digoxin and Body-Weight

This article reviews some of the important determinants of variation in drug disposition such as age, gender, body weight, diet, environmental influences, drug - protein interactions, compliance, drug - drug interactions, endogenous substances, disease states, circadian variation and genetics.

Topics: Adult; Aged; Aging; Body Weight; Circadian Rhythm; Digoxin; Drug Interactions; Female; Genetic Variation; Humans; Life Style; Male; Patient Compliance; Pharmaceutical Preparations; Protein Binding; Sex Factors

Topics: Age Factors; Aged; Blood Pressure; Blood Proteins; Body Weight; Coronary Disease; Digoxin; Electrolytes; Female; Heart Diseases; Heart Rate; Humans; Kidney Function Tests; Male; Middle Aged

Topics: Age Factors; Aged; Anesthesia; Body Weight; Creatinine; Critical Care; Digitalis Glycosides; Digitoxin; Digoxin; Humans; Surgical Procedures, Operative; Time Factors

The use of digitalis in pulmonary heart disease has been a topic of great interest for a number of years. The physician's decision to use or not to use digitalis in pulmonary disease has often been an emotional rather than a reasoned one. The diagnostic difficulties from a clinical point of view in separation of pulmonary from cardiac symptoms and findings have also been confusing. The fact that small doses of digitalis may have an inotropic effect on the cardiac muscle has been a difficult concept for many physicians to adopt. On the other hand, the larger doses of digitalis that are often necessary to control the ventricular response in supraventricular arrhythmias sometimes gives rise to confusion. We shall attempt to review the subject in detail and examine indications, contraindications, toxicity, dosage, assessment of benefit, and role of digitalis serum levels in patient management.

Topics: Arrhythmias, Cardiac; Body Weight; Digitalis Glycosides; Digoxin; Humans; Pulmonary Heart Disease

Topics: Animals; Body Weight; Digitalis Glycosides; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Liver Diseases; Myocardial Contraction; Protein Binding; Structure-Activity Relationship; Thyroid Diseases; Tissue Distribution

Topics: Arrhythmias, Cardiac; Body Weight; Cardiac Glycosides; Digitoxin; Digoxin; Humans; Intestinal Absorption; Methods; Strophanthins

Topics: Administration, Oral; Adult; Arrhythmias, Cardiac; Body Weight; Digoxin; Dose-Response Relationship, Drug; Humans; Kidney; Male; Thyroid Diseases

Topics: Administration, Oral; Age Factors; Attitude to Health; Biological Availability; Body Weight; Digitalis Glycosides; Digoxin; Drug Tolerance; Feedback; Half-Life; Humans; Intestinal Absorption; Kidney; Kinetics; Liver; Quality Control; Tablets; Thyroid Diseases; Time Factors

Fourteen obese patients (body mass index = 34-47 kg/m2; mean = 40 kg/m2) with lumbar cerebrospinal fluid pressure (Pcsf) above 20 cm water in 10 of the 14 patients were treated with digoxin with a serum concentration of at least 1.0 nmol/L (0.8 ng/ml) for 6 months. Pcsf decreased significantly during digoxin medication (p < 0.005). Although there were no diet restrictions, all patients decreased in weight (range: 3-25 kg; mean = 10.6 kg) during the 6 months (p < 0.001). When digoxin medication was stopped in 3 patients, prompt weight increase occurred. Most patients needed progressively increased digoxin doses to attain stabilized serum concentrations at the stipulated level, in 5 patients more than 0.5 mg a day. Five of 13 patients developed diabetes mellitus during the digoxin medication. The larger the dose of digoxin, the greater the risk for diabetes mellitus to occur.

Topics: Adult; Body Mass Index; Body Weight; Cerebrospinal Fluid Pressure; Diabetes Mellitus; Digoxin; Female; Humans; Intracranial Hypertension; Middle Aged; Obesity, Morbid; Time Factors; Treatment Outcome; Weight Loss

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.

Topics: Adult; Aged; Aged, 80 and over; Aging; Anti-Arrhythmia Agents; Body Weight; Calcium Channel Blockers; Computer Simulation; Creatinine; Digoxin; Drug Combinations; Drug Interactions; Female; Humans; Male; Middle Aged; Models, Biological; Quinidine; Regression Analysis; Verapamil

The purpose of this study was to determine whether digoxin is effective in patients with chronic, stable mild to moderate heart failure.. Digoxin has been a traditional therapy in heart failure, but methodologic limitations in earlier studies have prevented definitive conclusions regarding its efficacy.. Withdrawal of digoxin (placebo group, n = 46) or its continuation (digoxin group, n = 42) was performed in a prospective, randomized, double-blind, placebo-controlled multicenter trial of patients with chronic, stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and digoxin.. Patients withdrawn from digoxin therapy showed worsened maximal exercise capacity (median change in exercise time -96 s) compared with that of patients who continued to receive digoxin (change in exercise time +4.5 s) (p = 0.003). Patients withdrawn from digoxin therapy showed an increased incidence of treatment failures (p = 0.039) (39%, digoxin withdrawal group vs. 19%, digoxin maintenance group) and a decreased time to treatment failure (p = 0.037). In addition, patients who continued to receive digoxin had a lower body weight (p = 0.044) and heart rate (p = 0.003) and a higher left ventricular ejection fraction (p = 0.016).. These data provide strong evidence of the clinical efficacy of digoxin in patients with normal sinus rhythm and mild to moderate chronic heart failure secondary to systolic dysfunction who are treated with diuretics.

Topics: Body Weight; Chronic Disease; Digoxin; Diuretics; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Exercise Test; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Stroke Volume; Substance Withdrawal Syndrome; Time Factors; Treatment Failure; Ventricular Function, Left

The effect of spironolactone on cardiac contractility indices was studied by externally recording systolic time intervals in four digitalized and four non-digitalized patients with ischaemic heart disease. A negative inotropic effect was found after spironolactone 100mg b.i.d. in all eight patients, as measured by an increase in pre-ejection period index PEPI (p less than 0.01), and the ratio between pre-ejection period and left ventricular ejection time PEP/LVET (p less than 0.001), while pre- and afterload remained constant. As expected, digoxin exerted a positive inotropic effect, as a decrease was observed in PEPI (p less than 0.01), and PEP/LVET (p less than 0.001). It was not possible to ascertain whether the observed effect was caused by a pharmacological interaction at receptor level between spironolactone and digoxin, or indirectly to changes in endogenous substances e.g. aldosterone. The results suggest that spironolactone may have unintended side effects in patients with severe heart failure and that its use be reevaluated.

Topics: Aged; Blood Pressure; Body Weight; Coronary Disease; Depression, Chemical; Digoxin; Drug Interactions; Humans; Middle Aged; Myocardial Contraction; Potassium; Spironolactone; Systole

Topics: Adult; Aged; Body Weight; Clinical Trials as Topic; Digoxin; Female; Humans; Male; Middle Aged

Topics: Administration, Oral; Age Factors; Aged; Body Weight; Creatinine; Digoxin; Electrocardiography; Female; Heart Block; Heart Diseases; Humans; Kidney; Male; Middle Aged; Radioimmunoassay; Sex Factors

Topics: Adult; Aged; Body Height; Body Weight; Computers; Digoxin; Electrocardiography; Female; Heart Failure; Humans; Kidney Function Tests; Male; Middle Aged; Prospective Studies

Intravenous digoxin loading dose recommendations differ between clinical guidelines and Food and Drug Administration packaging for acute rate control.. The objective of this study was to assess the safety and efficacy of intravenous digoxin loading in patients who received ≤12 µg/kg and >12 µg/kg of digoxin using ideal body weight (IBW).. This single center retrospective cohort study with exempt status from the local Institutional Review Board included patients who received intravenous digoxin and had a serum digoxin concentration (SDC) drawn. Digoxin doses >36 hours after the first dose were excluded. Patients who received a total of >12 µg/kg and ≤12 µg/kg IBW were compared. The primary endpoint was frequency of SDCs ≥1.2 ng/mL, which have been shown to be associated with increased mortality.. A total of 244 patients were included (144 receiving >12 µg/kg and 100 receiving ≤12 µg/kg). There were significantly more SDC ≥1.2 ng/mL in the >12 µg/kg group than the ≤12 µg/kg group (50.6% vs. 30.0%; adjusted odds ratio, 3.19; 95% confidence interval [CI]: 1.79-5.84), with no difference in rate control failure. Major limitations of the study include retrospective nature and possible selection bias.. Compared to patients who received digoxin doses ≤12 µg/kg IBW, patients who received >12 µg/kg IBW had higher rates of SDC ≥1.2 ng/mL. This suggests that appropriate weight-based dosing with 8 to 12 µg/kg IBW has the potential to be a safer approach to digoxin loading, rather than frequently used dosing strategies that result in doses >12 µg/kg.

Topics: Body Weight; Digoxin; Humans; Ideal Body Weight; Retrospective Studies

We describe the case of a patient on continuous venovenous hemodiafiltration with atrial fibrillation with rapid ventricular response and hypotension requiring vasopressor use, which warranted digoxin therapy. In the absence of guidelines specifying appropriate digoxin dosing in patients undergoing continuous venovenous hemodiafiltration, anecdotal evidence-guided digoxin dosing was performed for this patient using plasma digoxin concentration-based therapeutic drug monitoring. We use this case to demonstrate the potential role of physiologically based pharmacokinetic modeling in assisting therapeutic decision making.

Topics: Aged; Atrial Fibrillation; Body Weight; Cardiotonic Agents; Continuous Renal Replacement Therapy; Digoxin; Drug Dosage Calculations; Drug Monitoring; Hemodiafiltration; Humans; Hypotension; Kidney Function Tests; Male; Models, Biological; Point-of-Care Systems; Renal Insufficiency

A population pharmacokinetic/pharmacodynamic model of digoxin in adult subjects was originally developed by Reuning et al in 1973. They clearly described the 2-compartment behavior of digoxin, the lack of correlation of effect with serum concentrations, and the close correlation of the observed inotropic effect of digoxin with the calculated amount of drug present in the peripheral nonserum compartment. Their model seemed most attractive for clinical use. However, to make it more applicable for maximally precise dosage, its model parameter values (means and SD's) were converted into discrete model parameter distributions using a computer program developed especially for this purpose using the method of maximum entropy. In this way, the parameter distributions became discrete rather than continuous, suitable for use in developing maximally precise digoxin dosage regimens, individualized to an adult patient's age, gender, body weight, and renal function, to achieve desired specific target goals either in the central (serum) compartment or in the peripheral (effect) compartment using the method of multiple model dosage design. Some illustrative clinical applications of this model are presented and discussed. This model with a peripheral compartment reflecting clinical effect has contributed significantly to an improved understanding of the clinical behavior of digoxin in patients than is possible with models having only a single compartment, and to the improved management of digoxin therapy for more than 20 years.

