Effects Of Mexiletine Research Articles

Effects of mexiletine and its pyrroline derivative on NaV1.4 and NaV1.5 by automated patch-clamp: Toward safer anti-myotonic drugs

Effects of mexiletine and its pyrroline derivative on NaV1.4 and NaV1.5 by automated patch-clamp: Toward safer anti-myotonic drugs

Effects of mexiletine on a race-specific mutation in Nav1.5 associated with long QT syndrome.

Mutations in cardiac Nav1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Nav1.5 mutations vary across race-ethnic groups. The Nav1.5 mutation P1090L was linked with familial long QT syndrome (LQTS) and was identified as an ethnic-specific variant in Asians. To explore the role of the P1090L in the LQT syndrome, we characterized the effects of the mutation on the Nav1.5 channel function. We found that the P1090L mutation altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by the mutation. Mexiletine modified the recovery and development of inactivation of the mutation and reduced the mutated channel's availability. We characterized that the P1090L is a gain-of-function, the mutation presented a larger window current and increased channel availability. Treatment with mexiletine rescued the dysfunctional inactivation of the mutation. The results might potentially enable a mechanism-based approach to the treatment of LQTS.

Verification of the Efficacy of Mexiletine Treatment for the A1656D Mutation on Downgrading Reentrant Tachycardia Using a 3D Cardiac Electrophysiological Model.

The SCN5A mutations have been long associated with long QT variant 3 (LQT3). Recent experimental and computation studies have reported that mexiletine effectively treats LQT3 patients associated with the A1656D mutation. However, they have primarily focused on cellular level evaluations and have only looked at the effects of mexiletine on action potential duration (APD) or QT interval reduction. We further investigated mexiletine’s effects on cardiac cells through simulations of single-cell (behavior of alternant occurrence) and 3D (with and without mexiletine). We discovered that mexiletine could shorten the cell’s APD and change the alternant’s occurrence to a shorter basic cycle length (BCL) between 350 and 420 ms. The alternant also appeared at a normal heart rate under the A1656D mutation. Furthermore, the 3D ventricle simulations revealed that mexiletine could reduce the likelihood of a greater spiral wave breakup in the A1656D mutant condition by minimizing the appearance of rotors. In conclusion, we found that mexiletine could provide extra safety features during therapy for LQT3 patients because it can change the alternant occurrence from a normal to a faster heart rate, and it reduces the chance of a spiral wave breakup. Therefore, these findings emphasize the promising efficacy of mexiletine in treating LQT3 patients under the A1656D mutation.

TH-186. Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

TH-186. Muscle velocity recovery cycles as pharmacodynamic biomarker: Effects of mexiletine in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

Effects of Mexiletine on a Race-specific Mutation in Nav1.5 Associated With Long QT Syndrome.

The voltage-gated sodium channel Nav1.5 plays an essential role in the generation and propagation of action potential in cardiomyocytes. Mutations in Nav1.5 have been associated with LQT syndrome, Brugada syndrome, and sudden arrhythmia death syndrome. Genetic studies showed that Nav1.5 mutations vary across race-ethnic groups. Here we investigated an Asian-specific mutation Nav1.5-P1090L associated with LQT syndrome. We found that Nav1.5-P1090L mutation perturbed the sodium channel function. It altered the gating process of the channel and exhibited an enhanced window current. Treatment with mexiletine reversed the depolarization shift of the steady-state inactivation produced by P1090L. Mexiletine also modified the recovery from steady-state inactivation and the development of inactivation of P1090L. It rescued the dysfunctional inactivation of P1090L and reduced the P1090L channel’s availability.

Is mexiletine ready for prime time in patients with Type 2 Long QT Syndrome?

