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Impact of ginkgo biloba on the pharmacokinetics of digoxin.

Many medications are known to alter digoxin pharmacokinetics, including the herbal medication St. John's wort. An open-labeled, randomized, crossover trial was conducted in eight healthy human volunteers to determine if ginkgo biloba (GB) also alters the pharmacokinetics of digoxin. On two occasions separated by 2 weeks, subjects ingested digoxin, 0.5 mg. One week prior to each study phase, half of the volunteers were randomly initiated on GB therapy, 80 mg three times daily, that continued until the end of the study phase. Immediately prior to and for 36 hours following digoxin ingestion, multiple blood samples were collected for digoxin plasma concentration determination. No significant difference between treatments was observed with respect to AUC(0- infinity ) (digoxin alone: 21.0 +/- 8.6 [ng/mL] x h; digoxin + GB: 25.6 +/- 13.2 [ng/mL] x h). Additionally, no significant difference between therapies was observed with respect to C(max), T(max), or Cl(o). In six subjects, k(e) and t(1/2) were able to be determined. These parameters also did not differ significantly between treatments. In conclusion, within the context of the specific GB product used during this investigation, the concomitant use of GB and digoxin did not appear to have any significant effect on the pharmacokinetics of orally administered digoxin in healthy volunteers.

Adult↗

The influence of calcium antagonists on plasma digoxin concentration.

Several investigators have independently discovered that the calcium antagonist, verapamil, causes a 60-80% increase in plasma digoxin. Pharmacokinetic studies indicate, that the elevated plasma digoxin level is due to verapamil-induced inhibition of both renal and extrarenal digoxin clearance. No significant changes in single-dose digoxin pharmacokinetics were observed during nifedipine coadministration . To elucidate the clinical relevance of this interaction, we investigated the influence of verapamil on digoxin-induced inotropism as assessed from systolic time intervals. In single-dose trials, the verapamil-induced elevation of plasma digoxin was associated with a more sustained reduction in left ventricular ejection time as compared to control. Correspondingly, the concentration-response relationship of digoxin inotropism was unaffected by verapamil. In-vitro studies showed that verapamil had no influence on the number of digitalis receptors on human lymphocytes. In accordance, verapamil enhanced the digoxin-induced elevation of intracellular sodium concentration possibly reflecting an increased receptor effect. The plasma digoxin elevation resulting from verapamil coadministration seems cardioactive with regard to both inotropism and toxic effects.

Digoxin↗

Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression.

AIMS: Studies revealing conflicting results of the functional significance of MDR1 exon 26 C3435T SNP on the disposition of digoxin in different ethnic groups led us to perform a meta-analysis on published data investigating the influence of C3435T SNP on the pharmacokinetics of digoxin and the expression of MDR1. METHODS: Meta-analysis was performed on data from published studies investigating the influence of MDR1 C3435T SNP on digoxin pharmacokinetics, as well as MDR1 expression in Caucasian and Japanese populations. The following outcomes were included: exposures to digoxin measured by area under the concentration-time curve and maximum concentration, the mean intestinal MDR1 mRNA expression and P-gp expression in the absence of digoxin administration. RESULTS: The overall results of the meta-analysis in Caucasian and Japanese subjects suggested no major influence of the C3435T SNP on exposure levels of digoxin as determined by AUC(0-4 h) or AUC(0-24 h) although C(max) values for digoxin were lower in wild-type (CC) subjects compared with subjects harbouring TT genotypes. Subgroup analysis by ethnic populations showed the oral availability of digoxin to be lower in wild-type Caucasian populations compared with wild-type Japanese subjects. No causal relationships were detected between the C3435T SNP and MDR1 mRNA or protein expression. CONCLUSIONS: Our meta-analysis of available studies indicates that the synonymous MDR1 C3435T SNP does not affect the pharmacokinetics of digoxin and the expression of MDR1 mRNA. Future studies should focus on the impact of MDR1 haplotypes on the pharmacokinetics of MDR1 substrates rather than the C3435T SNP alone.

Administration, Oral↗

Effects of quinidine and disopyramide on serum digoxin concentrations.

Although quinidine and digoxin are frequently given together, it has only recently become apparent that serum digoxin concentration may rise during quinidine treatment. A prospective study was performed to compare the effects of quinidine and disopyramide in patients receiving maintenance digoxin therapy. During quinidine administration serum digoxin concentration rose by more than 50% in seven of nine patients (the mean concentration rising from 1.43 +/- 0.20 to 2.61 +/- 0.43 nmol/l, P < 0.005). During the disopyramide treatment a small rise in serum digoxin was noted (mean 1.3 +/- 0.16 to 1.5 +/- 0.19 nmol/l, P < 0.05). We suggest that digoxin doses should be reduced immediately prior to commencing quinidine therapy in patients already receiving adequate maintenance digoxin, and patients should be followed carefully for evidence of digoxin toxicity. Disopyramide appears a suitable alternative anti-arrhythmic drug to quinidine in patients on maintenance digoxin.

