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BMC Medical Research Methodology Apr 2023Joint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how...
Joint modelling of longitudinal processes and time-to-event outcomes in heart failure: systematic review and exemplar examining the relationship between serum digoxin levels and mortality.
BACKGROUND
Joint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how and why it is being applied to heart failure research.
METHODS
A systematic review of major medical databases of studies which used joint modelling within heart failure alongside an exemplar; joint modelling repeat measurements of serum digoxin with all-cause mortality using data from the Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial.
RESULTS
Overall, 28 studies were included that used joint models, 25 (89%) used data from cohort studies, the remaining 3 (11%) using data from clinical trials. 21 (75%) of the studies used biomarkers and the remaining studies used imaging parameters and functional parameters. The exemplar findings show that a per unit increase of square root serum digoxin is associated with the hazard of all-cause mortality increasing by 1.77 (1.34-2.33) times when adjusting for clinically relevant covariates.
CONCLUSION
Recently, there has been a rise in publications of joint modelling being applied to heart failure. Where appropriate, joint models should be preferred over traditional models allowing for the inclusion of repeated measures while accounting for the biological nature of biomarkers and measurement error.
Topics: Humans; Heart Failure; Digoxin; Cohort Studies; Models, Statistical; Research Design; Cardiotonic Agents
PubMed: 37076796
DOI: 10.1186/s12874-023-01918-4 -
BMC Pediatrics Dec 2019Given its narrow therapeutic range, digoxin's pharmacokinetic parameters in infants are difficult to predict due to variation in birth weight and gestational age,...
BACKGROUND
Given its narrow therapeutic range, digoxin's pharmacokinetic parameters in infants are difficult to predict due to variation in birth weight and gestational age, especially for critically ill newborns. There is limited evidence to support the safety and dosage requirements of digoxin, let alone to predict its concentrations in infants. This study aimed to compare the concentrations of digoxin predicted by traditional regression modeling and artificial neural network (ANN) modeling for newborn infants given digoxin for clinically significant patent ductus arteriosus (PDA).
METHODS
A retrospective chart review was conducted to obtain data on digoxin use for clinically significant PDA in a neonatal intensive care unit. Newborn infants who were given digoxin and had digoxin concentration(s) within the acceptable range were identified as subjects in the training model and validation datasets, accordingly. Their demographics, disease, and medication information, which were potentially associated with heart failure, were used for model training and analysis of digoxin concentration prediction. The models were generated using backward standard multivariable linear regressions (MLRs) and a standard backpropagation algorithm of ANN, respectively. The common goodness-of-fit estimates, receiver operating characteristic curves, and classification of sensitivity and specificity of the toxic concentrations in the validation dataset obtained from MLR or ANN models were compared to identify the final better predictive model.
RESULTS
Given the weakness of correlations between actual observed digoxin concentrations and pre-specified variables in newborn infants, the performance of all ANN models was better than that of MLR models for digoxin concentration prediction. In particular, the nine-parameter ANN model has better forecasting accuracy and differentiation ability for toxic concentrations.
CONCLUSION
The nine-parameter ANN model is the best alternative than the other models to predict serum digoxin concentrations whenever therapeutic drug monitoring is not available. Further cross-validations using diverse samples from different hospitals for newborn infants are needed.
Topics: Digoxin; Ductus Arteriosus, Patent; Female; Forecasting; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Linear Models; Male; Neural Networks, Computer; Retrospective Studies
PubMed: 31881933
DOI: 10.1186/s12887-019-1895-7 -
Acta Veterinaria Scandinavica 1975In experiments on swine and goats the renal excretion of digoxin was examined, and it was found that the renal clearance of non-protein-bound digoxin in swine was lower...
In experiments on swine and goats the renal excretion of digoxin was examined, and it was found that the renal clearance of non-protein-bound digoxin in swine was lower than creatinine clearance which expresses filtration clearance. Correlation analysis showed that the renal clearance of digoxin in swine was not significantly influenced by the concentration of non-protein-bound digoxin in plasma and the pH of the urine, while there was a significant positive correlation between the clearance and the urine flow rate (Table 4). On the other hand, the renal clearance of digoxin in goats was significantly influenced by the concentration of non-proteinbound digoxin in plasma and by urine pH (Table 4). From these results it is concluded that glomerular filtration and back-diffusion are involved in the renal handling of digoxin in both swine and goats. In addition active tubular secretion is also involved in the renal excretion of digoxin in goats.
