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PubMed1978

Depressant effect of digoxin on atrioventricular conduction in man.

We examined the effect of chronically administered digoxin on atrioventricular (A-V) conduction in nine cardiac transplant recipients. We assessed A-V conduction by measuring the duration from the pacing stimulus to the onset of the QRS complex (S'R interval) and by determining the occurrence of Wenckebach periodicity during rapid atrial pacing. We made measurements during a control period and during a period of digoxin administration of up to 37 days. During the digoxin period, the cycle length at which Wenckebach block occurred was prolonged by 14% of the control value and the S'R interval was significantly prolonged at paced rates of 110 beats per minute and faster. After digoxin was discontinued, the Wenckebach periodicity and S'R interval returned to control values. Atropine and propranolol did not alter digoxin's effect on A-V conduction. We conclude that digoxin exerts a direct (or non-neurally mediated) depressant effect upon A-V conduction in man, although the stress of tachycardia is necessary to demonstrate the effect.

Atrioventricular Node↗

PubMed1980

The physiologic effects of digoxin under steady-state drug conditions in newborn and adult sheep.

The physiologic response to the chronic administration of digoxin was studied in 12 adult and 13 newborn sheep. Vascular pressures, cardiac output, isovolumic contraction phase indexes and systolic time intervals were measured before and after 2 weeks of digoxin therapy. Physiologic measurements were correlated with drug levels in plasma and myocardium. Resting myocardial function in newborns exceeded that in ewes. In ewes, the heart rate decreased from 98 to 74 beats/min, the preejection period (PEP) decreased from 76 to 57 msec, the ratio of PEP to left ventricular ejection time (LVET) decreased from 0.323 to 0.223 and dP/dt max increased from 2415 to 3460 mm Hg . sec-1 as plasma concentrations of digoxin increased to a mean of 1.8 ng/ml. Although the final steady-state plasma concentration of digoxin in newborn lambs averaged 1.7 ng/ml, cardiac output, PEP, PEP/LVET and dP/dt max did not change significantly from baseline values. These studies suggest that developmental differences in the physiologic response to digoxin are due either to a limited capacity for improvement in myocardial contractility shortly after birth or to an age-related difference in the effect of digoxin on myocardial tissue.

Aging↗

PubMed1999

Double-blind placebo-controlled trial of digoxin in symptomatic paroxysmal atrial fibrillation.

BACKGROUND: Digoxin is commonly prescribed in symptomatic paroxysmal atrial fibrillation (AF) but has never been evaluated in this condition. METHODS AND RESULTS: From a multicenter registry, 43 representative patients with frequent symptomatic AF episodes were recruited into a randomized, double-blind crossover comparison of digoxin (serum concentration, 1.29+/-0.35 nmol/L) and placebo. The study end point was the occurrence of 2 AF episodes (documented by patient-activated monitors), censored at 61 days. The median time to 2 episodes was 13.5 days on placebo and 18.7 days on digoxin (P<0. 05). The relative risk (95% CI) of 2 episodes (placebo:digoxin) was 2.19 (1.07 to 4.50). A similar effect was seen on the median time to 1 episode: increased from 3.5 to 5.4 days (P<0.05), relative risk 1. 69 (0.88 to 3.24). The mean+/-SD ventricular rates during AF recordings during placebo and digoxin treatment were 138+/-32 and 125+/-35 bpm, respectively (P<0.01). Twenty-four-hour ambulatory ECG recordings did not show significant differences in the frequency or duration of AF or in ventricular rate. CONCLUSIONS: Digoxin reduces the frequency of symptomatic AF episodes. However, the estimated effect is small and may be due to a reduction in the ventricular rate or irregularity rather than an antiarrhythmic action.

Ambulatory Care↗

PubMed2006

Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial.

