A comparative study of serotonin and norepinephrine as adjuncts to improve cutaneous antinociception of mexiletine in response to skin pinpricks in rats.

As adrenaline, serotonin and norepinephrine are two other vasoconstrictors and both of which have been proved to increase the quality and duration of local anesthetics when added as adjuvants. However, the difference in the improvement of the nociception of local anesthetics between the two adjuvants remains unclear. The purpose of this study was to assess the cutaneous nociception of mexiletine by coadministration with serotonin and norepinephrine. Subcutaneous injection of drugs or combinations includes mexiletine 0.6, 1.8, 6.0 µmol, serotonin 1.6500 µmol, noradrenaline 0.8895 nmol, saline, mexiletine 1.8 and 6.0 µmol, respectively combined with serotonin 0.4125, 0.8250, 1.6500 µmol and noradrenaline 0.0356, 0.1779, 0.8895 nmol, with each injection dose of 0.6 ml. The nociception of mexiletine alone and mexiletine coadministered with serotonin and norepinephrine was assessed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous antinociception (P < 0.05, 0.01, or 0.001). Compared with mexiletine (1.8 µmol), adding norepinephrine (except for lowest dose) and serotonin to mexiletine (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action (P < 0.01 or 0.001). Mexiletine (6.0 µmol) combined with norepinephrine and serotonin extended the duration of cutaneous antinociception when compared with mexiletine (6.0 µmol) alone (P < 0.05, 0.01, or 0.001). Both serotonin and norepinephrine improve the sensory block and enhances the nociceptive block duration of mexiletine, and serotonin is superior to that of norepinephrine.

Is systemic administration of local anesthetic agents effective for relieving neuropathic pain? A Cochrane Review summary with commentary.

BACKGROUND: The role of systemic use of local anesthetics in the treatment of neuropathic pain (NP) is still unclear. OBJECTIVE: To assess the efficacy and safety of systemic local anesthetics for NP. METHODS: To summarize and to discuss the rehabilitation perspective on the published Cochrane Systematic Review "Systemic administration of local anesthetic agents to relieve neuropathic pain" by Challapalli V et al.RESULTS:The review included 30 RCTs including patients with NP treated with iv lidocaine, oral mexiletine, lidocaine and mexiletine, or oral tocainide. Low-to-moderate quality of the evidence suggest that intravenous lidocaine or oral mexiletine may slightly reduce NP vs placebo, but the efficacy of these drugs is comparable to anticonvulsants or morphine. CONCLUSIONS: Systemic administration of local anesthetics is not supported by scientific evidence for pain relief as well as for functional improvement.

Characterisation of mexiletine's 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.

Comparison of Adrenaline and Dexmedetomidine in Improving the Cutaneous Analgesia of Mexiletine in Response to Skin Pinpricks in Rats.

BACKGROUND: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear. OBJECTIVE: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr. METHODS: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 µmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 µmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL. RESULTS: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 µmol), adding Dex or Adr to Mex (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 µmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 µmol) alone. A high dose of Adr is more effective with Mex 1.8 µmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 µmol combined with any dose of Adr is superior to that of Dex. CONCLUSIONS: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.

A Multi-Centered Case Series Highlighting the Clinical Use and Dosing of Lidocaine and Mexiletine for Refractory Cancer Pain.

Lidocaine infusion for pain control has been used for years. While some centers transition from continuous infusion lidocaine to oral mexiletine, there are no published studies to guide this conversion in pain and palliative care settings. This is a retrospective case series of 10 cancer patients across four institutions, with attention to dosing of both agents, and subsequent decrease in morphine-equivalent daily dosing (MEDD). The mean age was 55 years (range 34-78). The mean bolus dose of lidocaine was 1.6 mg/kg, infused over an average of 24 minutes, followed by a mean continuous infusion rate of 1.1 mg/kg/hr, and the infusion was continued for an average of 14.1 hours (range of 0.2 - 28 hours). The mean starting daily mexiletine dose was 400 mg (in 2-3 divided doses) and final dosing averaged 500 mg/day. The mean MEDD prior to starting lidocaine was 1118 mg/24 hours, which, by the time of final mexiletine dosing, was 882 mg/24 hours, a 21% MEDD reduction. The average hospital length of stay was 14 days. There was no lidocaine-induced toxicity and no lidocaine levels were obtained. Two of the 10 patients stopped mexiletine early, one from confusion four days after initiation of mexiletine, and the other after six weeks due to dizziness and visual changes. For cancer patients with suboptimal pain control on large doses of opioid, lidocaine infusion followed by oral mexiletine was well tolerated and effective.

