Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in HepG2 spheroids / 药物分析学报

Three-dimensional(3D)cell spheroid models combined with mass spectrometry imaging(MSI)enables innovative investigation of in vivo-like biological processes under different physiological and patho-logical conditions.Herein,airflow-assisted desorption electrospray ionization-MSI(AFADESI-MSI)was coupled with 3D HepG2 spheroids to assess the metabolism and hepatotoxicity of amiodarone(AMI).High-coverage imaging of＞1100 endogenous metabolites in hepatocyte spheroids was achieved using AFADESI-MSI.Following AMI treatment at different times,15 metabolites of AMI involved in N-desethylation,hydroxylation,deiodination,and desaturation metabolic reactions were identified,and according to their spatiotemporal dynamics features,the metabolic pathways of AMI were proposed.Subsequently,the temporal and spatial changes in metabolic disturbance within spheroids caused by drug exposure were obtained via metabolomic analysis.The main dysregulated metabolic pathways included arachidonic acid and glycerophospholipid metabolism,providing considerable evidence for the mechanism of AMI hepatotoxicity.In addition,a biomarker group of eight fatty acids was selected that provided improved indication of cell viability and could characterize the hepatotoxicity of AMI.The combination of AFADESI-MSI and HepG2 spheroids can simultaneously obtain spatiotemporal infor-mation for drugs,drug metabolites,and endogenous metabolites after AMI treatment,providing an effective tool for in vitro drug hepatotoxicity evaluation.

Prevalencia de medicamentos que prolongan el intervalo QT en salas de cardiología de un hospital de alta complejidad / Drug induced prolongation of Q-T interval in cardiology wards

Resumen: Antecedentes: La prevalencia del síndrome del QT largo (SQTL) producido por medicamentos es una de las reacciones adversas que en el último tiempo ha aumentado en prevalencia y mortalidad. No solamente ocurre con el uso de medicamentos para el tratamiento de cardiopatías, sino también en medicamentos con otra acción terapéutica. Objetivo: Evaluar la prevalencia del síndrome del SQTL inducido por medicamentos en salas de cardiología de un hospital de alta complejidad. Métodos: Estudio prospectivo, de tipo descriptivo y de corte transversal en 36 pacientes cardiópatas, que consistió en evaluar la frecuencia del uso de medicamentos que son capaces de producir un SQTL y la prevalencia de este efecto adverso. Los datos clínicos se recolectaron de la ficha clínica y de entrevistas con los pacientes. Se efectuó un seguimiento para detectar la aparición de prolongación del intervalo QT. Los resultados obtenidos fueron presentados por medio de estadística descriptiva (programa estadístico Statgraphics Centurion, versión XVI). No hubo estadística inferencial dada la ausencia de un grupo control. Resultados: 41,7%, de los 36 pacientes presentaron SQTL que en 86,7% de ellos fue asociado a un medicamento. Los medicamentos más frecuentemente asociados a este efecto adverso fueron Amiodarona (38,5%) y Ondansetrón (23,1%), y el factor de riesgo mayormente involucrado fue el sexo femenino (61,5%). Conclusión: Existió una alta prevalencia del uso de medicamentos que producen un SQTL, destacándose que existen medicamentos utilizados para otras patologías que también pueden producirlo.

Abstract: Background: The prevalence of the Long QT interval syndrome (LQTS) associated to drugs has increased en the last decades along with an increased mortality due to this condition. It occurs not only with drugs used to treat cardiac disease but also to other drugs. Aim: To evaluate the prevalence of drug induced LQTS in cardiology wards of a high complexity hospital. Method: This is a prospective, descriptive and cross sectional study in 36 patients with heart disease. The use of drugs known to affect the QT interval along with the frequency of LGTS were evaluated. Clincal data was obtained from clinical records and personal interviews. Patients were followed for the appearance of LQTS. Descriptive were used to present the results. No inferential statistics were used as no control group was involved (Statgraphics Centurion, version XVI). Results: 41.7% of the 36 patients developed LQTS and the association with drugs was present in 86.7% of them. The drugs most commonly identified were amiodarone (38.5%) and ondansetron (23.1%) of patients. Female geneder was the most common associated condition (61.5%). Conclusion: There was a frequent use of drugs known to produce LQTS, but other drugs may also be associated int this group of patients with heart disease admitted to intensive or intermediate care facilities.

Efficacy and speed of conversion of recent onset atrial fibrillation using oral propafenone versus parenteral amiodarone: A randomized controlled comparative study

Background: Atrial fibrillation is the most commonly encountered arrhythmia. Several antiarrhythmic agents are effective in restoring and maintaining sinus rhythm. Aim of the work: To compare the efficacy and rapidity of conversion of recent onset atrial fibrillation using oral propafenone versus intravenous infusion of amiodarone. Methods: The study included 200 patients with recent onset atrial fibrillation. Patients were equally divided into 2 groups; group A where intravenous infusion amiodarone was given and group B where oral propafenone was administrated. The effectiveness and the time needed for conversion of atrial fibrillation to sinus rhythm were compared in both groups. Results: The success of conversion of atrial fibrillation to sinus rhythm was 83% in group A and 85% in group B, p-value ¼ 0.699. The time elapsed from drug administration till conversion of atrial fibrillation was 9.07 ± 5.04 hours in group A versus 3.9 ± 1.54 hours in group B, p-value ¼ 0.001. In both groups, patients who showed failed conversion had a significantly larger left atrial diameter and a significantly higher high sensitivity C-reactive protein (hsCRP) level. Conclusion: Oral propafenone was faster than parenteral amiodarone in the conversion of recent onset atrial fibrillation to sinus rhythm. Patients with failed conversion had a bigger left atrial diameter and a higher hsCRP when compared to patients with successful conversion

