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At least 793 records · Page 44Linked to original sources
PubMed1987

Cardiovascular time course after digoxin administration in left ventricular dysfunction after coronary artery bypass grafting.

Intravenous digoxin, 1 mg, was administered over 8 hours to 10 cardiac patients with left ventricular (LV) dysfunction after coronary artery bypass grafting. The cardiovascular effects of digoxin were monitored over 20 hours by indwelling pulmonary artery and radial artery lines and were compared with those of a control group of 10 patients who had normal postoperative LV function. Digoxin administration produced an increased cardiac index and mean arterial blood pressure within 2 hours. Within 4 hours after digoxin administration pulmonary artery wedge pressure in patients receiving digoxin was significantly lower than in control patients. At 16 hours there was a significant increase in both the LV stroke work and LV stroke work index in patients receiving digoxin vs control patients. Two patients receiving digoxin and 3 control patients had changes in cardiac rhythm during the study. Thus, digoxin can be safely administered to postoperative patients with LV dysfunction and is an acceptable inotropic agent.

Arrhythmias, Cardiac↗
PubMed1985

Influence of quinidine on the intestinal secretion of digoxin and digitoxin in guinea pigs.

The secretion of digoxin and digitoxin into in situ perfused jejunal and colonic segments of normal or quinidine treated guinea pigs was studied. Quinidine was administered intravenously by constant rate infusion resulting in a quinidine plasma concentration of about 6 micrograms/ml. After 2 h digoxin or digitoxin was injected i.v. (10 micrograms/kg). The quinidine treatment enhanced the plasma concentration of [3H]digoxin to about 140% as compared to controls, whereas the [3H]digitoxin concentration was not influenced by the quinidine infusion. Both, digoxin and digitoxin were secreted against a concentration gradient into the intestinal lumen. During the experimental period of 180 min controls secreted 0.24% of the administered digoxin dose per cm of jejunal and 0.13% per cm of colonic segment. Quinidine treatment resulted in a decrease of the jejunal digoxin secretion to about 80% of the control values. In both, jejunum and colon the concentration ratio between lumen and plasma (L/P) was diminished by quinidine to 50% as compared with the controls. The amount of [3H]digitoxin secreted into the intestinal segments was decreased by quinidine from 0.19% of the dose/cm to 0.13% in the jejunal and from 0.17% to 0.12% in the colonic segments, respectively. The decrease of the L/P ratio for [3H]digitoxin was more pronounced in the colon (58%) than in the jejunum (77% of the control values). As compared with controls the content of [3H]digoxin in the jejunal as well as colonic tissue was decreased by quinidine to 60% or 73%, respectively. On the other hand quinidine increased the tissue content of [3H]digitoxin in jejunum (+56%) and colon (+88%). In conclusion quinidine inhibits the intestinal secretion of both, digoxin and digitoxin, possibly by different mechanisms.

Animals↗
PubMed1988

Inaccuracies in digoxin measurement.

Six commercial digoxin immunoassay kits were evaluated for their accuracy of calibration and their extent of interference by digoxin-like immunoreactive substance (DLIS). Calibration accuracy was investigated with digoxin reference standards in pooled human serum. The Abbott and Becton Dickinson kits underestimate while the other kits overestimate digoxin concentration. The magnitude of this bias generally increases with increasing concentration of digoxin. Sera from digoxin-free patient populations with potential DLIS interference--pregnant women, newborns, hypertensives, and uremics--were analyzed with each kit. Healthy subjects not on digoxin therapy served as controls. Groups with DLIS interference, as exemplified by a significant difference of p less than 0.05 from controls, are: Abbott--newborns and pregnant women; Becton Dickinson--newborns and pregnant women; Dade--no difference; Dupont--newborns, uremics, pregnant women, and hypertensives; Kallestad--newborns; and Syva--newborns. The limitations of each individual digoxin method should be realized for DLIS interference and bias, and patient results from that method should be interpreted accordingly.

Adult↗
PubMed2003

Evidence for a non-MDR1 component in digoxin secretion by human intestinal Caco-2 epithelial layers.

