Livogrit prevents Amiodarone-induced toxicity in experimental model of human liver (HepG2) cells and Caenorhabditis elegans by regulating redox homeostasis.

Treatment with cationic amphiphilic drugs like Amiodarone leads to development of phospholipidosis, a type of lysosomal storage disorder characterized by excessive deposition of phospholipids. Such disorder in liver enhances accumulation of drugs and its metabolites, and dysregulates lipid profiles, which subsequently leads to hepatotoxicity. In the present study, we assessed pharmacological effects of herbal medicine, Livogrit, against hepatic phospholipidosis-induced toxicity. Human liver (HepG2) cells and in vivo model of Caenorhabditis elegans (N2 and CF1553 strains) were used to study effect of Livogrit on Amiodarone-induced phospholipidosis. In HepG2 cells, Livogrit treatment displayed enhanced uptake of acidic pH-based stains and reduced phospholipid accumulation, oxidative stress, AST, ALT, cholesterol levels, and gene expression of SCD-1 and LSS. Protein levels of LPLA2 were also normalized. Livogrit treatment restored Pgp functionality which led to decreased cellular accumulation of Amiodarone as observed by UHPLC analysis. In C. elegans, Livogrit prevented ROS generation, fat-6/7 gene overexpression, and lysosomal trapping of Amiodarone in N2 strain. SOD-3::GFP expression in CF1553 strain normalized by Livogrit treatment. Livogrit regulates phospholipidosis by regulation of redox homeostasis, phospholipid anabolism, and Pgp functionality hindered by lysosomal trapping of Amiodarone. Livogrit could be a potential therapeutic intervention for amelioration of drug-induced phospholipidosis and prevent hepatotoxicity.

Efficacy, safety, and economy of shensongyangxin capsules for the treatment of coronary heart disease arrhythmia: a meta-analysis of randomized controlled trials.

Background: Shensong Yangxin Capsules (SSYX) is a proprietary Chinese medicine commonly, used in the treatment of arrhythmia. In recent years, a flurry of randomized controlled trials of SSYX was reported in the treatment of Coronary heart disease arrhythmia in China. However, these experiments have not been systematically evaluated by economics. The purpose of this study was to assess the efficacy, safety, and economy of the SSYX in the treatment of arrhythmia in patients with coronary heart disease. Methods: With "Shensong Yangxin Capsules" "Coronary Heart Disease" "Coronary Atherosclerotic Heart Disease"and "Arrhythmia" as the subject words, the relevant journals and conference papers were searched manually in China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP, PubMed, Web Of Science, CBM, Embase and The Cochrane Library. The literature of randomized controlled trials of SSYX in the treatment of coronary heart disease arrhythmia was searched until November 2022. All data were analyzed using RevMan 5.3 Sotware and combined with cost-effectiveness for economic evaluation. Results: Twenty randomized controlled trials were included in this study, with a total of 2011 cases. The meta-analysis showed that the therapeutic effect of SSYX-metoprolol is superior to that of metoprolol alone. SSYX is superior to amiodarone in improving the total clinical effective rate, reducing the incidence of adverse reactions, and reducing the junction premature beats. There was no significant difference between the SSYX and amiodarone in the curative effect of ECG, ventricular premature complexes, and atrial premature beats. The results of pharmacoeconomics show that SSYX has a cost-effectiveness advantage in treating coronary heart disease arrhythmia. Single-factor sensitivity analysis also confirmed the stability of the results. In summary, SSYX has a curative effect, safety, and economy in treating coronary heart disease arrhythmia.

Amiodarone but not propafenone impairs bioenergetics and autophagy of human myocardial cells.

