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PubMed1990

[Interpretation of postmortem digoxin levels: evaluating a "corrective factor" for postmortem blood digoxin concentration].

Interpretation of postmortem serum digoxin levels is made difficult above all by a possible prefinal or postmortem rise in digoxin concentrations in the blood. To compensate for this postmortem increase, Eriksson et al. (1984) divided the level of postmortem digoxin in femoral venous blood by a factor of 1.5; in the opinion of these authors, postmortem digoxin levels still exceeding "therapeutic levels" after division by 1.5 are an index of digoxin overdose. The diagnostic value of this "correction factor" was investigated. In 56 cases with documented digoxin medication, samples of postmortem femoral venous blood were taken and the level of digoxin determined. In none of the cases had there been a clinical diagnosis of digoxin intoxication. Fifty percent of the measured values were above "therapeutic levels" (0.7 ng/ml to 2.2 ng/ml). Following division by 1.5, 20% of the cases still showed levels exceeding 2.2 ng/ml; the highest "corrected" value was 4.44 ng/ml. Taking into account the length of time between final dosage and death, individual differences in sensitivity to digitalis glycoside, and the complexity of ante- and postmortem dispersion processes, we concluded for the cases we studied that an (undetected) digoxin overdose was not even likely in those cases whose postmortem values after division by 1.5 lie above "therapeutic levels". The "correction factor" proposed by Eriksson et al. (1984) is only of limited diagnostic value; at best the "corrected" values can give an approximate indication of the corresponding antemortem serum digoxin concentrations. In particular, "corrected" values only a little above "therapeutic levels" could not confirm suspicion of an overdose with sufficient certainty.

Adolescent↗
PubMed2003

Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction.

AIMS: A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms. METHODS: In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg x kg(-1) digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay. RESULTS: Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) +/- SD 23 +/- 5.2 vs. 14 +/- 2.9 microg x L(-1) x h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) +/- SD 34 +/- 39 vs. 57 +/- 41 mL min-1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin. CONCLUSIONS: Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.

Administration, Oral↗
PubMed1993

Effect of endogenous digoxin-like factor and digoxin antibody on myocardial Na+, K(+)-pump activity and ventricular arrhythmias in acute myocardial ischaemia in rats.

OBJECTIVE: The aim was to study whether a circulating sodium pump inhibitor (endogenous digoxin-like factor) contributes to the genesis of early ventricular arrhythmias in acute myocardial ischaemia in rats. METHODS: Effects of digoxin antibody (260 micrograms.kg-1) on the incidence of ventricular arrhythmias, plasma digoxin-like immunoreactivity (DELFIA immunoassay), Na+, K+, and Mg2+ ions, and activity of the ouabain sensitive Na+, K(+)-pump in different regions of myocardium have been studied in propranolol naive and propranolol pretreated rats exposed to acute coronary artery ligation. Adult male Wistar rats were divided into six experimental groups: (1) saline pretreated controls; (2) saline pretreated coronary artery ligated rats; (3) coronary artery ligated rats pretreated with 260 micrograms.kg-1 digoxin antibody; (4) propranolol pretreated controls; (5) propranolol pretreated rats with acute myocardial ischaemia; (6) rats with acute myocardial ischaemia pretreated with both propranolol and digoxin antibody. RESULTS: Acute myocardial ischaemia in saline pretreated rats was associated with a twofold increase of plasma digoxin-like immunoreactivity and ventricular arrhythmias, but did not lead to changes in myocardial Na+, K(+)-pump activity. Pretreatment of coronary artery ligated rats with digoxin antibody reduced the total duration of ventricular tachycardia and ventricular fibrillation during a 15 minute postligation period from 201 (SEM 34) to 46(18) seconds (p < 0.002) but did not alter activity of the myocardial Na+, K(+)-pump. In rats pretreated with propranolol, acute myocardial ischaemia was associated with a twofold inhibition of the Na+, K(+)-pump in left atrial and left ventricular myocardium, and with a 69% increase in plasma K+ concentration. Administration of digoxin antibody to propranolol pretreated coronary artery ligated rats in parallel with the antiarrhythmic effect prevented the increase in plasma K+ concentration and inhibition of Na+, K(+)-pump in the left atrial, but not the left ventricular myocardium. CONCLUSIONS: A circulating digoxin-like factor contributes to the pathogenesis of myocardial ischaemia induced ventricular arrhythmias. As propranolol pretreatment of coronary artery ligated rats inhibited the Na, K(+)-pump in myocardium, the inhibitory effect of endogenous digoxin-like factor on Na+, K(+)-ATPase was probably masked in propranolol naive animals by the stimulatory action of catecholamines on Na+, K(+)-ATPase described previously.