BACKGROUND: About half of the 5 million heart failure patients in the United States have diastolic heart failure (clinical heart failure with normal or near-normal ejection fraction). Except for candesartan, no drugs have been tested in randomized clinical trials in these patients. Although digoxin was tested in an appreciable number of diastolic heart failure patients in the Digitalis Investigation Group ancillary trial, detailed findings from this important study have not previously been published. METHODS AND RESULTS: Ambulatory chronic heart failure patients (n = 988) with normal sinus rhythm and ejection fraction > 45% (median, 53%) from the United States and Canada (1991 to 1993) were randomly assigned to digoxin (n = 492) or placebo (n = 496). During follow-up with a mean length of 37 months, 102 patients (21%) in the digoxin group and 119 patients (24%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.63 to 1.07; P = 0.136) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality. Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Use of digoxin was associated with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR, 0.79; 95% CI, 0.59 to 1.04; P = 0.094) but also a trend toward an increase in hospitalizations for unstable angina (HR, 1.37; 95% CI, 0.99 to 1.91; P = 0.061). CONCLUSIONS: In ambulatory patients with chronic mild to moderate diastolic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme inhibitor and diuretics, digoxin had no effect on natural history end points such as mortality and all-cause or cardiovascular hospitalizations.

Aged↗

PubMed1988

The effect of digoxin on contractility and fatigue of isolated guinea pig and rat hemidiaphragms.

Digoxin could improve diaphragm contractility and fatigability if inhibition of sodium-potassium adenosine triphosphatase enhances calcium influx from extracellular sources, or it could impair contractility and worsen fatigue if it impairs maintenance of the membrane potential. We studied the effects of digoxin on isometric force production, fatigue, and recovery in isolated, directly stimulated, guinea pig and rat diaphragms. Digoxin had no effect on maximal twitch or tetanic tensions compared with control diaphragms in either rat (2 ng/ml to 20 micrograms/ml) or guinea pig (2 ng/ml to 2 micrograms/ml) hemidiaphragms. Digoxin worsened high frequency fatigue and impaired recovery from fatigue in guinea pigs (200 ng/ml to 2 micrograms/ml) but not in rat (2 micrograms/ml) hemidiaphragms. We conclude that digoxin has no effect on diaphragm contractility. Hypopolarization of the membrane potential is the likely cause for the increased fatigability. The difference in responsiveness between species is likely due to insensitivity of rat sodium-potassium adenosine triphosphatase to digoxin.

Aminophylline↗

PubMed1998

Digoxin-like immunoreactivity in early infantile death.

The aim of this study was to determine if the level of digoxin-like immunoreactivity in post-mortem sera obtained from infants differs according to the cause of death and if the level is related to age, post-mortem interval, cardiac pathology or adrenal weight. Twelve infants whose deaths were attributed to sudden infant death syndrome (SIDS), and 11 infants who died from other causes, had blood sampled between 3 to 53 hours post-mortem from their right atrial cavity. Digoxin-like immunoreactivity was measured, using a specific and sensitive digoxin radioimmunoassay, and was detected in 7 of the infants who died of SIDS and 7 of those who died from other causes. The highest levels were seen in two patients who died from meningococcal sepsis and haemorrhage, hyperpyrexia and encephalopathy syndrome, respectively. No correlation was detected between the digoxin-like immunoreactivity level, gender, age at death, post-mortem interval or cardiac pathology. Digoxin-like immunoreactivity levels correlated with adrenal weight. It is concluded that digoxin-like immunoreactivity is frequently found in infant sera, but levels are not specific to and are no higher in SIDS infants than infants dying of other conditions.

Cardenolides↗

PubMed2004

No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers.

The interaction potential of digoxin and ximelagatran, an oral direct thrombin inhibitor being developed for the prevention and treatment of thromboembolic disease, was investigated in this randomized, double-blind, 2-way crossover study. On 2 separate occasions, healthy female and male volunteers (n = 16) received ximelagatran 36 mg or placebo twice daily for 8 days separated by a 4- to 14-day washout period. All volunteers received a single oral dose of digoxin 0.5 mg on day 4 of both study periods. No interaction between ximelagatran and digoxin was detected in the pharmaco-kinetic parameters (using a 90% confidence interval [CI] of least squares mean estimate ratios), including melagatran (the active form of ximelagatran) AUC(tau) and C(max) and digoxin AUC(t) and C(max). Digoxin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran was observed in this study.

Administration, Oral↗

PubMed2001

Decrease of intracranial pressure and weight with digoxin in obesity.

