Oral Mexiletine Research Articles

Mexiletine shortened QTc interval in an age-dependent manner but suppressed ventricular arrhythmias at all age in children with long QT syndrome type 8

Abstract Background long QT syndrome (LQTS) type 8 (LQT8) is caused by mutations in CACNA1C, a gene encoding the α-subunit of voltage-gated Ca2+ channels. Mexiletine is sodium channel blocker which is often utilized for patients with LQTS type 3. Recently, the potential QT shortening effect of mexiletine in patients with LQTS type 2, however the efficacy for LQT8 patients have not been elucidated sufficiently. Purpose The study aimed to examine the efficacy of mexiletine for LQT8 children. Methods and Results The study consisted of 5 LQT8 children diagnosed at age <18 years from 4 families (female n=2). Three cases diagnosed on the first day of life, others during school-aged period. The mean age at diagnosis was 3.8 ± 4.9 years. The CACNA1C mutations identified in the patients were R518C (Case No.1), R858H (No.2), M1476R (No3 and 4), and G402S (No.5). We analyzed response in 12-lead electrocardiogram (ECG) parameters to mexiletine (3mg/kg, Max 125mg) intravenous infusion over 10 minutes. 12-lead ECGs were recorded at rest and 10 minutes after infusion. Two of them were received in the school-age period (No.1 and 2), two were in the neonatal period (No.4 and 5), and another was twice in both periods (No.3). QTc was drastically shortened in school-aged children (No.1: 521/456ms, No.2: 691/556, No.3: 568/532ms), while 3 neonatal cases showed no QTc shortening (No.3: 481/479ms, No.4: 600/601ms, No.5: Pre 689ms/Post 714ms) (Figure). T wave alternans (TWA) that had occurred incessantly in the neonatal case No.4 dramatically suppressed a few seconds after mexiletine infusion. In addition, torsades de pointes (TdP) had been recorded in 2 cases (No.2 and 5). Then, case No.2 and 5 started combination therapy of oral mexiletine and β-blocker, and No.4 mexiletine therapy. They had no cardiac event during medication for several years, although case No.2 suffered recurrent cardiac events because of non-compliance to mexiletine. Conclusion Mexiletine shortened QTc interval in school-aged children with LQT8, but not in neonates. Regardless of QTc shortening, mexiletine successfully reduced TWA and TdP at all age of LQT8 children.Mexiletine infusion test

Comparison of Oral Procainamide and Mexiletine Treatment of Recurrent and Refractory Ventricular Tachyarrhythmias

Background: Antiarrhythmic therapy for recurrent ventricular arrhythmias (VAs) in patients having undergone catheter ablation and in whom amiodarone and/or beta-blockers were ineffective or contraindicated is a controversial issue. Purpose: The present study sought to compare the efficacy and tolerability of oral procainamide and mexiletine in patients with recurrent ventricular arrhythmias when the standard therapy strategy failed. Methods: All patients with an implantable cardioverter defibrillator (ICD) treated with oral procainamide or mexiletine for recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) in two cardiology divisions between January 2010 and January 2020 were enrolled. Patients were divided into group A (oral procainamide) and group B (mexiletine) and the two groups were compared to each other. The primary endpoint was the efficacy of therapy; the secondary endpoint was the discontinuation of therapy. All events that occurred during procainamide or mexiletine treatment were compared with a matched duration period before the initiation of the therapy. Antiarrhythmic therapy was considered effective when a ≥80% reduction of the sustained ventricular arrhythmias burden recorded by the ICD was achieved. Results: A total of 68 consecutive patients (61 males, 89.7%; mean age 74 ± 10 years) were included in this retrospective analysis. After a median follow-up of 19 months, 38 (56%) patients had a significant reduction in the VA burden. After multivariable adjustment, therapy with procainamide was independently associated with an almost 3-fold higher efficacy on VA suppression compared to mexiletine (HR 2.54, 95% CI 1.06–6.14, p = 0.03). Only three patients (9%) treated with procainamide presented severe side effects (dyspnea or hypotension) requiring discontinuation of therapy compared with six patients (18%) treated with mexiletine who interrupted therapy because of severe side effects (p = 0.47). Conclusions: Compared to mexiletine, oral procainamide had a higher efficacy for the treatment of recurrent and refractory VAs, and showed a good profile of tolerability.

