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1.
Europace ; 26(6)2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38702961

RESUMEN

AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS AND RESULTS: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) and primary efficacy outcome (cardiovascular death, stroke, and hospitalization for worsening of heart failure (HF) or acute coronary syndrome) during SCB intake for patients with ERC (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) patient-years, adjusted P = 0.015]. Sinus rhythm at 2 years was similar between groups [SCB 537/610 (88); SCBnever 472/579 (82)]. CONCLUSION: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.


Asunto(s)
Antiarrítmicos , Flecainida , Bloqueadores de los Canales de Sodio , Humanos , Anciano , Masculino , Femenino , Resultado del Tratamiento , Persona de Mediana Edad , Flecainida/uso terapéutico , Flecainida/efectos adversos , Antiarrítmicos/uso terapéutico , Antiarrítmicos/efectos adversos , Bloqueadores de los Canales de Sodio/uso terapéutico , Bloqueadores de los Canales de Sodio/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Factores de Tiempo , Frecuencia Cardíaca/efectos de los fármacos , Accidente Cerebrovascular
2.
Zhonghua Er Ke Za Zhi ; 61(11): 983-988, 2023 Nov 02.
Artículo en Chino | MEDLINE | ID: mdl-37899337

RESUMEN

Objective: To analyze the efficacy and safety of the sodium channel blockers (SCB) antiseizure medication in the treatment of focal epilepsy in infants under 6 months of age. Methods: This was a case series study. Infants with focal epilepsy with onset within 6 months of age and treated with SCB attending the Department of Neurology of Beijing Children's Hospital from June 2016 to April 2022 were collected. The clinical data, auxiliary examinations, SCB application, efficacy, adverse reactions, and prognosis were analyzed retrospectively. Patients were grouped according to type of seizure and epileptic syndrome, age of onset and etiology. Chi square test and Fisher exact test were used to analyze the differences between groups statistically. Results: A total of 118 infants were enrolled, 65 males and 53 females, with an age of epilepsy onset of 56 (4, 114) days. Developmental and epileptic encephalopathy was diagnosed in 60 infants, 39 had self-limited neonatal and (or) infantile epilepsy, and 19 had non-syndromic focal epilepsy. Application of SCB: 106 used oxcarbazepine, 2 used lacosamide, 9 switched from oxcarbazepine to lacosamide or a combination of 2 SCB, and 1 used oxcarbazepine, lacosamide, and lamotrigine successively; oxcarbazepine was the first choice in 46 cases. The age at which SCB was applied was 103 (53, 144) days. The children were followed up for 6 months to 6 years. SCB was effective in 89 cases (75.4%), including 70 cases (59.3%) who achieved seizure freedom. The seizure-free rate was higher in the focal epilepsy only group than in the group with other seizure types (64.4% (65/101) vs. 4/17, χ²=9.99, P<0.05). The responder and seizure-free rates were all higher in the group with the onset age of >3-6 months than the group >1-3 months (84.4% (38/45) vs. 62.5% (20/32), 73.3% (33/45) vs. 46.9% (15/32), χ²=4.85 and 5.58, both P<0.05). With the exception of variants in the PRRT2 gene, those with variants in sodium or potassium channels had higher responder and seizure-free rates than those with variants in other genes(86.2% (25/29) vs. 45.5% (10/22), 62.1% (18/29) vs. 22.7% (5/22), χ²=9.65 and 7.82,both P<0.05). The most common adverse event was transient hyponatremia, which happened in 66 cases (55.9%). There were 9 cases of rash, which subsided in 6 cases after discontinuing oxcarbazepine and switching to lacosamide, and 7 cases of electrocardiogram abnormalities, which improved after withdrawing oxcarbazepine and changing to lacosamide in 1 case. Conclusion: SCB are effective and tolerable in the treatment of focal epilepsy in infants under 6 months of age, with better efficacy in patients with genetic variants of the sodium or potassium channel, focal seizures only, and seizure onset >3-6 months of age.


