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PubMed1986

Renal handling and effects of [3H]digoxin and interactions with quinidine in the avian kidney.

Renal handling and effects of tritium digoxin and interactions with quinidine in the avian kidney were studied using a modified Sperber technique. Results showed that tritium digoxin was extracted at the peritubular side of the nephron in a process competitively inhibited by increasing amounts of unlabelled digoxin. Light microscope autoradiography showed distinct concentrations of silver grains only over distal tubules in the injected kidney. Inhibition of the proximal tubular transport systems for organic anions and cations, respectively, did not change extraction. Addition of quinidine to the injection solution up to an estimated concentration of 1.4 X 10(-5) M in systemic blood significantly lowered 1 min peritubular extraction of tritium digoxin. However, when the amount of quinidine was further increased, extraction of tritium digoxin augmented significantly. Tritium recovery in urine after renal portal bolus injection of tritiated and unlabelled digoxin already showed a distinct ipsilateral peak 2 min after injection with an equally distinct peak of ipsilateral sodium excretion appearing 1 min later. When quinidine was added to the bolus ipsilateral tritium recovery in urine (0-7 min) was halved, with the true tubular excretion fraction (TTEF) lowered by two-thirds, but without changes in the magnitude of ipsilateral natriuresis. Contralateral natriuresis increased more than four-fold with quinidine in the bolus in spite of unchanged tritium recovery in the urine. Thus, our results show tritium digoxin to be extracted from peritubular blood through a specific process probably localized to the distal nephron of the avian kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Does any correlation exist between a high plasma digoxin level and an electrocardiogram in older and younger patients?

In a group of 171 patients aged 65 to 92 years and 58 patients aged 35 to 64 years, plasma digoxin level measuring 2.5-6.2 nmol/l correlated with the clinical symptoms and the electrocardiogram. Conduction disturbances and arrhythmias as well as the P-R interval, P-T-Q index, and corrected Q-T interval in the ECG were analyzed. Clinical symptoms of hypersaturation with digitalis were present in 55.5% of the elderly and 34.4% of the younger patients. Conduction disturbances were found in 43.2% of the elderly and 20.6% of the younger patients, while arrhythmias appeared in 40.3% of the elderly and 29.3% of the younger patients: 16.3% of the elderly and 50.1% of the younger patients were without these changes. A correlation between the P-R interval and high plasma digoxin level in the elderly (p < 0.01) and younger patients (p < 0.05), as well as between the P-T-Q index and high plasma digoxin level in the elderly (p < 0.01), was found. There was no correlation between the corrected Q-T interval and high plasma digoxin level in both groups. No correlation was found between the high plasma digoxin level and serum creatinine level in both groups, or between the high plasma digoxin level and serum potassium level in both groups, although many patients had chronic renal failure. The effect of digitalis has not been shown to be a cause of specific changes in an electrocardiogram either in the elderly or in younger patients. However, the association between prolonged P-R interval, as well as changes in the P-T-Q index, and high plasma digoxin level has been found more often in the elderly than in younger patients.

Adult↗
PubMed2004

Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques.

This work had two separate aims: to evaluate different modeling techniques and to make a detailed structural characterization of CYP2C9. To achieve these goals, the consensus principal component analysis (CPCA) technique and distance measurements were used to explore available crystal structures, newly built homology models, and repeated molecular dynamics simulations. The CPCA was based on molecular interaction fields focused on the active site regions of the proteins and include detailed amino acid analysis. The comparison of the CYP2C9 and CYP2C5 crystal structures revealed differences in the flexible regions such as the B-C and F-G loop and the N and C termini. Cross homology models of CYP2C9 and CYP2C5, using their respective crystal structures as templates, indicated that such models were more similar to their templates than to their target proteins. Inclusion of multiple templates slightly improved the similarity to the crystal target in some cases and could be recommended even though it requires a careful manual alignment process. The application of molecular dynamics simulations to highly flexible proteins such as cytochromes P450 is also explored and the information is extracted by the CPCA. Advantages and drawbacks are presented for the different modeling techniques. Despite the varying modeling success, the models give insight and understanding by the mutual forming and discarding of hypotheses. This is a dynamic process since the crystal structures are improving with time and, therefore, the answers to the models are also changing accordingly.

