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PubMed1983

Effects of discontinuing maintenance digoxin therapy in patients with ischemic heart disease and congestive heart failure in sinus rhythm.

To evaluate the importance of oral maintenance digoxin therapy in chronic congestive heart failure (CHF), 24 patients in sinus rhythm on maintenance digoxin for documented CHF were studied prospectively on and off the drug. The average duration of therapy was 39 months (range 2 to 180). All 24 patients had documented coronary artery disease (CAD): 22 were in New York Heart Association functional class III and 2 in class II. Twenty-one patients (88%) were receiving diuretic or vasodilator therapy, or both, before digoxin discontinuance. At 1 month off digoxin and with no increase in doses of other medications excepting minor increases in antianginal therapy in 2 patients, no difference was observed in the group as a whole in symptoms, resting heart rate, arterial blood pressure, physical findings, weight, cardiothoracic ratio, radiographic signs of pulmonary congestion, radionuclide left ventricular ejection fraction (LVEF), duration of symptom-limited treadmill exercise (14 patients), or CHF score, compared with evaluation during maintenance digoxin therapy. Similar results were obtained in a subgroup of 9 patients with a resting LVEF less than 0.35 (0.27 +/- 0.02; mean +/- standard error of the mean). Six patients had a decrease and 5 patients an increase in LVEF of greater than or equal to 0.05 units after cessation of digoxin. Off digoxin, the CHF score increased by only 1 point in 2 patients, but also decreased in 2 patients. Thus, in this study population comprised of patients with CAD with documented CHF, most of whom were receiving diuretics or vasodilators, or both, digoxin withdrawal had no adverse clinical or hemodynamic effects.

Adult↗
PubMed1991

Digoxin-induced vasoconstriction of normal and atherosclerotic epicardial coronary arteries.

This study evaluated the effect of bolus infusion of digoxin (0.014 mg/kg in 10 minutes, intravenously) on large coronary arteries measured by quantitative digital angiography. Twenty-two patients (mean age +/- standard deviation 47 +/- 12 years) divided into 3 groups were studied. The effects of digoxin infusion (after 10 and 20 minutes) and sublingual administration of isosorbide dinitrate were investigated in group I (patients with angiographically normal coronary arteries, n = 9) and in group II (patients with atherosclerotic coronary arteries, n = 8). To determine whether the effects of digoxin were mediated by activation of alpha-adrenergic receptors, coronary angiography was performed in group III after alpha-adrenoceptor blockade (phentolamine 0.11 mg/kg, intravenously) (n = 5). Ten minutes after the end of digoxin infusion, the cross-sectional area decreased from 7.7 +/- 4.1 to 6.0 +/- 2.2 mm2, and after 20 minutes to 5.6 +/- 2.6 mm2 (p less than 0.05) in group I. Isosorbide dinitrate reverted digoxin-induced vasoconstriction as cross-sectional area increased to 8.5 +/- 3.4 mm2 (p = not significant versus baseline). Twenty minutes after digoxin infusion, heart rate significantly decreased from 79 +/- 16 to 74 +/- 13 beats/min (p less than 0.01). Ten minutes after digoxin infusion, peripheral vascular resistance increased significantly from 1,396 +/- 693 to 1,693 +/- 984 dynes.s.cm-5 (p less than 0.05), whereas cardiac output did not change. Twenty minutes after digoxin infusion, minimal stenosis diameter decreased significantly from 1.6 +/- 0.5 to 1.4 +/- 0.5 mm (p less than 0.05) in group II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography, Digital Subtraction↗
PubMed1991

Effect of digoxin on contractility and symptoms in infants with a large ventricular septal defect.

