Effect of physical exercise on the digoxin concentrations in skeletal muscle and serum in man

Summary. Seven healthy men performed an exercise on a bicycle ergometer during one hour after 2 weeks intake of digoxin and with the last dose taken 24 hours before the exercise. Blood samples and skeletal muscle biopsies (m. quadriceps femoris, vastus lateralis) were taken before and after the exercise for analysis of serum and skeletal muscle digoxin concentrations. A percutaneous needle biopsy technique was used for muscle sampling and digoxin was analysed by radioimmunoassay. One minute after completion of the exercise a significantly higher digoxin concentration was found in the thigh muscle than before exercise, indicating an increased digoxin binding in this muscle. Serum digoxin concentration decreased significantly during exercise. After exercise serum digoxin concentration increased again but was still, 30 min after exercise, significantly lower than before exercise.     

Effect of physical activity on the day-to-day variation in serum digoxin concentration

Summary. Physical exercise has been found to increase digoxin binding in working skeletal muscle along with a concomitant decrease in serum digoxin concentration. In a recent study on healthy volunteers, moderate physical activity during maintenance digoxin treatment was shown to decrease the renal excretion of digoxin secondary to this redistribution of the drug, thereby affecting the body content of digoxin. In the present study the influence of changes in everyday physical activities, carried out during a 10-h period after ingestion of the daily maintenance digoxin dose, on the steady-state serum digoxin concentration (24 h after the last dose) was studied in 10 digoxin-treated outpatients (61–81 years of age). Compared to normal daily activity, complete bed rest for 10 h after ingestion of the maintenance dose did not affect the steady-state serum digoxin concentration. The lack of such an influence may be explained either by a low degree of everyday physical activity in the investigated patients or to a compensatory increase in the renal excretion of digoxin during the night preceding the serum digoxin measurement. Thus, standardization of physical activity 1–2 h before blood sampling is adequate when analysing the serum digoxin concentration in elderly outpatients.     

PRESCRIBING DIGOXIN IN GERIATRIC UNITS–EXERCISE AND REDISTRIBUTION OF DRUG

In subjects capable of normal everyday activity, exercise has been shown to lower the serum digoxin concentration by increasing uptake into skeletal muscle. A randomized cross-over study of the effect on the serum digoxin concentration of treatments consisting of rest for, or exercise during, 30 min was carried out in 20 elderly patients undergoing rehabilitation. In one patient exercise was associated with a marked (40%) reduction in the serum digoxin concentration. In the remainder there was a very small, but statistically significant, fall in concentration in the exercise as compared with the rest period. Unexpectedly low serum digoxin concentrations in in-patients of geriatric units, may occasionally be an artefact due to temporary redistribution of digoxin.     

Binding of digoxin to slow- and fast-twitch skeletal muscle fibres

Summary. We have found previously great interindividual variations in the binding of digoxin to skeletal muscle even after standardized rest. The present study was performed in order to find out if there is a difference in the binding of digoxin to slow-and fast-twitch fibres in man at rest and after moderate exercise. Seven healthy digitalized subjects (digoxin 0·50 mg/day) were investigated after 90 min of supine rest and after a 1 h moderate bicycle exercise. Muscle biopsy specimens were taken immediately before and 5 min after exercise and dissected under a microscope to single fibres. After histochemical typing of all fibres the digoxin content in slow-and fast-twitch fibres was measured separately. At rest, digoxin binding to slow-twitch fibres was 33% higher than to fast-twitch fibres (P<0·01). During exercise the digoxin binding increased by 28% in slow-twitch fibres but was unchanged in fast-twitch fibres. The difference in digoxin binding to the two fibre types may explain, at least partly, the interindividual variations in the binding of digoxin to skeletal muscle.     

Validity of unbound digoxin measurements by immunoassays in presence of antidote (Digibind).

