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1.
Acta Neurol Scand ; 140(1): 48-55, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953593

RESUMO

INTRODUCTION: Aggressive behavior is commonly associated with epilepsy and can be influenced by the antiepileptic drugs (AEDs) taken. Sodium channel blockers, specifically the carboxamides derivatives such as carbamazepine and oxcarbazepine, are some of the AEDs considered to have a favorable psychiatric effect profile. OBJECTIVES: We aimed to assess whether the carboxamide analogue eslicarbazepine acetate (ESL) has any effect on the levels of anger in patients with epilepsy. MATERIAL AND METHODS: We prospectively recruited adult patients with epilepsy on treatment with ≦2 active AEDs, who required AED addition or substitution, excluding patients with active psychiatric disorders. All patients completed anger level (STAXI-2), depression-anxiety (HADS), and quality of life (QOLIE-10) assessments, and were evaluated at baseline and within 3-6 months after treatment initiation. RESULTS: Of 78 patients receiving ESL, as add-on therapy or in substitution of a previous AED, were recruited into the ESL group, with an average age of 48 years and 54% men. We used a control group of 58 patients receiving AEDs other than carboxamides. CONCLUSIONS: Patients overall showed improvements in anger levels, mood, and quality of life during the follow-up. A history of psychiatric disorders was a limiting factor to improve anger levels. As compared to controls, anger levels improved in ESL patients independently from seizure control. Therefore, ESL seems to exert a favorable influence on the anger levels of otherwise healthy patients with epilepsy, including those unresponsive to seizure control. The potential ESL anti-aggressive effect should be studied in patients with epilepsy and active psychiatric disorders.


Assuntos
Ira/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Bloqueadores dos Canais de Sódio/uso terapêutico
2.
Seizure ; 65: 172-175, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30721874

RESUMO

PURPOSE: Lacosamide (LCM) is a recently developed sodium channel blocker (SCB), which acts mainly on the slow activation state in sodium channels. Although LCM shares a range of dose-dependent adverse effects with traditional SCBs, it has several advantages in that it does not induce hepatic drug metabolizing enzymes and has less risk of drug interactions and idiosyncratic adverse effects. METHODS: We retrospectively analyzed the efficacy and tolerability of switching from traditional SCBs to LCM. The reason for the switch was classified as insufficient efficacy, adverse effects, or concern about metabolic derangement, resulting in conditions such as atherosclerosis and osteoporosis, with long-term use of traditional SCBs. RESULTS: Seventy-five patients were switched to LCM from traditional SCBs. The overall rate of successful switching was high (81.3%, 61/75 patients). However, the success rate was strongly dependent on the reason for the switch; patients with insufficient efficacy on SCBs had less chance of a successful switch (71.8%, 28/39 patients) than those with adverse effects (89.5%, 17/19) or concerns about metabolic derangement (94.1%, 16/17, p = 0.038). Patients with insufficient efficacy were significantly younger (p = 0.004) and had a higher chance of drug-resistant epilepsy (p = 0.004) than those in the other two groups. CONCLUSIONS: Our study shows that switching from traditional SCBs to LCM is usually successful and the likelihood of a successful switch is higher in patients when the reason for the switch is adverse effects or concerns about metabolic derangement on traditional SCBs.


Assuntos
Anticonvulsivantes/uso terapêutico , Substituição de Medicamentos , Epilepsia/tratamento farmacológico , Lacosamida/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Interações de Medicamentos , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
3.
J Headache Pain ; 20(1): 20, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782116

