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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 -
The American Journal of Medicine Dec 2020Digoxin reduces the risk of heart failure hospitalization but has no effect on mortality in patients with heart failure without atrial fibrillation in the randomized...
BACKGROUND
Digoxin reduces the risk of heart failure hospitalization but has no effect on mortality in patients with heart failure without atrial fibrillation in the randomized controlled trial setting. Observational studies of digoxin use in patients with atrial fibrillation have suggested a higher risk for poor outcomes. Less is known about this association in patients with heart failure and atrial fibrillation, the examination of which was the objective of the current study.
METHODS
We conducted an observational propensity score-matched study of predischarge digoxin initiation in 1768 hospitalized patients with heart failure and atrial fibrillation in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, balanced on 56 baseline characteristics (mean age, 79 years; 55% women; 7% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated for the 884 patients initiated on digoxin compared with 884 not initiated on digoxin.
RESULTS
HRs (95% CIs) for 30-day, 2-year, and 4-year all-cause mortality were 0.80 (0.55-1.18; P = .261), 0.94 (0.87-1.16; P = .936), and 1.01 (0.90-1.14; P = .729), respectively. Respective HRs (95% CIs) for heart failure readmission were 0.67 (0.49-0.92; P = .014), 0.81 (0.69-0.94; P = .005), and 0.85 (0.74-0.97; P = .022), and those for all-cause readmission were 0.78 (0.64-0.96; P = .016), 0.90 (0.81-1.00; P = .057), and 0.91 (0.83-1.01; P = .603). These associations were homogeneous between patients with left ventricular ejection fraction ≤45% vs >45%.
CONCLUSIONS
Among hospitalized older patients with heart failure (HFrEF and HFpEF) and atrial fibrillation, initiation of digoxin was associated with a lower risk of heart failure readmission but had no association with mortality.
Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Cardiotonic Agents; Digoxin; Female; Heart Failure; Humans; Male; Retrospective Studies; Treatment Outcome
PubMed: 32603789
DOI: 10.1016/j.amjmed.2020.05.030 -
Cellular and Molecular Biology... Aug 2022Heart failure is one of the common cardiovascular diseases, and digoxin is required in the list of drug treatments. Considering the positive effect of this drug on heart...
Heart failure is one of the common cardiovascular diseases, and digoxin is required in the list of drug treatments. Considering the positive effect of this drug on heart failure, unfortunately, its therapeutic and toxic serum levels are different and very close to each other in different people. This study aimed to investigate the digoxin serum level in heart failure patients. For this purpose, we examined 32 patients with heart failure and digoxin users in this cross-sectional descriptive study. Some important factors involved in determining digoxin toxicity, such as age, gender, creatinine, creatinine clearance, cardiac output, urea, potassium, calcium, and digoxin levels, were measured. Statistical analysis showed that digoxin serum level increases with age (p<0.01). The increase in digoxin serum level was related to urea, creatinine, and potassium serum levels (p<0.01). In general, it seems that to prevent the increase of digoxin serum level and poisoning with it, it is necessary to continuously control the serum level of this drug in the form of serum measurement or according to its clearance.
Topics: Humans; Creatinine; Cross-Sectional Studies; Digoxin; Heart Failure; Potassium; Urea
PubMed: 36800827
DOI: 10.14715/cmb/2022.68.8.18 -
Current Problems in Cardiology Aug 2023The study evaluates the characteristics and trends of digoxin use during outpatient visits with atrial fibrillation in the US from 2006 to 2015.We conducted a... (Review)
Review
The study evaluates the characteristics and trends of digoxin use during outpatient visits with atrial fibrillation in the US from 2006 to 2015.We conducted a retrospective analysis of adult (age >/= 18) patient visits to office-based physicians from National Ambulatory Medical Care Survey (NAMCS) database between 2006-2015. The International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify patients with Atrial fibrillation. Visits in which digoxin was listed as medication were analyzed with descriptive statistics. Multivariable logistic regression analysis was used to identify the predictors of usage of digoxin. Of a weighted sample of 108,113,894 patient visits, 17,617,853 (16.3%) visits included use of digoxin. Patients who used digoxin had a mean age of 75 ± 0.7 years and were predominantly Caucasian (92.56%). Among the patients who used digoxin, 24% had a diagnosis of heart failure. Multivariate analysis showed that the increased likelihood of digoxin utilization was associated with female sex (adjusted odds ratio (AOR) 1.34, 95% CI 1.05-1.71, p = .019), heart failure (aOR 1.51, 95% CI 1.05-1.17, p = .025), and usage of ³5 medications (aOR 5.32, 95% CI 3.67-7.71, p = <0.001). Among the visits with Atrial fibrillation, the percentage of visits with digoxin usage decreased from 23% in 2006 to 9% in 2013 and then again increased to 14% in 2015(P-trend <0.001). This is the first study to examine the use of digoxin in atrial fibrillation patients in a big outpatient setting. During 2006-2015, the percentage of digoxin prescriptions in atrial fibrillation patients has declined. Predictors of digoxin use in atrial fibrillation patients are female sex, congestive heart failure and higher number of concurrent medications.
