Voltage-gated Sodium Channel Blocker Research Articles

Phenyl isoxazole voltage-gated sodium channel blockers: Structure and activity relationship

Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.

Clinical response and tolerability of eslicarbazepine in treatment of partial onset seizures: impact of a novel metabolic pathway

Clinical response and tolerability of eslicarbazepine in treatment of partial onset seizures: impact of a novel metabolic pathway Enrique Serrano1, Cynthia L Harden21Comprehensive Epilepsy Center, Department of Neurology, University of Miami, Miami, FL, USA; 2Comprehensive Epilepsy Care Institute, Long Island Jewish School of Medicine, Hofstra North Shore, New Hyde Park, NY, USAAbstract: Epilepsy is a common chronic neurological condition affecting 50 million people worldwide. Because at least 30% of patients with partial seizures do not achieve seizure control with the current antiepileptic drugs, there remains an urgent need for novel antiepileptic drugs with more favorable safety profiles. Eslicarbazepine acetate (formerly known as BIA 2-093) is a novel voltage-gated sodium channel blocker used as adjunctive therapy in the treatment of refractory partial-onset seizures. Eslicarbazepine acetate is a dibenzazepine that is chemically related to carbamazepine and oxcarbazepine, designed to avoid production of active metabolites, as occurs with both carbamazepine and oxcarbazepine. Carbamazepine is metabolized by the liver to the active metabolite, carbamazepine-10, 11-epoxide, which contributes to clinical toxicity. Eslicarbazepine acetate is reduced by esterases in the liver to the active metabolite eslicarbazepine, the S (+) enantiomer of licarbazepine,27 without production of the 10,11-epoxide, resulting in a lower drug interaction potential and fewer adverse neurological effects. Further, while oxcarbazepine is a prodrug that is metabolized into both the S- and R- enantiomers of licarbazepine, eslicarbazepine acetate is metabolized to solely the S- enantiomer of licarbazepine. Eslicarbazepine acetate stabilizes the inactivated state of the voltage-gated sodium channels, preventing their return to an activated state and sustaining repetitive neuronal firing. Eslicarbazepine acetate also has a higher affinity for the inactivated state of the sodium channel compared with the resting state, suggesting enhanced selective inhibition of rapidly firing neurons associated with epileptic discharges. Consequently, eslicarbazepine acetate is less likely to bind to normally active neurons, and, therefore, less likely to cause adverse neurological effects. In clinical trials, eslicarbazepine acetate shows significant efficacy in reducing seizure frequency, and a favorable adverse effect profile at once per day doses of 800 mg or 1200 mg. This novel antiepileptic drug is a promising addition to the treatments for people with partial epilepsy.Keywords: antiepileptic drugs, neurotransmission, seizures

Sodium channel mechanosensitivity: pay a-tension to voltage sensor movement

Sodium channel mechanosensitivity: pay a-tension to voltage sensor movement

Targeting voltage-gated sodium channels for treatment for chronic visceral pain

Voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability, and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity and chronic pain. In particular, chronic visceral pain, the central symptom of functional gastrointestinal disorders such as irritable bowel syndrome, is a serious clinical problem that affects a high percentage of the world population. In spite of intense research efforts and after the dedicated decade of pain control and research, there are not many options to treat chronic pain conditions. However, there is a wealth of evidence emerging to give hope that a more refined approach may be achievable. By using electronic databases, available data on structural and functional properties of VGSCs in chronic pain, particularly functional gastrointestinal hypersensitivity, were reviewed. We summarize the involvement and molecular bases of action of VGSCs in the pathophysiology of several organic and functional gastrointestinal disorders. We also describe the efficacy of VGSC blockers in the treatment of these neurological diseases, and outline future developments that may extend the therapeutic use of compounds that target VGSCs. Overall, clinical and experimental data indicate that isoform-specific blockers of these channels or targeting of their modulators may provide effective and novel approaches for visceral pain therapy.