RESUMO

BACKGROUND: Trigeminal neuralgia is one of the most characteristic and difficult to treat neuropathic pain conditions in patients with multiple sclerosis. The present narrative review addresses the current evidence on diagnostic tests and treatment of trigeminal neuralgia secondary to multiple sclerosis. METHODS: We searched for relevant papers within PubMed, EMBASE and the Cochrane Database of Systematic Reviews, taking into account publications up to December 2018. RESULTS: Trigeminal neuralgia secondary to multiple sclerosis manifests with facial paroxysmal pain triggered by typical manoeuvres; neurophysiological investigations and MRI support the diagnosis, providing the definite evidence of trigeminal pathway damage. A dedicated MRI is required to identify pontine demyelinating plaques. In many patients with multiple sclerosis, neuroimaging and surgical evidence suggests that neurovascular compression might act in concert with the pontine plaque through a double-crush mechanism. Although no placebo-controlled trials have been conducted in these patients, according to expert opinion the first-line therapy for trigeminal neuralgia secondary to multiple sclerosis relies on sodium-channel blockers, i.e. carbamazepine and oxcarbazepine. The sedative and motor side effects of these drugs frequently warrant an early consideration for neurosurgery. Surgical procedures include Gasserian ganglion percutaneous techniques, gamma knife radiosurgery and microvascular decompression in the posterior fossa. CONCLUSIONS: The relatively poor tolerability of the centrally-acting drugs carbamazepine and oxcarbazepine highlights the need to develop new selective and better-tolerated sodium-channel blockers. Prospective studies based on more advanced neuroimaging techniques should focus on how trigeminal anatomical abnormalities may be able to predict the efficacy of microvascular decompression.


Assuntos
Dor Facial , Esclerose Múltipla/complicações , Neuralgia do Trigêmeo , Carbamazepina/uso terapêutico , Descompressão Cirúrgica/métodos , Dor Facial/etiologia , Dor Facial/terapia , Humanos , Imagem por Ressonância Magnética , Neuralgia/tratamento farmacológico , Neuroimagem/métodos , Oxcarbazepina , Estudos Prospectivos , Radiocirurgia/métodos , Bloqueadores dos Canais de Sódio/uso terapêutico , Gânglio Trigeminal/cirurgia , Neuralgia do Trigêmeo/diagnóstico , Neuralgia do Trigêmeo/etiologia , Neuralgia do Trigêmeo/terapia
4.
J Binocul Vis Ocul Motil ; 69(1): 13-17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806169

RESUMO

PURPOSE: We report the first case of congenital ocular neuromyotonia (ONM) and the results of strabismus surgery for this patient's co-existing cranial nerve (CN) III palsy. PATIENTS AND METHOD: The patient presented at 18 months with strabismus that had reportedly been present since the time of birth. On exam, she had persistent exotropia (RXT) and hypertropia (RHT) with episodes of esotropia in the right eye that could be evoked by sustained left gaze. A diagnosis of ONM with partial CN III palsy was made. T1-weighted, T2-weighted, and fluid-attenuated inversion recovery magnetic resonance imaging failed to reveal intracranial pathology. RESULTS: Gaze induced intermittent esotropia resolved with carbamazepine. Surgery was performed to improve the patient's RXT and RHT. Post-operatively, the patient's RXT had improved from 12 to 15 prism diopters (∆) at near and 20∆ at a distance to 10∆ RXT at near with no horizontal deviation at distance. Her deviation has remained stable for 13 years, as has her neurological exam and good state of health. CONCLUSION: This case demonstrates that ONM may present congenitally and adds to the body of knowledge regarding surgical outcomes on concurrent CN palsies in these patients.


Assuntos
Síndrome de Isaacs/congênito , Doenças do Nervo Oculomotor/congênito , Estrabismo/congênito , Carbamazepina/uso terapêutico , Movimentos Oculares , Feminino , Humanos , Lactente , Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/terapia , Músculos Oculomotores/inervação , Doenças do Nervo Oculomotor/diagnóstico , Doenças do Nervo Oculomotor/cirurgia , Procedimentos Cirúrgicos Oftalmológicos , Bloqueadores dos Canais de Sódio/uso terapêutico , Estrabismo/diagnóstico , Estrabismo/terapia
5.
Prostate ; 79(1): 62-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30242862