The effect of digoxin on contractility and symptoms in infants with a large ventricular septal defect (VSD) is controversial. Nineteen infants with symptoms of congestive heart failure due to a VSD were studied with load-independent indexes during 4 study periods: (1) before any medication; (2) while on chronic diuretics; (3) while on both diuretics and digoxin; and (4) while on diuretics alone, to determine if digoxin: (a) increases "contractility" when added to diuretic therapy; and (b) improves symptoms. Symptoms, signs (heart and respiratory rates, and weight gain), shortening fraction, preload (left ventricular end-diastolic dimension), afterload (left ventricular end-systolic wall stress) and contractility were measured at each period. The difference between the measured and predicted velocities of circumferential fiber shortening for the measured left ventricular end-systolic wall stress served as an index of contractility. Eighteen infants also underwent catheterization. Mean pulmonary-to-systemic blood flow ratio was 3:1. When digoxin was added to diuretics, contractility index was significantly greater than in control subjects (0.13 +/- 0.15 vs 0.0 +/- 0.12 circ/s, p = 0.04). When patients were again on diuretics alone (after discontinuation of digoxin), contractility index was no longer different. Symptoms and signs were not significantly improved by either diuretics or digoxin. It is concluded that in infants with a large left-to-right VSD shunt and receiving digoxin and diuretics, contractility index was significantly greater than in control subjects. However, neither diuretics alone nor in combination with digoxin improved symptoms significantly.

Digoxin↗
PubMed1992

Acute hemodynamic effects of digoxin alone or in combination with other vasoactive agents in patients with congestive heart failure.

Although digitalis preparations have been in use for greater than 200 years, it is only within the last 2 decades that the central hemodynamic and neurohumoral effects occurring over several hours following intravenous administration of digoxin have been investigated in patients with congestive heart failure (CHF). Although digoxin has been shown to stimulate myocardial contractility in tissue preparations, its positive inotropic activity does not consistently translate into improvements in hemodynamic measurements in humans. Digoxin given intravenously results in increased cardiac index and decreased heart rate, left ventricular filling pressure, and right atrial pressure, as well as in acute attenuation of neurohumoral abnormalities, in patients with chronic CHF who have abnormal baseline hemodynamic measurements. Unlike other drugs with positive inotropic activity, however, digoxin does not influence hemodynamics in normal volunteers or in CHF patients in whom hemodynamics have been normalized with other therapies. These differing effects may be related to the drug's diverse peripheral vascular effects in CHF patients in whom vasodilation may occur in comparison with those that occur in normal subjects in whom the peripheral vasoconstrictor effects may prevent the inotropic effects of the drug from being translated into an increase in cardiac output. The hemodynamic effects of digoxin in patients with chronic CHF due primarily to diastolic dysfunction have not been fully investigated. Intravenous digoxin produces hemodynamic effects in patients with CHF associated with acute myocardial infarction, but these changes are small compared with those resulting from the administration of dobutamine. Digoxin does not appear to influence hemodynamic measurements in patients with right ventricular dysfunction unless concomitant left ventricular failure is present. In patients with chronic left ventricular dysfunction, the hemodynamic effects of intravenous digoxin and vasodilators are enhanced when these agents are given in combination.

Cardiotonic Agents↗
PubMed1986

No increase in serum digoxin concentration with high-dose diltiazem.

The effect of incremental diltiazem dosing during concomitant digoxin administration over a four-week period in eight healthy adult volunteers (mean age, 28 +/- 4 years) was studied. The study group received 0.25 mg of digoxin twice daily for two days, after which they received 0.25 mg daily for the duration of the study. Following baseline electrocardiographic evaluation and measurement of trough digoxin levels, all subjects received 120 mg of diltiazem daily for one week, then 240 mg daily for one week, followed by 360 mg daily for one week. Resting electrocardiographic parameters (heart rate, P-R interval), renal function, electrolyte values, and digoxin and diltiazem concentrations were measured weekly. Daily administration of 360 mg of diltiazem plus 0.25 mg of digoxin resulted in a significant decrease in heart rate (from 68 +/- 9 beats per minute to 61 +/- 10 beats per minute; p less than 0.05), a marginal increase in P-R interval (from 169 +/- 22 msec to 179 +/- 21 msec; p = 0.08), and no significant change in trough serum digoxin concentration (from 0.85 +/- 0.08 ng/ml to 0.90 +/- 0.08 ng/ml; p = NS). The administration of up to 360 mg of diltiazem per day with 0.25 mg of digoxin per day was not associated with significant increases in serum digoxin concentrations in healthy subjects.

