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Pesquisa : D02.092.831.500 [Categoria DeCS]
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[PMID]:29241232
[Au] Autor:Nates JL; Cattano D; Costa FS; Chelly JE; Doursout MF
[Ad] Endereço:Department of Critical Care Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 112, Houston, TX 77030, USA, jlnates@mdanderson.org.
[Ti] Título:Thromboelastographic assessment of the impact of mexiletine on coagulation abnormalities induced by air or normal saline intravenous injections in conscious rats.
[So] Source:Diving Hyperb Med;47(4):228-232, 2017 Dec.
[Is] ISSN:1833-3516
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Thromboelastography (TEG) in venous air embolism (VAE) has been poorly studied. We induced coagulation abnormalities by VAE in a rat model, assessed by TEG with and without mexiletine, a lidocaine analogue local anesthetic. METHODS: Twenty-three Sprague Dawley rats instrumented under isoflurane anesthesia and allowed to recover five days prior to the experiments were randomized into three experimental groups: 1) VAE (n = 6); 2) VAE and mexiletine (n = 9); and 3) normal saline (NS) alone (control group, n = 8). Blood samples were collected at baseline, one hour (h) and 24 h in all groups and analyzed by TEG to record the R, K, angle α and MA parameters. RESULTS: In Group 1, VAE decreased significantly R at 1 h (31%), K at 1 h (59%) and 24 h (34%); α increased significantly at 1 h (30%) and 24 h (22%). While R returned to baseline values within 24 h, K, MA and α did not. In group-2 (Mexiletine + VAE), K and R decreased at 1 h (48% and 29%, respectively) and at 24 h the changes were non-significant. Angle α increased at 1 h (28%) and remained increased for 24 h (25%). In group 3 (NS), only R was temporarily affected. MA increased significantly at 24 h only in the VAE alone group. CONCLUSION: As expected, VAE produced a consistent and significant hypercoagulable response diagnosed/confirmed by TEG. Mexiletine prevented the MA elevation seen with VAE and corrected R and K time at 24 h, whereas angle α remained unchanged. Mexiletine seemed to attenuate the hypercoagulability associated with VAE in this experiment. These results may have potential clinical applications and deserve further investigation.
[Mh] Termos MeSH primário: Anestésicos Locais/farmacologia
Transtornos da Coagulação Sanguínea/diagnóstico
Transtornos da Coagulação Sanguínea/etiologia
Embolia Aérea/sangue
Mexiletina/farmacologia
Tromboelastografia
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Transtornos da Coagulação Sanguínea/prevenção & controle
Distribuição Aleatória
Ratos
Ratos Sprague-Dawley
Cloreto de Sódio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, Local); 1U511HHV4Z (Mexiletine); 451W47IQ8X (Sodium Chloride)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.28920/dhm47.4.228-232


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[PMID]:28673509
[Au] Autor:Gualdani R; Cavalluzzi MM; Tadini-Buoninsegni F; Lentini G
[Ad] Endereço:Dipartimento di Chimica "Ugo Schiff", Università di Firenze, via della Lastruccia 3, 50019 Sesto Fiorentino (FI), Italy. Electronic address: roberta.gualdani@uclouvain.be.
[Ti] Título:Discovery of a new mexiletine-derived agonist of the hERG K channel.
[So] Source:Biophys Chem;229:62-67, 2017 Oct.
[Is] ISSN:1873-4200
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in the rapid component (I ) of cardiac action potential repolarization phase. A large number of structurally different compounds block hERG and cause a high risk of arrhythmias. Among the drugs that block hERG channel, a few compounds have been identified as hERG channel activators. Such compounds may be useful, at least in theory, for the treatment of long term QT syndrome. Here we describe a new activator of hERG channel, named MC450. This compound is a symmetric urea, derived from (R)-mexiletine. Using patch-clamp recordings, we found that MC450 increased the activation current of hERG channel, with an EC of 41±4µM. Moreover MC450 caused a depolarizing shift in the voltage dependence of inactivation from -64.1±1.2mV (control), to -35.9±1.4mV, whereas it had no effect on the voltage dependence of activation. Furthermore, MC450 slowed current inactivation and the effect of MC450 was attenuated by the inactivation-impaired double mutant G628C/S631C.
[Mh] Termos MeSH primário: Canal de Potássio ERG1/agonistas
Canal de Potássio ERG1/metabolismo
Mexiletina/análogos & derivados
Mexiletina/química
Ureia/análogos & derivados
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Avaliação Pré-Clínica de Medicamentos
Canal de Potássio ERG1/genética
Células HEK293
Seres Humanos
Mexiletina/metabolismo
Mexiletina/farmacologia
Mutagênese Sítio-Dirigida
Técnicas de Patch-Clamp
Estereoisomerismo
Ureia/química
Ureia/metabolismo
Ureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ERG1 Potassium Channel); 0 (MC450 compound); 1U511HHV4Z (Mexiletine); 8W8T17847W (Urea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE


