Serum digoxin determination in outpatients--need for standardization

1 Blood samples were taken from 30 outpatients for serum digoxin analysis before and after 5 min-4 h of rest in the supine position. 2 The digoxin concentration increased significantly during rest and a steady-state concentration was reached after approximately 2 h of rest. 3 The mean increase in serum digoxin after 2 h of rest was 23% with a considerable range, i.e. 0-75% (0-0.6 nmol/l). 4 On the analogy of a previous finding of a decrease in serum digoxin concentration during exercise in healthy subjects ingesting digoxin, the present results suggest that everyday physical activity affects the serum digoxin concentration. Standardized rest in the supine position prior to collecting blood samples from outpatients is therefore necessary for reliable serum digoxin determinations.     

Pharmacokinetics of various single intravenous and oral doses of omeprazole

Summary The effect of a therapeutic dose of oral salbutamol on serum and skeletal muscle digoxin concentrations has been studied in volunteers digitalised with digoxin. On one occasion a biopsy was taken from the quadriceps after 2 h of supine rest and then 3–4 mg salbutamol was given orally. Blood samples were taken before and after that dose and another muscle biopsy specimen was taken from the same thigh 180 min after the medication. On another occasion control blood sampling, ECG and blood pressure recordings were made but without muscle biopsies or salbutamol administration.Compared to the control measurements, salbutamol decreased the serum digoxin concentration (0.30 nmol·1^–1). It also reduced the serum potassium concentration (0.58 mmol·1^–1).The digoxin concentration in skeletal muscle did not change significantly after the intake of salbutamol. Thus, even a therapeutic oral dose of salbutamol reduces the serum digoxin concentration in man.     

Physical exercise and binding of digoxin to skeletal muscle — Effect of muscle activation frequency

Summary Ten healthy subjects who had ingested 0.5 mg digoxin daily for at least 10 days, performed a 1-hour bicycle exercise test on two occasions, 24 h after the latest dose, with the same work load but at two different pedalling rates, 40 and 80 rpm. During exercise the mean digoxin concentration in the thigh muscle increased by 8% at 40 rpm (n.s.) and by 29% at 80 rpm (p<0.01). The serum digoxin concentration decreased by 39% at both pedalling rates (p<0.001). The results suggest that the increase in skeletal muscle digoxin concentration during exercise is related to the neuromuscular activation frequency. The digoxin concentration in erythrocytes was measured in 16 healthy subjects before and 1 minute after a 1-hour bicycle exercise test. The erythrocyte digoxin concentration decreased by 12% (p<0.01) during the exercise indicating that the increased uptake of digoxin in skeletal muscle during exercise influences the digoxin concentration in other tissues.     

The effect of everyday exercise on steady state digoxin concentrations

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58-74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P less than .01) change in serum digoxin concentrations. Significant (P less than .01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t-test with Bonferroni correction. A weak correlation (r = 0.74, r2 = 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris.

We screened the antiischemic, hemodynamic, and inotropic effects of different dosages of the new calcium channel blocker Ro 40-5967 in 65 patients with stable effort-induced angina pectoris. In a double-blind way, patients were randomized to recieve a single oral dose of 50, 100, or 200 mg Ro 40-5967 or placebo, given as a drinking solution. Left ventricular ejection fraction (LVEF), blood pressure (BP), and heart rate (HR) were measured at rest and during a supine bicycle exercise test on day 0 (baseline) and 2 h after drug intake on day 1. Twenty-four hours later, the bicycle exercise test was repeated. Ro 40-5967 improved exercise duration and resting LVEF. After 200 mg, exercise time increased significantly from 8.4 +/- 0.8 min (mean +/- SEM) to 9.6 +/- 0.7 min (p = 0.018), and LVEF at rest increased from 54.5 +/- 2.2 to 58.1 +/- 2.6% (p = 0.045). Time to 0.1 mV ST-segment depression increased significantly from 4.3 +/- 0.8 to 5.5 +/- 0.9 min in the 100-mg group (p = 0.013) and from 4.3 +/- 1.3 to 5.4 +/- 1.5 min in the 200-mg group (p = 0.027). Maximum ST-segment depression decreased significantly at all dose levels (p = 0.01), with the maximum decrease noted in the 200-mg group (from 0.21 +/- 0.03 to 0.15 +/- 0.02 mV, p = 0.004). BP, HR, and rate-pressure product did not change significantly at rest or at maximum exercise. A single dose of Ro 40-5967 has antiischemic properties in patients with stable angina pectoris, with maximum effects obtained after 200 mg. No signs of negative inotropy were noted, and the drug was well tolerated.     