Fourteen obese patients (body mass index = 34-47 kg/m2; mean = 40 kg/m2) with lumbar cerebrospinal fluid pressure (Pcsf) above 20 cm water in 10 of the 14 patients were treated with digoxin with a serum concentration of at least 1.0 nmol/L (0.8 ng/ml) for 6 months. Pcsf decreased significantly during digoxin medication (p < 0.005). Although there were no diet restrictions, all patients decreased in weight (range: 3-25 kg; mean = 10.6 kg) during the 6 months (p < 0.001). When digoxin medication was stopped in 3 patients, prompt weight increase occurred. Most patients needed progressively increased digoxin doses to attain stabilized serum concentrations at the stipulated level, in 5 patients more than 0.5 mg a day. Five of 13 patients developed diabetes mellitus during the digoxin medication. The larger the dose of digoxin, the greater the risk for diabetes mellitus to occur.

Adult↗

PubMed1992

Lack of acipimox-digoxin interaction in patient volunteers.

1. A study was carried out to find out if digoxin and acipimox interact. 2. Six elderly patients on digoxin were each given acipimox 150 mg three daily for a week, after informed consent. Digoxin and acipimox plasma concentrations and urinary excretion were measured after the first dose of acipimox and after a week of treatment. 3. Data were fitted to a one-compartment oral absorption model. Areas under the plasma concentration-time curve, plasma and renal clearances, and elimination half-life were computed. 4. There was no significant difference in digoxin plasma concentrations and kinetic parameters before and after acipimox administration. Acipimox kinetics were not affected by the concomitant ingestion of digoxin. 5. The patients' clinical condition remained stable during the study. 6. Thus there was no evidence for an adverse interaction between digoxin and acipimox in human subjects under the conditions of this study.

Aged↗

PubMed1985

Evaluation of a digoxin pharmacokinetic monitoring service in a community hospital.

This study was done to determine the effects of a pharmacokinetic service (PKS) on digoxin concentration monitoring and patient outcomes, including length of stay and toxicity measures. Two-hundred and eighteen consecutive patients with digoxin concentrations outside a target range were studied using a prospective before and after design. Demographic, diagnostic, and digoxin monitoring data were collected. The after group received PKS intervention by a clinical pharmacist. Results showed that the number of digoxin sample obtained was reduced by 22 percent in the after group and plasma concentrations were less often in the toxic range. The after group had significantly shorter lengths of stay (15.3 vs. 11.6 d) and fewer incidences of in-hospital digoxin toxicity (11.1 vs. 2.2 percent). Clinical pharmacist intervention was found to be associated with significant changes in patient outcomes, including length of stay and morbidity. The cost of the PKS was offset by savings resulting from the reduction in digoxin assays alone.

Adult↗

PubMed1985

The effects of activated charcoal on digoxin and digitoxin clearance.

The effect of multiple oral doses of activated charcoal on digitalis glycoside kinetics was studied to determine whether an activated charcoal regimen might have utility in treating patients with digitalis toxicity. Normal subjects were given intravenous infusions of digoxin 0.75 mg/70 kg or digitoxin 1 mg/70 kg iv followed by either water alone or water with activated charcoal in divided doses in a randomized crossover design. A subject with chronic renal failure was also given digoxin 0.5 mg/70 kg iv followed by water alone or water with activated charcoal. In six normal subjects, treatment with activated charcoal did not increase digoxin clearance (Cl) significantly (16.79 +/- 1.70 vs. 22.68 +/- 3.51 L/h). However, digitoxin Cl did increase significantly, from 0.24 +/- 0.01 to 0.47 +/- 0.04 L/h. In the renal failure subject, digoxin Cl increased from 3.6 L/h to 10.1 L/h. We conclude that the activated charcoal regimen is probably useful in patients with digitoxin toxicity. Although similar benefit is limited in patients with normal renal function who develop digoxin toxicity, it is possible that activated charcoal will be useful in patients with prolonged digoxin elimination due to renal dysfunction.

Adult↗

PubMed1990

Effect of cimetidine on oral digoxin absorption.

