Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with I_KATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD₉₀-Epi, MAPD₉₀-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD₉₀-Epi, MAPD₉₀-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ²=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ²=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.
Rabbits ; Animals ; Quinidine/therapeutic use* ; Mexiletine/therapeutic use* ; Pinacidil/therapeutic use* ; Sodium ; Ranolazine/therapeutic use* ; Electrophysiologic Techniques, Cardiac ; Arrhythmias, Cardiac/drug therapy*

Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be beta-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during beta-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation.
Adolescent ; Adrenergic beta-Antagonists/*adverse effects/therapeutic use ; Defibrillators, Implantable ; Diagnosis, Differential ; Diagnostic Techniques, Cardiovascular ; Epinephrine/*diagnostic use ; Female ; Humans ; Long QT Syndrome/classification/*diagnosis/genetics/therapy ; Mexiletine/*therapeutic use ; Pedigree ; *Syncope

The present study was designed to investigate the putative effect of neurosteroid modulation on global ischaemia-reperfusion-induced cerebral injury in mice. Bilateral carotid artery occlusion followed by reperfusion, produced a significant rise in cerebral infarct size along with impairment of grip strength and motor coordination in Swiss albino mice. Administration of carbamazepine (16 mg/kg, i.p.) before global cerebral ischaemia significantly attenuated cerebral infarct size and improved the motor performance. However, administration of indomethacin (100 mg/kg, i.p.) attenuated the neuroprotective effect of carbamazepine. Mexiletine (50 mg/kg, i.p.) did not produce significant neuroprotective effect. It may be concluded that the neuroprotective effect of carbamazepine may be due to increase in synthesis of neurosteroids perhaps by activating enzyme (3alpha HSD) as indomethacin attenuated the neuroprotective effect of carbamazepine. The sodium channel blocking effect of carbamazepine may not be involved in neuroprotection as mexiletine, a sodium channel blocker, did not produce significant neuroprotective effect.
Animals ; Carbamazepine ; Carotid Arteries ; Hand Strength ; Indomethacin ; Mexiletine ; Mice* ; Neuroprotective Agents ; Neurotransmitter Agents ; Reperfusion ; Sodium Channels

An 82-yr-old man was presented with fever and cough accompanied by generalized erythematous rash. He had taken mexiletine for 5 months, as he had been diagnosed with dilated cardiomyopathy and ventricular arrhythmia. Laboratory studies showed peripheral blood eosinophilia and elevated liver transaminase levels. Chest radiographs showed multiple nodular consolidations in both lungs. Biopsies of the lung and skin lesions revealed eosinophilic infiltration. After a thorough review of his medication history, mexiletine was suspected as the etiologic agent. After discontinuing the mexiletine and starting oral prednisolone, the patient improved, and the skin and lung lesions disappeared. Subsequently, mexiletine was confirmed as the causative agent based on a positive patch test. Drug-induced hypersensitivity syndrome is a severe adverse reaction to drugs and results from treatment with anticonvulsants, allopurinol, sulfonamides, and many other drugs. Several cases of mexiletine-induced hypersensitivity syndrome have been reported in older Japanese males with manifestation of fever, rash, peripheral blood eosinophilia, liver dysfunction without other organ involvement. Here, we report a case of mexiletine-induced hypersensitivity syndrome which presented as eosinophilic pneumonia in a Korean male.
Aged, 80 and over ; Anti-Arrhythmia Agents/*adverse effects ; Arrhythmias, Cardiac/drug therapy ; Cardiomyopathy, Dilated/drug therapy ; Drug Hypersensitivity/*diagnosis/etiology ; Exanthema/pathology ; Humans ; Lung/pathology/radiography ; Male ; Mexiletine/*adverse effects ; Pulmonary Eosinophilia/*chemically induced/*diagnosis ; Syndrome ; Tomography, X-Ray Computed

Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel alpha2-delta ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment.
Analgesics, Opioid ; Antidepressive Agents ; Calcium Channels ; Capsaicin ; Chronic Pain ; Fibromyalgia ; Lidocaine ; Ligands ; Mexiletine ; N-Methylaspartate ; Neuralgia ; Neuromuscular Agents ; Norepinephrine ; Pain Management ; Serotonin ; Sleep Deprivation ; Tramadol

We report our therapeutic experience in a patient with complex regional pain syndrome (CRPS) related to brachial plexitis. A 16-year-old female suffered from excruciating burning pain and allodynia abruptly developed on left shoulder. Cervical MRI was normal. Electrodiagnostic findings were compatible with acute brachial plexopathy. Hand swelling, dystrophic color change, desquamation, and anhidrosis were displayed. Three-phase bone scan revealed increased radio-uptake on left upper extremity. The course of the disease was slowly progressive with wax and wane pattern. Pain became gradually intractable to all therapeutic modalities and medications. She gradually improved with long-term multimodal pain management. After 2 years of disease-free period, CRPS recurred and the extent was more severe than the first attack. We tried oral mexiletine, risedronate, high dose multi-vitamin, and leukotriene modulator which were effective in reducing pain and allodynia. Hand swelling gradually subsided and functional regain was obtained.
Adolescent ; Brachial Plexus Neuritis ; Brachial Plexus Neuropathies ; Burns ; Female ; Hand ; Humans ; Hyperalgesia ; Hypohidrosis ; Magnetic Resonance Imaging ; Mexiletine ; Pain Management ; Rehabilitation ; Risedronate Sodium ; Shoulder ; Upper Extremity