The Effect of Age and Everyday Exercise on Steady-State Plasma Digoxin Concentrations

Age-related physiologic changes may significantly alter the disposition and pharmacologic characteristics of many drugs. The elderly are the most frequent users of digoxin because of increased prevalence of atrial fibrillation and congestive heart failure. This study was conducted to confirm the decrease in digoxin concentrations during exercise, to determine if age is a factor in this decrease, and to explore the difference between chronologic age and physiologic age. Eighteen men age 50–85 years were treated with digoxin for more than 1 month before enrolling and had serum digoxin concentrations of 0.4-2.0 μg/L. They were evaluated during a 3-hour period in the morning (A.M. dose withheld). Blood samples were obtained every 10 minutes during sequential 60-minute periods of rest (phase I), walking (phase II), and rest (phase III). There were no significant differences in mean concentration between phases II and I (p<0.76), phases III and phase I (p<0.70), or phases II and III (p<0.37). The effect of age was positively correlated with the mean concentration of phase II but was not statistically significant (p<0.62). Statistically significant correlations were seen only between the exercise phase and serum albumin and Mini-Mental Status Examination scores. We conclude that exercise has minimal, if any, clinically relevant effects on plasma digoxin concentrations. Increasing chronologic age has no influence on a decrease in the concentrations with exercise; a younger physiologic age may play a role.     

Monoamine uptake inhibition by plasma from healthy volunteers after single oral doses of the antidepressant milnacipran

Summary Beta₂-receptor stimulation has been reported to increase the concentration of³H-ouabain in rat skeletal muscle. The present study was undertaken to see if beta₂-adrenoceptor stimulation by i.v. injection of salbutamol had any influence on the pharmacokinetics of digoxin in man. Ten volunteers were digitalized with digoxin and were investigated on two occasions. On each occasion a muscle biopsy was taken from the quadriceps after 2 h of supine rest. An injection of salbutamol 4 µg·kg^–1 b.wt. or saline was then given intravenously. Blood samples were taken before and after the injection and further muscle biopsy was taken from the same thigh 120 min after the injection.Compared to the injection of saline, salbutamol caused a decrease in the serum digoxin and potassium concentrations. The change in serum potassium was significantly correlated with that in digoxin. The digoxin concentration in skeletal muscle was not significantly changed by either the salbutamol or saline injections.     

Dissociation between duration of plasma catecholamine and blood pressure responses to beta-adrenergic blockade in normotensive subjects during physical exercise

Summary The influence of acute and chronic treatment with the adrenergic beta-receptor blocking agent propranolol (P) on blood pressure (BP), heart rate (HR) and plasma catecholamine concentration (CA) was studied in 7 normotensive healthy volunteers, and in 5 normotensive patients with cardiac neurosis, at rest, during physical exercise and after sudden withdrawal of the drug. The first oral dose of P 120 mg as well as chronic treatment (3×80 mg/day for 3 months) caused a significant reduction in HR and supine BP. Resting values of CA were not changed. After sudden withdrawal of the long-term therapy with P, supine BP and HR returned to normal, and again, resting levels of CA remained unchanged. A physical exercise test, performed 2 1/2 days after withdrawal of the betablocker, was not indicative of a transient sympathetic hyper-response. Striking effects of the drug on CA were observed during acute and chronic treatment with P when physical exercise was performed (bicycle ergometer, 150 W). Exercise values of CA were about twice as high during P treatment as without the drug, when the exercise test was performed 2 h after the first oral dose. At the same time, however, exercise BP and HR were significantly reduced. Similar reactions during the exercise test were also seen during chronic treatment with P, when the test was performed 2 hours after the last dose of the drug. But, when the exercise test was undertaken during chronic treatment 8 h after drug intake, the drug effect on CA had disappeared, whereas the effects on BP and HR still were present. The dissociation during chronic treatment between the effect on the duration of plasma CA and that of the pharmacodynamic responses to beta-adrenergic blockade with P is the principal finding of the study. A hypothesis is offered for interpretation of the observations. The time interval between measurement of drug effect and drug intake must be carefully observed in assessing different or controversial drug responses.     

