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PubMed1983

The effect of ibuprofen on serum digoxin concentrations.

This study was undertaken to determine the effects of ibuprofen (Motrin), in daily doses of at least 1600 mg, on steady-state digoxin concentrations. A total of 12 ambulatory patients (10, female; 2, male), with a mean age of 66 years (38-81 yr), completed the study. An initial baseline serum digoxin level was obtained, with follow-up levels at 7 days and, whenever possible, 28 days after ibuprofen initiation. Serum creatinine concentrations were not significantly different from baseline to 7 or 28 days of ibuprofen therapy. Results show a statistically significant (p less than 0.05) increase in digoxin levels after seven days of ibuprofen. The mean increase was 59 percent (range, 10.7-325.4 percent), with 10 of the 12 patients displaying increased seven-day levels. Digoxin levels drawn 28 days after ibuprofen initiation were not statistically different from baseline or seven-day digoxin levels.

Aged↗
PubMed1985

Estimation of the steady-state volume of distribution for digoxin: a comparison of model-independent methods with a two-compartment model in healthy volunteers.

Digoxin serum concentration vs. time data have been described in the literature by a linear two-compartment model. When calculating the steady-state volume of distribution for digoxin after oral dosing, a computer fitting program is often used because of the complex first-order absorption, two-compartment model employed. Since computer programs are not always available, we computed and compared the steady-state volume of distribution/bioavailability for digoxin using both a model-independent (area) and compartmental approach. Six healthy subjects participated in the study; each received digoxin 0.2 mg in capsule form daily for ten days. The mean steady-state volume of distribution/bioavailability calculated by noncompartmental analysis was 785 L and the mean for compartmental analysis was 784 L. The small difference between methods suggests that area analysis offers a simpler alternative to computerized compartmental fitting to determine this parameter for digoxin.

Adult↗
PubMed1997

Digoxin-macrolide drug interaction.

Macrolide antibiotics appear to be able to enhance the oral bioavailability of digoxin by altering the gastrointestinal flora that metabolize digoxin to less active dihydro metabolites, thus leading to increased serum digoxin concentrations and possible digoxin toxicity in select patients stabilized on digoxin therapy. This interaction may be of clinical importance in up to 10% of the population. Currently, the orally administered erythromycin, clarithromycin, and roxithromycin have been implicated. Although realistically this interaction may be encountered rarely, when it does occur, it can be of clinical significance.

Aged↗
PubMed2004

A trial of automated safety alerts for inpatient digoxin use with computerized physician order entry.

OBJECTIVE: Automated clinical decision support (CDS) has shown promise in improving safe medication use. The authors performed a trial of CDS, given both during computerized physician order entry (CPOE) and in response to new laboratory results, comparing the time courses of clinician behaviors related to digoxin use before and after implementation of the alerts. DESIGN: Alerts were implemented to notify of the potential risk from low electrolyte concentrations or unknown digoxin or electrolyte concentrations during CPOE. Alerts were also generated in response to newly reported hypokalemia and hypomagnesemia in patients given digoxin. MEASUREMENTS: Clinician responses to the alerts for six months were compared with responses to similar situations for six months prior to implementation. RESULTS: During CPOE, checking for unknown serum values increased after implementation compared with control at one hour: 19% vs. 6% for digoxin, 57% vs. 9% for potassium, and 40% vs. 12% for magnesium as well as at 24 hours (p < 0.01 for all comparisons). Electrolyte supplementation increased with newly reported hypokalemia and hypomagnesemia after implementation at one hour: 35% vs. 6% and 49% vs. 5% for potassium and magnesium, respectively, as well as at 24 hours (p < 0.01 for all comparisons). During CPOE, supplementation for hypokalemia was not improved, whereas supplementation for hypomagnesemia improved at one hour (p < 0.05). CONCLUSION: Overall, the alerts improved the safe use of digoxin. During CPOE, alerts associated with missing levels were effective. For hypokalemia and hypomagnesemia, the alerts given during CPOE were not as effective as those given at the time of newly reported low electrolytes.

Anti-Arrhythmia Agents↗
PubMed1985

Protein binding of endogenous digoxin-immunoactive factors in human serum and its variation with clinical condition.

