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Bulletin of Experimental Biology and... Mar 2023The effects of cardiotonic steroids (ouabain and digoxin) on the bone formation were studied using the organotypic tissue culture in combination with confocal...
The effects of cardiotonic steroids (ouabain and digoxin) on the bone formation were studied using the organotypic tissue culture in combination with confocal microscopy. The expression of α- and α-isoforms of Na,K-ATPase was detected in cells of the bone tissue of 12-day-old chicken embryos. Ouabain in a concentrations 10 M (comparable with its endogenous concentration) can modulate transducer function of Na,K-ATPase and control the growth and proliferation bone tissue cells. Unlike ouabain, digoxin is not involved in the regulation of bone tissue growth in a 12-day-old chicken embryo.
Topics: Animals; Chick Embryo; Ouabain; Sodium-Potassium-Exchanging ATPase; Digoxin; Protein Isoforms; Sodium; Bone Remodeling
PubMed: 37046115
DOI: 10.1007/s10517-023-05768-4 -
Cardiovascular Drugs and Therapy Aug 2023Publishe d decades after several randomized controlled trials (RCT) demonstrating decreased hospitalizations and no effect on all-cause mortality with digoxin use, a... (Review)
Review
PURPOSE
Publishe d decades after several randomized controlled trials (RCT) demonstrating decreased hospitalizations and no effect on all-cause mortality with digoxin use, a series of meta-analyses linking digoxin treatment and mortality have contributed to a narrower application of this medication for the management of heart failure (HF) and atrial fibrillation (AF). Given the conflicting data from the earlier RCTs and more recent meta-analyses, there is a growing polarization among providers for and against the use of digoxin in managing these conditions.
METHODS
To help close this divide, we provide a perspective on the literature with special attention to the quality of both older and more recent studies on this subject.
RESULTS
The data from the highest quality studies we have, RCTs, suggest that digoxin use in patients with HF and/or AF is associated with improvement in several areas of outcomes including functional capacity, symptom management, reduced hospitalizations, fewer deaths due to HF, and treatment of refractory chronic heart failure with rEF, and may even have overall mortality benefit when serum digoxin concentrations are within therapeutic range. These effects are more pronounced in patients with EF < 25% and NYHA Class II-IV and at highest risk for hospitalization.
CONCLUSION
As the risk of confounding factors was minimized by the study design, the likelihood that positive outcomes were identified with digoxin use increased. Clinicians and researchers need further adequately designed and powered RCTs exploring the connection between digoxin therapy and mortality, hospitalizations, and symptom management.
Topics: Humans; Digitalis; Randomized Controlled Trials as Topic; Digoxin; Heart Failure; Atrial Fibrillation
PubMed: 34748147
DOI: 10.1007/s10557-021-07287-8 -
Frontiers in Cardiovascular Medicine 2023The current recommendations for monitoring digoxin, a narrow therapeutic index drug, are limited to confirming medication use or investigating suspicion of toxicity and... (Review)
Review
The current recommendations for monitoring digoxin, a narrow therapeutic index drug, are limited to confirming medication use or investigating suspicion of toxicity and fail our oath to do no harm. Numerous meta-analyses evaluating digoxin use consistently recommend frequent monitoring to maintain the level of 0.5 to ≤1.0 ng/ml because higher levels lead to increased morbidity and mortality without benefit. Data from the United States National Poison Control Center (2012-2020) show annual deaths due to digoxin of 18-36 compared to lithium's 1-7, and warfarin's 0-2 respectively. The latter drugs also have narrow therapeutic indexes like digoxin yet are more carefully monitored. Recognition of digoxin toxicity is impaired as levels are not being routinely checked after medications are added to a patient's regimen. In addition, providers may be using ranges to guide treatment that are no longer appropriate. It is imperative that monitoring guidelines and laboratory therapeutic levels are revised to reduce morbidity and mortality due to digoxin. In this review, we provide a comprehensive literature review of digoxin monitoring guidelines, digoxin toxicity, and evidence to support revising the ranges for serum digoxin monitoring.
PubMed: 37465455
DOI: 10.3389/fcvm.2023.1179892 -
Journal of the American College of... Aug 2019
Topics: Cardiotonic Agents; Digitalis; Digoxin; Heart Failure; Humans; Stroke Volume
PubMed: 31370953
DOI: 10.1016/j.jacc.2019.06.021 -
International Journal of Environmental... Apr 2021Although digoxin is important in heart rate control, the utilization of digoxin is declining due to its narrow therapeutic window. Misdiagnosis or delayed diagnosis of...
Although digoxin is important in heart rate control, the utilization of digoxin is declining due to its narrow therapeutic window. Misdiagnosis or delayed diagnosis of digoxin toxicity is common due to the lack of awareness and the time-consuming laboratory work that is involved. Electrocardiography (ECG) may be able to detect potential digoxin toxicity based on characteristic presentations. Our study attempted to develop a deep learning model to detect digoxin toxicity based on ECG manifestations. This study included 61 ECGs from patients with digoxin toxicity and 177,066 ECGs from patients in the emergency room from November 2011 to February 2019. The deep learning algorithm was trained using approximately 80% of ECGs. The other 20% of ECGs were used to validate the performance of the Artificial Intelligence (AI) system and to conduct a human-machine competition. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the performance of ECG interpretation between humans and our deep learning system. The AUCs of our deep learning system for identifying digoxin toxicity were 0.912 and 0.929 in the validation cohort and the human-machine competition, respectively, which reached 84.6% of sensitivity and 94.6% of specificity. Interestingly, the deep learning system using only lead I (AUC = 0.960) was not worse than using complete 12 leads (0.912). Stratified analysis showed that our deep learning system was more applicable to patients with heart failure (HF) and without atrial fibrillation (AF) than those without HF and with AF. Our ECG-based deep learning system provides a high-accuracy, economical, rapid, and accessible way to detect digoxin toxicity, which can be applied as a promising decision supportive system for diagnosing digoxin toxicity in clinical practice.
