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At least 163 records · Page 9Linked to original sources
PubMed1991

Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans.

The interaction between digoxin and verapamil was studied in six patients (mean age +/- SD, 61 +/- 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady-state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady-state plasma concentrations of digoxin, from 0.80 +/- 0.24 to 1.15 +/- 0.40 nmol/L (p less than 0.01). The biliary clearance of digoxin decreased by 43%, from 187 +/- 89 to 101 +/- 55 ml/min (p less than 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 +/- 31 versus 173 +/- 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.

Bile↗
PubMed1977

[The importance of body weight in treatment with digoxin and digoxin derivatives (author's transl)].

A total of 1109 determinations of digoxin concentration in serum were performed in 317 patients with cardiac failure during oral maintenance therapy with digoxin, beta-acetyldigoxin and beta-methyldigoxin. It was shown that the optimal therapeutic serum concentration (1.21 to 1.70 ng/ml) can be obtained reliably if the dosage of digoxin and its derivatives is based on the body weight. The daily doses recommended for oral maintenance therapy are 4mug/kg for beta-methyldigoxin, 5 mug/kg for beta-acetyldigoxin, and 8 mug/kg for digoxin. For initiating cardiac therapy the double maintenance dose can be prescribed once. Digoxin derivatives should be preferred to digoxin when choosing the drug.

Aged↗
PubMed1977

[Relationship between digoxin-induced cardiac arrhythmias and serum-digoxin levels (author's transl)].

The serum-digoxin level was measured by radio-immunoassay (Immutope) on 245 patients in a coronary care unit. Cardiac arrhythmias were assumed to be digoxin-induced if they disappeared after the drug had been stopped. Patients who had received digitoxin or spironolactone were excluded. The results indicated a normal digoxin range of 1.52 +/- 0.2 ng/ml and a toxic one of 2.78 +/- 0.38 ng/ml. First degree A-V block, atrial ectopic beats and ventricular ectopics with variable coupling intervals were frequently associated with serum-digoxin levels of 1.5-2.5 ng/ml, while higher grade A-V block, atrial tachycardia, bigeminy and atrial tachycardia with block were more frequent with higher serum-digoxin levels (greater than 3.0 ng/ml). Atrial arrhythmias were especially frequent with serum levels above 3.0 ng/ml. This suggests different sensitivities of atrial and ventricular myocardium. Atrial arrhythmias thus in general indicate a higher degree of toxicity at high serum levels, while ventricular ectopic beats occur both with high serum levels and also with increased digoxin sensitivity of the ventricles.

Arrhythmias, Cardiac↗
PubMed1971

The isolation of digoxin-specific antibody and its use in reversing the effects of digoxin.

Specific antibodies to digoxin were isolated from antisera of sheep immunized with a digoxin-human serum albumin conjugate. The antibody was purified by adsorption to an immunoadsorbent, synthesized by coupling a ouabain-ribonuclease conjugate to bromoacetyl-cellulose, followed by elution with 25 mM ouabain. Ouabain was dissociated from antibody by denaturation in 6 M guanidine. The renatured antibody bound 1.6 mol of digoxin per mol and had an association constant of 1.6 x 10(8) M(-1). At near-stoichiometric concentrations, either purified antibody to digoxin, or its papain-digested product (Fab-Fc), reversed digoxin-induced: (a) inhibition of (86)Rb transport in human erythrocytes, (b) increase in developed tension in isolated guinea-pig atrial strips, and (c) ventricular tachycardia in intact dogs, and also corrected digoxin-induced automaticity in isolated guineapig atrial strips.

Adsorption↗
PubMed2000

Phage display-selected sequences of the heavy-chain CDR3 loop of the anti-digoxin antibody 26-10 define a high affinity binding site for position 16-substituted analogs of digoxin.