Topics: Age Factors; Body Weight; Cardiotonic Agents; Computer Simulation; Creatinine; Digoxin; Dose-Response Relationship, Drug; Humans; Models, Biological; Sex Factors

To obtain more information regarding the influence of various covariates on the disposition of digoxin in Chinese neonates and infants, routine clinical pharmacokinetic data were retrospectively collected from 131 hospitalized patients. A nonlinear mixed effects modeling (NONMEM) method was applied to the data. A one-compartment/first-order absorption model was employed to estimate the influence of total body weight (allometric power model), postnatal age, serum creatinine, gender, presence of heart congestive failure, and concomitant medications on apparent total clearance and apparent drug distribution of digoxin. Pharmacokinetic parameter estimates for CL/F and V/F were 0.147 L∙h(-1)∙kg(-1) and 15.7 L/kg, respectively. Total body weight and postnatal age were identified as the important factors affecting total clearance of digoxin; total body weight was the covariate identified to influence the apparent distribution volume. Both internal (bootstrap method, visual predictive checks, and normalized prediction distributed error) and external validation supported the stable and predictive performance of the final model. We concluded that the model can be used to choose an appropriate dose regimen in Chinese neonates and infants.

Topics: Age Factors; Asian People; Body Weight; Cardiotonic Agents; Creatinine; Digoxin; Female; Heart Failure; Humans; Infant; Infant, Newborn; Male; Models, Biological; Predictive Value of Tests; Retrospective Studies

From a search of the available literature, a database of 22 drugs of all charge types and several different therapeutic classes was compiled to compare rat and human biliary clearance data. Dog biliary excretion data were also found for nine of the drugs. For 19 of the 22 drugs (86%), rat unbound biliary clearance values, when normalized for body weight, exceeded those for humans by factors ranging from 9 to over 2500-fold, whereas human/dog differences were much less dramatic. It was possible to define hepatic uptake and efflux transporter involvement for many of the drugs. On the basis of the findings, it is postulated that regardless of the biliary efflux transporters implicated, when drugs do not require active hepatic uptake to access the liver there may be fairly insignificant differences in rat, dog, and human biliary clearance. Conversely, when the organic anion-transporting polypeptide drug transporters are involved, one may expect at least a 10-fold discrepancy in rat to human biliary clearance normalized for body weight and corrected for plasma protein binding.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bile; Body Weight; Dogs; Drug Administration Routes; Humans; Liver; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Organic Anion Transporters; Pharmaceutical Preparations; Protein Binding; Rats; Species Specificity

This study was designed to clarify the influence of long-term enteral nutrition (EN) on the pharmacokinetics of digoxin. Rats were fed EN diets (semi-digested, digested, and elemental) for 4 weeks, then digoxin (0.05 mg/kg) was administered orally. The AUC(0-∞) and k(a) of digoxin were significantly reduced in the semi-digested diet group versus the control, while the AUC(0-∞) was significantly increased in the digested and elemental diet groups. The mRNA level of Slco1a4 was significantly reduced at the upper small intestine in all EN groups. Further, the expression levels of P-glycoprotein (P-gp) protein and Abcb1a mRNA were increased at the same site in all EN groups, and the increases were significant in the elemental diet group. Cyp3a2 protein and mRNA expressions were significantly reduced in the liver in the digested and elemental diet groups. Abcb1a mRNA was also significantly reduced in the kidney in these groups. These results indicate that the absorption kinetics at the small intestine is influenced by semi-digested diet, and the elimination kinetics in the liver and kidney are influenced by digested and elemental diet. Semi-digested diet also altered digoxin pharmacokinetics in humans. Thus, the effect of long-term EN on digoxin pharmacokinetics depended on the dietary components.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Body Weight; Cardiotonic Agents; Cytochrome P-450 CYP3A; Digoxin; Enteral Nutrition; Male; Membrane Proteins; Organ Size; Rats; Rats, Sprague-Dawley

The purpose of this study is to investigate the regulation of P-glycoprotein expression in the kidney under diabetic condition. Renal P-glycoprotein expression was examined in inbred mice with type 1 or type 2 diabetes by Western blotting. The underlying mechanisms of P-glycoprotein regulation were examined in Madin-Darby canine kidney type II (MDCK-II) cells by Western blotting or qRT-PCR. (3)H-digoxin uptake was measured for P-glycoprotein activity in cells under various treatments. The results showed that P-glycoprotein expression was lower in kidneys of diabetic mice than in controls. In MDCK-II cells, treatments with insulin or IL-6 did not cause any change in P-glycoprotein expression, whereas TNF-α tended to increase P-glycoprotein expression at a concentration of 1 ng/ml. On the other hand, P-glycoprotein expression was reduced under high glucose conditions (450 mg/dl), while superoxide production was increased, and the reduction in P-glycoprotein expression was abolished by N-acetylcysteine (an antioxidant) and staurosporine (a nonselective PKC inhibitor). Treatment with oxidizing agents (H(2)O(2), BSO) or PMA (a PKC activator) reduced P-glycoprotein expression. Antioxidant (N-acetylcysteine or glutathione) co-treatment abolished the H(2)O(2)-induced and BSO-induced reduction in P-glycoprotein expression, whereas it did not prevent the effect of PMA. The PMA-induced P-glycoprotein down-regulation was prevented by co-treatment of LY333531 (a PKC-β inhibitor). (3)H-digoxin levels were higher in MDCK-II cells with high glucose, PMA or H(2)O(2) treatments. In conclusion, P-glycoprotein expression is lower in kidneys of diabetic mice and in MDCK-II cells under high glucose conditions. Hyperglycemia induced reactive oxygen species and activated PKC in MDCK-II cells, leading to the decrease in P-glycoprotein expression.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood Glucose; Body Weight; Cell Membrane; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Digoxin; Dogs; Down-Regulation; Female; Hyperglycemia; Insulin; Interleukin-6; Kidney; Madin Darby Canine Kidney Cells; Male; Mice; Protein Kinase C; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Topics: Aged; Anti-Arrhythmia Agents; Body Weight; Digoxin; Drug Interactions; Drug Monitoring; Electrocardiography; Emergency Nursing; Emergency Treatment; Female; Heart Arrest; Heart Block; Humans; Immunoglobulin Fab Fragments; Medical History Taking; Nursing Assessment; Practice Guidelines as Topic

To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data.. The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (nonmem), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated.. Estimates generated by nonmem indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)0.645 x Conc (ng/mL)(-0.724) x GA (weeks)0.8. The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%.. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.

Topics: Body Weight; Cardiotonic Agents; Digoxin; Dose-Response Relationship, Drug; Drug Monitoring; Female; Gestational Age; Humans; Infant, Newborn; Japan; Male; Models, Biological; Nonlinear Dynamics; Retrospective Studies; Software

To determine whether a sex-based difference in digoxin pharmacokinetics exists in patients receiving long-term digoxin therapy for chronic heart failure or atrial fibrillation.. Single-center, retrospective review of medical records.. University-based teaching hospital and outpatient clinic.. Sixty-seven adults (32 men, 35 women) with chronic heart failure or atrial fibrillation who were receiving digoxin therapy.. Serum digoxin concentrations and daily digoxin doses were obtained from patients' medical records. Daily doses were adjusted for patients' actual and ideal body weight and body mass index (BMI). The ratio between the serum digoxin concentration and each of the adjusted daily doses of digoxin was compared between men and women. The mean +/- SD serum digoxin concentration was 0.85 +/- 0.51 ng/ml for men compared with 1.02 +/- 0.51 ng/ml for women. Mean +/- SD unadjusted doses of digoxin were 0.180 +/- 0.063 and 0.164 +/- 0.059 mg/day for men and women, respectively; the difference was not statistically significant. Ratios of serum digoxin concentration to daily digoxin doses did not differ by sex when doses were estimated with actual or ideal weight. Only the ratio of the digoxin concentration to the BMI-adjusted dose was significantly different between men and women (0.14 +/- 0.09 and 0.19 +/- 0.11, respectively, p<0.05).. Sex-based differences in digoxin pharmacokinetics were absent when actual or ideal body weight was used. However, the ratio of serum digoxin concentration to daily digoxin dose adjusted for BMI differed by sex. Because digoxin is distributed to lean body mass, use of the BMI could have overadjusted body weight, leading to inaccurate pharmacokinetic assumptions and calculations. The pharmacokinetics of digoxin do not appear to differ by sex.

Topics: Aged; Atrial Fibrillation; Body Mass Index; Body Weight; Cardiotonic Agents; Digoxin; Female; Heart Failure; Humans; Male; Middle Aged; Retrospective Studies; Sex Characteristics

Digoxin is eliminated mainly by the kidney through glomerular filtration and P-glycoprotein (P-gp) mediated tubular secretion. Toddlers and young children require higher doses of digoxin per kilogram of bodyweight than adults, although the reasons for this have not been elucidated. We hypothesized there is an age-dependant increase in P-gp expression in young children. The objectives of this study were to elucidate age-dependant expression of renal P-gp and its correlation with changes in the clearance rate of digoxin. FVB mice were killed at different ages to prepare total RNA for P-gp expression studies. Semi-quantitative RT-PCR was conducted to analyze mdr1a and mdr1b ontogeny in the kidney at: birth, 7, 14, 21, 28 and 45-d old adults. The pharmacokinetics of digoxin (7 microg/kg) was studied in mice of the same age groups. Newborn and Day 7 levels of both mdr1a and mdr1b were marginal. Day 21 mdr1b levels were significantly higher than both Day 14 and Day 28 levels. Digoxin clearance rates were the highest at Day 21, with significant correlation between P-gp expression and clearance values. Increases in digoxin clearance rates after weaning may be attributed, at least in part, to similar increases in P-gp expression.

