digoxin and Kidney-Failure--Chronic

Topics: Adrenergic beta-Antagonists; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Digoxin; Humans; Incidence; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Factors; Stroke; Thromboembolism

Heart failure (HF) is a syndrome characterized by upregulation of the sympathetic nervous system and abnormal responsiveness of the parasympathetic nervous system. Studies in the 1980s and 1990s demonstrated that inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors improved symptoms and mortality in HF resulting from systolic dysfunction, thus providing a framework to consider the use of β-blockers for HF therapy, contrary to the prevailing wisdom of the time. Against this backdrop, this article reviews the contemporary understanding of the sympathetic nervous system and the failing heart.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Afferent Pathways; Angiotensin Receptor Antagonists; Autonomic Nervous System Diseases; Brain; Cardiac Imaging Techniques; Cardiotonic Agents; Digoxin; Efferent Pathways; Exercise Therapy; Exercise Tolerance; Forecasting; Heart Failure; Humans; Kidney Failure, Chronic; Muscle, Skeletal; Myocardial Infarction; Norepinephrine; Oxidative Stress; Polymorphism, Genetic; Receptors, Adrenergic; Receptors, Adrenergic, beta; Reflex; Renin-Angiotensin System; Sleep Apnea, Obstructive; Sympathetic Nervous System

Topics: Biotransformation; Digitalis Glycosides; Digoxin; Humans; Kidney Failure, Chronic

Topics: Adult; Digitalis Glycosides; Digoxin; Female; Humans; Hypertension; Infant, Newborn; Kidney Failure, Chronic; Liver Diseases; Male; Pregnancy

The ability of extracts of mammalian plasma and tissue to mimic the biologic activities of the digitalis glycosides has suggested the existence of endogenous regulators for Na, K ATPase. Purification of plasma extracts has identified several classes of circulating lipids with digitalis-like activity including free fatty acids, lysophospholipids, and arachidonic acid metabolites of the lipoxygenase pathway. Circulating steroids with digitalis-like activity include dehydroepiandrosterone sulfate and hydrocortisone. Evidence for other, more unique compounds has also been published although their structure has not yet been determined. Analysis of tissue suggests that hypothalamus contains a unique, low molecular digitalis-like factor (DLF) which also circulates in plasma. Some studies suggest that the hypothalamic factor is also present in other parts of the brain and in the adrenal. Some of these endogenous DLF may function as modulators of cardiovascular function by regulating renal sodium excretion and peripheral vascular resistance in both physiological and pathophysiological situations.

Topics: Animals; Arachidonic Acids; Blood Proteins; Blood Volume; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Lipids; Natriuretic Agents; Peptides; Pregnancy; Saponins; Steroids

Digitalis glycosides continue to place high on the list of prescribed drugs. Digoxin is 8th on prescriptions written in the United States in 1980, digitoxin 16th, and digitalis leaf 23rd. There is little doubt that most physicians continue to believe these drugs are useful. The application of more definite indications, smaller doses, and the recognition of the role of pharmacokinetics and drug interactions make use of the glycosides more challenging than ever before in 1985.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Age Factors; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Biological Availability; Bretylium Tosylate; Deslanoside; Digitalis Glycosides; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Heart Failure; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Kidney Failure, Chronic; Lidocaine; Metabolic Clearance Rate; Myocardial Infarction; Obesity; Phenytoin; Potassium; Pulmonary Heart Disease; Thyroid Diseases

Topics: Afferent Pathways; Angiotensin II; Animals; Arteries; Biological Transport; Blood Pressure; Blood Proteins; Blood Vessels; Blood Volume; Body Fluids; Brain Chemistry; Cross Circulation; Digoxin; Endocrine Glands; Erythrocytes; Glucosephosphate Dehydrogenase; Hormones; Humans; Hypothalamus; In Vitro Techniques; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Leukocytes; Liver; Malpighian Tubules; Molecular Weight; Myocardium; Natriuretic Agents; Norepinephrine; Osmolar Concentration; Protein Biosynthesis; Proteins; Sodium; Sodium Chloride; Sodium-Potassium-Exchanging ATPase; Tissue Extracts