Abstract Background Mexiletine has been proven effective in shortening the duration of ventricular repolarization and reducing the arrhythmic events in type 3 Long QT Syndrome (LQT3). Initial reports indicate that mexiletine might also be effective in patients with type 2 Long QT Syndrome (LQT2, caused by loss-of-functions variants on KCNH2 gene, coding for HERG potassium channel), but this issue has not been investigated in detail. Purpose We quantified the electrocardiographic (ECG) effects of mexiletine in a cohort of LQT2 patients. Methods Twelve-lead ECGs were collected before and after the administration of mexiletine to evaluate the drug's effect on the heart rate-corrected QT interval (QTc). QTc intervals were classified as being (1) at “high-risk” if >500 ms or (2) “normal” if <460 ms, before and after the administration of the drug. KCNH2 variants were defined as (1) trafficking-deficient or (2) non-trafficking-deficient, based on functional studies. Results We tested the maximum tolerated dose of mexiletine in 20 patients (11 males, 55%), who were 17±16 years old at diagnosis, affected by genetically established LQT2. The mean age at the beginning of mexiletine administration was 23±15 years and the mean daily dose administered was 9±2 mg/kg/day. Before mexiletine, the mean QTc interval was 527±53 ms and 10/20 (50%) patients had high-risk QTc values (i.e. QTc >500 ms). After mexiletine, the mean QTc interval shortened to 484±47 ms in the overall population (p=0.001). In the majority of patients (18/20, 90%; Figure 1) QTc interval shortened, with a mean shortening of 42±28 ms, and a high-interindividual variability (range of shortening from 86 ms to 8 ms). Just 2 (10%) patients did not show any reduction of the QTc, despite receiving the highest adult dosages of mexiletine in our cohort (up to 10 mg/kg/day). As compared to baseline conditions, after mexiletine the proportion of patients with high risk QTc values (>500 ms) decreased non-significantly from 50% to 35% (p=0.52). Furthermore, in only 6/20 (30%) patients the QTc normalized (i.e. QTc <460 ms) after the initiation of treatment. The effect of mexiletine was not influenced by gender (p=0.89) or by the functional effect of the KCNH2 mutation (trafficking-deficient vs. non-trafficking-deficient variants, p=0.41). The effect of mexiletine in LQT2 patients was inferior to the one previously observed in a cohort of 34 LQT3 patients, who had similar QTc values at baseline and received similar dosages of mexiletine, but showed a significantly higher reduction of the average QTc interval (63±37 ms in LQT3 vs. 42±28 ms in LQT2, p=0.02). Conclusions Mexiletine induces a reduction of the QTc interval in most LQT2 patients, but many patients remain with high-risk QTc values after receiving the drug. The demonstration that an average QTc shortening of 42 ms is enough to reduce arrhythmic events is necessary, before the introduction of mexiletine in clinical practice for LQT2. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)

Characterisation of mexiletine\u2019s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

The ‘translational therapeutic index’ (TTI) is a drug’s ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. Our aim was to evaluate a novel integrated approach for generating a TTI for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF). We templated the current best available class 1b antiarrhythmic, mexiletine, using the rat Langendorff preparation. Mexiletine’s beneficial effects on the incidence of VF caused by 120 min regional ischaemia were contrasted with its concurrent adverse effects (on several variables) in the same hearts, to generate a TTI. Mexiletine 0.1 and 0.5 µM had no adverse effects, but did not reduce VF incidence. Mexiletine 1 µM reduced VF incidence to 0% but had adverse effects on atrioventricular conduction and ventricular repolarization. Separate studies undertaken using an intraventricular balloon revealed no detrimental effects of mexiletine (1 and 5 µM) on mechanical function, or any benefit against reperfusion-related dysfunction. Mexiletine’s TTI was found to be less than two, which accords with its clinical therapeutic index. Although non-cardiac adversity, identifiable from additional in vivo studies, may reduce the TTI further, it cannot increase it. Our experimental approach represents a useful early-stage integrated risk/benefit method that, when TTI is found to be low, would eliminate unsuitable class 1b drugs prior to next stage in vivo work, with mexiletine’s TTI defining the gold standard that would need to be bettered.