Cardiac and extra-cardiac side effects of common antiarrhythmic agents might be related to drug-induced mitochondrial dysfunction. Supratherapeutic doses of amiodarone have been shown to impair mitochondria in animal studies, whilst influence of propafenone on cellular bioenergetics is unknown. We aimed to assess effects of protracted exposure to pharmacologically relevant doses of amiodarone and propafenone on cellular bioenergetics and mitochondrial biology of human and mouse cardiomyocytes. In this study, HL-1 mouse atrial cardiomyocytes and primary human cardiomyocytes derived from the ventricles of the adult heart were exposed to 2 and 7 µg/mL of either amiodarone or propafenone. After 24 h, extracellular flux analysis and confocal laser scanning microscopy were used to measure mitochondrial functions. Autophagy was assessed by western blots and live-cell imaging of lysosomes. In human cardiomyocytes, amiodarone significantly reduced mitochondrial membrane potential and ATP production, in association with an inhibition of fatty acid oxidation and impaired complex I- and II-linked respiration in the electron transport chain. Expectedly, this led to increased anaerobic glycolysis. Amiodarone increased the production of reactive oxygen species and autophagy was also markedly affected. In contrast, propafenone-exposed cardiomyocytes did not exert any impairment of cellular bioenergetics. Similar changes after amiodarone treatment were observed during identical experiments performed on HL-1 mouse cardiomyocytes, suggesting a comparable pharmacodynamics of amiodarone among mammalian species. In conclusion, amiodarone but not propafenone in near-therapeutic concentrations causes a pattern of mitochondrial dysfunction with affected autophagy and metabolic switch from oxidative metabolism to anaerobic glycolysis in human cardiomyocytes.

AMIODARONE AND THYROID DYSFUNCTION.

Thyroid gland has a key role in maintaining the body homeostasis. Thyroxine is the main hormone secreted from the thyroid gland, its effect being predominantly achieved after the intracellular conversion of thyroxine to triiodothyronine, which exhibits a higher affinity for the receptor complex, thus modifying gene expression of the target cells. Amiodarone is one of the most commonly used antiarrhythmics in the treatment of a broad spectrum of arrhythmias, usually tachyarrhythmias. Amiodarone contains a large proportion of iodine, which is, in addition to the intrinsic effect of the medication, the basis of the impact on thyroid function. It is believed that 15%-20% of patients treated with amiodarone develop some form of thyroid dysfunction. Amiodarone may cause amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). AIT is usually developed in the areas with too low uptake of iodine, while AIH is developed in the areas where there is a sufficient iodine uptake. Type 1 AIT is more common among patients with an underlying thyroid pathology, such as nodular goiter or Graves' (Basedow's) disease, while type 2 mostly develops in a previously healthy thyroid. AIH is more common in patients with previously diagnosed Hashimoto's thyroiditis. Combined types of the diseases have also been described. Patients treated with amiodarone should be monitored regularly, including laboratory testing and clinical examinations, to early detect any deviations in the functioning of the thyroid gland. Supplementary levothyroxine therapy is the basis of AIH treatment. In such cases, amiodarone therapy quite often need not be discontinued. Type 1 AIT is treated with thyrostatic agents, like any other type of thyrotoxicosis. If possible, the underlying amiodarone therapy should be discontinued. In contrast to type 1 AIT, the basic pathophysiological substrate of which is the increased synthesis and release of thyroid hormones, the basis of type 2 AIT is destructive thyroiditis caused by amiodarone, desethylamiodarone as its main metabolite, and an increased iodine uptake. Glucocorticoid therapy is the basis of treatment for this type of disease.

Cardioprotective effects of amiodarone in a rat model of epilepsy-induced cardiac dysfunction.

