Comparison of medigoxin and digoxin in the control of atrial fibrillation.

1 Medigoxin (Lanitop) 300 microgram/day and digoxin (Lanoxin) 500 microgram/day were compared in cross-over studies on healthy volunteers and on patients with uncontrolled atrial fibrillation. Serum glycoside concentrations were measured by radioimmunoassay and ventricular rates by ECG. The two regimens appeared to be therapeutically equivalent. 2 The mean serum glycoside concentration in the steady state and the rate at which this state was attained were similar with both drug regimens in the healthy volunteer group. The between-subject variation in serum glycoside concentration was not significantly less during medigoxin administration. 3 The renal clearance of serum glycoside was much lower during medigoxin administration both in healthy volunteers and in patients. This was not due to a difference in serum protein binding. The relatively small dosage requirement for medigoxin was attributed partly to a lower clearance rate and partly to more nearly complete absorption. 4 During the first 2 weeks of the patient study there was a substantial rise in mean serum glycoside concentration and a corresponding fall in ventricular rate. This was attributed to more consistent self-administration of digoxin. The subsequent change to medigoxin had no further effect on mean glycoside concentration, ventricular rate or frequency of ventricular ectopic beats. 5. An attempt to compare the onset of the ventricular rate response to a single oral dose of medigoxin with that to digoxin gave inconclusive results.     

Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses

Normal subjects were given 0.75 mg of intravenous digoxin as a bolus and a 1-hr infusion, Radio-immunoassayed serum concentrations obtained over 48 hr and urinary excretion rates over 6 days were simultaneously fitted to a two- compartment open model by computer nonlinear least-squares regression. Serum concentration data alone were also fitted by this program. There was good agreement in calculated parameters between the two routes of administration in five of eight subjects, but the infusion mode of administration produced less variability in the apparent pharmacokinetic constants. The half-life values obtained from serum concentration data alone (24.2 hr) underestimated the half-lives obtained by the simultaneous fit (44.1 hr). The steady-state volume of distribution of digoxin averaged 590±164 liters (±1 sd).The renal clearance of digoxin (140±41 ml/min/1.73 m ² )was significantly higher than creatinine clearance (101±13 ml/min/ 1.73 m ² ),indicating tubular secretion of the drug. Digoxin body clearances were 188±44 ml/min/ 1.73 m ² ,indicating elimination of 25% of the dose by nonrenal mechanisms. Urinary excretion data are essential for proper pharmacokinetic analysis of digoxin disposition and reveal a slower rate of elimination than that suggested by earlier studies which determined only serum concentrations.Supported in part by Grant 20852 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Maintenance of subacute digoxin toxicosis in normal beagles

Subacute, nonfatal digoxin toxicosis was maintained in 10 beagles for a period of 17–20 days employing an iv loading dose of 0.125–0.150 mg/kg and daily iv maintenance doses of 0.015 mg/kg. Six of the dogs were also given, concurrent with the digoxin administration, the osmotic agent isosorbide (4, 8, or 12 mg/kg daily), po, for 2 consecutive 6-day periods separated by 1 day to test its effects on digoxin toxicosis. Two water, 4 digoxin-water, and 2 isosorbide control dogs were included in the test series. Electrocardiographic changes, reduction in food intake and weight loss were accepted as signs of digoxin toxicosis. Electrocardiographic signs of digoxin action persisted in 9 of the 10 animals. Nine of 10 animals receiving digoxin lost weight, and food intake was reduced in all digoxin-treated groups. The iv loading dose of 0.150 mg/kg appeared to be maximal for 100% survival. The simultaneous administration of isosorbide at all dose levels did not alter the signs of digoxin toxicosis.     

Comparison between imipramine and desipramine in normal subjects and their action in depressive patients

Summary Differences in action between imipramine (Tofranil^®) and desipramine (Pertofran^®), a metabolite of imipramine, in normal persons and in depressive patients are described. Correlations with the pharmacological findings of each comparative substance are discussed. If the comparison is limited to the therapeutic action, the two substances show rather similar properties, although there are some differences which seem to us important. On the other hand, the two comparative substances differ much more clearly in their effects in healthy subjects, where even opposite effects can be observed. Namely desipramine in the healthy subject shows a rather potent depressor effect and a slow onset of action, whereas in patients the drug has a short latent period and has a certain stimulant effect. Imipramine on the other hand acts rather slowly in patients but more quickly in healthy persons. It has scarcely any stimulant action, either in normal subjects or in depressive patients.     