Caco-2 epithelial layers were used as a model to re-evaluate the mechanism(s) by which intestinal digoxin absorption is limited by its active secretion back into the lumen. It is widely recognised that intestinal secretion of digoxin is mediated by the ATP-binding cassette (ABC) transporter Multidrug Resistance 1, MDR1. In MDR1-transfected Madin-Darby canine kidney, MDCKII, cell monolayers, digoxin secretion was reduced by the MDR1 inhibitor cyclosporin A, whereas no inhibition was seen in the presence of MK-571, 3-([(3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl]-[(3-dimethylamino-3-oxoprphyl)-thio)-methyl]-thio) propanoic acid, a Multidrug Related Protein (MRP) inhibitor. In contrast, digoxin secretion by Caco-2 epithelia was significantly inhibited by both cyclosporin A and MK-571, suggesting that an additional non-MDR1 component may contribute to this transport. Since digoxin secretion by MRP2-transfected MDCKII monolayers was increased by only 1.2-fold relative to controls, it is likely that the contribution of MRP2 to digoxin secretion by Caco-2 cells is negligible. An additional MK-571-sensitive secretory pathway for digoxin, together with MDR1, is likely to mediate digoxin secretion in Caco-2 epithelia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1985

Maintenance digoxin dosage and steady-state plasma concentration in infants and children.

To define the relationship between digoxin dose and plasma concentration and the changes in body growth, 1181 plasma digoxin levels were measured in 644 infants and children receiving maintenance digoxin therapy. The drug was given intravenously to 166 patients and orally to 478. A significant linear correlation between dose and plasma concentration was observed (r 0.346 to 0.767 in the intravenous and 0.264 to 0.664 in the oral groups). Dosage differences explained 7% to 60% of the variability in digoxin plasma concentrations in various age and weight groups. The linear regression slope was greater in younger age groups, especially preterm infants weighing less than 1500 gm, and tended to decrease with age. The data (1) allow an approximate prediction of plasma concentrations of digoxin and their variability associated with changes in dosages in various pediatric age and weight groups, (2) permit an estimate of other pharmacokinetic determinants of digoxin plasma concentration and their changes with age, and (3) suggest that larger changes in digoxin doses in older children are necessary to achieve the same change in serum concentration that is achieved with smaller dose changes in the young infant. As a result, premature infants are more sensitive to and require smaller digoxin doses.

Age Factors↗
PubMed2002

Interaction of digoxin with antihypertensive drugs via MDR1.

The multidrug transporter MDR1 (P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive drugs of various types was examined by using the MDR1 overexpressing LLC-GA5-COL150 cells, which were established by transfecting MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. These cells construct monolayers with tight junctions, and enable the evaluation of transcellular transport. The MDR1 was highly expressed on the apical membrane (urine side). The basal-to-apical and apical-to-basal transcellular transport of [3H]digoxin in LLC-GA5-COL150 cells was time- and temperature-dependent. The basal-to-apical transport of [3H]digoxin was markedly increased, whereas the apical-to-basal transport was decreased in LLC-GA5-COL150 cells, compared with the host LLC-PK1 cells, suggesting that [3H]digoxin was a substrate for MDR1. Most of the Ca2+ channel blockers used here markedly inhibited basal-to-apical transport and increased apical-to-basal transport. Exceptions were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory effects on transcellular transport of [3H]digoxin. Alpha-blocker doxazosin and beta-blocker carvedilol also inhibited transcellular transport of [3H]digoxin, but none of the angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists used here were active. These observations will promote understanding of the digoxin-drug interactions resulting from their actions on MDR1, and which may aid in avoiding these unexpected effects of digoxin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Is maintenance digoxin necessary in patients with sinus rhythm?

Discontinuation of digoxin in 56 patients with sinus rhythm who had been taking it for a long time did not produce clinical deterioration in 33 of 34 patients whose pre-withdrawal steady-state plasma-digoxin concentration was less than 0.8 ng/ml; fast atrial fibrillation developed in the other patient. 22 patients had plasma-digoxin levels between 0.8 and 2.0 ng/ml before withdrawal--of these, 7 deteriorated without digoxin (5 had atrial fibrillation, which was associated with congestive heart-failure, measurement of the pre-injection period/left-ventricular ejection time (P.E.P./L.V.E.T.) ratio suggested that digoxin did exert a sustained positive inotropic effect. Thus, successful discontinuation of digoxin was possible in 86% of the total group and was more likely when the plasma-digoxin concentration was below 0.8 ng/ml. Unexpected atrial fibrillation was the commonest development inthe 8 patients in whom digoxin withdrawal was unsuccessful.

