Artemisinin conferred cytoprotection to human retinal pigment epithelial cells exposed to amiodarone-induced oxidative insult by activating the CaMKK2/AMPK/Nrf2 pathway.

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)ɑ (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.

The possible effects of chronic administration of amiodarone hydrochloride on the seminiferous tubules of adult male albino rats: histological and biochemical study.

Amiodarone hydrochloride is an antiarrhythmic agent that is widely prescribed. However, it has serious side effects that approximately affect the whole body organs. In our study, we aimed to assess the possible effects of chronic administration of two different doses of amiodarone hydrochloride on the oxidative and inflammatory parameters as well as the histological morphology and ultrastructure of the seminiferous tubules of adult male albino rats. Forty rats were divided into four groups; Control group 1: each rat did not receive any drugs at all. Control group 2: each rat received 3 ml of 0.16% methylcellulose, orally and daily for 4 weeks. Low dose amiodarone group: each rat received 3 ml of 0.16% methylcellulose contained 3.6 mg amiodarone, orally and daily for 4 weeks. High dose amiodarone group: each rat received 3 ml of 0.16% methylcellulose contained 7.2 mg amiodarone, orally and daily for 4 weeks. Blood samples were collected for measuring serum levels of malondialdehyde, superoxide dismutase, interleukin-6 and tumor necrosis factor-alpha. Testes specimens were examined to assess the morphological changes and the level of expression of caspase-3 apoptotic marker. The results indicated that; amiodarone hydrochloride could induce a dose-dependent toxicity, causing oxidative stress, inflammation, cellular degeneration, deposition of collagen and enhanced apoptosis in the seminiferous tubules.

Bio-spectroscopic investigation linking changes of retinal structure with short-term administration of Amiodarone and revealing the ameliorative effect of vitamin E supplementation.

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.

Comparison of Amiodarone Loading Dosage in the Treatment of Postoperative Atrial Fibrillation: High Versus Standard Dose Treatment.

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with poor outcomes, including hemodynamic instability, stroke, myocardial infarction, and death. In hemodynamic stable patients, the rhythm-control strategy is more advantageous than rate control. Current standard intravenous amiodarone administration has limited success and a delayed effect; the acute success rate is 44% (8-12 h to several days). PURPOSE: The aim of this study was to evaluate the effectiveness of higher amiodarone loading dosage to restore sinus rhythm in patients with POAF after noncardiac surgery. METHODS: This is a prospective, randomized, controlled single-center study. The study included 39 patients with POAF, divided into group I (n=27) (intravenous 600 mg amiodarone loading dosage over 2 h and infusion of 50 mg/h over a 24-h period) and group II (n=12) (standard protocol; 300 mg of bolus intravenously in 30 min and infusion of 50 mg/h over a 24-h period). The primary endpoint of the study was a restoration of sinus rhythm at the 24th hour. RESULTS: Baseline clinical, laboratory and echocardiographic characteristics of both groups were similar. The patients with higher loading amiodarone dosage had earlier restoration of sinus rhythm (2.38±1.41 vs 8.66±2.87 h, respectively; p=0.015). There was no significant difference in achieving sinus rhythm at the 24th hour between both groups. CONCLUSION: Higher loading amiodarone dosage increased early conversions to sinus rhythm compared with standard amiodarone protocol in patients with POAF.

Identifying Subgroups with Differential Responses to Amiodarone among Cardiac Arrest Patients with a Shockable Rhythm at Hospital Arrival using the Machine Learning Approach.