Aryl Hydrocarbon Hydroxylases↗
PubMed1972

Effects of renal function on plasma digoxin levels in elderly ambulant patients in domiciliary practice.

An investigation into the relations between the daily dose of digoxin, drug regimen, serum digoxin concentration, and creatinine and digoxin clearance was carried out in a group of elderly ambulant patients in domiciliary practice. Moderate to severe impairment of renal function was found both in patients taking digoxin and in elderly control subjects. Plasma digoxin levels were not related to blood urea concentrations or creatinine clearance. Digoxin clearance was less than creatinine clearance. Now that plasma digoxin levels can be measured relatively easily their estimation should become part of clinical practice.

Aged↗
PubMed1978

Do patients take digoxin?

Plasma digoxin concentrations on admission to hospital have been compared with levels on day 8 in a group of 50 patients who were maintained on their preadmission digoxin doses for 7 days. In the absence of a change in renal function, 18 patients (36%) had higher levels on day 8 and were considered to be non-compliant: a further 7 patients (14%) had lower levels on day 8 suggesting that before admission they had been taking more than their prescribed digoxin dose. Fifty per cent were, therefore, taking their digoxin improperly. In addition, an incorrect dose of digoxin may have been prescribed in 14 patients (28%) with plasma digoxin concentrations either below 0.8 ng/ml (1.02nmol/l) or above 2.0 ng/ml (2.56 nmol/l) on day 8. Long-term compliance was assessed by comparing day 8 'steady state' digoxin levels with those obtained at outpatient follow-up. Thirty of the original group were studied at 4 weeks when 27 per cent were considered non-compliant, and 20 at 3 months when 30 per cent were non-compliant. These results have serious implications both for drug prescribing and for the treatment of disease, and suggest that a problem of communication exists between doctors and their patients.

Aged↗
PubMed1989

Clinical, haemodynamic, and pharmacological effects of withdrawal and reintroduction of digoxin in patients with heart failure in sinus rhythm after long term treatment.

A randomised, double blind, placebo controlled, crossover study of digoxin withdrawal and reintroduction was carried out over two periods of eight weeks each after long term treatment. Forty four patients with stable heart failure in sinus rhythm and plasma digoxin concentrations over 0.8 ng/ml were studied. Their progress was assessed by clinical criteria, by haemodynamic measurements (systolic time intervals and echocardiography), and by pharmacological measurements of erythrocytic sodium pump numbers and activity. After withdrawal of digoxin clinical deterioration occurred in only 25% of the patients. Furthermore, in only 9% of cases was digoxin reintroduction thought to be necessary. There was deterioration in only 11% of the patients during digoxin treatment. Deterioration during digoxin withdrawal was accompanied by changes in systolic time intervals, but similar, albeit smaller changes in systolic time intervals also occurred in patients with no deterioration. Deterioration was accompanied by changes in the pharmacological effects of digoxin on the erythrocytes, consistent with a loss of effect, and these changes did not occur in those who did not deteriorate. The occurrence of deterioration could not be predicted by any clinical, haemodynamic, or pharmacological measurements made before withdrawal.

Adult↗
PubMed1991

Influence of physical exercise on serum digoxin concentration and heart rate in patients with atrial fibrillation.

Heart rate and serum digoxin concentration in eight patients with atrial fibrillation were studied at rest and during exercise when initial serum digoxin concentrations were zero and at low and high therapeutic values. Eight patients with ischemic heart disease and in sinus rhythm were studied for comparison. Though the serum digoxin concentration decreased significantly during exercise, the absolute reduction in heart rate was the same at rest and during exercise in patients with atrial fibrillation. Compared with the control patients in sinus rhythm, the heart rate in patients with atrial fibrillation was not adequately controlled during exercise by any serum digoxin concentration tested despite a reduction in heart rate with increasing digoxin concentration. The effects of digoxin on heart rate regulation in atrial fibrillation are complex and include direct effects on the myocardium as well as indirect effects mediated by modulation of the autonomic nervous system; the present results indicate that the drug is not displaced from the target organs by decreasing serum concentrations during exercise. In atrial fibrillation, because the demands on the filter function of the atrioventricular node are highly unphysiological, the effect of digoxin on heart rate during exercise is not adequate.

