Estudo pré-clínico do potencial terapêutico do análogo de mexiletina, JME-209: impacto na inflamação pulmonar induzida por fumaça de cigarro / Preclinical study of the therapeutic potential of the mexiletine analogue, JME-209: impact on cigarette smoke-induced pulmonary inflammation

A doença pulmonar obstrutiva crônica (DPOC) é uma disfunção inflamatória que acomete os pulmões, caracterizada pela obstrução progressiva e parcialmente irreversível das vias aéreas. Atualmente, inexistem medicamentos que possam controlar satisfatoriamente os quadros inflamatório e enfisematoso dos pacientes, justificando a necessidade de descoberta de novos fármacos para o tratamento da DPOC. Nosso grupo de pesquisa sintetizou e avaliou a atividade anti-inflamatória e espasmolítica de análogos estruturais do anestésico local mexiletina, dentre os quais destacou-se o análogo não anestésico JME-209. O principal objetivo deste trabalho foi avaliar o potencial broncodilatador e anti-inflamatório do JME-209, elucidando sua viabilidade no tratamento da DPOC. Verificamos em nossos estudos, que o composto apresentou atividade anti-espasmódica otimizada, em comparação a mexiletina, confirmada por sua ação sobre o relaxamento da musculatura lisa traqueal em estudos in vitro. A atividade bronco-relaxante in vivo revelou que JME-209 apresentou tempo de ação broncodilatadora comparável ao agente farmacológico de referência clínica salmeterol

JME-209 foi também, eficiente em inibir alterações patológicas decorrentes do estímulo com LPS como a broncoconstrição, hiper-reatividade e a inflamação. O composto se destacou também, por inibir alterações fisiopatológicas decorrentes da provocação com LPS em um modelo de refratariedade a glicocorticoides, considerado de difícil tratamento. De maneira interessante, o tratamento com JME-209 reduziu o influxo de neutrófilos nas vias aéreas de camundongos submetidos ao modelo de inflamação pulmonar induzida por exposição à fumaça de cigarro em um efeito relacionado com a redução dos níveis de citocinas pró-inflamatórias no tecido pulmonar. O análogo apresentou também, importante atividade sobre o dano oxidativo, refletida pela redução dos níveis de malondialdeído no tecido pulmonar. Concluímos que JME-209 faz parte de uma família de análogos de mexiletina que combina, de fato, propriedades broncodilatadoras e anti-inflamatórias que o credenciam como legítimo candidato a controlar situações fisiopatológicas associadas a doenças pulmonares como a DPOC e outras. (AU)

A Case of Long QT Syndrome Type 3 Aggravated by Beta-Blockers and Alleviated by Mexiletine: The Role of Epinephrine Provocation Test

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.

Effect of Neurosteroid Modulation on Global Ischaemia-Reperfusion-Induced Cerebral Injury in Mice

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.

Interactions of rosiglitazone and anti-arrhythmic drugs in animal model

Background: Diabetes increases the risk of vascular problems by two times compared with a healthy individual, with deposition of fats in blood vessel and this includes cardiovascular disease. The treatment regimens for patients suffering from both diseases generally include prolonged use of anti-diabetic drugs for diabetes and anti-arrhythmic drugs for cardiac arrhythmias.Aim:The aim of the study is to compare the influence of Mexiletine and Disopyramide on the pharmacodynamics (PDs) of Rosiglitazone in normal and diabetic rats.Materials and Methods:The study was conducted in normal rats and diabetic induced rats (with Alloxan monohydrate 100 mg/kg body weight). Albino rats weighing between 160 and 280 g were administered oral doses of Rosiglitazone 0.72 mg/kg, Mexiletine 36 mg/kg, or Disopyramide 18 mg/kg of bodyweight and their combination, with 1 week of washout between treatments. Eighteen rats were divided into three sub-sets with six rats in each sub-set. After 4 days, the blood glucose was estimated to confirm the diabetes. The Analysis of Covariance (ANCOVA) using MedCalc® software Version 11.6.1.0 was performed to analyze mean change in blood glucose between treatments with body weight as co-variable and treatment as factor for normal and diabetic rats.Results:No statistically significant difference in mean change in blood glucose between Rosiglitazone in comparison with Rosiglitazone + Mexiletine or Rosiglitazone + Disopyramide was observed in normal and diabetic rats (P = 0.606). The maximum mean change in blood glucose for Rosiglitazone and Rosiglitazone + Mexiletine or Rosiglitazone + Disopyramide was observed at 1 h and 8 h in normal and diabetic rats. The post hoc analysis showed baseline correction method has increased the reliability of the results (P < 0.001).Conclusion:The study concludes that PD activity of Rosiglitazone was not affected by the anti-arrhythmic drugs. This study introduced a new statistical methodology for analyzing the blood glucose endpoint