Mexiletine for recurrent ventricular tachycardia in adult patients with structural heart disease and implantable cardioverter defibrillator: an EHRA systematic review

The aim of the study was to systematically review evidence on the effectiveness and safety of oral mexiletine administered in monotherapy or in combination with other antiarrhythmic drugs for recurrent ventricular arrhythmia (ventricular tachycardia/ventricular fibrillation, VT/VF) in adult patients with structural heart disease (SHD) and implantable cardioverter defibrillators (ICDs). We systematically searched MEDLINE, Embase, and CENTRAL databases from inception to 27 August 2021 for prospective and retrospective studies investigating mexiletine in the target population. The main outcome was the reduction of ICD therapy. The main safety outcome was the presence of any serious adverse events (SAEs) leading to mexiletine discontinuation. Study quality was assessed using the Cochrane risk of bias tool or the Newcastle-Ottawa scale. Four studies comprising 86 mexiletine recipients were included in the review. We also obtained individual data of 50 patients from two studies. Ischaemic cardiomyopathy (ICM) was present in 86% of patients. The quality of included studies was moderate/low. A narrative review was undertaken as studies varied widely in terms of study population and treatment. Across studies, mexiletine treatment (with or without amiodarone) seemed to consistently reduce the number of ICD therapies especially in a population where catheter ablation (CA) was unsuccessful or contraindicated. In ICM patients deemed eligible for CA, mexiletine seemed to be inferior to CA. Mexiletine was discontinued in 14% of cases, mainly for gastrointestinal or neurological SAE. Mexiletine seems to be an option for the long-term treatment of recurrent VT/VF in adult patients with SHD, especially ICM, and ICD in whom CA was unsuccessful or not suitable.

Comparison between oral procainamide and mexiletine for the treatment of recurrent and refractory ventricular tachyarrhythmias

Abstract Funding Acknowledgements Type of funding sources: None. Background The antiarrhythmic therapy of recurrent ventricular arrhythmias in patients having undergone catheter ablation and in whom amiodarone and/or beta blockers were ineffective or contraindicated, is a controversial issue. Purpose The present study sought to compare the efficacy and tolerability of oral procainamide and mexiletine in patients with recurrent ventricular arrhythmias, when the standard therapy strategy failed. Methods All patients with an implantable cardioverter defibrillator (ICD) treated with oral procainamide or mexiletine for recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF) in 2 Cardiology Divisions between January 2010 and January 2020 were enrolled. The patients were divided in group A (oral procainamide) and group B (mexiletine) and the 2 groups were compared to each other. The primary endpoint was the efficacy of therapy; the secondary endpoint was the discontinuation of therapy. All the events occurring during procainamide or mexiletine treatment were compared with a matched duration period before the initiation of the therapy. Antiarrhythmic therapy was considered effective when an ≥80% reduction of the sustained ventricular arrhythmias (SVA) burden recorded by the ICD was achieved. Results A total of 68 consecutive patients (61 males, 89.7%; mean age 74 ± 10 years) were included in this retrospective analysis. In 27 (39.7%) patients catheter ablation of VT was attempted before therapy initiation. A concomitant therapy with amiodarone was present in 25 (36.8%) patients. The mean dose of procainamide was 1207±487 mg/die. The mean dose of mexiletine was 576±66 mg/die. After a median follow-up of 19 months, 38 (56%) patients had a significant reduction in the SVA burden. After multivariable adjustment (Table 1), therapy with procainamide was independently associated with an almost 3-fold higher efficacy on VA suppression compared to mexiletine (HR 2.54, 95% CI 1.06-6.14, p=0.03). Similar results (HR 2.89, 95% CI 1.26-6.62, p=0.01) were found after adjustment using inverse probability weighting by a propensity score including age, gender, left ventricular ejection fraction, ischemic heart disease and concomitant amiodarone therapy. Only 3 patients (9%) treated with procainamide presented severe side effects (dyspnea or hypotension) requiring discontinuation of therapy against 6 patients (18%) treated with mexiletine who interrupted therapy because of severe side effects (p=0.47). Conclusions Compared to mexiletine, oral procainamide has a higher efficacy for the treatment of recurrent and refractory VAs and shows a good profile of tolerability Table 1. Multivariable Cox Proportional Hazards Analysis of Baseline Covariates in Relation to effective VAs suppression.

