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Purpose of Review: Despite ongoing research into alternative postsurgical pain treatments, opioids remain widely used analgesics regardless of associated adverse effects, including dependence and overdose, as demonstrated throughout the current opioid crisis. This is likely related to a failure in proving the efficacy of alternative analgesics in clinical trials, despite strong evidence supporting the potential for effective analgesia through in vitro studies. While NaV1.7 and NaV1.8 channels have shown to be key components of pain perception, studies regarding pharmacological agents utilizing these channels as targets have largely failed to demonstrate the efficacy of these proposed analgesics when compared to current multimodal pain treatment regimens., Recent Findings: However, the novel NaV1.8 channel inhibitor, VX-548 has surpassed previously studied NaV1.8 inhibitors in clinical trials and continues to hold promise of a novel efficacious analgesic to potentially be utilized in multimodal pain treatment on postsurgical patients. Additionally, NaV1.8 is encoded by the SCN10A, which has been shown to be minimally expressed in the brain, suggesting a lower likelihood of adverse effects in the CNS, including dependence and abuse. Novel pharmacologic analgesics that are efficacious without the significant side effects associated with opioids have lacked meaningful development. However, recent clinical trials have shown promising results in the safety and efficacy of the pharmacological agent VX-548. Still, more clinical trials directly comparing the efficacy of VX-548 to standard of care post-surgical drugs, including opioids like morphine and hydromorphone are needed to demonstrate the long-term viability of the agent replacing current opioids with an unfavorable side effect profile., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: Sodium channel blockers (SCBs) have traditionally been utilized as anti-seizure medications by primarily targeting the inactivation process. In a drug discovery project aiming at finding potential anticonvulsants, we have identified arbidol, originally an antiviral drug, as a potent SCB. In order to evaluate its anticonvulsant potential, we have thoroughly examined its biophysical properties as well as its effects on animal seizure models., Experimental Approach: Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice., Key Results: Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Na v 1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Na v 1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model., Conclusions and Implications: Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs., (© 2024 British Pharmacological Society.)

The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: The present investigation evaluated integration of novel medication technology to enhance treatment options, while improving patient outcomes in acute pain management. In this regard, we focused on determining the role of development and utilization of cutting-edge pharmaceutical advancements, such as targeted drug delivery systems, as well as non-pharmacologic interventions in addressing acute pain states. Further research in this area is warranted related to the need for increased patient comfort and reduced adverse effects., Recent Findings: Recent innovations and techniques are discussed including pharmacologic drugs targeting sodium and calcium channels, peptide-based pharmacologic drugs, and non-medicinal methods of alleviating pain such as soothing music or virtual reality. The present investigation included review of current literature on the application of these innovative technologies, analyzing mechanisms of action, pharmacokinetics, and clinical effectiveness. Our study also investigated the potential benefits in terms of pain relief, reduced side effects, and improved patient adherence. The research critically examines the challenges and considerations associated with implementing these technologies in acute pain management, considering factors like cost, accessibility, and regulatory aspects. Additionally, case studies and clinical trials are highlighted which demonstrate practical implications of these novel medication technologies in real-world scenarios. The findings aim to provide healthcare professionals with a comprehensive understanding of the evolving landscape in acute pain management while guiding future research and clinical practices toward optimizing their use in enhancing patient care., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4., Methods and Results: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]., Conclusion: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org., Competing Interests: Conflict of interest: A.R.: Consultant fees, travel grants or lecture fees from Medtronic, Biosense Webster, Abbott, Boston Scientific, Ablamap, Philips, Cardiofocus, Bayer, Pfizer and Novartis, Edwards and Lifetech. Committee: German Society of Cardiology (Select-chair of EP community). L.E.: Grants/contracts: research support by the German heart foundation. Consulting fees Boston Scientific, lecture fees for various medical companies. Society, committee: German Society of Cardiology; European Society of Cardiology; European Heart Rhythm Society. K.B.: no COIs. J.C.: Participation on a data safety monitoring board: Anthos, Johnson and Johnson, Enso, Bayer, Charité. H.C.: Grants/contracts: ZonMw grant no. 104021005 RACE 9 Device-based rate vs. rhythm control treatment in patients with symptomatic recent-onset atrial fibrillation in the emergency department (RACE 9). Consulting fees: InCarda Therapeutics, Roche, Sanofi, Atricure. Payment or Honoraria: Medtronic. Participation on a data safety monitoring board or advisory board: Chair DSMB Decision trial. Committee/society: DZHK, German Centre for Cardiovascular research. A.G.: Grants/contracts: Maestria Grant EU 965286. Consulting fees: Sanofi-Aventis, Bayer, Astra Zeneca, Daiichi Sankyo, BMS/Pfizer, Viofor, Boston Scientific, Medtronic, Menarini. G.B.: Chair, advisory board to AFNET e.V., no payment. M.L.: No COIs. A.M.: Consulting fees: Medtronic, Johnson and Johnson, Boston Scientific, LifeTech. Lecture honoraria: Medtronic, Johnson and Johnson, Lifetech, Pfizer, Boston Scientific, Bayer, Bristol Meyer Squibb. L.R.: No COIs. U.S.: Grants/contracts: EU: CATCH ME, MAESTRIA, Personalize AF, REPAIR, Dutch Heart foundation, RACE V Embrace. Consulting fees: Roche advisory board, YourRhythmics BV. Payment or honoraria: Johnson and Johnson. Patents: non-invasive classification of AF with ECG. Society/Committee: Board of directors of AFNET. Stock or stock options: YourRhythmics BV. E.V.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. K.W.: All support payment for manuscript: AFNET. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific, Novartis. A.Z.: Support for present manuscript: AFNET: payments made to my institution. Outside this work: Biotronik: payments made to my institution. Grants/contracts: Biotronik, Resmed. Payment/honoraria: Boston scientific. H.H.: Unconditional Research Grants through the University of Hassels and Antwerp: Abbott, Medtronic, Biotronik, Boston scientific, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer–BMS. Payment or honoraria: Bayer, Biotronik, Bristol Myers Squibb, Daiichi Sankyo, Milestone Pharmaceuticals, Centrix India, CTI Germany, European Society of Cardiology, Medscape, Springer healthcare. Participation on a data safety monitoring board or advisory board: Member, DSBM Prestige-AF. S.W.: Grants: Boston Scientific, Consulting fees: Boston Scientific, Abbott. Speakers Bureau: BSCI; Abbott, BMS, Medtronic. L.F.: Institutional government or charity research support: European Union Horizon 2020 MAESTRIA [grant agreement number 965286 (MAESTRIA)] European Union Horizon 2020 CATCH ME, [grant agreement number 633196 (CATCH ME), European Union Horizon 2020 AFFECT-EU, grant agreement number 847770 (AFFECT-EU)] Institutional governmental support, National Institute for Health and Care Research NIHR, Medical Research Council (UK), German Centre for Cardiovascular Research DZHK. Support for attending meetings: ESC, EHRA, and ESC working groups, ARVC patient organization (charity). Patents planned issued or pending: L.F. is listed as inventor of two patents (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). Society/committee: BHF project grant committee (charity). BHF chair committee visits (charity), AFNET steering committee (charity), ARVC patient organization (charity). Equipment and analytics to AFNET for AFNET 9: Preventicus, Trial costs to AFNET for AFNET 9: Daiichi Sankyo. R.S. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 648131, from the European Union’s Horizon 2020 research and innovation programme under the grant agreement no. 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239). Wolfgang Seefried project funding German Heart Foundation. Lecture fees and advisory board fees from BMS/Pfizer and Bayer. Society/committee: ESC stroke council nucleus member. C.M.: Grants or contracts: Research funding from German Center for Cardiovascular Research (Promotion of women scientists programme; FKZ 81X3710112); Deutsche Stiftung für Herzforschung; Dr. Rolf M. Schwiete Stiftung; NDD; Loewenstein Medical. Payment or honoraria: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, Abbott. Support for attending meetings: AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Novo Nordisk. Participation on a data safety monitoring board or advisory board: Boehringer Ingelheim/Lilly; Novo Nordisk. P.K.: P.K. was partially supported by European Union AFFECT-AF (grant agreement 847770), and MAESTRIA (grant agreement 965286), British Heart Foundation (PG/17/30/32961; PG/20/22/35093; AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, grant numbers DZHK FKZ 81X2800182, 81Z0710116, and 81Z0710110), German Research Foundation (Ki 509167694), and Leducq Foundation. P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation. P.K. is listed as inventor on two issued patents held by University of Hamburg (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. P.K. is board member of the ESC and speaker of the board AFNET., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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 SCN1A L263V 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 Scn1a L263V 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 Na V 1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1a L263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1A L263V 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., Competing Interests: Competing interests statement:The authors declare no competing interest.