OBJECTIVE: To establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detection of mexiletine by liquid chromatography tandem mass spectrometry. METHODS: After simple protein precipitation of the blood sample with acetonitrile, the organic solvent layer diluted with LC mobile solvent was separated by Allure PFP Propyl column, confirmed and quantified by MS/MS in the multi-reaction monitoring (MRM) mode via positive electrospray ionization. RESULTS: Mexiletine and naloxone (internal standard) got ideal resolution under the selected analytical condition. The correlation coeficient of linear calibration curve was over 0.9999 within the mexiletine concentration range 0.02-10 microg/mL. The relative standard deviations were under 10% for intra-day and under 15% for inter-day, and the detection limit was 0.01 microg/mL. CONCLUSION The established LC-MS/MS method is simple, rapid, sensitive, unaffected by matrix effect and appropriate for detection of mexiletine in blood in the field of therapeutic drug monitoring and forensic toxicology.
Anti-Arrhythmia Agents/chemistry* ; Forensic Medicine ; Humans ; Mexiletine/poisoning* ; Molecular Structure ; Naloxone/chemistry* ; Reproducibility of Results ; Sensitivity and Specificity ; Spectrometry, Mass, Electrospray Ionization/methods* ; Tandem Mass Spectrometry/methods*

AIMTo establish an HPLC-fluorescent spectrometric method for the determination of mexiletine hydrochloride in plasma after derivatization with fluram.

METHODSFluram acetone solution was added to the deproteinized plasma with acetone to obtain the derivative of mexiletine. The HPLC method was performed on a column of Allitima C18 (150 mm x 4.6 mm, 5 microns) with the mobile phase of methanol-water-diethylamine-phosphoric acid buffer (2.4 mol.L-1, pH 4.0) (70:28:2), and the detective wavelength were set at Ex 392 nm and Em 480 nm.

RESULTSMexiletine has a liner range over the concentration range from 0.100-6.400 mg.L-1. The lowest detectable concentration of this method was 5 micrograms.L-1 (S/N > or = 4). The intra-day and inter-day RSDs were 1.34%-5.31%, respectively.

CONCLUSIONThis method is simple, selective and can be used for therapeutic drug monitoring (TDM) and pharmacokinetic studies of mexiletine.

Anti-Arrhythmia Agents ; blood ; pharmacokinetics ; Chromatography, High Pressure Liquid ; methods ; Fluorescamine ; chemistry ; Humans ; Mexiletine ; blood ; pharmacokinetics

BACKGROUND AND OBJECTIVES: Congenital long QT syndrome (LQTS) is characterized by the prolongation of the QT interval, frequent episodes of syncope and Torsades de Pointes (TdP). The clinical features and electrocardiographic findings in Korean patients with LQTS have not been reported. SUBJECTS AND METHODS: We retrospectively analyzed the clinical characteristics, ECG features and response to treatments in 11 patients (6 men, 5 women) with congenital LQTS. RESULTS: The mean age at the time of the first episode was 19.4+/-22.6 years old (range: 170 years). Clinical presentations were syncope, seizure or sudden cardiac death (SCD). Predisposing factors included exercise, sudden startle or sleep. Only three patients showed familial histories of syncope or SCD. The average QTc interval was 0.58+/-0.05 second (range: 0.47-0.61 seconds). T wave morphologies were classified as normal-appearing, broad-based, low amplitude/bifid or late onset. For its management, bblockers were used in 7 patients. In 2 patients, whose clinical events were related with to an increased vagal tone or were aggravated by bblocker therapy, mexiletine was prescribed. When bradycardia or AV block was documented, pacemakers were implanted. For 2 patients at high risk of sudden cardiac death, cardioverter-defibrillators were implanted. During a mean follow up period of 23.5+/-20.2 months (range: 364 months), symptoms (cardiac arrest) recurred in 1 patient. CONCLUSION: Congenital LQTS is a heterogeneous disease, showing diverse clinical manifestations, ECG features, and response to pharmacological management. Further research on the genotype-phenotype relationship will refine the management, enabling gene-specific treatment of this life-threatening disease.
Arrhythmias, Cardiac ; Atrioventricular Block ; Bradycardia ; Causality ; Death, Sudden ; Death, Sudden, Cardiac ; Electrocardiography* ; Follow-Up Studies ; Humans ; Long QT Syndrome* ; Male ; Mexiletine ; Retrospective Studies ; Seizures ; Syncope ; Torsades de Pointes

Erythromelalgia is a rare disease characterized by palmar and plantar erythema, burning pain and local increase in temperature. Secondary erythromelalgia most commonly appears secondary to myeloproliferative disorders, essential thrombocytosis and polycythemia vera. The pain associated with erythromelalgia is often severe and recalcitrant. So far no properly performed therapeutic trials have been published. We present a case of erythromelalgia of both hands and feet in a 52 year old man. A twice daily cervical and lumbar epidural block of mepivacaine 0.5% and mexiletine 100 mg given orally resuletd in complete resolution of the syndrome. After 3 months, the symptom recurred mildly.
Bupivacaine* ; Burns ; Erythema ; Erythromelalgia* ; Foot ; Hand ; Humans ; Mepivacaine ; Mexiletine* ; Middle Aged ; Myeloproliferative Disorders ; Polycythemia Vera ; Rare Diseases ; Thrombocytosis