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

The role of systemic use of local anesthetics in the treatment of neuropathic pain (NP) is still unclear. To assess the efficacy and safety of systemic local anesthetics for NP. 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. Systemic administration of local anesthetics is not supported by scientific evidence for pain relief as well as for functional improvement.

Gating Properties of Mutant Sodium Channels and Responses to Sodium Current Inhibitors Predict Mexiletine-Sensitive Mutations of Long QT Syndrome 3.

BackgroundLong QT syndrome 3 (LQT3) is caused by SCN5A mutations. Late sodium current (late I Na) inhibitors are current-specific to treat patients with LQT3, but the mechanisms underlying mexiletine (MEX) -sensitive (N1325S and R1623Q) and -insensitive (M1652R) mutations remains to be elucidated.MethodsLQT3 patients with causative mutations were treated with oral MEX following i.v. lidocaine. Whole-cell patch-clamp techniques and molecular remodeling were used to determine the mechanisms underlying the sensitivity to MEX.ResultsIntravenous administration of lidocaine followed by MEX orally in LQT patients with N1325S and R1623Q sodium channel mutation shortened QTc interval, abolished arrhythmias, and completely normalized the ECG. In HEK293 cells, the steady-state inactivation curves of the M1652R channels were rightward shifted by 5.6 mV relative to the WT channel. In contrast, the R1623Q mutation caused a leftward shift of the steady-state inactivation curve by 15.2 mV compared with WT channel, and N1325S mutation did not affect steady-state inactivation (n = 5–13, P < 0.05). The extent of the window current was expanded in all three mutant channels compared with WT. All three mutations increased late I Na with the greatest amplitude in the M1652R channel (n = 9–15, P < 0.05). MEX caused a hyperpolarizing shift of the steady-state inactivation and delayed the recovery of all three mutant channels. Furthermore, it suppressed late I Na in N1325S and R1623Q to a greater extent compared to that of M1652R mutant channel. Mutations altered the sensitivity of Nav1.5 to MEX through allosteric mechanisms by changing the conformation of Nav1.5 to become more or less favorable for MEX binding. Late I Na inhibitors suppressed late I Na in N1325S and R1623Q to a greater extent than that in the M1652R mutation (n = 4–7, P < 0.05).ConclusionThe N1325S, R1623Q, and M1652R mutations are associated with a variable augmentation of late I Na, which was reversed by MEX. M1652R mutation changes the conformation of Nav1.5 that disrupt the inactivation of channel affecting MEX binding, corresponding to the poor response to MEX. The lidocaine test, molecular modeling, and drugs screening in cells expressing mutant channels are useful for predicting the effectiveness of late I Na inhibitors.

Termination of SUNCT with intravenous lignocaine followed by oral mexiletine

Background: The trigeminal autonomic cephalalgias (TACs) are a group of debilitating, pathophysiologically similar headache syndromes characterized by facial pain and autonomic symptoms in areas supplied by the trigeminal nerve. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is among the rarest of the TAC syndromes and can be particularly recalcitrant to treatment. Case: We describe the case of a 50-year old woman with difficult-to-control SUNCT whose pain was completely aborted within hours of commencing intravenous lignocaine therapy and was maintained pain-free after transitioning to oral mexiletine. Conclusion: This is the first report of successful transition from intravenous lignocaine to oral mexiletine in SUNCT, and we suggest that this treatment should be tried early in difficult-to-control SUNCT. This therapy is safe, effective and with minimal side effects if administered in an appropriate manner.

