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PubMed1985

Characterization of digoxin binding and daunorubicin uptake by isolated mature rat cardiac myocytes.

Myocytes isolated from ventricular muscle of mature rat heart have been used for characterization of digoxin binding and to establish whether a relationship exists between digoxin binding and uptake of daunorubicin. High- and low-affinity digoxin binding sites have been identified; respectively, 0.9 +/- 0.1 X 10(7) sites/myocyte, Kd 70-77 nM and 7 +/- 2 X 10(7) sites/myocyte, Kd 1.4-1.7 microM. Myocytes accumulate daunorubicin to an intracellular concentration 30-40 times that in the medium. We find no evidence that saturation of digoxin binding sites alters daunorubicin uptake or that daunorubicin influences binding of digoxin. Alteration of sarcolemmal membrane properties is demonstrated by inhibition of amino acid transport reflected in protein synthesis rates. Calmodulin activation of phosphodiesterase appears insensitive to daunorubicin.

Amino Acids↗
PubMed1983

A rapid semi quantitative capillary enzyme immunoassay for digoxin.

A rapid and sensitive enzyme immunoassay (EIA) which does not require highly trained personnel or specialised instrumentation is described for the estimation of digoxin in serum, plasma or whole blood samples. The method is based on the ability of digoxin in a clinical sample to inhibit the binding of urease-conjugated sheep-antidigoxin immunoglobulin to a glass capillary tube coated internally with a human serum albumin-digoxin conjugate. The bound enzyme activity can then be measured using a substrate solution containing urea and a pH indicator, most suitably bromocresol purple. The enzymic hydrolysis of urea produces ammonia which causes a vivid yellow to purple colour change in the pH indicator. Plasma samples from 92 patients receiving digoxin were screened in parallel with reference plasma containing 1.3 or 3.8 nmol/l digoxin. The results were available within a total test time of 30 min, and showed excellent correlation with those obtained by radioimmunoassay.

Cross Reactions↗
PubMed1979

Differential effect of potassium on the action of digoxin and digoxigenin in guinea-pig heart.

The effect of potassium on the binding of digoxin or digoxigenin to isolated Na+, K+-ATPase was compared with that of potassium on the positive inotropic action of the agents in guinea-pig hearts. The binding of digoxigenin to the enzyme in vitro was reduced to a greater extent by potassium than was the binding of digotoxin. The digoxigenin-induced increase in the force of contraction of left atrial preparations estimated at steady state was reduced at higher potassium concentrations. Potassium had a lesser effect when digoxin was used as the inotropic agent. In contrast, potassium concentrations. Potassium had a lesser effect when digoxin was used as the ininotropic agent. In contrast, potassium reduced the rate of development and also the rate of loss of the positive inotropic action of digoxin observed with left atrial and Langendorff preparations, respectively, to a greater extent than those of digoxigenin. The loss of the positive inotropic effect was more rapid with digoxigenin than with digoxin at each KCl concentration. These data support the contention that the extent of the interaction of digitalis with Na+,K+-ATPase determines the degree of the positive inotropic effect.

Animals↗
PubMed1983

How increased sodium influx enhances digoxin-induced arrhythmias in guinea-pig atrial muscle.

The hypothesis that digitalis-induced arrhythmias occur when Na,K-ATPase inhibition exhausts the sodium pump reserve capacity, producing an accumulation of intracellular Na+, was tested by reducing the reserve capacity in isolated left atrial muscle of guinea pig heart and estimating specific digoxin binding and Na,K-ATPase activity in atrial muscle homogenized at the onset of digoxin-induced arrhythmias. Reductions in reserve capacity were produced by either increasing the stimulation frequency of the atrial muscle or adding a sodium ionophore, monensin, to the media bathing the tissue. As stimulation frequency was increased, both the time required to produce arrhythmias with a given concentration of digoxin and the amount of digoxin bound to sarcolemmal Na,K-ATPase at the onset of arrhythmias were reduced. Similarly, monensin treatment produced reductions in the time to arrhythmia and in digoxin binding and Na,K-ATPase inhibition observed at the onset of arrhythmias. These results support the above proposal suggesting that a decrease in reserve capacity of the sodium pump enhances cardiac sensitivity to digitalis-induced arrhythmias.