We previously identified endogenous digoxin-like immunoactivity in serum from pregnant women, newborn infants, and patients in renal failure. This activity is due to an endogenous factor(s) that cross-reacts with antibodies raised against digoxin. Using serum from the above sources as well as serum and urine from normal individuals, we further characterized these immunoreactive factors. The factors are water soluble, heat stable, and neutral in molecular charge. That isolated from serum has an apparent mol wt of 200 daltons, as estimated by membrane partitioning. The factor from urine has twice this apparent mol wt, an apparent higher affinity for the digoxin antisera, and is less resistant to acid hydrolysis. It may represent a conjugated metabolite of the factor from serum. The immunoactive factor in serum is noncovalently bound to serum protein, and we describe methods for estimating total, weakly protein-bound (i.e. heat-dissociable), tightly protein-bound (i.e. not heat-dissociable), and unbound (free) activity. Levels measured directly in serum by RIA represent the unbound and weakly protein-bound serum components. In normal subjects, over 90% of the total endogenous immunoactivity in serum is tightly but reversibly bound to protein and not detectable by direct measurement with conventional RIAs. Concentrations determined by direct measurement in serum from patients with renal failure [128 +/- 38 pg digoxin equivalents/ml (mean +/- SE)], pregnant women (141 +/- 12), and neonates (230 +/- 7) consistently exceeded those in normal subjects (61 +/- 3). Chromatography and ultrafiltration studies suggest that these differences are due to increased amounts of weakly protein-bound factor in these subjects rather than to a greater amount of total immunoactive factor. Altered protein binding of this endogenous factor seems to play a predominant role in the detection of digoxin-like immunoactivity in human serum. Our data also suggest that carrier proteins may play a prominent role in the transport of this endogenous immunoactive factor in blood.

Adult↗
PubMed2002

MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs.

The multidrug transporter, MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs was examined in vitro by using the MDR1-overexpressing LLC-GA5-COL150 cells, which were established by transfection with human MDR1 cDNA into porcine kidney epithelial LLC-PK(1) cells. Amiodarone, its active metabolite monodesethyl-amiodarone (DEA), and quinidine markedly inhibited the basal-to-apical transport (renal secretion) of [(3)H]digoxin and increased the apical-to-basal transport (reabsorption), but cibenzoline and lidocaine showed slight inhibition of the transport, and disopyramide and mexiletin had no such effects. The IC(50) values for amiodarone, DEA and quinidine on [(3)H]digoxin transport in LLC-GA5-COL150 cells were 5.48 microM, 1.27 microM and 9.52 microM, respectively. These were comparable to, or only several times the achievable concentration in clinical use, suggesting that MDR1 could be responsible for the drug interaction between digoxin and amiodarone found in clinical reports and that DEA contributes the elevation of digoxin serum concentration. Similarly, dipyridamole altered the transport, but isosorbide showed only slight modification of the transport. The IC(50) value for dipyridamole was 40.0 microM, also only several times the achievable concentration in clinical use, indicating a risk of interaction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Inhibition of DNA topoisomerases I and II, and growth inhibition of breast cancer MCF-7 cells by ouabain, digoxin and proscillaridin A.

We evaluated the cytotoxicity and underlying mechanisms of cardiac glycosides, including digoxin, ouabain and proscillaridin A, on the proliferation of breast cancer MCF-7 cells. In terms of inhibition of cell proliferation of MCF-7 cells, the compounds rank in the order proscillaridin A>digoxin>ouabain. While both digoxin and ouabain inhibited topoisomerase II catalytic activity at nanomolar concentrations (100 nM), neither agent inhibited topoisomerase I catalytic activity even at concentrations as high as 100 microM. On the other hand, proscillaridin A was a potent poison of topoisomerase I and II activity at nanomolar drug concentrations (30 nM, 100 nM, respectively), suggesting that this agent may produce its cytotoxic activity by targeting both enzymes simultaneously. These studies suggest that the stabilization of DNA-topoisomerase II complexes is closely linked to the mechanism of digoxin, ouabain and proscillaridin A cytotoxicity. The potential DNA-binding properties of the cardiac glycosides have been assessed by measuring the displacement of ethidium bromide from calf thymus DNA. These results indicate that digoxin, ouabain and proscillaridin A neither intercalate nor interact with the minor groove of DNA.

Breast Neoplasms↗
PubMed1989

Effect of quinidine on the hepatic uptake of digoxin in guinea pigs.