Comparison of Effect of Combined Intravenous Amiodarone and Surgical Closure of OS ASD in Adults with Surgical Closure alone on Sinus Conversion of Concomitant Atrial Fibrillation — A Retrospective Case Series Analysis

Closure of Atrial Septal Defect has been proposed to increase conversion of concomitant Atrial Fibrillation (AF) to Normal Sinus Rhythm (NSR). Amiodarone is known to convert AF to NSR. Our findings support the use of single intraoperative dose of intravenous Amiodarone for increased conversion of pre-operative AF to NSR in OS ASD patients undergoing closure on CPB, although the effect was short lasting

Amiodarona: fortalezas y debilidades / Amiodarone strengths and weaknesses

Prescritos en la práctica clínica por su eficacia. En su inicio se utilizó para tratar la angina de pecho. hoy día es usado para el tratamiento de cualquier forma de taquicardia. Objetivo: Reconocer la prescripción de la Amiodarona y sus efectos adversos. Métodos: Se realizó una revisión descriptiva en las bases de datos de Lilacs donde se encontraron 18 artículos y en PubMed/Medline (Mesh) 206 artículos, de los cuales se le aplicaron los criterios de inclusión a 51 artículos. Conclusiones: La amiodarona es uno de los antiarrítmicos más utilizados para el tratamiento de las arritmias, su variedad de efectos adversos y toxicidad es conocida, por tanto, los pacientes en tratamiento ameritan un minucioso monitoreo(AU)

Introduction: Amiodarone is one of the most prescribed antiarrhythmic drugs in clinical practice due to its efficacy. Initially it was used to treat angina pectoris, however, today it is used to treat any form of tachycardia. Objective: To identify the prescription of amiodarone and its adverse effects. Methods: A descriptive review was carried out in Lilacs databases where 18 articles were found and in PubMed/Medline (Mesh) 206 articles were retrieved. The inclusion criteria were applied to 51 articles. Conclusions: Amiodarone is one of the most widely used antiarrhythmic drugs for the treatment of arrhythmias, its variety of adverse effects and toxicity is known, therefore, patients undergoing treatment justify careful monitoring(AU)

Tireotoxicose induzida pela amiodarona - revisão de literatura e atualização clínica / Amiodarone-induced thyrotoxicosis - literature review & clinical update

Resumo A amiodarona é amplamente utilizada no tratamento de arritmias atriais e ventriculares, porém devido sua alta concentração de iodo, o uso crônico da droga pode induzir distúrbios tireoidianos. A tireotoxicose induzida pela amiodarona (TIA) pode descompensar e exacerbar anormalidades cardíacas subjacentes, provocando aumento da morbidade e mortalidade, principalmente em pacientes com fração de ejeção do ventrículo esquerdo <30%. Os casos de TIA são classificados em dois subtipos que direcionam a conduta terapêutica. Os riscos e benefícios de manter a amiodarona devem ser avaliados de maneira individualizada, e a decisão de continuar ou suspender a droga deve ser tomada conjuntamente por cardiologistas e endocrinologistas. O tratamento de TIA tipo 1 é semelhante ao do hipertireoidismo espontâneo, sendo indicado o uso de drogas antitireoidianas (metimazol e propiltiouracil) em doses elevadas. A TIA tipo 1 mostra-se mais complicada, pois apresenta proporcionalmente maiores números de recorrências ou até mesmo a não remissão do quadro, sendo recomendado o tratamento definitivo (tireoidectomia total ou radioiodo). TIA tipo 2 é geralmente autolimitada, mas devido a elevada mortalidade associada a tireotoxicose em pacientes cardiopatas, o tratamento deve ser instituído para que o eutireoidismo seja atingido mais rapidamente. Em casos bem definidos de TIA tipo 2, o tratamento com corticosteroides é mais efetivo do que o tratamento com drogas antitireoidianas. Em casos graves, independentemente do subtipo, a restauração imediata do eutiroidismo por meio da tireoidectomia total deve ser considerada antes que o paciente evolua com piora clínica excessiva, pois a demora na indicação da cirurgia está associada ao aumento da mortalidade.