Adult↗
PubMed1984

Effects of digoxin on the chronotropic responses to repetitive vagal stimulus bursts in the dog.

We studied the effects of digoxin on the chronotropic responses of the heart to repetitive bursts of vagal stimulation in chloralose-anesthetized dogs. The frequency of the stimulus bursts was increased linearly with time. Over a certain range of frequencies, the cardiac pacemaker became synchronized with the vagal stimulation in a 1:1 ratio of heart beats to stimulus bursts. Digoxin increased the range of cardiac cycle lengths over which 1:1 synchronization occurred during repetitive vagal stimulation. This increment in the range of synchronization varied directly with the dose of digoxin. Before digoxin was given, the range of cardiac cycle lengths over which synchronization occurred when the vagus nerve was stimulated with 10 pulses per burst was 272 +/- 50 (mean +/- SE) ms. However, after a cumulative dose of 120 micrograms/kg-1 digoxin had been given, the range of 1:1 synchronization increased to 396 +/- 32 ms. Digoxin did not appear to have a proportionately greater effect on those processes that take place in the phase of the cardiac cycle during which the pacemaker cells are maximally responsive than on those processes that occur in the phase of the cycle during which the pacemaker cells are minimally responsive. Therefore, we conclude that the augmented entrainment induced by digoxin is ascribable to its tendency to enhance the chronotropic response to vagal stimulation.

Anesthesia↗
PubMed1975

Inotropic responses to digoxin during hypoxia and autonomic blockade.

Inotropic responses to digoxin (0.08 mg/kg) were studied in dogs and compared with responses during hypoxemia and autonomic blockade. Changes in left ventricular contractility (VC) were assessed by constructing function curves relating left ventricular (dP/dt)max and stroke volume to end-diastolic pressure. Augmentation of VC was observed 20 min after digoxin infusion and continued to increase until termination of the experiment after 60 min. In animals subjected to autonomic blockade with practolol, TEAC, and atropine, the increases in VC after digoxin were substantially greater. Equally large increases occurred in blocked dogs during sustained hypoxia (Pao2 = 28 mmHg). However, in animals without blockade there was a progressive fall in VC during hypoxia despite digoxin infusion, although less than in those not given digoxin. Serum digoxin levels were measured by radioimmunoassay and did not differ significantly in blocked compared to unblocked dogs or in hypoxic compared to nonhypoxic animals. These findings indicate that digoxin protects the heart from the decrease in myocardial contractility which occurs during extended hypoxia. This protective effect is more pronounced in animals deprived of autonomic function, possibly reflecting the elimination of reflex sympathetic withdrawal ordinarily induced by digitalis.

Adrenergic beta-Antagonists↗
PubMed1986

Digoxin-like immunoreactive substance in renal failure: a reappraisal.

A digoxin-like immunoreactive substance (DLIS) has been described in the sera of patients with renal impairment. To further investigate this problem, we measured digoxin in 50 patients with elevated serum creatinine using 4 commercial digoxin immunoassay kits (3 radioimmunoassay methods and 1 fluorescence polarization immunoassay technique). Ten of the patients were receiving digoxin therapeutically, while the remainder were not receiving the drug. Two of the radioimmunoassay kits detected low amounts of DLIS in 23% of the subjects not receiving digoxin, the highest level being 0.5 nmol/l. No DLIS was detected by the other radioimmunoassay kit or by the fluorescence polarization technique. The majority of renal patients receiving digoxin had similar results by all 4 methods, although 2 patients differed by 0.6 nmol/l as measured by 2 of the radioimmunoassay kits. We conclude that the extent of interference by DLIS in digoxin immunoassays in patients with renal impairment is not as great as has been previously reported.