Study protocol for the MEXiletine hydrochloride administration trial: a placebo-controlled, randomised, double-blind, multicentre, crossover study of its efficacy and safety in spinal and bulbar muscular atrophy (MEXPRESS).

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. Cold exposure often leads to worsening of motor symptoms including paresis. Although mexiletine hydrochloride administration has been shown to be effective for the treatment of several muscular diseases, its effectiveness in SBMA has not been validated to date. The trial will test it as a symptomatic drug for cold paresis. This study is the first trial to evaluate the efficacy and safety of mexiletine hydrochloride administration in patients with SBMA. METHODS AND ANALYSIS: A placebo-controlled, randomised, double-blind, multicentre, crossover clinical trial will be conducted to assess the safety and efficacy of mexiletine hydrochloride in patients with SBMA. The eligible patients will be assigned randomly in a 1:1 ratio to two groups in a double-blind manner. Participants will take mexiletine hydrochloride (300 mg/day) or a placebo orally three times a day for 4 weeks (period 1). After a 1-week washout period, participants will take the other drug for 4 weeks (period 2). The primary endpoint is the difference in distal latencies between room temperature and cold exposure conditions. ETHICS AND DISSEMINATION: This study will be conducted in compliance with the Helsinki Declaration and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Japanese government and has been approved by the ethics committee of Nagoya University Graduate School of Medicine, as a central institutional review board, and by each facility. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000026150; Pre-results.

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis.

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.

Bioorthogonal Removal of 3-Isocyanopropyl Groups Enables the Controlled Release of Fluorophores and Drugs in Vivo.

Dissociative bioorthogonal reactions allow for chemically controlling the release of bioactive agents and reporter probes. Here we describe 3-isocyanopropyl substituents as masking groups that can be effectively removed in biological systems. 3-Isocyanopropyl derivatives react with tetrazines to afford 3-oxopropyl groups that eliminate diverse functionalities. The study shows that the reaction is rapid and can liberate phenols and amines near-quantitatively under physiological conditions. The reaction is compatible with living organisms as demonstrated by the release of a resorufin fluorophore and a mexiletine drug in zebrafish embryos implanted with tetrazine-modified beads. The combined benefits of synthetic ease, rapid kinetics, diversity of leaving groups, high release yields, and structural compactness, make 3-isocyanopropyl derivatives attractive chemical caging moieties for uses in chemical biology and drug delivery.

False-positive amphetamine results on several drug screening platforms due to mexiletine.

OBJECTIVE: False-positive urine drug of abuse screening (UDS) results can have serious implications in clinical practice, particularly when confirmation assay results are not immediately available to providers making medical decisions. Often it is not possible to identify the specific medication or other interfering compound that is responsible for the false-positive UDS result. Even when a potential interference is reported in the literature or package insert for one assay, the applicability to other UDS platforms/assays is often unknown. Mexiletine has been suggested as a cause of false-positive amphetamine results, but never confirmed as the causative agent in previous reports. The goal of this study was to confirm this drug as a cross-reacting compound in amphetamine screening tests. METHODS: We evaluated several amphetamine screening assays: the Syva EMIT II Plus and the Roche KIMS automated immunoassays, along with the Noble Split-Specimen and Synchron QuikScreen point-of-care assays. RESULTS: Urine samples from two patients treated with mexiletine were positive on all amphetamine screens but confirmed negative by mass spectrometry. Drug-free urine spiked with mexiletine caused positive results on all assays, although the EMIT II Plus and KIMS assays cross-reacted at lower mexiletine concentrations than the point-of-care assays. CONCLUSION: This report confirms that mexiletine can cross-react on several amphetamine screening assays. Assay manufacturers are encouraged to evaluate mexiletine cross-reactivity, and providers and laboratories should be aware of the potential for false-positive amphetamine screening results in patients taking mexiletine.

Case Report: Utility of Ketamine, Lidocaine, and Mexiletine as Nonopioid Adjuvants in Complex Cancer-Associated Pain.

Ketamine, lidocaine, and mexiletine are potential nonopioid adjuvant medications for the use of refractory cancer-related pain, particularly when opioids are demonstrating limited objective benefit. This is a case report of a single patient admitted to a large academic medical center in the United States. The patient is a 43-year-old woman with a history of Crohn's disease complicated by rectal squamous cell carcinoma and complex, progressive, and intractable pelvic and rectal pain. Over the course of hospitalization, her pain demonstrated limited opioid responsiveness despite marked fluctuations of her oral morphine equivalent doses. She also demonstrates variable responsiveness to ketamine. Lidocaine continuous infusion ultimately proves beneficial, and she is discharged after conversion to oral mexiletine. An overview of the hospital system's protocols for ketamine and lidocaine continuous infusions for pain and considerations for transitioning to mexiletine from lidocaine infusion are included.