Adult↗
PubMed1987

Serum digoxin levels and mortality in 5,100 patients.

A retrospective study of 5,100 patients on digoxin, with a four-week follow up after digoxin levels were measured, was done to determine the mortality rate. A significant increase in mortality was correlated with an increasing serum digoxin level, up to 50% at a level of 6.0 ng/mL and more. Clinical toxicity was suspected in only 0.25% of all patients on digoxin, although almost 10% had levels above the therapeutic range. Deliberate digoxin overdoses were fatal in 50% of cases. This study shows a correlation between increasing digoxin levels and increasing mortality rates. We recommend the use of serum digoxin measurements to identify those asymptomatic patients with elevated levels. The physician should seriously consider the indications for initiating or continuing digoxin treatment in any patient because of an increased mortality in patients with levels of more than 1.0 ng/mL.

Adult↗
PubMed1985

Hyperkalemia complicating digoxin toxicity in a patient with renal failure.

We describe the occurrence of hyperkalemia in a stable hemodialysis patient who developed digoxin toxicity. The patient had been receiving digoxin for 2 years. His maintenance digoxin dose was increased from 0.125 to 0.25 mg three times a week, which resulted in a toxic serum level of 4.9 ng/mL (therapeutic range is 0.8 to 2.0 ng/mL). As a consequence of the digoxin toxicity, he became hyperkalemic (7.8 mEq/L), and this value returned to normal only after the digoxin level was lowered by a combination of oral charcoal and dialysis. This study shows how readily hyperkalemia can occur in an anephric patient manifesting digoxin toxicity. Thus, potentially lethal hyperkalemia can occur in hemodialysis patients who ingest therapeutic quantities of digoxin. Digoxin toxicity should be added to the differential diagnosis of hyperkalemia in patients with renal failure. This can occur despite the absence of a history of massive ingestion of a cardiac glycoside.

Aged↗
PubMed2000

High-performance liquid chromatography with on-line post-column immunoreaction detection of digoxin and its metabolites based on fluorescence energy transfer in the far-red spectral region.

The combination of immunoassays with separation techniques such as chromatography can result in enhanced selectivity and sensitivity. This paper describes an on-line chromatography with immunochemical post-column fluorescence energy transfer detection for digoxin and its metabolites. R-phycoerythrin (PE) was used as the donor and an indodicarbocyanine dye (Cy5) as the acceptor label. These labels allow the detection in the far-red spectral region, which is more selective for biological samples. Hence, digoxin was labeled with PE using the activated digoxigenin-NHS-ester and monoclonal anti-digoxin antibody was labeled with Cy5. Digoxin and its metabolites was injected into the HPLC system followed by post-column injection of R-phycoerythrin labeled digoxin and by Cy5 labeled anti-digoxin antibody. Incubation time was provided using an open tubular reactor coil at room temperature. The detection was performed by measurement of the sensitized emission of Cy5 at 670 nm due to fluorescence energy transfer from PE labeled with digoxin. The system was optimized with regard to the concentrations of the used post-column reagents as well as incubation time and temperature. The dynamic range of digoxin spiked in 0.01 M phosphate buffer (pH 7.4) was 0.05 to 10 ng/ml with a correlation coefficient of 0.989. The limit of detection was 33 pg/ml. The precision of two controls, 0.4 and 4 ng/ml, was found to be 2.2 and 8.7% RSD, respectively, accuracy was 10.7 and 20.3% (n=6 in each case).

Antibodies↗
PubMed2003

A rapid and sensitive LC/MS/MS assay for quantitative determination of digoxin in rat plasma.