Background: There are few reports of studies on the differential effects of amiodarone among out-of-hospital cardiac arrest (OHCA) patients with a shockable rhythm at hospital arrival. The present study aimed to investigate the clinical heterogeneity of OHCA patients with a shockable rhythm upon hospital arrival and to identify subgroups with differential responses to amiodarone, using a machine learning approach. Methods: We used the Japanese nationwide OHCA registry of the Japanese Association for Acute Medicine for this study; data from OHCA patients with a shockable rhythm at hospital arrival were included in the analyses. The primary outcome was a favorable neurological outcome at 30 days. We developed a scoring system by the weighting method with logistic likelihood loss to identify patient subgroups showing differential effects of amiodarone from the point of view of the neurological outcome and survival at 30 days. Results: Among the 68,111 cases of OHCA in the registry, the data of 2333 OHCA patients with an initial shockable rhythm at hospital arrival were analyzed. The developed score identified higher age, longer interval between the call to the emergency medical service and hospital arrival, absence of a "witness", no defibrillation prior to hospital arrival, hypothermia at hospital arrival, and pre-hospital epinephrine administration as variables that were significantly associated with a beneficial effect of amiodarone. Based on the results of the developed scoring system, 47% (1107/2333) of the patients were considered to greatly benefit from amiodarone administration, whereas 53% (1226/2333) of patients were considered to not benefit from amiodarone administration. The effect of amiodarone on the neurological outcome at 30 days varied significantly among the subgroups identified by the developed score ( OR interaction : 1.07 [95% confidence interval (CI): 0.99-1.13], p = 0.005). Conclusions: We successfully developed a model that could discriminate between OHCA patients with an initial shockable rhythm at hospital arrival who would benefit or not benefit from the administration of amiodarone in terms of the neurological outcome at 30 days. There was clinical heterogeneity among OHCA patients with a shockable rhythm in terms of their response to amiodarone.

Life-threatening amiodarone-induced thyrotoxicosis - Personalized approach to radical treatment.

Objective: Amiodarone is an iodine-rich molecule and an effective antiarrhythmic drug. It is a first-line treatment for patients with life-threatening ventricular arrhythmias and for prevention in patients at high risk. The use of amiodarone may cause serious adverse effects such as pharmacotherapy-resistant, life-threatening amiodarone-induced thyrotoxicosis (AIT)leading to rapid deterioration of the patient's condition.According to the European Thyroid Association (ETA) guidelines, emergency thyroidectomy is the first-line treatment option in these cases. ; however, is not always feasible in the clinical setting due to the high anesthetic risk.We aimed to assess the clinical course and results of urgent thyroidectomy and 131-I therapy in patients with severe AIT with worsening of cardiac status. Methods: Retrospective analysis of the clinical course and outcomes of life-threatening AIT refractory to pharmacotherapy in patients hospitalized at a tertiary endocrinology center between 2014 and 2022. Results: An electronic database search identified 75 patients hospitalized for severe AIT. At the time of AIT diagnosis, median Thyroid-stimulating hormone (TSH) concentration was 0.001 mIU/L (range 0.001-0.35), fT4 63.2 pmol/L (range 9.0 - >100), and fT3 10.2 pmol/L (range 3.8-49.3). All patients received optimal conservative treatment. Among them, 20 required urgent radical therapy due to worsening arrhythmias and/or AIT-related heart failure. In this group, 6 patients died before any radical treatment was applied, 6 underwent total thyroidectomy, while 8 patients were successfully treated with 131-I (in 6 cases after rhTSH stimulation). The median dose of 131-I used for the therapy was 784MBq (range 627-860). The decision to treat with 131-I despite low but detectable 131-I uptake (median value 6 %) was made in cases of significant contraindications to anesthesia due to refractory ventricular arrhythmias, exacerbation of severe heart failure unresponsive to cardiac treatment, myocardial infarction during AIT course, massive pulmonary embolism. Conclusion: The decision regarding the optimal time and type of radical treatment of AIT refractory to pharmacotherapy is critical for patients management and should not be delayed. Urgent therapy with 131-I may be an effective therapeutic option in patients who are unsuitable for thyroidectomy due to the high risk of anesthesia.

The effect of strain effect on WS2 monolayer as a potential delivery carrier for anti-myocardial infarction drug: First-principles study.