The heavy-chain CDR3 region of the high affinity (K(a) = 1.3 x 10(10) M(-)1) anti-digoxin monoclonal antibody 26-10 was modified previously to shift its specificity, by substitution of tryptophan 100 by arginine, toward binding analogs of digoxin containing substitutions at position 16. To further change specificity, two 5-mer libraries of the randomly mutagenized phage-displayed 26-10 HCDR3 region (positions 94-98) were panned against digoxin-bovine serum albumin (BSA) as well as against 16-acetylgitoxin-BSA. When a mutant Fab that binds 16-substituted analogs preferentially was used as a parent sequence, clones were obtained with affinities for digoxin increased 2-4-fold, by panning on digoxin-BSA yet retaining the specificity shift. Selection on 16-acetylgitoxin-BSA, however, resulted in nine clones that bound gitoxin (16-OH) up to 150-fold higher than the wild-type 26-10, due to a consensus mutation of Ser(H95) to Gly(H95). The residues at both position H95 (serine) and position H100 (tryptophan) contact hapten in the crystal structure of the Fab 26-10-digoxin complex. Thus, by mutating hapten contact residues, it is possible to reorder the combining site of a high affinity antibody, resulting in altered specificity, yet retain or substantially increase the relative affinity for the cross-reactive ligand.

Antibodies↗
PubMed1990

Novel anti-digoxin monoclonal antibodies with different binding specificities for digoxin metabolites and other glycosides.

Spleen cells of BALB/c mice immunized with a digoxin-bovine serum albumin conjugate were fused with P3-X63-Ag8.653 mouse myeloma cells. Seven monoclonal antibodies (MAb) selected by indirect ELISA were produced, purified and characterized. All the MAb were IgG1 isotypes. The apparent equilibrium association constants (Ka) of four of the MAb, determined by Scatchard analysis of the RIA data, ranged from 1 x 10(9) M-1 to 5.9 x 10(9) M-1. The estimated Ka values of the three other MAb were found to be between 4.8 x 10(7) M-1 and 5.9 x 10(8) M-1. Using digoxin and eighteen structurally-related compounds, the seven MAb could be divided into five groups based on their binding specificities assessed by an inhibition immunoenzymatic test. The MAb in Groups I and II, in particular, showed very different specificity profiles: the two MAb in Group I had low cross-reactivity with cardioinactive digoxin metabolites, whereas the high affinity MAb in Group II recognized all the digoxin metabolites tested. The MAb in Group I might be useful in a digoxin immunoassay and the Group II MAb in therapeutic reversal of digoxin intoxication.

Animals↗
PubMedDate not supplied

[3H]Digoxin in the optic tract in digoxin intoxication.

Normal and chronically hypokalemic dogs were infused with [3H]digoxin until ventricular tachycardia occurred, at which point the concentration of digoxin was measured in all tissues involved in vision. The highest concentration was found in the choroid-retina of the eye, and this was considered the most likely site for the various visual changes seen in digitalis intoxication in man. Chronic hypokalemia did not influence the concentration or distribution of digoxin in the optic tract. It is speculated that the increased digoxin level in the extracranial part of the optic nerve is due to a weakness in the blood-retina barrier where the optic nerve fibers pass through the retina. One eye was left in situ for 3 days after death to study post-mortem changes in digoxin distribution. Vitreous humor analysis is being used to study the cause of death in man, but we found an increase in the vitreous humor digoxin level after death due to loss from its primary binding site in the choroid-retina. A similar effect would be expected with any drug bound to the retina and would have to be taken into account when considering the cause of death forensic pathology.

Animals↗
PubMed1990

Effect of digoxin Fab antibodies on five digoxin immunoassays.