A Case of Mexiletine-induced Hypersensitivity Syndrome Presenting as Eosinophilic Pneumonia

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.

Pharmacologic Management of Chronic Pain

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.

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

Therapeutic Experience in a Patient with Complex Regional Pain Syndrome Related to Brachial Plexitis: A case report

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.

Determination of mexiletine in human blood by liquid chromatography-tandem mass spectrometry / 法医学杂志

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.

HPLC-fluorescent spectrometric determination of serum mexiletine concentration after derivatization with fluram / 药学学报

<p><b>AIM</b>To establish an HPLC-fluorescent spectrometric method for the determination of mexiletine hydrochloride in plasma after derivatization with fluram.</p><p><b>METHODS</b>Fluram 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.</p><p><b>RESULTS</b>Mexiletine 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.</p><p><b>CONCLUSION</b>This method is simple, selective and can be used for therapeutic drug monitoring (TDM) and pharmacokinetic studies of mexiletine.</p>

Clinical and Electrocardiographic Features of Patients with Congenital Long QT Syndrome

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.

Epidural Block of Bupivacaine and Mexiletine for Erythromelalgia / 대한마취과학회지

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.

Initiation of Torsades de pointes by head-up tilt test in congenital long QT syndrome patient

Long QT syndrome is a cardiac disorder of repolarization which is characterized by elctrocardiographic abnormalities including prolonged QT interval, T-wave abnormalities and polymorphic ventricular tachycardia known as Torsades de Pointes. Its clinical manifestation are recurrent syncope, seizure, and sudden death. Recently,we experienced Torsades de Pointes(TdP) by head-up tilt test in 24 year-old female patient presenting recurrent syncope and long QT interval. Beta-blocker and left cervicothoracic sympathetic ganglionectomy were not effictive, then we tried mexiletine. After mexiletine medication, the QT interval was significantly shortened and there was no more syncope.

A Case of Becker's Type Congenital Myotonia / 영남의대학술지

Congenital myotonia is a hereditary disorder of the skeletal muscle. The most characteristic features of the disease are myotonia and variable muscular hypertrophy. Molecular biologic investigations have revealed that mutations in the gene of the human skeletal muscle chloride ion channel protein are a cause of the disease. The Becker's type congenial myotonia is clinically similar to the autosomal dominantly inherited congenital myotonia (Thomsen's disease). Both disorders are characterized electrophysiologically by increased excitability of muscle fibers, reflected in clinical myotonia. In general, Becker's type congenital myotonia is more severe than Thomsen's disease in muscular hypertrophy and weakness. The authors recently experienced a 25-year-old female patient who has no family-related disease history and who has conspicuous muscular hypertrophy and the stiffness with muscles which occurred from the age of 3 or 4. Clinically she showed the authors a percussion myotonia. On electrophysiological study, exercise and repetitive stimulation of the abductor digiti quinti muscle disclosed a decline in the compound muscle action potential. Biopsy of biceps muscle revealed enlargement of muscle fibers with marked nuclear internalization. After the oral taking the Mexiletine, the patient showed a favorable turn a little with her stiffness of muscles. So we authors are reporting one case of Becker's type congenital myotonia with review of literatures.