Measurement of unbound digoxin in presence of Fab fragments may be useful in management of overdoses. The analysis can be performed on serum directly or on ultrafiltrate of serum. The architecture of the immunoassay may influence the validity of results obtained using these two approaches. We tested this hypothesis by preparing serum mixtures containing various concentrations of digoxin and Digibind and analyzed them by the immunoassays before and after ultrafiltration. Four samples collected from Digibind-treated patients were also analyzed before and after ultrafiltration. The slopes and the y-intercepts of the measured versus the expected values for serum and its ultrafiltrate overlapped for the MEIA digoxin assay. For other three immunoassays tested (ACS:180, Stratus, and On-Line), either the slope or the intercept for measured versus the expected results for serum were significantly different (P < 0.05) than those for ultrafiltrate. Following addition of digoxin and Digibind, differences in results for serum analyzed directly or after ultrafiltration were < 0.50 ng/ml. Comparable samples from digoxin-overdosed patients treated with Digibind had differences of > 1.0 ng/ml. Previous claims reporting direct analysis of digoxin in presence of antidote but not having used patient samples for validation should be revisited. To date, analysis of serum ultrafiltrate by an immunoassay proven not to have matrix bias remains the most accurate approach in measuring unbound digoxin in presence of antidote.     

Application of two-point assay of digoxin serum concentration in studying population pharmacokinetics in Egyptian pediatric patients with heart failure: does it make sense?

Digoxin pharmacokinetics (PK) was studied among a selected group of Egyptian pediatric patients (n = 40) with an age range of 0.33 to 15 years. All the patients had heart failure and were maintained on i.v. digoxin (10 microg/kg/d in 2 equal doses). For population PK analysis, 2 serum samples of digoxin were taken per patient. From 30 patients' trough (before the next dose) and 4 hours postdose samples were obtained, while in the other 10 patients, 0.5- and 6-hour postdose samples were taken. Serum concentrations were measured by fluorescence polarization immunoassay. PK modeling was performed using NONMEM software on log-transformed serum digoxin data. The best structural covariate-free model was a linear 2-compartment model with an exponential error model for intersubject variability and an additive model for intrasubject variability. Serum creatinine (SCR) was a significant covariate for clearance. The final population PK parameters were CL (L/h) = 0.388 - [0.78 x (SCR-0.6)], V1 (L/kg) = 1.38, Q (L/h/kg) = 0.48, V2 (L/kg) = 9.11, where CL is the total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, and Q is intercompartment clearance. A bootstrap resampling for internal validation achieved excellent agreement with the original data sets for PK parameters. In conclusion, 2 points of digoxin concentration allow good regression analysis for clearance-covariate relationship. The inclusion of SCR into the final model might allow better selection of initial maintenance dose of the drug. A prospective study on larger sample size of pediatric patients is recommended for clinical validation of the final model.     

EFFECTS OF ORAL PRAZOSIN ON TOTAL PLASMA DIGOXIN LEVELS

Prazosin and digoxin are frequently coadministered in clinical practice. To determine the effects of oral prazosin treatment on steady-state digoxin levels, 20 patients receiving a constant maintenance dose of digoxin, who had normal renal and liver functions and were not receiving any other treatment, were given 5 mg of prazosin for 3 days. Plasma digoxin levels were measured before, on days 1 and 3 of prazosin treatment, and after prazosin had been discontinued. It was found that prazosin significantly increased plasma digoxin levels. On discontinuation of prazosin digoxin levels returned to their previous values.     

阿奇霉素对地高辛血药浓度的影响

目的 探讨阿奇霉素对地高辛血药浓度的影响.方法长期口服地高辛且血药浓度稳定在0.5～2.0 ng/mL的心力衰竭患者316例,其中158例纳入试验组(口服或静脉滴注阿奇霉素),余下158例纳入对照组(未接受阿奇霉素治疗);酶放大免疫法测定试验组使用阿奇霉素前后的外周血地高辛浓度,并与对照组进行比较.结果 试验组患者在使用阿奇霉素5 d后地高辛血药浓度由(1.1±0.5)ng/mL升高至(1.5±0.5)ng/mL(P<0.05),大于2.0 ng/mL者13例(占8.2%);老年(≥60岁)患者地高辛浓度增高尤其明显(P<0.01).试验组地高辛浓度为(1.5±0.5)ng/mL,高于对照组的(1.1±0.3)ng/mL(P<0.05).结论 阿奇霉素可导致地高辛血药浓度升高,尤其是老年患者;应避免同时使用阿奇霉素和地高辛,减少毒性反应.     