Benzazepines↗
PubMed1988

Appropriateness of digoxin use in medical outpatients.

PURPOSE: Digoxin is the third most commonly prescribed drug, yet limited information exists about its use in outpatients. Therefore, 242 medical outpatients receiving digoxin at our hospital were studied to evaluate the appropriateness of its use, defined by: (1) current or past supraventricular arrhythmias and/or (2) left ventricular systolic dysfunction (ejection fraction less than 45 percent). PATIENTS AND METHODS: Charts of 242 patients receiving digoxin were obtained. The patients were divided into groups based upon their physician's stated indication for digoxin therapy. Patients with only a clinical diagnosis of congestive heart failure (CHF) underwent echocardiography or radionuclide angiography to quantify left ventricular systolic function. Those with documented supraventricular arrhythmias and/or those with confirmed left ventricular systolic dysfunction were classified as appropriate candidates for digoxin. RESULTS: Ninety-five percent of patients received digoxin for appropriate indications; 75 percent had confirmed supraventricular arrhythmias (27 percent also had CHF) and 20 percent with normal sinus rhythm had documented systolic dysfunction. However, physicians had difficulty in the clinical assessment of left ventricular function; 18 percent of patients with sinus rhythm and CHF by the Framingham scoring system and 20 percent of those with supraventricular arrhythmias and CHF had preserved systolic function. An S3 was present in 15 percent of patients with preserved ejection fraction and CHF and in 69 percent with low ejection fraction; hypertension was significantly more common in the former group. Noninvasive assessment of systolic function was obtained in 97 percent of patients independent of this study, yet some patients without supraventricular arrhythmias and with documented preservation of systolic function continued to receive the drug. CONCLUSION: Noninvasive assessment of left ventricular function, which appears to have become routine, is of value in the appropriate utilization of digoxin, since clinicians' assessment of left ventricular function may be inaccurate. Physicians also do not always discontinue digoxin therapy when indicated.

Aged↗
PubMed1990

A longitudinal study of maternal digoxin-like immunoreactive substances in normotensive pregnancy and pregnancy-induced hypertension.

The serum of women in the third trimester of pregnancy demonstrates cross-reactivity with some commercially available antibodies to digoxin. A number of studies have suggested that levels of this digoxin-like immunoreactive substance(s) are further increased in patients with pregnancy-induced hypertension, and some have proposed that the digoxin-like immunoreactive substance could be useful as a predictor of pregnancy-induced hypertension. We measured digoxin-like immunoreactive substance levels every 2 weeks throughout the third trimester in 170 women; of these, 20 developed hypertension. Digoxin-like immunoreactive substance levels rose with gestational age. A graph of the slope of digoxin-like immunoreactive substance plotted against gestational age was fitted for the results obtained from each woman. There was no significant difference in the mean rate of increase of digoxin-like immunoreactive substance level per week between pregnancy-induced hypertension and normotensive pregnancy, nor was there any difference between these two groups at any gestational age studied. These results suggest that measuring digoxin-like immunoreactive substance levels is not useful as a predictor of pregnancy-induced hypertension.

Blood Pressure↗
PubMed1989

Comparative ability of digoxin and an aminosugar cardiac glycoside to bind to and inhibit Na+,K+-adenosine triphosphatase. Effect of potassium.