Digoxin is a cardiac glycoside that is widely used for the treatment of congestive heart failure. To evaluate pharmacokinetics of digoxin in rats, a sensitive LC/MS/MS assay was developed and validated for the determination of digoxin concentration in rat plasma. For detection, a Sciex API3000 LC/MS/MS with atmospheric pressure ionization (API) mass spectrometry turbo ion spray inlet in the positive ion-multiple reaction monitoring mode was used to monitor precursor-->product ions of m/z 798.6-->651.6 for digoxin and m/z 577.6-->433.3 for oleandrin, the internal standard (IS). The standard curve was linear (r(2)>or=0.999) over the digoxin concentration range of 0.1-100 ng/ml in plasma for digoxin. The mean predicted concentrations of the quality control samples deviated by <5.8% from the corresponding nominal values; the intra-assay and inter-assay precision of the assay were within 8.6% relative standard deviation. At the lower limit of quantitation (LLQ) of 0.1 ng/ml, the mean deviation of predicted concentrations from the nominal value was within 3.7%. The extraction recoveries of digoxin and internal standard were 82.7+/-3.9 and 105.9+/-2.3%, respectively. The present method was successfully applied to characterization of pharmacokinetic profiles of digoxin in rats after oral administration.

Administration, Oral↗
PubMed1984

Application of a computerized medical decision-making process to the problem of digoxin intoxication.

A computerized medical decision-making system was used to monitor signs and predisposing factors of digoxin intoxication in patients receiving digoxin. This process automatically reviewed the patient's data base nightly for drug interactions, laboratory data and electrocardiographic findings with known association with digoxin intoxication. These decisions were formated into a "digoxin alert report" and sent to line printers in the nursing division to be placed on the individual patients' charts. To assess the effect of these reports on patient management, a randomized double-blind study was undertaken. Patients were assigned to an alert or nonalert group. Alert reports were withheld from charts of patients in the nonalert group. A medical record review was subsequently carried out, wherein the physician's orders were searched to identify actions taken with possible relation to the digoxin alerts. The computer monitored 396 patients over a 3 month period. Of these, 211 (53%) were randomized to the alert group and 185 (47%) to the nonalert group. Seventy-two percent of patients received at least one alert. The most frequently occurring alerts included: hypoxemia, hypokalemia, concurrent use of a beta-adrenergic blocking agent, renal insufficiency and ventricular arrhythmia. Results from the record review demonstrated a 22% increase in physician actions for the alert group. Specifically, patients in the alert group were 2.7 times more likely to have a serum digoxin determination ordered and 2.8 times more likely to have digoxin withheld on the day of a digoxin alert than were patients in the nonalert group.

Aged↗
PubMed1984

Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications.

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.

Adult↗
PubMed1997

Patients with mild heart failure worsen during withdrawal from digoxin therapy.

OBJECTIVES: We investigated whether patients with mild heart failure due to left ventricular systolic dysfunction were at risk of worsening during digoxin withdrawal. BACKGROUND: Deterioration during digoxin withdrawal is often believed to be restricted to patients with moderate to severe clinical evidence of heart failure. To test this hypothesis, we studied the outcome of patients categorized by treatment assignment and a clinical signs and symptoms heart failure score in two rigorously designed clinical heart failure trials: the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) trial. METHODS: Potential differences in treatment failure, left ventricular ejection fraction and exercise capacity were evaluated in three groups of patients: those with mild heart failure (score < or = 2) who were withdrawn from digoxin (Dig WD Mild); those with moderate heart failure (score > 2) who were withdrawn from digoxin (Dig WD Moderate); and patients who continued receiving digoxin regardless of heart failure score (Dig Cont). RESULTS: Heart failure score at randomization did not predict outcome during follow-up in Dig Cont-group patients. Dig WD Mild-group patients were at increased risk of treatment failure and had deterioration of exercise capacity and left ventricular ejection fraction compared with that in Dig Cont-group patients (all p < 0.01). Patients in the Dig WD Moderate group were significantly more likely to experience treatment failure than patients in either the Dig WD Mild or Dig Cont group (both p < 0.05). CONCLUSIONS: Patients with systolic left ventricular dysfunction were at risk of clinical deterioration after digoxin withdrawal despite mild clinical evidence of congestive heart failure.

Aged↗
PubMed2001

The role of P-glycoprotein in limiting intestinal regional absorption of digoxin in rats.