Recent Developments Regarding Voltage-Gated Sodium Channel Blockers for the Treatment of Inherited and Acquired Neuropathic Pain Syndromes

Chronic and neuropathic pain constitute significant health problems affecting millions of individuals each year. Pain sensations typically originate in sensory neurons of the peripheral nervous system which relay information to the central nervous system (CNS). Pathological pain sensations can arise as result of changes in excitability of these peripheral sensory neurons. Voltage-gated sodium channels are key determinants regulating action potential generation and propagation; thus, changes in sodium channel function can have profound effects on neuronal excitability and pain signaling. At present, most of the clinically available sodium channel blockers used to treat pain are non-selective across sodium channel isoforms and can contribute to cardio-toxicity, motor impairments, and CNS side effects. Numerous strides have been made over the last decade in an effort to develop more selective and efficacious sodium channel blockers to treat pain. The purpose of this review is to highlight some of the more recent developments put forth by research universities and pharmaceutical companies alike in the pursuit of developing more targeted sodium channel therapies for the treatment of a variety of neuropathic pain conditions.

Antinociceptive action of carbamazepine on thermal hypersensitive pain at spinal level in a rat model of adjuvant-induced chronic inflammation

Systemic carbamazepine, a voltage-gated sodium channel blocker, has been reported to dose-dependently reduce inflammatory hyperalgesia. However, the antinociceptive effects of carbamazepine on the spinal cord in inflammatory conditions are unclear. The aim of the present study was to evaluate the antinociceptive effects of carbamazepine on the spinal cord in a chronic inflammatory condition. In Sprague-Dawley rats, a chronic inflammatory condition was induced by complete Freund's adjuvant (CFA) inoculation into the tail. Tail flick (TF) latencies were measured following intraperitoneal carbamazepine, or intrathecal carbamazepine or tetrodotoxin injection in intact rats and in the chronic inflammatory rats. From the values of TF latency at 60min after drug injection, the effective dose required to produce 50% response (ED(50)) of each drug was derived. Carbamazepine attenuated thermal responses with both systemic and intrathecal administration. The effect was more evident in rats with chronic inflammation than in intact rats; the ED(50s) of intraperitoneal carbamazepine in intact and inflamed rats were 12.39 and 1.54mg/kg, and those of intrathecal carbamazepine were 0.311 and 0.048nmol, respectively. Intrathecal tetrodotoxin also clearly inhibited the response, with ED(50s) of 1.006pmol in intact rats and 0.310pmol in inflamed rats. The relative potencies of intrathecal carbamazepine versus tetrodotoxin for inhibition were approximately 1:150-1:300 in intact and inflamed rats. These results indicate that the inhibition of voltage-gated sodium channels, at least tetrodotoxin-sensitive channels, may contribute to the antinociceptive effect of carbamazepine on CFA-induced inflammatory pain, since lower doses of intrathecal carbamazepine and tetrodotoxin attenuated thermal responses to a greater extent in inflamed rats than in intact rats.

Kisspeptin-Evoked Calcium Signals in Isolated Primary Rat Gonadotropin- Releasing Hormone Neurones

Background: Kisspeptin and its cognate receptor GPR54 are the central driving forces in the hypothalamus-pituitary-gonadal axis essential for sexual maturation and reproduction. Kisspeptin/GPR54 signalling stimulates gonadotropin-releasing hormone (GnRH) neurones and induces pulsatile GnRH release. The molecular signalling pathway by which kisspeptin stimulates GnRH neurones is currently under investigation. Methods: Primary GnRH neurones were isolated from young adult rats and loaded with the calcium indicator Fura Red. Cytosolic calcium was measured while the cells were stimulated with kisspeptin. Results: GnRH neurones show a maintained increase of cytosolic calcium upon stimulation with 100 nM kisspeptin-10. The calcium elevation was inhibited 30% by 1 µM tetrodotoxin, a voltage-gated sodium channel blocker, and 76% by 30 µM SKF96365, an inhibitor of receptor-mediated calcium entry. Furthermore, removal of extracellular calcium completely abolished the kisspeptin-induced calcium elevation. Conclusion: Our results suggest that the major part of the kisspeptin-evoked calcium signal is generated by an action potential-independent calcium influx, possibly through channels of the classical transient receptor potential type, with an additional influx through voltage-gated calcium channels activated by sodium action potentials.

