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PubMed2005

Relationship between loperamide-induced sedative effect and digoxin pharmacokinetics in healthy Japanese subjects.

PURPOSE: Loperamide-induced suppressive effects on central nervous system closely relate to a lack of or decline in the P-glycoprotein (P-gp) function. The aim of this study was to determine the loperamide-induced sedative effect quantitatively and to investigate possible alterations in the pharmacokinetics of digoxin, a substrate for P-gp, in Japanese subjects. METHODS: Loperamide hydrochloride (2 mg) was administered orally to 26 subjects and the critical flicker-fusion frequency threshold (CFF) values were measured every 30 min separately by portable instrument. Further, digoxin (0.25 mg) was administered to 8 subjects, and the plasma concentration was determined. RESULTS: In five subjects who complained of drowsiness, the CFF values more remarkably decreased compared with those in the other subjects. The Tmax and mean residence time (MRT) values of digoxin pharmacokinetics in four subjects with drowsiness were significantly lower and Cmax was higher than those in four subjects with marginal effect. Moreover, there were good correlations between the CFF value-time profile and the Cmax, Tmax, and MRT of digoxin. CONCLUSIONS: The determination of the CFF value after oral administration of loperamide will be useful for evaluating varied P-gp function and for anticipating individual variations in the disposition of P-gp substrates in humans.

Adult↗
PubMed1975

Serum digoxin levels using an 125I-labelled antigen: Validation of method and observations on cardiac patients.

1. Determinations of serum digoxin levels utilizing commercially available kits with an 125I-labelled antigen were precise and not materially different from results obtained with a 3H-labelled antigen. 2. In order to approximate the steady state level, serum digoxin levels should be drawn either before or at least six hours following the administration of an oral tablet. 3. Concomitantly given thiazide diuretics did not interfere with the absorption of a tablet of digoxin. 4. In the digitalized patient, slow alterations in serum levels after oral administration appeared well correlated with, at least, the negative chronotropic effects of the drug. 5. Maximal exercise testing, a maneuver often applied to cardiac patients, does not significantly alter the serum digoxin level.

Administration, Oral↗
PubMed1982

Comparative electrophysiologic effects of digoxin in the nonsedated chronically instrumented puppy.

The electrophysiologic effects of acute but not chronic administration of cardiac glycosides have been studied. Nineteen chronically instrumented beagle puppies underwent 2-week courses of parenteral digoxin in three dosage regimens: six received digoxin, 0.04 mg/kg/day; seven received 0.03 mg/kg/day; and 11 received 0.02 mg/kg/day. Mean serum concentrations were 3.2 ng/ml, 1.3 ng/ml, and 1.0 ng/ml, respectively. Significant electrophysiologic effects on sinus node function were produced only by the highest dose. Atrioventricular node conduction was significantly delayed among animals receiving both high and middle dosages. All three regimens significantly effected atrioventricular specialized conduction system functional refractory periods. Atropine decreased digoxin-induced effects on all measured parameters but totally eliminated the digoxin effect on the corrected sinus node recovery time.

Aging↗
PubMed1980

Digoxin-quinidine interaction. Changes in canine tissue concentration from steady state with quinidine.

Tissue concentrations of tritiated digoxin inthe dog are altered by simultaneous administration of quinidine. Serum levels rise as tissue concentration decreases significantly in all tissue except brain tissue, where an increase of 51 percent is noted over that of the control digitalized state. The digitalis toxicity associated with digoxin-quinidine interaction appears to be associated with rising brain levels of digoxin and falling levels in the myocardium. These findings suggest a neurally mediated form of toxicity with this interaction related to a change in the space of distribution. The question of possible loss of inotropic effect associated with diminished myocardial digoxin concentration requires further study.

Animals↗
PubMed1982

Mechanism of additive effects of digoxin and quinidine on contractility in isolated cardiac muscle.

To evaluate the mechanism of the effect of the interaction of digoxin and quinidine on myocardial contractility, ferret right ventricular papillary muscles were isolated and the effects of digoxin, 4 x 10(-7) M, quinidine, 1 x 10(5) M and atropine, 1.5 x 10(-6) M, on peak developed force, peak rate of development of force (dF/dt) and time to peak tension were determined. The addition of quinidine to muscles treated with digoxin increased developed force 18 percent (p = 0.006) and dF/dt 35 percent (p = 0.001) without significantly changing time to peak tension. This effect was abolished by pretreatment with atropine. Quinidine alone increased developed force 35 percent (p less than 0.001) and dF/dt 70 percent (p less than 0.001) and decreased time to peak tension 22 percent (p less than 0.001) from pretreatment control values. Atropine alone increased developed force 17 percent (p = 0.02) and dF/dt 32 percent (p = 0.001) and decreased time to peak tension 13 percent (p = 0.003) from pretreatment control values. The addition of quinidine to muscles treated with atropine or of atropine to muscles treated with quinidine did not significantly change developed force, dF/dt or time to peak tension from values with either drug alone. It is concluded that digoxin and quinidine in these doses have additive effects of myocardial contractility, and that this interaction is at least partially mediated through antagonism of cholinergic influences by quinidine.