Topics: Adult; Humans; Female; Aged; Male; Digoxin; Atrial Fibrillation; Retrospective Studies; Heart Failure; Health Care Surveys
PubMed: 35460684
DOI: 10.1016/j.cpcardiol.2022.101209 -
Journal of Molecular Recognition : JMR Oct 2021In this study, we presented elective, sensitive, and rapid UV-Vis spectrophotometry and calorimetric assay for the recognition of digoxin. Therefore, cysteamine-gold...
In this study, we presented elective, sensitive, and rapid UV-Vis spectrophotometry and calorimetric assay for the recognition of digoxin. Therefore, cysteamine-gold nanoparticles (Cys A-AuNPs) in the presence of cysteine acid amine and Silver nanoparticles in the presence of tetramethyl benzidine and hydrogen peroxide (AgNPs-TMB [3,3',5,5'-tetramethylbenzidine]-H O ) were synthesized and utilized as the desired probe. Finally, color variation of probes was observed in the absence and presence of digoxin. Obtained results indicate that the color of Cys A-AuNPs changed from dark pink to light in the absence and the presence of digoxin, respectively. Also, the color of AgNPs-TMB-H O changed from dark blue to light blue, in the absence and the presence of digoxin, respectively. Moreover, UV-Vis spectroscopies results indicate digoxin with a low limit of quantification of 0.125 ppm in human plasma samples which linear range was 0.125 to 11 ppm.
Topics: Benzidines; Colorimetry; Cysteamine; Digoxin; Gold; Humans; Hydrogen Peroxide; Limit of Detection; Metal Nanoparticles; Molecular Probes; Sensitivity and Specificity; Spectrophotometry, Ultraviolet
PubMed: 34106492
DOI: 10.1002/jmr.2917 -
The Journal of General Virology Apr 2023Drug repurposing is a valuable source of new antivirals because many compounds used to treat a variety of pathologies can also inhibit viral infections. In this work, we...
Drug repurposing is a valuable source of new antivirals because many compounds used to treat a variety of pathologies can also inhibit viral infections. In this work, we have tested the antiviral capacity of four repurposed drugs to treat Bunyamwera virus (BUNV) infection in cell cultures. BUNV is the prototype of the order, a large group of RNA viruses that includes important pathogens for humans, animals and plants. Mock- and BUNV-infected Vero and HEK293T cells were treated with non-toxic concentrations of digoxin, cyclosporin A, sunitinib and chloroquine. The four drugs inhibited BUNV infection with varying potency in Vero cells, and all except sunitinib also in HEK293T cells, with digoxin rendering the lowest half maximal inhibitory concentration (IC). Since digoxin rendered the best results, we selected this drug for a more detailed study. Digoxin is an inhibitor of the Na/K ATPase, a plasma membrane enzyme responsible for the energy-dependent exchange of cytoplasmic Na for extracellular K in mammalian cells and involved in many signalling pathways. Digoxin was shown to act at an early time point after viral entry reducing the expression of the viral proteins Gc and N. Effects on the cell cycle caused by BUNV and digoxin were also analysed. In Vero cells, digoxin favoured the transition from G1 phase of the cell cycle to S phase, an effect that might contribute to the anti-BUNV effect of digoxin in this cell type. Transmission electron microscopy showed that digoxin impedes the assembly of the characteristic spherules that harbour the BUNV replication complexes and the morphogenesis of new viral particles. Both BUNV and digoxin induce similar changes in the morphology of mitochondria that become more electron-dense and have swollen cristae. The alterations of this essential organelle might be one of the factors responsible for digoxin-induced inhibition of viral infection. Digoxin did not inhibit BUNV infection in BHK-21 cells that have a digoxin-resistant Na/K ATPase, which suggests that the effects of the blockade of this enzyme is a key factor of the antiviral activity of digoxin in BUNV-infected Vero cells.