CONTEXT: Myocardial infarction is one of the major health challenges. It is of great significance to develop potential delivery carriers for new anti-myocardial infarction drugs. In this paper, based on first-principles calculations, monolayer WS2 with excellent photoelectric properties was verified as a carrier for the anti-myocardial infarction drug amiodarone (AMD). Studies have shown that the WS2-adsorbed AMD system (WS2@AMD) maintains structural stability and produces an adsorption energy of-2.12 eV. Mulliken charge analysis shows that electrons are transferred from WS2 atoms to AMD atoms. Among them, C, N and O obtained the maximum values of 0.51,0.37 and 0.56 e electrons, respectively, while H and I lost the maximum values of 0.32 and 0.24 e electrons, respectively. The optical response of WS2 adsorbed AMD system is similar to that of WS2. The light absorption coefficients of the two materials in the near ultraviolet region and the visible region can reach the order of 105 cm-1 and 104 cm-1, and the strain makes the light absorption peak red-shifted. The feasibility of temperature-controlled release mechanism of WS2 as AMD carrier was discussed. This theoretical work helps to improve the performance of two-dimensional nanomaterials and make them better as drug delivery carriers to improve the therapeutic effect of myocardial infarction. These results indicate that the WS2 monolayer has potential applications in the development of drug delivery carriers. METHODS: In this study, based on first-principles calculations, the CASTEP simulation software package was used to study the structure and properties of materials. The interaction between electrons and ions is considered by using Ultrasoft pseudopotentials. In order to eliminate the spurious interaction between adjacent structures caused by periodic calculations, a vacuum space no less than 18 Å is placed in the vertical direction if necessary. Different functions may produce different density functional calculation results. Due to the low sensitivity of the crystal structure to the calculation details, the PBE functional under the generalized gradient approximation (GGA) was initially used for structural optimization, and the energy cutoff value was set to 500 eV. Grimme 's dispersion correction was used to make the results more accurate. The Brillouin zone (BZ) is sampled by a 7 × 7 × 1 K-point grid to ensure the reliability of the original lattice calculation. The lattice vector and atomic coordinates are relaxed, and the tolerance of each atom is less than 0.01 eV/Å. The energy tolerance at the atomic position is less than 10-7 eV/atom. When calculating the band gap, the HSE06 hybrid functional is used to modify the optimized structure of the PBE functional to obtain more accurate results. Spin-polarized DFT calculations were performed to calculate the electronic structure.

QT Prolongation Preceding Ventricular Fibrillation After Amiodarone Administration: A Case Report.

Atrial fibrillation (AF) is the most common long-term arrhythmia in adults. Rhythm control in patients with AF involves efforts to restore and maintain sinus rhythm and is accomplished by medication, catheter ablation, or electrical cardioversion. Amiodarone represents one of the most commonly used antiarrhythmic medications. Prolonged use of amiodarone can lead to many side effects. One of the most severe side effects is drug-induced long QT syndrome (LQTS), which can cause malignant arrhythmias and sudden cardiac death. We presented a case of a 52-year-old male who was admitted to the Coronary Unit due to first diagnosed AF with a rapid ventricular response. After amiodarone infusion was administrated the patient lost consciousness and the monitor displayed torsades de pointes (TdP) ventricular tachycardia with rapid conversion to ventricular fibrillation (VF). Cardiac resuscitation with two direct current (DC) shocks was performed. The patient was stabilized, and restoration of sinus rhythm with significant QT prolongation on the ECG was noted. This is a rare case of short-term amiodarone administration causing LQTS, TdP, and VF. The findings or observations emphasize the significance of diligent ECG monitoring during amiodarone treatment.

A Case of Amiodarone-Induced Thyrotoxicosis Presenting With Methimazole-Induced Agranulocytosis.

Amiodarone is a class III anti-arrhythmic drug found to be effective in treating multiple life-threatening arrhythmias, including paroxysmal atrial fibrillation. Despite its effectiveness, amiodarone has been found to result in thyroid dysfunction. Amiodarone-induced thyrotoxicosis (AIT) is classified as type 1, which often develops in those with autoimmune hyperthyroid conditions, or type 2, which occurs because of destructive thyroiditis in an apparently normal thyroid. Differentiating between both types often poses a clinical and therapeutic dilemma, as AIT 1 is treated with thionamides, whereas AIT 2 requires steroids for treatment. We present a case of a patient with AIT who was treated empirically for both subtypes with methimazole and prednisone without clinical improvement. Methimazole was later stopped due to concern for agranulocytosis, and the patient was then treated with cholestyramine, metoprolol, and prednisone. Given persistent thyrotoxicosis, the decision was made to proceed with surgical intervention. The patient underwent a successful total thyroidectomy without complications. The patient's condition clinically improved post-surgery and was discharged home on post-operative day 2 in stable condition. Prednisone was tapered over two weeks, and he was started on a weight-based dose of levothyroxine. He continues to follow up in our clinic for postoperative hypothyroidism and is clinically and biochemically euthyroid.