Cardiac dysfunction is one of the leading causes of death in epilepsy. The anti-arrhythmic drug, amiodarone, is under investigation for its therapeutic effects in epilepsy. We aimed to evaluate the possible effects of amiodarone on cardiac injury during status epilepticus, as it can cause prolongation of the QT interval. Five rat groups were enrolled in the study; three control groups (1) Control, (2) Control-lithium and (3) Control-Amio, treated with 150 mg/kg/intraperitoneal amiodarone, (4) Epilepsy model, induced by sequential lithium/pilocarpine administration, and (5) the epilepsy-Amio group. The model group expressed a typical clinical picture of epileptiform activity confirmed by the augmented electroencephalogram alpha and beta spikes. The anticonvulsive effect of amiodarone was prominent, it diminished (p < 0.001) the severity of seizures and hence, deaths and reduced serum noradrenaline levels. In the model group, the electrocardiogram findings revealed tachycardia, prolongation of the corrected QT (QTc) interval, depressed ST segments and increased myocardial oxidative stress. The in-vitro myocardial performance (contraction force and - (df/dt)max ) was also reduced. Amiodarone decreased (p < 0.001) the heart rate, improved ST segment depression, and myocardial contractility with no significant change in the duration of the QTc interval. Amiodarone preserved the cardiac histological structure and reduced the myocardial injury markers represented by serum Troponin-I, oxidative stress and IL-1. Amiodarone pretreatment prevented the anticipated cardiac injury induced during epilepsy. Amiodarone possessed an anticonvulsive potential, protected the cardiac muscle and preserved its histological architecture. Therefore, amiodarone could be recommended as a protective therapy against cardiac dysfunction during epileptic seizures with favourable effect on seizure activity.

Identification of Two Different Phenotypes of Patients with Amiodarone-Induced Thyrotoxicosis and Positive Thyrotropin Receptor Antibody Tests.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AIT1) due to Graves' disease (GD). However, the TRAb role and function in AIT have not been clarified. Methods: A retrospective cohort study of 309 AIT patients followed at a single academic center over a 30-year period. AIT TRAb-positive patients (n = 21, 7% of all cases) constituted the study group; control groups consisted of type 2 AIT (AIT2) TRAb-negative patients (n = 233), and 100 non-AIT patients with GD. Clinical and biochemical data at diagnosis and during the course of disease were compared. Histological samples of patients who had total thyroidectomy were reviewed. Stored serum samples were used for a functional assay of TRAb class G immunoglobulins (IgGs) in Chinese hamster ovary (CHO) cells stably transfected with complementary DNA encoding for the TSH receptor. Results: TRAb-positive patients were grouped according to color flow Doppler sonography, radioactive iodine thyroid uptake, and duration of amiodarone therapy before thyrotoxicosis in type 1 (n = 9, 43%; TRAb1) or type 2 (n = 12, 57%; TRAb2) AIT. TRAb1 patients had clinical and biochemical features indistinguishable from GD controls, and were responsive to methimazole. Conversely, TRAb2 patients had clinical features similar to AIT2 controls, and were responsive to glucocorticoids, but not to methimazole. The CHO cell functional assay demonstrated that TRAb1 IgGs had a stimulatory effect on cyclic AMP production, which was absent in TRAb2 IgGs. Pathology in TRAb1 showed hyperplastic thyroid follicles and mild lymphocyte infiltration, reflecting thyroid stimulation. On the contrary, TRAb2 samples revealed follicle destruction, macrophage infiltration, and sometimes fibrosis, consistent with a destructive process. Conclusions: Almost 60% of TRAb-positive AIT patients had a destructive thyroiditis. TRAb-positive tests in AIT patients do thus not necessarily imply a diagnosis of GD and AIT1, and should be evaluated in the clinical and biochemical setting of each AIT patient and confirmed by measuring thyroid-stimulating immunoglobulins.

Clinical Efficacy and Safety of Shensong Yangxin Capsule-Amiodarone Combination on Heart Failure Complicated by Ventricular Arrhythmia: A Meta-Analysis of Randomized Controlled Trials.