We compared the abilities of digoxin and aminogalactose digitoxigenin (ASI-222) to bind to, or inhibit, purified dog heart Na+,K+-ATPase in the presence of 1, 10, or 80 mM potassium chloride. Changing the potassium concentration from 1 to 10 mM increased the dose producing 50% inhibition of enzyme activity (IC50) by 9- and 2.5-fold for digoxin and ASI-222 respectively. Raising the potassium concentration to 80 mM increased the IC50 for digoxin 3-fold but did not alter significantly the IC50 for ASI-222. Equilibrium binding studies showed that this enzyme exhibited a single class of specific binding sites for both digoxin and ASI-222. Raising the potassium concentration did not affect the maximum number of binding sites (Bmax) but increased the apparent dissociation constant (KD) for digoxin. Potassium differentially affected the affinity and number of binding sites for ASI-222; raising the potassium concentration from 1 to 10 mM did not affect the Bmax or the KD, but raising it to 80 mM increased both. The effect of i.v. infusion of potassium chloride upon cardiac upon cardiac arrhythmias produced by i.v. infusion of digoxin or ASI-222 in anesthetized dogs was also determined. Infusion of potassium chloride reversed the cardiac arrhymias due to digoxin to normal rhythm, but not those due to ASI-222. In conclusion, the interaction of digoxin and the polar digitalis agent, ASI-222, with dog heart Na+,K+-ATPase was differentially affected by potassium. These agents also also produced cardiac arrhythmias, which were differentially affected by potassium.

Animals↗
PubMed1993

Ca2+ channel antagonists inhibit the intestinal absorption of digoxin in the guinea-pig.

Simultaneous administration of digoxin and Ca2+ channel antagonists results in an increased plasma level of digoxin. A possible mechanism underlying this interaction might be the influence of Ca2+ channel antagonists on the enteral absorption of digoxin. To study this interaction, two groups of experiments were performed with guinea-pigs. In the first group, the influence of Ca2+ channel antagonists on the rate of enteral absorption of digoxin in vivo was studied. In the second group, the influence of Ca2+ channel antagonists on the transfer of digoxin through the wall of the isolated everted small intestine in vitro was investigated. The intravenously determined minimal lethal dose of digoxin 30 min after its intraduodenal administration was increased in animals pretreated with either verapamil, diltiazem, nifedipine or nicardipine. Addition of either verapamil or diltiazem to the solution on the mucosal side of isolated everted small intestine sacs decreased the transfer of digoxin through the intestinal wall. Similar results obtained in both groups indicate that, under our experimental conditions, Ca2+ channel antagonists inhibit the enteral absorption of digoxin in the guinea-pig.

Animals↗
PubMed1991

Dialyzability and binding of digoxin-like immunoreactive factors (DLIF) with serum macromolecules in uremic patients on hemodialysis.

Digoxin-Like Immunoreactive Factors (DLIF) which cross-react with antidigoxin antibodies are present in elevated concentrations in patients on hemodialysis, uremia, hypertensives, liver failure, pre-eclampsia and premature birth. DLIF may have a potential role as a natriuretic hormone with a speculated low molecular weight (less than 1000). We studied the dialyzability and bindings of DLIF with serum components in hemodialysis patients. We analyzed DLIF concentrations in sera and protein free ultrafiltrates of 31 patients and 22 normal volunteers using a fluorescence polarization assay for digoxin. The DLIF concentrations were expressed as nmol/L Digoxin Equivalent. The gel filtration analysis was done using three different Bio-Gel columns with molecular weight cut-offs of 10,000, 20,000 and 40,000. Molecules with lower molecular weight than cut-off were absorbed in the column. Only 3 out of 22 normal volunteers (13.6%) showed measurable DLIF. However 23 out of 31 patients (74.2%) showed measurable DLIF. The concentrations of DLIF were significantly higher in patients with renal failure on hemodialysis (P less than 0.05) by both chi-squared and Fisher's exact test. We observed no statistically significant difference in the concentrations of DLIF in pre and post-dialysis sera, indicating that DLIF were not filtered during hemodialysis. We observed no DLIF activity in the protein free ultrafiltrates of any DLIF positive sera (patients and normal volunteers), indicating that unlike digoxin (where we observed 70-80% of total digoxin concentrations in ultrafiltrates), DLIF were strongly bound to serum components. With Bio-Gel filtration experiments (five different serum pools), we recovered all DLIF activities in the fraction equivalent to the void volume of the column with Bio-Gel P6 and P10 columns, indicating that DLIF were almost completely bound to serum components with molecular weight greater than 20,000. On the other hand, we recovered no DLIF activities in the void volume when the same serum pools were passed through the Bio-Gel P30 column, indicating that DLIF were strongly bound to serum macromolecules with molecular weight less than 40,000. In sharp contrast, when serum containing digoxin was subjected to the same series of experiments, we recovered only 20-30% of digoxin concentrations in void volume with all three columns as expected since digoxin is only 25% bound to albumin (MW 67,000).