Adult↗

Transfer of digoxin across the placenta and into breast milk.

Eleven mothers given digoxin throughout pregnancy because of rheumatic heart disease were studied. Digoxin was identified in the placenta and, for the first time, in milk. Paired cord and maternal blood samples obtained at parturition showed lower digoxin levels in cord blood than in maternal blood. The total tissue-bound digoxin level in the placenta correlated closely with maternal digoxin levels. These findings suggest strongly the presence of a placental barrier for digoxin. Similar digoxin concentrations (0.825 +/- 0.015 nmol/l) were found in milk samples obtained daily between the third and seventh days post partum. The half-life of digoxin in the newborn was 36.2 +/- 5.43 hours (Mean +/- SEM); thus all the digoxin present at birth would be excreted within 10 to 11 days.

Adolescent↗

Renal function and digoxin clearance during quinidine therapy.

To investigate further the handling of digoxin by the kidneys during quinidine therapy, clearances of digoxin, 51Cr-EDTA, PAH and endogenous creatinine were measured together with beta 2-microglobulin in the urine before and during quinidine therapy in 10 patients on maintenance digoxin therapy. Renal clearance of digoxin (corrected for 30% plasma binding) decreased on the average by 55% (137 +/- 73 to 73 +/- 25 ml/min, mean +/- SD). The steady state plasma concentration of digoxin increased more than twofold (1 . 0 +/- 0 . 34 to 2 . 5 +/- 0 . 79 nmol/L, mean +/- SD). The clearances of 51Cr-EDTA and PAH were not altered during quinidine therapy, indicating that neither glomerular filtration nor total renal blood flow changed when quinidine was added. The ratio of the renal clearance of unbound digoxin to that of the glomerular filtration rate was above one for all 10 patients before quinidine, indicating the involvement of tubular secretion in the renal elimination of digoxin. After the administration of quinidine this ratio decreased in all patients (from 1 . 51 +/- 0 . 30 to 0 . 83 +/- 0 . 38, mean +/- SD). Some patients had ratios well below one suggesting re-absorption of digoxin. Beta 2-microglobulin excretion was unchanged during treatment with quinidine. It is concluded that a significant portion of the renal elimination of digoxin in man results from tubular secretion and that this excretory mechanism is inhibited by quinidine.

Aged↗

Effect of digoxin on ejection fraction in elderly patients with congestive heart failure.

To assess the effect of oral digoxin on left ventricular systolic function in elderly patients, radionuclide angiography was performed on 20 patients 74 years old or older before and after several weeks of oral digoxin. The mean age was 83.8 years. All had congestive heart failure or cardiomegaly, and all were in sinus rhythm. The ejection fraction was 0.36 +/- 0.10 (mean +/- SD) before digoxin; 0.45 +/- 0.09 after digoxin (P less than 0.01). A comparison group that did not receive digoxin had no significant improvement in ejection fraction. In ten patients serial radionuclide angiograms were repeated after increasing serum digoxin concentrations. Six demonstrated maximal improvement in ejection fraction at serum digoxin concentrations of 0.4-1.0 ng/ml. It is concluded that oral digoxin improves left ventricular ejection fraction in elderly patients with congestive heart failure or cardiomegaly who are in sinus rhythm. Some of these patients achieve maximal improvement in ejection fraction at serum digoxin concentrations of less than 1.0 ng/ml.

Administration, Oral↗

Mid- and long-term similarity of ventricular response to paroxysmal atrial fibrillation: digoxin versus placebo.

The effects of digoxin on ventricular response during atrial fibrillation (AF) and consequent effects on arrhythmic symptoms have still not been fully explained. This study investigated whether the treatment by digoxin contributes to mid- and long-term stabilization of ventricular cycles in patients with paroxysmal AF. A population of 45 patients with paroxysmal AF underwent 24-hour ECG recordings during each arm of a randomized crossover trial comparing digoxin and placebo. This yielded 30 Holter recordings from 22 patients that contained AF episodes lasting in excess of 2 minutes and with acceptably low Holter noise. Each AF episode was divided into nonoverlapping segments of 30 seconds and the distribution of RR intervals in each segment was compared with the distribution of all other AF segments in the same recording using the Kolmogorov-Smirnov test. The percentage of tests that revealed significant differences at levels of P < or = 0.01, and P < or = 0.001 were sorted according to the time between the segments compared. The comparisons of these results were performed between: (a) all recordings on placebo (n = 16) and all recordings on digoxin (n = 14), and (b) between recordings on placebo and on digoxin in 8 patients in whom paired analysis was possible. Adjacent AF segments (distance 0) differed significantly only in < 30% of both recordings on placebo and on digoxin. However, with increasing the distance between segments, the proportion of the significant differences between RR interval distributions increased more with placebo than with digoxin (P < 10(-300), Chi-square test). Paired data revealed larger differences between placebo and digoxin with increasing distance between segments. Thus in patients with paroxysmal AF, digoxin leads to more reproducible patterns of ventricular cycles that may be better tolerated clinically.