Endogenous digoxin-like immunoreactive factors eliminated from serum samples by hydrophobic silica-gel extraction and enzyme immunoassay

Elimination of endogenous digoxin-like immunoreactive factors (DLIF) that interfere with accurate measurement of digoxin requires use of a highly specific anti-digoxin antibody, or that DLIF be separated from digoxin before immunoassay. Several commercial digoxin-assay kits include a step for separating serum proteins and other substances from digoxin before immunoassay. We tested six different immunoassay methods (some having pretreatment steps) for their ability to detect DLIF in serum from patients in renal failure, pregnant women, and neonates, all of whom were not taking digoxin. Extracting digoxin on a column of derivatized silicagel eliminated detectable DLIF from serum as measured by enzyme immunoassay (EMIT; Syva Co.), but recovery of added digoxin was quantitative. In contrast, protein precipitation with 5-sulfosalicylic acid left significant amounts of DLIF in samples, most probably because the procedure (TDx assay; Abbott Labs.) disrupted protein-DLIF binding. A glass-bead radioimmunoassay (Immophase; Corning Medical) had the most digoxin-specific antisera. By preparative silica-gel-chromatography of serum we could eliminate or significantly minimize inaccurate digoxin measurements attributable to endogenous DLIF.     

Plasma catecholamines in Finnish sauna

Plasma catecholamines were measured by a modified single-isotope radioenzymic assay in five healthy medical students during and after a Finnish sauna bath with or without previous beta-blockade. The plasma noradrenaline rose more than twofold after 10 min in the hot room (100 degrees C) while the plasma adrenaline content exhibited smaller increases. The plasma noradrenaline concentration remained elevated or further increased after 5 min in a cool swimming pool (22 degrees C) whereas the exposure to cool water restored the plasma adrenaline concentration to resting values. Plasma noradrenaline, but not adrenaline, was still markedly elevated after a rest period of 15 min after the cool pool. Oxprenolol (40 mg) given 30 min before the sauna did not alter the plasma catecholamine pattern although it effectively lowered the heart rate before, during, and after the exposure to the heat stress.     

异丙酚对老年人腹腔镜手术患者血浆内皮素、降钙素基因相关肽含量的影响

目的研究异丙酚在老年人腹腔镜手术麻醉中对患者血浆内皮素（ET）和降钙素基因相关肽（CGRP）含量的影响。方法40例腹腔镜手术病人，年龄60-70岁，ASAⅠ、Ⅱ级，随机分两组，每组20例，P组为异丙酚组，C组为对照组，分别于麻醉前、气腹前、气腹后10min、气腹后20min和气腹后40min，抽取静脉血测定ET和CGRP值。结果麻醉前后两组患者ET和CGRP水平差异无显著性（P〉0．05）。气腹后10minP组ET水平开始下降，40min时显著低于C组和气腹前，而C组气腹后ET水平显著增高（P〈0．05）。P组CGRP水平40min时较气腹前显著增高（P〈0．05）。而C组CGRP水平气腹后20min开始下降，40min时显著低于P组（P〈0．05）。结论腹腔镜CO2气腹可致机体ET水平升高，异丙酚能够拮抗ET，并能提高体内CGRP水平。可减轻老年人在腹腔镜手术中的心血管应激反应。     

Analytical performance of a monoclonal digoxin assay by dry chemistry on the Vitros 950

