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Arhiv Za Higijenu Rada I Toksikologiju 2022Natural cardiac glycosides have positive inotropic heart effects but at high, toxic doses they can cause life-threatening cardiac arrhythmias. Here we present the first...
Natural cardiac glycosides have positive inotropic heart effects but at high, toxic doses they can cause life-threatening cardiac arrhythmias. Here we present the first Croatian case of a 16-year-old girl who attempted suicide by eating dried oleander leaves, which contain natural cardiac glycosides, and her treatment with a specific antidote. The girl presented with an oedema of the uvula indicating local toxicity, severe bradycardia, first-degree atrioventricular block, drowsiness, and vomiting. Having taken her medical history, we started treatment with atropine, intravenous infusion of dextrose-saline solution and gastroprotection, but it was not successful. Then we introduced digoxin-specific Fab antibody fragments and within two hours, the patient's sinus rhythm returned to normal. Cases of self-poisoning with this oleander are common in South-East Asia, because it is often used as a medicinal herb, and digoxin-specific Fab fragments have already been reported as effective antidote against oleander poisoning there. Our case has taught us that it is important to have this drug in the hospital pharmacy both for digitalis and oleander poisoning.
Topics: Humans; Female; Adolescent; Suicide, Attempted; Nerium; Antidotes; Digoxin; Cardiac Glycosides; Plant Poisoning; Immunoglobulin Fab Fragments; Eating
PubMed: 38146758
DOI: 10.2478/aiht-2023-74-3752 -
Cells Dec 2023Inflamed and infected tissues can display increased local sodium (Na) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a...
Inflamed and infected tissues can display increased local sodium (Na) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a Na/Ca-exchanger 1 (NCX1)-dependent increase in intracellular Na levels. This results in augmented osmoprotective signaling and enhanced proinflammatory activation, such as enhanced expression of type 2 nitric oxide synthase and antimicrobial function. In this study, the role of elevated intracellular Na levels in macrophages was investigated. Therefore, the Na/K-ATPase (NKA) was pharmacologically inhibited with two cardiac glycosides (CGs), ouabain (OUA) and digoxin (DIG), to raise intracellular Na without increasing extracellular Na levels. Exposure to HS conditions and treatment with both inhibitors resulted in intracellular Na accumulation and subsequent phosphorylation of p38/MAPK. The CGs had different effects on intracellular Ca and K compared to HS stimulation. Moreover, the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) was not upregulated on RNA and protein levels upon OUA and DIG treatment. Accordingly, OUA and DIG did not boost nitric oxide (NO) production and showed heterogeneous effects toward eliminating intracellular bacteria. While HS environments cause hypertonic stress and ionic perturbations, cardiac glycosides only induce the latter. Cotreatment of macrophages with OUA and non-ionic osmolyte mannitol (MAN) partially mimicked the HS-boosted antimicrobial macrophage activity. These findings suggest that intracellular Na accumulation and hypertonic stress are required but not sufficient to mimic boosted macrophage function induced by increased extracellular sodium availability.
Topics: Humans; Sodium; Cardiac Glycosides; Ouabain; Macrophages; Sodium Chloride; Sodium Chloride, Dietary; Caffeine; Anti-Infective Agents
PubMed: 38132136
DOI: 10.3390/cells12242816 -
Emergencias : Revista de La Sociedad... Dec 2023To analyze factors related to the use of digoxin to treat patients with acute heart failure (AHF) in emergency departments (EDs) and the impact of digoxin treatment on...
OBJECTIVES
To analyze factors related to the use of digoxin to treat patients with acute heart failure (AHF) in emergency departments (EDs) and the impact of digoxin treatment on short-term outcomes.
MATERIAL AND METHODS
We included patients diagnosed with AHF in 45 Spanish EDs. The patients, who were not undergoing long-term treatment for heart failure, were classified according to whether or not they were given intravenous digoxin in the ED. Fifty-one patient or cardiac decompensation episode variables were recorded to profile ED patients treated with digoxin. Outcome variables studied were the need for hospital admission, prolonged stay in the ED (> 24 hours) for discharged patients, prolonged hospitalization (> 7 days) for admitted patients, and all-cause in-hospital or 30-day mortality. The associations between digoxin treatment and the outcomes were studied with odds ratios (ORs) adjusted for patient and AHF episode characteristics.
