RESUMEN
Long term use of Amiodarone (AMIO) is associated with the development of ocular adverse effects. This study investigates the short term effects, and the ameliorative consequence of vitamin E on retinal changes that were associated with administration of AMIO. This is accomplished by investigating both retinal structural and conformational characteristics using Fourier transform infrared spectroscopy (FTIR) and Fundus examination. Three groups of healthy rabbits of both sexes were used; the first group served as control. The second group was orally treated with AMIO (160 mg /kg body weight) in a daily basis for two weeks. The last group orally received AMIO as the second group for two weeks then, oral administration of vitamin E (100 mg/kg body weight) for another two weeks as well. FTIR results revealed significant structural and conformational changes in retinal tissue constituents that include lipids and proteins due to AMIO administration. AMIO treatment was associated with fluctuated changes (increased/decreased) in the band position and bandwidth of NH, OH, and CH bonds. This was concomitant with changes in the percentage of retinal protein constituents in particularly α-helix and Turns. AMIO facilitates the formation of intra-molecular hydrogen bonding and turned retinal lipids to be more disordered structure. In conclusion, the obtained FTIR data together with principal component analysis provide evidence that administration of vitamin E following the treatment with AMIO can ameliorate these retinal changes and, these biophysical changes are too early to be detected by Fundus examination.
Asunto(s)
Amiodarona , Retina , Vitamina E , Animales , Vitamina E/farmacología , Vitamina E/administración & dosificación , Amiodarona/administración & dosificación , Amiodarona/farmacología , Conejos , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Espectroscopía Infrarroja por Transformada de Fourier , Masculino , Femenino , Suplementos DietéticosRESUMEN
BACKGROUND: Ocular toxicity is a severe adverse effect that limits the chronic clinical use of the antiarrhythmic drug amiodarone. Here, we aimed to evaluate the cytoprotective effect of artemisinin and explore the potential signalling pathways in human retinal pigment epithelial (RPE) cell cultures. METHODS: D407 cell cultures were exposed to amiodarone and the impact of artemisinin was evaluated. The key parameters included lactate dehydrogenase (LDH) release, intracellular reactive oxygen species (ROS) generation, and the mitochondrial membrane potential (MMP). We also assessed the protein levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), phosphorylated adenosine monophosphate-activated protein kinase (AMPK)É (p-AMPK), calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and nuclear factor erythroid 2-related factor 2 (Nrf2). RESULTS: Artemisinin reduced the cytotoxicity induced by amiodarone, as reflected by decreased LDH release, ROS generation, and MMP disruption. Additionally, artemisinin increased p-AMPK, CaMKK2, and Nrf2 protein levels. Inhibition of AMPK, CaMKK2, or Nrf2 abolished the cytoprotective effect of artemisinin. AMPK activation and Nrf2 knockdown further supported its protective role. CONCLUSIONS: Artemisinin protected RPE cells from amiodarone-induced damage via the CaMKK2/AMPK/Nrf2 pathway. The in vivo experiments in mice confirmed its efficacy in preventing retinal injury caused by amiodarone. These results suggest that an artemisinin-based eye formulation could be repurposed for treating amiodarone-induced ocular toxicity.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Amiodarona , Artemisininas , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina , Citoprotección , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Especies Reactivas de Oxígeno , Epitelio Pigmentado de la Retina , Transducción de Señal , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Humanos , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Citoprotección/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Amiodarona/efectos adversos , Amiodarona/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Artemisininas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Ratones , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patologíaRESUMEN
Amiodarone is an antiarrhythmic drug which may be associated with thyroid dysfunction. Type I amiodarone-induced thyrotoxicosis (AIT) is treated with thionamides and type II AIT is treated with glucocorticoids. Combined therapy is used in mixed or indeterminate forms. When medical treatment is unsuccessful, radioiodine ablation or thyroidectomy is considered. This report reviews a case of AIT refractory to conventional treatment. Despite high doses of methimazole and prednisone, the patient remained clinically and biochemically thyrotoxic. Cholestyramine, a bile salt sequestrant, was used as an off-label adjunctive treatment resulting in significant improvement and achievement of euthyroidism that may also be in part due to the expected natural timeline of recovery from AIT after several months. The patient subsequently trended towards hypothyroidism with symptomatic weight gain and cold intolerance for which he was initiated on levothyroxine.