Abstract Amiodarone is widely used in treating atrial and ventricular arrhythmias; however, due to its high iodine concentration, the chronic use of the drug can induce thyroid disorders. Amiodarone-induced thyrotoxicosis (AIT) can decompensate and exacerbate underlying cardiac abnormalities, leading to increased morbidity and mortality, especially in patients with left ventricular ejection fraction <30%. AIT cases are classified into two subtypes that guide therapeutic management. The risks and benefits of maintaining the amiodarone must be evaluated individually, and the therapeutic decision should be taken jointly by cardiologists and endocrinologists. Type 1 AIT treatment is similar to that of spontaneous hyperthyroidism, using antithyroid drugs (methimazole and propylthiouracil) at high doses. Type 1 AIT is more complicated since it has proportionally higher recurrences or even non-remission, and definitive treatment is recommended (total thyroidectomy or radioiodine). Type 2 AIT is generally self-limited, yet due to the high mortality associated with thyrotoxicosis in cardiac patients, the treatment should be implemented for faster achievement of euthyroidism. Furthermore, in well-defined cases of type 2 AIT, the treatment with corticosteroids is more effective than treatment with antithyroid drugs. In severe cases, regardless of subtype, immediate restoration of euthyroidism through total thyroidectomy should be considered before the patient progresses to excessive clinical deterioration, as delayed surgery indication is associated with increased mortality.

Silymarin's defensive role against hepatotoxicity induced by amiodarone in albino rats / El efecto defensivo de silimarin contra la hepatotoxicidad inducida por amiodarona en ratas albinas

SUMMARY: Amiodarone (AMD), an orally powerful antidysrhythmic medication that has caused hepatotoxicity on long-term administration, is commonly used across the world. Silymarin ameliorative effects (SLM); this research elucidated the magnitude of the damage to the liver tissue in AMD. We divided 24 albino rats evenly into four groups given daily doses by gastric tube for eight weeks as follows; the 1st group acted as a control group; the 2nd group received SLM; the 3rd group received AMD; and the 4th group received AMD parallel to SLM. Liver tissues prepared for light, electron microscopic and serum samples screened for biomarkers (I)liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); (II) oxidative and antioxidant stress, malondialdehyde (MDA) and superoxide dismutase (SOD); and (III) inflammatory markers, tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6). The findings showed that AMD caused hepatic histological changes that included congestion of the blood vessels, leucocytic infiltration and cytoplasmic vacuolation. Ultrastructural degeneration of the mitochondria, endoplasmic reticulum swelling, nuclear pyknosis and increased fat droplets and lysosomes were observed. The biochemical findings showed an increase in the AMD group's ALT and AST activities. The group of rats treated with AMD and SLM, increased the improvements in histology and ultrastructure, while the ALT and AST levels were reduced. Our findings collectively agreed that SLM has a protective impact on AMD hepatotoxicity which can be due to its antioxidant properties.

RESUMEN: La amiodarona (AMD) es un fuerte medicamento antiarrítmico administrado por vía oral que ha causado hepatotoxicidad en la administración a largo plazo utilizado con frecuencia en todo el mundo. Efectos de mejora de la silimarina (SLM); esta investigación analizó la magnitud del daño al tejido hepático en la DMAE. Dividimos 24 ratas albinas de manera uniforme en cuatro grupos que recibieron dosis diarias por sonda gástrica durante ocho semanas de la siguiente manera; el primer grupo fue designado como grupo control; el segundo grupo recibió SLM; el tercer grupo recibió AMD; y el cuarto grupo recibió AMD en paralelo a SLM. Se prepararon tejidos hepáticos para muestras de suero, microscopía de luz y electrónica y se analizaron para biomarcadores (I) enzimas de daño hepático, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST); (II) estrés oxidativo y antioxidante, malondialdehído (MDA) y superóxido dismutasa (SOD); y (III) marcadores inflamatorios, factor de necrosis tumoral alfa (TNF-a) e interleucina-6 (IL-6). Los hallazgos mostraron que la DMAE genera cambios histológicos hepáticos que incluyen congestión de los vasos sanguíneos, infiltración leucocítica y vacuolación citoplásmica. Se observó una degeneración ultraestructural de las mitocondrias, aumento del retículo endoplásmico, picnosis nuclear y aumento de gotitas de grasa y lisosomas. Los hallazgos bioquímicos mostraron un aumento en las actividades de ALT y AST del grupo AMD. El grupo de ratas tratadas con AMD y SLM, aumentó las mejoras en histología y ultraestructura, mientras que se redujeron los niveles de ALT y AST. Nuestros hallazgos coincidieron colectivamente en que SLM tiene un impacto protector sobre la hepatotoxicidad de AMD debido a sus propiedades antioxidantes.

The influence of the gut microbiota on the bioavailability of oral drugs

Due to its safety, convenience, low cost and good compliance, oral administration attracts lots of attention. However, the efficacy of many oral drugs is limited to their unsatisfactory bioavailability in the gastrointestinal tract. One of the critical and most overlooked factors is the symbiotic gut microbiota that can modulate the bioavailability of oral drugs by participating in the biotransformation of oral drugs, influencing the drug transport process and altering some gastrointestinal properties. In this review, we summarized the existing research investigating the possible relationship between the gut microbiota and the bioavailability of oral drugs, which may provide great ideas and useful instructions for the design of novel drug delivery systems or the achievement of personalized medicine.

