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Scientific Reports Jun 2024Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of...
Allosteric modulation of muscarinic acetylcholine receptors (mAChR) has been identified as a potential strategy for regulating cholinergic signaling in the treatment of various neurological disorders. Most positive allosteric modulators (PAMs) of mAChR enhance agonist affinity and potency, while very few PAMs (e.g., amiodarone) selectively enhance G protein coupling efficacy. The key structural features of amiodarone responsible for enhancement of mAChR efficacy were examined in CHO cells expressing M receptors. Subsequent incorporation of these structural features into previously identified allosteric modulators of potency (i.e., n-benzyl isatins) generated ligands that demonstrated similar or better enhancement of mAChR efficacy, lower in vivo toxicity, and higher allosteric binding affinity relative to amiodarone. Notable ligands include 8a, c which respectively demonstrated the strongest binding affinity and the most robust enhancement of mAChR efficacy as calculated from an allosteric operational model. Amiodarone derivatives and hybrid ligands were additionally screened in wildtype zebrafish (Danio rerio) to provide preliminary in vivo toxicity data as well as to observe effects on locomotor and turning behaviors relative to other mAChR PAMs. Several compounds, including 8a, c, reduced locomotor activity and increased measures of turning behaviors in zebrafish, suggesting that allosteric modulation of muscarinic receptor efficacy might be useful in the treatment of repetitive behaviors associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders.
Topics: Animals; Zebrafish; Receptor, Muscarinic M1; Allosteric Regulation; CHO Cells; Cricetulus; Acetylcholine; Locomotion; Ligands; Muscarinic Agonists
PubMed: 38942828
DOI: 10.1038/s41598-024-65445-y -
Journal of Arrhythmia Jun 2024Atrial fibrillation (AF) is the most frequent arrhythmia after cardiac surgery causing a range of clinical symptoms and treatments that develop in around one-third of...
Evaluation of the effect of small single intravenous dose of amiodarone on the prevention of arrhythmias in patients who underwent coronary artery bypass graft surgery: A randomized controlled trial.
BACKGROUND
Atrial fibrillation (AF) is the most frequent arrhythmia after cardiac surgery causing a range of clinical symptoms and treatments that develop in around one-third of coronary artery bypass surgery patients. We aimed to evaluate the effect of Amiodarone in preventing arrhythmia in patients undergoing coronary artery bypass surgery.
METHOD
In this double-blind randomized clinical trial, 60 patients candidate for coronary artery bypass surgery above the age of 18 were included and randomly divided into two groups of intervention, receiving an infusion of Amiodarone (3 mg/kg) 10 min (in 100 cc Normal saline) before declamping of the aorta, and a control group, receiving 100 cc of saline 10 min before declamping of the aorta. The patient's demographic, clinical features, and hospital and clinical course were recorded.
RESULTS
After undergoing operation, 22 (36.67%) of patients were developed arrhythmia. The Amiodarone group demonstrated significantly lower reperfusion ventricular fibrillation (RVF) rates (26.7% vs. 70%; = .001) and AF occurrence (13.3% vs. 60%; < .001) during the initial 24 h after surgery compared to the placebo group. There was no significant difference between the two groups regarding the need for D/C shock after removing the aortic clamp. ( = .117) Furthermore, the intensive care unit stay among the amiodaron group was significantly lower than the control group (2.43 vs. 3.07 days; = .013).
CONCLUSION
The predictive properties in the administration of single intravenous low-dose Amiodarone 10 min before the declamping of the aorta can significantly lower the rates of RVF and AF after coronary artery bypass grafting, while also decreasing hospitalization duration.
PubMed: 38939762
DOI: 10.1002/joa3.12986 -
Scientific Reports Jun 2024The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use...
The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Anticoagulants; Bayes Theorem; China; Cytochrome P-450 CYP2C9; International Normalized Ratio; Vitamin K Epoxide Reductases; Warfarin; East Asian People
PubMed: 38937509
DOI: 10.1038/s41598-024-65048-7 -
Naunyn-Schmiedeberg's Archives of... Jun 2024The dreaded nosocomial pathogen Clostridioides difficile causes diarrhea and severe inflammation of the colon, especially after the use of certain antibiotics. The...