Acute Disease↗
PubMed2001

A single H:CDR3 residue in the anti-digoxin antibody 26-10 modulates specificity for C16-substituted digoxin analogs.

We constructed Fab libraries of bacteriophage-displayed H:CDR3 mutants in the high-affinity anti-digoxin antibody 26-10 to determine structural constraints on affinity and specificity for digoxin. Libraries of mutant Fabs randomized at five or 10 contiguous positions were panned against digoxin and three C16-substituted analogs, gitoxin (16-OH), 16-formylgitoxin and 16-acetylgitoxin. The sequence data from 83 different mutant Fabs showed highly restricted consensus patterns at positions H:100, 100a and 100b for binding to digoxin; these residues contact digoxin in the 26-10:digoxin co-crystal structure. Several mutant Fabs obtained following panning on digoxin-BSA showed increased affinity for digoxin compared with 26-10 and retained the wild-type (wt) Trp at position 100. Those Fabs selected following panning on C16-substituted analogs showed enhanced binding to the analogs. Replacement of H:Trp100 by Arg resulted in mutants that bound better to the analogs than to digoxin. This specificity change was unexpected, as C16 lies on the opposite side of digoxin from H:CDR3. Substitution of wt Trp by Arg appears to alter specificity by allowing the hapten to shift toward H:CDR3, thereby providing room for C16 substituents in the region of H:CDR1.

Amino Acid Sequence↗
PubMed1991

Enhanced clearance of specifically bound digoxin from human myocardial and skeletal muscle samples by specific digoxin antibody fragments: subsequent complete digitalis glycoside receptor (Na,K-ATPase) quantification.

The effect of digoxin antibody fragments (Fab) on clearance of specifically bound digoxin from its specific receptor (Na, K-ATPase) was studied in human heart left ventricle (LV) and vastus lateralis skeletal muscle (SK) samples obtained postmortem. Initially, [3H]digoxin was bound to samples at conditions giving high relative occupancy of receptor. Half-life (t1/2) for its net release from LV in buffer was 32.2, 6.7, and 0.9 h at 0 degrees, 30 degrees, and 37 degrees C, respectively. For SK, t1/2 was 5.4 h in buffer at 30 degrees C. Inhibition of rebinding of digoxin by addition of specific digoxin Fab (5 x 10(-7) M) or excess unlabeled digoxin (1 x 10(-4) M) to buffer at 30 degrees C increased net release rate for specifically bound digoxin 2.5- to 3.0-fold in heart and SK. [3H]Digoxin was also bound to samples at conditions giving low relative occupancy. Samples were subsequently washed in buffer containing 5 x 10(-7) M specific digoxin Fab for 16 h at 30 degrees C. This wash reduced occupancy of receptors by digoxin from 10 to 0.5% in LV and from 9 to 0.3% in SK, respectively. At variance with wash at 37 degrees C, this procedure allowed subsequent vanadate-facilitated complete quantification of Na,K-ATPase by [3H]ouabain binding; values were 378 +/- 13 and 370 +/- 12 pmol/g wet weight (p greater than 0.6) in LV and 309 +/- 19 and 315 +/- 16 pmol/g wet weight (p greater than 0.7) in SK with and without previous wash, respectively (mean +/- SEM, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Acute digoxin overdose in a newborn with renal failure: use of digoxin immune Fab and peritoneal dialysis.