Topics: Animals; Blood Proteins; Creatinine; Digoxin; Goats; Kidney; Protein Binding; Swine; Urea
PubMed: 1211330
DOI: 10.1186/BF03546646 -
Journal of the American College of... Jul 1985To assess the effects of digoxin as single therapy and in combination with quinidine in the treatment of atrial fibrillation, the atrial fibrillation threshold was...
To assess the effects of digoxin as single therapy and in combination with quinidine in the treatment of atrial fibrillation, the atrial fibrillation threshold was determined from the right atrial appendage and Bachmann's bundle in 11 open chest dogs. In group 1 (six dogs), the atrial fibrillation threshold was determined at baseline, post-quinidine (10 mg/kg intravenously) and then post-digoxin (50 micrograms/kg intravenously). In group 2 (five dogs), the order of drug administration was reversed. The results of this study were: 1) Digoxin had no significant effect on the atrial fibrillation threshold when given alone. 2) Quinidine significantly increased the atrial fibrillation threshold (p less than 0.002) and the addition of digoxin resulted in a further increase in threshold (p less than 0.002). 3) Quinidine produced greater suppression of atrial fibrillation induction at the right atrial site than at the Bachmann's bundle site, suggesting differential effects of quinidine on atrial fibers.
Topics: Animals; Atrial Fibrillation; Differential Threshold; Digoxin; Dogs; Drug Combinations; Drug Interactions; Electric Stimulation; Quinidine
PubMed: 4008768
DOI: 10.1016/s0735-1097(85)80262-x -
Journal of the American College of... May 1985Digoxin, the cardiac glycoside most frequently used in clinical practice in the United States, can be given orally or intravenously and has an excretory half-life of 36... (Review)
Review
Digoxin, the cardiac glycoside most frequently used in clinical practice in the United States, can be given orally or intravenously and has an excretory half-life of 36 to 48 hours in patients with serum creatinine and blood urea nitrogen values in the normal range. Since the drug is excreted predominantly by the kidney, the half-life is prolonged progressively with diminishing renal function, reaching about 5 days on average in patients who are essentially anephric. Serum protein binding of digoxin is only about 20%, and differs markedly in this regard from that of digitoxin, which is 97% bound by serum albumin at usual therapeutic levels. Digitoxin is nearly completely absorbed from the normal gastrointestinal tract and has a half-life averaging 5 to 6 days in patients receiving usual doses irrespective of renal function. The bioavailability of digoxin is appreciably less than that of digitoxin, averaging about two-thirds to three-fourths of the equivalent dose given intravenously in the case of currently available tablet formulations. Recent studies have shown that gut flora of about 10% of patients reduce digoxin to a less bioactive dihydro derivative. This process is sensitive to antibiotic administration, creating the potential for important interactions among drugs. Serum or plasma concentrations of digitalis glycosides can be measured by radioimmunoassay methods that are now widely available, but knowledge of serum levels does not substitute for a sound working knowledge of the clinical pharmacology of the preparation used and careful patient follow-up.
Topics: Absorption; Biological Availability; Cardiac Glycosides; Cost-Benefit Analysis; Digitoxin; Digoxin; Half-Life; Humans; Kinetics; Radioimmunoassay; Time Factors
PubMed: 3921586
DOI: 10.1016/s0735-1097(85)80462-9 -
International Immunopharmacology Oct 2022Relatively low-grade inflammatory of osteoarthritic joints is characterized by synovitis and a catabolic and proinflammatory state of the chondrocytes and plays an...