Animals↗
PubMed1988

Interaction of BAY K-8644 with effects of digoxin in the dog heart-lung preparation.

Concentration-dependent effects of BAY K-8644, a dihydropyridine calcium channel agonist, on heart rate (HR), left atrial pressure (LAP) and maximal rate of left intraventricular pressure rise (+dP/dtmax) were compared with those of isoproterenol and digoxin in dog heart-lung preparations during exposure to 0.8 vol% halothane. All three agents reduced LAP to nearly equal levels at maximally effective concentrations. Maximal increases in +dP/dtmax induced by BAY k-8644 and digoxin were of similar magnitude (35 and 31%, respectively), and both agents increased HR slightly. Isoproterenol elevated both +dP/dtmax and HR more than twice as much as the other agents. At a concentration which produced only small changes by itself, BAY K-8644 markedly increased the effects of digoxin on LAP and +dP/dtmax. Furthermore, the same concentration of BAY K-8644 significantly reduced toxic effects of digoxin (arrhythmogenesis, elevation of LAP, reduction in systemic output). These data indicate that in the isolated blood-perfused heart digoxin's positive inotropic action may be enhanced by an appropriate concentration of BAY K-8644, while adverse effects are diminished.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Endogenous digoxin-immunoreactive substance in normal and preeclamptic pregnancies.

AIMS: To determine the potential use of a digoxin-immunoreactive substance in the prediction of preeclampsia, to study the relationship between serum levels of this substance and gestational age, and to evaluate the correlation between this substance and blood pressure findings in preeclamptic pregnancies. METHODS: Serum digoxin-immunoreactive substance concentrations were measured by RIA (double antibody radioimmunoassay) in normotensive (n = 14) and preeclamptic (n = 17) pregnant women in their third trimesters. Statistical evaluation was performed with the Mann-Whitney U-test and correlation-regression analysis. RESULTS: The mean (+/- S.E.) digoxin-immunoreactive substance levels in the normal and preeclamptic patients were 0.29 +/- 0.06 and 0.31 +/- 0.05 ng/ml, respectively, the slightly higher level in the hypertensive group being statistically non-significant. Serum digoxin-immunoreactive substance levels did not demonstrate good correlation with gestational age and systolic blood pressure in preeclamptic pregnancies. CONCLUSIONS: An endogenous digoxin-immunoreactive substance is present in the sera of third trimester pregnant women, but it does not contribute to the pathogenesis or prediction of preeclampsia.

Adolescent↗
PubMed1988

Digoxin-like immunoreactive factor in rat plasma: effect of sodium and calcium intake.

Studies have been performed in rats to determine whether an endogenous material capable of binding to digoxin antibodies is present in the plasma. Such a material has been shown in other species and has been hypothesized to represent an endogenous ligand for the receptor on Na-K ATPase through which cardiac glycosides act. In rats consuming a normal rodent chow (1% calcium by weight) and drinking deionized water, endogenous binding of digoxin antibody in radioimmunoassay amounted to 23.1 +/- 4.6 fM digoxin equivalents/100 microliter of plasma (mean +/- SEM, n = 8). Since a hypothetical role for such an endogenous ligand is the regulation or renal sodium excretion by inhibition of renal Na-K ATPase, the effect of increased sodium intake on plasma levels of this digoxin-like immunoreactive factor (DLIF) was studied. Animals consuming the same chow, but drinking 0.5% NaCl solution in place of water for a 4 week period showed significantly greater DLIF in plasma which was measured at 109.2 +/- 20.3 fM digoxin equivalents/100 microliter of plasma (p less than 0.001). Because DLIF has been implicated in the pathogenesis of hypertension we also studied the effects of calcium intake on plasma levels of DLIF. In previous studies we have shown that rats allowed to drink 0.5% saline develop a moderate hypertension which can be reversed with calcium supplementation. In the present studies, 3 dietary calcium subgroups (0.01% Ca, 1.0% Ca and 4% Ca) were formed among animals drinking water or 0.5% saline for 4 weeks. No effect of low calcium intake on plasma DLIF was found either in water or saline drinkers. However, calcium supplementation produced a significant reduction in plasma DLIF in both water and saline drinking animals.