Animals↗
PubMed1985

Digoxin and the susceptibility of the canine heart to countershock-induced arrhythmia.

This study investigated the effects of therapeutic and subtoxic doses of digoxin on the risk of ventricular tachycardia (VT) after graded, transthoracic shocks in anesthetized dogs. A series of direct current shocks (5, 10, 25, 50, 75, 100, 150 and 200 J) was delivered to 33 normal dogs and 6 dogs with a healed (32 +/- 7 days) myocardial infarct (MI). In 10 untreated dogs, the duration of post-shock VT was highly reproducible when 3 separate series of shocks were delivered at 2-hour intervals. In 6 normal dogs treated with oral digoxin (0.5 mg/day for 5 to 7 days), a series of shocks delivered before and during treatment (serum levels 1.5 +/- 0.5 ng/ml) resulted in the same duration of post-shock VT. In 18 normal and 6 dogs with MI, a series of shocks was given before and 90 minutes after a therapeutic dose of digoxin (0.05 mg/kg intravenously). At this dose of digitalis (serum level 2.5 +/- 1.0 ng/ml), there was no difference in the duration of post-shock VT in either normal dogs or dogs with MI. A third series of shocks was given after achieving subtoxic digitalization with additional intravenous digoxin (0.01 mg/kg) every 30 minutes until a premature ventricular stimulus evoked a repetitive ventricular response. The subtoxic doses of digitalis (serum levels 13.9 +/- 4.7 ng/ml) increased the duration of post-shock VT in both normal dogs (100%) and dogs with MI (700%) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study.

The effects of the digitalis glycosides on systemic vascular resistance (SVR) in patients with congestive heart failure (CHF) are controversial. Most investigators report a reduction in total SVR, an action that has been attributed primarily to withdrawal of elevated sympathetic tone. Direct proof of this hypothesis is lacking, however, and the roles played by the renin-angiotensin-aldosterone and vasopressin systems have not been fully explored. Moreover, in several studies of patients with CHF, SVR did not decrease after the administration of digitalis. To clarify these issues, the hemodynamic and hormonal effects of digoxin were correlated in 11 normotensive men in sinus rhythm with CHF due to dilated cardiomyopathy. Patients were evaluated at rest and during submaximal exercise before and 6 hours after the intravenous infusion of 1.0 mg of digoxin (mean serum concentration 1.7 ng/ml). With digoxin therapy, heart rate, pulmonary wedge pressure and right atrial pressure declined and cardiac output increased. Although vasopressin was unchanged, both plasma norepinephrine concentrations and plasma renin activity decreased, the reduction in norepinephrine correlating with the increase in cardiac output. Despite these hemodynamic and hormonal effects, there was no change in total SVR at rest or during exercise. It is concluded that the improvement in cardiac function with digoxin in this patient group was a result of the inotropic properties of the drug, without an associated reduction in impedance. The failure of total SVR to decrease despite decreases in plasma norepinephrine levels and plasma renin activity might be explained by concomitant digitalis-induced vasoconstriction, impaired ability of arterioles to dilate in CHF, or offsetting alterations in other vasoactive hormone systems.

Cardiomyopathy, Alcoholic↗
PubMed1986

Serum magnesium levels in symptomatic atrial fibrillation and their relation to rhythm control by intravenous digoxin.

To study the effect of hypomagnesemia on control of atrial fibrillation (AF), serum magnesium levels were determined in 45 consecutive patients with symptomatic AF; 20% were hypomagnesemic (serum magnesium less than 1.5 mEq/liter). In a blinded treatment protocol, hypomagnesemic patients required twice the amount of intravenous digoxin to effect control of AF (p less than 0.05). Underlying diagnoses, blood chemistries and the use of other medications that could affect digoxin therapy were similar for the 2 groups. Diuretic therapy before inclusion into the study was not significantly associated with hypomagnesemia. Thus, hypomagnesemia is common among patients with symptomatic AF. Moreover, it appears to interfere with the effect of intravenous digoxin on AF. These results suggest that monitoring of serum magnesium and, where necessary, replacement of magnesium deficiency may be beneficial in patients with symptomatic AF for whom digoxin therapy is being contemplated.

Adrenergic beta-Antagonists↗
PubMed1986

Effect of digoxin on the electrocardiogram at rest and during exercise in healthy subjects.

