Clinical evaluation of oral mexiletine therapy in the treatment of ventricular arrhythmias

Rutledge, John C.; Harris, Fred J.; Amsterdam, Ezra A.

doi:10.1016/s0735-1097(85)80482-4

Cited by 16 publications

(11 citation statements)

References 18 publications

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“…Our study is concordant with previous studies showing that treatment with mexiletine is safe and sufficiently tolerated [8][9][10][11]. The percentage of patients with mexiletine intolerance was low (18%).…”

Section: Discussionsupporting

confidence: 92%

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Efficacy and tolerability of mexiletine treatment in patients with recurrent ventricular tachyarrhythmias and implantable cardioverter-defibrillator shocks

Sobiech¹,

Lewandowski²,

Zając³

et al. 2017

Kardiol Pol

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A b s t r a c tBackground: Antiarrhythmic treatment of patients with recurrent ventricular tachyarrhythmia, in whom catheter ablation and amiodarone treatment were ineffective or contraindicated, is an unsolved clinical problem. Aim:The study aims to evaluate the efficacy and tolerability of mexiletine in patients with recurrent ventricular tachyarrhythmias and/or electrical storm events, in whom standard treatment strategies failed to prevent ventricular tachyarrhythmia. Methods:We performed a retrospective cohort analysis of all patients treated with mexiletine for recurrent ventricular tachycardia and/or ventricular fibrillation in our institution between January 2011 and September 2015. The primary endpoints were total number of electrical storm events and ventricular tachycardia/ventricular fibrillation (VT/VF) episodes after the beginning of mexiletine therapy. Secondary endpoints were total number of implantable cardioverter-defibrillator (ICD) therapies and discontinuation of the therapy. Events were compared with a matched duration period before initiating mexiletine. Patients served as self-controls.Results: Seventeen patients were included in the study; 11 patients were males. Mean age was 64.2 ± 15.4 years. The median time of mexiletine treatment was eight months (interquartile range [IR]: 1-22 months). The mexiletine dose was 600 mg/day in 13 patients and 400 mg/day in four patients. In four patients the dose was modified during treatment in a range from 400 to 600 mg/day depending on clinical decision. Treatment with mexiletine significantly reduced the number of electrical storm events (14 episodes Conclusions:Mexiletine was a sufficiently tolerated antiarrhythmic drug in short-term treatment of ventricular tachyarrhythmias in the studied population. Mexiletine may be effective in the treatment of recurring ventricular tachyarrhythmias or electrical storm events.

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Section: Discussionsupporting

confidence: 92%

“…Mexiletine successfully reduced the number of premature ventricular contractions as well as VT, without compromising ejection fraction of left ventricle in some studies [9,10]. Despite these findings caution should be taken during mexiletine treatment in patients with decreased ejection fraction, and this requires further studies.…”

Section: Discussionmentioning

confidence: 97%

Efficacy and tolerability of mexiletine treatment in patients with recurrent ventricular tachyarrhythmias and implantable cardioverter-defibrillator shocks

Sobiech¹,

Lewandowski²,

Zając³

et al. 2017

Kardiol Pol

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“…Experimental design and protocol. Mexiletine was evaluated at up to 5 μM on the expectation based on clinical reports that adverse effects on contractile function would require a higher concentration than that evoking adverse effects on the ECG 38 . Each group was compared with a vehicle control group (all n = 9).…”