Animals↗
PubMed1994

Effects of digoxin on regional diaphragm function after thoracotomy in awake sheep.

The effects of digoxin on diaphragmatic contraction were studied in 12 sheep, within 6 days after a right thoracotomy, during the period of intense diaphragmatic inhibition. Diaphragmatic function was assessed by implanting sonomicrometry crystals and electromyographic (EMG) electrodes in both the costal and crural diaphragmatic regions. Awake sheep were studied before and after intravenous digoxin (0.04 mg/kg) during both quiet breathing (QB) and during CO2 rebreathing, until the fractional concentration of expired CO2 (FETCO2) reached 0.10. After digoxin infusion, during both QB and at FETCO2 of 0.10, esophageal and transdiaphragmatic pressures increased (P < 0.05). After digoxin infusion no changes were measured for end-expiratory resting length, shortening fraction, shortening velocity or EMG activity of either diaphragmatic segment or for respiratory frequency, ventilation, tidal volume and FETCO2. We conclude that intravenous digoxin given to awake sheep after a thoracotomy increases Pdi, but does not alter diaphragmatic shortening nor alter the level of diaphragmatic activation either during QB or at FETCO2 of 0.10.

Animals↗
PubMed1977

Sensitive radioimmunoassay for digoxin in plasma and urine.

A reproducible and sensitive radioimmunoassay for digoxin in either serum, plasma or urine is described. Using 0.5 ml of serum or plasma, the assay sensitivity is 0.05 ng of digoxin/ml. The antiserum and tracer solutions employed are available in a kit sold in the United States. All other reagents were prepared in the laboratory. The assay allows measurement of digoxin in plasma or serum for 96 hours after single 0.5 mg doses of digoxin; this is necessary in human bioavailability studies to accurately estimate the total area under the digoxin concentration, time curve from zero to infinite time. In contrast, with the kit assay, employing 0.2 ml of plasma or serum, it has been reported that the 12 hr serum digoxin levels, after single 0.5 mg doses, are, in most subjects, below the sensitivity limit (about 0.5 ng/ml) of the assay.

Anticoagulants↗
PubMed1994

Syntheses of europium-labeled digoxin derivatives and their use in time-resolved fluoroimmunoassay.

A simple and efficient method of derivatizing and labeling the terminal sugar ring of digoxin (and other steroid glycosides) is described. The terminal sugar ring was oxidized by periodate to dialdehyde, followed by a reaction with the aminooxy group of heterobifunctional spacer reagent. Usually, reductive amination is needed to stabilize the Schiff base-type compounds produced in reactions between amino and aldehyde groups. Here the oxime compounds produced are stable wherefore the reductive amination step can be avoided and the reaction gives high yields without significant side reactions. After characterization the digoxin dioxime derivatives formed were labeled with europium chelates. These labeled digoxin derivatives bearing one or two europium-containing chelates, coupled via different spacers, were purified and tested in a competitive time-resolved fluoroimmunoassay. Several digoxin-specific monoclonal antibodies were also tested to determine the most suitable antibody-tracer combination, which was then employed to develop a simple competitive time-resolved fluoroimmunoassay for digoxin.

Aldehydes↗
PubMed1989

Digoxin or verapamil or metoprolol for heart rate control in patients with mitral stenosis--a randomised cross-over study.