Asunto(s)
Epilepsias Parciales , Bloqueadores de los Canales de Sodio , Niño , Femenino , Masculino , Recién Nacido , Humanos , Lactante , Bloqueadores de los Canales de Sodio/efectos adversos , Oxcarbazepina , Lacosamida , Estudios Retrospectivos , Epilepsias Parciales/tratamiento farmacológico , Convulsiones , Sodio , Anticonvulsivantes/efectos adversos
3.
Respir Physiol Neurobiol ; 312: 104043, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36871863

RESUMEN

Pathological excessive cough is a serious clinical problem in many patients. It is no doubt that an increased activation and sensitization of airway vagal C-fibres in disease stems from dysregulation of the neural pathways that control cough. Due to the limited efficacy and unwanted side effects of current antitussives, there is a continual demand for the development of a novel more effective antitussive. Since voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs became a promising and attractive neural target. Current studies establish that NaV1.7 and NaV1.8 inhibitors have the potential to suppress cough. In this study, we demonstrated that inhaled aerosol of NaV1.7 inhibitor PF-05089771 (10 µM) and NaV1.8 inhibitor A-803467 (1 mM) mixture inhibited the capsaicin-induced cough by ≈ 60 % and citric acid-induced cough by ≈ 65 % at doses that did not modify respiratory rate. Our previous and present studies indicate that NaV1.7 and NaV1.8 may present promising therapeutic targets for antitussive therapy.


Asunto(s)
Antitusígenos , Canales de Sodio Activados por Voltaje , Cobayas , Animales , Tos/inducido químicamente , Tos/tratamiento farmacológico , Tos/metabolismo , Antitusígenos/uso terapéutico , Canales de Sodio Activados por Voltaje/metabolismo , Nervio Vago/fisiología , Bloqueadores de los Canales de Sodio/efectos adversos
4.
Heart Rhythm ; 19(10): 1595-1603, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35835363

RESUMEN

BACKGROUND: Sodium channel blocker (SCB) infusion is used to unmask the electrocardiographic pattern of Brugada syndrome. The test may also induce premature ventricular complexes (PVCs) in individuals without Brugada pattern, the clinical relevance of which is little known. OBJECTIVE: The purpose of this study was to describe the prevalence of short-coupled (Sc) PVCs induced by ajmaline or flecainide in patients with suspected or documented severe ventricular arrhythmias. METHODS: We reviewed the SCB tests performed in 335 patients with suspected ventricular arrhythmias and structurally normal hearts in 9 centers. ScPVCs were defined as frequent and repetitive PVCs with an R-on-T pattern on SCB tests. Repeated SCB tests were performed in 7 patients and electrophysiological mapping of ScPVCs in 9. RESULTS: Sixteen patients (8 men; mean age 36 ± 11 years) showed ScPVCs and were included. ScPVCs appeared 229 ± 118 seconds after the initiation of infusion and displayed coupling intervals of 288 ± 28 ms. ScPVC patterns were monomorphic in 12 patients, originating from the Purkinje system in mapped patients. Repetitive PVCs were induced in 15 patients (94%) including polymorphic ventricular tachycardias in 9 (56%). SCB infusion was repeated 45 (interquartile range 0.6-46) months later and induced identical ScPVC in all. SCB test was the only mean to reveal the malignant arrhythmia in 6 patients. Catheter ablation was performed in 9 patients, resulting in arrhythmia elimination in 8 with a follow-up of 6 (interquartile range 2-9) years. CONCLUSION: SCB can induce ScPVC, mostly from Purkinje tissue, in a small subset of patients with idiopathic ventricular arrhythmias. Its high reproducibility suggests a distinct individual mechanism.


Asunto(s)
Ablación por Catéter , Taquicardia Ventricular , Complejos Prematuros Ventriculares , Adulto , Ajmalina , Electrocardiografía/métodos , Flecainida , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Bloqueadores de los Canales de Sodio/efectos adversos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/epidemiología , Taquicardia Ventricular/etiología
5.
Neuromuscul Disord ; 31(6): 546-550, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33903020

RESUMEN

Ranolazine is an anti-ischemic drug often used along with statins in patients with ischemic heart disease. Ranolazine-induced proximal myopathy or rhabdomyolysis have been rarely reported, but toxic effects of statins could not be completely ruled out in those cases. We report a 68-year-old man with ranolazine-induced myopathy who presented with respiratory insufficiency and head drop. Creatine kinase level was normal. The Patient continued to worsen despite statin cessation but markedly improved after stopping ranolazine. Muscle biopsy showed excessive lipid accumulation predominantly in type 1 myofibers. The precise mechanism of toxicity is not clear. Treating physicians should be aware of this rare but potentially debilitating adverse effect of ranolazine. Prognosis is good upon discontinuation of the offending drug.