Following digoxin Fab antibody (FAB) administration in digitalis-toxic patients, total serum digoxin concentrations (SDCS) become elevated, but do not correlate with pharmacologic activity. In an attempt to accurately measure free (pharmacologically active) SDC in the presence of FAB, we assessed the utility of five digoxin immunoassays: fluorescence polarization immunoassay (FPIA), ultrafiltration with FPIA (ULTRA-FPIA), enzyme multiplied immunoassay (EMIT), radioimmunoassay (RIA), and American Dade's STRATUS (STRATUS). To normal human serum samples containing 2 and 4 ng/ml of digoxin, FAB was added in escalating quantities of 0-1.9 micrograms. In addition, 1.9 micrograms of FAB was added to two serum samples containing no digoxin. SDCS reported by FPIA for each 2 ng/ml samples, in order of ascending FAB doses, were 2.08, 1.94, 2.02, 1.99, 1.95, and 1.93 ng/ml, while the SDCS from the ULTRA-FPIA were 2.00, 1.76, 1.56, 1.36, 1.16, and 0.98 ng/ml. Results similar to the ULTRA-FPIA were obtained with the STRATUS, RIA, and EMIT, although the SDCS from the EMIT (p less than 0.05) samples exhibited greater fluctuation. The 4 ng/ml samples demonstrated similar patterns among the assays although no statistical differences were noticed between EMIT and ULTRA-FPIA. Samples containing FAB without digoxin only adversely affected the RIA, which reported mean SDCS from the two identically prepared samples of 5.8 and 7.8 ng/ml. Except for the FPIA, the SDC measured by the assays directly correlated with the amount of FAB in the sample, demonstrating the ability of these assays to measure free SDC.

Digoxin↗
PubMed1995

A new digoxin immunoassay substantially free of interference by digoxin immunoreactive factor.

We have evaluated the new Roche digoxin "On Line" procedure for use in a pediatric population with particular interest in the potential for interference by digoxin-like immunoreactive factor (DLIF). An initial study comparing digoxin values obtained with the new Roche procedure with determinations on an Abbott TDx, American Dade Stratus, and COBAS-FARA using Microgenics Cedia reagents, found good correlations with these established methods. The Roche method was suitably precise and utilized either serum or plasma. Interference by DLIF was assessed by analyzing specimens from patients not receiving digoxin but likely to contain DLIF, with the argument that non-zero values represent cross-reactivity of anti-digoxin antibodies with DLIF endogenous to these specimens. When specimens from neonates, women with second/third trimester pregnancies, and patients with renal and liver failure were assayed with the Roche, Stratus, and TDx methods, all three methods measured DLIF in some specimens, but the Roche method possessed the lowest overall DLIF interference. The modest extent of DLIF interference and the requirement of a small amount of specimen make the Roche method superior in monitoring digoxin in a pediatric population.

Digoxin↗
PubMed1997

Digoxin intoxication in a patient with end-stage renal disease: efficacy of digoxin-specific Fab antibody fragments and peritoneal dialysis.

Digoxin intoxication is a serious medical problem, and impairment of renal function is a common risk factor for toxicity. Digoxin specific antibody fragments (Fab) is the most effective treatment available for severe digitalis intoxication. The use of Fab therapy in a patient with renal disease is considered as effective as in patients with normal renal function, although the increased risk of rebound digoxin toxicity mandates a longer period of observation. In patients with kidney failure, neither digoxin nor Fab can be removed efficiently from the systemic circulation by hemodialysis or continuous arteriovenous hemofiltration. Knowledge about the clearance of both compounds by peritoneal dialysis is limited. The authors describe a patient with end stage renal disease who was treated with Fab and peritoneal dialysis for life threatening digoxin intoxication. Like other forms of dialysis, peritoneal dialysis, even when performed in an intensive schedule, is not associated with an enhanced clearance of digoxin.

Biological Availability↗
PubMed1983

The diagnostic value of determination of intraerythrocytic sodium and potassium concentrations versus plasma digoxin concentration in digoxin intoxication.

Plasma digoxin measurements have proved unserviceable as a means of differentiating between toxic and non-toxic patients. In order to assess the value of a biological effect of digoxin in this discrimination, intraerythrocytic sodium and potassium concentrations were determined in 55 chronically digitalized patients of whom 10 were digoxin-intoxicated according to ECG criteria. Digitoxicity was associated with elevated intraerythrocytic sodium concentration (mean +/- SEM 19.3 +/- 1.2 versus 11.3 +/- 0.3 mmol/l, p less than 0.001) and reduced intraerythrocytic potassium concentration (94.6 +/- 2.3 versus 100.0 +/- 0.6 mmol/l, p less than 0.001) compared to non-toxic patients. Mean (+/- SEM) plasma digoxin concentrations in the two groups were 3.14 +/- 0.41 and 1.57 +/- 0.09 nmol/l, respectively (p less than 0.001). When diagnosing toxicity in chronically digitalized patients, plasma digoxin and intraerythrocytic sodium determinations showed sensitivities of 60 and 100%, respectively. The predictive values of a positive test were 75% for plasma digoxin and 83% for intraerythrocytic sodium.