Topics: Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Cattle; Digoxin; Dogs; Edema; Guinea Pigs; Humans; Hypertension; Hypothalamus; Kidney Failure, Chronic; Kidney Tubules; Muscle Proteins; Potassium; Rabbits; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

The authors refer to the technique of the serum digoxin enzyme immunoassay, and they report the results of 297 dosages concerning 111 hospitalized patients. The normal plasmatic rates are of 1,4 +/- 0,6 microgram/l in patients who present no sign of digitalic overdosage. The rates are of 5,2 +/- 1,6 microgram/l in cases of intoxication. The difference between these rates is greatly significant (p less than 0.001). The limit between therapeutic and toxic rates is situated around 3 microgram/l with an overlapping from 2 to 3 microgram/l. Authors then examine the individual factors that intervene in digoxin metabolism and especially study the influence of age, myocardic factors and renal insufficiency. On the basis of these results and review of the literature, they emphasize the interest of serum digoxin determination in the diagnosis of digitalis toxicity, as well as in the management of high risk patients, and of cardiopathies difficult to stabilize.

Topics: Aged; Aging; Digoxin; Electrolytes; Enzyme-Linked Immunosorbent Assay; Heart Diseases; Humans; Kidney Failure, Chronic; Middle Aged; Myocardium

Topics: Digitalis Glycosides; Digitoxin; Digoxin; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Failure, Chronic

Topics: Arrhythmias, Cardiac; Digitalis Glycosides; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Poisoning; Vision Disorders

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: Adrenergic beta-Antagonists; Creatinine; Digitalis Glycosides; Digoxin; Humans; Kidney Failure, Chronic; Pindolol; Practolol; Propranolol

Topics: Acid-Base Imbalance; Aged; Atropine; Cardiac Complexes, Premature; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Heart Block; Heart Failure; Heart Ventricles; Humans; Kidney Failure, Chronic; Phenytoin; Potassium; Tachycardia

Topics: Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Heart Failure; Humans; Hyperthyroidism; Hypothyroidism; Intestinal Absorption; Kidney Failure, Chronic; Molecular Conformation; Obesity

Topics: Anti-Bacterial Agents; Antihypertensive Agents; Cardiac Glycosides; Clofibrate; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Humans; Kidney Failure, Chronic; Phenytoin; Protein Binding; Sulfonamides; Triamterene

Topics: Adsorption; Analgesics; Anesthetics; Anti-Bacterial Agents; Anticoagulants; Antihypertensive Agents; Diet Therapy; Dietary Proteins; Digoxin; Forecasting; Hemodialysis, Home; Humans; Hypnotics and Sedatives; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis; Time Factors; Tranquilizing Agents; Transplantation, Homologous

Topics: Age Factors; Arrhythmias, Cardiac; Calcium; Child; Coronary Care Units; Digitalis Glycosides; Digoxin; Electric Countershock; Electrocardiography; Endocrine System Diseases; Heart Diseases; Heart Failure; Heart Rate; Heart Valve Diseases; Humans; Kidney Failure, Chronic; Liver Diseases; Lung Diseases; Magnesium; Obesity; Ouabain; Poisoning; Potassium; Psychophysiologic Disorders; Pulmonary Heart Disease; Thyroid Diseases; Time Factors

An enzyme-linked immunosorbent assay is described for the measurement of ouabain in human plasma. This assay is specific for ouabain, strophanthidin, and ouabagenin, with other steroids, including digoxin and vasopressor hormones, exhibiting negligible cross-reactivity. Assay sensitivity was 0.06 nmol/L if 1 mL plasma was extracted and less than 0.005 nmol/L when 20 mL plasma was analyzed. Extracted plasma samples showed ouabainlike immunoreactivity that diluted in parallel with the ouabain standard curve. Repeated extraction and assay of single plasma samples, however, did not produce consistent results in the assay. Increased specificity was obtained by high-performance liquid chromatography of sample extracts before assay. When high-performance liquid chromatographic profiles of plasma spiked with ouabain standard or following bolus intravenous injections of ouabain into normal human volunteers were compared with profiles of unspiked plasma, there was no support for the immunoreactive material in the latter samples being ouabain. We propose that if ouabain is present in the human circulation, its concentration is less than 0.005 nmol/L.