Blood Proteins↗
PubMed1993

The chronic effects of long-term digoxin administration on Na+/K(+)-ATPase activity in rat tissues.

We have studied the effects of digoxin administration on Na+/K(+)-ATPase activity in heart, liver, muscle, renal medulla and aorta in the rat. Adult male rats were either treated with digoxin for 3 days, 7 days (5 mg/kg per day) or 3 months (3 mg/kg per day). Another group of rats were treated with the vehicle as controls. At the end of the experimental period, blood samples were taken for digoxin measurements, the animals were sacrificed, and the heart, liver, kidney, skeletal muscle and aorta were removed, homogenised and assayed for Na+/K(+)-ATPase activity. In all tissues except the aorta Na+/K(+)-ATPase activity was measured by an enzyme coupled reaction. Na+/K(+)-ATPase activity in the aorta was measured by a fluorometric potassium dependent 3-O-methyl fluorescein phosphatase activity. Plasma digoxin concentration in the digoxin group was 5.34 nmol/l (S.E.M., 0.09) in the 3-day group and 4.38 (0.68) and 4.89 (0.73) nmol/l in the 7-day and 3-month groups, respectively. After treatment for 3 days and 7 days, the Na+/K(+)-ATPase activity in all tissues was significantly lower in the digoxin group (the decrease in activity ranging from 13.4% in muscle to 46.9% in the renal medulla). After 3 months of treatment, Na+/K(+)-ATPase activity in all the tissues except the aorta was similar in the digoxin and control groups. In the aorta the activity remained low. We conclude that in rats digoxin administration causes upregulation of the Na+/K(+)-ATPase in most tissues.

Animals↗
PubMed1995

Activated charcoal increases digoxin elimination in patients.

Digoxin continues to be an important cause of drug toxicity. On the basis of a healthy volunteer study, activated charcoal has been proposed as a treatment for digoxin chronic intoxication. In order to evaluate the effect of activated charcoal on digoxin elimination in intoxicated patients during routine practice, we reviewed all Serum Digoxin Level Requests for adult in-patients from 1991 to 1993, with digoxin levels > 2.5 ng/ml. Of a total of 39 cases, 23 had been treated with activated charcoal while 16 had not. Digoxin elimination half-life during activated charcoal therapy was 36 h (S.D. 14 h; 95% C.I. 30-42 h) while in the non-treated group it was 68 h (S.D. 19 h, 95% C.I. 57-78). Calculated total body clearance of digoxin was 55 ml/min (S.D. 17 ml/min; 95% C.I. 45-64 ml/min) for the non-treated group versus 98 ml/min (S.D. 34 ml/min; 95% C.I. 83-113 ml/min) for the group receiving charcoal, representing an 78% increase in digoxin elimination.

Aged↗
PubMed1989

Comparative hemodynamic and neurohormonal effects of intravenous captopril and digoxin and their combinations in patients with severe heart failure.

The effects of intravenous captopril and intravenous digoxin given separately and in combination on rest and exercise hemodynamics were studied in 16 patients with severe heart failure and sinus rhythm. When given separately, both captopril and digoxin decreased the pulmonary capillary wedge pressure by, respectively, 24% (p = 0.003) and 34% (p = 0.004) and systemic vascular resistance by 23% (p = 0.09) and 20% (p = 0.03). Only digoxin increased cardiac index by 23% (p = 0.03) and stroke work index by 52% (p = 0.01). During maximal exercise, captopril alone decreased systemic vascular resistance by 28% (p = 0.0002) and increased cardiac index by 33% (p = 0.02). Digoxin alone decreased pulmonary capillary wedge pressure by 11% (p = 0.04) and increased stroke work index by 44% (p = 0.01). The combination of captopril and digoxin resulted in a decrease in pulmonary capillary wedge pressure and systemic vascular resistance and an increase in cardiac index and stroke work index both at rest and during exercise that was greater than values observed with either drug given alone. Cardiac index response to the combination of captopril and digoxin correlated with baseline serum aldosterone concentration (r = 0.81, p less than 0.001) and plasma renin activity (r = 0.74, p less than 0.0002). A significant decrease in norepinephrine concentration was noted after digoxin was administered alone or added to captopril. These findings demonstrate that in patients with severe heart failure, the acute administration of captopril and digoxin has an independent salutary hemodynamic effect. The combination of these agents, however, has an adjunctive effect on cardiac function at rest and during exercise.