Neuronal electrochemical signals involve the flux of sodium ions through voltage-gated sodium channels (Na V ) located in the neurolemma. Of the nine sodium channel subtypes, Na V -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 Na V channel activity, including: (1) charged local anaesthetic derivatives; (2) Na V channel toxins and associated small peptide blockers; (3) regulation of Na V channel accessory proteins; and (4) genetic manipulation of Na V channel function. While the translation of preclinical findings to a viable treatment in humans has remained a challenge, a greater understanding of Na V channel physiology could lead to the development of a new stream of therapies aimed at alleviating chronic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors were employees of Boehringer Ingelheim at the time the research was conducted., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The formalin test is one approach to studying acute pain in rodents. Similar to formalin, injection with glutamate and veratrine can also produce a nociceptive response. This study investigated whether opioid-related compounds could suppress glutamate- and veratrine-induced nociceptive responses in mice at the same dose. The administration of morphine (3 mg/kg), hydromorphone (0.4 mg/kg), or fentanyl (0.03 mg/kg) suppressed glutamate-induced nociceptive response, but not veratrine-induced nociceptive response at the same doses. However, high doses of morphine (10 mg/kg), hydromorphone (2 mg/kg), or fentanyl (0.1 mg/kg) produced a significant reduction in the veratrine-induced nociceptive response. These results indicate that high doses are required when using morphine, hydromorphone, or fentanyl for sodium channel-related neuropathic pain, such as ectopic activity. As a result, concerns have arisen about overdose and abuse if the dose of opioids is steadily increased to relieve pain. In contrast, trimebutine (100 mg/kg) and fentanyl analog isobutyrylfentanyl (iBF; 0.1 mg/kg) suppressed both glutamate- and veratrine-induced nociceptive response. Furthermore, nor-isobutyrylfentanyl (nor-iBF; 1 mg/kg), which is a metabolite of iBF, suppressed veratrine-induced nociceptive response. Besides, the optimal antinociceptive dose of iBF, unlike fentanyl, only slightly increased locomotor activity and did not slow gastrointestinal transit. Cancer pain is a complex condition driven by inflammatory, neuropathic, and cancer-specific mechanisms. Thus, iBF may have the potential to be a superior analgesic than fentanyl.