Cimetidine is a commonly prescribed histamine 2-receptor antagonist used in the treatment of gastric acid-related disorders. Cimetidine can interact with a number of drugs, including theophylline, benzodiazepine sedative hypnotics, warfarin, and antiarrhythmics. Problems may occur in patients receiving drugs with a narrow therapeutic index when combined with cimetidine. Contrasting reports have been published on the potential interaction between digoxin and cimetidine. This study focuses on cimetidine's effect on the pharmacokinetic disposition of chronic digoxin usage. Six hospitalized patients with stable congestive heart failure received their usual maintenance dose of digoxin 0.125-0.25 mg/d po. After confirming steady-state digoxin concentrations, cimetidine 300 mg po q6h was administered. Two patients were dropped from the study. Analysis of digoxin serum concentrations, area under the curve, and the rate of elimination suggested no significant differences in digoxin parameters when combined with cimetidine.

Administration, Oral↗

PubMed1991

Comparison of steady-state serum concentrations of digoxin in tablets (Lanoxin) and capsules (Lanoxicaps) in the elderly.

The bioavailability of digoxin in solution (Lanoxicaps, 90-100 percent) is superior to that of Lanoxin tablets (60-80 percent) in young healthy volunteers. The alleged bioequivalence of digoxin in tablets (Lanoxin 0.25, 0.125 mg) and capsules (Lanoxicaps 0.2, 0.1 mg) was studied in 20 elderly inpatients (14 women, 6 men, aged 84 +/- 5 years), treated with digoxin for atrial fibrillation. In a crossover design, steady-state digoxin concentrations were measured in 16 patients after once-daily administration of Lanoxin 0.125 mg or Lanoxicaps 0.1 mg, each for at least ten days. Four other patients took Lanoxin 0.25 mg and Lanoxicaps 0.2 mg successively. The steady-state digoxin concentrations were statistically significantly different, being 1.3 +/- 0.5 nmol/L for Lanoxin and 0.9 +/- 0.4 nmol/L for Lanoxicaps (p = 0.003). Whereas in young healthy volunteers the bioavailability of digoxin from Lanoxicaps (90-100 percent) exceeds that from Lanoxin (80 percent), in elderly patients the absorption appears to be similar. This suggests a lower than expected bioavailability of Lanoxicaps, which may result in subtherapeutic serum concentrations.

Aged↗

PubMed2003

Endogenous digoxin, hemispheric dominance and family bonding behavior.

The isoprenoid pathway produces endogenous digoxin which can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in individuals with differing family bonding patterns. The patterns were compared in those with right hemispheric and left hemispheric dominance. Digoxin synthesis was increased with upregulated tryptophan catabolism (increased levels of serotonin, strychnine and nicotine) and down regulated tyrosine catabolism (decreased levels of dopamine, noradrenaline and morphine) in those with reduced family bonding and right hemispheric chemical dominance. Digoxin synthesis was reduced with down regulated tryptophan catabolism (decreased levels of serotonin, strychnine and nicotine) and upregulated tyrosine catabolism (increased levels of dopamine, noradrenaline and morphine) in those with increased family bonding and left hemispheric chemical dominance. Hypothalamic digoxin plays a central role in the regulation of family bonding behavior. Hemispheric chemical dominance in relation to digoxin status is also crucial.

Adult↗

PubMed1985

Hemodynamic consequences of inotropic support with digoxin or amrinone in lambs with ventricular septal defect.

Inotropic support with digoxin is commonly used in patients with left ventricular volume overload due to ventricular septal defect (VSD). However, the hemodynamic consequences of inotropic agents with VSD have not been experimentally explored. We studied two inotropic agents, digoxin and amrinone, in chronically instrumented lambs with left ventricular volume overload due to a surgically created VSD. Intravenous digoxin (40 micrograms/kg) produced serum levels of 3.5 +/- 0.9 ng/ml (mean +/- SD) in seven lambs 60 min after administration, reduced the heart rate by 16% (172 to 149 beats/min, p less than 0.05), increased the stroke volume 16% (29.8 to 34.5 ml/beat, p less than 0.05) but did not significantly alter the systemic flow index (Qs), the pulmonary flow index (Qp), or the volume of left to right shunt (QL-R, 6.74 to 6.77 liter/min/m2). The mean left atrial pressure (LA) was unchanged (17.6 versus 17.1 mm Hg) following digoxin. Chronic digoxin use in four lambs for 4 days (25 +/- 8 micrograms/kg/8 h) produced trough serum levels of 1.2 +/- 0.2 ng/ml. There was no additional hemodynamic effect compared to acute digoxin, the Qp/Qs ratio was unchanged (3.10 versus 3.08) and evidence of left ventricular volume overload (LA - 14.0 versus 13.4) was unchanged. Amrinone lowered the systemic resistance index in a dose dependent fashion. The peak reduction of 20% (25.3 to 20.3 U/m2, p less than 0.01) occurred at 20 min after an intravenous (3 mg/kg) bolus in seven lambs. The Qs increased from 2.58 to 3.10 liter/min/m2 (p less than 0.01). The Qp was unchanged, thus the Qp/Qs ratio was lowered by 16% (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopyridines↗