Topics: Animals; Antibodies; Antibody Specificity; Chromatography, High Pressure Liquid; Cross Reactions; Digoxin; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Heart Failure; Humans; Kidney Failure, Chronic; Ouabain; Pre-Eclampsia; Pregnancy; Rabbits; Sensitivity and Specificity; Steroids; Strophanthidin; Vasopressins

Digoxin-like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin, including those patients with end-stage renal disease. The structure and physiologic significance of this compound are unknown, and the fate of DLIS after renal transplantation has not been studied. The authors prospectively evaluated 163 patients (not receiving digoxin) before and after transplantation for the presence of DLIS. Three different assays were used: radioimmunoassay (RIA), affinity mediated immunoassay (ACA), and fluorescence polarization immunoassay (TDX I). Depending on the assay method used, 11% (RIA), 6% (ACA), and 9% (TDX) of patients had detectable DLIS pretransplant. Using all 3 assays, a total of 34 patients (21%) were found to have DLIS. The mean serum digoxin concentration was 0.41 +/- 0.13 ng/mL (range: 0.2-1.2 ng/mL) and DLIS was detectable by greater than 1 assay method in seven patients. DLIS persisted longer in patients who had delayed allograft function (13.7 +/- 7 days) than in those who did not (3 +/- 1.9 days), P less than .05. In summary, detection of DLIS in renal transplant recipients appears to be an infrequent occurrence when using a single digoxin assay method. When detected, the concentration of DLIS is often below the usual therapeutic range for digoxin and disappears once allograft function is established. The authors conclude that the presence of DLIS is unlikely to be clinically significant in the renal transplant population.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Saponins; Sodium-Potassium-Exchanging ATPase

Minimal pharmacokinetic data on digoxin immune Fab are currently available, especially in patients with impaired renal function. The serum concentration-time profiles of total digoxin, free digoxin, and digoxin immune Fab in four patients with moderate to severe renal impairment who received digoxin immune Fab are presented. The calculated elimination half-life of digoxin immune Fab was 25-73 hours. The calculated elimination half-life of total digoxin was 24-72 hours. Free digoxin concentrations rebounded to a peak of 1-2.9 ng/mL 44-97 hours after the administration of digoxin immune Fab. The areas under the curve for digoxin immune Fab were 213-1026 micrograms.h/mL, and total body clearances were 2.3-7.1 mL/min. The total digoxin concentrations peaked at 14-33 times the pre-Fab digoxin concentrations 5-30 hours after digoxin immune Fab administration. In comparing these data with data available from patients with normal renal function, the half-life of digoxin immune Fab and total digoxin was longer, the peak total digoxin concentration occurred later, the ratio of the peak total digoxin concentration to pre-Fab digoxin concentration was larger, and the rebound in free digoxin occurred later in patients with renal impairment. The Fab dose should not be reduced in patients with renal impairment; however, post-Fab monitoring should be extended to compensate for the prolonged half-life of Fab and later rebound of free digoxin.

Topics: Adult; Aged; Digoxin; Female; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Poisoning; Time Factors

The effect of multiple oral doses of activated charcoal on digitalis glycoside kinetics was studied to determine whether an activated charcoal regimen might have utility in treating patients with digitalis toxicity. Normal subjects were given intravenous infusions of digoxin 0.75 mg/70 kg or digitoxin 1 mg/70 kg iv followed by either water alone or water with activated charcoal in divided doses in a randomized crossover design. A subject with chronic renal failure was also given digoxin 0.5 mg/70 kg iv followed by water alone or water with activated charcoal. In six normal subjects, treatment with activated charcoal did not increase digoxin clearance (Cl) significantly (16.79 +/- 1.70 vs. 22.68 +/- 3.51 L/h). However, digitoxin Cl did increase significantly, from 0.24 +/- 0.01 to 0.47 +/- 0.04 L/h. In the renal failure subject, digoxin Cl increased from 3.6 L/h to 10.1 L/h. We conclude that the activated charcoal regimen is probably useful in patients with digitoxin toxicity. Although similar benefit is limited in patients with normal renal function who develop digoxin toxicity, it is possible that activated charcoal will be useful in patients with prolonged digoxin elimination due to renal dysfunction.