Uso de antiarrítmicos na presença de disfunçäo vantricular esquerda / Antiarrhythmic drugs in patients with left ventricular dysfunction

Com o aumento da sobrevida da populaçäo nos últimos anos e com a melhoria no tratamento do infarto agudo do miocárdio, maior número de pacientes apresenta-se na clínica com maior chance de apresentar arritmias cardíacas de gravidade variável.Muitos desses pacientes necessitam tratamento anti-arrítmico, que, na maioria dos centros, ainda é baseado na administraçäo de medicamentos.Os pacientes sobreviventes de morte súbita cardíaca, ou com miocardiopatia dilatada de origem isquêmica ou idiopática, apresentam graus variáveis de disfunçäo ventricular.Quanto mais comprometida a fraçäo de ejeçäo, pior o grau funcional desses pacientes e maiores riscos de arritmias potencialmente letais, ameaçadoras à vida.Do ponto de vista anatomopatológico, a disfunçäo ventricular caracteriza-se por células isquêmica, entremeadas por células saudáveis e áreas de necrose.É justamente nesse substrato que as arritmias se origianm e é exatamente sobre esta regiäo que os fármaco antiarrítmicos exercem seus efeitos eletrofisiológicos.Há vários estudos demonstrando que quando pior o estado da funçäo ventricular, menor a eficácia desses medicamentos.Em outras palavras, exatamente os pacientes com arritmia mais grave, que mais necessitam do efeito antiarrítmico desses agentes, säo os que menos se beneficiam.A Maioria dos medicamentos disponíveis para o tratamento da arritmias cardíacas exerce algum efeito depressor da funçäo ventricular.Quanto maior esse efeito depressor da funçäo ventricular é mais acentuada nos pacientes com piores graus funcionais e, por essa razäo, devem ser prescritos com cautela nessa populaçäo...

Fármaco antiarrítmicos / Anti-arrhythimia agents

O diagnóstico correto do tipo de arritmia cardíaca é a primeira etapa na avaliação do paciente. A necessidade da terapêutica antiarrítmica deve ser cuidadosamente avaliada para, em seguida, decidir se a abordagem será farmacológica ou não. A escolha do fármaco antiarrítmico deve ser individualizada, considerando-se a farmacocinética e as interaçöes medicamentosas. A identificação e correção de condiçöes associadas (isquemia miocárdica, disfunção ventricular, distúrbios eletrolíticos) e a avalização periódica da função dos órgãos responsáveis pela metabolização e excreção das drogas são fundamentais para minimizar os efeitos pró-arrítmicos.

Tachycardia Induced Cariomyopathy in Childhood

PURPOSE: Dilated cardiomyopathy in children is usually progressive and leads to death in several years. Chronic tachyarrhythmia has been shown to cause dilated cardiomyopathy in human and animals and this ventricular dysfuntion is usually reversible after control of the arrhythmia. The uncontrolled chronic tachycardia may be a curable cause of dilated cardiomyopathy in some patients. We describe six children who had persistent chronic tachycardia and ventricular dysfunction that improve significantly after control of the arrhythmia. METHODS: We retrosepctively reveiwed the medical records, electrocardiograms, Holter recordings, Echcardiographic reports of 6 children with the tachycardia induced ventricular dysfunction who have been managed at Sejong general hospital and Asan medical center from January 1992 to June 1995. RESULTS: 1) The causes of referral were dilated cardiomyopathy in 2 and tachyarrhythmia in 4. The age at diagnosis was 4 to 36 months old and follow-up period was 6 to 29 months. The symptoms of congestive heart failure were seen in 3 children. 2) The mechanisms of thachyarrhythmia causing cardiomyopathy were atrial ectopic tachycardia in 2, chaotic atrial rhythm in 3 and junctional ectopic tachycardia in 1. Atrial ectopic tachycardia has improved after combined treatment with amidarone and atenonl. One case of chaotic atrial rhythm has improved spontaneously and other 2 cases of chaotic arial rthythm have improved after treatment with digoxin or after combined therapy with amidarone and digoxin. Junctional ectopic tachycardia is partially controlled with mexiletine. 3) The shortening fractions of left ventricle at diagnosis were 14-21% and improved to over 30% in all after 2 to 9 months of follow-up. CONCLUSIONS: We have shown that control of persistent tachycardia resolved the left ventricular dysfunction. We suggest that patients with dilated cardiomyopathy be carefully screened for tachyarrhythmia as a curable cause of ventricular dysfunction and that left ventricular function be assessed in the asymptomatic patients with persistent tachycardia.