Falla hepática subaguda secundaria a hepatotoxicidad severa por medicamentos: reporte de caso / Subacute liver failure secondary to severe drug-related hepatotoxicity: case report

La falla hepática aguda es una patología rara con una mortalidad alta y causas variadas, entre ellas, la hepatotoxicidad secundaria al uso de medicamentos, con un diagnóstico diferencial difícil, en particular en presencia de polifarmacia. Esta patología se asocia con falla orgánica multisistémica que puede hacer necesario el trasplante hepático si no se logra la estabilización del paciente. Se presenta el caso de una mujer de 50 años con un cuadro de 6 semanas de evolución, consistente en dolor en hipocondrio derecho, náuseas e ictericia generalizada, quien presentó falla hepática aguda de tipo subagudo que finalmente requirió trasplante hepático. Se describe el abordaje diagnóstico hacia la identificación de una etiología medicamentosa probable por el uso de amiodarona, con la evolución positiva de la paciente después de 3 años de seguimiento postrasplante.

Acute liver failure is a rare disease with high mortality and a multitude of causes, including drug-induced liver injury, with a difficult differential diagnosis, particularly in the presence of polypharmacy. This pathology is associated with multisystemic organic failure which may require liver transplantation if patient stabilization is not achieved. We present the case of a 50-year-old woman with a 6-week history of right upper quadrant pain, nausea and generalized jaundice, who presented subacute liver failure which ultimately required liver transplantation. We describe the diagnostic approach towards the identification of a probable drug-related cause, due to the use of amiodarone, with a positive outcome for the patient after 3 years of post-transplant follow-up.

Toxicidad pulmonar aguda por amiodarona con dosis baja de impregnación: reporte de caso / Acute amiodarone pulmonary toxicity with low impregnation dose: case report

Se sabe que la amiodarona, un potente antiarrítmico, causa toxicidad pulmonar. La neumonitis intersticial crónica es la presentación más común. Sin embargo, la toxicidad pulmonar aguda es rara y provoca una mayor mortalidad. Se presenta un paciente de 61 años con fibrilación auricular persistente que, tras tratamiento por un mes con amiodarona vía oral a dosis baja de impregnación de 400 miligramos al día, desarrolló toxicidad pulmonar aguda secundaria al antiarrítmico confirmada por radiografía y tomografía. Su caso tuvo resolución después de la suspensión del fármaco y tratamiento con esteroides.

Amiodarone, considered a potent antiarrhythmic, is known to cause pulmonary toxicity. Chronic interstitial pneumonitis is the most common presentation. However, acute pulmonary toxicity is rare and has a higher case fatality rate. We present a 61-year-old patient with persistent atrial fibrillation who, after a one-month treatment with oral amiodarone at a low dose impregnation of 400 mg/day, develops acute pulmonary toxicity, with radiographic and tomographic resolution after antiarrhythmic suspension and steroid treatment.

Stability-indicating HPLC method for determination of amiodarone hydrochloride and its impurities in tablets: a detailed forced degradation study

Resumo Amiodarone hydrochloride is one of the most important drugs used to treat arrhythmias. The USP monograph for amiodarone hydrochloride describes an HPLC method for the quantification of seven impurities, however, this method shows problems that result in unresolved peaks. Moreover, there is no monograph for tablets in this compendium. Thus, a stability indicating HPLC method was developed for the determination of amiodarone, its known impurities and degradation products in tablets. A detailed forced degradation study was performed submitting amiodarone API, tablets and placebo to different stress conditions: acid and alkaline hydrolysis, oxidation, metal ions, heat, humidity, and light. Amiodarone hydrochloride API was susceptible to degradation in all stress conditions. The tablets also showed degradation in all environments, except in acidic condition. The analytes separation and quantification were achieved on an Agilent Zorbax Eclipse XDB-C18 column (100 x 3.0 mm, 3.5 µm). The mobile phase was composed of 50 mM acetate buffer pH 5.5 (A) and a mixture of methanol-acetonitrile (3:4, v/v) (B) in gradient elution. The method was validated in the range of 350-650 µg/mL for assay and 10-24 µg/mL for impurities determination. Therefore, this method can be used both for stability studies and routine quality control analyses.

Pre-operative embolization of thyroid arteries in a case of refractory amiodarone-induced thyrotoxicosis. Case report / Embolización preoperatoria de las arterias tiroideas en un caso de tirotoxicosis refractaria por amiodarona. Reporte de caso

Abstract Introduction: Amiodarone has become one of the main antiarrhythmic drugs. However, it may cause a wide variety of adverse effects, sometimes severe. Amiodarone-induced thyroid dysfunction is one of the best known problems, resulting in either thyrotoxicosis or hypothyroidism. Case presentation: A patient who, after 2 years of using amiodarone for the control of atrial fibrillation, developed thyrotoxicosis, refractory to conventional medical treatment. To optimize the patient's clinical condition before total thyroidectomy, embolization of thyroid arteries was performed. Conclusion: Embolization of the thyroid arteries as bridge therapy to thyroidectomy is an uncommon alternative in patients with amiodarone-induced hyperthiroidism. However, this treatment was useful to improve our patient's symptoms and to optimize the anesthetic/surgical procedure.