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., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

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., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Voltage-gated sodium channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of natural products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Kα radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC 50 of 0.73 ± 0.03 µM. We demonstrated that compound 2 (3 µM) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V 1/2 values were changed from -39.54 ± 2.77 mV to -65.53 ± 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 μM) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests The authors declare no competing interests.

Introduction: Mexiletine is a class IB sodium-channel blocker. Unlike class IA or IC antiarrhythmic drugs, mexiletine rather shortens than prolongs action potential duration; therefore, it is less associated with proarrhythmic effects., Areas Covered: Recently, new European Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death were published, including a reappraisal of some established older antiarrhythmic drugs., Expert Opinion: Mexiletine offers a first-line, genotype-specific treatment strategy for LQT3 patients as emphasized by the most recent guidelines. Besides this recommendation, current study reports suggest that in therapy-refractory ventricular tachyarrhythmias and electrical storms adjunctive mexiletine treatment may offer the possibility of stabilizing patients with or without concomitant interventional therapy such as catheter ablation.

Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients., Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants., Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature., Significance: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication., (© 2023 International League Against Epilepsy.)

Ethnopharmacological Relevance: Faeces Bombycis (silkworm excrement, called Cansha in Chinese), is the dried faeces of the larvae of silkworm. According to the theories of traditional Chinese medicine recorded in "Compendium of Materia Medica", Faeces Bombycis has often been prescribed in traditional Chinese medicine for the treatment of recurrent headache, rheumatalgia, rubella and itching et al. However, the bioactive components and their exact mechanisms underlying the pain-relieving effects remain to be revealed., Aim of the Study: The present study aimed to evaluate the analgesic effect of Faeces Bombycis extract (FBE) on migraine, explore the main active constituents and investigate the pharmacological mechanisms for its pain relief., Materials and Methods: The bioactivity of different extracts from Faeces Bombycis was tracked by the nitroglycerin (NTG)-induced migraine model on rats and identified by NMR spectroscopic data. Whole-cell patch clamp technique, an electrophysiological method, was used to screen the potential targets and study the mechanism of action for the bioactive compound. The following targets have been screened and studied, including Nav1.7 sodium channels, Nav1.8 sodium channels, TRPV1 channels and TRPA1 channels. The trigeminal ganglion neurons were further used to study the effects of the identified compound on neuronal excitability., Results: By testing the bioactivity of the different extracts proceedingly, fraction petroleum ether showed higher anti-migraine activity. Through further step-by-step isolations, 7 compounds were isolated. Among them, phytol was identified with the highest yield and displayed a potent anti-migraine effect. By screening the potential ion channel targets for migraine, phytol was found to preferentially block the inactivated state of Nav1.7 sodium channels with half-inhibition concentration 0.32 ± 0.05 μM. Thus, the effects of phytol on the biophysical properties of Nav1.7 sodium channels were further characterized. Phytol induced a hyperpolarizing shift of voltage-dependent inactivation and slowed the recovery from inactivation. The affinity of phytol became weaker in the inactivation-deficient Nav1.7 channels (Nav1.7-WCW). And such an effect was independent on the local anesthetic site (Nav1.7 F1737A). Consistent with the data from recombinant channels, the compound also displayed state-dependent inhibition on neuronal sodium channels and further decreased the neuronal excitability in trigeminal ganglion neurons. Moreover, besides Nav1.7 channel, phytol also antagonized the activation of TRPV1 and TRPA1 channels at micromolar concentrations with a weaker affinity., Conclusion: Our results demonstrated that phytol is the major anti-migraine ingredient of Faeces Bombycis and alleviates migraine behaviors by acting on Nav1.7 sodium channels in the trigeminal ganglion neurons. This study provided evidences for the therapeutic application of Faeces Bombycis and phytol on migraine disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A diagnosis of Brugada syndrome (BrS) is based on the presence of a type 1 electrocardiogram (ECG) pattern, either spontaneously or after a Sodium Channel Blocker Provocation Test (SCBPT). Several ECG criteria have been evaluated as predictors of a positive SCBPT, such as the β-angle, the α-angle, the duration of the base of the triangle at 5 mm from the r'-wave (DBT- 5 mm), the duration of the base of the triangle at the isoelectric line (DBT- iso), and the triangle base/height ratio. The aim of our study was to test all previously proposed ECG criteria in a large cohort study and to evaluate an r'-wave algorithm for predicting a BrS diagnosis after an SCBPT. We enrolled all patients who consecutively underwent SCBPT using flecainide from January 2010 to December 2015 in the test cohort and from January 2016 to December 2021 in the validation cohort. We included the ECG criteria with the best diagnostic accuracy in relation to the test cohort in the development of the r'-wave algorithm (β-angle, α-angle, DBT- 5 mm, and DBT- iso.) Of the total of 395 patients enrolled, 72.4% were male and the average age was 44.7 ± 13.5 years. Following the SCBPTs, 24.1% of patients (n = 95) were positive and 75.9% (n = 300) were negative. ROC analysis of the validation cohort showed that the AUC of the r'-wave algorithm (AUC: 0.92; CI 0.85-0.99) was significantly better than the AUC of the β-angle (AUC: 0.82; 95% CI 0.71-0.92), the α-angle (AUC: 0.77; 95% CI 0.66-0.90), the DBT- 5 mm (AUC: 0.75; 95% CI 0.64-0.87), the DBT- iso (AUC: 0.79; 95% CI 0.67-0.91), and the triangle base/height (AUC: 0.61; 95% CI 0.48-0.75) ( p < 0.001), making it the best predictor of a BrS diagnosis after an SCBPT. The r'-wave algorithm with a cut-off value of ≥2 showed a sensitivity of 90% and a specificity of 83%. In our study, the r'-wave algorithm was proved to have the best diagnostic accuracy, compared with single electrocardiographic criteria, in predicting the diagnosis of BrS after provocative testing with flecainide.