Topics: Humans; Animals; Chlorocebus aethiops; Bunyamwera virus; Vero Cells; Digoxin; Sunitinib; HEK293 Cells; Antiviral Agents; Cell Culture Techniques; Adenosine Triphosphatases; Mammals
PubMed: 37010894
DOI: 10.1099/jgv.0.001838 -
Drugs - Real World Outcomes Jun 2024Digoxin is a widely prescribed drug for congestive heart failure and atrial fibrillation. Digoxin has a narrow therapeutic index and toxicity can develop quite easily....
BACKGROUND
Digoxin is a widely prescribed drug for congestive heart failure and atrial fibrillation. Digoxin has a narrow therapeutic index and toxicity can develop quite easily. Digoxin immune fab (DIF) is an effective treatment for toxicity, however there are limited studies characterizing its impact on clinical outcomes in real-world clinical practice.
OBJECTIVES
The aim of this study was to identify factors and healthcare outcomes associated with digoxin immune fab (DIF) treatment in patients with confirmed/suspected digoxin toxicity.
METHODS
An IRB-approved retrospective chart review of digoxin toxic patients (2011-2020) presenting at an academic healthcare system was conducted. Demographic and clinical data were collected. Patients were stratified by DIF treatment versus non-DIF treatment. DIF utilization patterns (appropriate, use when not indicated, or underutilized) were determined using pre-defined criteria. Severe digoxin toxicity was defined as having one or more of the following: mental status disturbances, antiarrhythmic therapy, acute renal impairment or dehydration, serum digoxin concentration (SDC) > 4 ng/mL, or serum K+ > 5 mEq/mL. Logistic multivariable regression analysis evaluated factors associated with DIF use. All statistical analyses were performed in R version 4.1.
RESULTS
Data from 96 patients (non-DIF treated group = 49; DIF treated group = 47) were analyzed. DIF was used appropriately in 70 patients (73%), underutilized in 19 (20%), and administered to 7 (7%) patients when it was not indicated. Several clinical parameters differentiated the DIF from the non-DIF group (p < 0.05) including higher mean SDC (3.41 ± 1.63 vs 2.87 ± 1.17), higher mean potassium (5.33 ± 1.48 vs 4.55 ± 0.87), more toxicity severity (85% vs 49%), and more likely to require cardiac pacing (26% vs 4%). Digoxin toxicity resolved sooner in the DIF group (coefficient - 0.702, 95% CI - 1.137 to - 0.267) (p < 0.01) and they had shorter intensive care unit lengths of stay (12.4 ± 20.3 vs 24.4 ± 28.7 days; p = 0.018). The all-cause mortality rate in patients appropriately managed with DIF therapy versus those patients where DIF was underutilized was 11% and 21%, respectively.
CONCLUSIONS
Based on our study population, DIF therapy appears to be beneficial in limiting duration of toxicity and intensive care unit lengths of stay in digoxin toxic patients. Although DIF was appropriately utilized in most cases, there was a relatively high proportion of cases in which DIF treatment was either underutilized or not indicated.
PubMed: 38839728
DOI: 10.1007/s40801-024-00435-0 -
BMC Nephrology Oct 2021Digoxin is used in patients with chronic heart failure (CHF) who remain symptomatic despite optimal medical treatment. Impaired renal function is commonly associated...
INTRODUCTION
Digoxin is used in patients with chronic heart failure (CHF) who remain symptomatic despite optimal medical treatment. Impaired renal function is commonly associated with CHF. We investigated the relation between digoxin use and change in renal function over time in patients with CHF.
METHODS
One thousand two hundred forty-one patients with symptoms and signs of CHF (average age 72 years (64% male), and median NTproBNP 1426 ng/l (interquartile range 632-2897) were divided into four groups: never on digoxin (N = 394); digoxin throughout (N = 449); started digoxin at some point after baseline (N = 367); and stopped digoxin at some point after baseline (N = 31). The rate of change of estimated glomerular filtration rate (eGFR) was calculated using linear regression.
RESULTS
Patients on digoxin throughout had a significantly greater rate of decline in eGFR per year than patients not on digoxin throughout (mean (± standard deviation); - 5 (14) ml/min/1.73m per year v - 2 (11) ml/min/1.73m per year, P = 0.02). In those patients who started digoxin during follow up, there was no significant difference in the rate of decline in eGFR before and after starting digoxin. There was no correlation between baseline eGFR (or rate of decline in eGFR) and age, haemoglobin or NTproBNP. Compared to patients taking both angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) and beta-blocker (BB), patients who were not taking an ACEi/ARB or BB had a numerically faster rate of decline in eGFR, although this was not statistically significant.