μ-Conotoxin KIIIA Derivatives with Divergent Affinities versus Efficacies in Blocking Voltage-Gated Sodium Channels

The possibility of independently manipulating the affinity and efficacy of pore-blocking ligands of sodium channels is of interest for the development of new drugs for the treatment of pain. The analgesic mu-conotoxin KIIIA (KIIIA), a 16-residue peptide with three disulfide bridges, is a pore blocker of voltage-gated sodium channels, including neuronal subtype Na(V)1.2 (K(d) = 5 nM). At saturating concentrations, KIIIA incompletely blocks the sodium current of Na(V)1.2, leaving a 5% residual current (rI(Na)). Lys7 is an important residue: the K7A mutation decreases both the efficacy (i.e., increases rI(Na) to 23%) and the affinity of the peptide (K(d) = 115 nM). In this report, various replacements of residue 7 were examined to determine whether affinity and efficacy were inexorably linked. Because of their facile chemical synthesis, KIIIA analogues that had as a core structure the disulfide-depleted KIIIA[C1A,C2U,C9A,C15U] (where U is selenocysteine) or ddKIIIA were used. Analogues ddKIIIA and ddKIIIA[K7X], where X represents one of nine different amino acids, were tested on voltage-clamped Xenopus oocytes expressing rat Na(V)1.2 or Na(V)1.4. Their affinities ranged from 0.01 to 36 muM and rI(Na) values from 2 to 42%, and these two variables appeared to be uncorrelated. Instead, rI(Na) varied inversely with side chain size, and remarkably charge and hydrophobicity appeared to be inconsequential. The ability to manipulate a mu-conopeptide's affinity and efficacy, as well as its capacity to interfere with subsequent tetrodotoxin binding, greatly expands its scope as a reagent for probing sodium channel structure and function and may also lead to the development of mu-conotoxins as safe analgesics.

Sodium channel blockers for neuropathic pain

Importance of the field: The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity, chronic and neuropathic pain. In particular, neuropathic pain (e.g., postherpetic and trigeminal neuralgia, diabetic neuropathy and spinal cord injury) is a serious clinical problem that affects a high percentage of the world population. Because an altered sodium channel isoform expression profile has been considered one reason for the changes in neuronal excitability, there is a continuous quest for new selective molecules targeting sodium channels for the treatment of chronic pain.Areas covered in this review: PubMed, http://www.sciencedirect.com/, SciFinder® Scholar and http://ep.espacenet.com/ were used as sources for this review and patents between 2007 and September 2009 were taken into account for the sodium channel blockers molecular classes reviewed and discussed herein.What the reader will gain: The sodium channel blockers reported in this review have been categorized into different molecular classes on the basis of their wide structural diversity. This classification, somewhat arbitrary, does not necessarily reflect the presence of pharmacophoric elements but offers a useful way to discuss and comment on structurally homogenous classes of chemotypes recently patented.Take home message: The continuous discoveries in the field of sodium channel blockers, highlighted by the increasing numbers of patent applications published in the last few years and by the numbers of compounds currently in clinical development, underline the importance of this target for the treatment of neuropathic pain. The great difficulty in the design of new selective and active structures, not obtained from old VGSC blockers that are often associated with high risk of adverse effects, is a strong challenge for medicinal chemistry research.

Preceding Inhibition Silences Layer 6 Neurons in Auditory Cortex

A canonical feedforward circuit is proposed to underlie sensory cortical responses with balanced excitation and inhibition in layer 4 (L4). However, in another input layer, L6, sensory responses and the underlying synaptic circuits remain largely unclear. Here, cell-attached recordings in rat primary auditory cortex revealed that for the majority of L6 excitatory neurons, tonal stimuli did not drive spike responses, but suppressed spontaneous firings. Whole-cell recordings further revealed that the silencing resulted from tone-evoked strong inhibition arriving earlier than excitation. This pattern of inputs can be attributed to a parallel feedforward circuit with both excitatory and inhibitory inputs disynaptically relayed. In contrast, in the other neurons directly driven by thalamic input, stimuli evoked excitation preceding relatively weak inhibition, resulting in robust spike responses. Thus, the dichotomy of L6 response properties arises from two distinct patterns of excitatory-inhibitory interplay. The parallel circuit module generating preceding inhibition may provide a gating mechanism for conditional corticothalamic feedback.