Influence of physical exercise on the pharmacokinetics of propranolol

Summary The pharmacokinetics of propranolol after oral and intravenous administration was studied at rest and on an exercise day in 8 healthy subjects. On the exercise day the subjects performed physical exercise for 7 h, consisting of bicycle ergometer exercise at 50% of maximal work capacity and outdoor walking. Propranolol (80 mg p.o., or 0.2 mg/kg body weight i.v.) was administered 30 min before the start of the exercise. After oral administration the terminal phase halflife, (t1/2) and area under the curve (AUC) were both significantly reduced on the exercise day compared to the rest day. The bioavailability of propranolol was reduced by prolonged physical exercise and plasma levels of propranolol were about 30% lower at the end of the exercise day than at the end of the rest day. After intravenous administration, t1/2 was also reduced on the exercise day as compared to the rest day. AUC, clearance and volume of distribution did not differ on the two days. On the other hand, indocyanine green (ICG) clearance was significantly reduced during the bicycle ergometry periods on the exercise day. The combination of reduced ICG clearance, suggesting a reduction in hepatic blood flow, and a decreased t1/2 and unchanged clearance of propranolol on the exercise day was unexpected.     

The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects

AIMS: To investigate the effect of multiple oral dose treatment with the endothelin receptor antagonist bosentan on the pharmacokinetics of digoxin in healthy subjects. METHODS: This was an open-label, randomized, two-way crossover study in 18 evaluable young male subjects. They received, on two occasions which were separated by at least 2 weeks washout period, 0.375 mg digoxin once daily for 13 days following a loading dose of 0.375 mg given twice on the day before the once daily dosing regimen started. On one occasion treatment with 500 mg bosentan twice daily was started on the eighth day of digoxin treatment and continued for 1 week. Serum concentrations of digoxin were determined up to 24 h postdose on day 8 (first day of bosentan treatment) and day 14 (last day of bosentan treatment) of the digoxin treatment period. Plasma concentrations of bosentan were measured at two time points after the first bosentan dose and up to 12 h after the last morning dose of bosentan. Safety was assessed by adverse events, clinical laboratory tests, blood pressure and pulse rate measurements and ECG recordings. RESULTS: Steady-state of digoxin was always achieved after 7 days of treatment. Serum concentrations of digoxin were within the usual therapeutic range. Average steady-state Cmax and Ctr were 2-2.1 microg l-1 and 0.65-0.69 microg l-1, respectively, when given alone. Bosentan did not lead to statistically significant changes in Cmax and Ctr of digoxin. AUC (0,24h) of digoxin, however, was slightly reduced after 1 week of treatment with bosentan. The reduction was 12% on average with a narrow 95% confidence interval of 0-23%. Bosentan pharmacokinetic parameters after 1 week of treatment were as expected with a mean Cmax of 3260 microg l-1 and a mean AUC (0, 12h) of 12 600 microg l-1 h. CONCLUSIONS: Treatment with bosentan 500 mg twice daily for 1 week did not show clinically relevant effects on the pharmacokinetics of digoxin in healthy human subjects     

Serum digoxin concentration: increase after rest in different body positions.

If outpatients are allowed to rest in the supine position before their blood is sampled, serum digoxin increases. In a recent study, the serum digoxin concentration after 2-h standardized supine rest correlated better with the clinical status of patients than the value before rest. In the present study, 21 outpatients were studied on 2 consecutive days, approximately 24 h after the latest dose of digoxin. Blood samples for the assay of serum digoxin were taken on arrival at the department and after 1.5- and 2-h rest either supine or sitting (random order). The increases after 1.5-h rest were 12% (0-25%; p less than 0.001) and 12% (-3-47%; p less than 0.001), supine and sitting, respectively. The respective increases after 2-h rest were 14% (-11-32%; p less than 0.001) and 16% (0-74%; p less than 0.001). There were no statistically significant differences between the increases in serum digoxin concentration after supine and sitting rest. These results make it possible to recommend standardized rest in the sitting position (1.5-2 h) for outpatients before blood samples are collected when reliable serum digoxin analyses are of importance.     