Digoxin assay in plasma/serum samples is used for therapeutic measurements as a guide to clinical management of cardiac patients. A thin dry film multilayer monoclonal immunoassay for digoxin, Vitros, was evaluated for analytical performance. The effect of digoxin-like immunoreactive substances (DLIS) was studied assaying plasma samples taken from 100 renal disease patients, 62 hepatic disease patients and 40 pregnant women not receiving digoxin. The Vitros digoxin assay was compared with the AxSym digoxin II assay using plasma samples from 180 patients treated with digoxin. The results revealed satisfactory precision and accuracy for therapeutic drug monitoring purposes: the coefficient of variation (CV%) was lower than 5%; results for dilutions were linear in the range 0.4-3.9 microlg/L and mean analytical recovery was 105%. Measurable DLIS concentrations were observed in 29% of hepatic disease patients and in 7% of renal disease patients with apparent digoxin concentration ranging from 0.4 to 0.75 microg/L. The incidence of DLIS was comparable to that observed with AxSym digoxin II. Comparative results from patient samples gave a regression line equation: Yvitros 950=0.96XAxym +0.14, r=0.89. The data revealed a mean difference of 0.09+/-0.26 microg/L significantly greater than zero (p=0.02). We concluded that Vitros digoxin assay for precision, accuracy and extent of DLIS interference may be a good method for therapeutic drug monitoring; care needs to be taken since assay results generated by Vitros and AxSym analysers are not necessarily interchangeable.     

Endogenous digitalis-like factors in human milk.

We measured the concentration of endogenous digitalis-like factors (EDLFs) in milk or colostrum of women during nursing on different days after delivery. EDLF concentrations were assayed by a solid-phase RIA involving antidigoxin antibodies and by a radioreceptor assay (RRA) involving human placenta Na+/K(+)-ATPase. The mean (SD) EDLF concentrations as measured by RIA were 35.6 (19.4) ng of digoxin equivalents per liter in milk samples (n = 37) and 61.3 (12.5) ng/L in colostrum samples (n = 5); the mean EDLF concentration as measured by RRA in milk samples (n = 11) was 573 (717) ng/L (range 0-2098). EDLF concentration in milk is greater than circulating concentrations in healthy adults but is comparable with serum concentration in the third trimester of pregnancy. In milk and serum samples (n = 8) collected at the same time, heating and (or) extracting with Sep-Pak C18 cartridges before the RIA produced significantly different EDLF values from those in untreated serum (P less than 0.001) and milk (P = 0.035). EDLF in milk appeared to be not bound or weakly bound to milk protein, as indicated by the fact that boiling did not increase the digoxin-like immunoreactivity.     

Determination of digoxin in the blood of pregnant women, fetuses and neonates before and during anti-arrhythmic therapy, using four immunochemical methods

Four immunochemical methods for digoxin assay were used to analyse control samples, 33 amniotic fluid samples, 57 samples from digitalis-treated, non-pregnant women, 90 pregnancy serum samples, and 72 samples of fetal or neonatal serum with or without digoxin therapy. One hundred and five samples were also submitted to ultrafiltration before analysis. Three methods (RIA, TDX, AMERLITE) showed practically the same precision, while the precision of the DELFIA was markedly inferior. In the analysis of serum samples from digoxin-treated, non-pregnant women, RIA and TDX gave practically the same values, whereas AMERLITE and DELFIA gave significantly higher values. Pregnancy serum and fetal serum contain "digoxin-like immunoreactive factors", and the qualitative and quantitative effects of these interfering factors are different for each of the four methods. The greatest sensitivity to "digoxin-like immunoreactive factors" is shown by TDX and DELFIA, while the lowest interference by "digoxin-like immunoreactive factors" is found in the analysis of ultrafiltered samples, using the TDX method. The composition of the "digoxin-like immunoreactive factors" in pregnancy serum and in fetal serum is altered by digoxin therapy, and these changes have different effects on the various analytical methods. The concentration of "digoxin-like immunoreactive factors" in the serum of fetuses receiving digoxin is markedly lower than that of healthy fetuses. For the reliable monitoring of digoxin therapy in the maternal and fetal circulation, the blood samples must be submitted to ultrafiltration before analysis.     