Asunto(s)
Amiodarona , Antiarrítmicos , Resina de Colestiramina , Tirotoxicosis , Humanos , Tirotoxicosis/inducido químicamente , Tirotoxicosis/tratamiento farmacológico , Amiodarona/efectos adversos , Resina de Colestiramina/uso terapéutico , Masculino , Antiarrítmicos/efectos adversos , Tiroxina/uso terapéutico , Anticolesterolemiantes/efectos adversosAsunto(s)
Amiodarona , Antiarrítmicos , Humanos , Amiodarona/administración & dosificación , Amiodarona/efectos adversos , Amiodarona/historia , Antiarrítmicos/administración & dosificación , Antiarrítmicos/efectos adversos , Antiarrítmicos/historia , Fibrilación Atrial/tratamiento farmacológico , Informes de Casos como AsuntoRESUMEN
This case report presents the clinical course and management of a 62-year-old female patient with atrial fibrillation (AF) secondary to levothyroxine overdose along with an underlying secondary infection. The patient was admitted with sudden onset dyspnea, altered sensorium, and neurological deficits. Upon examination, she exhibited tachycardia, irregular heart sounds, and extensive crepitations in the respiratory system. Her electrocardiogram (ECG) showed an absent P wave with a varying RR interval. Laboratory investigations revealed abnormal thyroid function tests (TFTs) and raised polymorphonuclear cells, in addition to hyperglycemia. The patient was managed in the intensive care unit (ICU) with bilevel positive airway pressure (BiPAP) and supplemental oxygen, treated for AF with intravenous (IV) amiodarone, and her blood sugar was controlled with insulin infusion. Discontinuation of levothyroxine therapy was advised. Subsequently, her AF was terminated, and sinus rhythm was restored. Her neurological examination showed right-sided hemiplegia with aphasia. After 1 week of treatment, her TFTs normalized, and she was discharged on appropriate medication.
Asunto(s)
Fibrilación Atrial , Sobredosis de Droga , Tiroxina , Humanos , Femenino , Fibrilación Atrial/tratamiento farmacológico , Persona de Mediana Edad , Tiroxina/administración & dosificación , Tiroxina/uso terapéutico , Sobredosis de Droga/diagnóstico , Sobredosis de Droga/complicaciones , Electrocardiografía , Amiodarona/administración & dosificación , Amiodarona/efectos adversosRESUMEN
BACKGROUND: There are no randomized studies comparing the maintenance of sinus rhythm after catheter ablation (CA) concerning treatment with antiarrhythmic drugs (AA) in elderly patients with paroxysmal atrial fibrillation (AF). OBJECTIVES: To compare the clinical results of pulmonary vein (PV) isolation with the second-generation PVAC Gold catheter against AA treatment in elderly people with recurrent symptomatic paroxysmal AF, refractory to at least one AA, and without structural heart disease. METHODS: Sixty patients with paroxysmal AF ≥ 65 years old were randomized to two forms of treatment: group 1: CA and group 2: AA drugs. The primary outcome was the AF recurrence-free rate after at least one year of follow-up. Secondary outcomes were: progression to persistent forms of AF, impact on quality of life (QOLF), and complications. The significance level adopted in the statistical analysis was 5% (p<0.05). RESULTS: The AF recurrence-free rate was 80% (10% with amiodarone) in the CA group, after 1.3 procedures per patient and 65% in the AA group (60% with amiodarone), (p = 0.119) in an average follow-up of 719 days (Q1: 566; Q3: 730). The persistent AF free rate was 83.4% in the AC group and 67.7% in the AA group (p = 0.073) Both strategies showed an improvement in the AFQoL score during follow-up (p < 0.001), with no difference between the groups. Although without clinical repercussions or impact on the intellectual assessment test, 25% of patients in the CA group showed signs of cerebral embolization on brain MRI. CONCLUSIONS: Both strategies for maintaining sinus rhythm promoted an improvement in the quality of life of elderly patients with symptomatic AF, with no statistical difference in the clinical outcomes. Additional studies using technologies with a better safety profile are needed to evaluate the benefits of CA in elderly patients with AF.