Digitalis intoxication is a common problem, mainly because of the narrow margin of safety of digoxin. These patients may have concomitant renal failure. In patients who have renal failure and who have been treated with digoxin-Fab, the elimination of the digoxin-Fab complex is significantly delayed, and there is a risk of dissociation of the complex with rebound of free digoxin and recurrence of toxicity. The high molecular weight of digoxin and digoxin-Fab complex prevents its elimination by hemodialysis or continuous arteriovenous hemofiltration. A 3-day-old newborn with digoxin overdose and acute renal failure was treated with digoxin immune Fab and peritoneal dialysis. Low levels of total digoxin were measured in the dialyzate, indicating poor elimination of the digoxin-Fab complex through peritoneal dialysis.

Acute Kidney Injury↗
PubMed1996

Mixed-effect modeling for detection and evaluation of drug interactions: digoxin-quinidine and digoxin-verapamil combinations.

Mixed-effect modeling has been suggested as a possible tool to detect and describe drug interactions in patient populations receiving drug combinations for the treatment of disease states. The mixed-effect modeling program, NONMEM, was used to measure the effects of the well-known digoxin-quinidine and digoxin-verapamil drug interactions in 294 patients receiving oral digoxin as hospital inpatients. Fourteen percent of the population took either quinidine or verapamil concurrently with digoxin (mean quinidine dose = 857 +/- 397 mg/day, verapamil = 261 +/- 110 mg/day). Two regression models for digoxin oral clearance were used. Model 1 used the knowledge that digoxin is eliminated by both renal and nonrenal routes (TVCL = ClNR+m.CrCl, where TVCL is the population digoxin oral clearance, ClNR is the nonrenal clearance, and m is the slope of the line that relates creatinine clearance (CrCl) to digoxin clearance); model 2 used a more conventional regression approach with a simple series of multipliers. For both models, quinidine administration decreased population digoxin oral clearance by approximately 45% and verapamil therapy decreased population digoxin oral clearance by approximately 30%. These values are similar to those found by traditional drug interaction studies conducted in small patient or normal subject populations. Mixed-effect modeling can detect clinically relevant drug interactions and produce information similar to that found in traditional pharmacokinetic crossover study designs.

Adult↗
PubMed1986

The effect of digoxin-specific active immunization on digoxin toxicity and distribution in the guinea-pig.

In guinea-pigs intravenously infused with digoxin, prior immunization using a digoxin-human serum albumin conjugate increased by 3- and 2.4-fold, respectively, the digoxin doses causing the first signs of cardiotoxicity and death. At death, serum digoxin concentration was four times higher in immunized than in control animals. In the immunized guinea-pigs 50% of the serum digoxin was protein bound, presumably mainly to digoxin-specific antibodies, since in the controls the bound fraction was only 1-2%. Generally, tissue digoxin concentrations were not increased to the same extent as the lethal dose, and in the heart and lungs the increase was not significant. With cardiac (ventricle) subcellular fractions, there was no difference between control and immunized animals in the digoxin concentration of the 'microsomal' pellet. This subfraction contains the plasma membrane and the associated sodium pumps which are considered to be the sites at which the pharmacologically active digoxin binds. It seems likely, therefore, that the greater digoxin resistance in the immunized animals can be explained on the basis of reduced drug access to the site of action within the heart.

Animals↗
PubMed1982

Extracellular versus intracellular digoxin action on bovine myocardium, using a digoxin antibody and intracellular glycoside application.

1. The actions of externally and internally applied digoxin in heart ventricular muscle have been compared. 2. External application of digoxin (5 x 10(-8)--10(-7) M) had an inotropic effect, a steady level of twitch tension being reached at the end of about 3 hr. 3. Addition of an anti-digoxin antibody to the bathing solution prevented or reversed the digoxin effect, depending on the time of application. 4. The efflux of the antibody-[3H]digoxin-complex could be fitted by a single exponential with a half-time of 18 min. 5. In the absence of antibody, [3H]digoxin washout was two-compartmental with half-times of 4 and 72 min respectively. It is thought that the fast process signifies efflux from the extracellular space while the slow process reflects the washout of initially membrane bound glycoside. 6. When digoxin was applied by a cut end method, there was no effect on contractile strength. 7. The profile of radioactivity several hours following exposure to [3H]digoxin clearly indicated movement from cell to cell, the concentration of [3H]digoxin being above 10(-7) M in half the preparation at the end of 6 hr. Longitudinal diffusivity averaged 8.6 x 10(-8) cm-2 sec-1. 8. We conclude that digoxin has an inotropic effect when reaching the surface membrane of cardiac cells from the outside but is ineffective when applied from the inside.