Effects of Mexiletine on Cortical and Peripheral Nerve Hyperexcitability in Sporadic ALS (2531)

Effects of Mexiletine on Cortical and Peripheral Nerve Hyperexcitability in Sporadic ALS (2531)

The Effect of Sodium Channel Blocker, Mexiletine, on Body Weight in Type 2 Diabetes Patients with Visceral Obesity.

Objective:Mexiletine is an anti-arrhythmic agent also used for the treatment of painful diabetic neuropathy. In this study, the effect of mexiletine on body weight was evaluated in type 2 diabetes patients with diabetic neuropathy exhibiting visceral obesity.Methods:Type 2 diabetes patients with neuropathy exhibiting visceral obesity (n = 21) treated by mexiletine (300 mg/day) and a control group of type 2 diabetes patients with the same condition who received vitamin B12 (n = 12) were retrospectively evaluated. Body weight, waist circumference, hemoglobin A1c (HbA1c), blood pressure, liver function, serum lipids, and serum uric acid were assessed before and 6 months after the treatment.Results:Mexiletine significantly decreased body weight and waist circumference. The changes in body weight and waist circumference in 6 months in the mexiletine group were greater than in the control group. In metabolic parameters, there were significant decreases in triglyceride (TG) and serum uric acid. There were positive relationships between the change in body weight and the changes in TG, uric acid, alanine aminotransferase (ALT), and HbA1c.Conclusions:Mexiletine may affect body weight regulation. It ameliorated the metabolic parameters possibly by decreasing visceral fat. Further study should be performed to clarify the mechanism of the effect.

Mexiletine suppresses nodal persistent sodium currents in sensory axons of patients with neuropathic pain

To investigate changes in axonal persistent Na(+) currents in patients with neuropathic pain and the effects of mexiletine, an analogue of lidocaine, on axonal excitability properties. The technique of latent addition was used to estimate nodal persistent Na(+) currents in superficial radial sensory axons of 17 patients with neuropathic pain/paresthesias before and after mexiletine treatment. Brief hyperpolarizing conditioning currents were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an indicator of the magnitude of persistent Na(+) currents. Threshold changes at 0.2 ms in latent addition were greater in the neuropathic patients than in the normal controls (p<0.001). After mexiletine treatment, there was a reduction in clinical pain scores (p<0.001), associated with decreased threshold changes at 0.2 ms (p<0.001). In patients with neuropathy, nodal persistent Na(+) currents in large sensory fibers increase, and the abnormal currents can be suppressed by mexiletine. Pain reduction after mexiletine treatment raises the possibility that excessive Na(+) currents are also suppressed in small fibers mediating neuropathic pain. Latent addition can be used for indirect in vivo monitoring of nodal Na(+) currents in large sensory fibers, and future studies using this approach in small fibers would provide new insights into the peripheral mechanism of neuropathic pain.

Effect of Mexiletine on Dynamic Allodynia Induced by Chronic Constriction Injury of the Sciatic Nerve in Rats

Static and dynamic allodynia occurred in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Static allodynia was detected within 1 day after the CCI surgery, and persisted for 28 days. Dynamic allodynia displayed a slower course of development with a late onset, and statistically significant changes were achieved between 14 and 28 days after the surgery. Mexiletine at 10 and 30 mg/kg, s.c. produced a significant and dose-dependent inhibition of CCI-induced static and dynamic allodynia on day 14 post-surgery. Pregabalin, used as a reference drug, also significantly inhibited both static and dynamic allodynia at 30 and 60 mg/kg, p.o. These findings rationalize the clinical use of mexiletine for treatment of neuropathic pain.