Topics: Age Factors; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; ATP-Binding Cassette Transporters; Body Weight; Digoxin; Kidney; Metabolic Clearance Rate; Mice; Organ Size; RNA, Messenger

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating s

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Digoxin; Dihydropyridines; Enalapril; Heart; Hypertension; Losartan; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nifedipine; Organ Size; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium-Potassium-Exchanging ATPase; Tunica Media

Information about the pharmacokinetics of digoxin in paediatric patients is limited. We therefore aimed to investigate the effects of physiological factors on the digoxin clearance in Japanese paediatric patients.. We used routinely collected therapeutic drug monitoring data (n=544), derived from the steady-state serum concentrations of digoxin in 181 hospitalized paediatric patients.. Of those physiological factors which have been examined in this study, age and total body weight were most closely correlated with digoxin clearance. Data on neonates within the first postnatal month indicated a tendency towards lower clearance for premature neonates than full-term neonates (P<0.01). Digoxin clearance was reduced by spironolactone in patients younger than 4 months (P<0.05). Patients with congestive heart failure showed a lower digoxin clearance than the others (P<0.001). Serum creatinine and gender did not have a statistically significant effect on digoxin clearance.. Age and total body weight are important factors influencing digoxin clearance in children. Spironolactone affected digoxin clearance and needs to be considered when dosing paediatric subjects.

Topics: Age Factors; Body Weight; Cardiotonic Agents; Child; Child, Preschool; Digoxin; Drug Interactions; Female; Heart Failure; Humans; Infant; Infant, Newborn; Male; Sex Factors; Spironolactone

A change in the functioning of the liver as a result of experimental cholestasis could result in a change in the biotransformation of drugs. The aim of this study was to evaluate the effect of extrahepatic cholestasis on the pharmacokinetics of digoxin. The investigation was performed on male rabbits randomly divided into two groups: sham-operated and animals with bile-duct ligation. Digoxin (0.02 mg kg-1) was administered intragastrically as a single dose. Biomedical and anatomo-pathological tests and pharmacokinetic assays were performed before the operation and on the 6th day after surgery. A significant increase in area under the serum concentration-time curve and in mean residence time, a decrease in total body clearance, a reduction in the volume of distribution and increases in maximum concentration and the time to reach maximum concentration were observed in animals with the bile-duct ligation. These results suggest reduced elimination of digoxin in animals with obstructive cholestasis.

Topics: Administration, Oral; Animals; Body Weight; Cardiotonic Agents; Cholestasis, Extrahepatic; Digoxin; Male; Metabolic Clearance Rate; Rabbits

The effects of simultaneous active immunization against two cardiac glycoside drugs, digoxin and proscillaridin, have been examined in young spontaneously hypertensive and Wistar-Kyoto rats. Control animals were immunized with protein carrier only. Animals were studied from 5 weeks to 13 weeks of age. Effectiveness of immunization to produce antibody responses was assessed at the end of the study by estimating the titer of antibodies in plasma against both of the antigens. Robust antibody responses were obtained. Immunization had no effect on the normal growth of these animals. Further, immunization against cardiac glycosides did not change blood pressure in either strain of animals. Blood pressure in the SHR increased as anticipated as the weanling animals grew to maturity. These studies indicate that active immunization against cardiac glycosides does not alter blood pressure in the SHR in spite of strong evidence for increased levels of endogenous cardiac glycosides in this strain.

Topics: Animals; Antibodies; Blood Pressure; Body Weight; Digoxin; Hypertension; Proscillaridin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vaccination

Plasma digitalis-like substance and altered function of arterial Na+,K(+)-ATPase have both been linked with elevated blood pressure, but the influence of antihypertensive therapy on these factors remains unknown. Therefore, we treated spontaneously hypertensive rats and normotensive Wistar-Kyoto rats with the angiotensin-converting enzyme inhibitor quinapril for 10 weeks. The therapy markedly reduced blood pressure and plasma digoxin immunoreactivity, and it normalized the elevated plasma Na+:K+ ratio in the hypertensive animals. Relaxations of endothelium-denuded denervated arterial rings induced by return of potassium to the organ bath upon precontractions elicited by potassium-free solution were used to evaluate the function of vascular Na+,K(+)-ATPase. The rate of potassium relaxation was faster in quinapril-treated hypertensive rats and in both Wistar-Kyoto groups than in the hypertensive controls. Potassium relaxation was also effectively inhibited by the Na+,K(+)-ATPase inhibitor ouabain in all groups. In addition, arterial contractions to potassium chloride and relaxations to nitroprusside were examined. The contractions to lower concentrations of potassium chloride (20 mM) were enhanced in untreated hypertensive rats when compared with the other groups, although the maximal responses were corresponding in all groups. The time to reach base-line tension after washout of potassium chloride (125 mM) and the relaxations to nitroprusside did not differ in the study groups. In conclusion, the present results showed that long-term angiotensin-converting enzyme inhibition in parallel reduced plasma digoxin-like factor, enhanced arterial potassium relaxation (probably reflecting enhanced function of Na+,K(+)-ATPase) and normalized plasma Na+:K+ ratio in this type of genetic hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Digoxin; Heart; Immunoassay; Isoquinolines; Male; Organ Size; Potassium; Quinapril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Sodium-Potassium-Exchanging ATPase; Tetrahydroisoquinolines; Vasodilator Agents

To clarify the role of brain ouabain-like compound in reduced renal mass-saline hypertension, we examined the effects of intracerebroventricular infusion of the Fab fragments of antidigoxin antibody (Digibind) on the change in blood pressure of saline-drinking subtotally nephrectomized rats. Twenty male Wistar rats weighing 250 g each underwent subtotal nephrectomy. Two groups of 10 rats received intracerebroventricular infusion of Digibind (20 mg/ml) or normal sheep IgG (20 mg/ml) at a rate of 0.5 microliters/h for 11 days. All rats began to drink 1% NaCl solution after two days of infusion. Systolic blood pressure was measured by the tail-cuff method on days 2, 6 and 9 of infusion. Two groups of saline-drinking rats with reduced renal mass developed hypertension. However, systolic blood pressure was significantly higher in Digibind-infused rats than in IgG-infused rats (day 2, 144 +/- 3(SEM) vs. 133 +/- 1 mmHg, p < 0.05; day 6, 161 +/- 4 vs. 151 +/- 2 mmHg, 0.05 < p < 0.1, day 9, 181 +/- 8 vs. 155 +/- 2 mmHg, p < 0.05). In spite of similar renal dysfunction, plasma aldosterone concentrations, and plasma OLC levels, the accelerated increase in blood pressure was accompanied by a significantly impaired pressure-natriuresis relationship (0.089 +/- 0.013 vs. 0.131 +/- 0.013 mmol/day/mmHg, p < 0.05). These results indicate that chronic intracerebroventricular infusion of Digibind augmented reduced renal mass-saline hypertension in rats and suggest that brain ouabain-like compound may play a protective role against the elevation of blood pressure, at least in this model of hypertension.

Topics: Animals; Blood Pressure; Body Weight; Digoxin; Hypertension, Renal; Immunoglobulin Fab Fragments; Injections, Intraventricular; Male; Nephrectomy; Rats; Rats, Wistar; Sodium

The pathophysiological role of renal natriuretic depressor systems and endogenous digitalis like factor (EDLF) on blood pressure (BP) elevation was studied in reduced renal mass rats (RRM) with saline loading for a model of volume dependent hypertension. Fifty-four male Sprague-Dawley rats were operated on to remove varying proportions of their kidney mass (5/6 RRM, n = 13; 4/6 RRM, n = 16; 3/6 RRM, n = 12) or sham operated (control, n = 13). They were given 1% saline to drink for 4 weeks. BP was elevated significantly at the 1st week in 5/6 RRM and continued to increase until the 4th week, but this was not seen in the other 3 groups. Urine volume (UV) and urinary sodium excretion (UNaV) increased after saline loading in all groups. Urinary kallikrein excretion was significantly lower in order of the 5/6, 4/6 and 3/6 RRM at the basal state and after saline loading. A significant negative correlation was observed between urinary kallikrein and BP. Urinary PGE2 was increased in each RRM in order of the 5/6, 4/6 and 3/6 RRM groups. A significant positive correlation was observed between urinary PGE2 and BP, UV or UNaV. The basal urinary DA excretion was significantly lower in 3 RRMs than in the control. After saline drinking, urinary DA increased in 3 RRMs, while differences disappeared in the control and RRMs. Urinary EDLF increased immediately after the initiation of saline loading in all groups, except the control group, and returned to the basal level 2 weeks later in 3/6 and 4/6 RRM. Only in 5/6 RRM, the urinary EDLF remained higher than the basal level.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Blood Proteins; Body Weight; Cardenolides; Digoxin; Dinoprostone; Dopamine; Hypertension, Renal; Kallikreins; Kidney; Male; Natriuresis; Rats; Rats, Sprague-Dawley; Saponins; Sodium; Urodynamics

To assess the possible contribution of brain ouabain-like activity (OLA) to the pressor effects of high-sodium intake in Dahl salt-sensitive (Dahl S) rats, we assessed the effects of high (8%) on blood pressure (BP) and peripheral and brain OLA in Dahl on blood pressure (BP) and peripheral and brain OLA in Dahl S and Dahl salt-resistant (Dahl R) rats. On regular sodium intake, Dahl S and R had similar BP; however, by 7 wk of age adrenal and plasma OLA were 15-30% higher in Dahl S vs. R, whereas central OLA remained similar. On high-sodium intake, in Dahl S both peripheral and central OLA increased within 1 wk with additional increases after 3 wk. These increases preceded the rise in BP. In Dahl R rats, high sodium did not increase BP. However, 3 wk of high sodium did increase peripheral as well as central OLA, the latter to a lesser extent compared with Dahl S and not in the hypothalamus. These results are consistent with the concept that central OLA may be involved in the pressor responses to high sodium in Dahl S. Circulating OLA may play a role in the regulation of renal function to excrete excess sodium in both strains.