Topics: Adult; Charcoal; Digitoxin; Digoxin; Humans; Kidney Failure, Chronic; Kinetics; Male

The indication for digitalis treatment was investigated in a controlled and prospective study lasting 12 months in 110 patients on long-term haemodialysis. In ten patients, digitalis was needed because of tachyarrhythmia due to atrial fibrillation and in five because of recurrent pulmonary edema. In 57 patients receiving digitoxin, therapy was discontinued for 4 to 6 weeks, whereas 13 patients not yet treated with digitalis, received digitoxin for 4 weeks. Without digitoxin, trial fibrillation occurred in 4 patients, while no patient experienced atrial fibrillation with digitoxin (P = 0.002). In 13 patients, radiological findings (heart enlargement, pulmonary congestion) were better with digitoxin than without. Thus digitoxin appeared to be clearly indicated in 29% of the haemodialysed patients. Additionally, digitalis was indicated in 31 patients because of heart enlargement, pulmonary congestion and (or) previous pulmonary edema. Initially, 76% of the patients were receiving digitoxin, whereas, after the investigation, the rate was only 57% (P less than 0.001). The prospective frequency of clinically apparent digitoxin intoxication was low (3%) and so were the overall toxic plasma digitoxin levels (5%). Digitalis should be given deliberately but not restrictively to haemodialysis patients, since atrial fibrillation (13%) and heart failure (50%) are frequent and often concealed.

Topics: Adult; Aged; Atrial Fibrillation; Cardiomegaly; Clinical Trials as Topic; Digitalis; Digitoxin; Digoxin; Female; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plants, Medicinal; Plants, Toxic; Pulmonary Edema; Renal Dialysis; Tachycardia; Time Factors

The correct loading dose of digoxin in patients with advanced renal failure is still a matter of discussion. The effects has been studied of loading doses of digoxin 0.625 mg or 1.25 mg given over 48 h according to randomized crossover design to healthy volunteers and to two different groups of patients with renal impairment and the same mean endogenous creatinine clearance of about 15 ml/min. The subsequent maintenance dose for 4 days was digoxin 0.25 mg in the volunteers and 0.125 mg in both groups of patients. The minimum plasma digoxin concentrations before each dose was measured by radioimmunoassay and the plasma levels in the different groups have been compared. In the healthy volunteers no significant difference was found during the study, despite wide variation in the plasma digoxin concentration. In contrast, in patients with renal failure, the group with the higher loading dose showed significantly higher plasma concentrations 24, 36 and 48 h after drug administration, reaching the highest mean value of 2.2 ng/ml at 48 h. However, after 120 h of maintenance therapy a mean digoxin concentration of 1.3 ng/ml was found in both groups. Thus, despite different loading doses identical plasma concentrations were reached during administration of the same maintenance therapy. The higher plasma digoxin concentration obtained during administration of a higher loading dose might be the cause of arrythmias in individual patients.

Topics: Adult; Digoxin; Dose-Response Relationship, Drug; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Middle Aged; Time Factors

The management of the coexistence of heart disease and kidney disease is increasingly challenging for clinicians. Chronic kidney disease (CKD) is not only a prevalent comorbidity of patients with heart failure but has also been identified as a noteworthy risk factor for all-cause mortality and poor clinical outcomes. Digoxin is one of the commonest treatments for heart disease. There are few trials investigating the role of digoxin in patients with cardiorenal syndrome (CRS). This study aims to examine the association between digoxin usage and clinical outcomes in patients with CRS in a nationwide cohort.. We conducted a population-based study that included 705 digoxin users with CRS; each patient was age, sex, comorbidities, and medications matched with three non-users who were randomly selected from the CRS population. Cox proportional hazards regression analysis was conducted to estimate the effects of digoxin on the incidence of all-cause mortality, congestive heart failure (CHF) hospitalization, coronary artery disease (CAD) hospitalization, and end-stage renal disease (ESRD).. The all-cause mortality rate was significantly higher in digoxin users than in non-users (adjusted hazard ratio [aHR] = 1.26; 95% confidence interval [CI] = 1.09-1.46,. Digoxin should be prescribed with caution to patients with CRS.