The effect of mexiletine on the level of lipid peroxidation and apoptosis of endothelium following experimental subarachnoid hemorrhage

Objective: The role of apoptosis in etiopathogenesis of vasospasm is not clearly understood yet. It is widely accepted that protection of the endothelial cells from the process of apoptosis could have beneficial effects on cerebral vasospasm after subarachnoid hemorrhage (SAH). Mexiletine blocks sodium and calcium channels and activates ATP-sensitive K+ channels. Moreover, mexiletine is known to have potent antioxidant effects through inhibiting free-radical production.Methods: Twenty-one rabbits were allocated into three groups randomly. Group I was sham operated group (n=7). SAH occurred but no medication was given to the Group II rabbits (SAH only group) (n=7). Mexiletine (50 mg/kg, b.i.d., i.p.) was administered just before SAH and continued until 48 hours following SAH to the Group III rabbits (Mexiletine treated group) (n=7). The ApopTag peroxidase in situ apoptosis detection kit (Serologicals Corporation, former Intergen) was used to demonstrate apoptosis in a cross section of basillary arteries. Thiobarbituric acid reactive material was used to determine the lipid peroxidation levels.Results: There was a statistically significant difference between lipid peroxidation product levels of the control and SAH only groups (p<0.05). The level of lipid peroxidation production in Mexiletine treated group was significantly lower compared with SAH only group (p<0.05) but not significantly higher than the control group (p>0.05).Discussion: In the present study we investigated the antioxidant action of mexiletine on apoptosis of endothelium following a rabbit SAH model. This experimental study directly suggested that lipid peroxidation is an important step in development of apoptosis in endothelial cells and prevention of structural integrity of endothelial cell should play a beneficial role in attenuation of cerebral vasospasm. Mexiletine treatment prevented the increase in lipid peroxidation and cerebral vasospasm. Examination of endothelial cells by staining specific for apoptosis demonstrated significant protection of cell integrity in the treated group.

The effect of intravenously administered mexiletine on tinnitus-a pilot study

The effect of intravenously administered mexiletine on subjective tinnitus and hearing was studied in six patients, who initially responded positively to lidocaine. Distinct mexiletine-induced decreases in tinnitus loudness were demonstrated in three subjects, as reflected by maximum VAS (visual analogue scale) level reduction of 34%, 95%, and 100%, respectively. One subject reported change in tinnitus pitch, another one showed a slight (18% on VAS) tinnitus reduction, and one subject disclosed no effect. Side effects were seen only during one of seven infusions. Mexiletine induced shifts in pure-tone threshold, transient evoked otoacoustic emission, and acoustic reflex threshold, probably reflecting a reversible interference in the function of organ of Corti. The concentration effect relationship remained unclear and no general ‘therapeutic’ level could be identified. This study confirms the effect of mexiletine on the auditory function and its potential as a possible therapeutic agent or a model for further development in tinnitus pharmacotherapy.

The pH-dependent effect of mexiletine on IVS4 sodium channel mutants R1448H/C

The effects of extracellular pH (6.2, 7.4 and 8.2) and 0.1mM mexiletine, a channel blocker of the lidocaine type, are studied on two sodium channel mutations of the fourth voltage sensor, R1448H/C. The fast inactivated channel state to which mexiletine preferentially binds is destabilized by the mutations. In contrast to the expected low response of R1448H/C carriers, mexiletine is particularly effective in preventing exercise-induced stiffness and paralysis from which these patients suffer. Our measurements performed in the whole-cell mode on stably transfected HEK cells show for the first time that the mutations strikingly accelerate closed-state inactivation and, as steady-state fast inactivation is shifted to more negative potentials, stabilize the fast inactivated channel state in the potential range around the resting potential. At pH 7.4 and 8.2, the phasic mexiletine block is larger for R1448C (55%) and R1448H (47%) than for wild type (WT) channels (31%) due to slowed recovery from block (520 ms for R1448C versus 270 ms for WT at pH 7.4) although the recovery from inactivation is slightly faster for the mutants (1.9 ms for R1448C versus 3.8 ms for WT at pH 7.4). At pH 6.2, the effect of mexiletine is smaller and shows a relatively fast recovery from block. We conclude that enhanced closed-state inactivation expands the concept of a mutation-induced uncoupling of channel inactivation from activation to a new potential range and that the higher mexiletine efficacy in R1448H/C carriers than other myotonic patients, offering a pharmacogenetic strategy for mutation-specific treatment.