FUNDAMENTO: Não existem estudos randomizados comparando a manutenção do ritmo sinusal após ablação por cateter (AC) em relação ao tratamento com fármacos antiarrítmicos (AA) em pacientes idosos portadores fibrilação atrial (FA) paroxística. OBJETIVOS: Comparar os resultados clínicos do isolamento das veias pulmonares (VPs) com o cateter PVAC Gold de segunda geração com o uso de AA em idosos com FA paroxística sintomática, recorrente, apesar do uso de fármacos AA. MÉTODOS: Sessenta pacientes com FA paroxística ≥ 65 anos e sem cardiopatias estruturais foram randomizados para duas formas de tratamento: grupo 1: AC e grupo 2: AA. O desfecho primário foi a taxa livre de recorrência de FA após pelo menos um ano de seguimento. Os desfechos secundários foram: progressão para formas persistentes de FA, impacto na qualidade de vida (QVFA) e complicações. O nível de significância adotado na análise estatística foi de 5% (p<0,05). RESULTADOS: A taxa livre de recorrência de FA foi de 80% (10% com amiodarona) no grupo AC, após 1,3 procedimentos por paciente e de 65% no grupo AA (60% com amiodarona), (p = 0,119) num seguimento médio de 719 dias (Q1: 566; Q3: 730). A taxa livre de FA persistente foi de 83,4% no grupo AC e de 67,7% no grupo AA (p = 0,073). Ambas as estratégias apresentaram melhora no escore de QVFA durante o seguimento (p < 0,001), sem diferença entre os grupos. Embora sem repercussão clínica ou impacto no teste de avaliação intelectual, 25% dos pacientes do grupo PVAC apresentou sinais de embolização cerebral na RNM cerebral. CONCLUSÕES: Ambas as estratégias para manutenção do ritmo sinusal promoveram melhora na qualidade de vida de pacientes idosos com FA sintomática, sem diferença estatística nos desfechos clínicos preconizados. Estudos adicionais usando tecnologias com melhor perfil de segurança são necessários para avaliar os benefícios da AC em pacientes idosos com FA.
Asunto(s)
Antiarrítmicos , Fibrilación Atrial , Ablación por Catéter , Venas Pulmonares , Calidad de Vida , Humanos , Fibrilación Atrial/cirugía , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/terapia , Fibrilación Atrial/fisiopatología , Antiarrítmicos/uso terapéutico , Femenino , Masculino , Anciano , Ablación por Catéter/métodos , Resultado del Tratamiento , Venas Pulmonares/cirugía , Recurrencia , Amiodarona/uso terapéutico , Factores de TiempoRESUMEN
OBJECTIVE: High plasma levels of mono-N-desethylamiodarone (MDEA), an active amiodarone metabolite, may be associated with tissue toxicity in heart failure (patients with heart rhythm disturbances); therefore, a tool that can identify patients for whom therapeutic drug monitoring (TDM) of MDEA is required. This multicenter study aimed to develop a decision tree (DT) model that can identify patients with heart rhythm disturbances at high MDEA concentrations. MATERIALS AND METHODS: A multicenter retrospective cohort study was conducted, including 157 adult patients with heart failure who received oral amiodarone treatment. A χ2 automatic interaction-detection algorithm was used to construct a DT model. In the DT analysis, the dependent variable was set as an MDEA trough plasma concentration of ≥ 0.6 µg/mL during the steady-state period. Explanatory variables were selected as factors with p < 0.05 in multivariate logistic regression analysis. RESULTS: The adjusted odds ratios for the daily dose of amiodarone and body mass index were 1.01 (95% coefficient interval: 1.008 - 1.021, p < 0.001) and 0.91 (95% confidence interval: 0.834 - 0.988, p = 0.025), respectively. For DT analysis, the risk of reaching plasma MDEA concentrations ≥ 0.6 µg/mL was relatively high, combined with a daily dose of amiodarone > 100 mg and body mass index ≤ 22.3 kg/m2 at 69.0% (20/29), and its trend was also detected in the sensitivity analysis. CONCLUSION: Patients taking a daily amiodarone dose > 100 mg and with a body mass index ≤ 22.3 kg/m2 warrant TDM implementation for MDEA to minimize the risk of MDEA-induced tissue toxicity.