Adult↗

Organophosphate poisoning in pregnancy: a case report.

A 42-year-old pregnant woman (26 weeks of gestation, G(4)P(0+3)) presented at the emergency department with a two-hour history of dizziness, blurred vision and repeated vomiting. These symptoms started during the use of an undiluted insecticide liquid (diazinon 60 EC) while cleaning a small non-aired bathroom. After clinical and laboratory confirmation for organophosphate poisoning (plasma pseudocholinesterase levels 161 U/l), treatment with atropine and pralidoxime was started. She recovered within 7 days and delivered a healthy baby 12 weeks later (Apgar score 9 and 10) by elective cesarean section. The child showed no signs or symptoms of organophospate, atropine or pralidoxime exposure.

Adult↗

Characterization of digoxin-like materials in human cord serum.

Human cord serum contains substantial amounts of materials that cross-react in radioimmunoassays for digoxin. The average content of digoxin-like immunoreactivity in mixed cord serum is 0.3 +/- 0.05 ngE/ml compared to less than 0.05 ngE/ml in serum from normal adults. After solvent extraction, the major digoxin-like materials present in cord serum coelute on Sephadex LH-20 column with the steroid sulfate fraction. The steroid sulfates are digoxin-like materials because they cross-react in the digoxin RIA. If the amount of dehydroepiandrosterone sulfate, 16 alpha-hydroxydehydroepiandrosterone sulfate, and 15 beta-hydroxydehydroepiandrosterone sulfate present in cord serum and the amount of digoxin-like material present in the same serum are considered, then up to 90% of the digoxin-like materials present can be accounted for on the basis of the steroid sulfates present. However, although steroid sulfates contribute to the digoxin immunoreactivity in both serum and breast cyst fluid, digoxin-like materials are present in breast cyst fluid that are not present in cord serum.

Cross Reactions↗

Effects of nicorandil and verapamil, antianginal agents, on plasma digoxin concentrations in rats and dogs.

The effects of equihypotensive doses of nicorandil and verapamil on plasma digoxin concentrations have been assessed in rats and dogs. In a single digoxin dose study, digoxin (1 mg kg-1) alone, or in combination with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1) was given orally to rats. When given chronically to rats, a single dose of digoxin (1 mg kg-1) orally for 7 consecutive days was followed, on day 8, by digoxin alone, or together with nicorandil (5 mg kg-1) or verapamil (25 mg kg-1). In dogs, a loading dose of digoxin (50 micrograms kg-1) was given orally on day 1, then 25 micrograms kg-1 was administered for the following 6 days. On day 8, digoxin (50 micrograms kg-1) was given with nicorandil (5 mg kg-1) or verapamil (20 mg kg-1). In rats, the AUC0-24 and Cmax of plasma digoxin were enhanced significantly by coadministration of verapamil, but not by nicorandil. In dogs, verapamil significantly increased the Cmax of plasma digoxin, but not the AUC. Nicorandil had no effect on either parameter.

Animals↗

Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0-3)), AUC(0-24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0-3), AUC(0-24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0-3) and AUC(0-24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

Administration, Oral↗

Effect of digoxin on global respiratory muscle strength after cholecystectomy: a double blind study.