Aged↗
PubMed1983

The day-to-day variation in serum digoxin concentration. The Hørsholm digoxin study.

Serum digoxin concentration was measured in 70 medical patients 7 and 8 days after admission to hospital. The digoxin treatment taken at home was continued in hospital. There was no statistically significant difference between mean digoxin concentrations in samples taken at day 7 (1.52 nmol/l) and day 8 (1.48 nmol/l). The variation in serum digoxin concentration from day to day expressed as SD was 0.25 nmol/l; 95% confidence limits were +/- 0.51 nmol/l, and 99% confidence limits +/- 0.67 nmol/l. Variations in serum digoxin concentration were not correlated to age, sex, body weight, serum creatinine and the oral dose of digoxin.

Aged↗
PubMed1983

Correlation between manifestations of digoxin toxicity and serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH.

In 18 patients with gastrointestinal manifestations of digoxin toxicity the mean serum digoxin concentration (+/- SEM) was 3.16 micrograms/l (+/- 0.25), the calcium to potassium ratio 0.31 (+/- 0.01), and the mean arterial pH 7.406 (+/- 0.017). In contrast 19 patients with digoxin induced automaticity had a mean serum digoxin concentration of 1.24 micrograms/l (+/- 0.15; p less than 0.001), a calcium to potassium ratio of 0.38 (+/- 0.01; p less than 0.01), and an arterial pH of 7.498 (+/- 0.008; p less than 0.001). Eight out of 13 patients with digoxin induced cardiotoxicity had serum concentrations of the drug within the therapeutic range (0.8-2.0 micrograms/l). The calcium to potassium ratio, however, was lower than in the patients with automaticity (0.31 +/- 0.02; p less than 0.01) and the arterial pH was 7.370 (+/- 0.033; p less than 0.05). Serum magnesium concentrations were similar in all groups. In this study patients with digoxin induced gastrointestinal symptoms had high serum concentrations of the drug, whereas those with drug induced automaticity had therapeutic concentrations. This second group, however, was identified by their higher calcium to potassium ratios and higher pH values.

Arrhythmias, Cardiac↗
PubMed1975

Radioimmunoassay of serum digoxin in relation to digoxin intoxication.

Serum digoxin estimations were done in 98 patients receiving digoxin for heart failure of varied aetiology. Digoxin toxicity or the lack of it was determined on the basin of established electrocardiographic criteria. Fifty-two patients were classified as 'toxic' and 46 as 'non-toxic'. The difference is the mean digoxin levels between the two groups was highly significant (P less than 0.001). The mean serum digoxin level in 'non-toxic' patients was slightly higher than that found by other investigators. Fairly good correlations have been noted between different dosage schedules and various rhythm disturbances. Death was attributed to digoxin toxicity in only 2 patients who showed electrocardiographic evidence of intoxication at the time of death.

Aged↗
PubMed1972

The electrophysiologic effects of low and high digoxin concentrations on isolated mammalian cardiac tissue: reversal by digoxin-specific antibody.