Myxedema Coma: Recognition of a Rare Endocrine Emergency.

An 82-year-old patient with multiple comorbidities presented to the emergency department with progressive dyspnea, orthopnea, and anorexia. Despite initial treatment for community-acquired pneumonia and decompensated heart failure, her condition deteriorated, manifesting as severe hypotension, bradycardia, and refractory hypothermia. A detailed medical history and extensive systematic investigation led to the documentation of hypothyroidism complicated by myxedema coma, in the context of chronic amiodarone use and precipitated by sepsis. Treatment with intravenous levothyroxine and glucocorticoids resulted in significant clinical improvement, leading to eventual hospital discharge. This case highlights the complexity and diagnostic challenges of myxedema coma, emphasizing the importance of early recognition, appropriate application of diagnostic scoring systems, and describing key aspects of the proper management of this rare endocrine emergency, whose symptoms and clinical signs are nonspecific.

Incidence of All-Cause, Cardiovascular, and Atrial Fibrillation-Related Hospitalizations: Focus on Antiarrhythmic Drugs.

Background: Atrial fibrillation (AF) is associated with an increased risk of hospital admission, but few data on reasons for hospitalization and on the role of anti-arrhythmic drugs are available. Objectives: The purpose of this study was to investigate the incidence rate and factors associated with all-cause, cardiovascular, and AF-related hospitalizations. Methods: Prospective ongoing ATHERO-AF (Atherosclerosis in Atrial Fibrillation) cohort study enrolling AF patients on oral anticoagulants. Primary end points were all-cause, cardiovascular, and AF-related hospitalization, the latter defined as AF recurrences for paroxysmal AF and high-rate symptomatic AF episodes for persistent/permanent AF patients. Results: 2,782 patients were included (43.5% female; mean age was 74.6 ± 9.1 years). During a mean follow-up of 31 ± 26.8 months, 1,205 (12.1%/year) all-cause, 533 cardiac (5.7%/year), and 180 (2.0%/year) AF-related hospitalizations occurred. Predictors of AF-related hospitalizations were the use of flecainide/propafenone in both paroxysmal and persistent/permanent AF patients (HR: 1.861; 95% CI: 1.116 to 3.101 and 1.947; 95% CI: 1.069 to 3.548, respectively). Amiodarone (HR: 3.012; 95% CI: 1.835-4.943), verapamil/diltiazem (HR: 2.067; 95% CI: 1.117-3.825), and cancer (HR: 1.802; 95% CI: 1.057-3.070) but not beta-blockers and digoxin were associated with an increased risk of AF-related hospitalizations in persistent/permanent AF patients. Conclusions: Elderly AF patients frequently undergo hospitalizations for both cardiovascular and noncardiovascular causes. The use of anti-arrhythmic drugs was associated with an increased risk of AF-related hospitalization suggesting a scarce effect of these drugs in preventing AF episodes. Therefore, their use should be carefully considered and reserved for symptomatic patients with frequent AF recurrences.

Case Report: Amiodarone-induced multi-organ toxicity.