Increase in serum digoxin concentration produced by quinidine does not increase the potential for digoxin-induced ventricular arrhythmias in dogs

Chronic treatment of dogs with digoxin alone, quinidine alone and digoxin in combination with quinidine was initiated in dogs to assess changes in arrhythmogenic potential associated with the quinidine-induced increase in serum digoxin concentration observed during combined digoxin and quinidine treatment. The arrhythmogenic potential of digoxin was evaluated through the use of the acetylstrophanthidin (AcS) tolerance test. AcS was infused at a rate of 5 micrograms/kg/min until ventricular arrhythmias occurred during a drug-free period and during chronic treatment with digoxin, quinidine and digoxin plus quinidine. The dose of AcS required to initiate ventricular arrhythmias is inversely related to the arrhythmogenic potential of digoxin present at the time of AcS infusion. Administration of quinidine alone in two different dosage regimens produced serum quinidine concentrations of 5.99 +/- 1.18 and 2.99 +/- 0.43 micrograms/ml and significantly increased AcS tolerance, whereas digoxin alone, over a wide range of serum digoxin concentrations, significantly decreased AcS tolerance. This decrease in AcS tolerance was linearly related to the serum digoxin concentration. The addition of quinidine treatment to animals receiving digoxin resulted in a significant elevation in the steady-state serum digoxin concentration. However, the AcS tolerance determined during the elevated serum digoxin concentration induced by quinidine was greater than that determined during treatment with the same dose of digoxin alone. Thus, quinidine administration to animals receiving digoxin resulted in a significant increase in the steady-state serum digoxin concentration but did not increase the arrhythmogenic potential of digoxin over that observed during treatment with the same dose of digoxin alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Digoxin intoxication: the relationship of clinical presentation to serum digoxin concentration

A radioimmunoassay for serum digoxin concentration has been used to study the interrelationships of circulating levels of the drug and various factors in the clinical setting in 48 hospitalized patients with cardiac rhythm disturbances due to digoxin intoxication. 131 patients on maintenance doses of digoxin without toxicity and 48 patients with equivocal evidence of digoxin excess were also studied and compared with the toxic group.Patients with cardiac rhythm disturbances due to digoxin intoxication tended to be older and to have diminished renal function compared with the nontoxic group; body weight, serum potassium concentration, underlying cardiac rhythm, and nature of cardiac disease were not significantly different for the groups as a whole. Despite comparable mean daily digoxin dosages, digoxin intoxicated patients had a mean serum digoxin concentration of 3.7 +/-1.0 (SD) ng/ml, while nontoxic patients had a mean level of 1.4 +/-0.7 ng/ml (P < 0.001), 90% of patients without evidence of toxicity had serum digoxin concentrations of 2.0 ng/ml or less, while 87% of the toxic group had levels above 2.0; the range of overlap between the two groups extended from 1.6 to 3.0 ng/ml. Patients with atrioventricular block as their principal toxic manifestation had a significantly lower mean serum digoxin concentration than those in whom ectopic impulse formation was the chief rhythm disturbance.Patients with equivocal evidence of digoxin excess had received comparable daily maintenance doses of digoxin but had a mean serum concentration of 1.9 +/-0.8 ng/ml, intermediate between those of the nontoxic (P < 0.005) and toxic (P < 0.001) groups. Renal function as judged by mean blood urea nitrogen concentration was also intermediate.The data indicate that knowledge of the serum digoxin concentration, weighed in the clinical context, is useful in the management of patients receiving this drug.     