Asunto(s)
Fármacos Cardiovasculares/efectos adversos , Errores Innatos del Metabolismo Lipídico/inducido químicamente , Distrofias Musculares/inducido químicamente , Ranolazina/efectos adversos , Insuficiencia Respiratoria/etiología , Bloqueadores de los Canales de Sodio/efectos adversos , Anciano , Humanos , Masculino
6.
Medicine (Baltimore) ; 100(16): e25437, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879675

RESUMEN

BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of morbidity and mortality in clinical practice. This study aims to determine the ranolazine for prevention and treatment of atrial fibrillation. METHOD: This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols. Chinese electronic Database (CBM, Wanfang, and CNKI) and international electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) will be searched for all relevant published articles. We will apply no language or the year of publication restrictions. Study selection, data collection, and assessment of study bias will be conducted independently by a pair of independent reviewers. The Cochrane risk of bias (ROB) tool will be used for the risk of bias assessment. The quality of evidence will be evaluated by Grading of Recommendations Assessment Development and Evaluation (GRADE) system. The statistical analysis of this meta-analysis will be calculated by Review manager version 5.3. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: This review will evaluate the value of ranolazine interventions for patients with AF, and provide meaningful conclusions or high-level evidence for clinical practice and further research. TRIAL REGISTRATION: This study protocol was registered in open Science framework (OSF), (Registration DOI: 10.17605/OSF.IO/T6W9Q).


Asunto(s)
Antiarrítmicos/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Ranolazina/administración & dosificación , Prevención Secundaria/métodos , Bloqueadores de los Canales de Sodio/administración & dosificación , Antiarrítmicos/efectos adversos , Fibrilación Atrial/mortalidad , Fibrilación Atrial/prevención & control , Humanos , Metaanálisis como Asunto , Placebos/administración & dosificación , Placebos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Medición de Riesgo , Bloqueadores de los Canales de Sodio/efectos adversos , Resultado del Tratamiento
7.
Clin Transl Sci ; 14(4): 1272-1279, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33278330

RESUMEN

Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.


Asunto(s)
Mareo/epidemiología , Éteres Fenílicos/efectos adversos , Prolina/análogos & derivados , Bloqueadores de los Canales de Sodio/efectos adversos , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Mareo/inducido químicamente , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/tratamiento farmacológico , Éteres Fenílicos/administración & dosificación , Éteres Fenílicos/farmacocinética , Prolina/administración & dosificación , Prolina/efectos adversos , Prolina/farmacocinética , Bloqueadores de los Canales de Sodio/administración & dosificación , Bloqueadores de los Canales de Sodio/farmacocinética , Adulto Joven
8.
Ther Drug Monit ; 42(5): 754-759, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32941398

RESUMEN

BACKGROUND: Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects. METHODS: The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records. RESULTS: In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. By contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 mcg/mL (26.4 µmol/L) and 8.4 mcg/mL (33.6 µmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 µmol/L) and 7.5 mcg/mL (30 µmol/L), respectively. CONCLUSIONS: Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Lacosamida/efectos adversos , Lacosamida/uso terapéutico , Adulto , Pueblo Asiatico , Carbamazepina/efectos adversos , Carbamazepina/uso terapéutico , Interacciones Farmacológicas/fisiología , Monitoreo de Drogas/métodos , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Masculino , Fenobarbital/efectos adversos , Fenobarbital/uso terapéutico , Fenitoína/efectos adversos , Fenitoína/uso terapéutico , Bloqueadores de los Canales de Sodio/efectos adversos , Bloqueadores de los Canales de Sodio/uso terapéutico
9.
Perit Dial Int ; 40(4): 422-424, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32037958

RESUMEN

The residual renal function (RRF) in a peritoneal dialysis (PD) patient is clinically important because it contributes to dialytic adequacy, quality of life and mortality. We present the case of a patient in PD with a marked decrease in RRF. Even after the increase of dialysis, the patient maintained asthenia and anorexia, was prostrate and showed no improvement analytically. The study revealed hypothyroidism, iatrogenic due to the use of amiodarone. After suspension of the drug and replacement with levothyroxine, there was a normalization of thyroid function and recovery of RRF to baseline values. A thyroid dysfunction is associated with several changes in renal function, in most cases reversible after obtaining euthyroid state. The association between thyroid dysfunction and loss of RRF continues to be under-recognized. We should consider monitoring thyroid function annually as routine in this group of patients.