The effect of digoxin on the electrocardiogram at rest and during and after exercise was studied in 11 healthy subjects. Exercise was performed on a heart rate-controlled bicycle ergometer with stepwise increased loads up to a heart rate of 170 beats/min. The subjects were studied after peroral intake of digoxin at 2 dose levels and after withdrawal of digoxin. Administration of digoxin induced significant ST-T depression at rest and during exercise even at the small dose (2.4 +/- 0.8 microgram/kg body weight, mean +/- standard deviation). The ST-T changes were numerically small and dose-dependent. The most pronounced ST and T depression occurred at a heart rate of 110 to 130 beats/min. At higher heart rates the ST depression was less pronounced but still statistically significant. During the first minutes after exercise no significant digitalis-induced ST-T depression was seen. This reaction is not of the type usually seen in myocardial ischemia. Fourteen days after withdrawal of the drug there were no significant digitalis-induced ST-T changes at rest or during or after exercise.

Adult↗
PubMed1975

Pharmacokinetics of digoxin and digitoxin in patients undergoing hemodialysis.

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population. Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dialyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin. When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (plus or minus SE) of 0.84 plus or minus 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 plus or minus 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the parmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.

Adult↗
PubMed1990

To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis.

PURPOSE: To reappraise the effectiveness of digoxin for the treatment of congestive heart failure (CHF) in patients with sinus rhythm in light of data from recently published randomized controlled trials and to quantitatively assess its usefulness. STUDY IDENTIFICATION: Computerized searches of the MEDLINE database were performed, and the reference list of each retrieved article was reviewed. STUDY SELECTION: Review of more than 360 citations and the reference lists of 19 review articles and 61 potentially relevant articles revealed seven double-blind randomized controlled trials that were included in this overview. DATA EXTRACTION: Study quality was assessed and descriptive information concerning the study populations, the specific interventions, and clinically relevant outcome measurements was extracted. RESULTS OF DATA SYNTHESIS: The common odds ratio for CHF deterioration while receiving digoxin versus placebo was 0.28, with a 95% confidence interval of 0.16 to 0.49. Predictors of digoxin benefit included presence of a third heart sound and the severity and duration of CHF. CONCLUSION: Data from seven trials of high methodologic quality suggest that, on average, one out of nine patients with CHF and sinus rhythm derive a clinically important benefit from digoxin (with a 95% confidence interval of 1/33 to 1/5).

Digoxin↗
PubMed1988

Atrial natriuretic factor, digoxin-like immunoreactive substance, norepinephrine, epinephrine, and plasma renin activity in human fetuses and their alteration by fetal disease.

We measured five hormones presumably involved in fetal homeostasis in specimens obtained by cordocentesis for clinical indications from 106 fetuses. Norms for atrial natriuretic factor, digoxin-like immunoreactive substance, plasma renin activity, norepinephrine, and epinephrine were derived from fetuses ultimately shown to be free of detectable abnormality. Atrial natriuretic factor, digoxin-like immunoreactive substance, and plasma renin activity were unrelated to umbilical vessel source or gestational age. Digoxin-like immunoreactive substance was directly related to PCO2 (r = 0.63, p = 0.02). Digoxin-like immunoreactive substance level was elevated in all fetal disease states studied except isoimmunization. The level of atrial natriuretic factor was elevated in fetuses with immune hydrops (NS). Norepinephrine and epinephrine levels were higher in the umbilical artery than in the vein (p = 0.05 and 0.006, respectively). There was a significant correlation between norepinephrine and gestational age in normal fetuses (r = 0.7637, p less than 0.025) and between both catecholamines and many of the respiratory blood gas measurements, with pH and PCO2 being the major determinants. Most disease states were associated with an elevated norepinephrine concentration. There was a negative correlation between plasma renin activity and base deficit (p less than 0.0001). Plasma renin activity was elevated in fetuses with idiopathic growth retardation and nonimmune hydrops (p less than 0.05 for each). In summary, fetal homeostasis as reflected by these five hormones was altered by a variety of disorders. With these baseline values the effects of direct or indirect fetal therapy can begin to be studied.

Atrial Natriuretic Factor↗
PubMed1992

The MDR1 gene product, P-glycoprotein, mediates the transport of the cardiac glycoside, digoxin.

Digoxin, a widely used cardiac glycoside with a low therapeutic index, is known to interact with a large and diverse group of co-administered drugs, frequently leading to toxic accumulation of the glycoside. Establishing the mechanism(s) of these interactions, therefore, has potential clinical significance. The present studies implicate P-glycoprotein, the MDR1 gene product overexpressed in multidrug resistant cells, as the apical membrane protein responsible for the renal secretion of digoxin and provide an explanation for the occurrence of digoxin toxicity in the presence of certain co-administered medications. Since digoxin is considered a prototype for endogenous digitalis-like glycosides, the results also allow for speculation that endogenous digitalis-like glycosides may be the natural substrates for P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1977

Digoxin radioimmunoassay: a comparison of the assay performances using tritiated and 125I radioiodinated tracers.