Mexiletine treatment—induced inhibition of caspase-3 activation and improvement of behavioral recovery after spinal cord injury

It has been demonstrated in several experimental studies that apoptosis contributes to cellular damage after spinal cord injury (SCI). During apoptosis dying cells secrete additional mediators of apoptosis such as cytokines and free radicals which have additional toxic effects and exacerbate neuronal death. The aim of this laboratory study was to investigate the effects of mexiletine on caspase-3 activation and functional recovery and compare its post-SCI effectiveness with methylprednisolone. The rats were divided into five groups. Animals in the trauma group underwent traumatic interventions after laminectomy. Spinal cord contusion injury was produced using the weight-drop method. Animals in treatment groups received a single dose of methylprednisolone sodium succinate (Group C), single dose of mexiletine (Group D), or vehicle solution (saline; Group E) intraperitoneally immediately after injury. Hind-limb functions were assessed using the inclined plane technique and caspase-3 activity in tissue samples was measured 24 hours after SCI. Traumatic injury was found to increase tissue caspase-3 activity. In both treatment groups the drug prevented an increase in caspase-3 activity. Mexiletine treatment improved early behavioral recovery after SCI. The results obtained in this study demonstrated that mexiletine treatment inhibits caspase-3 activation and preserve/restore better neuronal function compared with methylprednisolone after experimental SCI.

The Effect of Dehydroepiandrosterone Sulfate (DHEAS) on Myotonia: Intracellular Studies

In order to find some appropriate medicine to suppress myotonia without decreasing muscle strength experiments were performed on myotonic (mto) mice whose Cl channel does not develop due to stop codon and serves as an animal model of myotonia. In myotonic dystrophy dehydroepiandrosterone is low in the serum and it has been reported that intravenous injections of DHEAS to human cases improves myotonia and activities of daily living. Three pairs of heterozygote mto mice, SWR/J-Clcn1(adr-mto/+) and ten Wistar rats were used. We performed intracellular recordings of myotonia from mto mice and the drug effects on insertion myotonia were recorded from the hemidiaphragm preparations of mto mice with different concentrations of DHEAS. Isometric twitch tension was recorded from rat hemidiaphragm preparations in Tyrode's solution and the effect of DHEAS on the muscle twitch tension was measured at different concentrations of DHEAS from 100 mg/l to 300 mg/l. The effect of mexiletine on ITT was also measured. In mto mice insertion myotonia was recorded as soon as the microelectrode was inserted in the muscle cells. When DHEAS was added to Tyrode's solution, insertion myotonia was suppressed. DHEAS decreased ITT up to 70% of the original value, though mexiletine decreased ITT to 30% of the original value. Therefore, the decrement of the muscle strength in DHEAS solution is much smaller than that of mexiletine. Since myotonic dystrophy shows progressive muscle weakness in addition to myotonia, medications like DHEAS are more favorable than the typical Na channel blocker.

Rate-dependent QRS prolongation during exercise testing associated with hyperkalemia

The present case showed gradual increase of QRS duration from 100 ms up to 180msec during an ergometer exercise test along with the heart rate increase. After exercise, QRS duration shortened and normalized. Laboratory test showed hyperkalemia (K = 8.0 mEq/l). T1 myocardial scintigraphy revealed exercise-induced transient ischemia in posterolateral region of left ventricle. Coronary angiography showed significant stenosis in the distal portion of left circumflex coronary artery. The increase of QRS duration was possibly due to the combination of hyperkalemia and the effect of mexiletine. The rate dependent blocking effect on sodium channel of mexiletine might be intensified under hyperkalemia.