Action Potentials↗
PubMed1979

Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog.

The effects of digoxin on monovalent cation active transport were determined in cardiac tissue obtained from dogs given inotropic, toxic, or lethal doses of digoxin. In hemodynamically monitored dogs, active uptake of the K+ analogue Rb+ was determined in vitro in a control myocardial biopsy, and then in serial biopsies from the same dog after the infusion of [3H]digoxin in doses sufficient to cause a sustained positive inotropic effect in the absence of toxicity, and finally after additional doses to induce overt toxicity. Nontoxic digoxin doses producing a mean increase of 20% in left ventricular (LV) dP/dt significantly reduced Rb+ active transport by 25% below control values. At the onset of digoxin-induced arrhythmias, maximal LV dP/dt was 53% above control whereas active Rb+ transport was reduced by 60% below baseline values (P less than 0.001). Control dogs given vehicle alone showed no significant change in contractility or in monovalent cation active transport. In another group of dogs given a lethal dose of digoxin, Rb+ active transport was reduced 59% below control levels at the onset of overt toxicity and was further reduced 80% below control at the time of onset of a fatal rhythm disturbance. When dogs were given high affinity digoxin-specific IgG or Fab fragments at the onset of overt toxicity, toxicity was rapidly reversed, and monovalent cation active transport increased to 51% of control at the time of restoration of sinus rhythm. Twenty-four hours after antibody reversal of arrhythmias, monovalent cation transport values approximated normal control levels. These data provide quantitative estimates of the extent of inhibition of monovalent cation transport by digoxin at inotropic, toxic, and lethal endpoints. Similar degrees of transport inhibition were present at the time of onset of digoxin-induced arrhythmias and at the time or arrhythmia reversal by digoxin-specific antibodies.

Animals↗
PubMed1976

The effect of digoxin antibody on the washout of tritiated digoxin and its inotropic effect from perfused rabbit hearts.

The reversal of digoxin effects by digoxin antibody (Ab) may be mediated by at least two mechanisms. First, the Ab may simply decrease the concentration of free digoxin in the perfusing medium, or second, the Ab may dislodge digoxin from its receptor. To pursue this problem, rabbit hearts were perfused for 20 min with Krebs-Henseleit solution (K-H) followed by a 30-min perfusion with [3H] digoxin in concentrations of 10(-7), 5x10(-7), and 10(-6) M. The hearts were then washed out with K-H alone or with K-H containing Ab. During washout the effluent was collected at 30-sec intervals and the concentration of [3H] digoxin measured in each sample. Washout was continued until the positive inotropic effect of digoxin had returned to its previous level. The [3H] digoxin washout curves were analyzed on the basis of statistical criteria and yielded three exponential components. During Ab washout the half-times t1/2 of these components were 0-25 +/- 0.07, 1.70 +/- 0.28, and 19.5 +/- 6.9 min, while during K-H washout the values were 0.28 +/- 0.02, 1.49 +/- 0.22, and 11.8 +/- 2.7. The decay of the inotropic effect of digoxin was similar during both washout conditions. The results indicate that the apparent tissue to perfusate concentration gradient for the washout of [3H] digoxin was not increased by Ab...

Animals↗
PubMedDate not supplied

[Serum digoxin in children treated with beta methyl digoxin].