Topics: Algorithms; Artificial Intelligence; Deep Learning; Digoxin; Electrocardiography; Humans; Retrospective Studies
PubMed: 33917563
DOI: 10.3390/ijerph18073839 -
The Medical Letter on Drugs and... Jan 2024
Topics: Humans; Atrial Fibrillation
PubMed: 38180321
DOI: 10.58347/tml.2024.1693a -
Drug Development Research Aug 2022In recent years, the drug repositioning strategy has gained considerable attention in the drug discovery process that involves establishing new therapeutic uses of...
In recent years, the drug repositioning strategy has gained considerable attention in the drug discovery process that involves establishing new therapeutic uses of already known drugs. In line with this, we have identified digoxin a cardiac glycoside, as a potent inhibitor of soluble epoxide hydrolase (sEH) enzyme employing in silico high throughput screening protocols and further confirmed using in vitro cell-free sEH inhibitory assay and in vivo preclinical studies in rodents for its repurposing in hyperalgesia, inflammation, and related disorders. Oral administration of digoxin at dose 0.2 mg/kg significantly reduced (p < .0001) the allodynia in mice induced by using hot plate (3.6 ± 1.9) and tail-flick test (7.58 ± 0.9). In addition, digoxin at a dose of 0.2 mg/kg showed marked reduction (94%, p < .0001) in acetic acid-induced abdominal contraction in rats. Further, digoxin also demonstrated antipyretic activity (37.04 ± 0.2, p < .0001) and showed notable reduction (0.60 ± 0.06) in carrageenan-induced paw edema in rats. Also, the histopathological evaluation revealed that digoxin treatment attenuated the edema, neutrophil infiltration, and alveolar septal thickening in lung tissue. These findings are novel and highlight the newer insights towards repurposing digoxin as a new lead in the treatment of hyperalgesia, inflammation, and related disorders.
Topics: Analgesics; Animals; Carrageenan; Digoxin; Drug Repositioning; Edema; Hyperalgesia; Inflammation; Mice; Pain; Rats
PubMed: 35315525
DOI: 10.1002/ddr.21935 -
JAMA Network Open Jul 2023Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR...
IMPORTANCE
Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR.
OBJECTIVE
To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date.
EXPOSURE
The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr.
MAIN OUTCOMES AND MEASURES
The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 μg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance.
RESULTS
A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 μg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 μg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003).
CONCLUSIONS AND RELEVANCE
Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.
Topics: Male; Adult; Humans; Aged; Glomerular Filtration Rate; Creatinine; Cohort Studies; Cystatin C; Baclofen; Hyperkalemia; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin; Digoxin; Neoplasms
PubMed: 37405775
DOI: 10.1001/jamanetworkopen.2023.21715 -
Antimicrobial Agents and Chemotherapy Oct 2023Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug...
Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
Topics: Adult; Humans; Cytochrome P-450 CYP1A2; Midazolam; Cytochrome P-450 CYP2D6; Caffeine; Rifampin; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Dextromethorphan; Tolbutamide; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Omeprazole; Drug Interactions; Tuberculosis, Pulmonary; Digoxin
PubMed: 37768317
DOI: 10.1128/aac.00683-23 -
The American Journal of Cardiology Nov 2022The role of digoxin in clinical practice has narrowed over time. Data on digoxin toxicity trends and outcomes are variable and lack granularity for treatment outcomes....
The role of digoxin in clinical practice has narrowed over time. Data on digoxin toxicity trends and outcomes are variable and lack granularity for treatment outcomes. This study aimed to address data gaps in digoxin toxicity trends and outcomes in patients treated with or without digoxin immune fab (DIF). This single-center analysis examined patients with signs/symptoms concerning digoxin toxicity, defined as hospital admission or emergency department visit with elevated digoxin serum concentrations (>2 ng/ml) and/or a primary diagnosis code of digoxin toxicity and/or DIF order. Between 2000 and 2020, 727 patients were identified with signs concerning for digoxin toxicity with a mortality rate of 12.7% during admission and 42.7% at 1 year. DIF was ordered in 9% of cases. Incidence of digoxin toxicity per 1,000 patients with a digoxin prescription and frequency of DIF treatment fluctuated over time without a clear trend toward increase or reduction. DIF-treated patients demonstrated a heavier co-morbidity burden and lower presenting heart rates (median 53 [39.5 to 69.5] vs 77 [64.0 to 91.5] beats/min, p <0.001), worse renal function (median estimated glomerular filtration rate, 30.3 [14.8 to 48.6] vs 40.0 [24.2 to 61.2] ml/min/1.73 m, p = 0.013), and higher potassium (median 4.5 [4.0 to 5.3] vs 4.3 [3.9 to 4.8] mEq/L, p = 0.022). Compared with a matched cohort, DIF-treated patients experienced a nonsignificant, numerically lower in-hospital mortality (8.2% vs 15.8%, p = 0.199) and 30-day all-cause hospitalization (14.3% vs 24.7%, p = 0.112) and similar 6-month and 1-year hospitalization and mortality. In conclusion, digoxin toxicity remains a pertinent public health issue despite reduction in digoxin utilization. DIF therapy is used in a medically complex population with a high-acuity illness at presentation and is associated with nonsignificant trends toward reduced in-hospital mortality and early readmission that are attenuated over time.
Topics: Humans; Cardiovascular Agents; Digoxin; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Heart Rate; Hospitalization; Potassium; Immunoglobulin Fab Fragments
PubMed: 36089419
DOI: 10.1016/j.amjcard.2022.08.004