The effect and choice of a drug to control heart rate for symptomatic improvement in patients with isolated mitral stenosis with normal sinus rhythm (n = 10) or atrial fibrillation (n = 10) were studied. Digoxin (0.25-0.5 mg daily), metoprolol (50-100 mg twice a day) and verapamil (40-80 mg three times a day) were evaluated for this purpose. An open randomised cross-over design was followed. The efficacy of a drug was evaluated by: (1) subjective improvement on a visual analog scale, and (2) objective improvement on repeated multi-stage symptom-limited treadmill exercise. In patients with sinus rhythm greater than or equal to 50% subjective improvement was seen in 90%, 40% and nil with metoprolol, verapamil and digoxin, respectively. The total work done by these patients was 1008 +/- 541 kpm (control), 2869 +/- 1418 kpm on metoprolol, 2369 +/- 884 kpm on verapamil and 1654 +/- 918 kpm on digoxin. In patients with atrial fibrillation greater than or equal to 50% subjective improvement was seen in 80%, 40% and 30% with verapamil, metoprolol and digoxin, respectively. The total work done by these patients was 555 +/- 232 kpm (control), 1379 +/- 553 kpm on verapamil, 1251 +/- 575 kpm on metoprolol and 716 +/- 340 kpm on digoxin. The degree of improvement on a drug appeared to be a function of its ability to control resting and exercise heart rates in two different rhythms in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Impact of neonatal treatment with cardioactive glycosides (digoxin, ouabain) on receptor binding capacity, blood level and cardiac function in the adult rat. Extension of the imprinting theory.

A single neonatal treatment with a cardioactive glycoside (ouabain, digoxin) altered the response of the adult rat to digitaloid treatment. As demonstrated by RIA, re-exposure to digoxin at 2 months of age was followed within 30 min by a more than twofold increase in serum digoxin over the not pretreated control and, although a steady concentration decrease followed, the experimental rats still had a higher serum digoxin level than the controls at 4 h. In the not presensitized control group the serum digoxin peak appeared at 60 min at a considerably lower level than the 30-min maximum of the experimental rats. Neonatal pretreatment with ouabain depressed myocardial ouabain binding, but enhanced the Na+ K+ -ATPase activity. The above differences were conspicuous in the functional response, yet a greater atrial response to the positive inotropic action of K-strophanthoside and a greater ventricular response to beta adrenergic excitation were readily seen in the experimental group. It follows that not only hormones, but also other ligands acting at receptor level can be regarded as potential inducers of imprinting.

Animals↗
PubMed1989

Increased exercise capacity after digoxin administration in patients with heart failure.

Failure to objectively assess the effect of digitalis on exercise capacity has resulted in controversy regarding its use in patients with chronic congestive heart failure. To clarify this situation, maximal treadmill testing with respiratory gas exchange analysis was performed on 11 patients (mean age 57 +/- 9 years) with chronic congestive heart failure with and without digoxin therapy. Ten of the 11 had a consistent third sound gallop, and the mean ejection fraction of the group was 24 +/- 10%. Rest heart rate was significantly higher (91 +/- 16 versus 102 +/- 16 beats/min; p less than 0.05) and rest systolic blood pressure was significantly reduced in the absence of digoxin (130 +/- 23 versus 121 +/- 15 mm Hg; p less than 0.05). No differences in heart rate or blood pressure were observed during exercise. Significant increases in ventilatory oxygen uptake were observed with digoxin submaximally (3.0 mph, 0% grade), at the gas exchange anaerobic threshold and at maximal exercise (mean increase of 2.6 ml/kg per min; p less than 0.02). An improvement in the estimated ratio of ventilatory dead space to tidal volume (VD/VT), an index of physiologic efficiency, occurred throughout exercise during digoxin therapy, and there was a significant negative correlation between the change in maximal oxygen uptake and change in maximal estimated VD/VT (r = -0.63; p less than 0.05). Thus, digoxin therapy is associated with a significant improvement in exercise capacity in patients with chronic heart failure, most likely due to an improved matching of ventilation to perfusion.