Background: Amiodarone is a class III antiarrhythmic drug that is commonly used in the clinic to treat ventricular arrhythmias and atrial fibrillation. We present a case report of the adverse effects of amiodarone and review its characteristics. Case report: A 73-year-old Asian female with a history of paroxysmal atrial fibrillation managed with amiodarone, well-controlled hypertension, and no substance abuse presented with gastrointestinal distress and dizziness, without chest pain or palpitations. Despite normal annual check-ups, she developed abnormal liver and thyroid function tests, and imaging revealed lung and liver changes suggestive of amiodarone toxicity. Discontinuation of amiodarone for sotalol led to symptom improvement and normalization of thyroid and liver functions, with imaging indicating recovery from interstitial fibrosis and reduced liver density. Discussion: Amiodarone, a widely used for treating ventricular and atrial arrhythmias, and with significant benefits in improving patient survival in cases of ventricular fibrillation. However, its long-term use is associated with serious adverse effects, including thyroid dysfunction, liver injury, and pulmonary toxicity, necessitating careful monitoring and management. Despite its efficacy, the need for research on early detection and management of amiodarone's side effects is crucial, highlighting the importance of regular monitoring and possibly adjusting therapy to mitigate these risks.

Amiodarone-Induced Anaphylaxis.

Background: Amiodarone-induced anaphylaxis is seldom reported. The mechanism of this anaphylaxis is unknown. Methods: A literature search was carried out with keywords "Amiodarone" and "Anaphylaxis" and "polysorbate 80" or "hypotension." A search using "amiodarone" in the FDA Adverse Event Reporting System (FAERS) from 1969 to 2024 was also conducted. Results: There are a total of 10 cases of amiodarone-induced anaphylaxis in the literature. Six patients were male. Ages ranged from 15 to 86 years old. Nine cases were triggered by intravenous injection (IV) and one by oral administration. Eight patients did not have previous exposure to amiodarone. The trigger times for IV amiodarone were immediate to 90 minutes. All nine cases of IV amiodarone resulted in hypotension (90%), with an immeasurable blood pressure (70%). Presentations included bronchospasm or a skin rash (60%), angioedema (40%), and unconsciousness (20%). Only one patient had a history of allergy to penicillin and sulfonamide. An amiodarone skin test was positive on one patient. Increased blood tryptase (4 cases), positive basophil activation test to amiodarone (2 cases), increased eosinophil count (1 case), and increased serum IgE (1 case) were reported. Amiodarone was terminated in 80% of the patients. Epinephrine, norepinephrine, antihistamine-1, or steroids were used to rescue patients. Four patients were intubated. All patients fully recovered. In the FAERS database, 89 cases of amiodarone-associated anaphylaxis were reported, resulting in 14 deaths. Conclusions: Solvent polysorbate 80, amiodarone, and iodide may contribute to amiodarone-induced anaphylaxis. Prompt treatment is the key to saving patients.

L-Carnitine Ameliorates Amiodarone-Mediated Alveolar Damage: Oxidative Stress Parameters, Inflammatory Markers, Histological and Ultrastructural Insights.

The aim of this study was to assess L-carnitine's effects on adult male rats' lung damage brought on by amiodarone, which is a potent antiarrhythmic with limited clinical efficacy due to potentially life-threatening amiodarone-induced lung damage. Because of the resemblance among the structural abnormalities in rats' lungs that follows amiodarone medication and pulmonary toxicity in human beings, this animal model may be an appropriate example for this disease entity. Amiodarone produced pulmonary toxicity in twenty-four healthy male albino rats (150-180 g) over a period of 6 weeks. Four groups of six rats each were established: control, sham, amiodarone, and L-carnitine plus amiodarone. Histological, ultrastructural, oxidative stress, and inflammatory markers were determined during a 6-week exposure experiment. Amiodarone-induced lung damage in rats may be brought on due to oxidative stress producing significant pulmonary cytotoxicity, as evidenced by the disruption of the mitochondrial structure, severe fibrosis, and inflammatory response of the lung tissue. Lungs already exposed to such harmful effects may be partially protected by the antioxidant L-carnitine. Biochemical markers of lung damage brought on by amiodarone include lung tissue levels of the enzyme's catalase, superoxide dismutase, and reduced glutathione. The levels of lipid peroxides in lung tissue measured as malondialdehyde increased significantly upon exposure to amiodarone. In addition, the levels of tumor necrosis factor alpha were significantly elevated in response to amiodarone. The effect of L-carnitine on amiodarone-induced pulmonary toxicity was studied in rats. It is interesting to note that the intake of L-carnitine in rats treated with amiodarone partially restored the biochemical and histopathological alterations brought on by amiodarone to their original levels. Tumor necrosis factor alpha levels were significantly reduced upon L-carnitine exposure. These results suggest that L-carnitine can be used to treat amiodarone-induced pulmonary dysfunction.