The dreaded nosocomial pathogen Clostridioides difficile causes diarrhea and severe inflammation of the colon, especially after the use of certain antibiotics. The bacterium releases two deleterious toxins, TcdA and TcdB, into the gut, which are mainly responsible for the symptoms of C. difficile-associated diseases (CDADs). Both toxins are capable of entering independently into various host cells, e.g., intestinal epithelial cells, where they mono-O-glucosylate and inactivate Rho and/or Ras GTPases, important molecular switches for various cellular functions. We have shown recently that the cellular uptake of the Clostridioides difficile toxins TcdA and TcdB (TcdA/B) is inhibited by the licensed class III antiarrhythmic drug amiodarone (Schumacher et al. in Gut Microbes 15(2):2256695, 2023). Mechanistically, amiodarone delays the cellular uptake of both toxins into target cells most likely by lowering membrane cholesterol levels and by interfering with membrane insertion and/or pore formation of TcdA/B. However, serious side effects, such as thyroid dysfunction and severe pulmonary fibrosis, limit the clinical use of amiodarone in patients with C. difficile infection (CDI). For that reason, we aimed to test whether dronedarone, an amiodarone derivative with a more favorable side effect profile, is also capable of inhibiting TcdA/B. To this end, we tested in vitro with various methods the impact of dronedarone on the intoxication of Vero and CaCo-2 cells with TcdA/B. Importantly, preincubation of both cell lines with dronedarone for 1 h at concentrations in the low micromolar range rendered the cells less sensitive toward TcdA/B-induced Rac1 glucosylation, collapse of the actin cytoskeleton, cell rounding, and cytopathic effects, respectively. Our study points toward the possibility of repurposing the already approved drug dronedarone as the preferable safer-to-use alternative to amiodarone for inhibiting TcdA/B in the (supportive) therapy of CDADs.
PubMed: 38935126
DOI: 10.1007/s00210-024-03248-8 -
Pharmaceuticals (Basel, Switzerland) May 2024Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some...
BACKGROUND
Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical efficacy.
METHODS
We studied 878 patients with persistent atrial fibrillation (AF) treated with a regimen of amiodarone and referred to electrical cardioversion (ECV), included prospectively in two Spanish registries. We analyzed the influence of body mass index (BMI), as well as overweight and obesity, in the efficacy of amiodarone for achieving pharmacologic cardioversion to sinus rhythm (SR) before ECV.
RESULTS
A total of 185 patients (21.1%) reverted to SR before ECV. Patients who reverted to SR had a lower BMI than those who did not revert (27.45 ± 4.36 kg/m vs. 29.11 ± 4.09 kg/m; < 0.001). We observed a progressively lower probability of reverting to SR in overweight and obese patients (normal weight 28.3%, overweight 21.3%, obesity 13.1%; < 0.001). In the logistic regression, BMI (kg/m) adjusted for other related variables remained as the main factor inversely related to reversion to SR (OR = 0.904 × kg/m); CI 75% 0.864-0.946).
CONCLUSIONS
We observed a negative relationship between an increased BMI and the efficacy of amiodarone for reversion to SR, suggesting a negative clinical impact of excess body fat in its efficacy.
PubMed: 38931360
DOI: 10.3390/ph17060693 -
BMJ Case Reports Jun 2024Flecainide is a medication used to treat supraventricular and ventricular tachyarrhythmias. Cases of overdoses are rare, however, can lead to significant cardiac...
Flecainide is a medication used to treat supraventricular and ventricular tachyarrhythmias. Cases of overdoses are rare, however, can lead to significant cardiac effects. In previous cases of flecainide toxicity, treatment with sodium bicarbonate, intravenous lipid emulsion and amiodarone have been reported to be effective in preventing cardiovascular collapse and reestablishing baseline rhythm. Here, we present a case of a man in his 40s presented with flecainide overdose with wide-complex tachycardia that was treated with intravenous sodium bicarbonate following failure of amiodarone to normalise QRS interval.
Topics: Humans; Flecainide; Male; Sodium Bicarbonate; Drug Overdose; Anti-Arrhythmia Agents; Electrocardiography; Adult; Infusions, Intravenous; Tachycardia; Amiodarone
PubMed: 38926125
DOI: 10.1136/bcr-2023-256391 -
PLoS Computational Biology Jun 2024Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed...
Patients with myocardial ischemia and infarction are at increased risk of arrhythmias, which in turn, can exacerbate the overall risk of mortality. Despite the observed reduction in recurrent arrhythmias through antiarrhythmic drug therapy, the precise mechanisms underlying their effectiveness in treating ischemic heart disease remain unclear. Moreover, there is a lack of specialized drugs designed explicitly for the treatment of myocardial ischemic arrhythmia. This study employs an electrophysiological simulation approach to investigate the potential antiarrhythmic effects and underlying mechanisms of various pharmacological agents in the context of ischemia and myocardial infarction (MI). Based on physiological experimental data, computational models are developed to simulate the effects of a series of pharmacological agents (amiodarone, telmisartan, E-4031, chromanol 293B, and glibenclamide) on cellular electrophysiology and utilized to further evaluate their antiarrhythmic effectiveness during ischemia. On 2D and 3D tissues with multiple pathological conditions, the simulation results indicate that the antiarrhythmic effect of glibenclamide is primarily attributed to the suppression of efflux of potassium ion to facilitate the restitution of [K+]o, as opposed to recovery of IKATP during myocardial ischemia. This discovery implies that, during acute cardiac ischemia, pro-arrhythmogenic alterations in cardiac tissue's excitability and conduction properties are more significantly influenced by electrophysiological changes in the depolarization rate, as opposed to variations in the action potential duration (APD). These findings offer specific insights into potentially effective targets for investigating ischemic arrhythmias, providing significant guidance for clinical interventions in acute coronary syndrome.