Adult↗
PubMed1991

Review of clinical experience with digoxin immune Fab (ovine).

Following the development of methods for eliciting and purifying digoxin-specific Fab fragments with high affinity and specificity for cardiac glycosides, clinical studies were undertaken as a multicenter, open-label trial to test safety and efficacy in patients with advanced and potentially life-threatening digitalis toxicity that failed to respond to conventional therapeutic measures. One-hundred fifty such patients were treated with digoxin-specific antibody fragments purified from immunoglobulin G (IgG) produced in sheep. Doses of Fab were equivalent to the amount of digoxin or digitoxin in the patient's body, as estimated from the medical history or serum concentration measurements. Of 150 patients included in this trial, detailed information is available on 148. One-hundred nineteen (80%) had resolution of all signs and symptoms of digitalis toxicity following specific Fab fragment infusions, 14 (10%) improved, and 15 (10%) showed no response. Among 14 patients with adverse events possibly or probably caused by Fab, the most common events were development of hypokalemia and exacerbation of congestive heart failure. Analysis of the available clinical data indicates that a treatment response was observed in at least 90% of patients with convincing evidence of advanced and potentially life-threatening digitalis toxicity. The data from this multicenter trial have been augmented by findings from an observational surveillance study conducted to monitor the safety and effectiveness of treatment with digoxin immune Fab (ovine) following commercial availability. In this experience, 74% of patients were judged to have a complete or partial response to treatment, and 12% no response. The response for the remaining 14% was not reported or reported as uncertain. In this clinical experience, digoxin-specific Fab was generally well tolerated and clinically effective in patients with potentially life-threatening digitalis toxicity.

Adolescent↗
PubMed1994

A comparison of amiodarone and digoxin for treatment of supraventricular arrhythmias after cardiac surgery.

Despite the widespread use of amiodarone in non-surgical patients, its role in the management of supraventricular tachyarrhythmias after cardiac surgery is not clear. We set out to compare the relative efficacy of amiodarone and digoxin in the management of atrial fibrillation and flutter in the early postoperative period. This prospective randomised trial comprised 30 patients, previously in sinus rhythm, who developed sustained atrial fibrillation or flutter following myocardial revascularisation, valve surgery or combined procedures. Amiodarone was administered as an intravenous loading dose followed by a continuous infusion. Digoxin was given as an intravenous loading dose followed by oral maintenance therapy. Electrocardiographic and haemodynamic monitoring was continued for 24 h after the commencement of treatment. There was a marked reduction in heart rate in both groups, mainly in the first 6 h, from 146 to 89 beats per minute in the amiodarone group and from 144 to 95 in the digoxin group. At the end of the 24 h, one of the 15 patients in the amiodarone group and 3 of the 15 patients in the digoxin group remained in atrial fibrillation. No patient in either group developed adverse reactions. We conclude that intravenous amiodarone therapy is safe and at least as effective as digoxin in the initial management of arrhythmias after cardiac surgery.

Aged↗
PubMed2003

Digoxin antibody prevents cerebral hemorrhage-induced hypertension.

BACKGROUND: Brain injury may induce hypertension. Because serum ouabain-like compound (OLC) has vasoconstrictor activity, digoxin antibody antihypertensive effects were evaluated using an intracerebroventricular (ICV) hemorrhage rat model. METHODS: Four ICV infused Wistar rat groups were studied: control; blood; blood plus digoxin antibody, and cerebrospinal fluid-like solution. Tail-cuff blood pressure, cumulative sodium balance, and serum OLC were measured. RESULTS: The ICV blood infusion increased blood pressure (BP) and OLC without sodium balance change. Digoxin antibody prevented BP and OLC rise. Blood pressure was positively correlated with OLC in blood and blood plus digoxin antibody rats (R = 0.63; P <.05). CONCLUSIONS: Cerebral hemorrhage increased OLC and BP, which were reversed by digoxin antibody administration.