Topics: Adrenal Glands; Animals; Biological Factors; Blood Pressure; Body Weight; Brain; Cardenolides; Digoxin; Heart Rate; Hypothalamus; Kidney; Male; Pituitary Gland; Pons; Rats; Rats, Inbred Strains; Saponins; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary; Species Specificity; Time Factors

Adrenocorticotrophin (ACTH) administration raises blood pressure in humans, sheep, and the rat. ACTH hypertension can be reproduced in sheep by combined infusion of aldosterone, 17 alpha-OH-progesterone, and 17 alpha,20 alpha-OH-progesterone, and in humans by cortisol. In the rat, ACTH hypertension is probably due to corticosterone. Progesterone treatment can prevent ACTH-induced hypertension in sheep. This study examined the ability of progesterone to antagonize the onset and development of ACTH-induced hypertension in Sprague-Dawley rats (n = 44). We also investigated the relationship of plasma digoxin-like substances (DLS) to ACTH hypertension. ACTH (0.5 mg/kg/day) significantly increased blood pressure (+24 +/- 5 mm Hg, P < .001) in association with an increase of water intake, urine output, and plasma sodium concentration, and a decrease of body weight and plasma potassium concentration. ACTH increased plasma DLS (+132 +/- 18 pg/mL, P < .01), and there was a positive correlation between DLS and blood pressure (r = 0.68, n = 22, P < .001). Progesterone (50 mg/kg/day) did not block the development of ACTH-induced hypertension in the rat. Although progesterone prevented the ACTH-induced rise in plasma sodium and glucose concentration, it did not prevent the decrease in plasma potassium concentration. The failure of progesterone to prevent ACTH-induced hypertension in the rat argues against a common "hypertensinogenic" mechanism for ACTH hypertension in sheep and rat. DLS may play a role in ACTH-induced hypertension in the rat.

Topics: Adrenocorticotropic Hormone; Animals; Blood Glucose; Blood Pressure; Body Weight; Digoxin; Drinking; Hypertension; Male; Organ Size; Potassium; Progesterone; Rats; Rats, Sprague-Dawley; Sodium

A volume-sensitive inhibitor of [Na,K]ATPase, termed the digitalis-like factor (DLF), is postulated to participate in hypertension. To test this hypothesis, end-stage renal failure patients on peritoneal dialysis were placed on a clinical protocol that brought about a gradual, sustained volume expansion. This was accompanied by significant increases in body weight (4.1 +/- 1.2 kg, p < 0.05), mean arterial pressure (18.2 +/- 6.4 mm Hg, p < 0.05), and serum DLF activity (4.7 +/- 1.9% inhibition, p < 0.05). Processing these patients' daily dialysates by ultrafiltration and high-performance liquid chromatography allowed for the identification of a single elution fraction having volume-sensitive [Na,K]ATPase inhibitory activity. This factor in turn was correlated with serum DLF activity (R = 0.60, p = 0.002), weight gain (R = 0.67, p = 0.0003), and mean arterial pressure (R = 0.59, p = 0.003). This factor was readily distinguished from ouabain and digoxin but was similar to the DLF isolated from amniotic fluid. These results suggest that volume expansion in renal failure patients on peritoneal dialysis gives rise to a unique volume-sensitive DLF that may contribute to these patients' increase in blood pressure.

Topics: Blood Pressure; Blood Proteins; Blood Volume; Body Weight; Cardenolides; Chromatography, High Pressure Liquid; Clinical Protocols; Digoxin; Hemodialysis Solutions; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase

The relationship between the digoxin elimination parameter (A%) and creatinine clearance (CLCr) was determined, from blood level data of 160 hospital patients receiving digoxin tablets. The linear regression equation obtained, which varied only slightly from that reported by Jelliffee previously, was used to predict serum digoxin concentrations in 140 patients of four age groups (50-60, 60-70, 70-80 and 80-90 years). The predictions made were found to be less biased and more precise, irrespective of the age of the patients, than those produced using another predictive method known as Dobbs method. However, correlation coefficients of predicted versus measured serum digoxin concentrations for each method did not differ significantly and frequency distribution analyses of prediction errors gave poor results (up to 63% only). Therefore, neither method can be considered to be superior to the other nor can they be said to ensure accurate predictions of serum digoxin concentrations.

Topics: Aged; Aged, 80 and over; Aging; Body Composition; Body Height; Body Surface Area; Body Weight; Creatinine; Digoxin; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Models, Biological

To determine whether digoxin protects the myocardium during the initial phases of hypertension and diabetes combined, adult male Wistar rats with two-kidney, one-clip renal hypertension and streptozotocin-induced diabetes mellitus were treated with digoxin (500 micrograms.kg-1.day-1) by gavage for 10 wk immediately after the onset of hypertension and diabetes. Systemic arterial blood pressures, ventricular pressures, the first time derivative of left ventricular pressure, diastolic wall stress, and the quantitative analysis of the number and distribution of myocardial lesions and capillary density of the myocardium were measured. In comparison to untreated hypertensive-diabetic animals, digoxin-treated rats showed a lesser elevation in left ventricular end-diastolic pressure and diastolic and systolic wall stress despite comparable degrees of hypertension and blood glucose levels. In addition, chamber diameter was smaller and the diffusion distance for oxygen was within normal values in animals treated with this glycoside. However, the numerical density of the foci of replacement fibrosis was similar to that found in untreated hypertensive-diabetic animals. In conclusion, digoxin reduces the magnitude of ventricular remodeling and diastolic wall stress in this model of hypertension and diabetes.

Topics: Animals; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Digoxin; Heart Rate; Hypertension, Renal; Male; Mathematics; Models, Cardiovascular; Myocardial Contraction; Myocardium; Rats; Rats, Inbred Strains; Reference Values; Ventricular Function, Left

Coenzyme Q10 (10 mg/kg/day) or digoxin (2 micrograms/kg/day) was given orally to cardiomyopathic hamsters (BIO 14.6) for 8 weeks from 12 weeks of age. The left ventricular weight per gram of body weight (mg/g) was lower (p less than 0.01) in the coenzyme Q10 group (3.09 +/- 0.13) than in the digoxin (3.32 +/- 0.20) and control (3.44 +/- 0.14) groups. Left ventricular function was evaluated in isovolumically beating hearts. Left ventricular developed pressure (63 +/- 5 vs. 54 +/- 10 mmHg, p less than 0.05), -dP/dt (1385 +/- 100 vs. 1211 +/- 136 mmHg/sec, p less than 0.05), and -dP/dt (1068 +/- 126 vs. 896 +/- 141 mmHg/sec, p less than 0.05) were greater in the coenzyme Q10 than in the control group. The time constant of left ventricular relaxation was shorter in the coenzyme Q10 group than in the control group (25 +/- 3 vs. 28 +/- 3 msec, p less than 0.05). By contrast, in the digoxin group, the indices of left ventricular function did not differ from the control group. These results suggest that coenzyme Q10, but not digoxin, attenuated disease progression and preserved left ventricular function in cardiomyopathic hamsters.

Topics: Animals; Body Weight; Cardiac Volume; Cardiomyopathies; Cricetinae; Digoxin; In Vitro Techniques; Mesocricetus; Myocardial Contraction; Ubiquinone; Ventricular Function, Left

Urinary immunoreactive endogenous digitalis-like substance (EDLS) excretion was studied in gradually reduced renal mass rats (RRM). Urinary EDLS increased immediately after the start of 1% NaCl ingestion, then it returned to the basal level 2 weeks later. Both urinary sodium excretion and urinary EDLS were significantly higher in 3/6 and 4/6 RRM than in control until 2 weeks after starting 1% NaCl. However, there was no difference in blood pressure between the groups. Transient EDLS increase may play an important role in maintaining sodium and water homeostasis, but its transient increase apparently does not contribute to blood pressure elevation.

Topics: Animals; Blood Pressure; Blood Proteins; Body Weight; Cardenolides; Digoxin; Male; Nephrectomy; Organ Size; Rats; Rats, Inbred Strains; Saponins; Sodium Chloride; Time Factors

The influence of digoxin on the autonomic nervous system was studied in rats by examining its effects on the levels of acetylcholine (Ach), a parasympathetic marker, and norepinephrine (NE), a sympathetic marker, in the rat myocardium. Ach and NE were measured by high performance liquid chromatography with electrochemical detection (HPLC-ECD). Digoxin was injected subcutaneously every day for 4 weeks. The administration of 0.35, 0.75, and 2.5 mg/kg of digoxin reduced Ach concentrations in the right atrium to about 80-90% of the control value. However, there was no change in the activity of choline acetyltransferase (ChAT) or acetylcholinesterase (AchE), or in the concentration of choline (Ch). Injection of 0.1 mg/kg of digoxin had no significant effect on Ach concentration. When 0.75 and 2.5 mg/kg of digoxin were injected, there was a significant increase in NE concentration in the right atrium. Neither 0.1 nor 0.35 mg/kg caused any changes. Digoxin (0.75 and 2.5 mg/kg) increased heart rate to about 110% of the control values. Thus, high doses of digoxin increase the NE concentration but decrease the Ach concentration in the rat heart, and these changes might be related to functional changes in the autonomic nervous system.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Body Weight; Choline; Choline O-Acetyltransferase; Digoxin; Heart; Heart Rate; Male; Myocardium; Norepinephrine; Rats; Rats, Inbred Strains; Time Factors

Digoxin was administered to dogs (n = 10) in congestive heart failure, at an oral dosage rate of 0.01 mg kg-1 lean body mass twice daily. Lean body mass was determined by reducing gross mass by the estimated degree of ascites and body fat. The dose was further adjusted for factors such as renal and hepatic function, the bioavailability of different formulations, and the size of the patient. Trough and peak serum digoxin concentrations were determined after 10 days of digitalisation, or when signs of toxicity became apparent. Serum digoxin concentrations in 6 of the 10 dogs were found to be partially or completely in the toxic or subtherapeutic range. This indicates that an oral digoxin dosage rate of 0.01 mg kg-1 lean body mass administered twice daily, even when adjusted appropriately for factors that affect digoxin pharmacokinetics, provides no more than a rough approximation of the precise dose required to provide serum digoxin concentrations within the therapeutic range. The observations also lend support to a recent recommendation that the digoxin dosage rate should be based on body surface area, although even when administered on this basis, serum digoxin concentrations outside of the therapeutic range could be anticipated.