PubMed: 38917196
DOI: 10.1371/journal.pcbi.1012244 -
Microbiology Spectrum Jun 2024() as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug...
UNLABELLED
() as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug resistance. The loss of antibiotic efficacy has raised interest in the identification of host-directed therapeutics (HDT) to develop novel treatment strategies for mycobacterial infections. In this study, we identified amiodarone as a potential HDT candidate that inhibited both intracellular and in primary human macrophages without directly impairing bacterial growth, thereby confirming that amiodarone acts in a host-mediated manner. Moreover, amiodarone induced the formation of (auto)phagosomes and enhanced autophagic targeting of mycobacteria in macrophages. The induction of autophagy by amiodarone is likely due to enhanced transcriptional regulation, as the nuclear intensity of the transcription factor EB, the master regulator of autophagy and lysosomal biogenesis, was strongly increased. Furthermore, blocking lysosomal degradation with bafilomycin impaired the host-beneficial effect of amiodarone. Finally, amiodarone induced autophagy and reduced bacterial burden in a zebrafish embryo model of tuberculosis, thereby confirming the HDT activity of amiodarone . In conclusion, we have identified amiodarone as an autophagy-inducing antimycobacterial HDT that improves host control of mycobacterial infections.
IMPORTANCE
Due to the global rise in antibiotic resistance, there is a strong need for alternative treatment strategies against intracellular bacterial infections, including () and non-tuberculous mycobacteria. Stimulating host defense mechanisms by host-directed therapy (HDT) is a promising approach for treating mycobacterial infections. This study identified amiodarone, an antiarrhythmic agent, as a potential HDT candidate that inhibits the survival of and in primary human macrophages. The antimycobacterial effect of amiodarone was confirmed in an tuberculosis model based on infection of zebrafish embryos. Furthermore, amiodarone induced autophagy and inhibition of the autophagic flux effectively impaired the host-protective effect of amiodarone, supporting that activation of the host (auto)phagolysosomal pathway is essential for the mechanism of action of amiodarone. In conclusion, we have identified amiodarone as an autophagy-inducing HDT that improves host control of a wide range of mycobacteria.
PubMed: 38916320
DOI: 10.1128/spectrum.00167-24 -
Cureus Jun 2024Amiodarone is commonly used to prevent and treat life-threatening cardiac arrhythmias. However, it is also known to have an extensive side effect profile. A rare adverse...
Amiodarone is commonly used to prevent and treat life-threatening cardiac arrhythmias. However, it is also known to have an extensive side effect profile. A rare adverse effect of amiodarone is epididymitis. Epididymitis is inflammation of the epididymis that causes moderate pain in the posterior scrotum. The patient, in this case, developed left scrotal pain seven months after starting amiodarone and presented with symptoms consistent with epididymitis. The patient's work-up included urinalysis with culture, treatment with antibiotics, and testicular ultrasound before being diagnosed with amiodarone-induced epididymitis. This diagnosis led to the discontinuation of amiodarone, which resulted in the complete resolution of the patient's symptoms within two weeks. This case report is intended to increase awareness of epididymitis as a possible adverse effect of amiodarone and to stress the importance of considering this when there are no apparent anatomical or infectious causes of epididymitis.
PubMed: 38915841
DOI: 10.7759/cureus.62861 -
Military Medicine Jun 2024Excess thyroid hormone is a well-documented risk factor for the development of atrial fibrillation (AF). The purpose of the study is to assess incidence of AF in...
INTRODUCTION
Excess thyroid hormone is a well-documented risk factor for the development of atrial fibrillation (AF). The purpose of the study is to assess incidence of AF in patients taking levothyroxine for hypothyroidism and correlate it with biochemical thyroid function.
MATERIALS AND METHODS
This was a retrospective cohort study of patients aged 18 years and older who were treated with levothyroxine. Exclusion criteria were pre-existing diagnosis of AF and use of amiodarone in the prior year. Patients were followed 2012 through 2019 and stratified into 4 groups based on mean thyroid-stimulating hormone (TSH) value or mean fT4 value in 2012. Primary outcome was incidence of AF. Rates of AF between groups were assessed via Poisson regression with control of underlying confounders.
RESULTS
Of 21,035 patients, 1091 (5.2%) developed AF during follow-up. Thyroid-stimulating hormone at baseline was not significantly associated with incident AF. Higher fT4 levels at baseline were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio 1.22; 95% CI, 1.03-1.44) for the highest quartile versus the lowest quartile of fT4.
CONCLUSIONS
In hypothyroid patients treated with levothyroxine, higher circulating fT4 levels are associated with increased risk of incident AF. There is no association of serum TSH with risk of AF. In patients at risk for AF, consideration should be given to avoiding fT4 levels in the highest quartile.
PubMed: 38913449
DOI: 10.1093/milmed/usae324