Resumen Introducción: La amiodarona se ha convertido en uno de los principales fármacos empleados en el manejo de las arritmias cardiacas. Sin embargo, puede llegar a presentar una amplia variedad de efectos adversos, en ocasiones graves. La alteración de la función tiroidea es uno de sus problemas más conocidos, que puede causar tanto hipertiroidismo como hipotiroidismo. Presentación del caso: Se presenta el caso de un paciente que, después de recibir durante dos años amiodarona para el control de una fibrilación auricular, desarrolló una tirotoxicosis refractaria al tratamiento médico clásico, por lo que se decidió realizar una embolización de las arterias tiroideas previa a tiroidectomía total, para lograr una optimización preoperatoria de su situación clínica. Conclusión: La embolización de las arterias tiroideas como terapia puente a la tiroidectomía es una alternativa poco empleada en pacientes con hipertiroidismo, más aun si es debido a la administración de amiodarona, con escasos datos publicados en la literatura. En nuestro caso fue de utilidad para mejorar la sintomatología del paciente y optimizar el procedimiento anestésico-quirúrgico.

Alteraciones endocrinas asociadas al uso medicamentos en el Programa Distrital de Farmacovigilancia de Bogotá durante el periodo 2012 a 2016 / Medication-use related endocrine disruption reported to the local pharmacovigilance program in Bogota, during 2012- 2016 / Alterações endócrinas associadas ao uso de medicamentos no Programa Distrital de Vigilância farmacológica em Bogotá no período 2012-2016

Objetivos. Conocer las reacciones adversas tipo endocrino asociado al uso de medicamentos y reportado al Programa Distrital de Farmacovigilancia de Bogotá durante el periodo 2012 a 2016. Materiales y métodos. Los reportes analizados corresponden al periodo del 1º de enero de 2012 al 31 de diciembre de 2016 del Programa Distrital de Farmacovigilancia. Su análisis se hizo mediante algoritmos de causalidad y por tipo de evento. Resultados. Se analizaron 85 reportes. Uno de ellos relacionado con una sospecha de problema de calidad del medicamento, los otros 84 relaciona-dos con reacciones adversas sobre los cuales se centró la investigación. De los 84 reportes, 36 (42,9 %) corresponden a reacciones adversas a medicamento tipo A y 26 (31 %) a reportes de reacciones adversas a medicamentos de tipo fallo terapéutico. Los principales efectos secundarios a los medicamentos fueron el aumento de los niveles de hormona paratiroidea por uso de cinacalcet en 27 (34,1 %) reportes, seguidas por el síndrome de Cushing relacionado con la administración de prednisolona en 12 (14,1 %), bocio por uso de adalimumab en 12 (14,1 %), hiperprolactinemia por el uso de risperidona en 10 (11,8 %) e hipotiroidismo inducido por amiodarona en 3 (3,4 %). Conclusiones. El desarrollo de estos estudios permite conocer las principales reacciones adversas que se presentan durante el uso habitual de los medicamentos, así como su perfil de seguridad.

Objective. Becoming familiar with medication-use related endocrine disruption reported to the local pharmacovigilance program in Bogotá during 2012-2016.Tools and methods. Analyzed reports are dated between January 1st, 2012 and December 31st, 2016 and were gathered from the Pharmacovigilance Program in Bogotá. The analysis of the said reports was conducted through causality algorithms and event type.Results. Out of 87 analyzed reports, two were not included in the study due to lack of information for its classification in one case and, medication-related problems in another case. 36 reports (42.9 %) were found to have adverse reaction to type A medications, while 26 reports (34.1%) were found to have medication related problem type therapeutic failure. The main medication related problems were associated to the use of Cinacalcet with increased levels of parathormone in 27 out of 87 analyzed reports in this study. Other medication related problems found were: Cushing Syndrome, associated with the use of prednisolone in 12 reports; Goiter associated to the use of adalimumab in 12 reports; Hyperprolactinemia associated to the use of Risperidone in 10 reports and, Hypothyroidism associated to the use of Amiodarone in 3 reports. Conclusions: Carrying out such studies allows for the understanding of the main medication-use problems that are shown during common use of medications, as well as their safety profile.

Objetivo. O objetivo do artigo é conhecer as alterações endócrinas associadas ao uso de medicamentos reportadas pelo Programa Distrital de Vigilância farmacológica em Bogotá. Materiais e métodos. Os reportes analisados correspondem ao período de janeiro de 2012 a dezembro 2016 e a analise foi realizada com algoritmos de causalidade e por tipo de evento. Resultados. Foram analisados 87 reportes, embora no final dois deles foram desconsiderados, um por corresponder a um problema relacionado com o medicamento e o outro por falta de informações para classifica-lo. Encontraram-se 36 (42%) de reportes associados a reações adversas perante os medicamentos tipo A e 26 (31%) de reportes de RAM tipo falho terapêutico. As principais RAM foram por uso de cinacalcet com aumento dos níveis de parathormona em 27 reportes (34%), seguidas de Síndrome de Cushing relacionado com prednisolona em 12 reportes (14,1%), bócio por uso de adalimumab em outros 12 re-portes, hiperprolactinemia por uso de risperidona em 10 casos (11,8%) e hipotiroidismo induzido por amiodarona em 3 casos. Conclusoes. O desenvolvimento destes estudos, permite conhecer as principais reações adversas causadas pelo uso habitual dos medicamentos mesmo como seu perfil de segurança.