Asunto(s)
Hipotiroidismo/complicaciones , Fallo Renal Crónico/etiología , Diálisis Peritoneal , Amiodarona/efectos adversos , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Hipotiroidismo/inducido químicamente , Hipotiroidismo/diagnóstico , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Bloqueadores de los Canales de Sodio/efectos adversos
11.
Acta Neurol Scand ; 141(4): 279-286, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31853958

RESUMEN

OBJECTIVE: Lacosamide (LCM) is an antiepileptic drug (AED) with insufficient clinical experience in patients with intellectual disability (ID). They often have more severe epilepsy with comorbidities. The objective was to evaluate the efficacy and tolerability of lacosamide (LCM) in patients with refractory epilepsy with and without ID in a real-life setting, taking drug monitoring (TDM) data into account therapeutic. METHODS: Retrospectively, we identified 344 patients using LCM from the TDM service covering the majority of the country, at the National Center for Epilepsy in Norway (2013-2018). Clinical and TDM data were available for 132 patients. RESULTS: Forty-four of the 132 patients (33%) had ID. The retention rate was significantly higher in the ID vs the non-ID group after 1 year (84% vs 68%, P < .05). By combining clinical and TDM data, we demonstrated that 37/38 responding patients had serum concentrations above the lower limit of the reference range (>10 µmol/L), and 16/17 with lower concentrations were non-responders. Mean serum concentration/dose ratios were similar in both groups, 0.06 and 0.07 µmol/L/mg. There were no significant differences regarding efficacy and tolerability. The risk of LCM withdrawal was significantly higher when LCM was added to sodium channel blockers, even if the latter was discontinued. SIGNIFICANCE: Lacosamide was generally well tolerated in patients with drug-resistant epilepsy, where one third had ID, and in these patients the retention rate was higher. The combination of clinical and TDM data could possibly facilitate LCM therapy in these vulnerable patients.


Asunto(s)
Anticonvulsivantes/efectos adversos , Monitoreo de Drogas , Epilepsia/tratamiento farmacológico , Lacosamida/efectos adversos , Bloqueadores de los Canales de Sodio/efectos adversos , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Epilepsia/complicaciones , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Lacosamida/uso terapéutico , Masculino , Persona de Mediana Edad , Bloqueadores de los Canales de Sodio/uso terapéutico
13.
BMC Neurosci ; 20(1): 62, 2019 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-31864286

RESUMEN

BACKGROUND: Sodium ion transportation plays a crucial role in the pathogenesis of hypoxic-ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na+/Ca+ exchanger. Considering these pharmacological profile, amiodarone may affect the influx-efflux balance of sodium ion in the hypoxic-ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic-ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na+/Ca+ exchanger during hypoxia-ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic-ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic-ischemic brain injury using a murine experimental model. RESULTS: Compared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic-ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic-ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 ± 6.9 vs. 24.2 ± 6.8 mm3, P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 ± 45.1 vs. 253.5 ± 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 ± 8.9 vs. 277.2 ± 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups. CONCLUSIONS: Amiodarone exacerbated brain injuries and neurological outcomes after hypoxic-ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic-ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.


Asunto(s)
Amiodarona/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Hipoxia-Isquemia Encefálica/fisiopatología , Bloqueadores de los Canales de Sodio/efectos adversos , Animales , Antiarrítmicos/efectos adversos , Encéfalo/patología , Edema Encefálico/patología , Edema Encefálico/fisiopatología , Modelos Animales de Enfermedad , Hipoxia-Isquemia Encefálica/patología , Masculino , Ratones Endogámicos C57BL , Neuroprotección/efectos de los fármacos , Bloqueadores de los Canales de Potasio/efectos adversos , Sodio/metabolismo
14.
Eur Heart J ; 40(37): 3097-3107, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504448

RESUMEN

AIMS: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). METHODS AND RESULTS: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74). CONCLUSION: We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.