Background: Shensong Yangxin capsule (SSYX) is a well-known traditional Chinese patent medicine for treating arrhythmia. Recently, a flurry of randomized controlled trials (RCTs) of SSYX combined with amiodarone (SSYX-amiodarone) was reported in the treatment of heart failure (HF) complicated by ventricular arrhythmia (VA) in China. However, these RCTs have not been systematically evaluated. Therefore, this study aimed to evaluate the efficacy and safety of SSYX-amiodarone in the treatment of heart failure complicated by ventricular arrhythmia (HF-VA). Methods: Seven electronic literature databases (the Cochrane Library, PubMed, EMBASE, China Biomedical database web, China National Knowledge Infrastructure Databases, Chinese Scientific Journal database and Wanfang database) were searched from their inceptions to June 1, 2020 to identify RCTs of SSYX-amiodarone in the treatment of HF-VA. The primary outcomes included the total effective rate and adverse events (ADRs). The secondary outcomes included the frequency of ventricular premature complexes, left ventricular ejection fraction, N terminal pro Btype natriuretic peptide (NT-proBNP), and QT dispersion (QTd). The quality of the included RCTs was assessed using the Cochrane risk-of-bias tool. All data was analyzed using RevMan 5.3 software. The registration number of this protocol is PROSPERO CRD42020196689. Results: There are Eighteen trials involving 1,697 patients were included in this study. Meta-analysis showed that SSYX-amiodarone group was superior to the amiodarone group in improving the total effective rate [RR = 1.21; 95%CI (1.16, 1.27); p < 0.01], meanwhile reducing the ADRs [RR = 0.65; 95%CI (0.45, 0.95); p = 0.03], VPCs [MD = 170.96; 95%CI (159.88, 182.04); p < 0.01] and QTd [MD = 8.39; 95%CI (6.91, 9.87); p < 0.01]. No significant difference of enhancing LVEF [MD = 4.32; 95%CI (-0.56, 9.20); p = 0.08] and reducing NT-proBNP [SMD = 0.17; 95%CI (-0.81, 1.14); p = 0.73] was observed between SSYX-amiodarone and amiodarone group. Conclusions: Despite the apparent positive findings reported, the evidence provided by this meta-analysis was still insufficient to support the routine use of SSYX-amiodarone for HF-VA due to the poor methodological quality of included studies. The overall effect should to be verified in further through more well-design clinical studies with reasonable sample and good methodological quality.

Grape seed extract protects against amiodarone - induced nephrotoxicity and ultrastructural alterations associated with the inhibition of biomarkers of inflammation and oxidative stress in rats.

Amiodarone (AMD) is one of the highly effective antiarrhythmic agents used for treating refractory arrhythmias. It is well known to have long-term administration side effects such as nephrotoxicity. The possible ameliorative effects of antioxidant grape seed extract; on the extent of tissue damage in AMD-induced nephrotoxicity has not been investigated before. Twenty-four albino rats were used in this study and divided into four groups (n = 6). The 1st group served as an untreated control group, under the same laboratory conditions, the 2nd group received (100 mg/kg/day) of grape seed extract (GSE), the 3rd group, AMD-treated group, received AMD (40 mg/kg/day) and the 4th group received both AMD and GSE in the same doses as the previous groups. AMD-treated group showed abnormal glomerular capillaries with wrinkling basement membranes damaged mesangial cells and distorted proximal tubules with plenty of lysosomes. Ultrastructural alterations were also observed in this group. This was also associated with a significant increase in biomarkers of kidney injury (creatinine), oxidative stress ((Decreased SOD and increased MDA) and biomarkers of inflammation IL-6) in comparison to the control group. Supplementation of GSE to AMD group for eight weeks counteracted these effects. It caused an improvement in histological and t ultrastructure changes of the renal tissues associated with decreased creatinine and biomarkers of oxidative stress and inflammation in comparison to AMD-treated group. We conclude that GSE protects against AMD-induced kidney injuries in rats, which is associated with the inhibition of biomarkers of inflammation and oxidative stress.

Use of an antiarrhythmic drug against acute selenium toxicity.

OBJECTIVE: Selenium is an essential trace element. But, selenium may have toxic effects in high doses. There are no proven antidotes or curative treatments for acut selenium toxicity. Treatment involves stopping the exposure and providing supportive care for symptoms. Therefore, it is necessary to find more effective substances in the treatment of selenium toxicity. The aim of this study was to increase the survival rate of animals by supporting the heart with amiodarone and to determine the effect of amiodarone on the pathological, hematological and biochemical parameters in acute selenium intoxication. METHODS: 64 Wistar-Albino rats were divided into four groups. Group I was given only distilled water, Group II was given 18 mg/kg dose of amiodarone, Group III was given 18 mg/kg amiodarone and 10 mg/kg sodium selenite and Group IV was given sodium selenite 10 mg/kg (LD50 dose)orally. RESULTS: 11 of the 16 animals in Group IV died within the first 48 h of drug administration. However, no deaths were observed in the rats in Group III. No hematological changes were observed. Biochemically, CK, CK-MB and LDH levels of Group IV were higher than the other groups on both the 2nd and 10th days. In Groups II and III, this serum level decreased, and vitamin B12 levels increased. In macroscopic inspections of the organs of Groups III and IV, slight paleness was detected. Histopathologically, degenerative changes in tissue were observed, especially in Group IV. CONCLUSION: This study shows that amiodarone application has a reducing effect on selenium toxicity. This was because amiodarone protected the heart by reducing CK and CK-MB levels and increased vitamin B12 levels, which play a role in the synthesis of S-adenosyl methionine that converts selenium into a nontoxic form.