Adult↗
PubMed1996

Digoxin reduces cardiac sympathetic activity in severe congestive heart failure.

OBJECTIVES: This study evaluated the effect of digoxin on cardiac sympathetic activity in patients with congestive heart failure. BACKGROUND: Digoxin favorably alters autonomic tone in heart failure. Whether it reduces cardiac sympathetic drive in the setting of heart failure is unknown. METHODS: Digoxin (0.25 mg intravenously) was administered to 12 patients with severe heart failure and elevated left ventricular end-diastolic pressure (> 14 mm Hg, Group A), 5 patients with less severe heart failure who had normal left ventricular end-diastolic pressure (> 14 mm Hg, Group B) and 6 patients with normal ventricular function. Seven additional patients with heart failure were studied as a time control group. Cardiac and total body norepinephrine spillover, systemic arterial pressure, left ventricular filling pressure and peak positive first derivative of left ventricular pressure were all assessed before and 30 min after administration of digoxin. RESULTS: In Group A there were no changes in hemodynamic variables or total body norepinephrine spillover after digoxin administration; however, there was a significant reduction in cardiac norepinephrine spillover (263 +/- 70 to 218 +/- 62 pmol/min, mean +/- SEM, p < 0.001). In contrast, in Group B, digoxin caused a significant increase in cardiac norepinephrine spillover that was not associated with any hemodynamic changes or a change in total body spillover. There were no hemodynamic changes or a change in total body spillover. There were no hemodynamic or spillover changes in the time control or normal ventricular function group. CONCLUSIONS: Digoxin, in the absence of detectable inotropic or hemodynamic effects, caused a reduction in cardiac norepinephrine spillover in patients with heart failure who had elevated filling pressures. This finding suggests a potentially beneficial primary autonomic action of digoxin in patients with severe heart failure.

Cardiotonic Agents↗
PubMed1991

Risk factors and manifestations of digoxin toxicity in the elderly.

The incidence of digoxin toxicity increases with age, largely because the two most common conditions that benefit from use of digoxin, congestive heart failure and atrial fibrillation, are markedly more prevalent in old age. Whether the elderly are more sensitive to the effects of digoxin because of age per se is unclear. However, several other factors render the elderly more susceptible to digoxin toxicity. These include an age-related decline in renal function and a decrease in volume of digoxin distribution. There is also an increase in the number of comorbid conditions, including cardiovascular and chronic obstructive pulmonary disease, which heighten susceptibility to digoxin toxicity. Moreover, treatment of these diseases with such interactive medications as quinidine and calcium channel blockers may increase the serum level of digoxin. Similarly, such electrolyte imbalances as hypokalemia and hypomagnesemia occur more frequently in the elderly as a result of diuretic therapy. However, recent data suggest that manifestations of digoxin toxicity among younger and older patients do not differ. Similar incidences of cardiac toxicity, gastrointestinal toxicity, and altered mental status are found in both patient populations. Treatment of digitalis toxicity in the elderly is the same as for younger patients. Response rates to Digibind are not diminished in the elderly.

Age Factors↗
PubMed1993

The impact of age on risk of adverse drug reactions to digoxin. For The Gruppo Italiano di Farmacovigilanza nell' Anziano.