Asunto(s)
Ajmalina/efectos adversos , Síndrome de Brugada/tratamiento farmacológico , Reglas de Decisión Clínica , Estudio de Asociación del Genoma Completo , Frecuencia Cardíaca/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Bloqueadores de los Canales de Sodio/efectos adversos , Ajmalina/uso terapéutico , Antiarrítmicos/efectos adversos , Antiarrítmicos/uso terapéutico , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/fisiopatología , Relación Dosis-Respuesta a Droga , Electrocardiografía , Femenino , Marcadores Genéticos , Técnicas de Genotipaje , Frecuencia Cardíaca/genética , Humanos , Infusiones Intravenosas , Masculino , Medición de Riesgo , Bloqueadores de los Canales de Sodio/uso terapéutico
15.
Respir Physiol Neurobiol ; 270: 103267, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31398537

RESUMEN

Cough in respiratory diseases is attributed to the activation of airway C-fibers by inflammation. Inflammatory mediators can act on multiple receptors expressed in airway C-fibers, nonetheless, the action potential initiation in C-fibers depends on a limited number of voltage-gated sodium channel (NaV1) subtypes. We have recently demonstrated that NaV1.8 substantially contributes to the action potential initiation in the airway C-fiber subtype implicated in cough. We therefore hypothesized that the NaV1.8 blocker A-803467 inhibits cough. We evaluated the cough evoked by the inhalation of C-fiber activator capsaicin in awake guinea pigs. Compared to vehicle, intraperitoneal or inhaled A-803467 caused 30-50% inhibition of cough at the doses that did not alter respiratory rate. We conclude that the NaV1.8 blocker A-803467 inhibits cough in a manner consistent with its action on the C-fiber nerve terminals in the airways. Targeting voltage-gated sodium channels mediating action potential initiation in airway C-fibers may offer a means of cough inhibition that is independent of the stimulus.


Asunto(s)
Compuestos de Anilina/uso terapéutico , Antitusígenos/uso terapéutico , Tos/tratamiento farmacológico , Furanos/uso terapéutico , Canal de Sodio Activado por Voltaje NAV1.8/efectos de los fármacos , Bloqueadores de los Canales de Sodio/uso terapéutico , Potenciales de Acción/efectos de los fármacos , Administración por Inhalación , Compuestos de Anilina/efectos adversos , Animales , Antitusígenos/efectos adversos , Bronquios/inervación , Relación Dosis-Respuesta a Droga , Furanos/efectos adversos , Cobayas , Inyecciones Intraperitoneales , Pulmón/inervación , Masculino , Fibras Nerviosas Amielínicas/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Bloqueadores de los Canales de Sodio/efectos adversos
16.
Ann Neurol ; 86(4): 626-640, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31340057

RESUMEN

OBJECTIVE: Drug-resistant epilepsy causes great clinical danger and still lacks effective treatments. METHODS: Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin-resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance. RESULTS: In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin-resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long-term low-frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off-target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug-resistant patients was related to the usage of sodium channel inhibitors. INTERPRETATION: These results highlight that the subicular pyramidal neurons may be a key switch control of drug-resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626-640.


Asunto(s)
Epilepsia Refractaria/fisiopatología , Epilepsia del Lóbulo Temporal/fisiopatología , Hipocampo/patología , Células Piramidales/efectos de los fármacos , Animales , Atrofia/patología , Clozapina/análogos & derivados , Clozapina/farmacología , Epilepsia Refractaria/patología , Estimulación Eléctrica/métodos , Epilepsia del Lóbulo Temporal/patología , Femenino , Humanos , Masculino , Inhibición Neural/fisiología , Optogenética , Fenitoína/farmacología , Ratas , Bloqueadores de los Canales de Sodio/efectos adversos , Canales de Sodio/efectos de los fármacos
17.
Epilepsia ; 60(7): 1353-1364, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31169908

RESUMEN

OBJECTIVE: Focal edema of the splenium of the corpus callosum (FESCC) is infrequently seen in patients with epilepsy who are undergoing video-electroencephalography (EEG) monitoring. It is diagnosed by qualitative visual inspection of the magnetic resonance imaging (MRI) and is usually assumed to be a dichotomous phenomenon. Rapid reduction of anticonvulsants has been proposed as a cause. In this study we investigate the relationship between dose reduction of anticonvulsants and the occurrence of FESCC, based on absolute drug doses. METHODS: We examined in detail the anticonvulsive therapy of all patients during video-EEG monitoring between 2014 and 2018. We compared patients with a radiologically diagnosed FESCC to controls in a 1:2 case-control analysis matched by age, epilepsy syndrome, and adjacent time of admission. In a separate correlation analysis, we examined quantitative effects of reduction of antiseizure drugs on diffusion restriction in the corpus callosum. RESULTS: Of 326 patients who had an MRI following video-EEG monitoring, 12 (3.7%) had FESCC. Antiseizure drugs were reduced to a significantly greater extent in FESCC patients than in the 24 controls (P < 0.001). Sodium channel-blocking antiseizure drugs were reduced (P < 0.001) and reintroduced (P < 0.001) significantly faster in FESCC patients, and the duration of anticonvulsant discontinuation was longer in FESCC patients (P < 0.001). The separate correlation analysis in 325 patients shows a weak correlation between diffusion restriction in the splenium and the reduction rate of sodium channel-blocking anticonvulsants (r = -0.15, P = 0.03) as well as the duration of their discontinuation (r = -0.16, P = 0.01). No such effects were found for anticonvulsants with other modes of action. SIGNIFICANCE: Our findings substantiate that FESCC is associated with high rates of dose reduction of anticonvulsants, specifically those acting on sodium channels. Our results cautiously suggest that reducing sodium-channel blockers has a small effect on diffusivity in the splenium below the visual threshold.