Infantile Epileptic Encephalopathy Associated With SCN2A Mutation Responsive to Oral Mexiletine

BackgroundGenetic 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. MethodWe describe two infants with medically refractory seizures due to a de novo SCN2A mutation. ResultsThe 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. ConclusionClass 1b antiarrhythmic agents, lidocaine and mexiletine, may be useful in infants with medically refractory early infantile epileptic encephalopathy secondary to mutations in SCN2A.

Pharmacotherapy for the prevention of chronic pain after surgery in adults

Chronic pain can often occur after surgery, substantially impairing patients' health and quality of life. It is caused by complex mechanisms that are not yet well understood. The predictable nature of most surgical procedures has allowed for the conduct of randomized controlled trials of pharmacological interventions aimed at preventing chronic postsurgical pain. The primary objective was to evaluate the efficacy of systemic drugs for the prevention of chronic pain after surgery by examining the proportion of patients reporting pain three months or more after surgery. The secondary objective was to evaluate the safety of drugs administered for the prevention of chronic pain after surgery. We identified randomized controlled trials (RCTs) of various systemically administered drugs for the prevention of chronic pain after surgery from CENTRAL, MEDLINE, EMBASE and handsearches of other reviews and trial registries. The most recent search was performed on 17 July 2013. Included studies were double-blind, placebo-controlled, randomized trials involving adults and evaluating one or more drugs administered systemically before, during or after surgery, or both, which measured pain three months or more after surgery. Data collected from each study included the study drug name, dose, route, timing and duration of dosing; surgical procedure; proportion of patients reporting any pain three months or more after surgery, reporting at least 4/10 or moderate to severe pain three months or more after surgery; and proportion of participants dropping out of the study due to treatment-emergent adverse effects. We identified 40 RCTs of various pharmacological interventions including intravenous ketamine (14 RCTs), oral gabapentin (10 RCTs), oral pregabalin (5 RCTs), non-steroidal anti-inflammatories (3 RCTs), intravenous steroids (3 RCTs), oral N-methyl-D-aspartate (NMDA) blockers (3 RCTs), oral mexiletine (2 RCTs), intravenous fentanyl (1 RCT), intravenous lidocaine (1 RCT), oral venlafaxine (1 RCT) and inhaled nitrous oxide (1 RCT). Meta-analysis suggested a modest but statistically significant reduction in the incidence of chronic pain after surgery following treatment with ketamine but not gabapentin or pregabalin. Results with ketamine should be viewed with caution since most of the included trials were small (that is < 100 participants per treatment arm), which could lead to the overestimation of treatment effect. Additional evidence from better, well designed, large-scale trials is needed in order to more rigorously evaluate pharmacological interventions for the prevention of chronic pain after surgery. Furthermore, available evidence does not support the efficacy of gabapentin, pregabalin, non-steroidal anti-inflammatories, intravenous steroids, oral NMDA blockers, oral mexiletine, intravenous fentanyl, intravenous lidocaine, oral venlafaxine or inhaled nitrous oxide for the prevention of chronic postoperative pain.

Erythromelagia: A Rare and Hard-to-Treat Condition: A 9-Year-Old Boy Responsive to Intravenous Lidocaine and Oral Mexilitene

Dear Editor: We would like to report our successful use of intravenous lidocaine and oral mexiletine in the treatment of erythromelalgia on a 9-year-old boy. One month prior to consult, he experienced progressive, burning pain in hands and feet that was relieved with cold water. The affected extremity demonstrated mild erythema, swelling, and warmth. He arrived to our institution derived from another hospital, reporting a pain intensity of 10/10 on the visual analog scale (VAS) with gabapentin as sole treatment, and no diagnosis to explain these signs and symptoms. Initially, the pediatric unit ordered oral acetaminophen, ketorolac, and pregabaline for neuropathic pain management, but there was no response after 4 days of treatment. Our pain unit evaluated the patient and performed a bolus injection of intravenous lidocaine (1 mg/kg in 20 mL of 0.9% saline over 1 minute), with good response, decreasing his …