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[PMID]:28341360
[Au] Autor:Pokorney SD; Mi X; Hammill BG; Allen LaPointe NM; Curtis LH; Al-Khatib SM
[Ad] Endereço:Electrophysiology Section, Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina. Electronic address: sean.pokorney@duke.edu.
[Ti] Título:Use of Antiarrhythmic Medications in Medicare Part D Patients With an Implantable Cardioverter-Defibrillator and Ventricular Tachycardia.
[So] Source:Am J Cardiol;119(9):1401-1406, 2017 May 01.
[Is] ISSN:1879-1913
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ventricular tachycardia (VT) is common in cardiomyopathy patients with an implantable cardioverter-defibrillator. This analysis evaluated antiarrhythmic medication use and change in use over time in patients with VT and structural heart disease. Query of Medicare claims identified patients with an implantable cardioverter-defibrillator and VT. Patients with atrial fibrillation or supraventricular tachycardia were excluded. Two cohorts were created of patients enrolled in Medicare Part D for the 12 months before 2007 and 2012. Patients were identified through a search for antiarrhythmic medication fills with a supply covering January 1 of the cohort year. Adjusted logistic regression modeling evaluated the association between patient characteristics and antiarrhythmic medication use. The 2007 (n = 2,334) and 2012 (n = 3,892) Medicare Part D cohorts had similar demographics: median age 76 years, 64%-67% male, and 87%-89% white. Of the 2007 cohort, 1,380 (59%) patients were on a beta blocker, and 484 (20.7%) were on an antiarrhythmic medication (70% amiodarone and 20% sotalol). Between 2007 and 2012, there was a statistically significant higher use of any antiarrhythmic medication (p = 0.014), beta blockers (p <0.0001), mexiletine (p = 0.005), and ranolazine (p <0.0001), while amiodarone use remained unchanged (p = 0.53). After multivariable adjustment, male gender and renal disease were associated with higher antiarrhythmic medication use. In conclusion, although antiarrhythmic medication and beta blocker use in patients with VT increased over time, <1 in 4 patients were on an antiarrhythmic medication and only 65% of the patients were on a beta blocker.
[Mh] Termos MeSH primário: Antiarrítmicos/uso terapêutico
Morte Súbita Cardíaca/prevenção & controle
Taquicardia Ventricular/terapia
[Mh] Termos MeSH secundário: Antagonistas Adrenérgicos beta/uso terapêutico
Idoso
Idoso de 80 Anos ou mais
Amiodarona/uso terapêutico
Bases de Dados Factuais
Desfibriladores Implantáveis
Cardioversão Elétrica
Feminino
Seres Humanos
Modelos Logísticos
Masculino
Medicare Part D
Mexiletina/uso terapêutico
Ranolazina/uso terapêutico
Bloqueadores dos Canais de Sódio/uso terapêutico
Sotalol/uso terapêutico
Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-Antagonists); 0 (Anti-Arrhythmia Agents); 0 (Sodium Channel Blockers); 1U511HHV4Z (Mexiletine); A6D97U294I (Sotalol); A6IEZ5M406 (Ranolazine); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170425
[Lr] Data última revisão:
170425
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170326
[St] Status:MEDLINE


