic variant.

Efficacy and tolerability of immediate switch from sodium channel blockers to Lacosamide.

Lacosamide (LCM) is a new-generation anti-seizure medication approved for monotherapy and add-on therapy for focal-onset epilepsy. It has novel pharmacodynamics and favorable pharmacokinetic qualities with good clinical response. This study aims to evaluate the effectiveness and tolerability of LCM when used in the immediate switch from sodium channel blockers in patients with focal-onset and generalized-onset epilepsies. This retrospective, multicenter observational study was conducted with adult patients who received LCM as mono- or polytherapy through immediate switch with 6 to 52 months follow-up. The clinical data obtained during the follow-up period were analyzed to assess retention rate, seizure freedom, more than 50% seizure reduction, and adverse effects. A total of 32 patients (eight females, 24 males) with a median age of 49.75 (range, 23-86) years, median age at epilepsy onset of 32.58 (range, 0.5-85) years, and median epilepsy duration of 17.17 (range, 1-46) years were included in this study. Seizure frequency was between 1 and 90 in the past 6 months. Seven (21.9%) of the patients had structural brain lesions and 27 (84.4%) of the patients had EEG abnormalities. The adverse effects leading to switching were hyponatremia, rash, elevated liver enzymes, pain, and erectile dysfunction. At 14.34 (range, 6-52) months follow-up, 30 (93.75%) patients in total retained LCM, 20 (66.7%) of them were seizure-free, and 13 were on LCM monotherapy. Responder rate was 81.25%. Eight (25%) of the patients experienced adverse effects after the immediate switch. One patient with generalized-onset epilepsy needed to quit LCM due to an increase in seizures. Seizure frequency did not change in three patients in the focal-onset group. Immediate switch to LCM showed favorable outcomes with a significant reduction in seizure frequency, high retention rates, and tolerable adverse effect profiles in both focal-onset and generalized-onset seizures.

Use, misuse, and pitfalls of the drug challenge test in the diagnosis of the Brugada syndrome.

The diagnosis of Brugada syndrome (BrS) requires the presence of a coved (Type 1) ST segment elevation in the right precordial leads of the electrocardiogram (ECG). The dynamic nature of the ECG is well known, and in patients with suspected BrS but non-diagnostic ECG at baseline, a sodium channel blocker test (SCBT) is routinely used to unmask BrS. There is little doubt, however, that in asymptomatic patients, a drug-induced Brugada pattern is associated with a much better prognosis compared to a spontaneous Type 1 ECG. The SCBT is also increasingly used to delineate the arrhythmogenic substrate during ablation studies. In the absence of a "gold standard" for the diagnosis of BrS, sensitivity and specificity of the SCBT remain elusive. By studying patient groups with different underlying diseases, it has become clear that the specificity of the test may not be optimal. This review aims to discuss the pitfalls of the SCBT and provides some directions in whom and when to perform the test. It is concluded that because of the debated specificity and the overall very low risk for future events in asymptomatic individuals, patients should be properly selected and counseled before SCBT is performed and that SCBT should not be performed in asymptomatic patients with a Type 2 Brugada pattern and no family history of BrS or sudden death.

Toward Overcoming Pyrethroid Resistance in Mosquito Control: The Role of Sodium Channel Blocker Insecticides.

Diseases spread by mosquitoes lead to the death of 700,000 people each year. The main way to reduce transmission is vector control by biting prevention with chemicals. However, the most commonly used insecticides lose efficacy due to the growing resistance. Voltage-gated sodium channels (VGSCs), membrane proteins responsible for the depolarizing phase of an action potential, are targeted by a broad range of neurotoxins, including pyrethroids and sodium channel blocker insecticides (SCBIs). Reduced sensitivity of the target protein due to the point mutations threatened malaria control with pyrethroids. Although SCBIs-indoxacarb (a pre-insecticide bioactivated to DCJW in insects) and metaflumizone-are used in agriculture only, they emerge as promising candidates in mosquito control. Therefore, a thorough understanding of molecular mechanisms of SCBIs action is urgently needed to break the resistance and stop disease transmission. In this study, by performing an extensive combination of equilibrium and enhanced sampling molecular dynamics simulations (3.2 µs in total), we found the DIII-DIV fenestration to be the most probable entry route of DCJW to the central cavity of mosquito VGSC. Our study revealed that F1852 is crucial in limiting SCBI access to their binding site. Our results explain the role of the F1852T mutation found in resistant insects and the increased toxicity of DCJW compared to its bulkier parent compound, indoxacarb. We also delineated residues that contribute to both SCBIs and non-ester pyrethroid etofenprox binding and thus could be involved in the target site cross-resistance.