Topics: Cardio-Renal Syndrome; Coronary Artery Disease; Digoxin; Heart Failure; Hospitalization; Humans; Kidney Failure, Chronic

We present a man undergoing regular haemodialysis sessions, who presented with non-specific symptoms of nausea, vomiting and light-headedness. He was found to have significantly raised serum digoxin concentrations, as well as a heart rate of 30 beats per minutes. An ECG showed complete heart block. He has a history of non-ischaemic dilated cardiomyopathy with resistant supraventricular and ventricular tachycardias and was on concomitant beta-blockade and digoxin. On questioning, he reported a gradual decline in his residual urine output over the past 6 months. He was reviewed by the cardiology team and required both pharmacological therapy for reversal of digoxin toxicity and temporary pacing in view of significant bradyarrhythmias. The beta-blockade and digoxin were discontinued. He was kept on continuous monitoring at the Cardiac Critical Care Unit. His symptoms resolved spontaneously once digoxin-specific antibody fragments were administered and temporary pacing successfully performed.

Topics: Aged; Anti-Arrhythmia Agents; Bradycardia; Cardiac Pacing, Artificial; Cardiomyopathy, Dilated; Digoxin; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Male; Protective Agents; Renal Dialysis; Risk Adjustment; Tachycardia, Supraventricular; Treatment Outcome

The treatment of elderly multimorbid patients according to clinical guidelines often results in polypharmacy. An individual risk assessment is required to consider the possibility of deprescribing especially potentially inappropriate medication in the elderly. This exemplary case report describes a medication review of a patient with multiple chronic cardiovascular diseases taking into account the impact on renal function.

Topics: Aged, 80 and over; Atrial Fibrillation; Carbazoles; Carvedilol; Diclofenac; Digoxin; Drug Interactions; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Myocardial Infarction; Potassium; Potentially Inappropriate Medication List; Propanolamines; Ramipril; Risk Factors; Spironolactone

This study investigated the impact of chronic kidney disease on all-causes and cardiovascular mortality in patients with atrial fibrillation treated with digoxin.. All patients with non-valvular atrial fibrillation and/or atrial flutter as hospitalization diagnosis from January 1, 1997 to December 31, 2012 were identified in Danish nationwide administrative registries. Cox proportional hazard model was used to compare the adjusted risk of all-causes and cardiovascular mortality among patients with and without chronic kidney disease and among patients with different chronic kidney disease stages within 180 days and 2 years from the first digoxin prescription.. We identified 37,981 patients receiving digoxin; 1884 patients had the diagnosis of chronic kidney disease. Cox regression analysis showed no statistically significant differences in all-causes (Hazard Ratio, HR 0.89; 95% confident interval, CI 0.78-1.03) and cardiovascular mortality (HR 0.88; 95%CI 0.74-1.05) among patients with and without chronic kidney disease within 180 days of follow-up period. No statistically significant differences was found using a 2 years follow-up period neither for all causes mortality (HR 0.90; 95%CI 0.79-1.03), nor for cardiovascular mortality (HR 0.87; 95%CI 0.74-1.02). No statistically significant differences was found comparing patients with and without estimated Glomerular Filtration Rate <30ml/min/1.73m2 and patients with different stages of chronic kidney disease, for all-causes and cardiovascular mortality within 180 days and 2 years from the first digoxin prescription.. This study suggest no direct effect of chronic kidney disease and chronic kidney disease stages on all-causes and cardiovascular mortality within both 180 days and 2 years from the first digoxin prescription in patients treatment-naïve with digoxin for non-valvular atrial fibrillation.

Topics: Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Fibrillation; Denmark; Digoxin; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Proportional Hazards Models; Registries; Retrospective Studies; Survival Analysis

Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30-50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.