Objectives: Antiepileptic and antiarrhythmic drugs inhibit voltage-gated sodium (Na + ) channels (VGSCs), and preclinical studies show that these medications reduce tumour growth, invasion and metastasis. We investigated the association between VGSC inhibitor use and survival in patients with breast, bowel and prostate cancer., Design: Retrospective cohort study., Setting: Individual electronic primary healthcare records extracted from the Clinical Practice Research Datalink., Participants: Records for 132 996 patients with a diagnosis of breast, bowel or prostate cancer., Outcome Measures: Adjusted Cox proportional hazards regression was used to analyse cancer-specific survival associated with exposure to VGSC inhibitors. Exposure to non-VGSC-inhibiting antiepileptic medication and other non-VGSC blockers were also considered. Drug exposure was treated as a time-varying covariate to account for immortal time bias., Results: During 1 002 225 person-years of follow-up, there were 42 037 cancer-specific deaths. 53 724 (40.4%) patients with cancer had at least one prescription for a VGSC inhibitor of interest. Increased risk of cancer-specific mortality was associated with exposure to this group of drugs (HR 1.59, 95% CI 1.56 to 1.63, p<0.001). This applied to VGSC-inhibiting tricyclic antidepressants (HR 1.61, 95% CI 1.50 to 1.65, p<0.001), local anaesthetics (HR 1.49, 95% CI 1.43 to 1.55, p<0.001) and anticonvulsants (HR 1.40, 95% CI 1.34 to 1.48, p<0.001) and persisted in sensitivity analyses. In contrast, exposure to VGSC-inhibiting class 1c and 1d antiarrhythmics was associated with significantly improved cancer-specific survival (HR 0.75, 95% CI 0.64 to 0.88, p<0.001 and HR 0.54, 95% CI 0.33 to 0.88, p=0.01, respectively)., Conclusions: Association between VGSC inhibitor use and mortality in patients with cancer varies according to indication. Exposure to VGSC-inhibiting antiarrhythmics, but not anticonvulsants, supports findings from preclinical data, with improved survival. However, additional confounding factors may underlie these associations, highlighting the need for further study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

The voltage-gated sodium (Na v ) channel is one of most important targets for treatment of epilepsy, and rufinamide is an approved third-generation anti-seizure drug as Na v 1.1 channel blocker. Herein, by triazenylation of rufinamide, we reported the triazenyl triazoles as new Na v 1.1 channel blocker for treatment of epilepsy. Through the electrophysiological activity assay, compound 6a and 6e were found to modulate the inactivation voltage of Na v 1.1 channel with shift of -10.07 mv and -11.28 mV, respectively. In the pentylenetetrazole (PTZ) mouse model, 6a and 6e reduced the seizure level, prolonged seizure latency and improved the survival rate of epileptic mice at an intragastric administration of 50 mg/kg dosage. In addition, 6a also exhibited promising effectiveness in the maximal electroshock (MES) mouse model and possessed moderate pharmacokinetic profiles. These results demonstrated that 6a was a novel Na v 1.1 channel blocker for treatment of epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis (CF), resulting in recurrent respiratory infections and exacerbations. Strategies to rehydrate airway mucus including inhibition of the epithelial sodium channel (ENaC) have the potential to improve mucosal defense by enhancing mucociliary clearance (MCC) and reducing the risk of progressive decline in lung function. In the current work, we evaluated the effects of AZD5634, an ENaC inhibitor that shows extended lung retention and safety profile as compared with previously evaluated candidate drugs, in healthy and CF preclinical model systems. We found that AZD5634 elicited a potent inhibition of amiloride-sensitive current in non-CF airway cells and airway cells derived from F508del-homozygous individuals with CF that effectively increased airway surface liquid volume and improved mucociliary transport (MCT) rate. AZD5634 also demonstrated efficacious inhibition of ENaC in sheep bronchial epithelial cells, translating to dose-dependent improvement of mucus clearance in healthy sheep in vivo. Conversely, nebulization of AZD5634 did not notably improve airway hydration or MCT in CF rats that exhibit an MCC defect, consistent with findings from a first single-dose evaluation of AZD5634 on MCC in people with CF. Overall, these findings suggest that CF animal models demonstrating impaired mucus clearance translatable to the human situation may help to successfully predict and promote the successful translation of ENaC-directed therapies to the clinic.