Concentrations of serum digoxin were measured by the polarized immunofluorescence Abbot TDx11 method in 59 samples from 53 children under treatment with mean beta methyl digoxin doses of 8.9 +/- 2.0 micrograms.kg.day. The therapeutic range for serum digoxin concentration was estimated to be 0.9 to 2.25 ng/ml. Simultaneous Na, K and creatine serum concentrations were measured. In 36 samples mean serum digoxin level was 1.52 +/- 0.45 ng/ml -within therapeutic range- and in only one of these cases clinical evidence of toxicity was apparent. In 15 samples digoxin level was above the therapeutic range and 11 patients of this group (73%) showed clinical signs of toxicity, consisting in arrythmias (six cases: supraventricular in 5 patients, ventricular in one child) and gastrointestinal symptoms (eight patients). Six patients with digoxin levels over therapeutic range and signs of digitalis toxicity had coincidental acute renal failure, which in 4 cases was subclinical--in 2 of these late it was pre-renal- and, in spite of this, all were inadvertently given the usual dosage of beta methyl digoxin. Almost invariably there was clinical evidence of toxicity when digoxin serum levels were above 2.4 ng/ml, so established maximal therapeutic level at 2.25 ng/ml seems adequate. Signs of digitalis toxicity must be looked on systematically in children treated with such drugs. In the critically ill or in children with acute renal failure it is necessary to monitor serum digoxin concentration. Among the clinical signs of toxicity, gastrointestinal symptoms are more frequent in children. An oral dose from 7 to 10 micrograms.kg.day of beta methyl digoxin in recommended.

Acute Kidney Injury↗
PubMedDate not supplied

A physician's office-based digoxin assay (Seralyzer) evaluated for interference by endogenous digoxin-like immunoreactive factors.

A digoxin test for a physician's office based-chemistry analyzer (Ames Seralyzer) was evaluated for possible interference by digoxin-like immunoreactive factors (DLIF). Sera from patients likely to have high concentrations of DLIF (renal and hepatic patients, pregnant women, and neonates) as well as from normal patients and umbilical cord blood were analysed by the Seralyzer digoxin immunoassay and by a fluorescence polarization digoxin immunoassay (Abbott TDx) known to detect DLIF. For all patients who were not taking digoxin (n = 85) only four patients (4.7 percent) measured apparent digoxin values greater than 0.2 ng per mL by the Seralyzer compared to 64 (75 percent) by the TDx analyzer. Measurements of DLIF from adrenal extracts demonstrated a 17-fold greater potency for detection of DLIF by the TDx (2.9 ng per mL) compared to the Seralyzer technique (0.18 ng per mL). However, recovery data suggest that the presence of digoxin reduces the potency of DLIF interference as a function of increasing digoxin concentrations especially for the TDx assay. This diminished DLIF crossreactivity in the presence of digoxin is one explanation for the comparable correlation observed for both non-renal and renal failure patients taking digoxin when measured by these two immunoassays.

Adrenal Glands↗
PubMed1977

Bioavailability of digoxin-hydroquinone complex: a new oral digoxin formulation.

A new oral digoxin formulation, a digoxin-hydroquinone complex (99% dissolution at 5 min), was evaluated in 12 healthy human volunteers with reference to bioavailability and extent and time of peak serum digoxin levels. This preparation was compared with a commercial digoxin tablet (26% dissolution at 5 min), digoxin elixir, and a parenteral digoxin solution. Bioavailability was assessed by the 24-hr area under the serum digoxin-time curve and 48-hr digoxin excretion in urine. The bioavailability of the complex was similar to that of the elixir but not statistically different from that of the tablet. The tablet was less bioavailable than the elixir. There was less interindividual variation in bioavailability with the complex than with the elixir. Peak serum digoxin levels were higher with the complex than the tablet and were achieved more quickly.

Administration, Oral↗
PubMed1998

Induction of digoxin-like material production, and the digoxin binding in the unicellular organism Tetrahymena by digitoxin.

Thin layer chromatographic, and laser-confocal microscopic analyses with a monoclonal antibody to digoxin also displaying high affinity to digoxigenin, were used to determine the presence and localization of cardioactive glycosides. Tetrahymena pyriformis was found to possess digitoxigenin-like material, but digoxin, digitoxin, digoxigenin, gitoxin and lanatoside C were not detected. Digitoxin treatment elicited the appearance of a digoxin-like material in the progeny generations. Digoxin was taken up by untreated Tetrahymena, especially strongly 24 h after digitoxin treatment. While the cardenolide was localized in vesicles of the cell body in untreated Tetrahymena, the engulfed digoxin appeared in the epiplasmic layer and also in the cilia after digitoxin pretreatment. Digoxin pretreatment did not increase digoxin uptake. These data indicate that Tetrahymena has: (1) the capacity to discriminate between closely related molecules; (2) the ability to induce digoxin-like material production; and/or (3) enzymes that can effect a digitoxin-digoxin transformation.