Co-Administration of Amiodarone Increases Bleeding by Affecting Rivaroxaban Pharmacokinetics in Patients with Atrial Fibrillation.

This study aimed to investigate the impact of the drug-drug interaction between rivaroxaban and amiodarone on the clinical outcomes in patients with non-valvular atrial fibrillation (NVAF), focusing on pharmacokinetic and pharmacodynamic (PK/PD) aspects. A prospective study enrolling 174 patients with NVAF who were treated with rivaroxaban was conducted. The patients were divided into two groups based on postoperative antiarrhythmic and anticoagulation strategies: the rivaroxaban group (Control group) and the rivaroxaban plus amiodarone group (Riv/Amio group). The trough plasma concentrations (Ctrough) of rivaroxaban, activated partial thromboplastin time (APTT), prothrombin time (PT), and the clinical outcomes between the two groups were compared. Patients receiving 20 mg of rivaroxaban in the Riv/Amio group had a higher concentration of rivaroxaban Ctrough than those in the Control group (p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban Ctrough was significantly increased in the Riv/Amio group. There was no significant difference in PT and APTT between the two groups. Regarding the clinical outcomes, the combination of rivaroxaban and amiodarone medication was associated with a higher incidence of bleeding events (p = 0.041; HR = 2.83, 95% CI 1.05-7.66) and clinically relevant non-major bleeding (p = 0.021; HR = 3.65, 95% CI 1.21-10.94). Finally, independent risk factors for bleeding in NAVF patients treated with rivaroxaban were identified as its combination with amiodarone (p = 0.044; OR = 2.871, 95% CI 1.028-8.023). The combination of rivaroxaban and amiodarone led to changes in rivaroxaban pharmacokinetics and an elevated risk of bleeding events. Therefore, physicians prescribing rivaroxaban medications should assess the potential bleeding risk associated with the concurrent use of amiodarone, particularly in patients with renal impairment.

Association of Amiodarone Use Prior to Orthotopic Heart Transplant with Post-Transplant Graft Dysfunction and All-Cause Mortality: A Systematic Review and Meta-Analysis.

BACKGROUND: There is conflicting data on the association between pre-orthotopic heart transplant (OHT) amiodarone use and post-OHT graft dysfunction (GD) leading to heterogeneity in clinical practice. METHODS: We performed a meta-analysis to evaluate whether pre-OHT amiodarone use was associated with meaningful increases in the incidence of GD, 30-day mortality, and 1-year mortality. Studies were identified by searching PubMed and the Cochrane Register of Clinical Trials. The Mantel-Haenszel method was used to calculate odds ratios (OR) and 95% confidence intervals (CI95) for each endpoint. RESULTS: 17 retrospective studies were identified that included 48,782 patients. 14 studies (n = 48,018) reported GD as an outcome. Pre-OHT amiodarone use was associated with increased odds of GD (OR 1.3, CI95 1.2-1.5, p < 0.001). 10 studies (n = 45,875) reported 30-day mortality based on amiodarone use. Pre-OHT amiodarone use was associated with increased odds of 30-day mortality (OR 1.4, CI95 1.2-1.5, p < 0.001). 5 studies (n = 41,404) reported 1-year mortality based on amiodarone use. Pre-OHT amiodarone use was associated with increased odds of 1-year mortality (OR 1.2, CI95 1.1-1.4, p < 0.001). The increase in absolute risk of GD, 30-day mortality, and 1-year mortality for patients with pre-OHT amiodarone use was 1.3%, 1.2%, and 1.4%, respectively. CONCLUSION: Pre-OHT amiodarone exposure was associated with increased odds of GD, 30-day mortality, and 1-year mortality. The increase in absolute risk for each endpoint was modest, and it is unclear to what extent, if any, pre-OHT amiodarone use should influence assessment of OHT candidacy.

A Fatal Consequence: Amiodarone-Induced Multiorgan Toxicity.