BACKGROUND: Upper abdominal surgery has been shown to impair the function of the respiratory muscles. In addition, controversial results have been reported concerning the effect of digoxin on the diaphragm. The aim of this study was to investigate further the mechanism(s) of respiratory muscle dysfunction after cholecystectomy and the effect of digoxin on the impaired respiratory muscle function. METHODS: Twenty three patients (four men) were studied before and 48 hours after surgery. Eleven received digoxin and 12 placebo. Respiratory muscle strength was assessed 48 hours after surgery by measuring mouth pressure during maximum static inspiratory (PImax) and expiratory (PEmax) efforts before and after 90 minutes of intravenous administration of 0.25 mg digoxin in a double blind, placebo controlled fashion. In addition, spirometric and pain measurements were performed. RESULTS: Postoperatively (+48 h) PImax and PEmax decreased significantly (p<0.01) from their preoperative values in both groups by a similar degree. After administration of digoxin or placebo only the digoxin group showed a significant increase in both PImax (p<0.02) and PEmax (p<0.05) with a mean increase of 15% for PImax and 12.3% for PEmax. The mean difference in PImax (DeltaPImax) and PEmax (DeltaPEmax) between the digoxin and placebo groups was 1.01 (95% CI 0.28 to 2.2) and 1.05 (95% CI 0.04 to 2.4), respectively. Estimates of postoperative pain did not differ between the two groups. Spirometric indices showed a similar restrictive defect postoperatively in both groups but did not change after digoxin or placebo. CONCLUSION: Digoxin improves the impaired global strength of the inspiratory and expiratory muscles after cholecystectomy and this may be clinically relevant. Muscle contractility could play a part in this impairment.

Adult↗

Sensitization of vagal cardiopulmonary baroreflex by chronic digoxin.

It has been recently reported that intracoronary acetylstrophanthidin injection acutely sensitizes the cardiac baroreflex (vagal afferents). We wondered whether chronic administration of digoxin also augmented the gain of this reflex. We treated seven dogs with digoxin intravenously (40 micrograms/kg loading dose followed by 15 micrograms.kg-1.day-1) for 7 days; eight additional dogs received vehicle for 7 days. With the dogs under chloralose anesthesia, we assessed the changes in renal nerve activity that resulted from stimulation of cardiopulmonary receptors with volume expansion (15 ml/kg of 6% dextran in saline) in digoxin- and vehicle-treated groups under control conditions, after sinoaortic denervation (SAD), and after SAD plus vagotomy. Under control conditions volume expansion resulted in decreases of renal nerve activity of 13.5 +/- 3.5%/mmHg increase in pulmonary artery wedge pressure in digoxin-treated dogs. This tended to be greater than the response of sham-treated dogs (-9.5 +/- 1.5%/mmHg increase). After SAD, renal nerve activity decreased 19 +/- 5%/mmHg increase in pulmonary artery wedge pressure in the digoxin group compared with only 8 +/- 1%/mmHg increase in the vehicle group. These responses were significantly different. The plasma digoxin level in the digoxin-treated group was in the therapeutic range (1.9 +/- 0.4 ng/ml). Vagotomy abolished the responses to volume expansion in both groups. Thus chronic digoxin treatment resulting in therapeutic plasma levels of digoxin sensitizes vagal afferents mediating the cardiopulmonary baroreflex influence on renal nerve activity.

Animals↗

Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors.

BACKGROUND: Despite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied. METHODS AND RESULTS: We studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20 +/- 0.07 to 0.39 +/- 0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67 +/- 0.22 to 1.22 +/- 0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7 +/- 9.6% to 27.1 +/- 11.8% (P = .007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4 +/- 10.4% to 23.7 +/- 8.9%) in the placebo group but not in patients who continued to receive digoxin (P = .002). CONCLUSIONS: The increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.

Aldosterone↗

Digoxin prevents ouabain and high salt intake-induced hypertension in rats with sinoaortic denervation.

Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabain-like activity ("ouabain") in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 microg/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 microg x kg(-1) x d(-1)). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 microg x kg(-1) x d(-1)) or intracerebroventricular (ICV) antibody Fab fragments (200 microg/d), which bind "ouabain" with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na+, K(+)-ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and "ouabain" in the brain, thereby delaying ouabain- and preventing high salt-induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain "ouabain" or ouabain.

Animals↗

Effect of exenatide on the steady-state pharmacokinetics of digoxin.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Adult↗

Erythromycin-induced digoxin toxicity.

The potential interaction between certain antibiotics and digoxin has been discussed in the literature; however, few cases of actual erythromycin-induced digoxin toxicity have been reported. We present a case in which an 86-year-old woman who was taking digoxin 0.25 mg/d developed probably digoxin toxicity after the administration of erythromycin for the treatment of otitis media and streptococcal pharyngitis. Her digoxin concentration increased from a trough of 1.9 to 5.1 nmol/L six days after the erythromycin was started. Digoxin was discontinued and restarted approximately six weeks later when the patient's atrial fibrillation and congestive heart failure recurred. Her digoxin dose at this time was 0.125 mg/d and resulted in steady-state concentrations of 1.2, 1.4, and 1.2 nmol/L over the next year. Erythromycin inhibition of Eubacterium lentum, which converts digoxin into digoxin-reduction products in the gut, is the proposed mechanism of this interaction.

Aged↗