To assess the association of age and other potential risk factors with digoxin toxicity, adverse drug reactions to digoxin (ADRDIG) were studied in all patients (n = 1338) on digoxin therapy consecutively admitted to 41 clinical wards throughout Italy during 4 months in 1988. At the time of admission, 28 patients (2.1%) had evidence of ADRDIG. In multivariate logistic regression analysis, significant associations with ADRDIG were found for age > or = 80 years compared to age 65-79 years (OR = 2.75, 95% CI = 1.17-6.45), daily digoxin dosage of > or = 0.25 mg (OR = 2.51, 95% CI = 1.16-5.47), serum creatinine > or = 120 mumol/L (OR = 3.75, 95% CI = 1.69-8.32), and for treatment with amiodarone, propafenone, quinidine or verapamil (OR = 2.60, 95% CI = 1.07-6.30). Those aged < 65 years had a similar risk of digoxin toxicity as those aged 65-79 years (OR = 1.07, 95% CI = 0.28-4.12). Adverse drug reactions to digoxin were found in 1 in 50 patients hospitalized on digoxin therapy. Patients aged 65-79 years were not at increased risk for digoxin toxicity compared to younger patients, while advanced age (> or = 80 years) was an independent risk factor for this outcome.

Adolescent↗
PubMed2006

The complexity of intestinal absorption and exsorption of digoxin in rats.

The potential multiple carrier-mediated mechanisms involved in the transport of digoxin in rat intestine were investigated by the rapid filtration method in rat intestinal brush-border vesicles (BBMV) and in vitro Ussing chambers. The uptake of digoxin showed a typical overshoot phenomenon in the presence of an inward proton gradient and an outward bicarbonate gradient, or an outward glutathione gradient in BBMV. Good fitting to an equation consisting of both saturable and linear terms was obtained using non-linear regression analysis. GF120918, a specific P-gp inhibitor, significantly increased the absorptive permeability of digoxin in rat ileum (7.02 x 10(-7) cm/s versus 2.11 x 10(-6) cm/s with GF120918) but the addition of DIDS (0.5 mM), an anionic transporter inhibitor, or bromosulfophthalein (0.1 mM), an Oatp inhibitor, in the presence of GF120918 decreased the absorptive permeability compared with GF120918 alone (2.11 x 10(-6) cm/s versus 1.46 x 10(-6) cm/s, p<0.01 and 2.11 x 10(-6) cm/s versus 1.60 x 10(-6) cm/s, p<0.05, respectively). The above results suggest the involvement of carrier-mediated uptake mechanism, possibly Oatp, in digoxin absorption. Interestingly, GF120918 (1 microM) did not abolish the polarized transport of digoxin in rat jejunum and ileum, and DIDS (0.5 mM), not a P-gp inhibitor, and MK571 (50 microM), an MRP-selective inhibitor, can also significantly decrease the exsorptive permeability of digoxin. This result indicates the involvement of non-P-gp efflux transporter in digoxin secretion and this transporter is DIDS and MK571-sensitive. Contrary to conventional concept, our studies show that intestinal absorption of digoxin may involve both active uptake and efflux transporters. Our study may have clinical implications in drug-drug or drug-food interactions involving transporters.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1998

Clinical predictors of worsening heart failure during withdrawal from digoxin therapy.

Previous work provides limited information concerning predictors of clinical deterioration after digoxin withdrawal. We investigated the association between selected baseline clinical characteristics and symptomatic deterioration in two similarly designed trials: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Cox proportional-hazards analysis found the following independent predictors of worsening during follow-up in the combined PROVED and RADIANCE patients: heart failure score, left ventricular ejection fraction, cardiothoracic ratio, use of an angiotensin-converting enzyme inhibitor, use of digoxin, and age. When these factors, except for digoxin use, were tested in the subgroup of patients withdrawn from digoxin, they all were significant independent predictors of worsening heart failure. In contrast, only use of angiotensin-converting enzyme inhibitor predicted deterioration in patients who continued digoxin. Patients with more congestive symptoms, worse ventricular function, greater cardiac enlargement, or who were not taking an angiotensin-converting enzyme inhibitor were significantly more likely to worsen early after digoxin discontinuation than patients without these characteristics.

Aged↗