RESULTS
Data for 15 549 patients (median age, 83 years; 55% women) were analyzed; 1430 (9.2%) were treated with digoxin. Digoxin was used more often in women, young patients, and those with better New York Heart Association (NYHA) classifications but more severe cardiac decompensation, especially if the trigger was atrial fibrillation with rapid ventricular response. Admissions were ordered for 75.4% of the patients overall (81.6% of digoxin-treated patients vs 74.8% of nontreated patients; P .001). The ED stay was prolonged in 38.3% of patients discharged from the ED (52.9% of digoxin-treated patients vs 37.2% of nontreated patients; P .001). The duration of hospital stay was prolonged in 48.1% (digoxin-treated, 49.3% vs 47.9%; P = .385). In-hospital mortality was 7.2% overall (6.9% vs 7.2%, P= .712), and 30-day mortality was 9.7% (9.3% vs 9.7%, P = .625). ED use of digoxin was associated with a prolonged stay in the department (adjusted OR, 1.883; 95% CI, 1.359-2.608) but not with hospitalization or mortality.
CONCLUSION
Digoxin continues to be used in one out of ten ED patients who are not already on long-term treatment with the drug. Digoxin use is associated with cardiac decompensation triggered by atrial fibrillation with rapid ventricular response, younger age, women, and patients with better initial NYHA function status but possibly more severe decompensation. Digoxin use leads to a longer ED stay but is safe, as it is not associated with need for admission, prolonged hospitalization, or short-term mortality.
Topics: Humans; Female; Aged, 80 and over; Male; Digoxin; Atrial Fibrillation; Heart Failure; Emergency Service, Hospital; Hospitalization
PubMed: 38116968
DOI: 10.55633/s3me/E08.2023 -
Clinical Science (London, England :... Dec 2023
PubMed: 38063217
DOI: 10.1042/CS-2022-0796C_COR -
Journal of Chemical Ecology Feb 2024The brilliant red Lilioceris merdigera (Coleoptera, Chrysomelidae) can spend its entire life cycle on the cardenolide-containing plant Convallaria majalis (lily of the...
The brilliant red Lilioceris merdigera (Coleoptera, Chrysomelidae) can spend its entire life cycle on the cardenolide-containing plant Convallaria majalis (lily of the valley) and forms stable populations on this host. Yet, in contrast to many other insects on cardenolide-containing plants L. merdigera does not sequester these plant toxins in the body but rather both adult beetles and larvae eliminate ingested cardenolides with the feces. Tracer feeding experiments showed that this holds true for radioactively labeled ouabain and digoxin, a highly polar and a rather apolar cardenolide. Both compounds or their derivatives are incorporated in the fecal shields of the larvae. The apolar digoxin, but not the polar ouabain, showed a deterrent effect on the generalist predatory ant Myrmica rubra, which occurs in the habitat of L. merdigera. The deterrent effect was detected for digoxin both in choice and feeding time assays. In a predator choice assay, a fecal shield derived from a diet of cardenolide-containing C. majalis offered L. merdigera larvae better protection from M. rubra than one derived from non-cardenolide Allium schoenoprasum (chives) or no fecal shield at all. Thus, we here present data suggesting a new way how insects may gain protection by feeding on cardenolide-containing plants.
Topics: Animals; Larva; Cardenolides; Ouabain; Coleoptera; Insecta; Digoxin
PubMed: 38062246
DOI: 10.1007/s10886-023-01465-8 -
Journal of Arrhythmia Dec 2023Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF....
OBJECTIVE
Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF. However, no studies have examined the relationship between antidepressant use and AF burden (time in AF). This retrospective cohort study examined cardiac implantable device-detected AF episodes and their relationship with antidepressant use, among other treatment factors.
METHODS
Consecutive patients from the Western Health Cardiology Department attending pacemaker checks between 2015 and 2021 were included. Patients with permanent AF were excluded, yielding 285 patients with no or paroxysmal AF, with a total of 772 patient encounters. Generalized estimating equations were used to model two processes: binary AF (present/absent) and the number of days in AF for patients with AF.
RESULTS
Each yearly increase with age was associated with an increase in the odds of developing AF (OR 1.03 [1.00-1.05], = .027). Male gender conferred a reduction in AF incidence (OR 0.30 [0.13-0.68], = .004). Digoxin use was associated with incident AF (OR 4.43 [1.07-18.4], = .04). Sotalol and heart-failure beta blocker use were associated with a decrease in AF burden (IRR 0.30 [0.12-0.78], = .013 and 0.33 [0.14-0.81], = .015). Selective serotonin reuptake inhibitor antidepressant use was associated with reduced AF burden (IRR 0.27 [0.09-0.81], = .019), as was selective serotonin/noradrenaline reuptake inhibitor use (IRR 0.07 [0.03-0.15], < .001).