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[PMID]:27743929
[Au] Autor:De Bellis M; Carbonara R; Roussel J; Farinato A; Massari A; Pierno S; Muraglia M; Corbo F; Franchini C; Carratù MR; De Luca A; Conte Camerino D; Desaphy JF
[Ad] Endereço:Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, 70125, Bari, Italy.
[Ti] Título:Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.
[So] Source:Neuropharmacology;113(Pt A):206-216, 2017 Feb.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.
[Mh] Termos MeSH primário: Miotonia/prevenção & controle
Canal de Sódio Disparado por Voltagem NAV1.4/fisiologia
Tocainide/farmacologia
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Canais de Potássio Éter-A-Go-Go/fisiologia
Seres Humanos
Masculino
Mexiletina/farmacologia
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/fisiologia
Miotonia/fisiopatologia
Ratos
Ratos Wistar
Reflexo de Endireitamento/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
Tocainide/efeitos adversos
Tocainide/análogos & derivados
Tocainide/uso terapêutico
Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ether-A-Go-Go Potassium Channels); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human); 0 (Voltage-Gated Sodium Channel Blockers); 1U511HHV4Z (Mexiletine); 27DXO59SAN (Tocainide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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Registro de Ensaios Clínicos
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[PMID]:28036334
[Au] Autor:Vicente J; Johannesen L; Hosseini M; Mason JW; Sager PT; Pueyo E; Strauss DG
[Ad] Endereço:Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
[Ti] Título:Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.
[So] Source:PLoS One;11(12):e0163619, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. METHODS AND RESULTS: In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). CONCLUSIONS: Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block. TRIAL REGISTRATION: NCT02308748 and NCT01873950.
[Mh] Termos MeSH primário: Biomarcadores/metabolismo
Coração/efeitos dos fármacos
Bloqueadores dos Canais de Sódio/farmacologia
Sódio/metabolismo
[Mh] Termos MeSH secundário: Adulto
Bloqueadores dos Canais de Cálcio/farmacologia
Estudos Cross-Over
Eletrocardiografia/métodos
Canais de Potássio Éter-A-Go-Go/metabolismo
Feminino
Frequência Cardíaca/efeitos dos fármacos
Seres Humanos
Lidocaína/farmacologia
Síndrome do QT Longo/metabolismo
Masculino
Mexiletina/farmacologia
Fenetilaminas/farmacologia
Bloqueadores dos Canais de Potássio/farmacologia
Sulfonamidas/farmacologia
Torsades de Pointes/metabolismo
Verapamil/farmacologia
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Biomarkers); 0 (Calcium Channel Blockers); 0 (Ether-A-Go-Go Potassium Channels); 0 (Phenethylamines); 0 (Potassium Channel Blockers); 0 (Sodium Channel Blockers); 0 (Sulfonamides); 1U511HHV4Z (Mexiletine); 98PI200987 (Lidocaine); 9NEZ333N27 (Sodium); CJ0O37KU29 (Verapamil); R4Z9X1N2ND (dofetilide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161231
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0163619