The objective of this work was to study the role of regional intestinal efflux activity of P-glycoprotein (Pgp) in situ in anesthetized rats in limiting the absorption of digoxin. A 10-cm portion of duodenum or jejunum, or 5-cm of colon was perfused single-pass with saline containing [(3)H]digoxin while the appearance of radioactivity in the blood was measured. Verapamil in the perfusate was used as a modulator of Pgp in the intestinal mucosa. Net water absorption, mucosal integrity, and intestinal motility of the isolated segment were monitored, as well as heart rate and blood pressure. Excretion of i.v. administered unlabelled digoxin, 1 mg/kg, into the intestine while perfusing the duodenum-proximal jejunum region, was studied for comparison. At a perfusate concentration of 1 mM, verapamil caused a dramatic increase in [(3)H]digoxin absorption rate from duodenum and jejunum, while the effect in colon was insignificant. At concentrations of 0.1, 1, and 2.5 mM in the duodenal perfusate, verapamil increased the absorption rate of [(3)H]digoxin in a dose-dependent manner. The lowest concentration almost doubled the rate without having any significant effects on the cardiovascular system, intestinal motility, or net absorption of water. The excretion rate of unlabelled digoxin from the blood into the gut lumen was found to be halved in the presence of 0.5 mM verapamil in the perfusate. Absorption rate of [(3)H]digoxin in the rat is likely limited by Pgp-mediated efflux. The data indicate that Pgp plays an important role for digoxin efflux in the small intestine only.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1980

The question of cumulation of digoxin metabolites in renal failure.

Using high-performance liquid chromatography (HPLC) to separate digoxin from its metabolites digoxigenin, digoxigenin-bis-digitoxoside, and digoxigenin-mono-digitoxoside with subsequent quantitation by 125I radioimmunoassay (RIA), we examined the plasma of patients on long-term oral digoxin therapy. Digoxin was also measured by RIA without prior HPLC separation. Nine patients requiring maintenance dialysis and 9 subjects with lesser degrees of renal impairment were studied. Trace amounts of 1 or more of the digoxin metabolites were found in the plasma of all dialysis patients while subjects with lesser degrees of renal failure had either none or only 1 metabolite in trace amounts. The ratio of HPLC digoxin without HPLC was 0.83 +/- 0.12 (SD) in renal failure patients and 1.06 +/- 0.09 in subjects with renal function (p less than 0.01). RIA overestimates the amount of digoxin in plasma of renal failure patients and in them from 6% to 42% of plasma digoxin, as determined by conventional 125I RIA, may represent compounds other than digoxin.

Chromatography, High Pressure Liquid↗
PubMed1983

Erythrocyte cation transport and age: effects of digoxin and furosemide.

The uptake of rubidium 86 (86Rb) by human erythrocytes was measured at various ages. Effects of digoxin and furosemide on this process were examined and, in the case of digoxin, related to its numbers of specific cellular binding sites. There were no significant effects of age on absolute cellular Rb uptake, digoxin-sensitive Rb uptake, or numbers of cellular binding sites for digoxin, but the ability of digoxin to inhibit digoxin-sensitive 86Rb uptake increased with age. The ability of furosemide to inhibit digoxin-insensitive 86Rb uptake did not change with age. Results suggest a dynamic contribution to altered sensitivity to digoxin in elderly persons.

Adolescent↗
PubMed1984

Digoxin biotransformation.

Serum digoxin and metabolites were assayed in plasma and urine by HPLC in 10 dialysis-dependent patients with end-stage renal failure (group I) and in five patients with comparatively normal renal function (group II) after ingestion of 150 muCi 3H-digoxin-12 alpha. Thirteen patients were on maintenance digoxin therapy and were at steady state. Metabolites found regularly but usually in small amounts, were 3 beta-digoxigenin and its mono- and bis-digitoxosides, and 3-keto and 3 alpha(epi)-digoxigenin. Quantitatively the most abundant metabolites were polar and averaged 26% (7 to 76) of the radioactivity in plasma 6 hr after drug, and 60% (11 to 88) for digoxin for all 15 patients. Neither values between group I and II for the polar metabolites nor digoxin differed significantly. The metabolites reacted with antibody to digoxin to varying degrees and may make up an important component of the serum digoxin concentration when determined by standard radioimmunoassay. In some patients, digoxin undergoes extensive biotransformation, mainly, we suggest by hydrolysis, oxidation, epimerization, and conjugation to polar end-metabolites.

Administration, Oral↗