Mexiletine or catheter ablation after amiodarone failure in the VANISH trial.

INTRODUCTION: In patients with ischemic heart disease and ventricular tachycardia (VT) refractory to high dose amiodarone, the two most common therapeutic options are adjunctive mexiletine therapy or catheter ablation. There are little existing data on the efficacy of these strategies. We examined the relative efficacy of adjunctive mexiletine and catheter ablation among patients enrolled in the VANISH trial. METHODS: All subjects enrolled in the VANISH trial who had VT refractory to high dose (≥ 300 mg daily) amiodarone at baseline were included. Per protocol, subjects randomized to escalated drug therapy received adjunctive mexiletine. RESULTS: Nineteen of the 259 patients were receiving high-dose amiodarone at baseline and 11 were randomized to escalated therapy with mexiletine and 8 to ablation. The adjunctive mexiletine group had a higher rate of the primary composite outcome (death, VT storm, or appropriate shock) in comparison to catheter ablation (HR 6.87 [2.08-22.8]). Over 90% of the patients in the adjunctive mexiletine/group experienced a primary endpoint during a median 9.2 months' follow-up. There was no difference in the rate of adverse events between the two groups. CONCLUSIONS: Mexiletine has limited efficacy in the treatment of recurrent VT despite high-dose amiodarone therapy, in patients with ischemic heart disease. Catheter ablation is a superior strategy in this population.

The effects of pure potassium channel blocker nifekalant and sodium channel blocker mexiletine on malignant ventricular tachyarrhythmias.

BACKGROUND: Patients with repetitive ventricular tachyarrhythmias - so-called electrical storm - frequently require antiarrhythmic drugs. Amiodarone is widely used for the treatment of electrical storm but is ineffective in some patients. Therefore, we investigated the efficacy of stepwise administration of nifekalant, a pure potassium channel blocker, and mexiletine for electrical storm. METHODS: This study included 44 patients with repetitive ventricular tachyarrhythmias who received stepwise therapy with nifekalant and mexiletine for electrical storm. Nifekalant was initially administered, and mexiletine was subsequently added if nifekalant failed to control ventricular tachyarrhythmias. RESULTS: Nifekalant completely suppressed recurrences of ventricular arrhythmias in 28 patients (64%), including 6 patients in whom oral amiodarone failed to control arrhythmias. In 9 of 16 patients in whom nifekalant was partially effective but failed to suppress ventricular arrhythmias, mexiletine was added. The addition of mexiletine prevented recurrences of ventricular tachyarrhythmias in 5 of these 9 patients (56%). There was no death associated with electrical storm. In total, the stepwise treatment with nifekalant and mexiletine was effective in preventing ventricular tachyarrhythmias in 33 of 44 patients (75%). There was no difference in cycle length of the ventricular tachycardia, QRS interval, QT interval, or left ventricular ejection fraction between patients who responded to antiarrhythmic drugs and those who did not. During follow-up, 8 patients had repetitive ventricular tachyarrhythmia recurrences, and the stepwise treatment was effective in 6 of these 8 patients (75%). CONCLUSIONS: The stepwise treatment with nifekalant and mexiletine was highly effective in the suppression of electrical storm.

Infantile Epileptic Encephalopathy Associated With SCN2A Mutation Responsive to Oral Mexiletine.

BACKGROUND: Genetic alterations are significant causes of epilepsy syndromes; especially early-onset epileptic encephalopathies and voltage-gated sodium channelopathies are among the best described. Mutations in the SCN2A subunit of voltage-gated sodium channels have been associated with benign familial neonatal-infantile seizures, generalized epilepsy febrile seizures plus, and an early-onset infantile epileptic encephalopathy. METHOD: We describe two infants with medically refractory seizures due to a de novo SCN2A mutation. RESULTS: The first child responded to intravenous lidocaine with significant reduction in seizure frequency and was successfully transitioned to enteral mexiletine. Mexiletine was subsequently used in a second infant with reduction in seizure frequency. CONCLUSION: Class 1b antiarrhythmic agents, lidocaine and mexiletine, may be useful in infants with medically refractory early infantile epileptic encephalopathy secondary to mutations in SCN2A.

Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.

BACKGROUND: Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients. OBJECTIVES: The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients. METHODS: The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine. RESULTS: The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097). CONCLUSIONS: Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy.

Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients With Type 3 Congenital Long QT Syndrome.