Experimental study of silybin-phospholipid complex intervention on amiodarone-induced fatty liver in mice / 中华肝脏病杂志

Objective@#To probe into the mechanism and interventional effects of silybin-phospholipid complex on amiodarone-induced steatosis in mice.@*Methods@#Eight-week-old male C57BL/6 mice were divided into three groups (5 mice in each group): a control group (WT) with normal diet, a model group with amiodarone 150mg/kg/d by oral gavage (AM), and an intervention group on amiodarone 150mg/kg/d combined with silybin-phospholipid complex(AM+SILIPHOS. All mice were fed their assigned diet for one week. Then, one week later, serum alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol and high-density lipoprotein were detected of each group. A liver pathological change was observed by oil red O and H&E staining. Ultrastructural pathological changes of hepatocytes were observed to evaluate the intervention effect by transmission electron microscopy. RT-q PCR was used to detect the expression of peroxisome proliferator-activated receptor alpha and its regulated lipid metabolism genes CPTI, CPTII, Acot1, Acot2, ACOX, Cyp4a10 and Cyp4a14 in liver tissues. Intra-group comparison was done by paired t-test. One-way ANOVA was used for comparison between groups and semi-quantitative data were tested using Mann-Whitney U test.@*Results@#Oil Red O and H&E staining results of liver tissue in the intervention group showed that intrahepatic steatosis was significantly reduced when compared to model group. Transmission electron microscopy showed that the model group had pyknotic nuclei, mitochondrial swelling, structural damage, and lysosomal degradation whereas the intervention group had hepatic nucleus without pyknosis, reduced mitochondrial swelling and slight structural damage than that of model group. RT-q PCR results showed that the expression of peroxisome proliferator-activated receptor alpha, CPTI, CPTII, Acot1, Acot2, ACOX, Cyp4a10 and Cyp4a14 were increased in the model group but the expression of CPTI, Cyp4a14, Acot1 and peroxisome proliferator-activated receptor alpha were decreased in the intervention group (P < 0.05).@*Conclusion@#Silybin-phospholipid complex can alleviate amiodarone-induced steatosis, and its mechanism may play a role in protecting mitochondrial function and regulating fatty acid metabolism. Thus, silybin-phospholipid complex has potential intervention effect on amiodarone-induced fatty liver.

Diagnosis and treatment of amiodarone-related thyroid dysfunction / 中国实用内科杂志

Amiodarone can lead to a series of thyroid dysfunction in antiarrhythmic patients, including hypothyroidism(AIH) or hyperthyroidism(AIT), which will lead to irreversible injury and even life-threatening. Therefore, the diagnosis,classification and management of amiodarone-related thyroid dysfunction is challenging, and standardized management is imperative. Combined with the basic viewpoints of the guidelines and evidence-based, in particular the”guidelines for the use of amiodarone” and the “guidelines for the management of 2018 ETA amiodarone-related thyroid dysfunction”, the diagnosis and treatment of amiodarone-related thyroid dysfunction is systematically described, Some opinions and suggestions were put forward to solve the clinical problems of amiodarone related thyroid dysfunction.

Therapeutic effect of propafenone and amiodarone on paroxysmal supraventricular tachycardia and their safety / 心血管康复医学杂志

Objective :To compare therapeutic effect of propafenone and amiodarone on paroxysmal supraventricular tachycardia (PSVT) and their safety .Methods : A total of 90 PSVT patients ,who were treated in our hospital from Jan 2013 to May 2018 ,were selected .Patients were randomly and equally divided into propafenone group and amio—darone group ,each group received corresponding medication based on routine treatment for 24h.Blood pressure , heart rate ,cardiac function indexes :LVEDV ,LVESV and LVEF before and after treatment ,cardioversion time , successful cardioversion rate within 60 min and incidence of adverse reactions during treatment were observed and compared between two groups .Results : There was no significant difference in successful cardioversion rate (propafenone group 91.11% vs.amiodarone group 93.33%, P＝1.000) between two groups .Compared with be—fore treatment ,on 24h after treatment ,there were significant reductions in blood pressure and heart rate in two groups , P＝0. 001 all ;but there was no significant difference between two groups before and after treatment , P＞0.05 all.Cardioversion time of propafenone group was significantly shorter than that of amiodarone group [ (12. 66 ± 2.06) min vs .(22. 80 ± 2.28 ) min ] , P＝ 0. 001 .Compared with propafenone group on 24h after treatment , there was significant rise in LVEF [ (63. 24 ± 3.67)% vs.(66. 83 ± 4.01)%] ,significant reductions in LVEDV [ (96.65 ± 5.24) ml vs.(92. 09 ± 4.37) ml] and LVESV [ (38.40 ± 2.87) ml vs.(30. 13 ± 7.34) ml] in amioda—rone group , P＝ 0. 001 all.Total incidence rate of adverse reactions in amiodarone group was significantly lower than that of propafenone group (8.89% vs.24. 44%) , P＝0. 048. Conclusion : Propafenone and amiodarone possess significant therapeutic effect on PSVT .Propafenone possesses shorter cardioversion time ,while amiodarone posses— ses less adverse reactions and improve cardiac function .Therefore ,medication should be selected properly according to patient′s specific condition in clinic .