CONCLUSION
The rate of decline in renal function is greater in patients with CHF who are taking digoxin.
Topics: Aged; Aged, 80 and over; Cardiotonic Agents; Digoxin; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Male; Middle Aged; Retrospective Studies; Time Factors
PubMed: 34702219
DOI: 10.1186/s12882-021-02562-0 -
Journal of Pharmacokinetics and... Aug 2023Enfortumab vedotin is an antibody-drug conjugate (ADC) comprised of a Nectin-4-directed antibody and monomethyl auristatin E (MMAE), which is primarily eliminated... (Review)
Review
Enfortumab vedotin is an antibody-drug conjugate (ADC) comprised of a Nectin-4-directed antibody and monomethyl auristatin E (MMAE), which is primarily eliminated through P-glycoprotein (P-gp)-mediated excretion and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. A physiologically based pharmacokinetic (PBPK) model was developed to predict effects of combined P-gp with CYP3A4 inhibitor/inducer (ketoconazole/rifampin) on MMAE exposure when coadministered with enfortumab vedotin and study enfortumab vedotin with CYP3A4 (midazolam) and P-gp (digoxin) substrate exposure. A PBPK model was built for enfortumab vedotin and unconjugated MMAE using the PBPK simulator ADC module. A similar model was developed with brentuximab vedotin, an ADC with the same valine-citrulline-MMAE linker as enfortumab vedotin, for MMAE drug-drug interaction (DDI) verification using clinical data. The DDI simulation predicted a less-than-2-fold increase in MMAE exposure with enfortumab vedotin plus ketoconazole (MMAE geometric mean ratio [GMR] for maximum concentration [C], 1.15; GMR for area under the time-concentration curve from time 0 to last quantifiable concentration [AUC], 1.38). Decreased MMAE exposure above 50% but below 80% was observed with enfortumab vedotin plus rifampin (MMAE GMR C, 0.72; GMR AUC, 0.47). No effect of enfortumab vedotin on midazolam or digoxin systemic exposure was predicted. Results suggest that combination enfortumab vedotin, P-gp, and a CYP3A4 inhibitor may result in increased MMAE exposure and patients should be monitored for potential adverse effects. Combination P-gp and a CYP3A4 inducer may result in decreased MMAE exposure. No exposure change is expected for CYP3A4 or P-gp substrates when combined with enfortumab vedotin.ClinicalTrials.gov identifier Not applicable.
PubMed: 37632598
DOI: 10.1007/s10928-023-09877-5 -
Current Problems in Cardiology Nov 2023The BRASH (bradycardia, renal failure, atrioventricular block, shock, and hyperkalaemia) syndrome is a recently recognized condition which may lead to life-threatening...
The BRASH (bradycardia, renal failure, atrioventricular block, shock, and hyperkalaemia) syndrome is a recently recognized condition which may lead to life-threatening complications if not correctly identified and treated early. We report here the case of a 74-year-old woman with type 2 diabetes, hypertension and atrial flutter who presented to the emergency department with 2-day history of dizziness, presyncope, and bradycardia, and a junctional rhythm at 61 beat per minute on initial ECG. She was on apixaban, digoxin, prazosin, and telmisartan. Serum biochemistry revealed severe hyperkalaemia with a potassium 8.4 mmol/L, creatinine 161 mmol/L, glucose 15.3 mmol/L and an upper normal digoxin level of 1.2 mmol/L (ref. 0.6-1.2). Arterial blood pH was 7.2. Given the constellation of biochemical and clinical findings a diagnosis of BRASH syndrome was made, though her blood pressure values at presentation were rather high (180/65-179/59 mmHg). The patient was rapidly stabilised with the administration of intravenous insulin and dextrose, fluid resuscitation, and zirconium cyclosilicate (SZC), followed by haemodialysis. Following the correction of the serum potassium to 4.7 mmol/L, a further ECG performed 6 hours later, showed a restoration of sinus rhythm with a rate of 65 bpm, normalization of the QRS duration. The digoxin and telmisartan were discontinued, and the patient was commenced on a calcium channel antagonist for hypertension. Clinicians should be alerted to patients who present with either a BRASH (shock) or BRAHH (hypertensive manifestation) where timely intervention is essential to avoid life-threatening brady-and tachyarrhythmias in these patients.
Topics: Aged; Female; Humans; Arrhythmias, Cardiac; Bradycardia; Diabetes Mellitus, Type 2; Digoxin; Hyperkalemia; Hypertension; Potassium; Telmisartan
PubMed: 37473946
DOI: 10.1016/j.cpcardiol.2023.101984