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Journal of the American College of... Mar 1985Quinidine elevates serum digoxin concentration in part by reducing the volume of distribution of digoxin, which implies that quinidine displaces digoxin from tissues.... (Comparative Study)
Comparative Study
Quinidine elevates serum digoxin concentration in part by reducing the volume of distribution of digoxin, which implies that quinidine displaces digoxin from tissues. The purposes of this study were to: 1) measure the effect of quinidine on tissue digoxin concentrations, and 2) determine if quinidine alters the relation between myocardial digoxin concentration and digoxin effect on myocardial monovalent cation transport. Eighteen dogs were treated with tritiated digoxin until the steady-state serum digoxin concentration was between 1.0 and 1.5 ng/ml. All dogs continued receiving the same dose of digoxin while nine dogs were given quinidine as well. Quinidine was continued until the serum digoxin concentration had increased by at least 25%. At the end of treatment, the serum digoxin concentration in dogs treated with digoxin was 1.2 +/- 0.1 ng/ml compared with 2.1 +/- 0.5 ng/ml in dogs treated with digoxin and quinidine in combination (p less than 0.001). Digoxin concentration in myocardium, skeletal muscle, liver, kidney, stellate ganglion, vagus nerve, femoral nerve, brain and brainstem medulla was higher in dogs treated with a combination of digoxin and quinidine than in dogs treated with digoxin alone, but remained proportional to the serum digoxin concentration in all tissues except the brainstem medulla. Myocardial monovalent cation transport was measured using rubidium-86. The effect of digoxin on myocardial monovalent cation transport did not increase as the serum and myocardial digoxin concentrations increased after quinidine administration.
Topics: Animals; Blood Gas Analysis; Blood Pressure; Brain; Digoxin; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Electrocardiography; Electrolytes; Kidney; Liver; Muscles; Myocardium; Quinidine; Radioisotopes; Rubidium
PubMed: 3973266
DOI: 10.1016/s0735-1097(85)80394-6 -
Clinical Therapeutics May 2021Dronedarone may increase digoxin plasma levels through inhibition of P-glycoprotein. Using real-world data, we evaluated the risk of digitalis intoxication in...
PURPOSE
Dronedarone may increase digoxin plasma levels through inhibition of P-glycoprotein. Using real-world data, we evaluated the risk of digitalis intoxication in concomitant users of dronedarone and digoxin compared digoxin-alone users.
METHODS
We used the Clinformatics DataMart, a US claims database, to identify adult patients with atrial fibrillation (AF) or atrial flutter (AFL) who concomitantly used dronedarone and digoxin and those who used digoxin alone between July 2009 and March 2016. Digitalis intoxication during follow-up until March 2016 was ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Adjusted hazard ratios (HR) for digitalis intoxication in concomitant users versus users of digoxin alone were estimated, controlling for age, sex, cohort entry year, number of medical encounters for AF or AFL, history of congestive heart failure, diabetes, hypertension, stroke, myocardial infarction, renal failure, use of drugs interacting with digoxin, and digoxin dose.
FINDINGS
Overall, 524 concomitant users and 32,459 users of digoxin alone were identified, among which 3 and 301 events of digitalis intoxication occurred during follow-up, respectively. Incidence rates were 17.25 and 9.17 cases per 1000 person-years, respectively. The adjusted HR for digitalis intoxication in concomitant users versus users of digoxin alone was 1.56 (95% CI, 0.50-4.88; P = 0.45). When digitalis intoxication was defined by ICD-9-CM and ICD-10-CM codes accompanied by laboratory testing for digoxin/digitoxin or hospitalization within 30 days, no events occurred in the concomitant users and 40 events occurred in the users of digoxin alone (incidence rate of 1.22 cases per 1000 person-years).
IMPLICATIONS
Concomitant use of dronedarone and digoxin was uncommon in this study, and no significant increase in the risk of digitalis intoxication with concomitant use was found.
Topics: Adult; Atrial Fibrillation; Atrial Flutter; Digitalis; Digoxin; Dronedarone; Humans
PubMed: 33888353
DOI: 10.1016/j.clinthera.2021.03.014 -
Annales de Biologie Clinique 2003Following administration of anti-digoxin Fab fragments, monitoring unbound digoxin concentrations may help ensure appropriate dosing, and prevent recrudescent toxicity.... (Review)
Review
Following administration of anti-digoxin Fab fragments, monitoring unbound digoxin concentrations may help ensure appropriate dosing, and prevent recrudescent toxicity. Ultrafiltration by using Centrifree system and measurement of digoxin in the ultrafiltrate is considered as reference technique. However, ultrafiltration method is cumbersome, costly, and some immunoassays are affected by matrix differences. Another approach is to analyse the serum directly by digoxin immunoassays without ultrafiltering it. The validity of results obtained depends on the architecture of the immunoassay and the amount of Fab in the sample. The old radioimmunoassays and usually the other competitive immunoassays give inaccurate results. The fluorescence polarization immunoassay (FPIA) slightly underestimates the total digoxin concentrations. Total digoxin levels obtained at 24 hours and 48 hours after treatment permit measurement of the half-life of digoxin Fab complexes and can be used to estimate when the patient can be redigitalized, if necessary. The sequential immunoassays usually overestimate the free digoxin concentrations. The differences observed are >25% and cannot be explained solely by albumin binding (normal range, 20% +/- 5%). To date, ultrafiltration remains the best strategy for accurate determination of digoxin concentrations in the presence of antidigoxin Fab fragments.