Oral mexiletine for lidocaine-responsive neonatal epilepsy

We report a patient with lidocaine-responsive neonatal epilepsy treated successfully with oral mexiletine. The patient was a male neonate who had seizures since 2days of age. While his seizures were refractory to phenobarbital, lamotrigine, vitamin B6, and midazolam, they were controlled by continuous lidocaine infusion. Oral mexiletine at serum levels of 0.2–0.4μg/ml was used successfully for long-term treatment of his seizures. No delay in psychomotor development was observed at the last follow-up at 20months of age. No mutation was identified in any of four genes: SCN1A, SCN1B, KCNQ2, and KCNQ3. Our patient demonstrates that oral mexiletine can be useful for long-term treatment of patients with lidocaine-responsive epilepsy.

Poster 322 Central Poststroke Pain Syndrome Secondary to Embolization of Shrapnel. Successful Treatment With Lidocaine Infusion and Oral Mexiletine. A Case Report

Poster 322 Central Poststroke Pain Syndrome Secondary to Embolization of Shrapnel. Successful Treatment With Lidocaine Infusion and Oral Mexiletine. A Case Report

Experience with oral mexiletine in primary erythromelalgia in children

Primary erythromelalgia is characterized by burning pain, redness, and warmth in the extremities. We present two cases of primary erythromelalgia both of whom presented with a history of several months of severe burning pain in both hands and feet. Both patients had received multiple pain medications with no improvement in symptoms. Pain was relieved by putting affected parts in ice cold water, which resulted in immersion injury of the affected parts. Both patients stopped taking part in school and social activities. We tried oral mexiletine, a class Ib antiarrythmic agent, in view of its reported role in various chronic painful conditions. Dramatic improvement was observed with its use. Both patients improved after several weeks of use, and there were fewer soaking episodes. We observed no adverse effects with mexilitine therapy.

A case of primary erythermalgia with encephalopathy

Sirs, Primary erythermalgia is an autosomal dominant disorder characterized by burning pain in the limbs [10]. Encephalopathic symptoms associated with primary erythermalgia have previously been reported but are not well understood [9]. A 19-year-old woman has been followed for primary erythermalgia from childhood. Her sister had a similar phenotype and died as a result of uncontrolled sepsis. Her father was also affected, but less severely. A mutation in SCN9A has been reported in this family [3] (family 4, exon 5, c.647T [ C, p.F216S). Her symptoms, which have become more intense over time, could not be relieved by sympathectomy, lidocaine injection, or morphine, but they improved moderately when treated with oral mexiletine combined with ice applied to her legs. At the end of 2007, the mexiletine was replaced by a low dose of clonazepam and paracetamol because of continuing discomfort. Two months later, she became drowsy and mentally confused, presenting with auditory and visual hallucinations, deep psychomotor slowdown, and cerebellar ataxia without focal deficit or pyramidal syndrome. Hypothermia (31 C), hypoglycemia (3.65 mmol l), and hypercalcemia (2.66 mmol l) were observed. Despite our advice, she continued to use ice to reduce the pain. A cerebrospinal fluid analysis and the cerebral magnetic resonance imaging (MRI) examination did not reveal any abnormalities. However, the electroencephalography (EEG) showed aspecific encephalopathic features. Following admission to hospital, the patient was treated with a combination of risperidone, clonazepam, oral steroid, and mexiletine, which improved the erythermalgia, encephalopathic symptoms, and laboratory anomalies. The hypothermia disappeared. The combined drug treatment was stopped within a few days, but mexiletine therapy was continued. A clue to the pathogenesis of primary erythermalgia was first reported by Yang et al. [11] and then confirmed by Drenth et al. [3], both of whom identified mutations in SCN9A, which encodes the Nav1.7 sodium channel. These mutations, such as p.F216S [1], cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations. In humans, Nav1.7 channels are selectively expressed in the peripheral nervous system within the dorsal root ganglion and sympathetic ganglion neurons [4]. The hyperexcitability produced by these SCN9A mutations appears to account, at least in part, for the pain experienced by patients [4]. However, our patient also presented symptoms of encephalopathy, hypothermia, and hypoglycemia. To date, the pathomechanism of this erythermalgiaassociated encephalopathy remains obscure. Two cases of primary erythermalgia associated with encephalopathy have been reported previously [6, 9]. One of these [9] was very similar to ours: a 15-year-old boy who developed hypothermia, somnolence, and ataxic gait. However, in this case, the brain MRI revealed increased signal intensity in the splenium of the corpus callosum, which is in contrast to our normal MRI findings, although the EEG was very J. Seneschal A. Taieb Department of Dermatology and Pediatric Dermatology, Saint Andre and Pellegrin Hospitals, Bordeaux University Hospitals, 1 Rue Jean Burguet, 33000 Bordeaux, France e-mail: julien.seneschal@free.fr