Topics: Animals; Body Surface Area; Body Weight; Digoxin; Dog Diseases; Dogs; Female; Heart Failure; Male

We measured the concentration of endogenous digoxin-like materials (EDLM) in the serum of spontaneously hypertensive rats (SHR) and three normotensive rat strains at four stages during growth using a sensitive RIA. In the SHR, there was a significant peak in the EDLM level between 0.057-0.087 ngE/mL at 6 to 8 weeks of age, shortly after the onset of hypertension. The EDLM concentration returned to normal levels by 20 weeks of age. Sprague-Dawley and Wistar-Kyoto rats had EDLM levels below 0.050 ngE/mL at all time points studied. In contrast, Fischer 344 rats displayed persistently elevated serum EDLM concentrations that exceeded 0.124 ngE/mL from 3 to 20 weeks of life. We conclude that (1) there are significant interstrain differences in serum EDLM levels in rats; and (2) the SHR has a unique peak in serum EDLM levels at 6 to 8 weeks of age, indicating a possible role for the substance in the inception of hypertension.

Topics: Age Factors; Animals; Blood Proteins; Body Weight; Cardenolides; Digoxin; Hypertension; Rats; Rats, Inbred F344; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Saponins

Topics: Aged; Body Weight; Digoxin; Female; Humans; Immunoglobulin Fab Fragments; Poisoning

Little is known about how different types of physicians use laboratory procedures in the management of outpatients with congestive heart failure. We therefore analyzed data from a national survey of randomly selected general practitioners, internists, and cardiologists to assess their management of outpatients with New York Heart Association class II congestive heart failure. Most of the 2704 respondents (90%) scheduled office visits between two and four months apart. Body weight, serum electrolytes, and chest roentgenograms were followed regularly by 98% or more of respondents, at median intervals of one to two months, three to five months, and 12 to 17 months, respectively. Serum digoxin levels in patients taking digoxin were followed by 90% of respondents at a median interval of 12 months. Echocardiography, radionuclide ventriculography, and exercise testing were used by fewer respondents (81%, 61%, and 61%, respectively), each at a median interval of 18 months or longer. Cardiologists were significantly more likely to follow patients using either echocardiography, radionuclide ventriculography, or exercise testing. The estimated yearly cost of following a class II congestive heart failure outpatient varied nearly fourfold from the lowest quartile of physicians ($303) to the highest ($1167). Cardiologists were disproportionately represented among the high-cost users. In addition, physicians who were younger or who practiced in an urban setting were significantly more likely to be high-cost users. Thus, simple laboratory tests were used most frequently to follow patients with heart failure, but differences in use of more expensive tests led to large differences in cost. Test use for similar patients is affected by characteristics of both the physician and practice setting.

Topics: Ambulatory Care; Body Weight; Clinical Laboratory Techniques; Digoxin; Electrocardiography; Electrolytes; Exercise Test; Heart Failure; Humans; Radiography

To investigate what effects a circulating digoxin-like factor (DLF) might have on sodium metabolism, we examined data collected on 1,327 individuals screened in the Cardiovascular Genetics Clinic at the University of Utah. This sample included 639 unmedicated adults, 582 youths under age 18, and 106 medicated hypertensive individuals, all on an unrestricted diet when attending clinic. No individuals look digitalis. A digoxin assay detected measurable levels of plasma DLF in 13.4% of the youths, 17.2% of the normotensive adults, and 25.5% of the hypertensive adults. In all three groups of individuals, those with a measurable DLF had a significantly lower erythrocyte ouabain sensitive sodium efflux rate constant (adjusted for age, sex and body mass) than those with no measurable DLF (p less than 0.01). Normotensive and hypertensive adults with measurable DLF also had an increased erythrocyte intracellular sodium level. Either the number of ouabain binding sites and/or the apparent affinity for ouabain were reduced for those with DLF levels in all three groups. There was a small nonsignificant increase in blood pressure for the normotensive adults and youths with a measurable DLF. We conclude that plasma DLF is associated with reduced ouabain sensitive sodium transport and increased intracellular sodium concentration, possibly due to changes in the number of or the competition for the Na+ - K+ ATPase sites.

Topics: Adult; Aging; Blood Pressure; Blood Proteins; Body Weight; Cardenolides; Child; Digoxin; Erythrocytes; Female; Humans; Hypertension; Male; Ouabain; Protein Binding; Radioimmunoassay; Saponins; Sodium

Problems in studying pharmacokinetic interactions with digoxin were evaluated using as a test model the examination of a possible interaction between digoxin and ethmozine in a group of 11 patients with cardiac disease. A single-blind, placebo-controlled, nonrandomized protocol design was used. Considerable intrapatient variability in day-to-day serum digoxin levels was documented that could not be accounted for by laboratory variability in digoxin assay measurements (mean coefficient of variation 10.1%) or alterations in blood urea nitrogen (BUN), serum creatinine, or body weight during the course of the study. No consistent, statistically significant alteration of mean serum digoxin levels occurred when the baseline, placebo, and ethmozine phases were compared, although the study design would have permitted detection of a 0.29-ng/ml alteration in mean serum digoxin levels. A discussion of the sources of variability in digoxin levels is provided.

Topics: Aged; Blood Urea Nitrogen; Body Weight; Cardiac Glycosides; Creatinine; Digoxin; Drug Interactions; Female; Humans; Male; Middle Aged; Moricizine; Osmolar Concentration; Phenothiazines; Radioimmunoassay

This study analyzes age, weight, and drug doses using cimetidine hydrochloride, flurazepam hydrochloride, and digoxin as tracers. Data were obtained for 1797 patients (mean age, 72 years) filling consecutive prescriptions from a national pharmacy service. With all three drugs, patients with lower weight received substantially higher doses with correlations of weight vs dose, based on milligrams per kilogram of body weight, ranging from -0.34 to -0.40. Because body weight declines with increasing age, lower-weight patients are also older and at greatest risk for drug toxicity. Patients weighing 50 kg or less (n = 155) received milligram-per-kilogram doses that were 31% to 46% higher than the group mean and 70% to 88% higher than patients weighing more than 90 kg. For all three study drugs, as patient weight declines, the mean milligram-per-kilogram dose rose sharply. There was no trend seen toward reducing doses for older patients. Low body weight, in addition to advanced age, is a major risk factor for overmedication. Physicians must recognize the need to reduce drug doses for their low-weight elderly patients.

Topics: Adult; Age Factors; Aged; Body Weight; Cimetidine; Digoxin; Drug Prescriptions; Flurazepam; Humans; Medication Errors; Middle Aged

In 1063 patients (greater than or equal to 60 years, 531 men, 532 women) the plasma concentration during digitalis maintenance therapy (metildigoxin, n = 356, beta-acetyldigoxin, n = 359, and digitoxin, n = 348) was determined and related to sex, age, body weight, serum potassium, renal function and the prescribed daily maintenance dose. Classification of treatment groups according to renal function (Crea less than or equal to 1.3 mg/dl parallel greater than 1.3 mg/dl) did not show any difference of the mean maintenance doses. In multiple linear regression analyses only a weak relationship between plasma digitalis concentration and the studied variables was found, which could be equally attributed to dose, creatinine and serum potassium in the digoxin derivative groups, whereas for digitoxin only body weight had a significant effect on the plasma concentration. During a maintenance dose of 0.07 or 0.1 mg/die which was given to 87% of patients in the digitoxin group, 70% were found to have plasma levels within the therapeutic range.

Topics: Acetyldigoxins; Aged; Body Weight; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Heart Failure; Humans; Kidney Function Tests; Medigoxin

A retrospective study of two groups of patients with a different plasma digoxin level (Group A: digoxin greater than or equal to 2 ng/ml, n = 32, Group B: digoxin less than 2 ng/ml, n = 34; total n = 66) showed a significantly lower creatinine clearance (p less than 0.05) in group A. This group also showed a weak correlation between the digoxin level and the length of observation (R = + 0.31, p less than 0.05, n = 29). Furthermore, a weak correlation between digoxin level and the ratio of average daily dosage to creatinine clearance was found for the total sample (R = + 0.30, p less than 0.05, n = 66). Patients treated for less than 7 days and with a higher digoxin level also had a higher dosage and worse renal function (p = 0.05, p = 0.01, respectively). A weak correlation also existed between the digoxin level and creatinine clearance and body weight for the whole sample (R = -0.29, p less than 0.05; R = -0.29, p less than 0.01, respectively; n = 66). The latter correlation was also found within each group. Apart from renal function, the medication taken and body weight seem to be useful variables in predicting impending elevation of the digoxin level. In this study these variables were found to be better suited for the said purpose than the ECG. These conclusions remain to be confirmed by means of a prospective study.

Topics: Acetyldigoxins; Age Factors; Arrhythmias, Cardiac; Body Weight; Creatinine; Digoxin; Dosage Forms; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Humans; Kidney Function Tests; Male; Medigoxin; Risk

A total of 36 plasma quinidine concentrations from nine hospitalized pediatric patients with cardiac arrhythmias were examined retrospectively to determine factors significantly affecting quinidine dosing. Each plasma quinidine concentration was obtained after at least 24 h of inpatient therapy. Doses of quinidine base varied from 7.7 to 45.6 mg/kg/day and from 179 to 921 mg/m2/day. Six of the eight children who responded to quinidine achieved normal sinus rhythm with plasma concentrations less than 2.0 micrograms/ml. Stepwise multilinear regression analysis demonstrated that the plasma concentration was significantly affected by the quinidine dose and by the time after the dose that the plasma was obtained, but not by the age of the patient. Patient population estimates were then derived to predict the quinidine dosage necessary to achieve given plasma concentrations. The group of patients receiving digoxin concurrently were predicted to obtain higher plasma quinidine levels on smaller doses and a shorter quinidine elimination half-life compared with those patients not on digoxin. While currently recommended quinidine doses by body weight are frequently insufficient, recommended quinidine doses by body surface area are excessive. Children require larger quinidine doses on a body weight basis and respond to a wide range of plasma quinidine concentration. Patient population estimates provide useful information on dosing of infrequently prescribed drugs in children.

Topics: Adolescent; Arrhythmias, Cardiac; Body Surface Area; Body Weight; Child; Child, Preschool; Digoxin; Humans; Infant; Infant, Newborn; Quinidine; Regression Analysis; Retrospective Studies

To define the relationship between digoxin dose and plasma concentration and the changes in body growth, 1181 plasma digoxin levels were measured in 644 infants and children receiving maintenance digoxin therapy. The drug was given intravenously to 166 patients and orally to 478. A significant linear correlation between dose and plasma concentration was observed (r 0.346 to 0.767 in the intravenous and 0.264 to 0.664 in the oral groups). Dosage differences explained 7% to 60% of the variability in digoxin plasma concentrations in various age and weight groups. The linear regression slope was greater in younger age groups, especially preterm infants weighing less than 1500 gm, and tended to decrease with age. The data (1) allow an approximate prediction of plasma concentrations of digoxin and their variability associated with changes in dosages in various pediatric age and weight groups, (2) permit an estimate of other pharmacokinetic determinants of digoxin plasma concentration and their changes with age, and (3) suggest that larger changes in digoxin doses in older children are necessary to achieve the same change in serum concentration that is achieved with smaller dose changes in the young infant. As a result, premature infants are more sensitive to and require smaller digoxin doses.