ChemInform Abstract: Discovery of Isoxazole Voltage Gated Sodium Channel Blockers for Treatment of Chronic Pain.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Recent advances in adjunctive therapy for epilepsy: Focus on sodium channel blockers as third-generation antiepileptic drugs

Voltage-gated sodium channel blockers like phenytoin and carbamazepine have long been used in the treatment of epilepsy. Brain sodium channels continue to be an important target of many newer second-generation (fosphenytoin, oxcarbazepine, lamotrigine, felbamate, topiramate, zonisamide) and third-generation (eslicarbazepine, brivaracetam, carisbamate, fluorofelbamate, elpetrigine, lacosamide, rufinamide, safinamide, vinpocetine) antiepileptic drugs (AEDs). Some of the newer drugs show either state-dependent antiepileptic action or sodium channel subtype selectivity, although most agents do not differentiate between these channel subtypes. The present review highlights the preclinical and clinical efficacy, pharmacokinetics, drug interactions and adverse event profiles. It also addresses AED selection of sodium channel blockers that constitutes the third generation of AEDs.

Effect of eslicarbazepine acetate on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects during a three-stage, open-label, multiple-dose, single-period study

Background: The anticoagulant warfarin, which is administered as a racemic mixture of R- and S-enantiomers, has been reported to interact with other drugs, including some antiepileptics. Eslicarbazepine acetate (ESL) is a once-daily voltage-gated sodium channel blocker that has been developed for the treatment of partial epilepsy and other indications. Objective: The aim of this work was to investigate whether multiple-dose administration of ESL had any effect on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers stabilized on warfarin at a subtherapeutic level. Methods: Subjects received ESL 1200 mg once daily for 8 days concomitantly with racemic warfarin, the dose of which had been individually optimized to a stable prothrombin international normalized ratio (INR) of 1.3 to 1.8 during a previous run-in phase (up to 21 days). Coadministration of ESL and warfarin was followed by a 7-day recovery period when warfarin was again administered alone. The effects of ESL on the steady-state pharmacokinetics of R- and S-warfarin and on the INR were assessed. For the R- and S-warfarin assay, blood sampling was to occur at stage 1 (run-in period), 3 days before starting ESL dosing; stage 2 (combined treatment period), on days 1 and 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 4, 6, and 7 at predose; and stage 3 (after the combined treatment period) on days 3, 5, and 7 predose, and on day 8 at 24 hours after the final warfarin dose. For determination of INR, blood sampling was to occur at stage 2 on days 1, 2, 4, 6, 7, and 8 at predose; and at stage 3 on days 1, 3, 5, and 7 at predose and on day 8 at 24 hours after the final warfarin dose. For the assay of the racemic mixture of the S- and the R-enantiomers (eslicarbazepine and R-licarbazepine), blood sampling was to occur at stage 2 on day 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 2, 4, 6, and 7 at predose. C max and AUC 0-t were defined as primary pharmacokinetic parameters. Tolerability was evaluated by monitoring adverse events, clinical laboratory safety tests, vital signs, and 12-lead ECG. Results: Of the 15 subjects enrolled, 13 (7 men and 6 women) completed the study. The mean (SD) age was 28.1 (7.3) years (range, 20–42 years), mean weight was 67.3 (10.7) kg (range, 54.0–84.4 kg), and 14 subjects (93.3%) were white. Reductions in S-warfarin C max (test:reference geometric means ratio [GMR] = 0.81 [90% CI, 0.76 to 0.86] and in S-warfarin AUC ss (test:reference GMR = 0.77 [90% CI, 0.72 to 0.82]) were observed, without any clinically relevant changes in the INR. The mean INR was 1.45 (0.10) when warfarin was used alone in stage 1 (control) and 1.51 (0.25) when ESL was added to warfarin in stage 2. In relation to stage 1, a slight mean INR increase of 4.04% [90% CI, 1.03% to 9.12%] was reported in stage 2. In stage 3, following discontinuation of ESL administration, a change of −5.42% in the INR was found [90% CI, −8.85% to −1.98%]. ESL was not associated with any clinically relevant changes in R-warfarin pharmacokinetic parameters. No deaths, serious adverse events, or discontinuations due to adverse events were noted, and no clinically relevant findings were reported for the other safety variables. During the course of the study, 9 subjects (60%) reported a total of 32 adverse events. Catheter-site ecchymosis, venipuncturesite hematoma, dizziness, vasovagal reaction, and adhesive-tape allergy were the most common adverse events reported. During coadministration of ESL and warfarin, 7 subjects reported a total of 17 adverse events, of which 6 (epigastric discomfort, asthenia, dizziness, lipothymia, irritability, and macular rash) were considered possibly related to treatment; only lipothymia reached moderate intensity, and all symptoms subsided without sequelae after ESL was discontinued. Conclusions: In this short-term study in healthy subjects, coadministration of warfarin and ESL 1200 mg once daily was associated with a small, but statistically significant, reduction in systemic exposure to S-warfarin. There was no statistically significant effect on R-warfarin pharmacokinetics or on coagulation as measured by the INR. Protocol identifier: UFH/BIA-2093-108.