Paroxysmal vascular acrosyndromes are related to a peripheral vasomotor disorder and presented as paroxysmal color changes of the fingers. They include primary Raynaud's phenomenon (RP), which is the most common, secondary RP and erythermalgia. They are to be distinguished from non-paroxysmal acrosyndromes such as acrocyanosis and chilblains, which are very frequent and often associated with RP, digital ischemia and necrosis, spontaneous digital hematoma and acrocholosis. The challenge of a consultation for a vascular acrosyndrome is to make positive diagnosis through history and clinical examination, and to specify its nature, to prescribe complementary exams. In any patient consulting for RP, assessment includes at least an antinuclear antibody test and capillaroscopy. For erythermalgia, a blood count and even a search for JAK2 mutation are required. A thryoid-stimulating hormon assay, a test for antinuclear antibodies, and a search for small fiber neuropathy are also performed. The treatment of RP is essentially documented for secondary RP where calcium channel blockers are indicated in first line, and iloprost in severe cases. The treatment of primitive erythermalgia is based on sodium channel blockers such as mexiletine or lidocaine infusions, and on drugs effective on neuropathic pain, such as gabapentin or amitryptiline, in case of erythermalgia associated with small fiber neuropathy. The treatment of erythermalgia associated with myeloproliferative syndromes is based on etiological treatment and aspirin., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Background: Eslicarbazepine acetate (ESL), a novel sodium channel blocker, is approved for mono and adjunctive treatment of partial epileptic seizures with or without secondary generalization. Its efficacy in primary generalized seizures has not yet been evaluated., Objective: To evaluate the efficacy and safety of ESL in primary generalized tonic-clonic seizures (PGTCS) in an observational study., Methods: The data were collected from a prospective population-based register. Effectiveness was measured as relative reduction in standardized seizure frequency (SSF), responder rate (≥ 50% reduction in SSF), and seizure freedom rate at 6 and 12 months after initiation of ESL. Safety and tolerability were evaluated using patients' diaries., Results: Fifty-six adult patients with PGTCS were treated with ESL as adjunctive therapy. Of these, 30.4% (n = 17) had myoclonic seizures in addition to PGTCS. The retention rate after 12 months was 80.4% (n = 45). After initiating ESL therapy, reduction in SSF for PGTCS on ESL was 56.0% after 6 months and 56.9% after 12 months (p &lt; 0.01), whereas myoclonic seizures did not show any significant improvement in frequency. The responder rate for PGTCS was 64.3% after 6 months and 66.1% after 12 months, and seizure freedom was achieved in 32.1% and 35.7%, respectively. Forty-three patients (73.2%) reported no side effects. Among the reported side effects of ESL therapy, headache (7.1%), dizziness (8.9%), tiredness (7.1%), nausea (5.4%), and hyponatremia (5.4%) were the most prevalent., Conclusions: Our data suggest that ESL may provide additional benefits in the treatment of patients with PGTCS and motivate randomized controlled trials in this indication., (© 2022. The Author(s).)

Background: β-Blockers (BBs), sodium channel blockers (SCBs), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs) are used to prevent or counter long QT syndrome (LQTS)-triggered syncope, seizures, and sudden cardiac death. The spectrum and extent of side effects/complications associated with these guideline-directed therapies (GDTs) remain unknown., Objective: The purpose of this study was to identify the types/prevalence of treatment-associated side effects/complications for patients with the most common LQTS subtypes after GDT., Methods: Retrospective analysis was performed on 1310 patients with type 1, 2, or 3 LQTS evaluated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic (average age at the time of diagnosis 22 ± 18 years; average length of follow-up 5 ± 5 years) and treated with ≥1 of the common GDTs for LQTS., Results: BBs were used in 1102 (84%), SCBs in 104 (8%), LCSD in 197 (15%), and an ICD was used in 251 (19%) patients. Overall, 727 (55%) patients reported at least 1 treatment-associated side effect/complication. A total of 490 of 1102 patients treated with BBs (44%) reported side effects, with fatigue (381 [35%]) being the most common; 28 of 104 SCB-treated patients (27%) reported side effects, most common being gastrointestinal distress/vomiting (18 [17%]); 80 of 197 patients (41%) reported side effects after LCSD, most reporting neuropathic pain (57 [29%]); and 129 of 251 patients (51%) experienced ≥1 complication after ICD implantation, including inappropriate shocks (46 [18%])., Conclusion: Although LQTS-triggered sudden cardiac death is uncommon in the properly treated patient, this study demonstrates that contemporary GDTs for LQTS are not innocuous. Their treatment-related side effects are not trivial and should compel an ongoing quest for new LQTS therapies., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Changes in Ca2 + influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca 2+ has been widely acknowledged, little is known about the role of Na + . Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na + as well as Ca2 + levels. In stable coronary artery disease patients ( n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment ( n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL -/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na + inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na + shuttling is required for a full cellular response to inflammation and that inhibition of Na + influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na + -Ca 2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

β-Cyfluthrin, a class II Pyrethroid, is an insecticide used worldwide in agriculture, horticulture (field and protected crops), viticulture, and domestic applications. β-Cyfluthrin may impair the function of biological systems; however, little information is available about its potential cardiotoxic effect. Here, we explored the acute toxicity of β-Cyfluthrin in isolated heart preparations and its cellular basis, using isolated cardiomyocytes. Moreover, β-Cyfluthrin effects on the sodium current, especially late sodium current (INa-L), were investigated using human embryonic kidney cells (HEK-293) cells transiently expressing human NaV1.5 channels. We report that β-Cyfluthrin raised INa-L in a dose-dependent manner. β-Cyfluthrin prolonged the repolarization of the action potential (AP) and triggered oscillations on its duration. Cardiomyocytes contraction and calcium dynamics were disrupted by the pesticide with a marked incidence of non-electronic-stimulated contractions. The antiarrhythmic drug Ranolazine was able to reverse most of the phenotypes observed in isolated cells. Lastly, ventricular premature beats (VPBs) and long QT intervals were found during β-Cyfluthrin exposure, and Ranolazine was able to attenuate them. Overall, we demonstrated that β-Cyfluthrin can cause significant cardiac alterations and Ranolazine ameliorated the phenotype. Understanding the insecticides' impacts upon electromechanical properties of the heart is important for the development of therapeutic approaches to treat cases of pesticides intoxication., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review., (Copyright © 2022. Published by Elsevier B.V.)