Section: Supplementary Studies Assessing Left Ventricular Contractilementioning

confidence: 99%

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

Hesketh

Wilder

Ranadive

et al. 2020

Sci Rep

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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. Coronary heart disease and acute myocardial infarction (AMI) constitute the largest cause of death worldwide 1 with sudden cardiac death (SCD) responsible for approximately 50% of lethality 2,3. Most SCD is due to ischaemia-induced arrhythmias, particularly ventricular fibrillation (VF) and ventricular tachycardia 4. Currently available antiarrhythmic drugs have failed against SCD 5. The reason for this is that the benefit afforded by those drugs found to suppress SCD is offset by adverse drug reactions (ADRs); in some trials, mortality was actually increased 6-8 while in other trials attempts to minimise ADR risk by use of lower drug doses resulted in loss of effectiveness 9,10. Presently the class 1b antiarrhythmic, mexiletine, and the non-selective class III drug, amiodarone 11 , are the only antiarrhythmics prescribed for SCD outside the hospital setting, but even these drugs are not considered sufficiently efficacious for use in the larger lower-risk populations 5,12 leaving a huge and longstanding unmet therapeutic need 4. Since amiodarone is an anomalous example of a class (III) that is otherwise discounted as a solution to SCD owing to proarrhythmia 5,12 , this leaves only class 1b agents as an avenue for new drug development. An essential part of the process of any new drug development is to mitigate against ADRs during the nonclinical phase. In view of this, we and oth...

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“…68 Using ambulatory monitoring Duff obtained an overall success rate of 48% (10/21) in patients with recurrent ventricular tachycardia unresponsive to conventional antianhythmic agents. 30 Seventeen patients in whom either mexiletine was ineffective alone in controlling ventricular tachycardia (10 patients) or in whom intolerable side effects developed despite control (7 patients) were reassessed with combination therapy consisting of a Class 74 Poole er aL7' Nademanee et al 76 Reiter et al 77 Moak et al 79 Hession I A agent and mexiletine. Effective control was obtained in 16 of 17 patients assessed by noninvasive monitoring techniques (94%).…”

Section: Factors Affecting Drug Efficacymentioning

confidence: 99%

“…Rutledge et al demonstrated long-term efficacy and tolerance with mexiletine in the treatment of ventricular arrhythmias in 25 % of 58 patients with cardiac disease of diverse etiologies, in whom prior conventional drugs had been unsuccessful. 74 Poole et al treated with mexiletine 5 1 patients (25 with ventricular fibrillation, 1 1 with sustained ventricular tachycardia, and 15 with nonsustained ventricular tachycardia) over 10f 16 months.7s Ischemic heart disease was present in 33 patients (66%). Arrhythmias recurred in 21 patients (41%).…”

Section: Factors Affecting Drug Efficacymentioning

confidence: 99%

Mexiletine: Pharmacology and therapeutic use

Manolis

Deering

Cameron

et al. 1990

Clinical Cardiology

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Summary:Mexiletine is a Class IB antianhythmic which has basic and clinical electrophysiologic properties similar to lidocaine. Like other Class I antiarrhythmic agents, mexiletine blocks the rapid inward sodium current responsible for phase 0 of the action potential. It has been noted in the clinical electrophysiology laboratory to have minimal effect on sinus node function and AV nodal and His-Purkinje system conduction. Pharmacokinetic studies have shown that oral absorption is rapid with bioavailability of 80-90%. Mexiletine is predominantly metabolized by the liver with elimination half-life of 9 to 12 hours.The antiarrhythmic effects of the primary drug's metabolites remain to be defined. Hernodynamic studies have shown mexiletine to have a lesser negative inotropic effect than procainamide or disopyramide. Although mexiletine as a single agent successfully suppresses 60 to 80% of spontaneous ventricular arrhythmias, it has lower efficacy in suppression of induced ventricular arrhythmias. Multiple studies have shown that as monotherapy mexiletine is effective in preventing the induction of ventricular tachycardia in approximately 20% of patients. When used in combination with a Class IA antiarrhythmic drug for suppression of induced ventricular arrhythmias, multiple investigators have reported greater efficacy. Neurological side effects (tremor, dizziness, memory loss) occur in approximately 10% of patients while gastrointestinal side effects (nausea, anorexia, gastric irritation) occur in up to 40% of patients. Proarrhythmia or other serious toxicity from the drug is uncommon.

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Clinical evaluation of oral mexiletine therapy in the treatment of ventricular arrhythmias

Cited by 16 publications

References 18 publications

Efficacy and tolerability of mexiletine treatment in patients with recurrent ventricular tachyarrhythmias and implantable cardioverter-defibrillator shocks

Efficacy and tolerability of mexiletine treatment in patients with recurrent ventricular tachyarrhythmias and implantable cardioverter-defibrillator shocks

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

Mexiletine: Pharmacology and therapeutic use

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