Severe neonatal non‐dystrophic myotonia secondary to a novel mutation of the voltage‐gated sodium channel (SCN4A) gene

We report on a patient with a severe, rare neonatal form of non-dystrophic myotonia. The patient presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness leading to severe hypoxia and loss of consciousness. Muscle biopsy was non-specific and electromyography revealed intense generalized myotonia. The myotonic episodes improved after introducing oral mexiletine and maintaining room temperature at 28 degrees C. The patient died at 20 months of age following a bronchopulmonary infection. A previously undescribed de novo heterozygous c.3891C > A change, which predicts p.N1297K in the SCN4A gene. Mutations within the voltage-gated sodium channel alpha-subunit gene (SCN4A) have been described in association with several phenotypes including paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis, and potassium-aggravated myotonias. The cold-sensitive episodes of stiffness followed by weakness suggested the diagnosis of channelopathy in our patient. However, her neonatal onset, the triggering of severe episodes by exposure to modest decreases in temperature, involvement of respiratory muscles with prolonged apnea, early-onset muscle hypertrophy, psychomotor retardation, and fatal outcome are evocative of a distinct clinical subtype. Our observation expands the phenotypic spectrum of sodium channelopathies.

Continuous intravenous lidocaine controls abdominal pain secondary to peritoneal carcinomatosis as a consequence of diffusion into ascites

9031 Background: Our team reported at the 42nd ASCO meeting that continuous, low-dose intravenous (IV) lidocaine is an effective method for pain relief in terminal patients with peritoneal carcinomatosis. Our aim was to explore the mechanism by which abdominal pain of terminally-ill patients with peritoneal carcinomatosis was improved by continuous IV lidocaine. Methods: 48 patients with peritoneal carcinomatosis due to GI (46) and GYN (2) malignancies were administered lidocaine at low-doses (0.4 and/or 0.8mg/kg- h) for &gt;24 hours, because opiates, NSAIDs, and other adjuvants were ineffective in relieving their abdominal pain. Pain (faces rating scale; 0-no pain, 5-worst pain), oral intake, side effects, and activities of daily life were quantified. Two days after beginning lidocaine, ascites was sampled to measure ascitic concentration of lidocaine, tumor markers and cytology. Results: Mean age (±SE) was 60±2. The volume of ascites was estimated to be 2,700±400ml by the ultrasound 5 points methodology. Abdominal symptoms improved in 1.5±0.2days after beginning lidocaine, and the pain scale decreased from 1.9±0.2 to 0.5±0.1; p&lt;0.001; 75% of patients had improvement in pain of whom 78% had complete relief of pain. Oral intake increased from 18% to 49% of baseline (p&lt;0.001), and 67% in those with improvement in pain had an increased volume of oral intake. There were no obvious differences in response to 0.4 and 0.8 mg/kg-h in patients receiving both doses. Serum concentrations of lidocaine at 0.4 and 0.8 mg/kg-h were 1.7±0.2 and 3.2±0.2 μg/ml, respectively; lidocaine concentrations in the ascites were 1.2±0.2 and 2.1±0.2 μg/ml. No patient complained of pain at the time of peritoneal puncture. Side effects included bradycardia of &lt;60 beats per minutes (3 patients). The duration of lidocaine administration was 23±3 days; 43% of patients were able to be discharged home for end-of-life care, with parenteral nutrition and continuation of lidocaine administration or oral mexiletine (300–450 mg/day) for adjuvant analgesia. Conclusions: Lidocaine diffuses into ascites and almost equilibrates with serum concentrations acting as a peritoneal anesthesia which, as a result, controls abdominal pain in patients with peritoneal carcinomatosis. No significant financial relationships to disclose.