Topics: Animals; Biological Transport, Active; Blood-Brain Barrier; Brain; Cells, Cultured; Kidney Failure, Chronic; Male; Membrane Transport Proteins; Pharmaceutical Preparations; Rats; Rats, Sprague-Dawley

Previous reports demonstrated that digitalis-like cardiotonic steroids (CTS) contribute to the pathogenesis of end-stage renal disease. The goal of the present study was to define the nature of CTS in patients with chronic kidney disease (CKD) and in partially nephrectomized (PNx) rats.. In patients with CKD and in healthy controls, we determined plasma levels of marinobufagenin (MBG) and endogenous ouabain (EO) and erythrocyte Na/K-ATPase activity in the absence and in the presence of 3E9 anti-MBG monoclonal antibody (mAb) and Digibind. Levels of MBG and EO were also determined in sham-operated Sprague-Dawley rats and in rats following 4 weeks of PNx.. In 25 patients with CKD plasma, MBG but not EO was increased (0.86 ± 0.07 versus 0.28 ± 0.02 nmol/L, P < 0.01) and erythrocyte Na/K-ATPase was inhibited (1.24 ± 0.10 versus 2.80 ± 0.09 μmol Pi/mL/h, P < 0.01) as compared to that in 19 healthy subjects. Ex vivo, 3E9 mAb restored Na/K-ATPase in erythrocytes from patients with CKD but did not affect Na/K-ATPase from control subjects. Following chromatographic fractionation of uremic versus normal plasma, a competitive immunoassay based on anti-MBG mAb detected a 3-fold increase in the level of endogenous material having retention time similar to that seen with MBG. A similar pattern of CTS changes was observed in uremic rats. As compared to sham-operated animals, PNx rats exhibited 3-fold elevated levels of MBG but not that of EO.. In chronic renal failure, elevated levels of a bufadienolide CTS, MBG, contribute to Na/K-ATPase inhibition and may represent a potential target for therapy.

Topics: Animals; Antibodies, Monoclonal; Bufanolides; Case-Control Studies; Chromatography, High Pressure Liquid; Cohort Studies; Digoxin; Erythrocytes; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Male; Middle Aged; Nephrectomy; Ouabain; Oxidative Stress; Prognosis; Prospective Studies; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Vasoconstrictor Agents

Topics: Adrenergic beta-Antagonists; Aged; Amiodarone; Atrial Fibrillation; Bisoprolol; Bradycardia; Calcium Channel Blockers; Cardiovascular Agents; Combined Modality Therapy; Digoxin; Diltiazem; Female; Humans; Hypothyroidism; Kidney Failure, Chronic; Myocardial Infarction; Pacemaker, Artificial; Renal Dialysis

The safety of prescribing digoxin in ESRD is unknown. Hypokalemia, which frequently occurs among dialysis patients, may enhance the toxicity of digoxin. Here, we analyzed the association between digoxin prescription and survival in a retrospective cohort using covariate- and propensity score-adjusted Cox models to minimize the potential for confounding by indication. Among 120,864 incident hemodialysis patients, digoxin use associated with a 28% increased risk for death (hazard ratio [HR] 1.28; 95% confidence interval 1.25 to 1.31). Increasing serum digoxin level was also significantly associated with mortality (HR 1.19 per ng/ml increase; 95% confidence interval 1.05 to 1.35). This increased mortality risk with level was most pronounced in patients with lower predialysis serum potassium (K) levels (HR 2.53 [P = 0.01] for K <4.3 mEq/L versus HR 0.86 [P = 0.35] for K >4.6 mEq/L). In conclusion, digoxin use among patients who are on hemodialysis associates with increased mortality, especially among those with low predialysis K concentrations.

Topics: Aged; Cardiotonic Agents; Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Renal Dialysis