Topics: Age Factors; Body Weight; Child; Child, Preschool; Digoxin; Drug Administration Schedule; Humans; Infant; Infant, Newborn; Infant, Premature; Kinetics; Radioimmunoassay; Reagent Kits, Diagnostic

Topics: Age Factors; Aged; Body Weight; Creatinine; Digoxin; Female; Humans; Male; Middle Aged; Sex Factors

Topics: Age Factors; Aged; Body Weight; Cardiomyopathy, Dilated; Creatinine; Digoxin; Female; Heart Failure; Humans; Male; Middle Aged; Models, Biological

A study was conducted to clarify the reliability of serum digoxin concentration (SDC) predictions in the absence of concurrent quinidine administration. The effects of age, sex, congestive heart failure (CHF), and the method used to estimate creatinine clearance were investigated. Data were collected from patients who were representative of those seen in clinical practice. Patients admitted to the study were required to have not received quinidine, to have stable renal function, to have been taking digoxin for ten consecutive days--the same dose and route of administration, and to have been categorized as having or not having CHF at the time of the SDC determination. There were 44 patients who qualified for admission to the study. SDCs were predicted on the basis of four methods for estimating creatinine clearance and four methods for estimating serum concentrations. After simple linear regression analysis, one method was found to have correlation coefficients ranging from 0.72 to 0.79, regardless of the method used to estimate creatinine clearance. In addition, analysis determined that age and presence of CHF were not factors affecting the reliability of predicted SDCs. Female patients had, on the average, a greater difference between measured and predicted SDCs; however, this was not statistically significant. Thus, in the absence of concurrent quinidine administration, SDCs may be estimated as long as the limitations of the method are acknowledged. Age, CHF, and the common methods used to estimate creatinine clearance do not significantly affect the reliability of predicted SDC values.

Topics: Adult; Aged; Aging; Body Height; Body Weight; Digoxin; Female; Heart Failure; Humans; Male; Middle Aged; Sex Factors

After obtaining samples at open heart surgery, serum and right atrial digoxin concentrations were measured in 25 children by a nonspecific, direct radioimmunoassay method (NS) and by a specific method in which digoxin was separated from its metabolites by HPLC before radioimmunoassay was applied to the digoxin fraction (S). Digoxin was detectable by S assay (sensitivity 0.1 ng/g) in 16 heart specimens and 22 serum samples. The mean and range of the S/NS ratio was 0.74 (0.23 to 2.63) for serum and 0.81 (0.068 to 1.38) for atrial tissue. By NS assay the mean and range of the atrial/serum ratio was 78.1 (2.4 to 340, n = 21) and by S assay the corresponding values were 100 (10.7 to 318, n = 15). A multiple linear regression indicated that 72.5% of the variance of the heart digoxin concentrations measured by S assay were accounted for by the variables height, body weight, daily digoxin dose before operation, plasma digoxin concentration by S assay, and BUN.

Topics: Adolescent; Analysis of Variance; Blood Urea Nitrogen; Body Height; Body Weight; Cardiac Surgical Procedures; Child; Child, Preschool; Chromatography, High Pressure Liquid; Digoxin; Female; Heart Atria; Humans; Infant; Male; Myocardium; Premedication; Radioimmunoassay

Topics: Body Weight; Digoxin; Humans; Obesity

Serial serum digoxin concentrations were measured over a 10-day period in 15 low birth weight infants requiring digoxin therapy. The calculated total body digoxin clearance (TBDC) was found to be highly dependent on gestational age and body weight, with dose-normalized, steady-state digoxin concentrations inversely related to the same factors. Because of the decreased TBDC in low birth weight infants, our data support the recent recommendations in the literature to reduce maintenance doses of digoxin in these infants. Our study has further demonstrated that the reduction should be proportional to both gestational age and body weight.

Topics: Birth Weight; Body Weight; Digoxin; Female; Heart Failure; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Male

This work undertakes, in a second part, the clinical exploration of 947 serum digoxin levels of 281 hospitalized patients on a cardiology ward. Our results, which coincide with those of other researchers, have led us to draw certain practical conclusions: the posology is determined first of all according to kidney function, weight and age of the patient. When the treatment is insufficient or, on the other hand, poorly tolerated, a serum digoxin level is performed permitting thus: 1) in the case of ineffective treatment: to be sure of the patient's cooperation, to increase the posology if the serum digoxin level is not in the toxic zone, to discover an eventual pharmacokinetic problem; 2) to establish the responsibility of digitalis (when there are signs of intolerance or of intoxication), in case of arrhythmia, in patients with pacemakers, when associated drugs are capable of causing similar adverse effects; 3) to better manage a digitalis treatment in a high risk patient (unstable renal function, advanced myocardial disease, chronic obstructive disease).

Topics: Age Factors; Aged; Body Weight; Digoxin; Female; Heart Diseases; Humans; Male; Middle Aged; Radioimmunoassay

To explore a possible interaction between digoxin and verapamil, a single-dose kinetic study of digoxin was performed and then repeated after 10 days of verapamil treatment in eight healthy subjects. Verapamil diminished the apparent central distribution volume of digoxin from 0.83 +/- 0.25 to 0.64 +2- 0.17 l/kg (P less than 0.05) and reduced total body clearance of digoxin from 3.28 +/- 0.58 to 2.15 +/- 0.66 ml/min/kg (P less than 0.001) by impairing both renal and extrarenal clearance. Biological digoxin half-life rose from 38.6 +/- 8.5 to 50.5 +/- 8.3 hr (P less than 0.005). Reduction of renal clearance of digoxin may be due to inhibition of tubular secretion. The underlying mechanisms of extrarenal interaction are not known, but impaired hepatic degradation of digoxin induced by verapamil should be considered.

Topics: Adult; Body Weight; Digoxin; Drug Interactions; Female; Half-Life; Humans; Kidney; Kinetics; Male; Middle Aged; Verapamil

Digoxin pharmacokinetics were studied in 16 obese (mean +/- SD weight, 100.2 +/- 36.8 kg) and 13 control (64.6 +/- 10.5 kg) subjects. All subjects had normal renal function and no other coexisting disease. After administration of 0.75 mg digoxin by intravenous infusion, multiple plasma samples obtained over the 96 hours following infusion were analyzed for digoxin concentration by radioimmunoassay. Pharmacokinetic parameters were determined by weighted iterative nonlinear least squares regression analysis. Elimination half-life (t 1/2) was not different between obese and control groups (35.6 +/- 10.5 vs 41.2 +/- 16.7 hours). Absolute volume of distribution (Vd) also was not different (981 +/- 301 vs 937 +/- 397 liters), nor was total clearance of digoxin (328 +/- 82 vs 278 +/- 87 ml/min). Elimination t 1/2 was significantly negatively correlated with clearance among all subjects (r = -0.46; p less than 0.01). Using percent ideal body weight (IBW) as a measure of obesity, no correlation was found between percent IBW and Vd (r = 0.03). Thus digoxin is similarly distributed into IBW in obese and normal weight subjects, and there is no significant distribution of digoxin into excess body weight over IBV. In addition, there is no difference in total metabolic clearance or elimination half-life between obese and control subjects. Digoxin loading and maintenance dosage should be calculated on the basis of IBW, which reflects lean body mass, rather than TBW, which reflects adipose tissue weight in addition to lean body mass.

Topics: Adult; Body Weight; Digoxin; Female; Half-Life; Humans; Kinetics; Male; Obesity; Regression Analysis

Topics: Body Weight; Digoxin; Diuretics; Heart Failure; Hemodynamics; Humans

Topics: Body Weight; Digoxin; Drug Interactions; Glomerular Filtration Rate; Humans

In 125 patients with hypertension in the clinical degree of severity II despite normal concentrations of creatinine and potassium in the serum at the age of more than 65 years significantly higher digoxin serum concentrations of 2.36 +/- 1.19 nmol/l (= 1.84 +/- 0.93 ng/ml) and intoxications than in younger patients with 1.45 +/- 0.55 nmol/l (= 1.13 +/- 0.43 ng/ml) were found. After discussion of the results of other investigators comes the recommendation in patients at an older age (beginning with about 65 years) and in renal insufficiency to apply digitoxin instead of digoxin, taking into consideration the mean maintenance dose of 0.1 mg/die.

Topics: Adult; Age Factors; Aged; Body Weight; Creatinine; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Potassium

Previous dosing schedules for digoxin in renal failure have considered the decrease in the elimination rate constant but not the decrease in the volume of distribution. A dosing schedule based on the creatinine clearance, body weight and volume of distribution has been developed from pharmacokinetic data taken from the literature. Its validity was tested in a clinical study of 35 patients with chronic renal insufficiency not requiring dialysis. The dosing schedule resulted in correct digitalization expressed as a steady state plasma digoxin concentration in the therapeutic range (0.5-2.0 ng/ml) in 25 out of 27 patients (93%). However, of 82 possible candidates for the study, it could not be performed in 47 (57%). The high drop-out rate was mainly due to the complicated dosing schedule and to the difficulty of repeatedly measuring creatinine clearance on a routine basis. Therefore, safe dosing of digoxin in renal insufficiency does not seem to be feasible in practice. Digitoxin may be a better alternative.

Topics: Adult; Aged; Body Weight; Creatinine; Digoxin; Female; Humans; Kidney Failure, Chronic; Kinetics; Male; Middle Aged

Polybrominated biphenyls (PBBs) stimulate hepatic drug metabolism in adult and developing rats. The purpose of this investigation was to determine the influence of PBBs on the development of the liver as an organ for chemical excretion. Exposure of developing rats to polybrominated biphenyls (PBBs) by feeding 50 ppm of PBBs to pregnant or lactating mothers and rat weanlings did not produce overt toxicity when compared to controls over a 49-day postnatal period. However, prenatal and postnatal dietary exposure to PBBs resulted in elevated liver weight. In 15-day-old rats, increased liver weight after PBBs was correlated with enhanced ouabain transport from plasma into bile. Liver weight was also elevated in 21-, 35- and 49-day-old rats treated with PBBs, but this effect was not associated with stimulation of ouabain transport in these animals. Stimulation of ouabain transport after PBBs in 15-day-old rats was associated with increased hepatic uptake of ouabain. Stimulation in 15-day-old rats and not older rats may be attributed to the relative importance of uptake for ouabain transport in 15-day-old rats.