Amiodarone is commonly used nowadays for the treatment of atrial fibrillation (AF). The wide use of this medication has led to the occurrence of adverse events, including pulmonary toxicity, hepatotoxicity, thyroid dysfunction, and many others. Higher doses of Amiodarone of ≥400 mg/day have been linked to increased complications. We present a case of a 70-year-old male with multivessel coronary artery disease (CAD) with ischemic cardiomyopathy and severe peripheral artery disease (PAD) who underwent an elective left femoral to posterior tibial bypass surgery followed by percutaneous coronary intervention (PCI) complicated by new-onset AF. The patient was loaded with 150 mg of intravenous (IV) Amiodarone followed by 360 mg infusion over six hours for chemical cardioversion. The patient was then maintained on oral Amiodarone 400 mg/day until the day of presentation when he complained of progressive dyspnea. Imaging was significant for diffuse ground glass opacities and interstitial thickening. The echocardiogram revealed an improved ejection fraction (EF) of 40% from 20%. The patient had worsening oxygenation despite adequate IV diuresis and developed severe acute respiratory distress syndrome (ARDS) requiring mechanical ventilation (MV). A bronchoscopy with bronchoalveolar lavage (BAL) showed diffuse alveolar hemorrhage (DAH) with a high lymphocyte count and negative infectious disease testing. Lab tests revealed elevated liver enzyme levels. There were also changes in thyroid function from baseline with elevated free T4 at 1.83 ng/dL (0.8-1.4 ng/dL), suppressed thyroid stimulating hormone (TSH) at 0.109 mIU/mL (0.4-4 mIU/mL), negative anti-thyroglobulin (TG) antibodies, and anti-thyroid peroxidase (TPO) antibodies indicating a type 2 Amiodarone-induced thyrotoxicosis. Unfortunately, the patient's condition deteriorated further despite appropriate treatment, and it was ultimately followed by his demise. Severe, fatal cases of Amiodarone toxicity are scarce, but more reports are being seen. We strongly believe clinicians should have a high index of suspicion for Amiodarone-related adverse events in elderly males with cardiopulmonary comorbidities. It is imperative to have an increased understanding, greater vigilance, and closer monitoring of pulmonary function tests (PFTs), laboratory tests, and imaging studies.

In vivo functional analysis of the cotton bollworm Helicoverpa armigera 24-dehydrocholesterol reductase (HaDHCR24) in phytosterol metabolism.

Insects have to obtain sterols from food due to the inability to synthesize this essential nutrient de novo. For lepidopteran insects, they can convert a variety of phytosterols into cholesterol to meet their growth needs. The final step of the cholesterol biosynthesis is the metabolism of desmosterol catalyzed by 24-dehydrocholesterol reductase (DHCR24). In this study, we identified a DHCR24 homolog in the cotton bollworm Helicoverpa armigera, designated as H. armigera 24-dehydrocholesterol reductase (HaDHCR24)-1. The quantitative expression analyses indicated that HaDHCR24-1 was highly enriched in the midgut where dietary sterol uptake occurs. Compared to the control, the DHCR24-1 mutant larvae generated by clustered regularly interspaced palindromic repeats (CRISPR) / CRISPR-associated nuclease 9 technology accumulated more desmosterol in the gut, while the content of cholesterol was significantly reduced. A similar phenomenon was observed when the DHCR24 inhibitor, amiodarone, was applied to the insects. Moreover, DHCR24-1 played an important role for the usage of ß-sitosterol, a major sterol in plants, in H. armigera, and loss of function of DHCR24-1 resulted in higher mortality on ß-sitosterol. However, the DHCR24 homolog does not necessarily exist in the genomes of all insects. The loss of this gene occurred more frequently in the insects feeding on animals, which further support the role of DHCR24-1 in using phytosterols. This gene may have important potential in developing new strategies to control herbivory pests in Lepidoptera and other insect orders.

Development, validation and long-term evaluation of a liquid chromatography-tandem mass spectrometry method for simultaneous quantification of amiodarone, desethylamiodarone and mexiletine in human plasma and serum.

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.