Relatively low-grade inflammatory of osteoarthritic joints is characterized by synovitis and a catabolic and proinflammatory state of the chondrocytes and plays an important role in osteoarthritis (OA) initiation and exacerbation. Our previous research showed cardiac glycoside compounds might be effective in OA synovitis. However, the effect of digoxin (DIG), an FDA-approved cardenolide, on inflammation inhibition of osteoarthritic joints has not been investigated. In the present study, a western blot analysis and immunofluorescence staining revealed that DIG alleviated OA synovitis by inhibiting the M1-like polarization of synovial macrophages in OA patients and collagenase-induced OA (CIOA, with considerable synovitis) mice. Subsequently, the exosomes produced by macrophages and M1-like macrophages treated with or without DIG were isolated and identified. According to miRNA sequencing analysis of these exosomes and subsequent target activity assays, we confirmed DIG controls OA inflammatory microenvironment and promotes chondrogenesis by, at least partly, downregulating the M1-like macrophage-derived exosomal miR-146b-5p/Usp3&Sox5 axis in vitro and in vivo. This research provides reliable experimental evidence supporting the clinical application of DIG as a disease-modifying drug for inflammation-associated OA. Additionally, the spectrum of diseases of inflammation controlled by DIG has been broadened, which prompting research interest in the new function of an "old" FDA-approved drug.
Topics: Animals; Digoxin; Inflammation; Macrophages; Mice; MicroRNAs; Osteoarthritis; Synovitis
PubMed: 35987145
DOI: 10.1016/j.intimp.2022.109135 -
Journal of Veterinary Internal Medicine 2009Atrial fibrillation (AF) with excessively high ventricular rates (VR) occurs in dogs with advanced heart disease. Rate control improves clinical signs in these patients.... (Randomized Controlled Trial)
Randomized Controlled Trial
Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs.
BACKGROUND
Atrial fibrillation (AF) with excessively high ventricular rates (VR) occurs in dogs with advanced heart disease. Rate control improves clinical signs in these patients. Optimal drug therapy and target VR remain poorly defined.
HYPOTHESIS
Digoxin-diltiazem combination therapy reduces VR more than either drug alone in dogs with high VR AF.
ANIMALS
Eighteen client-owned dogs (>15 kg) with advanced heart disease, AF, and average VR on 24-hour Holter > 140 beats per minute (bpm).
METHODS
After baseline Holter recording, dogs were randomized to digoxin or diltiazem monotherapy, or combination therapy. Repeat Holter evaluation was obtained after 2 weeks; dogs were then crossed over to the other arm (monotherapy or combination therapy) for 2 weeks and a third Holter was acquired. Twenty-four hour average VR, absolute and relative VR changes from baseline, and percent time spent within prespecified VR ranges (>140, 100-140, and <100 bpm) were compared. Correlations between serum drug concentrations and VR were examined.
RESULTS
Digoxin (median, 164 bpm) and diltiazem (median, 158 bpm) decreased VR from baseline (median, 194 bpm) less than the digoxin-diltiazem combination (median, 126 bpm) (P < .008 for each comparison). With digoxin-diltiazem, VR remained <140 bpm for 85% of the recording period, but remained >140 bpm for 88% of the recording period with either monotherapy. Serum drug concentrations did not correlate with VR.
CONCLUSIONS AND CLINICAL IMPORTANCE
At the dosages used in this study, digoxin-diltiazem combination therapy provided a greater rate control than either drug alone in dogs with AF.
Topics: Animals; Atrial Fibrillation; Cardiovascular Agents; Chronic Disease; Cross-Over Studies; Digoxin; Diltiazem; Dog Diseases; Dogs; Drug Therapy, Combination; Heart Rate
PubMed: 19645836
DOI: 10.1111/j.1939-1676.2009.0301.x -
Archives of Pathology & Laboratory... Aug 2010Hawthorn is an herb indicated for treating cardiac illness. Because a patient taking digoxin may also take hawthorn, we investigated potential interference of hawthorn...
CONTEXT
Hawthorn is an herb indicated for treating cardiac illness. Because a patient taking digoxin may also take hawthorn, we investigated potential interference of hawthorn in serum digoxin measurements using immunoassays as well as pharmacodynamic interaction between hawthorn and digoxin. Hawthorn contains alkaloids that are structurally similar to digoxin and may interfere with serum digoxin measurement using immunoassays. In addition, hawthorn has cardioactive properties similar to digoxin.
OBJECTIVE
To study potential pharmacodynamic interaction between hawthorn and digoxin.