Topics: Aging; Animals; Animals, Newborn; Biphenyl Compounds; Body Weight; Carbon Tetrachloride; Digoxin; Female; Liver; Organ Size; Ouabain; Polybrominated Biphenyls; Pregnancy; Rats

The relationship between different maintenance doses and the steady-state digoxin blood concentration was studied in 160 patients with heart failure. All patients received digoxin tablets of the same brand (Digacin). The bioavailability of this brand is 82% compared with an i.v. standard. During the treatment with daily doses of 0.2 mg and 0.3 mg average serum digoxin levels of 1.09 +/- 0.45 ng/ml and 1.33 +/- 0.53 ng/ml were measured in patients with normal renal function. The daily dose of 0.4 mg digoxin was in correlation to an average serum level of 1.75 +/- 0.81 ng/ml. 81% and 86% of all patients with normal renal function taking 0.2 or 0.3 mg digoxin every day were found to have levels in the range of 0.7 to 2.0 ng/ml. The influence of sex, age, height, body weight, maintenance dose, serum creatinine and serum potassium on the variance of the digoxin plasma levels was computed by multiple linear regression. The multiple correlation coefficient was r = 0.666, the coefficient of determination (100 r2) being 44.4%. Therefore 44.4% of the total variance could be explained by these variables. Individual variables accounted for the following percentages of the total variance: serum creatinine 29.1%; maintenance dose 14.5%; age 4.3%; and reciprocal of body weight 3.9%.

Topics: Aging; Biological Availability; Body Weight; Digoxin; Humans; Kidney Diseases; Tablets

308 digitalized out-patients with artificial cardiac pacemakers were explored for signs of glycoside toxicity with simultaneous determination of digoxin plasma levels 12 hours after the last dose. The incidence of different side effects commonly attributed to overdigitalization did not allow prediction of toxic plasma levels. 55% of all glycoside levels were within the therapeutic range, 34% were below 0.7 ng/ml and only 11% above 2.0 ng/ml. With the most commonly prescribed maintenance doses of the glycosides used (digoxin 0.5 mg, beta-acetyldigoxin 0.4 mg, beta-methyldigoxin 0.2 mg, lanatosid C 1.0 mg) therapeutic plasma levels were reached regularly in 60-65% of the patients. A significant correlation existed between plasma glycoside concentrations and renal function as well as age, but glycoside concentrations could not be correlated with the age of the patients. There were no indications for interactions of the different glycosides prescribed with diuretics or oral antidiabetics.

Topics: Adult; Age Factors; Aged; Body Weight; Cardiac Glycosides; Digoxin; Diuretics; Drug Interactions; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Lanatosides; Male; Middle Aged; Pacemaker, Artificial

Topics: Animals; Body Weight; Brain; Cats; Digoxin; Male; Myocardium; Time Factors; Vomiting

Six patients in sinus rhythm with congestive heart failure due to either myocardial infarction or cardiomyopathy, were given oral frusemide to eliminate oedema. Symptomatic relief occurred as body weight was reduced, and after a 'dry' basal weight had been achieved, progressive-load exercise testing was done to examine any benefit that derived from adding oral digoxin to the diuretic. Three pairs of sub-maximal exercise tests were done at intervals over three months, and the responses of each patient when using digoxin and diuretics were compared with those when using diuretics alone. One patient did not complete this study, because more frequent premature beats and increased angina followed the withdrawal of digoxin. For the five patients who completed three pairs of tests, there was no significant change in symptoms, in workload achieved, or in heart rate, respiratory rate, ventilation and respiratory quotient, whether digoxin was added or removed. It is concluded that in these patients where salt and water retention was controlled with diuretics, digoxin did not improve the capacity for exercise, and it is suggested that for such patients with myocardial disease in sinus rhythm, treatment should begin with diuretics.

Topics: Adult; Aged; Arrhythmia, Sinus; Body Water; Body Weight; Digoxin; Drug Therapy, Combination; Exercise Test; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged

Topics: Body Weight; Digoxin; Humans; Kidney Failure, Chronic; Renal Dialysis; Tablets; Time Factors

A total of 1109 determinations of digoxin concentration in serum were performed in 317 patients with cardiac failure during oral maintenance therapy with digoxin, beta-acetyldigoxin and beta-methyldigoxin. It was shown that the optimal therapeutic serum concentration (1.21 to 1.70 ng/ml) can be obtained reliably if the dosage of digoxin and its derivatives is based on the body weight. The daily doses recommended for oral maintenance therapy are 4mug/kg for beta-methyldigoxin, 5 mug/kg for beta-acetyldigoxin, and 8 mug/kg for digoxin. For initiating cardiac therapy the double maintenance dose can be prescribed once. Digoxin derivatives should be preferred to digoxin when choosing the drug.

Topics: Aged; Body Weight; Digoxin; Female; Heart Failure; Humans; Hyperthyroidism; Male; Middle Aged; Sex Factors

In patients of a cardiological practice, 121 digoxin serum concentrations were determined by radioimmunoassay (RIA). Some drugs were suspected of interfering with the RIA or with the pharmacokinetics of digoxin. Patients having such additional drugs or patients with elevated serum creatinine were not included. The daily maintenance dose of digoxin was roughly adjusted to body weight. Patients with 0.5 mg digoxin daily showed unexpectedly low serum digoxin levels not fully explained by the relatively high body weight. This dose group was not included in the following correlations. At a maintenance dose of 0.25 and 0.375 mg digoxin and in the age groups 40-69 years (n = 66) there was an approximately inverse proportionality between serum digoxin concentration (per 0.25 mg digoxin daily) and body weight. When all age classes from 20 to 89 years were included (n = 96), a week positive correlation between serum digoxin concentration (per 0.25 mg digoxin daily and per 69.28 kg body weight) and age was found. A similar positive correlation resulted between serum digoxin concentration (per 0.25 mg digoxin daily) and the reciprocal of the nomographically determined creatinine clearance, always within the normal serum creatinine range. Based on these correlations, two simplified formulas are presented to predict the serum concentration and therapeutic maintenance dose of digoxin. The formulas are valid for the normal serum creatinine range and for digoxin tablets of optimal bioavailability.

Topics: Adult; Age Factors; Aged; Body Weight; Coronary Disease; Creatinine; Digoxin; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Radioimmunoassay

1. The effect of treating rats with digoxin and thyroxine for 45 days has been studied. 2. Animals fed with digoxin gained significantly more weight than the control animals. 3. Treatment with digoxin, thyroxine or both produced a similar significant increase in the amount of Na+ + K+ -dependent adenosine triphosphatase in liver without an additive effect. 4. It is suggested that digoxin resistance in thyrotoxicosis may be related to this similarity in action.

Topics: Adenosine Triphosphatases; Animals; Blood Proteins; Body Weight; Digoxin; Enzyme Activation; Iodine; Liver; Ouabain; Potassium; Protein Binding; Rats; Sodium; Thyroxine

Many intoxications--up to 20%--and the often described "digitalis-incompatibility of old age" require a strict indication for this long term therapy and a critical discussion to conceptions like "old age-heart" and "insufficiency of old age-heart". The factors of uncertainty for efficient therapy -- unknown rates of resorption and elimination, mistakes in dosage by patients and interaction with other medicaments on account of the multimorbidity of old age -- demand a better control than only clinical observation and electrocardiography. In 25 patients the serum glycoside concentration was evaluated during several weeks at constant dose by radioimmunoassay and analyzed. Digoxin-assay has to be available as an "emergency-measure", since the early diagnosis of digitalis intoxication in old patients is often very difficult because of the ambiguous clinical picture. 63 patients of different age with normal function of the kidneys (endogenous creatinin-clearance, nephrography with iodine-131-hippuran) were treated with 0,75 mg digoxin/die orally and the serum glycoside concentration was evaluated after 8, 24 and 48 hours by radioimmunoassay; we only found a dependence on weight, but not on the age of our patients. In old age, digoxin is metabolized in the same way as in young age, but because of frequent kidney diseases, kidney function should be assessed carefully before long term digoxin therapy.

Topics: Age Factors; Aged; Body Weight; Cardiac Glycosides; Digoxin; Female; Heart Failure; Humans; Kidney; Long-Term Care; Male; Middle Aged; Radioimmunoassay; Time Factors

Topics: Adult; Aged; Body Weight; Digoxin; Heart Diseases; Humans; Middle Aged

Topics: Body Weight; Digoxin; Dose-Response Relationship, Drug; Heart Diseases; Heart Failure; Humans

The action of a drug depends on the quantity which reaches the site of its pharmacological action and how long it remains there. The necessary vital processes of the body dilute the active principle into different compartments of distribution, transform it into metabolites, and excrete it. Since a time duration of drug presence at the site of action is vital for the cure of disease, a comprehensive and quantitative expression of these time courses of drug distribution as a function of dose and route of administration is necessary for the establishment of proper dosage regimens for the treatment of disease and the avoidance of toxicities. The purpose of pharmacokinetics is to study these phenomena and to construct models suitable to explain them and to predict the behavior of drugs in conditions not yet studied. In this review some basic principles of pharmacokinetics (i.e. the compartment, the volume of distribution, the elimination half-life, etc.) are explained. Their clinical implications are shown in the case of multiple dose administration and in the study of the relations existing between blood levels of digoxin and the pharmacological action of this drug.

Topics: Body Weight; Digoxin; Drug Administration Schedule; Kinetics; Pharmacology

Serum glycoside concentration was 2.3 ng/ml or more in 299 patients digitalised with digoxin or digoxin derivatives. Mean serum glycoside concentration was 3.4 +/- 1.3 ng/ml (range 2.3-11.00 ng per ml). Usually, high serum concentrations were associated with advanced den or digoxin-derivative overdosage occurred in only 10% of patients. Almost three quarters of those with intoxication had impaired renal function. There was some evidence that low body-weight increased the potential risk of intoxication.