Animals↗
PubMed2006

The effect of pancreatic and biliary depletion on the in vivo pharmacokinetics of digoxin in pigs.

Several transporter systems in the liver and intestine are known to change their expression and function during cholestatic disease states. The objective of the present in vivo study was to investigate the effect of biliary depletion, as a method to mimic cholestasis, on the bioavailability and disposition of digoxin in biliary and pancreatic duct cannulated pigs. The study was divided in two parts. In the first part, a solution of 10 microg/kg digoxin was administered intravenously to the cannulated pigs with intact enterohepatic circulation (Control) and during depletion of the bile and pancreatic juice. In the second part, the same dose of digoxin was administered intraduodenally with intact enterohepatic circulation (Control) and during depletion of either bile or pancreatic juice or both. Biliary depletion decreased the flow of bile and pancreas juice as well as the amount of digoxin appearing in the bile. Deprivation of both bile and pancreas juice significantly increased the bioavailability of digoxin, the plasma AUC after enteral administration increased from 17.6+/-4.2 nmol/lh (Control) to 29.6+/-8.3 nmol/lh (P<0.05). The biliary clearance decreased significantly, from 0.22+/-0.11 l/h/kg (Control) to 0.04+/-0.03 l/h/kg during pancreatic and biliary depletion (P<0.05). There was a significant decrease in elimination half-life (P<0.05) and volume of distribution (P<0.01) during the depletion experiments while the systemic clearance remained unchanged. The results clearly suggest that biliary depletion trigger a short-term downregulation, most likely posttranscriptionally mediated, of a sinusoidal uptake transporter in the liver, possibly a pig ortholog of OATP.

Animals↗
PubMed2006

Verapamil versus digoxin and acute versus routine serial cardioversion for the improvement of rhythm control for persistent atrial fibrillation.

OBJECTIVES: The VERDICT (Verapamil Versus Digoxin and Acute Versus Routine Serial Cardioversion Trial) is a prospective, randomized study to investigate whether: 1) acutely repeated serial electrical cardioversions (ECVs) after a relapse of atrial fibrillation (AF); and 2) prevention of intracellular calcium overload by verapamil, decrease intractability of AF. BACKGROUND: Rhythm control is desirable in patients suffering from symptomatic AF. METHODS: A total of 144 patients with persistent AF were included. Seventy-four (51%) patients were randomized to the acute (within 24 h) and 70 (49%) patients to the routine serial ECVs, and 74 (51%) patients to verapamil and 70 (49%) patients to digoxin for rate control before ECV and continued during follow-up (2 x 2 factorial design). Class III antiarrhythmic drugs were used after a relapse of AF. Follow-up was 18 months. RESULTS: At baseline, there were no significant differences between the groups, except for beta-blocker use in the verapamil versus digoxin group (38% vs. 60%, respectively, p = 0.01). At follow-up, no difference in the occurrence of permanent AF between the acute and the routine cardioversion groups was observed (32% [95% confidence intervals (CI)] 22 to 44) vs. 31% [95% CI 21 to 44], respectively, p = NS), and also no difference between the verapamil- and the digoxin-randomized patients (28% [95% CI 19 to 40] vs. 36% [95% CI 25 to 48] respectively, p = NS). Multivariate Cox regression analysis revealed that lone digoxin use was the only significant predictor of failure of rhythm control treatment (hazard ratio 2.2 [95% CI 1.1 to 4.4], p = 0.02). CONCLUSIONS: An acute serial cardioversion strategy does not improve long-term rhythm control in comparison with a routine serial cardioversion strategy. Furthermore, verapamil has no beneficial effect in a serial cardioversion strategy.

Aged↗