PubMed1986

Digoxin- and digitoxin-like immunoreactive substances in amniotic fluid, cord blood, and serum of neonates.

Using four different digoxin kits, it was disclosed that the majority of various samples including amniotic fluid, cord blood, and serum from neonates contained substantial levels of digoxin-like immunoreactive substance. The differences in data seemed to be due to the range of epitopes which are recognized by antidigoxin antiserum. The day-to-day studies on sera serially obtained from infants at birth to 48 days old revealed that the level of the substance (0.31 +/- 0.12 ng/ml) in sera of the 1-day-old neonates rapidly declined to the level of 0.1 ng/ml by the 2nd postnatal wk and thereafter gradually declined. The immunological specificity and accuracy of the detection of digoxin-like immunoreactive substance was confirmed by a sample dilution test, a recovery test for standard digoxin, and an absorption test with antidigoxin antiserum. The amniotic fluid and cord blood also contained four to eight times more of a digitoxin-like immunoreactive substance than they did digoxin-like immunoreactive substance. A significant correlation was observed between the levels of digoxin-like immunoreactive substance and of digitoxin-like immunoreactive substance (p less than 0.01).

Amniotic Fluid↗

PubMed2005

Ontogeny of renal P-glycoprotein expression in mice: correlation with digoxin renal clearance.

Digoxin is eliminated mainly by the kidney through glomerular filtration and P-glycoprotein (P-gp) mediated tubular secretion. Toddlers and young children require higher doses of digoxin per kilogram of bodyweight than adults, although the reasons for this have not been elucidated. We hypothesized there is an age-dependant increase in P-gp expression in young children. The objectives of this study were to elucidate age-dependant expression of renal P-gp and its correlation with changes in the clearance rate of digoxin. FVB mice were killed at different ages to prepare total RNA for P-gp expression studies. Semi-quantitative RT-PCR was conducted to analyze mdr1a and mdr1b ontogeny in the kidney at: birth, 7, 14, 21, 28 and 45-d old adults. The pharmacokinetics of digoxin (7 microg/kg) was studied in mice of the same age groups. Newborn and Day 7 levels of both mdr1a and mdr1b were marginal. Day 21 mdr1b levels were significantly higher than both Day 14 and Day 28 levels. Digoxin clearance rates were the highest at Day 21, with significant correlation between P-gp expression and clearance values. Increases in digoxin clearance rates after weaning may be attributed, at least in part, to similar increases in P-gp expression.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1994

Development of glycoside-bound radiopharmaceuticals: novel radioiodination method for digoxin.

We combined 2-hydroxy-3-methylbenzoylhydrazide (HMBH) with glycosides as a novel method for the radioiodination of physiologically active glycosides. This method was tested using digoxin, which is one of the cardiac glycosides. A digoxin-HMBH conjugate was synthesized by periodate cleavage of the third sugar ring, and was readily radiolabeled with Na[125I] by the chloramine-T method. 125I labelled digoxin-HMBH conjugate retained Na+, K(+)-ATPase binding in vivo and in vitro, and also retained immunoreactivity to an anti-digoxin antibody. Thus, this 125I labelled digoxin-HMBH conjugate represents a potential radiopharmaceutical for Na+, K(+)-ATPase imaging, as well as for the radioimmunoassay of digoxin.

Animals↗