Comparison of bioavailability and pharmacokinetics of cimetidine in subjects with normal and impaired renal function

The bioavailability and pharmacokinetics of cimetidine were studied following single oral and intravenous doses in subjects with severely impaired renal function (SIRF) and normal renal function (NRF). Eight subjects with NRF and five patients with SIRF participated. Multiple blood samples were obtained up to 1440 minutes following both doses. Urine was also collected for 24 hours after each dose. The bioavailability of cimetidine was not significantly different between the two groups (78 +/- 15% in patients with SIRF and 62 +/- 17% in the NRF subjects). In subjects with NRF, a mean of 50.4% of the i.v. dose was excreted renally as unchanged drug and the mean serum half-life (t1/2) was 2.00 hours. The mean total body and renal clearances were 710.0 and 370.7 ml/min, respectively. In the SIRF group, a mean of 1.7% of the i.v. dose was excreted renally unchanged, and the mean t1/2 was 12.71 hours. The total body and renal clearances were 147.1 and 2.5 ml/min, respectively. Nonrenal clearance was 62% lower in the subjects with SIRF than in the NRF subjects. There is no significant difference in bioavailability of cimetidine between the patients with NRF and SIRF. The significantly lower nonrenal clearance of the patients with SIRF suggests that cimetidine metabolism may be impaired in uremic patients.     

Effects of amiodarone on oral and intravenous digoxin kinetics in healthy subjects

The effect of amiodarone on oral and intravenous pharmacokinetics of digoxin was studied in healthy volunteers. A single 0.5-mg dose of digoxin was administered orally to three subjects both before and after 2 weeks of oral amiodarone (200 mg daily), while three subjects received a 0.5-mg intravenous dose of the glycoside under the same experimental conditions. Two other subjects were given both oral and intravenous doses of digoxin at different times, in the absence and in the presence of amiodarone. After oral digoxin treatment, amiodarone increased peak serum concentration, total area under the serum concentration-time curve (AUC), and 5-day urinary recovery of the glycoside, without changes in peak time and absorption rate constant. During the intravenous study, no significant change occurred in AUC and urinary recovery after amiodarone administration. Absolute bioavailability, for the two subjects who received both oral and intravenous digoxin, increased by 36 and 43%, respectively, after amiodarone treatment. Bioavailability derived from the mean values of oral and intravenous AUCs was 33% greater with amiodarone treatment. Apparent volume of distribution and systemic, extrarenal, and renal clearances of oral digoxin were not modified by amiodarone, when corrected for the bioavailability factor. Amiodarone had no effect on these pharmacokinetic parameters during the intravenous study with the glycoside. Our data indicate that increased oral bioavailability is the most relevant change in digoxin pharmacokinetics during the interaction with amiodarone and this can account for the increase in the glycoside concentrations.     

Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter.     

Effect of digoxin on the heart in normal subjects: influence of isometric exercise and autonomic blockade: a noninvasive study.

1. Eight healthy subjects were studied before digoxin and after successive therapy periods of 1 week 0.125, 0.25 and 0.50 mg of digoxin. The mean serum concentrations (+/- s. d.) were 0.4 +/- 0.2, 0.6 +/- 0.3 and 1.4 +/- 0.5 nmol l-1, respectively. The effects of digitalis were studied by echocardiography and systolic time intervals at rest and after 3 min handgrip exercise. Effects of simultaneous autonomic blockade induced by atropine and propranolol were also examined. 2. Digoxin in increasing doses slowed the heart rate at rest; with the daily dose of 0.50 mg from 63 +/- 10 to 53 +/- 6 beats min-1, and fractional shortening rose from 28 +/- 6 to 33 +/- 3% (P less than 0.05 for both). Preload, afterload and cardiac output did not change. The electromechanic systolic time index (QS2I) decreased (P less than 0.001) and the observed alteration of QS2I was dose-related. 3. The influence of digoxin was similar during isometric exercise, except for unchanged fractional shortening. 4. During autonomic blockade digoxin slowed the intrinsic heart rate from 93 +/- 6 to 86 +/- 6 beats min-1 (0.25 mg) and to 83 +/- 6 beats min-1 (0.50 mg) (P less than 0.01 for both). QS2I was shortened (P less than 0.01). Echocardiographically determined ejection phase indices remained unchanged. 5. When handgrip stress was induced during autonomic blockade, digoxin evoked a clearcut increase in contractile function, resembling the effects of digoxin alone at rest. Thus, fractional shortening increased by 14% and QS2I decreased by 16 ms (P less than 0.01 for both). 6. We conclude that digoxin increases the contractility in normal heart without changes in loading conditions. The rise in inotropy at rest is obvious from both fractional shortening by echo and systolic time intervals. The same takes place during handgrip with autonomic blockade, when the heart lacks sympathetic support. The influence of long-term digoxin on heart rate is partly direct without autonomic mediation. The effect of digoxin is dose-dependent.     

Intersubject variation in absorption of digoxin in normal volunteers.