Topics: Aged; Aged, 80 and over; Digoxin; Drug Monitoring; Female; Humans; Immunoglobulin Fab Fragments; Male; Middle Aged; Ultrafiltration
PubMed: 14711605
DOI: No ID Found -
The Journal of Biological Chemistry Aug 2019Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the...
Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the pharmaceutical market. Among these drugs are plant-derived cardiac glycosides, which have been used by various cultures over millennia as both medicines and poisons. We report that digoxin and related compounds activate the NLRP3 inflammasome in macrophages and cardiomyocytes at concentrations achievable during clinical use. Inflammasome activation initiates the maturation and release of the inflammatory cytokine IL-1β and the programmed cell death pathway pyroptosis in a caspase-1-dependent manner. Notably, the same fluxes of potassium and calcium cations that affect heart contraction also induce inflammasome activation in human but not murine cells. Pharmaceuticals that antagonize these fluxes, including glyburide and verapamil, also inhibit inflammasome activation by cardiac glycosides. Cardiac glycoside-induced cellular cytotoxicity and IL-1β signaling are likewise antagonized by inhibitors of the NLRP3 inflammasome or the IL-1 receptor-targeting biological agent anakinra. Our results inform on the molecular mechanism by which the inflammasome integrates the diverse signals that activate it through secondary signals like cation flux. Furthermore, this mechanism suggests a contribution of the inflammasome to the toxicity and adverse events associated with cardiac glycosides use in humans and that targeted anti-inflammatories could provide an additional adjunct therapeutic countermeasure.
Topics: Animals; Cell Death; Cells, Cultured; Cytokines; Digoxin; Humans; Inflammasomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 31300552
DOI: 10.1074/jbc.RA119.008330 -
Tidsskrift For Den Norske Laegeforening... Nov 2016
Topics: Anti-Arrhythmia Agents; Digitoxin; Digoxin; Drug Substitution; Humans; Norway; Practice Guidelines as Topic
PubMed: 27830897
DOI: 10.4045/tidsskr.16.0810 -
International Journal of Cancer Aug 2012Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The...
Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non-users after adjustment for age- and calendar-time. For ovarian and cervical cancers, RRs in users and non-users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32-1.65; N = 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92-1.22; N = 207) and 1.00 (95% CI: 0.79-1.25; N = 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto-estrogen, have an increased risk of developing uterus cancers.
Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Denmark; Digoxin; Female; Humans; Middle Aged; Ovarian Neoplasms; Phytoestrogens; Risk Factors; Uterine Cervical Neoplasms; Young Adult
PubMed: 21913187
DOI: 10.1002/ijc.26424 -
Bioorganic & Medicinal Chemistry Aug 2015Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire...
Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.
Topics: Animals; Antineoplastic Agents; Benzylidene Compounds; Binding Sites; Brain; Cell Line; Cell Survival; Digoxin; HeLa Cells; Humans; Kidney; Molecular Docking Simulation; Protein Structure, Tertiary; Rats; Sodium-Potassium-Exchanging ATPase
PubMed: 26122772
DOI: 10.1016/j.bmc.2015.06.028 -
Cleveland Clinic Journal of Medicine Sep 2006Digoxin has been the cornerstone of the treatment of heart failure for more than 2 centuries. Now that newer therapies have been introduced that reduce the mortality... (Review)
Review
Digoxin has been the cornerstone of the treatment of heart failure for more than 2 centuries. Now that newer therapies have been introduced that reduce the mortality rate in heart failure and recent trials have failed to prove the same for digoxin, its use has significantly decreased. But a careful review of the multiple pharmacologic actions of digoxin and closer analysis of the results of recent trials suggest that digoxin may in fact continue to be an effective treatment for heart failure.
Topics: Atrial Fibrillation; Cardiotonic Agents; Digoxin; Heart Failure; Humans
PubMed: 16970134
DOI: 10.3949/ccjm.73.9.821 -
BMJ (Clinical Research Ed.) Apr 1989
Topics: Digoxin; Drug Interactions; Erythromycin; Gastric Emptying; Humans
PubMed: 2497912
DOI: 10.1136/bmj.298.6680.1101-b -
Electrophoresis May 2022Cardiac glycosides digoxin and digitoxin are used in therapy for the treatment of congestive heart failure. Moreover, these compounds can be responsible for intoxication...
Development of a new ultra-high-performance liquid chromatography-tandem mass spectrometry method for the determination of digoxin and digitoxin in plasma: Comparison with a clinical immunoassay.
Cardiac glycosides digoxin and digitoxin are used in therapy for the treatment of congestive heart failure. Moreover, these compounds can be responsible for intoxication cases caused by fortuitous ingestion of leaves of Digitalis. Due to the narrow therapeutic range of these drugs, therapeutic drug monitoring is recommended in the clinical practice. In this context, immunoassays-based methods are generally employed but digoxin- and digitoxin-like compounds can interfere with the analysis. The aim of this study was to develop and validate an original UPLC-MS/MS method for the determination of digoxin and digitoxin in plasma. The method shows adequate sensitivity and selectivity with acceptable matrix effects and very good linearity, accuracy, precision, and recovery. A simple liquid-liquid extraction procedure was used for sample clean-up. The method was applied for the analysis of n = 220 plasma samples collected in two different clinical chemistry laboratories and previously tested by the same immunoassay. The statistical comparison showed a relevant negative bias of the UPLC-MS/MS method versus the immunoassay. These results are consistent with an immunoassay overestimation of digoxin plasmatic levels due to cross-reaction events with endogenous digoxin-like substances.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Digitoxin; Digoxin; Immunoassay; Tandem Mass Spectrometry
PubMed: 35132652
DOI: 10.1002/elps.202100290