Asunto(s)
Amiodarona , Antiarrítmicos , Árboles de Decisión , Monitoreo de Drogas , Humanos , Amiodarona/efectos adversos , Amiodarona/administración & dosificación , Amiodarona/farmacocinética , Amiodarona/análogos & derivados , Estudios Retrospectivos , Masculino , Femenino , Anciano , Antiarrítmicos/efectos adversos , Antiarrítmicos/administración & dosificación , Antiarrítmicos/farmacocinética , Antiarrítmicos/sangre , Persona de Mediana Edad , Monitoreo de Drogas/métodos , Insuficiencia Cardíaca/tratamiento farmacológico , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Cardiac dysfunction, including arrhythmias, may be one of the main clinical manifestations of Becker muscular dystrophy (BMD). Amiodarone is widely used to treat arrhythmia. However, multi-systemic toxicity caused by amiodarone, especially hepatotoxicity, should not be neglected. Here, we introduce a novel case of multi-systemic amiodarone toxicity involving the liver, renal and coagulation in BDM patient with ABCB4 gene mutation. CASE PRESENTATION: We present a case of a 16-year-old boy admitted with heart failure and atrial fibrillation (AF). He was diagnosed with Becker muscular dystrophy (BMD) and gene testing showed comorbid mutations in gene DMD, ABCB4 and DSC2. Amiodarone was prescribed to control the paroxysmal atrial fibrillation intravenously. However, his liver enzyme levels were sharply elevated, along with cardiac shock, renal failure and coagulation disorders. After bedside continuous renal replacement therapy, the patient's liver function and clinical status rehabilitated. CONCLUSIONS: ABCB4 gene mutation might be involved in amiodarone-induced hepatotoxicity. Studies in a cohort might help to prove this hypothesis in the future.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Amiodarona , Antiarrítmicos , Insuficiencia Cardíaca , Distrofia Muscular de Duchenne , Mutación , Humanos , Amiodarona/efectos adversos , Amiodarona/administración & dosificación , Masculino , Adolescente , Insuficiencia Cardíaca/inducido químicamente , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antiarrítmicos/efectos adversos , Antiarrítmicos/uso terapéutico , Antiarrítmicos/administración & dosificación , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/complicaciones , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Fibrilación Atrial/tratamiento farmacológicoRESUMEN
Left ventricular assist devices (LVADs) are widely used as end-stage therapy in patients with advanced heart failure, whereas implantation increases the risks of development of sustained ventricular tachycardia at the later postimplantation stage. Therefore, this study aimed to evaluate the clinical efficacy of orally administered amiodarone and propranolol in 3 patients with ventricular tachycardia (VT) after LVAD implantation who were resistant to initial anti-antiarrhythmic drugs. This retrospective cohort study consisted of the initial evaluation of the clinical data of 14 adult patients who underwent implantation of LVAD between January 2019 and March 2021. A total of 3 patients with resistant VT were finally included. In all cases, the patients were initially administered amiodarone in the different doses intravenously to stabilize the critical condition, whereas its oral form along with that of propranolol was used as maintenance therapy in the first 2 cases. In the third case, amiodarone was withdrawn because of the risk of development of hyperthyroidism, while oral propranolol was used in the treatment. The assessment in the 16-month follow-up period after discharge did not show presence of non-sustained and sustained VT in all 3 cases. In the ventricular arrhythmia-free group, the total mortality rate within the follow-up period was 11.1â ±â 7.78 months in the 3 patients. We suggest that maintenance oral therapy of propranolol and amiodarone can significantly decrease the risks of complications in patients with VT after implantation of ventricular assist device in the long term.