Serum digoxin levels in patients of a general practice in Germany

Summary Serum digoxin levels were determined in 33 outpatients of a general practice in the countryside, on three occasions at intervals of 8 weeks. All the patients were on long term digoxin treatment, about 2 years on average. About 14 days after the first and the second visits the results of the measurements were sent to the patients, with a comment about their reliability in taking treatment according to the serum digoxin level. At the first visit half of the serum digoxin level were lower than 0.5 ng/ml; the mean serum concentration was 0.52 ng/ml. There was no correlation between serum concentration and age, dose or creatinine level; but there was with replies to the question about regularity of drug intake. The mean serum level at the second and the third visits was 0.88 ng/ml and 0.89 ng/ml, respectively. A correlation was found between the dose and the serum digoxin level. From these results it seems that compliance by the patient plays a major role in producing steady state levels of drugs.Dedicated to Professor Dr. R. Aschenbrenner on the occasion of his 70th birthday     

Effects of Terbinafine on the Pharmacokinetics of Digoxin in Healthy Volunteers

Study Objective . To assess the potential effects of terbinafine, a new synthetic allylamine antifungal agent, on the pharmacokinetics of a single 0.75-mg oral dose of digoxin. Design . Randomized, double-blind, placebo-controlled, crossover study consisting of two treatment periods. Subjects . Sixteen healthy men and women volunteers. Interventions . During treatment A, placebo was administered once/day for 12 days; during treatment B, terbinafine 250 mg was administered orally once/day for 12 days. The washout period between treatments was at least 2 weeks. A single 0.75-mg oral dose of digoxin was administered on day 8 of each period. Blood samples were collected after administration of digoxin to determine pharmacokinetics. Measurements and Main Results . Compared with placebo, terbinafine did not alter the time course of the digoxin serum levels. Although the time to maximum peak concentration with terbinafine was slightly reduced, the maximum concentration and area under the serum drug concentration-time curve from time zero to 120 hours were not significantly different with terbinafine than with placebo. No drug-related side effects were reported with either active treatment, and no clinically significant changes in vital signs, physical examination results, electrocardiograms, or clinical laboratory results were observed. Conclusions . No special dosage adjustments for digoxin appear to be necessary during concomitant therapy with terbinafine.     

Digitalis enhances exercise-induced hyperkalaemia

Summary In 9 patients with atrial fibrillation the effect of zero, low and high levels of serum digoxin on exercise-induced hyperkalemia was assessed by bicycle exercise tests.Exercise at each level of serum digoxin was associated with a significant (up to 20%) rise in plasma potassium. At a work load of 75 W the highest level of serum digoxin was associated with a significantly higher maximum plasma potassium concentration as compared to the maximum valueatazero serum digoxin.The enhancement of exercise-induced hyperkalemia may add to the arrhythmogenic effect of digitalis.     

Effect of salbutamol on digoxin pharmacokinetics

Summary A single dose of the ₂-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a ₂-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man.Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 g·kg^–1·h^–1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 g·kg^–1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a ₂-adrenoceptor-mediated increase in Na-K-ATPase activity.     

Lack of interaction between valaciclovir, the L-valyl ester of aciclovir, and digoxin

Aims Changes in both digoxin and aciclovir renal clearance following coadministration with some other renally eliminated drugs have been reported. The potential interaction of valaciclovir, with its antiherpetic metabolite aciclovir, and digoxin was investigated.
Methods Twelve healthy volunteers (seven males, five females) participated in an open, randomized, four-period crossover study. Valaciclovir, 1000  mg, was given alone on one occasion, and on another, after the second of two 0.75  mg digoxin doses administered 12  h apart. Blood samples and all urine were collected up to 12  h following the valaciclovir dose for aciclovir radioimmunoassay. On a third occasion, digoxin was given alone and on a fourth, with 1000  mg valaciclovir three times/day for 8 days starting 12  h before the first digoxin dose. Blood samples were taken up to 168  h and all urine collected up to 24  h following the second dose for digoxin radioimmunoassay.
Results There were no clinically significant differences in digoxin or aciclovir pharmacokinetic parameters when digoxin or valaciclovir was given alone or in combination.
Conclusions No dosage adjustment is required when valaciclovir and digoxin are coadministered.     

Physical exercise increases plasma concentrations of nicotine during treatment with a nicotine patch.

The effect of physical exercise on plasma nicotine concentrations was studied in eight healthy subjects treated with a nicotine patch releasing 14 mg 24 h-1. After 11 h of patch application, plasma nicotine concentrations were measured before and after 20 min of moderate bicycle exercise, or 20 min of rest. Mean plasma nicotine concentration increased from 9.8 to 11.0 ng ml-1 (P = 0.015) during physical exercise, and fell non-significantly from 10.5 to 10.2 ng ml-1 during rest. The increase in plasma nicotine concentration during exercise is similar to that observed for transdermal nitroglycerin, and may be related to an exercise-induced increase in blood flow in the patch area.     