RESUMO

BACKGROUND: Voltage-gated sodium channels (VGSCs) are involved in several cellular processes related to cancer cell growth and metastasis, including adhesion, proliferation, apoptosis, migration, and invasion. We here in investigated the effects of S0154 and S0161, two novel synthetic sodium channel blockers (SCBs), on human prostate cancer cells (PC3, DU145, and LnCaP) and a prostate cancer xenograft model. METHODS: The MTT assay was used to assess the anticancer effects of SCBs in PC3, DU145, and LnCaP cells. Sodium indicator and glucose uptake assays were used to determine the effects of S0154 and S0161 in PC3 cells. The impact of these SCBs on the proliferation, cell cycle, apoptosis, migration, and invasion of PC3 cells were determined using a CFDA-SE cell proliferation assay, cell cycle assay, annexin V-FITC apoptosis assay, transwell cell invasion assay, and wound-healing assay, respectively. The protein expression levels of Nav1.6, Nav1.7, CDK1, cyclin B1, MMP2, MMP9 in PC3 cells were analysis by Western blotting. The in vivo anticancer activity was evaluated using a PC3 xenograft model in nude mice. RESULTS: S0154 and S0161 both showed anticancer and anti-metastatic effects against prostate cancer cells and significantly inhibited cell viability, with IC50 values in the range of 10.51-26.60 µmol/L (S0154) and 5.07-11.92 µmol/L (S0161). Both compounds also increased the intracellular level of sodium, inhibited the protein expression of two α subunits of VGSCs (Nav1.6 and Nav1.7), and caused G2/M phase cell cycle arrest, with no or minor effects on cell apoptosis. Concentrations of 5 and 10 µmol/L of S0154 and S0161 significantly decreased the glucose uptake of PC3 cells. The compounds also inhibited the proliferation of PC3 cells and decreased their invasion in transwell assays. Furthermore, S0161 exerted antitumor activity in an in vivo PC3 xenograft model in nude mice, inhibiting the growth of the tumors by about 51% compared to the control group. CONCLUSIONS: These results suggest that S0154 and S0161 have anticancer and anti-metastasis effects in prostate cancer cells both in vitro and in vivo, supporting their further development as potential therapeutic agents for prostate cancer.


Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Próstata/patologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Eur J Pharmacol ; 844: 241-252, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30571955

RESUMO

A series of amino-2-cyclohexyl ester derivatives were studied for their ion channel blocking and antiarrhythmic actions in the rat and a structure-activity analysis was conducted. The compounds are similar in chemical structure except for ionizable amine groups (pK values 6.1-8.9) and the positional arrangements of aromatic naphthyl moieties. Ventricular arrhythmias were produced in rats by coronary-artery occlusion or electrical stimulation. The electrophysiological effects of these compounds on rat heart sodium channels (Nav1.5) expressed in Xenopus laevis oocytes and transient outward potassium currents (Kv4.3) from isolated rat ventricular myocytes were examined. The compounds reduced the incidence of ischemia-related arrhythmias and increased current threshold for induction of ventricular fibrillo-flutter (VFt) dose-dependently. As pK increased compounds showed a diminished effectiveness against ischemia-induced arrhythmias, and were less selective for ischemia- versus electrically-induced arrhythmias. Where tested, compounds produced a concentration-dependent tonic block of Nav1.5 channels. An increased potency for inhibition of Nav1.5 occurred when the external pH (pHo) was reduced to 6.5. Some compounds inhibited Kv4.3 in a pH-independent manner. Overall, the differences in antiarrhythmic and ion channel blocking properties in this series of compounds can be explained by differences in chemical structure. Antiarrhythmic activity for the amino-2-cyclohexyl ester derivatives is likely a function of mixed ion channel blockade in ischemic myocardium. These studies show that drug inhibition of Nav1.5 occurred at lower concentrations than Kv4.3 and was more sensitive to changes in the ionizable amine groups rather than on positional arrangements of the naphthyl constituents. These results offer insight into antiarrhythmic mechanisms of drug-ion channel interactions.


Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Ésteres/química , Ésteres/farmacologia , Ésteres/uso terapêutico , Coração/efeitos dos fármacos , Coração/fisiologia , Masculino , Isquemia Miocárdica/complicações , Oócitos/fisiologia , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Relação Estrutura-Atividade , Xenopus laevis
7.
Trials ; 19(1): 704, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587219

RESUMO

BACKGROUND: This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia. METHODS: This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics. RESULTS: Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change. CONCLUSIONS: Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.