The effects of digoxin on electrophysiologic properties were evaluated in isolated perfused cardiac tissue. In canine Purkinje fiber (PF)-ventricular muscle (VM) preparations, control measurements, using microelectrode technique, were made of: resting potential (RP), action potential (AP) amplitude, rate of rise, overshoot, duration (APD), membrane responsiveness, conduction velocity (CV), and refractory period. The preparation was then exposed to 1 x 10(-7) M digoxin and repeat measurements were carried out every 15 min. At slow (30/min) rates of stimulation APD initially prolonged then markedly shortened. With more rapid stimulation (75 and 120/min) no initial APD prolongation was observed. When stimulated at 75/min, RP and AP rate of rise, amplitude, and CV remained near control values for 60-75 min then rapidly decreased until electrical inexcitability (110+/-15 min). At that time fibers were perfused with serum containing digoxin-specific antibody (DSA) or one of a group of test solutions. In the preparations exposed to DSA, membrane characteristics improved by 15 min, and by 60 min approximated control values. No beneficial effect was seen with the various test solutions. DSA also reversed digoxin-induced enhanced phase 4 depolarization in PF. Effective (ERP) and Functional (FRP) refractory periods of rabbit atrioventricular (AV) node preparations were measured in the control state. The tissue was then exposed to 1 x 10(-7) M digoxin and refractory period measurements repeated. At a time when AV conduction prolonged by 20%, associated with marked prolongation of ERP and FRP, DSA or various test solutions were perfused. The prolongation in ERP, FRP, and AV conduction time rapidly returned to normal only in the DSA perfused tissue. It is concluded that DSA has the ability to reverse pronounced toxic electrophysiological effects of digoxin in in vitro cardiac tissue.

Action Potentials↗
PubMedDate not supplied

Digoxin assay anomalies due to digoxin-specific Fab immunotherapy.

We demonstrate that digoxin-specific Fab antibody fragments, used in the treatment of severe digitalis intoxication, cause a marked interference with both fluorescence excitation transfer immunoassays and radioimmunoassays for digoxin. In addition, we describe a rapid ultrafiltration method that avoids the Fab-induced interference and affords excellent accuracy and precision. This technique will provide a useful adjunct to the clinical evaluation of patients with digoxin toxicity who are recipients of antidigoxin immunotherapy by enabling a precise determination of their serum digoxin concentrations. By separating the free and protein-bound digoxin this technique also may be useful in evaluating serum digoxin concentrations in patients with abnormal plasma protein concentrations.

Aged↗
PubMed1976

Evaluation of two digoxin radioimmunoassay procedures in which 125I-labeled digoxin is used.

We present a comparative evaluation of two commercial kits, the "Quantitope" and "GammaCoat," for radioimmunoassay of digoxin in serum. These kits, in which iodine-125 is used as a label, proved to suitable for digoxin assay as determined by their reproducibility, sensitivity, precision, and a regression analysis. Hemolysis, lipemia, and icterus did not affect results. However, in some cases hypoalbuminemia falsely lowered the assayed digoxin concentration. Recovery of pure digoxin added to native patients' sera having low albumin concentration (24-28 g/liter) ranged from 67-105% with the Quantitope kit and 70-110% with the GammaCoat kit. Low serum albumin concentration did not always decrease the recovery of digoxin; this effect varied from serum to serum, which may indicate that there are factors other than albumin that affect the assay of digoxin.

Digoxin↗
PubMed1992

Endogenous digoxin-like immunoreactive factors (DLIF) as measured by the CEDIA digoxin assay and a fluorescence polarization immunoassay.

The sensitivity of a new homogeneous enzyme immunoassay for the determination of digoxin (CEDIA Digoxin assay) and a fluorescence polarization immunoassay (FPIA) to interference by digoxin-like immunoreactive factors (DLIF) was studied in sera from pregnant women, newborns, patients undergoing hemodialysis and patients with renal insufficiency, but without hemodialysis. None of the patients had been treated with digoxin or digitoxin. Cross-reactivity of DLIF in the CEDIA assay was generally lower than in the FPIA. Data on the distribution DLIF of values and method comparisons showed that sera of the four patient groups reacted in a completely different way in both assays, suggesting that the nature of DLIF in the four groups is not identical. Addition of digoxin to sera of patients not treated with this drug resulted in a reduction of the apparent DLIF concentration in the CEDIA assay and the FPIA. This shows that DLIF interference may be less pronounced in sera of patients undergoing digoxin therapy compared to untreated persons. Although the CEDIA assay is less sensitive to DLIF interference than the FPIA, further efforts are needed to reduce the extent of this interference.

Adult↗