Effect of protein concentration on the determination of digoxin in serum by fluorescence polarization immunoassay

Determination of digoxin by fluorescence polarization immunoassay (FPIA) with the Abbott "TDx" is significantly influenced by the concentration of total serum protein. Each 10 g/L increase in serum protein results in an 8% decrease in measured digoxin. Studies with [3H]digoxin confirmed that digoxin binds to the protein pellet during the trichloroacetic acid precipitation step before the immunoassay. Serum protein, or equal concentrations of albumin or gamma-globulin, exert an equivalent effect on the apparent digoxin value. Because the total protein concentration of the assay calibrators is low (50 g/L) compared with its reference interval in serum (60-80 g/L), results by FPIA may be expected to be low by an average of 16% (range, 8-24%). Digoxin results by FPIA will be most nearly accurate when the calibrators include a total protein concentration of about 70 g/L. Patients' specimens with abnormally high or low protein content will give falsely high or low results for digoxin.     

Relative efficacy of oral verapamil and digoxin alone and in combination for the treatment of patients with chronic atrial fibrillation

1. The efficacy of verapamil alone, or in combination with digoxin, was compared with digoxin alone in eight patients with chronic atrial fibrillation in this double-blind placebo-controlled study. 2. After 2 weeks on each treatment regimen, heart rate at rest and during progressive load treadmill exercise, left ventricular function at rest and nocturnal heart rate were measured. 3. Oral verapamil alone at a dose of 80 mg three times daily, or 40 mg of verapamil three times daily in combination with 0.25 mg of digoxin daily, was superior to digoxin alone in doses associated with high serum digoxin concentrations (mean +/- SEM 1.6 +/- 0.3 micrograms/l). This superiority manifested as greater control of heart rate during work rates equivalent to regular daily activities, and was not associated with deterioration in left ventricular function or worsening nocturnal bradycardia. 4. We conclude that the treatment of choice in patients with chronic atrial fibrillation is either 80 mg of verapamil three times daily or 40 mg of verapamil three times daily in combination with digoxin.     

Insulin in vivo increases the in vitro fall of plasma potassium concentration in human venous blood

Venous blood taken from fasting subjects at rest and incubated in vitro at room temperature for 120 min showed a mean fall in the plasma potassium concentration of 0.13 mmol l-1 (SEM 0.08, n = 6). Blood obtained 15 min after the intravenous administration of insulin (0.67 nmol kg-1 body weight) and incubated under the same conditions showed a significantly greater fall in the mean plasma potassium concentration of 0.33 mmol l-1 (SEM 0.09, P less than 0.05, n = 6). The addition of insulin (up to 33 nmol l-1) to blood taken from fasting subjects did not induce the phenomenon. The transfer of plasma from pre-insulin blood samples to blood cells obtained 15 min after insulin administration and vice versa indicated that the fall in plasma potassium concentration was a property of the 15 min post-insulin blood cells, presumably erythrocytes, rather than the plasma. The ouabain-suppressible component of 86Rb+ influx in erythrocytes obtained 15 min after the administration of insulin was virtually doubled compared to erythrocytes obtained before insulin suggesting increased activity of the sodium pump of erythrocytes.     

A unitized enzyme-labeled immunometric digoxin assay suitable for rapid testing

An enzyme-labeled immunometric assay has been developed for measuring digoxin concentrations in serum or plasma. Unitized, compartmentalized reagents are used with an automated sample-processing instrument. The enzyme activity of the processed sample, which is directly proportional to the digoxin concentration, is measured by using a reagent strip and the Ames Seralyzer reflectance photometer. The test takes less than 15 min, and digoxin concentrations are calculated from a two-point calibration line stored in the instrument. Within-run CVs for controls at four concentrations ranged from 2.3% to 3.8%; between-run CVs were from 1.5% to 2.6%. Results obtained with clinical serum samples correlated well (r greater than 0.96) with those obtained by fluorescent polarization immunoassay (Abbott TDx) and RIA (Clinical Assays and NML). This rapid and convenient method for monitoring digoxin concentrations in serum or plasma is particularly well suited for decentralized sites such as emergency rooms, urgent-care centers, and physicians' offices.