Effects of adrenaline and mental stress on serum digoxin concentration.

Physical activity and pharmacological stimulation of beta 2-adrenoceptors by salbutamol increase skeletal muscle digoxin binding with a secondary decrease in serum digoxin, possibly due to increased Na-K-ATPase activity. The present study was undertaken to examine if adrenaline (ADR) infusion and sympathoadrenal stimulation by mental stress affect the serum concentrations of digoxin and potassium. After 10 days on 0.50 mg digoxin orally, 35 healthy volunteers were investigated following 2 h of supine rest. They were divided into four groups: intravenous saline (placebo, n = 10). ADR infusion at the rates of 0.1 nmol kg-1 min-1 (ADR-L, n = 8), 0.4 nmol kg-1 min-1 (ADR-H, n = 7), or subjected to a mental stress [a color-word conflict test (CWT), n = 10]. Arterial blood samples were taken before and during the active period (50 min) and during the following 60 min (at rest) to analyze serum digoxin and potassium and plasma ADR and noradrenaline (NA). All variables were stable during placebo infusion. ADR infusions caused significant and dose-dependent decreases in serum digoxin (p less than 0.05 during ADR-L and p less than 0.001 during ADR-H) and serum potassium (p less than 0.05 and p less than 0.001, respectively). CWT, on the other hand, did not reduce serum digoxin and caused a slight decrease in serum potassium only in the poststress period. Thus, ADR caused dose-dependent shifts of digoxin and potassium, whereas mental stress failed to do so, possibly due to a modest ADR response and small increases in sympathetic nerve activity in skeletal muscle.     

A placebo controlled comparison of the effects of metoprolol and celiprolol on echo-Doppler measurements of cardiovascular function in normal volunteers.

1. This study used a continuous-wave echo-Doppler method (Exerdrop) to investigate the effects of beta-adrenoceptor antagonism and partial agonism on cardiovascular responses at rest and during dynamic exercise. 2. A double-blind, randomised, placebo controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers; single oral doses of medication were administered at weekly intervals. Rest and exercise (supine bicycle) haemodynamics were assessed at 0, 2, 4, 6 and 8 h following dosing. 3. Before dosing and after placebo, the aortic flow velocity, acceleration and velocity integral increased progressively during exercise, as did heart rate, blood pressure and cardiac output. 4. Following metoprolol 50 mg, heart rate was significantly reduced without change in systolic or diastolic blood pressure. Echo-Doppler peak acceleration and velocity decreased at rest. On exercise, heart rate and systolic blood pressure fell significantly; the increase in acceleration was significantly blunted compared with placebo (a decrease of 15.2% at rest and 22.9% at 75 watts; P < 0.01 vs placebo). Peak velocity fell significantly by 75 watts exercise. 5. Celiprolol 200 mg at rest significantly increased systolic blood pressure, peak acceleration and velocity. On exercise celiprolol, in contrast to metoprolol, did not reduce peak acceleration or peak velocity; however exercise heart rate and systolic blood pressure were significantly reduced. The difference between celiprolol and metoprolol in respect of peak acceleration persisted over the 8 h of the study. 6. These differences between metoprolol and celiprolol are compatible with the partial agonism of celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial uptake of digoxin in chronically digitalized dogs.

1 The time course of myocardial uptake of digoxin, increase in contractility and changes in myocardial potassium concentration was studied for 90 min following an intravenous digoxin dose to long-term digitalized dogs. 2 Nineteen dogs were investigated by the use of a biopsy technique which allowed sampling before and after administration of digoxin. 3 Ten minutes after administration of digoxin the myocardial concentration increased from 60 to 306 nmol/kg tissue, the myocardial concentration of digoxin was significantly lower (250 nmol/kg tissue) after 30 min and then increased again. 4 The transmural myocardial distribution of digoxin was uniform before and 90 min after administration of digoxin in long-term digitalized dogs but at 10 min after administration, both the subepicardial and the subendocardial concentration of digoxin were significantly lower than that of the mesocardial layer. 5 During the first 10 min the dp/dtmax increased to 135% of the control level. The increase remained unchanged during the rest of the study. 6 Myocardial potassium decreased throughout the study. 7 The M-configuration of the myocardial uptake curve and the non-uniformity of myocardial distribution of digoxin observed at 10 min after administrating digoxin to long-term digitalized dogs indicate that the distribution of myocardial blood flow may be changed during chronic digitalization.