In iodine-induced thyrotoxicosis, steroid therapy today could keep the surgical knife at bay.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) type 2, characterized as a destructive thyroiditis, is well described in the medical literature; however, iodine-induced thyrotoxicosis (IIT) is not, though the latter has similar features and can be managed similarly. CASE PRESENTATION: We present a 17-year-old female who presented with a history of an intermittent goiter with thyroid function tests (TFTs): thyroid-stimulating hormone (TSH)<0.015 (0.4-4 µU/mL), free thyroxine (T4)≥6 (0.7-2.1 ng/dL) and total triiodothyronine (T3) 651 (50-200 mg/dL). Thyroid antibodies were all negative. Despite methimazole therapy for 6 weeks, hyperthyroidism proved refractory to medical management. 123I scan uptake was suppressed. With hyperthyroidism being recalcitrant to therapy, a nutritional history revealed consumption of an iodine supplement containing at least 7 times the recommended daily allowance (RDA) for 5 years, contributing to the Jod-Basedow phenomenon. Urinary spot and 24-hour urinary iodine were both elevated. Though a surgical consult was obtained, surgery was cancelled once TFTs improved and then normalized with steroid therapy. The TFTs and urinary iodine levels remained normal post steroid therapy. CONCLUSIONS: We suggest that in addition to the need for a thorough nutritional history, a trial of corticosteroids should be utilized in the management of IIT which can present with findings similar to AIT type 2 which is recalcitrant to thionamide therapy. If successful, corticosteroids may delay or prevent surgical management thus avoiding possible complications with the latter approach.

Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone.

Phospholipidosis is a metabolic disorder characterized by intracellular accumulation of phospholipids. It can be caused by short-term or chronic exposure to cationic amphiphilic drugs (CADs). These compounds bind to phospholipids, leading to inhibition of their degradation and consequently to their accumulation in lysosomes. Drug-induced phospholipidosis (DIPL) is frequently at the basis of discontinuation of drug development and post-market drug withdrawal. Therefore, reliable human-relevant in vitro models must be developed to speed up the identification of compounds that are potential inducers of phospholipidosis. Here, hepatic cells derived from human skin (hSKP-HPC) were evaluated as an in vitro model for DIPL. These cells were exposed over time to amiodarone, a CAD known to induce phospholipidosis in humans. Transmission electron microscopy revealed the formation of the typical lamellar inclusions in the cell cytoplasm. Increase of phospholipids was already detected after 24 h exposure to amiodarone, whereas a significant increase of neutral lipid vesicles could be observed after 72 h. At the transcriptional level, the modulation of genes involved in DIPL was detected. These results provide a valuable indication of the applicability of hSKP-HPC for the quick assessment of drug-induced phospholipidosis in vitro, early in the drug development process.