Effect of quinidine on the hepatic uptake of digoxin was studied using isolated guinea pig hepatocytes and with the multiple indicator dilution method using perfused livers. The initial uptake rate of digoxin by isolated hepatocytes was significantly (p less than 0.05) decreased in the presence of quinidine or ouabain and at low temperature (27 degrees C). The influx rate constant to the liver (K1) of unbound digoxin was also decreased by quinidine or the metabolic inhibitor 2,4 dinitrophenol (DNP) in isolated perfused livers, while K1 of diazepam, which is thought to be taken up by a passive transport system, was not significantly changed in the presence of DNP. These findings suggest that an active transport system for digoxin may exist in the liver and may be inhibited by quinidine. We concluded that the quinidine-induce decreases in the hepatic distribution of digoxin may be attributed both to the decreased tissue binding and to the inhibition of uptake, which might be related to the decreased hepatic clearance.

Animals↗
PubMed1984

Effect of digoxin on plasma clearance and anticoagulant effect of warfarin in rats.

The possible effects of digoxin on the elimination and anticoagulant action of warfarin were examined in rats. The pharmacokinetic parameters of warfarin after a single i.v. (1.2 mg/kg) or repeated oral coadministration with anticoagulant (0.6 mg/kg on day 1, thereafter 0.3 mg/kg) and digoxin (50 micrograms/kg) were not significantly different as compared with those in the group treated with warfarin alone. However, prothrombin complex activity (PCA) following coadministration with the diuretic was significantly and relatively rapidly recovered as compared with that in the warfarin group. The amounts of warfarin extracted by liver 2 and 6 h after a single i.v. dosing or 3 and 8 h after repeated oral dosing in the coadministered group were significantly decreased as compared with those in the group received warfarin alone. The renal function (renal plasma flow rate (RPF) and glomerular filtration rate) in the group coadministered with digoxin was significantly higher than that in the group receiving warfarin alone. On the other hand, the fraction of warfarin bound to BSA or rat plasma and the plasma water were little changed in the presence of digoxin. These results suggest that a pharmacological interaction, the decrease in the anticoagulant action, is induced between warfarin and digoxin coadministered.

Aminohippuric Acids↗
PubMed1989

[Enhanced bioavailability of digoxin by gamma-cyclodextrin complexation: evaluation for sublingual and oral administrations in humans].

The inclusion complex of digoxin with gamma-cyclodextrin was prepared in a molar ratio of 1:4, and evaluated for sublingual and oral administrations in humans. In the dissolution tests of digoxin tablets, the increase in dissolution rate and decrease in acid hydrolysis were attained by gamma-cyclodextrin complexation. The serum levels of digoxin after sublingual and oral administrations to human healthy volunteers in the form of complex tablets were higher than the digoxin alone, particularly in the case of the sublingual form of gamma-cyclodextrin complex. The present data suggested that the sublingual administration of the rapid dissolving form of gamma-cyclodextrin complex may be useful for improving the bioavailability of digoxin due to the prevention of acid hydrolysis in stomach and the enhancement of drug absorption rate.

Administration, Oral↗
PubMed2000

Different effects of in vivo ouabain and digoxin on renal artery function and blood pressure in the rat.

To investigate vascular mechanisms in hypertension, we isolated renal arterial rings from rats with ouabain-dependent hypertension and studied their function. In rats infused with ouabain for 5 weeks, systolic and mean blood pressures (BP) were increased relative to controls. Contractions evoked by high KCl solutions were greater in rings from ouabain-infused rats whereas the threshold concentrations and EC50s for KCl and the peak caffeine contractures were not different. KCl contractures were not affected by 5 microM prazosin. Phenylephrine contractures were increased marginally in ouabain-infused rats, while acetylcholine-induced relaxation was normal. In vitro superfusion of rings with 10 nM ouabain or digoxin did not affect the measured parameters. Plasma ouabain, BP, and all evoked responses were normal one week following interruption of the ouabain infusion. In a second study, BP increased in ouabain (15 microg/kg/day, n= 23), but not digoxin (30 microg/kg/day, n=12), or vehicle-infused (n=16) rats. KCl contractures were greater in rings from ouabain-but decreased in rings from digoxin-infused rats, respectively and correlated with systolic and mean BP (r=0.69, n=30, p<0.005). Peak caffeine (25 mM) responses were similar but the area under the contraction was reduced in the vessels from ouabain-infused rats and correlated inversely with MBP (r=-0.47, n=33, p<0.02). We conclude that a voltage-dependent component of tone in the rat renal artery is reversibly and specifically augmented by in vivo administration of ouabain whereas it is diminished by in vivo digoxin. Vascular production of and response to nitric oxide does not appear to be impaired in the ouabain model. Alterations of intracellular Ca2+ storage and Ca2+ influx in response to in vivo ouabain may underlie the increase in renal vascular resistance and hypertension in this model. The opposite effects of ouabain and digoxin on the hemodynamic and vascular parameters in this study indicate that these agents have novel mechanisms of action in vivo that may not be mediated exclusively by sodium-potassium pumps.