Topics: Arrhythmias, Cardiac; Body Weight; Digoxin; Heart Block; Humans; Kidney Failure, Chronic; Tachycardia

The concentrations of digoxin in tissues of premature infants, full-term infants and older children obtained at autopsy were determined by a radioimmunoassay procedure. Infants were found to have much higher concentrations in the right and left ventricle (about 190 ng/g) than older children (about 70 ng/g) and adults as reported in the literature. Renal concentrations were lower in the premature group which may be related to their limited excretory capacity for digoxin. The relatively high myocardial concentrations of digoxin found in this study suggest that the usually recommended doses for infants may be excessive.

Topics: Age Factors; Autopsy; Body Weight; Child; Child, Preschool; Digoxin; Heart Failure; Humans; Infant; Infant, Newborn; Infant, Premature; Kidney; Muscles; Myocardium

Topics: Adrenocorticotropic Hormone; Aged; Aldosterone; Body Weight; Chromatography, Paper; Creatinine; Diet; Digoxin; Diuresis; Female; Glomerular Filtration Rate; Heart Failure; Humans; Liver Function Tests; Male; Middle Aged; Posture; Potassium; Radioimmunoassay; Renin; Sodium; Time Factors

Topics: Aged; Body Weight; Child; Creatinine; Digoxin; Female; Heart Ventricles; Humans; Iodine Radioisotopes; Kidney; Kidney Function Tests; Male; Middle Aged; Myocardium; Potassium; Radioimmunoassay; Regression Analysis; Sodium

Topics: Adult; Antibody Specificity; Biological Availability; Body Weight; Digoxin; Humans; Injections, Intravenous; Kinetics; Male; Radioimmunoassay; Time Factors; Tritium

Topics: Administration, Oral; Animals; Azepines; Benzoates; Body Weight; Digoxin; Dogs; Dose-Response Relationship, Drug; Drug Combinations; Female; Injections, Intraperitoneal; Lethal Dose 50; Male; Mice; Myoclonus; Rats; Time Factors; Vasodilator Agents

Topics: Adult; Aged; Body Surface Area; Body Weight; Digoxin; Female; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; Male; Middle Aged; Potassium; Radioimmunoassay; Time Factors; Urea

Topics: Age Factors; Blood Urea Nitrogen; Body Height; Body Weight; Creatinine; Diagnosis, Computer-Assisted; Digoxin; Drug-Related Side Effects and Adverse Reactions; Education, Medical, Continuing; Feedback; Half-Life; Humans; Kidney; Kinetics; Pharmaceutical Preparations; Sex Factors; Teaching

Topics: Adult; Aged; Body Height; Body Weight; Computers; Creatinine; Digoxin; Dose-Response Relationship, Drug; Female; Heart Diseases; Humans; Kidney; Male; Middle Aged; Regression Analysis

Topics: Biopharmaceutics; Body Weight; Digoxin; Drug Compounding; Humans; Solubility; Urea

Topics: Aging; Animals; Aorta; Body Weight; Bone and Bones; Calcinosis; Digoxin; Feeding Behavior; Female; Heart Rate; Hypothalamus; Longevity; Male; Mice; Mice, Inbred Strains; Myocardium; Organ Size; Sex Factors; Species Specificity; Spectrophotometry; Tooth

Topics: Adult; Age Factors; Aged; Body Weight; Carbon Dioxide; Creatinine; Digoxin; Diuretics; Electrocardiography; Female; Humans; Kidney Diseases; Magnesium; Male; Metabolic Diseases; Middle Aged; Radioimmunoassay; Sex Factors

Topics: Age Factors; Aged; Body Surface Area; Body Weight; Digoxin; Humans; Infant; Infant, Newborn; Middle Aged; Urea

A dosage schedule for digoxin medication is presented which has proved effective and safe in children of different ages with heart failure due to a variety of cardiac conditions. The plasma digoxin concentrations during maintenance therapy, using this schedule, agree closely with previously reported therapeutic adult plasma concentrations, though the results do not exclude the efficiency and safety of higher doses. A twice-daily dosage regimen is suggested.

Topics: Body Weight; Child, Preschool; Digoxin; Heart Failure; Humans; Infant; Infant, Newborn; Radioimmunoassay

Topics: Administration, Oral; Adult; Age Factors; Body Weight; Child, Preschool; Digoxin; Electrocardiography; Humans; Infant; Infant, Newborn; Infant, Premature; Poisoning; Radioimmunoassay

Topics: Administration, Oral; Adolescent; Adult; Animals; Body Height; Body Surface Area; Body Weight; Digoxin; Half-Life; Humans; Injections, Intramuscular; Male; Rabbits; Radioimmunoassay; Time Factors

Topics: Adult; Body Weight; Colorimetry; Digitalis Glycosides; Digitoxin; Digoxin; Fluorometry; Gastric Juice; Heart Defects, Congenital; Humans; Infant, Newborn; Kidney; Liver; Lung; Male; Methods; Myocardium

Topics: Animals; Body Weight; Celiac Disease; Cholestyramine Resin; Chromates; Chromium Radioisotopes; Common Bile Duct; Digoxin; Feces; Food; Intestine, Small; Ligation; Male; Rats; Stomach; Time Factors; Tritium; Urine

Topics: Age Factors; Aged; Body Height; Body Surface Area; Body Weight; Creatinine; Digoxin; Diuretics; Female; Heart Diseases; Humans; Iodine Radioisotopes; Iodohippuric Acid; Kidney Function Tests; Male; Radioimmunoassay

Topics: Animals; Antacids; Body Weight; Cholestyramine Resin; Digoxin; Fats; Feces; Intestinal Absorption; Male; Rats; Time Factors; Tritium

Topics: Administration, Oral; Adult; Age Factors; Biopharmaceutics; Body Weight; Capsules; Digoxin; Female; Humans; Intestinal Absorption; Male; Middle Aged; Radioimmunoassay; Tablets

Topics: Body Weight; Digoxin; Humans; Kidney

Topics: Administration, Oral; Arrhythmias, Cardiac; Body Weight; Computers; Digitalis Glycosides; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Humans; Injections; Kidney; Kinetics; Lanatosides; Myocardium

A daily infusion of 500-1,000 ml of 50% glucose containing 100-120 units of soluble insulin and 100-120 mEq of potassium chloride per litre was given to six patients suffering from hyponatraemia and congestive cardiac failure resistant to digoxin and diuretic therapy. In two patients there was no response, but four showed a striking improvement with a sodium and water diuresis, a rise in plasma sodium level, and in two cases a reversion from atrial fibrillation to sinus rhythm. It is suggested that insulin, glucose, and potassium given by the intravenous route in adequate dosage forms a useful adjunct to the management of severe congestive heart failure.

Topics: Adult; Aged; Atrial Fibrillation; Blood Pressure; Body Weight; Digoxin; Diuresis; Diuretics; Female; Glucose; Heart Failure; Humans; Hyponatremia; Injections, Intravenous; Insulin; Male; Middle Aged; Natriuresis; Potassium; Potassium Chloride; Sodium

Topics: Administration, Oral; Age Factors; Body Weight; Child, Preschool; Digoxin; Heart Diseases; Humans; Infant; Radioimmunoassay

Topics: Age Factors; Aged; Body Weight; Digitalis Glycosides; Digoxin; Education, Medical; Electrocardiography; Heart Failure; Hospitals, General; Humans; Kidney; Medical Audit; Methods; Middle Aged; Pulmonary Heart Disease; Quebec

Topics: Administration, Oral; Blood Proteins; Body Weight; Calcium; Celiac Disease; Digoxin; Feces; Humans; Intestinal Absorption; Lipids; Magnesium; Malabsorption Syndromes; Pancreatic Diseases; Xylose

Topics: Adipose Tissue; Adult; Body Weight; Digoxin; Female; Humans; Injections, Intravenous; Male; Obesity; Tritium

Topics: Asphyxia Neonatorum; Body Weight; Digoxin; Ductus Arteriosus, Patent; Female; Gestational Age; Heart Failure; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature, Diseases; Male; Organomercury Compounds; Respiratory Distress Syndrome, Newborn; Sex Factors

Topics: Aging; Animals; Aorta; Body Weight; Bone and Bones; Bradycardia; Calcium; Digoxin; Feeding Behavior; Female; Heart Rate; Hypothalamus; Longevity; Male; Mass Spectrometry; Mice; Microscopy, Electron; Minerals

Topics: Age Factors; Aged; Body Weight; Digoxin; Drug Hypersensitivity; Humans

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.

Topics: Age Factors; Arrhythmias, Cardiac; Body Weight; Computers; Digoxin; Heart Failure; Humans; Kidney; Potassium; Radioimmunoassay; Tachycardia; Tritium

Topics: Atrial Flutter; Birth Weight; Body Weight; Digoxin; Edema; Electrocardiography; Female; Fetal Diseases; Fetal Heart; Furosemide; Heart Failure; Heart Rate; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Pregnancy

Topics: Age Factors; Aged; Aminophylline; Arrhythmias, Cardiac; Body Weight; Digoxin; Epidemiologic Methods; Female; Furosemide; Heparin; Humans; Male; Massachusetts; Meperidine; Middle Aged; Morphine; Prochlorperazine; Statistics as Topic; Tachycardia

Topics: Blood Urea Nitrogen; Body Weight; Computers; Creatinine; Digoxin; Heart Failure; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Mathematics; Methods

Topics: Age Factors; Arteriosclerosis; Atrial Fibrillation; Body Weight; Digoxin; Edema; Female; Heart Failure; Heart Rate; Humans; Hypertension; Lung Diseases; Male; Middle Aged; Organ Size; Spirometry; Syphilis, Cardiovascular

Topics: Aged; Body Weight; Digoxin; Diuretics; Drug Synergism; Edema; Female; Furosemide; Glycosuria; Humans; Hypertension; Male; Middle Aged; Natriuresis; Potassium; Spironolactone; Strophanthins; Tolbutamide

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Baths; Blood Chemical Analysis; Blood Proteins; Body Weight; Burns; Child; Child, Preschool; Digoxin; Hexachlorophene; Humans; Infant; Infant, Newborn; Injections, Intravenous; Middle Aged; Norethandrolone; Sepsis

Topics: Body Weight; Cyanosis; Diagnosis, Differential; Digoxin; Ebstein Anomaly; Electrocardiography; Humans; Infant; Infant, Newborn; Phonocardiography