Assuntos
Analgésicos/uso terapêutico , Seleção de Pacientes , Doenças Raras/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Nervo Trigêmeo/efeitos dos fármacos , Neuralgia do Trigêmeo/tratamento farmacológico , Adulto , Idoso , Analgésicos/efeitos adversos , Método Duplo-Cego , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Medição da Dor , Doenças Raras/diagnóstico , Doenças Raras/metabolismo , Doenças Raras/fisiopatologia , Tamanho da Amostra , Bloqueadores dos Canais de Sódio/efeitos adversos , África do Sul , Fatores de Tempo , Resultado do Tratamento , Nervo Trigêmeo/metabolismo , Nervo Trigêmeo/fisiopatologia , Neuralgia do Trigêmeo/diagnóstico , Neuralgia do Trigêmeo/metabolismo , Neuralgia do Trigêmeo/fisiopatologia , Adulto Jovem
8.
Biomed Pharmacother ; 103: 823-828, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29684861

RESUMO

BACKGROUND: Retrospective studies of patients undergoing cancer surgery suggest the use of local anesthesia may decrease tumor recurrence and improve survival. The mechanisms on the benefits of local anesthesia on cancer recurrence are complex and remain to be elucidated. METHODS: This study investigated the effects of bupivacaine on various cellular activities of gastric cancer using proliferation, migration, apoptosis assay. The underlying mechanism was analyzed focusing on mitochondrial functions and the activities of Rho family members. RESULTS: We show that bupivacaine at low concentrations (eg, 0.01 and 0.05 mM) inhibits migration whereas only at high concentrations (1 and 5 mM) inhibits growth and survival in two human gastric cancer cell lines. Bupivacaine also significantly augments 5-Fluorouracil in inhibiting growth and survival but not migration in gastric cancer cells. In addition, the mechanisms of bupivacaine's action on the growth and survival are different from those on the migration. We demonstrate that bupivacaine inhibits gastric cancer cell growth and survival through inhibiting mitochondrial respiratory complex I and II, leading to decreased mitochondrial oxidation and ATP production. In contrast, bupivacaine inhibits gastric cancer cell migration through decreasing RhoA and Rac1 activities without affecting their expression. Particularly, we demonstrate that bupivacaine inhibits gastric cancer cell migration via inhibiting RhoA/ROCK/MLC pathway. We further show that the action of bupivacaine on mitochondrial functions, RhoA, and Rac1 activities are independent of sodium channel blockade. CONCLUSIONS: Our work demonstrates that bupivacaine has direct anti-cancer activities with the dominant inhibitory effects on gastric cancer migration rather than growth and survival. Our findings also guide a proper understanding and provide underlying mechanisms on how local aesthesis could affect cancer patients.


Assuntos
Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Movimento Celular/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Neoplasias Gástricas/metabolismo , Anestésicos Locais/uso terapêutico , Bupivacaína/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Bloqueadores dos Canais de Sódio/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico
9.
Sultan Qaboos Univ Med J ; 18(1): e13-e23, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29666676

RESUMO

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Although the majority of patients with CVD are treated with interventional procedures, a substantial number require medical therapy in terms of both prognosis and symptomatic relief. However, commonly used agents such as ß-blockers and calcium channel blockers reduce blood pressure in patients whose resting pressures are often already low. Ranolazine is a promising agent that does not have significant effects on blood pressure or heart rate. Use of this drug has been documented in various cardiovascular conditions, including ischaemic heart disease, heart failure and arrhythmias. This review article aimed to examine current evidence on the use of ranolazine in various cardiovascular conditions in order to determine whether it is a true pluripotent cardiovascular agent or, on the other hand, a "jack of all trades, master of none."