Effect of Wenxin granule combined with routine therapy on cardiac function, ventricular remodeling and local inflammatory response in patients with paroxysmal atrial fibrillation / 中国基层医药

Objective To explore the effects of Wenxin granule combined with conventional therapy on cardiac function,ventricular remodeling and local inflammatory response in patients with paroxysmal atrial fibrillation (PAF).Methods From February 2016 to February 2017,116 patients with PAF in the Integrated Traditional Chinese and Western Medicine Hospital of Taizhou were randomly divided into control group(55 cases) and combined group(61 cases) according to the digital table.The control group was treated with routine amiodarone hydrochloride tablets and enalapril maleate tablets,and the combined group was treated with Wenxin granule on the basis of the control group.The clinical efficacy of the two groups was compared,and the cardiac function,the level of inflammatory reaction and the index of ventricular remodeling before and after treatment were compared and analyzed in the two groups.The adverse reactions were observed and analyzed in the two groups.Results The total effective rate in the combined group was 93.44％,which was significantly higher than 76.36％ in the control group (x2 =6.745,P ＜ 0.05).After treatment,the left atrial diameter,the FS and CI levels in the combined group were significantly higher than those in the control group and before treatment (all P ＜ 0.05).The level of Pd in the combined group after treatment was (47.16 ± 0.80) ms,,which was significantly lower than that in the control group [(50.25 ± 0.75) ms] and that before treatment (t =21.395,48.318,all P ＜ 0.05).The levels of hs-CRP and BNP in the combined group were (7.12 ± 2.71) mg/L,(118.43 ± 11.16) ng/L,respectively,which were significantly lower than those in the control group [(11.21 ± 2.89) mg/L,(123.6 ± 11.27) ng/L] and before treatment (t =7.865,2.504,8.585,8.752,all P ＜0.05).After treatment,the LVEF level in the combined group was higher than that in the control group and before treatment (t =4.785,10.573,all P ＜ 0.05).The LVEDD and LVSV levels in the combined group were significantly lower than those in the control group and before treatment (t =9.089,2.313,10.890,4.299,all P ＜ 0.05).The total incidence rate of adverse reactions in the combined group was 6.56％,which was slightly lower than 7.28％ in the control group,but there was no statistically significant difference between the two groups(x2 =0.023,P＞0.05).Conclusion Wenxin granule combined with routine treatment in the treatment of PAF can significantly improve the clinical efficacy,improve the cardiac function obviously,delaye the ventricular remodeling,decrease the level of local inflammatory reaction significantly and the safety is high.

Therapeutic effects of irbesartan combined amiodarone on heart failure patients with atrial fibrillation and its influence on cardiac function ,plasma levels of Ang‐Ⅱ,NE and BNP／ / 心血管康复医学杂志

To study therapeutic effects of irbesartan combined amiodarone on heart failure (HF) patients with atrial fibrillation (AF) and its influence on cardiac function ,plasma levels of Ang‐Ⅱ,NE and BNP .Methods :A total of 98 HF patients with AF treated in our hospital from Sep 2016 to Sep 2017 were randomly divided into ami‐odarone group (received amiodarone based on routine treatment ) and combined treatment group (received irbesar‐ tan based on amiodarone group).Both group were treated for six months .HR ,BP ,cardiac function indexes ,plas‐ma levels of Ang‐Ⅱ,NE and BNP before and after treatment ,and incidence of adverse reactions were observed and compared between two groups .Results : Compared with before treatment ,after treatment ,there were significant reductions in HR ,BP ,LVEDd ,LVESd ,plasma levels of Ang‐Ⅱ,NE and BNP ,and significant rise in LVEF in two groups , P＜0. 05 or ＜0. 01. Compared with amiodarone group ,after treatment ,there were significant reduc‐tions in HR [(95. 6 ± 13.7) beats／min vs .(81. 4 ± 11. 8) beats／min] ,BP [(145. 7 ± 20.6)／(89.1 ± 11.4) mmHg vs.(132.3 ± 17.5)／(81.3 ± 10.2) mmHg] ,LVEDd [ (58.3 ± 5.2) mm vs.(53.2 ± 4.6) mm] ,LVESd [ (44. 2 ± 5. 1) mm vs.(38.1 ± 4.9) mm] ,plasma levels of Ang‐Ⅱ[(113.27 ± 10.14) pg／ml vs.(98.67 ± 8. 79) pg／ml] , NE [(1.90 ± 0. 31) pg／ml vs.(1.74 ± 0. 28) pg／ml] and BNP [(282.18 ± 54.16) pg／ml vs.(214. 36 ± 41. 25) pg／ml] ,and significant rise in LVEF [(39.8 ± 4.1)% vs.(48.6 ± 5. 5)%] in irbesartan group ,P＜0.01 all.There was no significant difference in incidence rate of adverse reactions during treatment between two groups , P＝ 0.712. Conclusion :Irbesartan combined amiodarone can effectively improve cardiac function ,reduce HR ,BP ,plasma lev‐els of Ang‐Ⅱ,NE and BNP with good safety in HF patients with AF .