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[PMID]:27367642
[Au] Autor:Pal K; Gangopadhyay G
[Ad] Endereço:a Chemical Biological and Macromolecular Sciences, S.N. Bose National Center for Basic Sciences , Kolkata , India.
[Ti] Título:Dynamical characterization of inactivation path in voltage-gated Na(+) ion channel by non-equilibrium response spectroscopy.
[So] Source:Channels (Austin);10(6):478-97, 2016 Nov.
[Is] ISSN:1933-6969
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inactivation path of voltage gated sodium channel has been studied here under various voltage protocols as it is the main governing factor for the periodic occurrence and shape of the action potential. These voltage protocols actually serve as non-equilibrium response spectroscopic tools to study the ion channel in non-equilibrium environment. In contrast to a lot of effort in finding the crystal structure based molecular mechanism of closed-state(CSI) and open-state inactivation(OSI); here our approach is to understand the dynamical characterization of inactivation. The kinetic flux as well as energetic contribution of the closed and open- state inactivation path is compared here for voltage protocols, namely constant, pulsed and oscillating. The non-equilibrium thermodynamic quantities used in response to these voltage protocols serve as improved characterization tools for theoretical understanding which not only agrees with the previously known kinetic measurements but also predict the energetically optimum processes to sustain the auto-regulatory mechanism of action potential and the consequent inactivation steps needed. The time dependent voltage pattern governs the population of the conformational states which when couple with characteristic rate parameters, the CSI and OSI selectivity arise dynamically to control the inactivation path. Using constant, pulsed and continuous oscillating voltage protocols we have shown that during depolarization the OSI path is more favored path of inactivation however, in the hyper-polarized situation the CSI is favored. It is also shown that the re-factorisation of inactivated sodium channel to resting state occurs via CSI path. Here we have shown how the subtle energetic and entropic cost due to the change in the depolarization magnitude determines the optimum path of inactivation. It is shown that an efficient CSI and OSI dynamical profile in principle can characterize the open-state drug blocking phenomena.
[Mh] Termos MeSH primário: Ativação do Canal Iônico
Canais de Sódio/efeitos dos fármacos
Canais de Sódio/metabolismo
Canais de Sódio Disparados por Voltagem/metabolismo
[Mh] Termos MeSH secundário: Simulação por Computador
Seres Humanos
Cinética
Potenciais da Membrana
Mexiletina/farmacologia
Análise Espectral
Termodinâmica
Canais de Sódio Disparados por Voltagem/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sodium Channels); 0 (Voltage-Gated Sodium Channels); 1U511HHV4Z (Mexiletine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160702
[St] Status:MEDLINE
[do] DOI:10.1080/19336950.2016.1205175


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[PMID]:27270116
[Au] Autor:Nguyen CE; Campbell C
[Ad] Endereço:Department of Paediatrics (Nguyen), London Health Sciences Centre; Paediatric Neurology Clinic (Campbell), Children's Hospital, London Health Sciences Centre; Department of Epidemiology and Clinical Neurological Sciences, Western University, London, Ont.
[Ti] Título:Myotonic dystrophy type 1.
[So] Source:CMAJ;188(14):1033, 2016 Oct 04.
[Is] ISSN:1488-2329
[Cp] País de publicação:Canada
[La] Idioma:eng
[Mh] Termos MeSH primário: Arritmias Cardíacas/fisiopatologia
Distrofia Miotônica/fisiopatologia
[Mh] Termos MeSH secundário: Idade de Início
Antecipação Genética/genética
Arritmias Cardíacas/mortalidade
Causas de Morte
Seres Humanos
Mexiletina/uso terapêutico
Distrofia Miotônica/tratamento farmacológico
Distrofia Miotônica/epidemiologia
Distrofia Miotônica/genética
Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Voltage-Gated Sodium Channel Blockers); 1U511HHV4Z (Mexiletine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE


  8 / 1320 MEDLINE  
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[PMID]:27267000
[Au] Autor:Roselli M; Carocci A; Budriesi R; Micucci M; Toma M; Di Cesare Mannelli L; Lovece A; Catalano A; Cavalluzzi MM; Bruno C; De Palma A; Contino M; Perrone MG; Colabufo NA; Chiarini A; Franchini C; Ghelardini C; Habtemariam S; Lentini G
[Ad] Endereço:Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via E. Orabona n. 4, 70126 Bari, Italy.
[Ti] Título:Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.
[So] Source:Eur J Med Chem;121:300-307, 2016 Oct 04.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.
[Mh] Termos MeSH primário: Antiarrítmicos/farmacologia
Antiarrítmicos/toxicidade
Mexiletina/farmacologia
Mexiletina/toxicidade
[Mh] Termos MeSH secundário: Animais
Antiarrítmicos/síntese química
Antiarrítmicos/química
Aorta/efeitos dos fármacos
Aorta/fisiopatologia
Sobrevivência Celular/efeitos dos fármacos
Técnicas de Química Sintética
Cães
Cobaias
Átrios do Coração/efeitos dos fármacos
Átrios do Coração/fisiopatologia
Células Hep G2
Seres Humanos
Células Madin Darby de Rim Canino
Mexiletina/síntese química
Mexiletina/química
Relaxamento Muscular/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 1U511HHV4Z (Mexiletine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE