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Ranolazina/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Ranolazina/administração & dosagem , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico
10.
Neurol Sci ; 39(6): 1065-1072, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29582177

RESUMO

Sodium channel blocking antiepileptic drugs (SCB-AEDs) are common effective medications available for epilepsy. However, not all patients respond to this regimen and drug resistance is frequently encountered. Rs2298771(c.3184A > G/p.Thr1067Ala) and rs3812718(IVS5N +5G > A) polymorphisms are two of the most common polymorphisms in the SCN1A gene, which is closely related to resistance to SCB-AEDs. Therefore, we have conducted a meta-analysis to investigate the contribution of the two polymorphisms to resistance of SCB-AEDs. The PubMed, Embase, MEDLINE, and Cochrane Library databases were searched up to September 2017, for studies on the association of SCN1A polymorphisms with resistance to SCB-AEDs. A fixed-effects or random-effects model was used to calculate the pooled odds ratios based on the results from the heterogeneity tests. A total of eight studies were eligible for the pooled analysis, of which eight studies included SCN1A rs3812718 polymorphism and four studies included SCN1A rs2298771 polymorphism. The results showed that SCN1A rs2298771 polymorphism was significantly associated with resistance to SCB-AEDs. (A vs. G: OR = 0.76, 95% CI 0.61-0.95, P = 0.02; AA vs. AG + GG: OR = 0.71, 95% CI 0.54-0.94, P = 0.022). However, no association was observed between SCN1A rs3812718 polymorphism and resistance to SCB-AEDs. Our results indicate that the A-allele of SCN1A rs2298771 polymorphism, especially AA genotype, may play an important role in responsiveness to SCB-AEDs, while SCN1A rs3812718 polymorphism is not associated with SCB-AEDs.


Assuntos
Anticonvulsivantes/uso terapêutico , Resistência a Medicamentos/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Bloqueadores dos Canais de Sódio/uso terapêutico , Estudos de Associação Genética , Humanos
11.
Trends Pharmacol Sci ; 39(3): 258-275, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29370938

RESUMO

Chronic pain is a global unmet medical need. Most existing treatments are only partially effective or have side effects that limit their use. Rapid progress in elucidating the contribution of specific genes, including those that encode peripheral voltage-gated sodium channels, to the pathobiology of chronic pain suggests that it may be possible to advance pain pharmacotherapy. Focusing on voltage-gated sodium channel NaV1.7 as an example, this article reviews recent progress in developing patient-specific induced pluripotent stem cells (iPSCs) and their differentiation into sensory neurons, together with advances in structural modeling, that have provided a basis for first-in-human translational studies. These new approaches will hopefully transform the treatment of pain from trial-and-error toward genomically guided, precision pharmacotherapy.


Assuntos
Terapia de Alvo Molecular/métodos , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Dor/tratamento farmacológico , Farmacogenética/métodos , Medicina de Precisão/métodos , Animais , Humanos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/genética , Dor/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico
12.
Mini Rev Med Chem ; 18(6): 476-482, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28685702

RESUMO

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a channelopathy characterized by adrenergic mediated ventricular arrhythmia. Untreated CPVT is a malignant syndrome with more than 50% of arrhythmic events and up to 25% of fatal or near-fatal cardiac events at 8 years follow-up. Prevention of sudden cardiac death starts with exclusion of competitive sports. Beta blockers (BB) are the cornerstone pharmacological therapy for the prevention of cardiac event in CPVT patients. Dose of BB should be highly tolerable, preferably nadolol. Efficiency of BB is undeniable but uncompleted. Therefore, on top of BB, one can propose the use of Calcium channel blockers or Class 1c antiarrythmic drugs. Indeed Flecainide allows reducing exercise- induced premature ventricular contraction and ventricular arrhythmia. Pharmacological management should be a stepwise approach with BB as the first line of choice. At each step of therapeutic changes, heart rhythm during exercise should be monitored by Holter monitoring and exercise testing. If the pharmacological management fails, left cardiac sympathetic denervation or implantation of cardioverter defibrillator should be considered.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Taquicardia Ventricular/tratamento farmacológico , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis , Eletrocardiografia , Humanos , Taquicardia Ventricular/complicações , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia
13.
Heart Rhythm ; 15(2): 277-286, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29017927