Asunto(s)
Anticonvulsivantes/efectos adversos , Edema Encefálico/inducido químicamente , Cuerpo Calloso , Bloqueadores de los Canales de Sodio/efectos adversos , Síndrome de Abstinencia a Sustancias/etiología , Adolescente , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Edema Encefálico/diagnóstico por imagen , Estudios de Casos y Controles , Niño , Preescolar , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Electroencefalografía , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Bloqueadores de los Canales de Sodio/administración & dosificación , Bloqueadores de los Canales de Sodio/uso terapéutico , Síndrome de Abstinencia a Sustancias/diagnóstico por imagen , Adulto Joven
19.
Clin Drug Investig ; 39(9): 873-887, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31172446

RESUMEN

BACKGROUND AND OBJECTIVE: Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that NaV1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel NaV1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. METHODS: This phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. RESULTS: Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. CONCLUSION: GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.


Asunto(s)
Azetidinas , Benzamidas , Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio , Adolescente , Adulto , Azetidinas/efectos adversos , Azetidinas/farmacocinética , Azetidinas/farmacología , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Benzamidas/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Placebos , Bloqueadores de los Canales de Sodio/administración & dosificación , Bloqueadores de los Canales de Sodio/efectos adversos , Bloqueadores de los Canales de Sodio/farmacocinética , Adulto Joven
20.
Pediatr Neurol ; 97: 43-49, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31122834

RESUMEN

BACKGROUND: Cluster seizures are life-threatening conditions. They may easily evolve into status epilepticus and are reported in up to 20% to 30% of patients with epilepsy. Sometimes cluster seizures become drug resistant, leading to the use of unconventional therapies. One of these unconventional approaches may be the use of lidocaine, which is a sodium-channel-blocking drug mostly known as a local anesthetic and antiarrhythmic agent. METHODS: We describe the outcome of four children who were treated with continuous intravenous infusion of 2% lidocaine due to drug-resistant focal cluster seizures. Lidocaine was administered as an initial dose of 1 mg/kg/hour and, subsequently, was increased to 2 to 4 mg/kg/hour. The therapy was continued for five to 10 days. Patients remained under careful cardiological surveillance during the treatment. RESULTS: Complete seizure remission was achieved in all four children. None of the patients experienced adverse events. Although seizures recurred in all patients within an average time of 2.4 months, they appeared with reduced frequency, and within the follow-up period (mean 7.5 months) no additional cluster seizures occurred. CONCLUSIONS: Treatment with lidocaine in pediatric cluster seizures may be useful and may be considered as a therapeutic option. Our patients encountered no side effects and experienced prolonged seizure remission, possibly resulting from the effect of lidocaine on sodium channels or from its anti-inflammatory properties. However, more studies are required to confirm the safety and long-term effectiveness of this approach. Clinicians should be aware of possible adverse effects and necessity of sustained cardiological surveillance during the treatment.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Lidocaína/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Adolescente , Anticonvulsivantes/administración & dosificación , Arritmias Cardíacas/inducido químicamente , Parálisis Cerebral/complicaciones , Niño , Preescolar , Evaluación de Medicamentos , Resistencia a Medicamentos , Epilepsia del Lóbulo Frontal/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Lidocaína/administración & dosificación , Lidocaína/efectos adversos , Masculino , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Bloqueadores de los Canales de Sodio/administración & dosificación , Bloqueadores de los Canales de Sodio/efectos adversos , Estado Epiléptico/etiología , Estado Epiléptico/prevención & control , Resultado del Tratamiento
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