Nursing of prevention of phlebitis caused by vein medication Amiodarone Hydrochloride / 中国生化药物杂志

Objective To research and analyze nursing measures of phlebitis caused by vein medication Amiodarone Hydrochloride. Methods 150 arrhythmias patients in the Traditional Chinese. Medicine Hospital of Wenling were selected as the subjects. The control group was given routine transfusion nursing, the experimental group was given comprehensive nursing intervention on the basis of the control group, saline irrigation before and after transfusion, observed the local reaction of patients, and controlled the concentration and external application of potato chips. Results After the corresponding nursing measures, in the control group, accounting for 46.7%. 35 cases of phlebitis occurred in the experimental group. The incidence of phlebitis in the experimental group was 16.0%, which was significantly lower than that (46.7%) in the control group, which was statistically significant (P<0.05). In the experimental group, the number of patients with I degree phlebitis was 8, and the proportion was 66.67%. In the control group, there were 7 cases of I degree phlebitis, accounting for 20%, which was statistically significant (P<0.05). In the experimental group, there were 4 cases of II degree phlebitis, the proportion was 33.33%, significantly lower than that (54.28%) of the control group (19 cases of II degree phlebitis) with statistical significance (P<0.05). Conclusion The application of comprehensive nursing measures in arrhythmia patients treated with Amiodarone Hydrochloride vein medication, could significantly reduce the occurrence of phlebitis and improve the curative effect with high safety and clinical significance.

Nursing of prevention of phlebitis caused by vein medication Amiodarone Hydrochloride / 中国生化药物杂志

Objective To research and analyze nursing measures of phlebitis caused by vein medication Amiodarone Hydrochloride. Methods 150 arrhythmias patients in the Traditional Chinese. Medicine Hospital of Wenling were selected as the subjects. The control group was given routine transfusion nursing, the experimental group was given comprehensive nursing intervention on the basis of the control group, saline irrigation before and after transfusion, observed the local reaction of patients, and controlled the concentration and external application of potato chips. Results After the corresponding nursing measures, in the control group, accounting for 46.7%. 35 cases of phlebitis occurred in the experimental group. The incidence of phlebitis in the experimental group was 16.0%, which was significantly lower than that (46.7%) in the control group, which was statistically significant (P<0.05). In the experimental group, the number of patients with I degree phlebitis was 8, and the proportion was 66.67%. In the control group, there were 7 cases of I degree phlebitis, accounting for 20%, which was statistically significant (P<0.05). In the experimental group, there were 4 cases of II degree phlebitis, the proportion was 33.33%, significantly lower than that (54.28%) of the control group (19 cases of II degree phlebitis) with statistical significance (P<0.05). Conclusion The application of comprehensive nursing measures in arrhythmia patients treated with Amiodarone Hydrochloride vein medication, could significantly reduce the occurrence of phlebitis and improve the curative effect with high safety and clinical significance.

Early Amiodarone-Induced Pulmonary Toxicity after Endovascular Aneurysm Repair: A Case Report.

Amiodarone is an antiarrhythmic drug that has been commonly used to treat supraventricular and ventricular arrhythmias. This drug is an iodine-containing compound that tends to accumulate in several organs, including the lungs. Especially, its main metabolically active metabolite desethylamiodarone can adversely affect many organs. A very well-known severe complication of amiodarone therapy is the amiodarone-induced pulmonary toxicity. This article presents the case study of an 82-year-old male patient with acute amiodarone-induced pulmonary toxicity. The patient underwent endovascular aneurysm repair for rapidly increasing abdominal aortic aneurysm. During the postoperative period the patient developed rapid atrial fibrillation and amiodarone therapy was initiated. Subsequently, the patient went into acute respiratory failure and was requiring high supplemental oxygen support and a chest X-ray revealed bilateral pulmonary infiltrates. During the hospital course the patient required mechanical ventilator support. With discontinuation of amiodarone, supportive therapy and steroid treatment patient symptoms significantly improved. Amiodarone-induced pulmonary toxicity must be considered in the differential diagnosis of all patients on the medication with progressive or acute respiratory symptoms. Early discontinuation of amiodarone and aggressive corticosteroid therapy should be considered as a viable treatment strategy.