RESUMO

BACKGROUND: Eleclazine (GS-6615) is a sodium channel blocker designed to improve the selectivity for cardiac late Na+ current (INa) over peak INa. OBJECTIVES: The goals of this study were to investigate the inhibition of late INa by eleclazine using a sample of long QT syndrome type 3 (LQT3) and overlap LQT3/Brugada syndrome mutant channels; to compare the apparent binding rates for eleclazine with those for other class 1 antiarrhythmic agents; and to investigate the binding site. METHODS: Wild-type human cardiac voltage-gated sodium channel (hNaV1.5) and 21 previously reported variants were studied using patch clamp recordings from a heterologous expression system. RESULTS: Eleclazine inhibited anemone toxin II-enhanced late INa from wild-type hNaV1.5 with a drug concentration that causes 50% block of 0.62 ± 0.12 µM (84-fold selectivity over peak INa). The drug concentration that causes 50% block of eleclazine to inhibit the enhanced late INa from LQT3 mutant channels ranged from 0.33 to 1.7 µM. At predicted therapeutic concentrations, eleclazine and ranolazine inhibited peak INa to a similar degree as assessed with 4 overlap LQT3/Brugada syndrome mutations. Eleclazine was found to interact with hNaV1.5 significantly faster than ranolazine and 6 other class 1 antiarrhythmic agents. Engineered mutations (F1760A/Y1767A) located within the local anesthetic binding site decreased the inhibition of late INa and peak INa by eleclazine. CONCLUSION: At predicted therapeutic concentrations, eleclazine elicits potent inhibition of late INa across a cohort of NaV1.5 mutant channels. These properties are consistent with a class 1b antiarrhythmic agent that associates with unusually rapid binding/unbinding rates.


Assuntos
Doença do Sistema de Condução Cardíaco/tratamento farmacológico , Síndrome do QT Longo/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Oxazepinas/uso terapêutico , Potenciais de Ação , Doença do Sistema de Condução Cardíaco/metabolismo , Doença do Sistema de Condução Cardíaco/fisiopatologia , Humanos , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Sódio/uso terapêutico
14.
Dtsch Med Wochenschr ; 142(21): 1586-1593, 2017 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-29046002

RESUMO

Patients with microvascular angina are characterized by angina pectoris with proof of myocardial ischemia in the absence of any relevant epicardial stenosis and without myocardial disease (type 1 coronary microvascular dysfunction according to Crea and Camici). Structural and functional alterations of the coronary microvessels (diameter < 500 µm) are the reason for this phenomenon. Frequently such alterations are associated with cardiovascular risk factors. Patients with angina pectoris without epicardial stenoses represent for 10 - 50 % of all patients undergoing coronary angiography depending on the clinical presentation. Diagnostic approaches include non-invasive (e. g. combination of coronary CT-angiography and positron emission tomography/echo Doppler-based coronary flow reserve measurements) as well as invasive procedures (coronary flow reserve measurements in response to adenosine, intracoronary acetylcholine testing). Pharmacological treatment of these patients is often challenging and should be based on the characterization of the underlying mechanisms. Moreover, strict risk factor control and individually titrated combinations of antianginal substances (e. g. beta blockers, calcium channel blockers, nitrates, ranolazine, ivabradine etc.) are recommended.


Assuntos
Angina Microvascular/diagnóstico , Angina Microvascular/terapia , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Vasoespasmo Coronário/complicações , Vasos Coronários/fisiopatologia , Humanos , Neuroestimuladores Implantáveis , Angina Microvascular/fisiopatologia , Isquemia Miocárdica/complicações , Condicionamento Físico Humano , Fatores de Risco , Bloqueadores dos Canais de Sódio/uso terapêutico
16.
Int J Clin Pharmacol Ther ; 55(9): 712-719, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28679467

RESUMO

OBJECTIVE: Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). METHODS: A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods. Patients were monitored for cough for 8 hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. RESULTS: Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. CONCLUSIONS: While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough.
.