Blood Proteins↗
PubMed1999

Digoxin delays recovery from tachycardia-induced electrical remodeling of the atria.

BACKGROUND: Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. METHODS AND RESULTS: We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. CONCLUSIONS: Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Animals↗
PubMed2000

Effects of digoxin on acute, atrial fibrillation-induced changes in atrial refractoriness.

BACKGROUND: Atrial fibrillation (AF) shortens the atrial effective refractory period (ERP) and predisposes to further episodes of AF. The acute changes in atrial refractoriness may be related to tachycardia-induced intracellular calcium overload. The purpose of this study was to determine whether digoxin, which increases intracellular calcium, potentiates the acute effects of AF on atrial refractoriness in humans. METHODS AND RESULTS: In 38 healthy adults, atrial ERP was measured at basic drive cycle lengths (BDCLs) of 350 and 500 ms after autonomic blockade. Nineteen patients had been treated with digoxin for 2 weeks. After a several-minute episode of AF, atrial ERP was measured serially at alternating BDCLs. Compared with pre-AF ERPs, the first post-AF ERPs were significantly shorter in both the digoxin and the control groups (P:<0.001). The post-AF ERP at a BDCL of 350 ms shortened to a greater degree in the digoxin group (37+/-16 ms) than in the control group (20+/-13 ms, P:<0.001); similar changes occurred at a BDCL of 500 ms. During post-AF determinations of the atrial ERP, secondary AF episodes occurred significantly more often in the digoxin group (32% versus 16%; P:<0. 04). CONCLUSIONS: After a brief episode of AF, digoxin augments the shortening that occurs in atrial refractoriness and predisposes to the reinduction of AF. These effects occur in the setting of autonomic blockade and therefore are more likely to be due to the effects of digoxin on intracellular calcium than to its vagotonic effects.

Administration, Oral↗
PubMed1981

Digoxin sensitivity in amyloid cardiomyopathy.

Digoxin (5 mg/ml) was added to 10-mg and 20-mg pellets of purified primary and secondary amyloid fibrils, a normal human liver and heart homogenate and a homogenate from the heart of a patient with amyloid cardiomyopathy who had not received digitalis. After centrifugation, the supernatants were recovered and assayed for digoxin concentrations. Aliquots from the sediments were studied for the presence of digoxin, using rabbits antidigoxin antiserum and an indirect immunofluorescent technique. The results showed that 0.11--0.13 ng/ml of digoxin bound per milligram of fibrils and could not be separated by repeated washings. Elution with citrate or changes in the pH of the buffer. Immunofluorescent studies demonstrated diffusely bright immunofluorescence with the fibril preparation and amyloid heart homogenate when reacted with digoxin and digoxin-specific antiserum. These studies demonstrate that isolated amyloid fibrils bind digoxin and suggest that this interaction may play some role in the sensitivity to digitalis that has been observed in some patients with amyloid cardiomyopathy.

Amyloid↗
PubMed1982

Digoxin-quinidine interaction in patients with chronic renal failure.

We evaluated the effect of quinidine on digoxin pharmacokinetic in six patients with severe renal failure. Quinidine reduced the total body clearance of digoxin from 1.87 to 1.06 l/hour (p less than 0.001), and prolonged the digoxin half-life of elimination from 5.20 to 9.61 days (p less than 0.01). The digoxin volume of distribution was unchanged. Renal clearance of digoxin was negligible; thus, the decrease in total body clearance was due to a decrease in the nonrenal clearance of digoxin. The mean trough serum concentrations of quinidine ranged from 1.0 to 3.0 micrograms/ml. We conclude that in patients with chronic renal failure, the dose of digoxin should be decreased by 50% if quinidine therapy is initiated.

Adult↗
PubMed1977

Differential effects of digoxin at comparable concentrations in tissues of fetal and adult sheep.

