Fentanyl Analogs Exert Antinociceptive Effects via Sodium Channel Blockade in Mice.

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.

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.

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.

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.

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.

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.

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.

Indications for mexiletine in the new ESC guidelines and beyond.

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.

Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel.

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 IC50 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 (V1/2 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.

The r'-Wave Algorithm: A New Diagnostic Tool to Predict the Diagnosis of Brugada Syndrome after a Sodium Channel Blocker Provocation Test.

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 ß-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 (ß-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 ß-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.

Sodium channel-inhibiting drugs and cancer-specific survival: a population-based study of electronic primary care data.

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.

Phytol from Faeces Bombycis alleviated migraine pain by inhibiting Nav1.7 sodium channels.

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.

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

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.

Eslicarbazepine Acetate as Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures in Adults: A Prospective Observational Study.

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 < 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.

Preclinical evaluation of the epithelial sodium channel inhibitor AZD5634 and implications on human translation.

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.

Discovery of triazenyl triazoles as Nav1.1 channel blockers for treatment of epilepsy.

The voltage-gated sodium (Nav) channel is one of most important targets for treatment of epilepsy, and rufinamide is an approved third-generation anti-seizure drug as Nav1.1 channel blocker. Herein, by triazenylation of rufinamide, we reported the triazenyl triazoles as new Nav1.1 channel blocker for treatment of epilepsy. Through the electrophysiological activity assay, compound 6a and 6e were found to modulate the inactivation voltage of Nav 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 Nav1.1 channel blocker for treatment of epilepsy.

Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ 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+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

[Paroxysmal vascular acrosyndromes: Practical approach to diagnosis and management]. / Acrosyndromes vasculaires paroxystiques : démarche pratique de diagnostic et de prise en charge.

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.

Spectrum and prevalence of side effects and complications with guideline-directed therapies for congenital long QT syndrome.

BACKGROUND: ß-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.