Objective: This study investigates the effects of PRAX-562 on sodium current (I Na ), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent I Na inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage-gated sodium channel (Na V ) blockers., Methods: Inhibition of I Na  was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA)., Results: PRAX-562 potently and preferentially inhibited persistent I Na induced by ATX-II or the SCN8A mutation N1768D (half-maximal inhibitory concentration [IC 50 ] = 141 and 75 nmol·L -1 , respectively) relative to peak I Na tonic/resting block (60× preference). PRAX-562 also exhibited potent use-dependent block (31× preference to tonic block). This profile is considerably different from standard Na V blockers, including carbamazepine (CBZ; persistent I Na IC 50 = 77 500 nmol·L -1 , preference ratios of 30× [tonic block], less use-dependent block observed at various frequencies). In contrast to CBZ, PRAX-562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX-562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half-maximal efficacious concentration = 4.3 nmol·L -1 , sLMA half-maximal tolerated concentration = 69.7 nmol·L -1 , protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity., Significance: PRAX-562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX-562 exhibited significantly improved preclinical tolerability compared with standard Na V blockers (CBZ and LTG), potentially due to the preference for persistent I Na . Preferential targeting of persistent I Na may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard Na V blockers have demonstrated efficacy but poor tolerability., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: The mechanisms by which sodium channel blockade and high-rate pacing modify electrogram (EGM) substrates of Brugada syndrome (BrS) have not been elucidated., Objective: The purpose of this study was to determine the effect of ajmaline and high pacing rate on the BrS substrates., Methods: Thirty-two patients with BrS (mean age 40 ± 12 years) and frequent ventricular fibrillation episodes underwent right ventricular outflow tract substrate electroanatomical and electrocardiographic imaging (ECGI) mapping before and after ajmaline administration and during high-rate atrial pacing. In 4 patients, epicardial mapping was performed using open thoracotomy with targeted biopsies., Results: Ajmaline increased the activation time delay in the substrate (33%; P = .002), ST-segment elevation in the right precordial leads (74%; P < .0001), and the area of delayed activation (170%; P < .0001), coinciding with the increased substrate size (75%; P < .0001). High atrial pacing rate increased the abnormal EGM duration at the right ventricular outflow tract areas from 112 ± 48 to 143 ± 66 ms (P = .003) and produced intermittent conduction block and/or excitation failure at the substrate sites, especially after ajmaline administration. Biopsies from the 4 patients with thoracotomy showed epicardial fibrosis where EGMs were normal at baseline but became fractionated after ajmaline administration. In some areas, local activation was absent and unipolar EGMs had a monophasic morphology resembling the shape of the action potential., Conclusion: Sodium current reduction with ajmaline severely compromises impulse conduction at the BrS fibrotic substrates by producing fractionated EGMs, conduction block, or excitation failure, leading to the Brugada ECG pattern and favoring ventricular fibrillation genesis., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Ranolazine is a second-line drug for the management of chronic coronary syndromes (CCS). Glucose-lowering and endothelial effects have also been reported with this agent. However, whether ranolazine may improve short-term glycemic variability (GV), strictly related to the prognosis of patients with type 2 diabetes (T2D), is unknown. Thus, we aimed to explore the effects of adding ranolazine to standard anti-ischemic and glucose-lowering therapy on long- and short-term GV as well as on endothelial function and oxidative stress in patients with T2D and CCS., Methods: Patients starting ranolazine ( n = 16) were evaluated for short-term GV, haemoglobin 1Ac (Hb1Ac) levels, endothelial-dependent flow-mediated vasodilation (FMD), and oxidative stress levels at enrolment and after 3-month follow-up. The same measurements were collected from 16 patients with CCS and T2D that did not receive ranolazine, matched for age, gender, and body mass index., Results: A significant decline in Hb1Ac levels was reported after 3-month ranolazine treatment (mean change -0.60%; 2-way ANOVA p = 0.025). Moreover, among patients receiving ranolazine, short-term GV indexes were significantly improved over time compared with baseline ( p = 0.001 for time in range; 2-way ANOVA p = 0.010). Conversely, no significant changes were reported in patients without ranolazine. Finally, greater FMD and lower oxidative stress levels were observed in patients on ranolazine at 3 months., Conclusions: Ranolazine added to standard anti-ischemic and glucose-lowering therapy demonstrated benefit in improving the glycemic status of patients with T2D and CCS. How this improvement contributes to the overall myocardial benefit of ranolazine requires further studies., Competing Interests: The authors declare that they have no conflict of interest related to the content of the manuscript., (Copyright © 2021 Annunziata Nusca et al.)