Effect of Mexiletine on Fenvalerate-Induced Nociceptive Response in Diabetic Mice

The effect of mexiletine on the nociceptive behavior induced by the intrathecal injection of fenvalerate, which predominantly activates tetrodotoxin-resistant (TTX-R) sodium channels, was studied in diabetic mice. The intrathecal injection of fenvalerate induced a characteristic behavioral syndrome that mainly consisted of reciprocal hind limb scratching directed toward caudal parts of the body and biting or licking of the hind legs in mice. The intensity of fenvalerate-induced nociceptive responses was significantly greater in diabetic mice than non-diabetic mice. This fenvalerate-induced behavior was dose-dependently inhibited by mexiletine (3 – 30 mg/kg, i.p.). Intrathecal pretreatment with fenvalerate produced thermal hyperalgesia and allodynia in the tail-flick test in naive mice. Furthermore, mexiletine at doses of 10 and 30 mg/kg, i.p., dose-dependently and significantly reduced fenvalerate-induced thermal hyperalgesia and allodynia in the tail-flick test in naive mice. These present data suggest that i.p. pretreatment with mexiletine produced dose-dependent inhibition of fenvalerate-induced hyperalgesia and allodynia in mice, especially diabetic mice. This effect may be, at least in part, mediated by the inhibition of TTX-R sodium channel-mediated nociceptive transmission in the spinal cord.

Effects of mexiletine on the canine model of sparfloxacin-induced long QT syndrome

Potential utility of mexiletine for the treatment of sparfloxacin-induced long QT syndrome was assessed using the in vivo halothane-anesthetized canine model. At 30 min after the administration of a supratherapeutic dose of sparfloxacin (30 mg/kg, i.v.), the mean blood pressure and heart rate decreased, whereas repolarization process and effective refractory period of the ventricular muscle were significantly prolonged. Additional administration of a clinically recommended dose of mexiletine (3 mg/kg, i.v.) at this time point increased the mean blood pressure, suppressed ventricular contraction, delayed atrioventricular as well as intraventricular conduction, and shortened repolarization process and effective refractory period. The extent of abbreviation of the repolarization was more prominent than that of the refractoriness, indicating that mexiletine could decrease the electrical vulnerability of the heart during sparfloxacin overdose. Thus, mexiletine may become a promising pharmacological strategy against the drug-induced long QT syndrome.

Effects of mexiletine on the canine cardiovascular system complicating cisapride overdose: potential utility of mexiletine for the treatment of drug-induced long QT syndrome.

The purpose of this study was to test the potential utility of mexiletine for the treatment of drug-induced long QT syndrome in vivo. Beagle dogs were anesthetized with halothane inhalation (n =7). Monophasic action potential (MAP) of the right ventricle, ECG, systemic and left ventricular pressure, cardiac output and effective refractory period (ERP) of the right ventricle were measured. The electrically vulnerable period was estimated by the difference between MAP duration and ERP. An intentionally high dose of 1 mg/kg, i.v. of cisapride decreased the heart rate, mean blood pressure, left ventricular contraction and cardiac output and prolonged the ventricular repolarization phase and ERP, in which the increment was greater in the former than in the latter, indicating the increase of electrical vulnerability. The left ventricular end-diastolic pressure and atrioventricular as well as intraventricular conduction were hardly affected. Additional administration of an antiarrhythmic dose of 3 mg/kg, i.v. of mexiletine increased the heart rate, decreased the left ventricular contraction and cardiac output, suppressed the atrioventricular as well as intraventricular conduction, and prolonged the ERP, but shortened the ventricular repolarization phase. There was no change in the afterload and preload of the left ventricle. Thus, mexiletine decreased the electrical vulnerability of the heart during cisapride overdose, suggesting that it may become a potential pharmacological strategy for drug-induced long QT syndrome.