Asunto(s)
Amiodarona , Antiarrítmicos , Propranolol , Taquicardia Ventricular , Humanos , Amiodarona/administración & dosificación , Amiodarona/efectos adversos , Propranolol/administración & dosificación , Propranolol/uso terapéutico , Masculino , Antiarrítmicos/administración & dosificación , Estudios Retrospectivos , Administración Oral , Persona de Mediana Edad , Taquicardia Ventricular/tratamiento farmacológico , Femenino , Adulto , Insuficiencia Cardíaca/tratamiento farmacológico , AncianoRESUMEN
Amiodarone and mexiletine are used for ventricular arrhythmias, for which a combination therapy of both anti-arrhythmic drugs (AADs) is not uncommon. Therapeutic drug monitoring (TDM) can be beneficial for clinical guidance of therapy, especially to correctly identify adverse events. Desethylamiodarone, the active metabolite of amiodarone, accumulates over time and is associated with serious adverse events. Therefore, simultaneous TDM for amiodarone, desethylamiodarone and mexiletine is advantageous in clinical practice. The presented LC-MS/MS method was validated for selectivity, matrix effect, linearity, accuracy, precision, carry-over and stability. The method was continuously evaluated during eight months of clinical use. The method was shown to be linear within the measured range of 0.1 to 10 mg/L for each component. The matrix effect was considered negligible. No interfering responses were found for amiodarone, desethylamiodarone and the isotopic-labeled internal standards. A constant and reproducible within-run contribution of 45.3 %, originating from the system, was identified for mexiletine. The systemic contribution to the peak area of the lowest quantifiable concentration of mexiletine affected the selectivity and carry-over effect measurements. Multiple measurements showed that regression adjusted concentrations were accurate and reproducible, indicating calibration correction was applicable. Sample stability was found to be within limits for all storage conditions and freeze-thaw cycles. Furthermore, long-term method evaluation with external controls resulted in stable measurements with a percentage coefficient of variance between 1.3 % and 6.3 %. The presented practical and reliable method is applicable for clinical TDM and will allow clinical practitioners to guide drug therapy of amiodarone and mexiletine.
Asunto(s)
Amiodarona , Mexiletine , Espectrometría de Masas en Tándem , Amiodarona/sangre , Amiodarona/análogos & derivados , Humanos , Espectrometría de Masas en Tándem/métodos , Mexiletine/sangre , Mexiletine/análogos & derivados , Mexiletine/química , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Modelos Lineales , Monitoreo de Drogas/métodos , Antiarrítmicos/sangre , Antiarrítmicos/farmacocinética , Límite de Detección , Estabilidad de Medicamentos , Sensibilidad y EspecificidadRESUMEN
Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, which often occurs within 30 postoperative days, especially peaking at 2-3 days. Antiarrhythmic medications such as amiodarone are recommended in clinical practice for the prophylaxis and treatment of POAF. However, conventional oral administration is hindered due to delayed drug action and high risks of systemic toxicity, and emerging localized delivery strategies suffer from a limited release duration (less than 30 days). Herein, we develop a microneedle (MN) patch for localized delivery of amiodarone to the atria in a "First Rapid and Then Sustained" dual-release mode. Specifically, this patch is composed of a needle array integrated with an amiodarone-loaded reservoir for a sustained and steady release for over 30 days; and an amiodarone-containing coating film deposited on the needle surface via the Langmuir-Blodgett technique for a rapid release at the first day. Upon this design, only one MN patch enables a higher drug accumulation in the atrial tissue at the first day than oral administration and simultaneously remains therapeutical levels for over 30 days, despite at a significantly reduced drug dosage (5.08 mg in total versus â¼10 mg per day), thereby achieving ideal preventive effects and safety in a rat model. Our findings indicate that this MN device provides a robust and efficient delivery platform for long-term prophylaxis of POAF.