Update on treatment of partial onset epilepsy: role of eslicarbazepine

Partial epilepsy comprises simple partial seizures, complex partial seizures, and secondarily generalized seizures, and covers more than 60% of patients with epilepsy. Antiepileptic drugs are generally considered to be the major therapeutic intervention for epilepsy but, despite a broad range of commonly used antiepileptic drugs, approximately 30% of adult patients and approximately 25% of children with epilepsy have inadequate seizure control. Eslicarbazepine acetate (ESL) is a novel voltage-gated sodium channel-blocking agent with presumed good safety and efficacy for adjunctive treatment of patients with drug-resistant partial epilepsy. ESL is a prodrug of eslicarbazepine (the active entity responsible for pharmacologic effects), and is rapidly and extensively hydrolyzed during first pass by liver esterases after oral administration. The half-life of eslicarbazepine at steady-state plasma concentrations is 20–24 hours, compatible with once-daily administration. ESL 800 mg and 1200 mg significantly reduces seizure frequency and shows a favorable safety profile in adult patients with drug-resistant partial-onset seizures, as demonstrated in previous Phase II and III trials. In children, ESL showed a clear dose-dependent decrease in seizure frequency with good tolerability. The most commonly reported adverse events associated with ESL are dizziness, somnolence, nausea, diplopia, headache, vomiting, blurred vision, vertigo, and fatigue. In conclusion, these characteristics suggest that ESL might be a valid and well tolerated treatment option for patients with drug-resistant partial-onset epilepsy. The convenience of once-daily dosing and a short, simple titration regimen would be of special interest for children, although conclusive published data are lacking to date. Hence, there is an urgent need to establish the therapeutic value of ESL in this special population in the near future.

Functional Expression of an Arachnid Sodium Channel Reveals Residues Responsible for Tetrodotoxin Resistance in Invertebrate Sodium Channels

Tetrodotoxin (TTX) is a potent blocker of voltage-gated sodium channels, but not all sodium channels are equally sensitive to inhibition by TTX. The molecular basis of differential TTX sensitivity of mammalian sodium channels has been largely elucidated. In contrast, our knowledge about the sensitivity of invertebrate sodium channels to TTX remains poor, in part because of limited success in functional expression of these channels. In this study, we report the functional characterization in Xenopus oocytes of the first non-insect, invertebrate voltage-gated sodium channel from the varroa mite (Varroa destructor), an ecto-parasite of the honeybee. This arachnid sodium channel activates and inactivates rapidly with half-maximal activation at -18 mV and half-maximal fast inactivation at -29 mV. Interestingly, this arachnid channel showed surprising TTX resistance. TTX blocked this channel with an IC(50) of 1 microM. Subsequent site-directed mutagenesis revealed two residues, Thr-1674 and Ser-1967, in the pore-forming region of domains III and IV, respectively, which were responsible for the observed resistance to inhibition by TTX. Furthermore, sequence comparison and additional amino acid substitutions suggested that sequence polymorphisms at these two positions could be a widespread mechanism for modulating TTX sensitivity of sodium channels in diverse invertebrates.

Synthesis and in vitro evaluation of 2,4-diamino-1,3,5-triazine derivatives as neuronal voltage-gated sodium channel blockers

Neuronal sodium channels blockers interfere with ion flux and have been used for managing neuropathic pain, epilepsy, and cerebral ischemic disorders. In the current study, four groups of 2,4-diamino-1,3,5-triazine derivatives were synthesized and investigated for their neuronal sodium channels binding activity. 5-Aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamines ( 4a– 4j) were found to have the best neuronal sodium binding activity among the four groups of triazines evaluated. Derivatives 4a– 4j blocked the sodium channels with IC 50 values ranged from 4.0 to 14.7 μM. The result from this study showed that analogues of 2,4-diamino-1,3,5-triazines could be used as leads for the discovery of neuronal sodium channels blockers for managing central nervous system related disorders.