Aims: In patients with Brugada syndrome (BrS) but without spontaneous Type-1 electrocardiogram, several electrocardiographic characteristics have been studied, including the β-angle. Previous studies suggested that the β-angle might be useful in distinguishing BrS-patients from patients with only suggestive repolarization patterns without performing sodium channel blocker provocation testing. In this study, we aimed to determine the diagnostic value of the β-angle in patients suspected of BrS., Methods and Results: A large cohort (n = 1430) of consecutive patients who underwent provocation testing was evaluated. β-angles were measured in leads V1, V2, and their corresponding positions over the second and third intercostal space. Receiver-operating characteristic curves were constructed and the diagnostic accuracy of previously reported β-angle cut-offs were calculated and evaluated. The importance of the β-angle for predicting the provocation test outcome was determined using a prediction model constructed with logistic regression. The optimum β-angle cut-off in our cohort for ruling out a positive provocation test was 15°; sensitivities were 80-98% and negative predictive values were 79-96% among the right precordial leads. Previously reported β-angle cut-offs performed less well, indicated by lower Youden indices. In the optimism-corrected prediction model [C-statistic: 0.78 (95% CI: 0.75-0.81)], the β-angle had large value (Z-score: 2.1-10.3) and aided construction of a nomogram to predict test outcome., Conclusion: To predict the outcome of provocation testing for BrS, the β-angle alone does not demonstrate strong diagnostic characteristics. However, the β-angle is an important variable to predict provocation test outcome and thus has added value., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: This multicenter study examined the effectiveness and tolerability of lacosamide (LCM) for children and young adults with epilepsy, particularly in patients who had previously been treated with other sodium channel blockers (SCBs) and the difference in effectiveness and tolerability when using other concomitant SCBs., Methods: We retrospectively studied the clinical information of patients aged <30 years given LCM to treat epilepsy. The effectiveness and adverse events (AEs) of LCM and the other SCBs were investigated. Factors related to the effectiveness and AEs of LCM, such as the number of antiepileptic drugs (AEDs) tried before LCM and concomitantly used SCBs, were also studied., Results: We enrolled 112 patients (median age = 11 years). One year after starting LCM, 29% of the patients were seizure free, and 50% had a ≥50% seizure reduction. Of the patients, 17% experienced AEs, the most common being somnolence. A ≥50% seizure reduction was observed for LCM in 30% of patients in whom other SCBs had not been effective. Lacosamide produced a ≥50% seizure reduction in 35% of the patients taking one concomitant SCB. By contrast, no patients had ≥50% seizure reduction, and 33% developed AEs, when LCM was administered concomitantly with two SCBs., Conclusions: Lacosamide was effective in 30% of children and young adults in whom other SCBs had not been effective. The effectiveness of LCM may differ from that of other SCBs, and it is worth trying in patients with epilepsy resistant to other AEDs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Selective sodium channel blockers (SSCBs) have a limited use in genetic generalized epilepsy (GGE), due to their well-known risk of seizure worsening. Although their therapeutic potential in GGE has been suggested by recent evidence, electro-clinical data supporting their prescription are lacking. We aimed to investigate SSCB safety and effectiveness in a GGE cohort., Methods: Subjects who received SSCBs and had ≥5-year follow-up were enrolled. Lamotrigine was excluded from analysis due to its broader pharmacodynamic spectrum and its better-documented efficacy in GGE., Results: Fifty-six patients (median follow-up 28.5 years) were included. The most used SSCB was carbamazepine in 40 subjects. At the last medical observation, only 9 subjects were still receiving SSCBs. The occurrence of generalized polyspike-wave discharges (GPSWDs) predicted reduced SSCB retention in Cox multivariate analysis. A seizure reduction ≥50% occurred in 53.5% (30/56) of subjects when considering all seizure types; however, the proportion of responders increased to 67.9% when considering only generalized tonic-clonic seizures (GTCS). GPSWDs were significantly associated with a reduced response rate, whereas GGE with GTCS only syndrome with a better outcome. The switch from SSCBs to antiseizure medications licensed for GGE improved seizure control in 65% of patients. Seizure worsening was reported in 5/56 patients; juvenile myoclonic epilepsy and a family history of epilepsy were significantly associated with seizure aggravation., Conclusion: SSCBs appeared effective on GTCS, but epilepsy aggravation and unsatisfactory control of other seizure types were not uncommon. Our study contributes to identifying new clinical and EEG variables associated with SSCB effectiveness and safety which may help neurologists in patients' management., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: β-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown., Methods: We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients., Results: Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], -49.43; 95% confidence interval [CI], -57.80 to -41.05, p < .001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11-0.47; p < .001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24-0.47; p < .001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62-23.09; p < .001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms)., Conclusions: Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best., (© 2021 Wiley Periodicals LLC.)

Objective: To examine the efficacy and tolerance of the antiseizure medications lacosamide (LCM) and levetiracetam (LEV) in patients with benign infantile epilepsy (BIE)., Methods: The clinical data of 24 children with BIE seen between 2014 and 2020 were collected retrospectively, and treatment, effectiveness, and adverse effects were examined. PRRT2 gene analysis was performed using Sanger sequencing., Results: Of the 24 children with BIE, 14 were treated with antiseizure medications. PRRT2 gene analysis was performed in 14 children, and mutations were identified in 4, including a pair of siblings. All five children treated with LCM became seizure-free, similar to those treated with carbamazepine. The LCM does was 2 mg/kg/day in all cases. There were no adverse effects in any patient treated with LCM. By contrast, both patients treated with LEV had seizure recurrence. In one patient, LEV was replaced with CBZ, resulting in seizure freedom., Conclusions: Low-dose LCM was effective and well tolerated in patients with BIE, whereas LEV was insufficiently effective., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Lamotrigine and other sodium-channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy-resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic-clonic seizures seems to play a major role., Methods: We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre-Bötzinger complex (PreBötC) and measured population as well as intracellular activity of the rhythm-generating network under normoxia and hypoxia in the presence or absence of AEDs., Results: We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED-modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBötC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage-dependent bursting activity in PreBötC pacemaker neurons, but led to a hypoxia-dependent shift of the action potential rheobase in all measured PreBötC neurons., Significance: Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium-dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre-Bötzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Purpose: Many pain-triggering nociceptor neurons express TRPV1 or TRPA1, cation-selective channels with large pores that enable permeation of QX-314, a cationic analogue of lidocaine. Co-application of QX-314 with TRPV1 or TRPA1 activators can silence nociceptors. In this study, we describe BW-031, a novel more potent cationic sodium channel inhibitor, and test whether its application alone can inhibit pain associated with tissue inflammation and whether this strategy can also inhibit cough., Experimental Approach: We tested the ability of BW-031 to inhibit pain in three models of tissue inflammation:- inflammation in rat paws produced by complete Freund's adjuvant or by surgical incision and a mouse ultraviolet (UV) burn model. We tested the ability of BW-031 to inhibit cough induced by inhalation of dilute citric acid in guinea pigs., Key Results: BW-031 inhibited Na v 1.7 and Na v 1.1 channels with approximately sixfold greater potency than QX-314 when introduced inside cells. BW-031 inhibited inflammatory pain in all three models tested, producing more effective and longer-lasting inhibition of pain than QX-314 in the mouse UV burn model. BW-031 was effective in reducing cough counts by 78%-90% when applied intratracheally under isoflurane anaesthesia or by aerosol inhalation in guinea pigs with airway inflammation produced by ovalbumin sensitization., Conclusion and Implications: BW-031 is a novel cationic sodium channel inhibitor that can be applied locally as a single agent to inhibit inflammatory pain. BW-031 can also effectively inhibit cough in a guinea pig model of citric acid-induced cough, suggesting a new clinical approach to treating cough., (© 2021 The British Pharmacological Society.)