Asunto(s)
Fibrilación Atrial , Agujas , Fibrilación Atrial/prevención & control , Fibrilación Atrial/tratamiento farmacológico , Animales , Ratas , Ratas Sprague-Dawley , Amiodarona/administración & dosificación , Amiodarona/química , Antiarrítmicos/administración & dosificación , Antiarrítmicos/química , Antiarrítmicos/farmacología , Masculino , Sistemas de Liberación de Medicamentos , Complicaciones Posoperatorias/prevención & controlRESUMEN
To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase. Electrophysiological analysis showed that inter-atrial conduction time and duration of burst pacing-induced AF increased in the chronic phase compared with those in the acute phase, but that atrial effective refractory period was hardly altered. Echocardiographic study revealed that diameters of left atrium, right pulmonary vein and inferior vena cava increased similarly in the acute and chronic phases. Histological evaluation indicated that hypertrophy and fibrosis in atrial tissue increased in the chronic phase. Electropharmacological characterization showed that i.v. pilsicainide effectively suppressed burst pacing-induced AF with increasing atrial conduction time and refractoriness of AVB dogs in chronic phase, but that i.v. amiodarone did not exert such electrophysiological effects. Taken together, AVB dogs in chronic phase appear to possess such pathophysiology as developed in the atria of early-stage AF patients, and therefore they can be used to evaluate drug candidates against early-stage AF.
Asunto(s)
Fibrilación Atrial , Remodelación Atrial , Bloqueo Atrioventricular , Modelos Animales de Enfermedad , Atrios Cardíacos , Animales , Perros , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/etiología , Bloqueo Atrioventricular/fisiopatología , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Remodelación Atrial/fisiología , Masculino , Antiarrítmicos/farmacología , Antiarrítmicos/uso terapéutico , Ecocardiografía , Amiodarona/farmacologíaRESUMEN
Amiodarone (AMD) is an effective antiarrhythmic drug, but its long-term usage strongly forms liver toxicity due to its accumulation tendency. The chard (Beta vulgaris L. var. cicla) is a unique plant which has a blood sugar-lowering effect and powerful antioxidant activity. The aim of the current study was to investigate the possible protective effects of chard on AMD-induced liver injury. Male Sprague-Dawley rats were divided into four groups. Control group, aqueous chard extract given group 500â mg/kg/day for one week, AMD given group 100â mg/kg/day for one week, AMD+Chard given group (at the same doses and times). They were sacrificed on the 8th day. The blood and liver samples were taken. The serum and liver biochemical parameters were found to be changed in AMD treated group. Chard administration reversed these parameters in serum and liver. In histological experiments, necrotic areas, mononuclear cell infiltration, the endothelial rupture in central vein, sinusoidal dilatation, hyperemia, dark eosinophilic cells and picnotic nucleus were observed in liver tissues of AMD treated group. Chard treatment reduced liver tissue damage. Considering results, we can suggest that chard prevented AMD induced liver injury biochemically and histologically.