Neonatal life-threatening arrhythmia responding to lidocaine, a probable LQTS3

Intrauterine and neonatal manifestations of congenital long QT syndrome (LQTS) are associated with a high cardiac risk. We present a newborn, with antecedents of intrauterine premature ventricular contractions, showing in his surface electrocardiogram (ECG): a QTc of 0.69 ms, 2:1 atrioventricular block, autolimited episodes of ventricular tachycardia and Torsade de Pointes. Intravenous esmolol therapy was started, being only partially effective. Because of the ECG phenotype, a LQTS3 is suspected, and intravenous lidocaine was started, achieving sinus rhythm, a normal QTc and no new episodes of ventricular tachycardia. Lidocaine was substituted for oral mexiletine, and esmolol for propranolol. During the follow-up the patient has remained asymptomatic under therapy with propranolol and mexiletine.

Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats

M58373, 4-[2-(4-hydroxy-4-{[ N-(4-isopropoxyphenyl)- N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride, is a novel compound, which has an inhibitory activity on neurotoxin binding to the site 2 of voltage-gated sodium channels. In this study, we investigated the effects of M58373 on substance P release from sensory neurons in vitro and pain behaviors/responses in rats, compared with mexiletine. M58373 (1–10 μM) inhibited veratridine-induced release of substance P from dorsal root ganglion cells. In the formalin test, oral M58373 (0.3–10 mg/kg) reduced the time spent in nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58373 (1–10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses in the uninjured paw. In contrast, oral mexiletine (10–100 mg/kg) had a narrow therapeutic dose range in both models because of the adverse effects on the central nervous system. These results suggest that M58373 is a favorable prototype for novel anti-neuropathic pain agents.