  9 / 1320 MEDLINE  
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[PMID]:27183983
[Au] Autor:Catalano A; Carocci A
[Ad] Endereço:Department of Pharmacy- Drug Sciences, University of Bari "Aldo Moro", via Orabona 4, 70126 Bari, Italy. alessia.catalano@uniba.it.
[Ti] Título:Antiarrhythmic Mexiletine: A Review on Synthetic Routes to Racemic and Homochiral Mexiletine and its Enantioseparation.
[So] Source:Curr Med Chem;23(29):3227-3244, 2016.
[Is] ISSN:1875-533X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Mexiletine is an oral class IB antiarrhythmic agent. Although it was primarily studied for the treatment of ventricular arrhythmias, it has been demonstrated to be useful also for the treatment of chronic painful diabetic neuropathy, neuropathic pain, skeletal muscle channelopathies, and recently amyotrophic lateral sclerosis. This review presents a detailed report on the different synthetic routes to racemic and homochiral mexiletine developed in the last decades, as well as analytical studies regarding enantioseparation methods and enantiomeric excess determination. Finally, some analogues of mexiletine reported in the literature, most of which along with pharmacological studies, have been mentioned.
[Mh] Termos MeSH primário: Antiarrítmicos/síntese química
Mexiletina/química
[Mh] Termos MeSH secundário: Antiarrítmicos/sangue
Antiarrítmicos/metabolismo
Antiarrítmicos/uso terapêutico
Arritmias Cardíacas/tratamento farmacológico
Cromatografia Líquida de Alta Pressão
Nefropatias Diabéticas/tratamento farmacológico
Seres Humanos
Mexiletina/sangue
Mexiletina/metabolismo
Mexiletina/uso terapêutico
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 1U511HHV4Z (Mexiletine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160518
[St] Status:MEDLINE


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[PMID]:27164696
[Au] Autor:Desaphy JF; Carbonara R; D'Amico A; Modoni A; Roussel J; Imbrici P; Pagliarani S; Lucchiari S; Lo Monaco M; Conte Camerino D
[Ad] Endereço:From the Departments of Biomedical Sciences and Human Oncology (J.-F.D.) and Pharmacy & Drug Sciences (R.C., J.R., P.I., D.C.C.), University of Bari Aldo Moro, Bari; Unit of Neuromuscular and Neurodegenerative Disorders (A.D.), Bambino Gesù Children's Hospital, Rome; Departments of Geriatrics, N
[Ti] Título:Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation.
[So] Source:Neurology;86(22):2100-8, 2016 May 31.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype. METHODS: Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp. RESULTS: The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition. CONCLUSIONS: Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.
[Mh] Termos MeSH primário: Mutação
Miotonia Congênita/tratamento farmacológico
Miotonia Congênita/genética
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
[Mh] Termos MeSH secundário: Linhagem Celular
Criança
Diagnóstico Diferencial
Feminino
Flecainida/farmacologia
Flecainida/uso terapêutico
Seres Humanos
Mexiletina/efeitos adversos
Mexiletina/farmacologia
Mexiletina/uso terapêutico
Miotonia Congênita/diagnóstico
Miotonia Congênita/fisiopatologia
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Testes Farmacogenômicos/métodos
Medicina de Precisão/métodos
Pesquisa Médica Translacional
Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human); 0 (Voltage-Gated Sodium Channel Blockers); 1U511HHV4Z (Mexiletine); K94FTS1806 (Flecainide)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160511
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000002721



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