Acetylcholine↗
PubMed1999

Contemporary utilization of digoxin in patients with atrial fibrillation. Clinical Quality Improvement Network Investigators.

OBJECTIVE: To define the contemporary practice patterns of digoxin utilization for the management of patients with atrial fibrillation (AF). METHODS: A retrospective medical records audit of 2490 patients with documented AF, from 12 Canadian hospitals and six outpatient clinics, during fiscal year 1993-1994, was conducted. RESULTS: There were 1158 women and 1332 men, with a mean age of 72 years; 956 patients were < 70 years of age and 1534 were > or = 70 years old. The majority of patients had nonvalvular AF (75% of those with a documented etiology). Paroxysmal AF (PAF) was documented in 800 patients, 936 had chronic AF, and 754 had new-onset AF. While the prescribing patterns were heterogeneous, the predominant strategy pursued in all subgroups appeared to be that of achieving rate control. Digoxin was the most commonly prescribed medication (79%) and was prescribed for the majority of patients in all subgroups, including patients with PAF (74%) and patients with a history of chronic AF who were currently in sinus rhythm (83%). Only 10% of the patients with PAF who were prescribed digoxin had congestive heart failure. Similarly, less than 25% of the patients with chronic AF who were prescribed digoxin after conversion to sinus rhythm had evidence of heart failure. CONCLUSIONS: In the absence of clinical trial evidence supporting either a strategy of antiarrhythmic therapy or rate control with anticoagulation, the appropriateness of the observed prescribing practices cannot be judged. However, digoxin is not the best rate-controlling agent for all patients and may be overused in certain subgroups of patients, such as those with PAF and those successfully converted to sinus rhythm.

Aged↗
PubMed1982

The effect of digoxin on exercise capacity and exercising cardiac function in cystic fibrosis.

The ability of digoxin to increase exercise capacity and stroke volume (SV) during exercise was evaluated in ten patients with cystic fibrosis (CF) ages 12 to 20 years with moderate to severe degrees of airway obstruction but no history of heart failure. A double-blind crossover trial of digoxin versus placebo was carried out. An evaluation of exercise performance was undertaken upon entry into the study, and after each of the one-week periods in which digoxin 0.25 mg/day or placebo was taken. Exercise testing consisted of a progressive exercise test on a cycle ergometer to measure maximum work capacity (Wmax) and a steady state test at 2/3 of the baseline Wmax. During the steady state test, the oxygen consumption and carbon dioxide production were measured and cardiac output (Q) was calculated by the indirect Fick (CO2) method. From Q and heart rate (HR), SV was derived. After digoxin, Wmax was unchanged. On steady state exercise HR was unchanged, but there was a slight but significant fall in Q due to a fall in SV. The decrease in SV was associated with exercising hypoxemia. We conclude that digoxin did not increase exercise capacity or improve exercising cardiac function in patients with moderate to severe airway obstruction due to CF.

Adolescent↗
PubMed1984

Effects of digoxin on exercise capacity and right ventricular function during exercise in chronic airflow obstruction.

We evaluated 12 patients with stable chronic airflow obstruction (CAO) and no clinical evidence of left ventricular disease to determine the effects of oral digoxin on exercise capacity (VO2 max) and on right ventricular pump function during exercise. In this randomized, double blind, placebo controlled, cross-over study, patients performed exercise tests and underwent measurement of ejection fractions after two weeks of therapy with oral digoxin (0.25 mg/day) and after two weeks of placebo. Incremental upright exercise testing to a symptom-limited maximum was performed on a cycle ergometer. Right and left ventricular ejection fractions (RVEF, LVEF) were obtained in the supine position at rest and at approximately 75 percent of the maximum workload by gated equilibrium radionuclide angiography. All patients had abnormal right ventricular function, manifested either by a low resting RVEF (less than 45 percent) or a subnormal response to exercise (less than 5 percent increase). The small increases in RVEF with digoxin (mean +/- SE) at rest (44 +/- 5 vs 41 +/- 4 percent) and during exercise (46 +/- 4 vs 44 +/- 3 percent) did not achieve statistical significance. With digoxin, small increases in exercise duration (10.0 +/- 1.5 vs 9.0 +/- 1.4 min), maximum workload achieved (48 +/- 6 vs 42 +/- 5 W), VO2 max (0.85 +/- 0.06 vs 0.81 +/- 0.06 L/min), and oxygen-pulse (O2-P) (6.6 +/- 0.5 vs 6.3 +/- 0.4 ml/beat) occurred. Only the increase in O2-P was significant (p less than 0.05). From this study we conclude that digoxin does not significantly improve exercise capacity in severe chronic airflow obstruction with impaired right ventricular function, nor does it improve RVEF either at rest or during supine submaximal exercise.