This study tested the hypothesis that carbamazepine (CBZ) reduces irritability/aggression among individuals >6 months post-traumatic brain injury (TBI). Seventy individuals were enrolled in a parallel-group, randomized, double-blind, placebo-controlled, forced-titration trial of CBZ ( n  = 35) versus placebo ( n  = 35). Participants were randomly assigned to receive CBZ or placebo 42 days with outcome assessed at baseline and Day 42. Dose was titrated up to 400 mg CBZ or placebo equivalent two times daily. Symptoms of irritability and aggression were measured using the Neuropsychiatric Inventory Irritability (NPI-I) and Aggression (NPI-A) domains as a composite measure (NPI-I/A). Global impression of change was recorded from participant, observer, and study clinician. The CBZ group did not differ significantly from the placebo group ( p  = 0.60 and 0.59 for NPI-I/A observer and participant ratings, respectively). High placebo effects were observed with minimal clinically important difference in observer NPI-I/A 57% in CBZ group and 77% in placebo group ( p  = 0.09). Findings were similar for participant ratings. Eighteen of 35 had therapeutic CBZ level ≥4. Therapeutic sample analysis revealed similar high placebo response and non-significant differences except clinician ratings favoring CBZ. Non-serious adverse events occurred more frequently in the CBZ group with greater nervous system effects. CBZ up to 400 mg two times daily was not superior to placebo at reducing irritability/aggression according observers and participants. Large placebo effects may have masked the detection of differences. Clinician rating metrics suggest benefit, and thus, CBZ should remain a treatment option for the experienced brain injury clinician. Data are provided that may aid treatment decisions.

Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5-2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD 50 , TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity.

Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination.

Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like betablockers or calcium channel inhibitors, with frequent suboptimal results. While being the gold standard practice for the management of drug refractory HCM patients, septal reduction therapy (SRT) remains an invasive procedure with associated surgical risks and it requires the expertise of the operating centre, thus limiting its accessibility. It is therefore with high interest that researchers look for pharmacological alternatives that could provide higher rates of success. With new data gathering these past years as well as the development of a new drug class showing promising results, this review provides an up-to-date focused synthesis of existing medical treatment options and future directions for HCM pharmacological treatment.

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that is mainly associated with variants in SCN1A. While drug-resistant epilepsy is the most notable feature of this syndrome, numerous symptoms are present that have significant impact on patients' quality of life. In spite of novel, third-generation anti-seizure treatment options becoming available over the last several years, seizure freedom is often not attained and non-seizure symptoms remain. Precision medicine now offers realistic hope for seizure freedom in DS patients, with several approaches demonstrating preclinical success. Therapeutic approaches such as antisense oligonucleotides (ASO) and adeno-associated virus (AAV)-delivered gene modulation have expanded the potential treatment options for DS, with some of these approaches now transitioning to clinical trials. Several of these treatments may risk the exacerbation of gain-of-function variants and may not be reversible, therefore emphasizing the need for functional testing of new pathogenic variants. The current absence of treatments that address the overall disease, in addition to seizures, exposes the urgent need for reliable, valid measures of the entire complement of symptoms as outcome measures to truly know the impact of treatments on DS. Additionally, with so many treatment options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Antidepressants exert their analgesic effects by inhibiting the reuptake of noradrenaline. Several antidepressants have been shown to block the sodium channels, which might contribute to their analgesic potency. The aim of this study was to determine whether serotonin-noradrenaline reuptake inhibitors (SNRIs) could produce antinociceptive effects via sodium channel blockade using the veratrine test in mice. Furthermore, the effects of these agents on the veratrine test were examined to elucidate the effects of several antidepressants and tramadol on sodium channels. The administration of duloxetine (10 mg/kg) and venlafaxine (30 mg/kg) suppressed cuff-induced mechanical allodynia; however, these antinociceptive effects were only partially suppressed by atipamezole. Furthermore, duloxetine and venlafaxine demonstrated antinociceptive effects via sodium channel blockade, as assayed by the veratrine test. In addition, several antidepressants, including amitriptyline, paroxetine and mirtazapine, reduced veratrine-induced nociception. In contrast, milnacipran and tramadol did not alter the veratrine-induced nociception. These results indicated that, in addition to the primary action of SNRIs on monoamine transporters, sodium channel blockade might be involved in the antinociceptive activities of duloxetine and venlafaxine, but not milnacipran., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)