Discovery of a novel class of isoxazoline voltage gated sodium channel blockers

Analogs of the previously reported voltage gated sodium channel blocker CDA54 were prepared in which one of the amide functions was replaced with aromatic and non-aromatic heterocycles. Replacement of the amide with an aromatic heterocycle resulted in significant loss of sodium channel blocking activity, while non-aromatic heterocycle replacements were well tolerated.

Discovery of isoxazole voltage gated sodium channel blockers for treatment of chronic pain

A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na v1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na v1.7 inhibitory activity.

Membrane trauma and Na+ leak from Nav1.6 channels

During brain trauma, white matter experiences shear and stretch forces that, without severing axons, nevertheless trigger their secondary degeneration. In central nervous system (CNS) trauma models, voltage-gated sodium channel (Nav) blockers are neuroprotective. This, plus the rapid tetrodotoxin-sensitive Ca2+ overload of stretch-traumatized axons, points to "leaky" Nav channels as a pivotal early lesion in brain trauma. Direct effects of mechanical trauma on neuronal Nav channels have not, however, been tested. Here, we monitor immediate responses of recombinant neuronal Nav channels to stretch, using patch-clamp and Na+-dye approaches. Trauma constituted either bleb-inducing aspiration of cell-attached oocyte patches or abrupt uniaxial stretch of cells on an extensible substrate. Nav1.6 channel transient current displayed irreversible hyperpolarizing shifts of steady-state inactivation [availability(V)] and of activation [g(V)] and, thus, of window current. Left shift increased progressively with trauma intensity. For moderately intense patch trauma, a approximately 20-mV hyperpolarizing shift was registered. Nav1.6 voltage sensors evidently see lower energy barriers posttrauma, probably because of the different bilayer mechanics of blebbed versus intact membrane. Na+ dye-loaded human embryonic kidney (HEK) cells stably transfected with alphaNav1.6 were subjected to traumatic brain injury-like stretch. Cytoplasmic Na+ levels abruptly increased and the trauma-induced influx had a significant tetrodotoxin-sensitive component. Nav1.6 channel responses to cell and membrane trauma are therefore consistent with the hypothesis that mechanically induced Nav channel leak is a primary lesion in traumatic brain injury. Nav1.6 is the CNS node of Ranvier Nav isoform. When, during head trauma, nodes experienced bleb-inducing membrane damage of varying intensities, nodal Nav1.6 channels should immediately "leak" over a broadly left-smeared window current range.

Effect of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects

Eslicarbazepine acetate (ESL) is a new-generation voltage-gated sodium channel blocker, which has been demonstrated to be effective and well tolerated in the treatment of epilepsy. The primary objective of this study was to investigate the effect of ESL on the pharmacokinetics of digoxin. This study was a randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy subjects (six men and six women). The study included two 8-day treatment periods with a washout of >or=10 days. In each period, subjects received either ESL 1200 mg once-daily or placebo, concomitantly with a loading oral dose of digoxin 0.5 mg on days 1 and 2, followed by a once-daily maintenance dose of 0.25 mg on days 3-8. Maximum serum digoxin plasma concentrations (C(max)) were reached (t(max)) at 0.5-2.0 h post-dose (median = 1.0 h) and at 0.5-4.0 h post-dose (median = 1.0 h) with Reference (digoxin plus placebo) and Test (digoxin plus ESL) treatments, respectively. The Test/Reference digoxin geometric mean ratios and 90% confidence intervals (90% CI) were 0.96 and 0.90-1.03 for the area under the plasma concentration-time curve over the dosing interval (AUC(0-24)) and 0.85 and 0.68-1.07 for C(max). The 90% CI was within the bioequivalence range (0.80-1.25) for AUC(0-24), thus demonstrating bioequivalence. The 90% CI was outside the 0.80-1.25 range for digoxin C(max), but it appeared to be caused by a higher variability in digoxin C(max) following co-administration of digoxin with placebo than with ESL. Co-administration of ESL and digoxin was well tolerated. Concomitant administration of ESL has no clinically relevant effect in the systemic exposure to digoxin.