Asunto(s)
Amiodarona , Beta vulgaris , Enfermedad Hepática Inducida por Sustancias y Drogas , Extractos Vegetales , Ratas Sprague-Dawley , Animales , Masculino , Amiodarona/farmacología , Ratas , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Extractos Vegetales/farmacología , Extractos Vegetales/química , Beta vulgaris/química , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Antiarrítmicos/farmacología , Antiarrítmicos/químicaRESUMEN
While implantable cardioverter-defibrillator (ICD) shocks are a lifesaving therapy, they can negatively affect the patient's quality of life. Amiodarone is commonly combined with ß-blockers (BB) in ICD recipients. However, this combination therapy's efficacy in preventing shocks compared to standard BB monotherapy is not well studied. The aim of this systematic review and meta-analysis is to determine if combined amiodarone and BB therapy improves prevention of ICD shock delivery compared to BB monotherapy. We performed a comprehensive literature search using PubMed, Cochrane, and Web of Science databases, for studies that assess the impact of amiodarone and BB versus BB monotherapy in patients with an ICD. The primary outcome was a total number of ICD shocks delivered by the end of the study period. Four studies: three retrospective studies and one randomized controlled trial (RCT), with a total of 5818 patients with ICDs, were included in the analysis. Follow-up periods ranged from 1 to 5 years. The combined amiodarone and BB group was not associated with a significantly lower number of ICD shocks compared to the BB monotherapy group (OR, 0.76; 95% CI, 0.44-1.31; P = .32). A combination therapy of amiodarone and BB was not associated with any further reduction in ICD shocks, hospitalizations, or mortality. Additional RCTs are recommended to further validate our findings.
Asunto(s)
Antagonistas Adrenérgicos beta , Amiodarona , Antiarrítmicos , Desfibriladores Implantables , Quimioterapia Combinada , Humanos , Amiodarona/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Antiarrítmicos/uso terapéutico , Resultado del TratamientoRESUMEN
The difficulty in swallowing is a frequent problem when oral solid dosage forms (conventional tablets or capsules) are administered to paediatric population or patients with dysphagia. An interesting alternative to overcome these problems are non-conventional formulations like chewable gels, commonly known as 'gummies'. Therefore, this work addresses the design, development and characterization of gummies using gelatine and pectin, for the vehiculization of the antiarrhythmic amiodarone (AMIO). Applying a Design of Experiments (DoE) approach, four gelatine (GG1-GG4) and eight pectin formulations (PG1-PG8) were developed. Considering the obtained results for responses during DoE evaluation (i.e., volume, syneresis, hardness, and gumminess), GG3 and PG8 were selected for complete characterization. Water activity, pH, drug content, texture parameters (adhesiveness, springiness, cohesiveness, and fracturability), disintegration time, in vitro dissolution, and microbiological features were evaluated. The obtained results were within the expected values for this type of formulation. The dissolution profiles showed a 94 % - 99 % of the AMIO content released for GG3 and PG8, respectively, so they could be considered suitable as immediate release dosage forms. In conclusion, the chewable gels were successfully developed and characterised, suggesting a potential means to accomplish a final prototype for the improvement of congenital cardiopathies treatment.
Asunto(s)
Amiodarona , Antiarrítmicos , Geles , Cardiopatías Congénitas , Pectinas , Amiodarona/administración & dosificación , Amiodarona/química , Humanos , Pectinas/química , Antiarrítmicos/administración & dosificación , Antiarrítmicos/química , Cardiopatías Congénitas/tratamiento farmacológico , Gelatina/química , Animales , Niño , Administración Oral , Liberación de Fármacos , Composición de Medicamentos/métodos , Solubilidad , Química Farmacéutica/métodosRESUMEN
INTRODUCTION: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. METHODS: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). RESULTS: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. DISCUSSION: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous singlelead ECGs collected from freely moving dogs and monkeys.