CONCLUSIONS
Older age, female gender and digoxin are associated with a higher odds of developing incident AF. Sotalol, heart failure beta blockers and serotonin-based antidepressants are associated with reduced AF burden. Further prospective study into the effects of antidepressants on atrial arrhythmias is warranted.
PubMed: 38045466
DOI: 10.1002/joa3.12948 -
Biological & Pharmaceutical Bulletin 2023Jabara juice and its component narirutin inhibit the activity of organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1, which are considered to play...
Jabara juice and its component narirutin inhibit the activity of organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1, which are considered to play significant roles in the intestinal absorption of fexofenadine. In this study, we investigated the effects of jabara juice on the intestinal absorption of fexofenadine in mice and the inhibitory effects of jabara juice and narirutin on the permeation of fexofenadine using Caco-2 cell monolayers and LLC-GA5-COL300 cell monolayers. In the in vivo study, the area under the plasma concentration-time curve (AUC) of fexofenadine in mice was increased 1.8-fold by jabara juice. In the permeation study, 5% jabara juice significantly decreased the efflux ratio (ER) of fexofenadine for Caco-2 monolayers. Furthermore, the ERs of fexofenadine and digoxin, which is a typical substrate of P-glycoprotein (P-gp), for LLC-GA5-COL300 cell monolayers were decreased in a concentration-dependent manner by jabara juice extract, suggesting that jabara juice may increase the intestinal absorption of fexofenadine by inhibiting P-gp, rather than by narirutin inhibiting OATPs. The present study showed that jabara juice increases the intestinal absorption of fexofenadine both in vivo and in vitro. The intestinal absorption of fexofenadine may be altered by the co-administration of jabara juice in the clinical setting.
Topics: Humans; Mice; Animals; Caco-2 Cells; Food-Drug Interactions; Terfenadine; Food; Organic Anion Transporters; Intestinal Absorption
PubMed: 38044133
DOI: 10.1248/bpb.b23-00479 -
Frontiers in Pharmacology 2023Adverse effects of intravenous digoxin vary from patients and disease status, which should be closely monitored. To explore the safety profile of intravenous digoxin...
Adverse effects of intravenous digoxin vary from patients and disease status, which should be closely monitored. To explore the safety profile of intravenous digoxin in acute heart failure with reduced ejection fraction (HFrEF) among Chinese patients. A clinical prospective, single-center, single-arm, open-label exploratory clinical trial was performed in patients with acute HFrEF at Wuhan Asia Heart Hospital. A fixed dose of 0.5 mg digoxin was used intravenously once per day for 3 days. The normalized dosage of digoxin (NDD), toxic serum digoxin concentration (SDC), and adverse reactions of intravenous digoxin were recorded. A total of 40 patients were recruited in the study. The SDC increased from 1.03 ± 0.34 ng/mL to 1.95 ± 0.52 ng/mL during treatment. 50% (20/40) patients reached a toxic SDC of 2.0 ng/mL, and toxic effects were seen in 30% (12/40) patients. Estimated glomerular filtration rate (eGFR) < 60 mL/min [HR: 5.269; 95% CI: 1.905-14.575, = 0.001], NDD ≥7 μg/kg [HR: 3.028; 95% CI: 1.119-8.194, = 0.029], and ischemic cardiomyopathy [HR: 2.658; 95% CI: 1.025-6.894, = 0.044] were independent risk factors for toxic SDC. Toxic SDC was effectively identified [area under the receiver operating characteristic (ROC) curve = 0.85, < 0.001] using this model, and patients would have a higher risk of toxicity with more risk factors. Intravenous digoxin of 0.5 mg was safe and effective for initial dose but not suitable for maintenance treatment in Chinese patients with acute HFrEF. Patients who had lower eGFR, received higher NDD, and had ischemic cardiomyopathy should be closely monitored to avoid digoxin toxicity.
PubMed: 38026938
DOI: 10.3389/fphar.2023.1291896 -
Frontiers in Oncology 2023Network targeting of disease-specific nodes represents a useful principle for designing combination cancer therapy. In this case of a patient with relapsed...