Animals↗
PubMed1982

The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects.

Single-dose investigations in healthy subjects have demonstrated substantial impairment of renal and extrarenal clearance of digoxin during coadministration of verapamil. A longitudinal study has been performed to assess the changes in digoxin disposition during long-term verapamil therapy. After one week of verapamil 240 mg/d mean plasma digoxin had risen from 0.21 +/- 0.01 ng/ml (SE) to 0.34 +/- 0.01 ng/ml(p less than 0.01), and renal digoxin clearance had fallen from 197.57 +/- 17.37 ml/min to 128.20 +/- 10.33 ml/min (p less than 0.001). These changes gradually subsided, and after six weeks, renal digoxin clearance had normalized and plasma digoxin had declined to 0.27 +/0 0.02 ng/ml (NS). The 24-h urinary recovery of digoxin increased from 46.46 +/- 3.23% before to 69.78 +/- 3.69% (p less than 0.001) after six weeks of verapamil co-administration, and this elevation persisted throughout the study. The verapamil-induced suppression of renal digoxin elimination disappears over a few weeks of drug exposure, whereas the inhibition of the extrarenal clearance of digoxin seems to persist.

Adult↗
PubMed1984

Quinidine-induced changes in serum and skeletal muscle digoxin concentration; evidence of saturable binding of digoxin to skeletal muscle.

Eleven patients with atrial fibrillation on maintenance digoxin therapy were investigated by analysis of serum (SDC) and skeletal muscle (SMDC) digoxin concentrations before and 24 h and 2 weeks after starting quinidine treatment. After cardioversion the maintenance dose of digoxin was reduced in order to obtain the same steady-state SDC after 2 weeks, as before quinidine. SDC was increased by quinidine therapy from 1.56 to 2.40 nmol/l after 24 h. With the reduced digoxin dose SDC was 1.68 nmol/l after 2 weeks. The ratio SMDC/SDC decreased after 24 h of quinidine treatment from 35.4 to 29.0 (p less than 0.01). After 2 weeks of quinidine treatment with the reduced digoxin dose, the ratio had risen to 38.1, which did not differ significantly from the initial ratio. The present data suggest that the reduced skeletal muscle binding of digoxin during quinidine therapy is due to saturation of digoxin binding sites secondary to the increase in the total body load of digoxin at steady-state, and not to direct interference by quinidine with digoxin binding sites.

Aged↗
PubMed1987

Comparative effects of nadolol-digoxin combination therapy and digoxin monotherapy for chronic atrial fibrillation.

In some patients with chronic atrial fibrillation, treatment with digitalis alone may fail to produce a satisfactory decrease in heart rate at rest or during exercise or emotional stress. Findings of a few clinical studies suggest that beta blockade in combination with digitalis therapy may be of benefit in these patients. In a randomized, double-blind, placebo-controlled, parallel-group, 8-week study of 32 patients with chronic atrial fibrillation, the effects of digoxin therapy alone were compared with a combination of digoxin and nadolol. Criteria for entry into the study included ventricular rate at rest greater than or equal to 80/min or greater than or equal to 120/min with exercise, and serum digoxin levels within the therapeutic range. After digoxin dose titration to produce therapeutic levels, digoxin dosage remained constant throughout the balance of the study. After a 2-week, single-blind placebo lead-in period, patients were randomized to receive either digoxin plus placebo or a combination of digoxin and nadolol. The dose of nadolol/placebo was titrated from 20 to 120 mg daily as tolerated. Twenty-four hour ambulatory electrocardiographic (Holter) recordings, symptom-limited exercise treadmill tests and serum digoxin and nadolol levels were obtained at the end of the single and double-blind treatment periods. Comparing endpoint with baseline, results from Holter recordings showed that patients treated with a combination of digoxin and nadolol had significant (p less than 0.001) decreases in 24 hour average (78 +/- 4 to 63 +/- 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