Asunto(s)
Amiodarona , Electrocardiografía , Síndrome de QT Prolongado , Moxifloxacino , Torsades de Pointes , Animales , Moxifloxacino/administración & dosificación , Moxifloxacino/farmacología , Perros , Amiodarona/administración & dosificación , Amiodarona/farmacología , Electrocardiografía/efectos de los fármacos , Electrocardiografía/métodos , Torsades de Pointes/inducido químicamente , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Macaca fascicularis , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Bloqueadores de los Canales de Potasio/administración & dosificación , Bloqueadores de los Canales de Potasio/farmacología , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismoRESUMEN
Mycobacterium tuberculosis (Mtb) as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug resistance. The loss of antibiotic efficacy has raised interest in the identification of host-directed therapeutics (HDT) to develop novel treatment strategies for mycobacterial infections. In this study, we identified amiodarone as a potential HDT candidate that inhibited both intracellular Mtb and Mycobacterium avium in primary human macrophages without directly impairing bacterial growth, thereby confirming that amiodarone acts in a host-mediated manner. Moreover, amiodarone induced the formation of (auto)phagosomes and enhanced autophagic targeting of mycobacteria in macrophages. The induction of autophagy by amiodarone is likely due to enhanced transcriptional regulation, as the nuclear intensity of the transcription factor EB, the master regulator of autophagy and lysosomal biogenesis, was strongly increased. Furthermore, blocking lysosomal degradation with bafilomycin impaired the host-beneficial effect of amiodarone. Finally, amiodarone induced autophagy and reduced bacterial burden in a zebrafish embryo model of tuberculosis, thereby confirming the HDT activity of amiodarone in vivo. In conclusion, we have identified amiodarone as an autophagy-inducing antimycobacterial HDT that improves host control of mycobacterial infections. IMPORTANCE: Due to the global rise in antibiotic resistance, there is a strong need for alternative treatment strategies against intracellular bacterial infections, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria. Stimulating host defense mechanisms by host-directed therapy (HDT) is a promising approach for treating mycobacterial infections. This study identified amiodarone, an antiarrhythmic agent, as a potential HDT candidate that inhibits the survival of Mtb and Mycobacterium avium in primary human macrophages. The antimycobacterial effect of amiodarone was confirmed in an in vivo tuberculosis model based on Mycobacterium marinum infection of zebrafish embryos. Furthermore, amiodarone induced autophagy and inhibition of the autophagic flux effectively impaired the host-protective effect of amiodarone, supporting that activation of the host (auto)phagolysosomal pathway is essential for the mechanism of action of amiodarone. In conclusion, we have identified amiodarone as an autophagy-inducing HDT that improves host control of a wide range of mycobacteria.
Asunto(s)
Amiodarona , Autofagia , Macrófagos , Mycobacterium tuberculosis , Tuberculosis , Pez Cebra , Amiodarona/farmacología , Autofagia/efectos de los fármacos , Animales , Pez Cebra/microbiología , Humanos , Macrófagos/microbiología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Modelos Animales de Enfermedad , Mycobacterium avium/efectos de los fármacos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Lisosomas/microbiologíaRESUMEN
BACKGROUND: Out-of-hospital cardiac arrest (OHCA) complicated by refractory ventricular fibrillation (VF) is associated with poor outcome. Beta-1-receptor selective blockade might overcome refractory VF and improve survival. This trial investigates the efficacy and safety of prehospital landiolol in OHCA and refractory VF. METHODS: In this randomized, double-blind, placebo-controlled pilot trial, patients with OHCA and recurrent or refractory VF (at least 3 defibrillation attempts and last rhythm shockable), pretreated with epinephrine and amiodarone, were allocated to receive add-on treatment with landiolol or placebo. Landiolol was given as a 20 mg bolus infusion. The primary efficacy outcome was time from trial drug infusion to sustained return of spontaneous circulation (ROSC). Safety outcomes included the onset of bradycardia and asystole. RESULTS: A total of 36 patients were enrolled, 19 were allocated to the landiolol group and 17 to the placebo group. Time from trial drug infusion to sustained ROSC was similar between treatment groups (39 min [landiolol] versus 41 min [placebo]). Sustained ROSC was numerically lower in the landiolol group compared with the placebo group (7 patients [36.8%] versus 11 patients [64.7%], respectively). Asystole within 15 min of trial drug infusion occurred significantly more often in the landiolol group than in the placebo group (7 patients [36.8%] and 0 patients [0.0%], respectively). CONCLUSION: In patients with OHCA and refractory VF who are pretreated with epinephrine and amiodarone, add-on bolus infusion of landiolol 20 mg did not lead to a shorter time to sustained ROSC compared with placebo. Landiolol might be associated with bradycardia and asystole.