The preparation of 125I-labelled tracer for digoxin radioimmunoassay (125I monoiodinated 3-succinyl digoxigenin-1-tyrosine) is described, and its performance in radioimmunoassay of plasma samples is compared with that obtained with tritiated digoxin. The accuracy levels were assessed through the evaluation of different potential sources of systematic errors, such as interference from digoxin-related molecules and plasma proteins and methodological artefacts possibly associated with the immunocomplex instability, and through a series of checks including the recovery and parallelism tests and the correspondence of results obtained with the two tracers. The slope and the repeatability with time of the calibration curves and the spread of replicate estimates were taken into consideration to assess the assay precision. An essential equivalence in terms of reliability of measurement was proved for the two methodological variants, so that practical aspects and economic factors remain the main criteria to evaluate the relative merits: from this point of view, the advantages of using 125I-labelled tracer, as an alternative to tritiated digoxin, are discussed.

Digoxin↗
PubMed1977

Lack of effect on brain stem and cerebral cortex Na+, K+-ATPase during heart block produced by chronic digoxin treatment.

The autonomic nervous system has been shown to play an important role in digitalis toxicity. In order to determine whether the central nervous system could be digitalis' site of action, the effect of chronic treatment with toxic doses of digitalis on brain Na+,K+-ATPase was studied in the dog. After four weeks of digoxin treatment, Na+,K+-ATPase activity of the brainstem or cerebral cortex was unaffected at the time when digitalis toxicity (heart block) was apparent. ATP-dependent (3H)-ouabain binding to these tissues was also unaffected indicating that a significant occupancy of brain Na+,K+-ATPase by digoxin did not occur during chronic drug treatment. In contrast, cardiac Na+,K+-ATPase was markedly inhibited with the concomitant binding of digoxin to the enzyme. Since Na+,K+-ATPase is the most digitalis sensitive system identified to date, it appears that digoxin does not affect neuronal function directly.

Adenosine Triphosphatases↗
PubMed1982

The effect of digoxin on cardiovascular responses to hypoxia and reoxygenation in anesthetized dogs.

To clarify the efficacy of digitalis in acute hypoxia and reoxygenation, we estimated the effects of digoxin on cardiovascular hemodynamics in anesthetized dogs. Hypoxia caused significant increases in aortic pressure, pulmonary artery pressure, left ventricular (LV) pressure, rate of change in LV pressure (LVdp/dt), cardiac output (CO) and plasma catecholamines. These changes in LVdp/dt, CO and plasma catecholamines induced by hypoxia were returned to the control levels within 3 min by reoxygenation with 70% O2. The injection of digoxin (0.05 mg/kg) in hypoxic dogs resulted in significant increases in LVdp/dt, CO and stroke volume (SV) but no changes in levels of plasma catecholamines, heart rate, mean aortic pressure and mean pulmonary artery pressure. However, the injection of digoxin resulted in no significant changes in cardiovascular response to reoxygenation. Our experiments demonstrate that digoxin caused significant increases in CO, SV and LVdp/dt in dogs with hypoxia but resulted in no significant changes in cardiovascular responses to reoxygenation.

Anesthesia↗
PubMed1987

Increases in CSF norepinephrine associated with the onset of digoxin-induced arrhythmias.

The present study utilized a time course of CSF catecholamine concentrations during peripheral digoxin administration in vivo to provide a clarification of central catecholaminergic mechanisms involved in digitalis cardiotoxicity. A continuous peripheral digoxin infusion produced significant increases in CSF norepinephrine just prior to arrhythmogenesis in anesthetized dogs. Phentolamine pretreatment significantly increased the arrhythmogenic and lethal doses of digoxin. These results suggest that activation of central noradrenergic neurons may be the initiating factor in digoxin-induced arrhythmogenesis.

Animals↗
PubMed1983

Changes in erythrocyte sodium, sodium transport and 3H ouabain binding capacity during digoxin administration in the pig.

Time course of the changes in erythrocyte sodium content, sodium transport, 3H ouabain binding capacity and Na+, K+-ATPase activity were measured for 14 weeks, in 6 young pigs treated with digoxin and in 6 control pigs. After one week of treatment the erythrocyte sodium content increased from 5.4 mmol/kg cells to 6.9 mmol/kg cells and the efflux rate constant of sodium decreased. With prolonged treatment the erythrocyte sodium content returned to normal and the 3H ouabain binding capacity increased by week 5. The plasma digoxin concentration decreased from 1.1 ng/ml at week 5 to 0.6 ng/ml at week 8 probably due to the decline in dose (microgram/kg) of digoxin with age. The efflux rate constant of sodium and Na+, K+-ATPase activity were higher towards the end of treatment. It is concluded that with prolonged administration of digoxin there is an increase in erythrocyte sodium pump units.

Animals↗