The absorption of oral digoxin preparations was evaluated following single-dose administration of 0.5 mg of digoxin to 16 normal volunteers in a randomized crossover design. Absorption was estimated using the cumulative excretion of digoxin in urine for 7 days and the area under the 24-hr serum digoxin concentration curve (AUC). Significant intersubject variability was observed with both parameters, but this variability was greater for the AUC. After intravenous administration, the 7-day digoxin excretion was 68% of the dose. The elixir and a rapid dissolution tablet were significantly better absorbed (84.5 and 77.8%, respectively) than was a slow dissolution tablet (66.7%), as reflected by the fraction of the amount excreted in the urine following intravenous administration of the same dose. There was a highly significant correlation between the cumulative digoxin excretion in urine during the first 2 days compared to 7 days (r = +0.972,p less than 0.001). Bioavailability of oral digoxin preparations can be reliably determined by comparison of the cumulative 2-day excretion of digoxin following a single dose.     

Comparison of the effects of atenolol and practolol on exercise tachycardia in normal subjects.

The relationship between cumulative doses of practolol and atenolol and resultant decreases in exercise tachycardia has been examined in 4 healthy volunteers. Continuous intravenous infusions of practolol (0.4 mg/kg), atenolol (0.12 mg/kg) and saline were administered between 7 and 12 minutes of bicycle exercise. The mean (+/- S.E.M.) heart rate (HR) at 7 min. for practolol (133 +/- 5.1) and atenolol (132 +/- 2.8) were significantly (p less than .01) reduced to 115 +/- 2.3 and 104 +/- 2.9 beats/min. respectively. The pre-infusion HR in the saline study (132 +/- 1.2) was unchanged (133 +/- 4.6) at 12 min. The relationship between the log cumulative dose of each drug and the per cent fall in HR/min was linear for each subject. The log dose-response curve (mean of 4 subjects) for practolol (y = 9.6x + 18.1) was more horizontal than for atenolol (y = 18.4x + 38.6).     

Effect of urapidil on steady-state serum digoxin concentration in healthy subjects

Summary In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investgated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over.The absorption characteristics C_max and t_max of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%–103%).Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.     

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     

Comparison of the pharmacokinetics of digoxin and dihydrodigoxin in cats in single-dose studies

Summary Pharmacokinetics of ³H-dihydrodigoxin and ³H-digoxin after single intravenous and intraduodenal administration in cats are compared. Data could be described by an open two compartment body model. The half-life in plasma of dihydrodigoxin after initial rapid distribution is 4.6 h compared to 10.4 h after digoxin administration. The volume of tissue distribution of dihydrodigoxin is 7 times smaller than that of digoxin (0.31 l versus 2.05 l). The specific uptake of dihydrodigoxin into myocardium and some other tissues is very low. Over 5.5 h the cumulative biliary and urinary elimination of dihydrodigoxin is definitely higher (45.7% versus 14.4%).An unexpected peak in TLC plates after dihydrodigoxin administration in blood, bile and urine was identified to be the sodium salt of the opened lactone structure: dihydrodigoxin acid.     

Cyclosporin-erythromycin interaction in normal subjects.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.     

Naloxone induces miosis in normal subjects

In a placebo-controlled trial, pupillary constriction was measured in healthy non-addicted subjects and in opiate addicts by using static computer-assisted pupillometry. In contrast to earlier reports, a clear-cut pupillary constriction was observed in healthy persons after a single intravenous injection of 0.4 mg naloxone. No significant changes of pupillary size were recorded in the same subjects after the administration of a placebo. In methadone-maintained subjects, the IV administration of 0.4 mg naloxone caused a significant pupillary dilatation. From these data it can be concluded that naloxone seems to have a central pharmacological action not only in opiate addicts, but also in healthy persons. This is demonstrable by studying the miotic response.     

The comparative cardiovascular effects of digoxin and food alone and in combination in normal males

Summary In a double-blind, interindividual comparative study 30 healthy volunteers were randomly allocated to oral treatment with 5 or 10 mg of dihydroergotamine (DHE) or placebo once daily for 16 days. Regional basic venous blood volume (BBV), pressure dependent venous capacitance (C_v) of the calf, resting heart rate and blood pressure were determined on Days 1 and 15 of treatment. Plasma concentrations of DHE were monitored on Days 2 and 16.Due to spontaneous vasodilation BBV varied considerably, showing that it is an inappropriate parameter for investigating the venoconstrictor activity of DHE. C_v remained unchanged after the first dose of DHE but it had declined significantly on both dosage regimens at the end of the treatment phase. In contrast, the blood concentration profiles of DHE were comparable at the beginning and the end of the trial. The discrepancy can best be explained by the existence of an effect compartment, e.g. smooth vascular musculature, which slowly becomes filled with DHE and/or its active metabolites. The venoconstrictor activity of DHE exhibited a significant dose-response relationship.