Digoxin↗
PubMed1989

Inotropic response to digoxin and dopamine in patients with severe sepsis, cardiac failure, and systemic hypoperfusion.

We studied the inotropic response to dopamine and digoxin in 20 patients with severe sepsis and left ventricular failure. Left ventricular failure was defined as a left ventricular stroke work index less than or equal to 40 g.m/m2 at a pulmonary artery wedge pressure greater than or equal to 15 mm Hg. Hemodynamic assessment was obtained before and following administration of digoxin 10 micrograms/kg IV or dopamine, 5 to 12 micrograms/kg/min IV. Patients treated with digoxin demonstrated a significant increase in LVSWI. The LVSWI increased 13 +/- 10 percent in the dopamine-treated patients compared with 74 +/- 16 percent in the digoxin patients (p less than 0.02). We conclude that digoxin exhibited significant inotropic activity in patients with sepsis.

Aged↗
PubMed1984

A radioimmunoassay for digoxin in human urine.

We report a digoxin radioimmunoassay in human urine employing commercially available reagents. The calibration curve has a mean correlation coefficient of -0.994 and is linear up to 16.0 micrograms/l. The average coefficients of variation between and within the runs are 3.6% and 3.5% respectively. The assay has a recovery of 101.4% and 98.9% at low and high levels of digoxin excretion respectively. Dihydrodigoxin at concentrations of 4, 8 and 16 micrograms/l has relative cross reactivities of 12.0%, 7.7% and 4.8% respectively. The assay was applied to compare within-patient and between-patient variability during treatments with Lanoxin and Lanoxicaps at steady-state. Precision, sensitivity, broad range linearity, convenience of commercially available reagents, insignificant cross reactivity of dihydrodigoxin with the digoxin antibody complex and urinary digoxin excretory data at different dilutions validate our assay for routine monitoring of urinary digoxin.

Biological Availability↗
PubMed1979

Some observations on serum concentrations of digitoxin and digoxin.

Serum concentrations of digitoxin and digoxin were measured in 145 cases with various heart diseases receiving maintenance doses of digitalis. Digitalis toxicity was seen in only 2 cases (1.4%). Day-to-day variation of serum concentration while taking the same daily dose was small in digitoxin therapy (13.8%), but a considerable variation was seen in digoxin therapy (24.4%). Serum concentrations of both digitoxin and digoxin were measured in the patients receiving digitoxin, and there was a positive correlation between the two (r = 0.66, p less than 0.001). This fact suggested that the effect of digitoxin was the sum of the effects of digitoxin and its metabolite, digoxin. In the patients taking digoxin, digitoxin was not detected in the serum. Serum digitoxin level had a significantly positive correlation to serum albumin level, presumably because digitoxin was retained in serum in the bound form to albumin. Minimal effective level, 10 ng/ml, was however obtained with higher daily dose of digitoxin in patients with lower serum albumin.

Adolescent↗
PubMed1997

Advances in the management of digoxin toxicity in the older patient.

Digoxin intoxication is a common problem in the elderly. In its mildest forms it may go undiagnosed, but in severe cases it is often fatal. Altered digoxin pharmacokinetics, attributable to the physiological changes associated with aging, underlying illness, and drug-drug interactions all contribute to the occurrence of digoxin toxicity. Advanced age, male gender, initial hyperkalaemia, underlying heart disease, and advanced atrioventricular block at the time of admission are poor prognostic factors. Supportive care alone is often insufficient. Digoxin-specific Fab therapy may result in dramatic recovery from digoxin intoxication, but it must be administered early and in a an adequate dosage if reductions in mortality are to be achieved.

Aged↗