Tirotoxicosis inducida por amiodarona (TIA): un reto diagnóstico y terapéutico / Amiodarone-induced thyrotoxicosis (TIA): a diagnostic and therapeutic challenge

Resumen La tirotoxicosis inducida por amiodarona (TIA) se presenta en 5-12% de los pacientes tratados con ese medicamento, tiene el potencial de exacerbar una enfermedad cardiaca, lo que incrementa la morbilidad o mortalidad de los pacientes. Existen 2 tipos de TIA, con mecanismos fisiopatológicos diferentes; es importante distinguir entre ellos ya que el tratamiento es diferente. Sin embargo esta distinción en ocasiones es complicada. Se presenta el caso de una paciente de 81 años con antecedente de leucemia mieloide aguda, que cursó con aumento de volumen de cuello 48 h después de haber sido egresada por un cuadro de fibrilación auricular (FA) tratada con infusión de amiodarona. Bioquímicamente con tirotoxicosis y reaparición de la FA. Se sospechó de una TIA. Para enfocar el tratamiento es indispensable distinguir entre los 2 tipos de tirotoxicosis inducida por amiodarona. El ultrasonido Doppler y el gammagrama tiroideo pueden ser útiles para establecer el diagnóstico. Se deben considerar las comorbilidades de los pacientes, así como los efectos secundarios al momento de establecer el tratamiento.

Abstract Amiodarone induced thyrotoxicosis (AIT) appears on the 5-12% of patients, it potentially can exacerbate a cardiac illness, leading to an increase in the morbility/mortality of patients. Two types of AIT exist, each one with a different etiology. It is important to distinguish between them to be able to establish a treatment. However, sometimes it can be quite difficult. Case Report: An 81 year-old woman, with a history of acute myelod leukemia, showed up with thyroid enlargement at the ER. She was discharged 48 h earlier, after an atrial fibrillation (AF) episode which was controlled with amiodarone IV infusion. Because the biochemical diagnosis of thyrotoxicosis and reaparition of AF,an AIT was suspected. To be able of distinguishing between the two types of AIT is essential to establish a treatment. The use of a thyroid doppler sonography and a thyroid scintigraphy is helpful. The comorbidities of the patient and the possible side effects should be taken into account when deciding the treatment.

Long QT syndrome secondary to drug interaction between hydroxychloroquine and amiodarone / Síndrome de QT largo secundario a la interacción entre hidroxicloroquina y amiodarona

Abstract: A 67-year-old female patient with a diagnosis of heart failure with preserved ejection fraction secondary to severe mitral regurgitation in treatment with metoprolol, spironolactone, and digoxin. She was diagnosed systemic lupus erythematosus (SLE) because of the presence of arthritis, alopecia, thrombocytopenia, direct positive Coombs +++, positive ANAs 1:1,280 and positive lupus anticoagulant. The rheumatology service indicated hydroxychloroquine 200 mg every 24 hours. She presented atrial fibrillation, and amiodarone was initiated. Two weeks later the patient was admitted because of presyncope, electrocardiogram showed sinus bradycardia with long QT interval. A temporary pacemaker was placed, and hydroxychloroquine and amiodarone suspended. Twenty-four hours later, a new electrocardiogram was taken showing pacemaker rhythm with reduction of the QT interval. After 72 hours the temporary pacemaker was removed and on the fifth day the patient was discharged with an electrocardiogram in sinus rhythm with a corrected QT (Bazett) of 456 miliseconds. The hydroxychloroquine was reinitiated following discharge. She presented another episode of atrial fibrillation, and was treated with amiodarone, hydroxychloroquine was suspended previously, and she did not present prolongation of QT interval. The long QT syndrome was present when amiodarone and hydroxychloroquine interacted.(AU)

Resumen: Paciente femenina de 67 años, con diagnóstico de insuficiencia cardiaca con fracción de expulsión preservada, secundaria a insuficiencia mitral severa, en tratamiento con metoprolol, espironolactona y digoxina. Le fue diagnosticado lupus eritematoso sistémico, debido a la presencia de artritis, alopecia, trombocitopenia, Coombs directo positivo +++, anticuerpos antinucleares positivos 1:1,280 y anticoagulante lúpico positivo. El Servicio de Reumatología indicó hidroxicloroquina 200 mg cada 24 horas. Presentó fibrilación auricular, por lo que se le inició amiodarona. Dos semanas posteriores la paciente es ingresada debido a un episodio de presíncope, se le realizó electrocardiograma que demostró bradicardia sinusal con un intervalo QT prolongado. Se le colocó un marcapasos temporal, además de que se suspendió hidroxicloroquina y amiodarona. Después de 72 horas se retiró el marcapasos, y al quinto día se egresó con un electrocardiograma en ritmo sinusal con el intervalo QT corregido por Bazett de 456 milisegundos. La hidroxicloroquina fue reiniciada al egreso. La paciente presentó otro episodio de fibrilación auricular y fue tratada con amiodarona, previa suspensión de hidroxicloroquina, sin presentar prolongación del intervalo QT. El síndrome de QT largo sólo se presentó con la interacción de amiodarona con hidroxicloroquina.(AU)