Safety and efficacy of early radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation complicated with amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone is an antiarrhythmic drug that is frequently used to control atrial fibrillation (AF). Many patients with AF are afraid of the risk of ablation and take amiodar-one, some patients develop amiodarone-induced thyrotoxicosis (AIT). The purpose of the study was to investigate the safety and efficacy of early radiofrequency catheter ablation in patients with paroxysmal AF complicated with AIT. METHODS: From the 146 consecutive patients with paroxysmal AF who had been treated with amiodarone and underwent 3-dimensional mapping system guided circumferential pulmonary vein isolation (PVI) at our center from January 2013 to June 2014, 20 had developed AIT. Thirty controls with normal thyroid function and matched for baseline characteristics were selected. RESULTS: Pulmonary vein isolation was completed in all patients without serious complications and with similar procedural (170.60 ± 14.80 vs. 158.18 ± 9.06 min; p = 0.062) and X-ray exposure (16.48 ± 2.15 vs. 15.36 ± 1.57 min; p = 0.058) time in AIT vs. control groups; however, upon coronary sinus catheter pacing (from 300 ms to 200 ms) after intrave-nous isoproterenol administration 30 min post PVI, rates of induction of AF (35% vs. 3.33%; p = 0.005) and of non-pulmonary vein-related atrial tachyarrhythmias (50% vs. 6.67%; p = 0.01) were higher, while those for atrial flutter (15% vs. 3.33%; p = 0.17) and atrial tachycardia (15% vs. 6.67%; p = 0.31) were similar, as was the recovery of conduction of pulmonary vein potential (15% vs. 30%; p = 0.191). In AIT vs. control group, atrial tachyarrhythmia recurrence rate was higher at 3 months (45% vs. 16.67%, p = 0.032) but not between 3 and 12 months (30% vs. 23.33%; p = 0.418) follow-up. CONCLUSIONS: Early catheter ablation for paroxysmal AF in patients with AIT appeared safe and effective albeit with higher atrial tachyarrhythmia recurrence rate up to 3 months but not beyond 12 months after PVI relative to controls.

Rational design, synthesis and 2D-QSAR study of novel vasorelaxant active benzofuran-pyridine hybrids.

Reaction of 3-aryl-1-(benzofuran-2-yl)-2-propen-1-ones 3a-c with malononitrile in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol proceeds in a regioselective manner to afford 2-alkoxy-4-aryl-6-(benzofuran-2-yl)-3-pyridinecarbonitriles 4-37, which also obtained by treating ylidenemalononitriles 6a-q with 2-acetylbenzofuran 1 in the presence of sufficient amount of sodium alkoxide in the corresponding alcohol. The new chemical entities showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique. Compounds 11, 16, 21, 24 and 30 exhibited remarkable activity compared with amiodarone hydrochloride the reference standard used in the present study. CODESSA-Pro software was employing to obtain a statistically significant QSAR model describing the bioactivity of the newly synthesized analogs (N=31, n=5, R(2)=0.846, R(2)cvOO=0.765, R(2)cvMO=0.778, F=27.540. s(2)=0.002).

[Hemoptysis during concomitant treatment with rivaroxaban and amiodarone in a patient with a history of pulmonary disease]. / Krwioplucie w trakcie jednoczesnego leczenia rywaroksabanem i amiodaronem u chorego z obciazonym wywiadem plucnym.

UNLABELLED: Rivaroxaban, a selective inhibitor of active factor X, is metabolized by cytochrom P450 3A4 (CYP3A4) and is a substrate for transporter protein--P-glycoprotein (P-gp). Amiodarone, an antiarrhytmic agent, is classified as moderate CYP3A4 and P-gp inhibitor. A CASE REPORT: A 75-year-old male, who underwent lobectomy for bronchiectasis many years ago, is presented. For one year the patient was treated with rivaroxaban (20 mg/d) due to venous thromboembolism and recurrent episodes of atrial fibrillation. Two weeks after amiodarone initiation (200 mg/d) hemoptysis occurred and computed tomography revealed unilateral pulmonary infiltrates with ground-glass opacities limited to the lower lobe of the left lung. The symptoms disappeared following discontinuation of the two medications and did not recur while rivaroxaban was reintroduced in a dose of 15 mg/d; measurement of anti-Xa activity confirmed it as a therapeutic dose. Amiodarone, that had been used for a short time and well tolerated a few years before, was definitely withdrawn. CONCLUSIONS: The authors suggest, that the concomitant use of rivaroxaban and amiodarone should be very careful in patients with a history of pulmonary disease.