DESIGN
The effects of hawthorn extract on serum digoxin measurements using Digoxin III (Abbott Laboratories, Abbott Park, Illinois) and the Tina-Quant digoxin assay (Roche Diagnostics, Indianapolis, Indiana) were investigated using 2 different brands of extract. To study the pharmacodynamic interaction between hawthorn and digoxin, we used an isolated adult rat cardiomyocyte system, measuring calcium transients by real-time fluorescence spectrophotometry.
RESULTS
Hawthorn interfered only with the Digoxin III immunoassay but had no effect on the Tina-Quant assay. Both hawthorn extracts increased intracellular calcium levels, but the lack of additive response with digoxin suggests both may bind to the same site of Na, K adenosine triphosphatase.
CONCLUSION
Because of interference of hawthorn with a digoxin immunoassay and pharmacodynamic interaction with digoxin, a patient receiving digoxin should avoid hawthorn.
Topics: Aniline Compounds; Animals; Calcium; Calcium Signaling; Cells, Cultured; Contraindications; Crataegus; Digoxin; Drug Interactions; Immunoassay; Male; Myocytes, Cardiac; Plant Extracts; Rats; Xanthenes
PubMed: 20670141
DOI: 10.5858/2009-0404-OA.1 -
European Journal of Hospital Pharmacy :... Nov 2021Our previous retrospecive study evaluating the appropriateness of serum digoxin concentration (SDC) measurements revealed errors in the timing of blood specimen...
OBJECTIVES
Our previous retrospecive study evaluating the appropriateness of serum digoxin concentration (SDC) measurements revealed errors in the timing of blood specimen collection in 98% of the tests. The aim of this study is to evaluate the appropriateness of the SDC measurements and the factors involved in inappropriate test-ordering, after training health personnel in digoxin therapeutic drug monitoring.
METHODS
This is a training-based quasi-experimental study. The residents and nurses of the Cardiology Clinic were trained first in December 2017, and refresher training courses were carried out every month throughout the study. The medical data of the inpatients receiving digoxin therapy were recorded prospectively, between January and December 2018. The appropriateness of the physicians' orders for SDC measurement was evaluated according to the criteria of the right indication and right timing of blood collection. The results are presented by descriptive statistics, Student's t-test and χ analysis.
RESULTS
A total of 232 SDC tests were ordered for 121 patients (age: 71.0±12.6 years, 56.2% women). Of these orders,129 (55.6%) were considered appropriate: 205 (88.4%) for indication and 129 (62.9%) for blood collection timing. There was a significant correlation between inappropriate order for SDC test and the age of the patient, female gender, impairment of renal function tests, high levels of serum BNP and the number of medications used (P<0.005).
CONCLUSIONS
Approximately a one-half decrease in inappropriate tests compared with our previous study results imply that education has a positive effect on physician behaviour. However, physicians' concerns due to increased risk factors for the patient still play a role in inappropriate test-ordering.
Topics: Aged; Aged, 80 and over; Digoxin; Drug Monitoring; Female; Humans; Male; Middle Aged
PubMed: 34697048
DOI: 10.1136/ejhpharm-2019-002078 -
British Journal of Clinical Pharmacology Jul 2015The objective of the present study was to review the available pharmacokinetic evidence for the utility of cystatin C (CysC) as a marker of renal function to predict the... (Review)
Review
The objective of the present study was to review the available pharmacokinetic evidence for the utility of cystatin C (CysC) as a marker of renal function to predict the dose of renally excreted drugs.The bibliographic search used PubMed and EMBASE databases, from its inception through to January 2014, with the following keywords 'pharmacokinetics' and 'cystatin C'.Sixteen pharmacokinetic publications were identified and seven drugs primarily excreted by the kidney were studied. Among them, only one study was performed in children, the others were performed in adults and/or elderly subjects, either healthy volunteers or patients with variable clinical conditions, such as cystic fibrosis and cancer. Most of studies (n = 13/16) demonstrated that CysC was better correlated with clearance/trough concentration of evaluated drugs compared with creatinine.Our review supports that CysC is a good marker of renal function to predict dose of renally excreted drugs. Efforts should be made to evaluate the impact of CysC in special populations in order to define its clinical value in dosing optimization.
Topics: Anti-Infective Agents; Antineoplastic Agents; Biomarkers; Cystatin C; Digoxin; Humans; Kidney Function Tests
PubMed: 25655191
DOI: 10.1111/bcp.12602