Network targeting of disease-specific nodes represents a useful principle for designing combination cancer therapy. In this case of a patient with relapsed leptomeningeal glioblastoma, comprehensive molecular diagnosis led to the identification of a disease network characterized by multiple disease-specific synthetic lethal vulnerabilities involving DNA repair, REDOX homeostasis, and impaired autophagy which suggested a novel network-targeting combination therapy (NTCT). A treatment regimen consisting of lomustine, olaparib, digoxin, metformin, and high dose intravenous ascorbate was employed using the principle of intra-patient dose escalation to deliver the treatment with adequate safety measures to achieve a definitive clinical result.
PubMed: 38023264
DOI: 10.3389/fonc.2023.1210224 -
Scientific Reports Nov 2023Lung adenocarcinoma (LUAD) is one of the most widespread and fatal types of lung cancer. Oxidative stress, resulting from an imbalance in the production and accumulation...
Lung adenocarcinoma (LUAD) is one of the most widespread and fatal types of lung cancer. Oxidative stress, resulting from an imbalance in the production and accumulation of reactive oxygen species (ROS), is considered a promising therapeutic target for cancer treatment. Currently, immune checkpoint blockade (ICB) therapy is being explored as a potentially effective treatment for early-stage LUAD. In this research, we aim to identify distinct subtypes of LUAD patients by investigating genes associated with oxidative stress and immunotherapy. Additionally, we aim to propose subtype-specific therapeutic strategies. We conducted a thorough search of the Gene Expression Omnibus (GEO) datasets. From this search, we pinpointed datasets that contained both expression data and survival information. We selected genes associated with oxidative stress and immunotherapy using keyword searches on GeneCards. We then combined expression data of LUAD samples from both The Cancer Genome Atlas (TCGA) and 11 GEO datasets, forming a unified dataset. This dataset was subsequently divided into two subsets, Dataset_Training and Dataset_Testing, using a random bifurcation method, with each subset containing 50% of the data. We applied consensus clustering (CC) analysis to identify distinct LUAD subtypes within the Dataset_Training. Molecular variances associated with oxidative stress levels, the tumor microenvironment (TME), and immune checkpoint genes (ICGs) were then investigated among these subtypes. Employing feature selection combined with machine learning techniques, we constructed models that achieved the highest accuracy levels. We validated the identified subtypes and models from Dataset_Training using Dataset_Testing. A hub gene with the highest importance values in the machine learning model was identified. We then utilized virtual screening to discover potential compounds targeting this hub gene. In the unified dataset, we integrated 2,154 LUAD samples from TCGA-LUAD and 11 GEO datasets. We specifically selected 1,311 genes associated with immune and oxidative stress processes. The expression data of these genes were then employed for subtype identification through CC analysis. Within Dataset_Training, two distinct subtypes emerged, each marked by different levels of immune and oxidative stress pathway values. Consequently, we named these as the OX and IM subtypes. Notably, the OX subtype showed increased oxidative stress levels, correlating with a worse prognosis than the IM subtype. Conversely, the IM subtype demonstrated enhanced levels of immune pathways, immune cells, and ICGs compared to the OX subtype. We reconfirmed these findings in Dataset_Testing. Through gene selection, we identified an optimal combination of 12 genes for predicting LUAD subtypes: ACP1, AURKA, BIRC5, CYC1, GSTP1, HSPD1, HSPE1, MDH2, MRPL13, NDUFS1, SNRPD1, and SORD. Out of the four machine learning models we tested, the support vector machine (SVM) stood out, achieving the highest area under the curve (AUC) of 0.86 and an accuracy of 0.78 on Dataset_Testing. We focused on HSPE1, which was designated as the hub gene due to its paramount importance in the SVM model, and computed the docking structures for four compounds: ZINC3978005 (Dihydroergotamine), ZINC52955754 (Ergotamine), ZINC150588351 (Elbasvir), and ZINC242548690 (Digoxin). Our study identified two subtypes of LUAD patients based on oxidative stress and immunotherapy-related genes. Our findings provided subtype-specific therapeutic strategies.
Topics: Humans; Adenocarcinoma of Lung; Immunotherapy; Oxidative Stress; Lung Neoplasms; Radioimmunotherapy; Tumor Microenvironment
PubMed: 38017020
DOI: 10.1038/s41598-023-47659-8