Electrocardiogram (ECG) electrodes and carotid arterial and superior vena caval (SVC) catheters were placed in eight nonpregnant ewes and 11 fetuses (109-129 days gestation) to measure heart rate, arterial presssure, P-R interval, left ventricular pre-ejection period (PEP), and left ventricular ejection time (LVET), before and after digoxin infusion into the SVC. After the ewes were killed, the steady state concentration of digoxin in plasma was related to the concentration in midbrain and left ventricular free wall. Although concentrations of digoxin in tissue differed between fetuses and ewes, tissue-plasma ratios were similar; the myocardial-plasma ratio was 87 for fetuses and 90 for ewes and the midbrain-plasma ratios were 6.4 and 5.3, respectively. In spite of these similarities, physiological and toxic effects differed at comparable plasma concentrations. Reduction in PEP/LVET ratio was greater in ewes than fetuses, and P-R interval prolongation was linearly related to digoxin concentration in fetuses but uncommon at plasma concentrations below 2 ng/ml in ewes. Arrhythmias occurred in six ewes, but in only one fetus, even though the mean steady state concentration of digoxin in plasma was 4.5 ng/ml in the fetuses and 2.3 ng/ml in the ewes. Atropine had little effect on digoxin-induced P-R interrval prolongation, and isoproterenol produced no tachyarrhythmias in the fetuses. Age-related differences in inotropic and arrhythmogenic effects of digoxin exist exist and are related to differences in drug response rather than drug kinetics; this provides experimental support for the different dosage responses.

Animals↗
PubMed1972

Biologic activity of digoxin-specific antisera.

Digoxin-specific antibodies are capable of removing essentially all intracellular digoxin from rat renal cortical slices or from human erythrocytes. In removing digoxin from erythrocytes, these antibodies are capable of reversing an effect of the drug on cellular potassium transport. This study provides direct evidence that antibodies are capable of removing, and thereby reversing the biological effect of, physiologically active low molecular weight substances after they have been taken up by mammalian cells. This biologic property of digoxin-specific antibodies suggests that autidigoxin sera may prove useful in the reversal of digoxin toxicity. Rapid and essentially quantitative removal of digoxin from red cells by antibody is not accompanied by an immediate restoration of patassium influx to normal levels. Identification of the mechanism of this phenomenon may provide useful information concerning the mode of action not only of digoxin, but also of the cation transport system of human erythrocytes.

Animals↗
PubMed2003

Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects.

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter.

Adult↗
PubMed2003

Effects of continuous exposure to digoxin on MDR1 function and expression in Caco-2 cells.

The Caco-2 cell line has been used widely for studying intestinal permeability and several transport functions, and express the multidrug resistance transporter MDR1/P-glycoprotein. Previously, the transient exposure to digoxin for 24 h was found to induce MDR1 mRNA in Caco-2 cells. Here, a digoxin-tolerant Caco-2 subline (Caco/DX) was newly established by the continuous exposure of Caco-2 cells to digoxin, and the effects of continuous exposure to digoxin on MDR1 were examined. The 50% growth inhibitory concentration (IC(50)) values for digoxin in Caco-2 and Caco/DX cells were 17.2 and 81.4 nM, respectively. The IC(50) values for paclitaxel, an MDR1 substrate, were 1.0 and 547 nM, respectively, whereas the cytotoxicity of 5-fluorouracil was comparable in both cells. The uptake and efflux of Rhodamine123, an MDR1 substrate, in Caco/DX cells were significantly less and greater, respectively, than those in Caco-2 cells, and these transports were affected by the addition of ciclosporin. The expression of MDR1 mRNA in Caco/DX cells was approximately 2- and 1.7-fold compared with Caco-2 cells and Caco-2 cells treated with 100 nM digoxin for 24 h, respectively. On the other hand, MRP1 mRNA in Caco/DX cells was unchanged. These observations confirmed that the continuous exposure to digoxin, as well as the transient exposure, induced MDR1 in Caco-2 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