Tachycardia Induced Cariomyopathy in Childhood

PURPOSE: Dilated cardiomyopathy in children is usually progressive and leads to death in several years. Chronic tachyarrhythmia has been shown to cause dilated cardiomyopathy in human and animals and this ventricular dysfuntion is usually reversible after control of the arrhythmia. The uncontrolled chronic tachycardia may be a curable cause of dilated cardiomyopathy in some patients. We describe six children who had persistent chronic tachycardia and ventricular dysfunction that improve significantly after control of the arrhythmia. METHODS: We retrosepctively reveiwed the medical records, electrocardiograms, Holter recordings, Echcardiographic reports of 6 children with the tachycardia induced ventricular dysfunction who have been managed at Sejong general hospital and Asan medical center from January 1992 to June 1995. RESULTS: 1) The causes of referral were dilated cardiomyopathy in 2 and tachyarrhythmia in 4. The age at diagnosis was 4 to 36 months old and follow-up period was 6 to 29 months. The symptoms of congestive heart failure were seen in 3 children. 2) The mechanisms of thachyarrhythmia causing cardiomyopathy were atrial ectopic tachycardia in 2, chaotic atrial rhythm in 3 and junctional ectopic tachycardia in 1. Atrial ectopic tachycardia has improved after combined treatment with amidarone and atenonl. One case of chaotic atrial rhythm has improved spontaneously and other 2 cases of chaotic arial rthythm have improved after treatment with digoxin or after combined therapy with amidarone and digoxin. Junctional ectopic tachycardia is partially controlled with mexiletine. 3) The shortening fractions of left ventricle at diagnosis were 14-21% and improved to over 30% in all after 2 to 9 months of follow-up. CONCLUSIONS: We have shown that control of persistent tachycardia resolved the left ventricular dysfunction. We suggest that patients with dilated cardiomyopathy be carefully screened for tachyarrhythmia as a curable cause of ventricular dysfunction and that left ventricular function be assessed in the asymptomatic patients with persistent tachycardia.

Arritmias por Reperfusion Coronaria: Mecanismos Fisiopatologicos y Estudio Farmacologico / Coronary reperfusion arrhythmias: Physiopathologic mechanisms and pharmacological study

Las arritmias que aparecen despues de la recirculacion sanguinea de una arteria coronaria previamente obstruida, han sido objeto de estudio de multiples investigadores desde finales de la decada de los 70 hasta nuestros dias, debido a la posibilidad de que estos tipos de trastornos del ritmo cardiaco pueden llevar a la muerte a pacientes en los que se libera un espasmo coronario o se produce la lisis de un trombo coronario. Con el presente trabajo tuvimos la oportunidad de profundizar en el conocimiento fisiopatologico de estas arritmias ventriculares, para ello utilizamos un modelo experimental animal de probada eficacia en este tipo de estudio. En el empleamos tres antiarritmicos clase I: prajmalina, lidocaina y mexiletine con el objetivo de conocer y analizar los efectos de estas drogas sobre la tension arterial, la frecuencia cardiaca y la incidencia de las arritmias por reperfusion coronaria. Nuestra investigacion arrojo una disminucion notable del por ciento de incidencia de arritmias en el grupo de animales tratados con mexiletine a diferencia de los resultados obtenidos con el resto de las series. Tambien en todos los grupos experimentales se registraron hipotension y bradicardia significativas al ser comparadas con su control: se emplearon para este analisis estadistico la "t" de Student para muestras pareadas (p < 0,05)