Aspectos morfológicos de la enfermedad hepática inducida por drogas / Morphological Issues of Drug Induced Liver Disease

La enfermedad hepática inducida por drogas es un fenómeno multifacético y su espectro morfológico es muy variado imitando cualquier patrón de daño hepático, tanto en pacientes expuestos en forma aguda o crónica, en aquellos susceptibles en forma idiosincrática a una dosis terapéutica o por toxicidad intrínseca, a su vez puede estar afectada por otros factores como son los genéticos, la edad o el sexo, el estado nutricional, la exposición a otros fármacos o la existencia de una enfermedad de base; puede ser la única manifestación clínica del efecto adverso de una droga o estar acompañado de manifestaciones sistémicas o de otros órganos, e incluso puede llegar a ser fatal (1). Su incidencia no está bien definida, algunos estudios afirman que la incidencia global es variable encontrándose entre 1-15 x 100.000 personas/año, en USA ocurren 20 nuevos casos x 100.000 habitantes/año. Se han descrito como causantes de lesión hepática más de 900 drogas, productos herbales, homeopáticos, suplementos dietéticos o toxinas, sean productos naturales o de la industria farmacéutica, utilizados o no en dosis terapéuticas, que son las responsables de aproximadamente 15% de consultas y hospitalizaciones por ictericia, hepatitis aguda o crónica; en la población adulta, por encima de los 50 años, llega a 40% de todos los casos de hepatitis. Es también la causante de 11-50% de casos de falla hepática aguda. Los datos publicados indican que los antibióticos son responsables entre un 27-46% de los casos, seguidos por medicamentos para enfermedades del sistema nervioso central entre 13-17%, antiinflamatorios y analgésicos de 5-17% y los productos herbales 9%. Nuevos biomarcadores y el uso de microRNA se están estudiando y serán prometedores en un futuro cercano para identificar pacientes que puedan presentar hepatotoxicidad inducida por medicamentos. Son tantos los tipos de lesión hepática atribuidos a estos agentes que solo podremos dar algunos ejemplos en este artículo, basados en los patrones de daño hepático y enfatizando la importancia de una adecuada y profunda correlación clínica (2, 3).

Drug-induced liver disease is a multifaceted phenomenon which has a varied morphological spectrum that mimics other patterns of liver damage both in cases of acute drug exposure and in cases of chronic exposure to drugs. Those patients who are idiosyncratically susceptible at the therapeutic dose or to intrinsic toxicity may also be affected by other factors including genetic factors, age, sex, nutritional status, exposure to other drugs and the existence of an underlying disease. The only clinical manifestation of the disease may be the adverse effect of a drug, but it can also be accompanied by systemic manifestations and manifestations in other organs, and it can even be fatal (1). The incidence of drug-induced liver disease is not well defined, but some studies claim that its overall annual incidence varies between 1/100,000 people and 15/100,000 people. In the United States, twenty new cases per 100,000 inhabitants occur every year. More than 900 natural and pharmaceutical drugs, herbal medicines, homeopathic products, dietary supplements and toxins have been reported to cause liver damage. This can occur whether or not they are used at normal therapeutic doses. These cases are responsible for about 15% of consultations and hospitalizations for jaundice, acute hepatitis, and chronic hepatitis in adults above the age of 50, and in up to 40% of all cases of hepatitis. Drug-induced liver disease also accounts for 11% to 50% of all cases of acute liver failure. Published data indicate that antibiotics are responsible for between 27% and 46% of cases, that drugs for diseases of the central nervous system are responsible for between 13% and 17%, anti-inflammatory and analgesic agents are responsible for between 5% and 17%, and herbal products are responsible for 9%. New biomarkers and the use of microRNA are being studied and may become promising alternatives in the near future for identifying patients susceptible to drug-induced hepatotoxicity. There are so many types of liver damage attributed to these agents that only give some examples can be provided in this article. These examples have been chosen on the basis ofn the patterns of liver damage with emphasis on the importance of proper and thorough clinical correlation (2, 3).

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

AIMS: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. METHODS AND RESULTS: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. CONCLUSION: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.