Assuntos
Antitussígenos/uso terapêutico , Doença Crônica/tratamento farmacológico , Tosse/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Eur J Neurosci ; 46(3): 1887-1896, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28635024

RESUMO

Nav 1.1 (SCN1A) channels primarily located in gamma-aminobutyric acid (GABA)ergic fast-spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast-spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability. Further, reduced functionality of Nav 1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Nav 1.1 channels available for studying pharmacological modulation of interneuron function. In the current study, we identified a small molecule Nav 1.1 activator, 3-amino-5-(4-methoxyphenyl)thiophene-2-carboxamide, named AA43279, and provided an in vitro to in vivo characterization of the compound. In HEK-293 cells expressing human Nav 1.1 channels, AA43279 increased the Nav 1.1-mediated current in a concentration-dependent manner mainly by impairing the fast inactivation kinetics of the channels. In rat hippocampal brain slices, AA43279 increased the firing activity of parvalbumin-expressing, fast-spiking GABAergic interneurons and increased the spontaneous inhibitory post-synaptic currents (sIPSCs) recorded from pyramidal neurons. When tested in vivo, AA43279 had anti-convulsive properties in the maximal electroshock seizure threshold test. AA43279 was tested for off-target effects on 72 different proteins, including Nav 1.2, Nav 1.4, Nav 1.5, Nav 1.6 and Nav 1.7 and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of Nav 1.1 channels.


Assuntos
Anticonvulsivantes/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Convulsões/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Tiofenos/farmacologia , Potenciais de Ação , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Potenciais Pós-Sinápticos Excitadores , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Células HEK293 , Humanos , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/uso terapêutico
19.
J Cardiovasc Pharmacol ; 70(3): 159-167, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28654510

RESUMO

Late sodium channel current (late INa) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late INa inhibition have been suggested to be (1) suppression of intracellular calcium [Cai]-mediated rhythmic activity (through reduction in Cai secondary to the decrease in intracellular sodium [Nai]) and (2) normalization of repolarization. Endogenous late INa is a small current and acceleration of the heart rate decreases late INa density. Late INa influx may significantly contribute to Nai loading, but it seems to largely occur under the combined conditions of augmented late INa density, bradycardia, and prolonged repolarization. At the same time, the relative contribution of late INa (including endogenous) in any type of prolonged cardiac repolarization is critical. Sodium channel blockers inhibit both late INa and peak INa, and a specific block of late INa might be achieved at slow and normal but seems not at rapid activation rates, at which peak INa, a much greater current, is also likely to be inhibited. The antiarrhythmic potential of a specific inhibition of late INa seems to best fit for, or may be limited to, the prevention of arrhythmias associated with prolonged repolarization, but it seems to be applicable to all types of arrhythmic abnormalities with elongated cardiac repolarization.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/fisiologia , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Humanos , Ranolazina/farmacologia , Ranolazina/uso terapêutico , Bloqueadores dos Canais de Sódio/farmacologia
20.
CNS Drugs ; 31(7): 527-534, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28523600

RESUMO

Sodium channel blockers have been the mainstay of the pharmacological management of focal and generalised tonic-clonic seizures for more than 70 years. The focus of this paper will be on phenytoin, carbamazepine, lamotrigine, oxcarbazepine, rufinamide, lacosamide and eslicarbazepine acetate. All these antiepileptic drugs have similar efficacy and share similar dose-dependent, adverse effect profiles, although phenytoin, carbamazepine and oxcarbazepine are more likely to cause idiosyncratic reactions than the others. With the exception of lamotrigine, rufinamide and lacosamide, all are enzyme inducers and most are minor teratogens; although data on teratogenicity are sparse with lacosamide and eslicarbazepine acetate. There is increasing evidence that these drugs differ mechanistically, with the newer agents, lacosamide and eslicarbazepine acetate, having their major pharmacological effect on the slow inactivation state of the sodium channel, which may be associated with better tolerability at higher dosage, although hard evidence in support of this observation is currently not available. Rufinamide is licensed only for Lennox-Gastaut syndrome in children aged 4 years and above. There is a move away from using enzyme inducers, particularly phenytoin and carbamazepine, in everyday clinical practice. There seems little doubt, however, that some sodium channel blockers will have an enduring place in the management of epilepsy well into the 21st century.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Epilepsia/metabolismo , Humanos , Bloqueadores dos Canais de Sódio/efeitos adversos , Bloqueadores dos Canais de Sódio/farmacologia
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