BACKGROUND: Mexiletine is often used for medical therapy in LQT3 patients, however, the usefulness of mexiletine infusion test for LQT3 patients has not been reported. The aim of this study was to evaluate the usefulness of mexiletine infusion test for detecting LQT3 patients. METHODS AND RESULTS: We analyzed response in 12-lead electrocardiogram parameters measured in II or V5 to i.v. mexiletine infusion (2 mg/kg) during sinus rhythm among 31 genotype-positive LQT patients (29 ± 18 years, 12 male). Change in QTc interval after mexiletine was compared between LQT3 (n=15, 24 ± 21 years, 9 male) and other LQT patients (4 LQT1 and 12 LQT2; 34 ± 14 years, 3 male). Baseline RR, QT, and QTc interval were not different between the 2 groups (981 ± 182 vs. 1,023 ± 192 ms; 550 ± 94 vs. 524 ± 75 ms; 556 ± 66 vs. 520 ± 62 ms, respectively). While QTc interval was shortened with mexiletine in both groups (P<0.0001 vs. baseline), degree of QTc shortening (∆QTc) was significantly larger in LQT3 than in LQT1/LQT2 patients (99 ± 39 vs. 48 ± 32 ms; P=0.0004). The sensitivity, specificity and predictive accuracy of mexiletine infusion test for differentiating LQT3 from LQT1/LQT2 were 86.7%, 81.3% and 81.3%, respectively, and the optimal cut-off for ∆QTc was 69 ms on receiver operating characteristic analysis. No pro-arrhythmic event was observed. CONCLUSIONS: Pronounced shortening of QT interval with mexiletine may facilitate genetic testing in patients with LQT3 syndrome.

Behavioral and pharmacological characteristics of bortezomib-induced peripheral neuropathy in rats.

Bortezomib, an effective anticancer drug for multiple myeloma, often causes peripheral neuropathy which is mainly characterized by numbness and painful paresthesia. Nevertheless, there is no effective strategy to escape or treat bortezomib-induced peripheral neuropathy (BIPN), because we have understood few mechanism of this side effect. In this study, we evaluated behavioral and pathological characteristics of BIPN, and investigated pharmacological efficacy of various analgesic drugs and adjuvants on mechanical allodynia induced by bortezomib treatment in rats. The repeated administration of bortezomib induced mechanical and cold allodynia. There was axonal degeneration of sciatic nerve behind these neuropathic symptoms. Furthermore, the exposure to bortezomib shortened neurite length in PC12 cells. Finally, the result of evaluation of anti-allodynic potency, oral administration of tramadol (10 mg/kg), pregabalin (3 mg/kg), duloxetine (30 mg/kg) or mexiletine (100 mg/kg), but not amitriptyline or diclofenac, transiently relieved the mechanical allodynia induced by bortezomib. These results suggest that axonal degeneration of the sciatic nerve is involved in BIPN and that some analgesic drugs and adjuvants are effective in the relief of painful neuropathy.

Mexiletine metabolites: a review.

Mexiletine belongs to class IB antiarrhythmic drugs and it is still considered a drug of choice for treating myotonias. However some patients do not respond to mexiletine or have significant side effects limiting its use; thus, alternatives to this drug should be envisaged. Mexiletine is extensive metabolized in humans via phase I and phase II reactions. Only a small fraction (about 10%) of the dose of mexiletine administered is recovered without modifications in urine. Although in the past decades Mex metabolites were reported to be devoid of biological activity, recent studies seem to deny this assertion. Actually, several hydroxylated metabolites showed pharmacological activity similar to that of Mex, thus contributing to its clinical profile. Purpose of this review is to summarize all the studies proposed till now about mexiletine metabolites, regarding structureactivity relationship studies as well as synthetic strategies. Biological and analytical studies will be also reported.

Combination drug therapy for patients with intractable ventricular tachycardia associated with right ventricular cardiomyopathy.

BACKGROUND: Drug therapy for patients with right ventricular (RV) cardiomyopathy refractory to single-drug therapy and ablation has not been well defined. METHODS: We reviewed our entire RV cardiomyopathy database (31 patients) and found four patients presenting with ventricular arrhythmias of RV origin refractory to single-drug therapy. These patients underwent complete evaluation for arrhythmogenic right ventricular cardiomyopathy (ARVC). RESULTS: Following the revised 2010 task force criteria, of these four patients, three were diagnosed with ARVC, and one with cardiac sarcoidosis. These patients proved to be refractory to drug monotherapy and either failed or deemed to not be candidates for endocardial ablation. Their arrhythmias were ultimately controlled with combinations of sotalol, flecainide, and mexiletine. CONCLUSIONS: In our experience, combination drug therapy is an effective treatment strategy for patients with ventricular tachycardia refractory to monotherapy and, in some cases, ablation. In addition, flecainide appears to be safe and effective for those with RV cardiomyopathy without significant left ventricular dysfunction.