Digoxin and Mexiletine Sensitivity in a Collie with the MDR1 Mutation

A 9-year-old, 29.6-kg, female spayed Collie was referred to the University of Wisconsin–Madison Veterinary Medical Teaching Hospital (VMTH) for evaluation of tachycardia. Past history included surgery for patent ductus arteriosus (PDA) at 9 months of age. The ductus remained patent after surgery, although the murmur had changed in quality. The owner elected not to pursue a second surgery or the use of thrombotic coils, and the dog remained asymptomatic until 9 years of age. An ECG was performed at the VMTH; results were consistent with paroxysmal ventricular tachycardia, with a heart rate of 180 beats/min. Lidocaine (2 mg/kg IV) was administered as a bolus to suppress the arrhythmia, and continued as a constant rate infusion at 60 mg/kg/min. Radiographs of the thorax revealed pulmonary edema and pleural effusion with cardiomegaly, aneurysmal dilatation of the descending aorta, enlarged pulmonary vessels, and a bulge of the main pulmonary artery, findings consistent with PDA and biventricular congestive heart failure. Serum biochemistry values and total T4 concentration reported by the referring veterinarian were within the reference range with the exception of total protein (4.8 g/dL, reference range 5.0–7.4 g/dL), consistent with movement of protein into the pleural and alveolar spaces. Additional medications given on the day of admission included furosemide (2.7 mg/kg) IV once, and then 1.7 mg/kg PO q8h, digoxin 0.002 mg/kg PO in the morning and 0.004 mg/kg PO in the evening, and enalapril 0.51 mg/kg PO q12h. Doppler echocardiography, performed after the arrhythmia was controlled, documented continuous flow in the pulmonary artery, moderate to severe mitral valve regurgitation with mitral valve thickening, left atrial and left ventricular dilation, and myocardial failure (fractional shortening 12%, reference range 25– 35%). Lidocaine was tapered and discontinued on the 2nd hospital day, and oral mexiletine was administered at a dosage of 5.1 mg/kg PO q8h. The dog had no interest in eating and vomited immediately after the 2nd mexiletine dose. Oral famotidine and metoclopramide were administered with the cardiac medications, and the dog was discharged on the 3rd hospital day. Seven days after the initial presentation for tachycardia, the dog re-presented to the VMTH for anorexia and abnormal mentation. The owner reported that the dog was being force-fed, and a 3-hour episode of circling had occurred at home. In addition, the dog had not reacted normally to stimuli in the home environment since beginning the medications. On physical examination, the cardiac rhythm was regular and the dog appeared dehydrated. A serum digoxin concentration was obtained 8 hours after dosing, and the dog was administered 500 mL lactated Ringer’s solution SC. The owner was advised to not administer the next dose of furosemide and to discontinue administration of digoxin. The serum digoxin concentration, reported the next day, was 4.5 ng/mL (reference range, 0.8–1.2 ng/ mL). The dog presented again to the VMTH on an emergency basis 3 days later with a history of repeated vomiting and continued anorexia. Current medications included enalapril and mexiletine at the previously prescribed dosages. Subcutaneous fluid administration was repeated, and treatment with metoclopramide and famotidine was again recommended with continuation of the enalapril (0.51 mg/kg q12h) and mexiletine (5.1 mg/kg q8h). One week later, the dog had another episode of confusion and anxiety, characterized by walking into walls, uncontrollable pacing, and attempting to crawl under furniture. The dosage of mexiletine was reduced to q12h on the basis of suspicion of mexiletine toxicosis, and further reduced by the owner to q24h administration after 2 days. The dog was re-examined 20 days after the 1st presentation. The dog had lost 3.4 kg, which was 11.5% of her initial body weight, over 20 days. The owner reported that the dog was no longer anxious or excited since decreasing administration of mexiletine to once daily, and that appetite was returning. An ECG revealed a heart rate of 120 beats/min and sinus rhythm without ventricular arrhythmias. Mexiletine neurotoxicosis was suspected on the basis of the history, and administration of the drug was discontinued. A buccal swab DNA sample was obtained to determine if the dog had a functional defect in Pglycoprotein (P-gp) on the basis of adverse reactions to digoxin and mexiletine. Swabs were submitted for MDR1 genotyping. DNA was extracted using previously published methods and used as a template for polymerase chain reaction amplification. Labeled amplicons were detected using amplified fragment length polymorphism and analyzed. Primers were designed such that they spanned the mutation area, base pairs 294–297 of the canine MDR1 gene (GenBank From the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI (Henik, Kellum); and the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA (Bentjen, Mealey).

The congenital long QT syndromes from genotype to phenotype: clinical implications

The long QT syndrome (LQTS) is a genetic disorder responsible for many sudden deaths before age 20. The identification of several LQTS genes, all encoding cardiac ion channels, has had a major impact on the management strategy for both patients and family members. Genotype-guided therapy allows more effective individually tailored therapy. Therapeutic options, including beta-blockers, left cardiac sympathetic denervation, and implantable defibrillators are discussed for patients of known and of unknown genotype. The recent identification of modifier genes which amplify the effect of an LQTS mutation may change the approach to risk stratification.