Topics: Digitalis; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis

Digoxin overdose is closely related to Chronic Kidney Disease and creatinine dosage adjustment is usually needed. Our goal was to assess the advantages of serum creatinine and the MDRD equation to detect hidden renal insufficiency to reduce the overdose Digital risk.. We describe all digoxin samples processed and registered in our hospital laboratory database for a year. Patients under 18 years and samples below therapeutic ranges were excluded. Chi square (p<0.05), ROC curves and logistic regression analysis were conducted. SPSS software was used.. Between 1228 digoxin samples taken to 679 patients (273 men, 77 +/- 10 years old , and 406 women 82 +/- 8 years old), 14% were over therapeutic range (28 men and 67 women). Significant differences were observed in over dosage between high creatinine group regarding to normal creatinine group (31% vs. 10% in men, 44% vs. 15% in women). ROC curves showed that the most accurate levels to predict digoxin over dosage were MDRD<56 ml/min/1.73 m(2) in men and MDRD<52 ml/min/1.73 m(2) in women. 68% of over dosage men had declines of MDRD levels, compared to 61% with high creatinine levels, 81% of over dosage women had declines of MDRD compared to 51% with elevated creatinine levels.. Even in patients with normal creatinine levels, chronic kidney disease enhances digoxin over dose risk. Using the decline of glomerular filtration rate estimated by the MDRD equation is better than elevated creatinine levels to detect digoxin overdose, thus constituting a very useful tool to reduce the risk of overdose, especially among women.

Topics: Aged; Aged, 80 and over; Algorithms; Creatinine; Cross-Sectional Studies; Digoxin; Drug Overdose; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; ROC Curve

Topics: Aged; Cardiotonic Agents; Digoxin; Drug Monitoring; Female; Heart Failure; Humans; Immunoassay; Kidney Failure, Chronic; Male

Not only the renal clearance but also the hepatic clearance of drugs varies with the progression of renal failure. The aim of this study was to investigate the effects of human uremic serum and various uremic toxins on the hepatic uptake of digoxin (DX), a drug mainly excreted into bile in patients with severe renal failure, using isolated rat and human hepatocytes as model systems. Uremic serum inhibited the uptake of DX into rat hepatocytes in a concentration-dependent manner, whereas normal serum did not affect the uptake. In addition, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol (PC) concentration dependently inhibited the uptake. CMPF and PC at the concentration of 400 microM, which is within the plasma concentration range attained in patients with renal failure, inhibited the uptake of DX into rat hepatocytes by 27% and 23%, respectively. In human hepatocytes, 10% uremic serum, 400 microM CMPF, and 400 microM PC inhibited the uptake of DX by 23.3%, 23.4%, and 28.2%, respectively. In conclusion, our results suggest that hepatic uptake of DX is likely to be inhibited by uremic toxins, such as CMPF and PC, present in the serum of patients with renal failure.

Topics: Animals; Biological Transport, Active; Cresols; Digoxin; Dose-Response Relationship, Drug; Furans; Hepatocytes; Humans; Kidney Failure, Chronic; Liver; Male; Propionates; Rats; Rats, Sprague-Dawley; Renal Dialysis; Uremia

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Digoxin; Dizziness; Electrocardiography; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Male; Muscle Weakness; Vision Disorders

Glomerular filtration rate (GFR) is the best index of kidney function. Mathematical estimations of GFR, based on serum creatinine (SCr), are a clinically useful method to follow renal function, but have certain limitations which need to be considered. Convention supports the use of Cockcroft-Gault (CG) for the purposes of drug dosing. The impact of using the modification of diet in renal disease (MDRD) formula has not been formally evaluated with respect to drug dosing; especially in an elderly multi-ethnic population. A cross-sectional study of long-term care facility patients was conducted to demonstrate the impact of the use of different formulae in the elderly for the purposes of medication dosing.. Patients with ESRD were excluded. GFR was calculated for all subjects using the four-variable modified MDRD equation (re-expressed using isotope-dilution mass spectrometry-based creatinine values) and the CG equation (corrected for body surface area). Discordance was defined as a reclassification of one stage of chronic kidney disease (CKD) by using a different formula. Calculated GFR from each formula was used to calculate the doses of two drugs: amantadine and digoxin, to demonstrate the potential impact of the use of different formulae on the risk of drug toxicity.. A total of 180 patients were identified with a mean age of 85 years, of which 30% were Asian. Mean MDRD-GFR and CG-GFR in the same group were different (72.9 ml/min/1.73 m(2) vs 52.1 ml/min/1.73 m(2)). Only 37.2% of the patients were categorized in the same stage of CKD by both methods. When MDRD was used in place of CG to determine drug dose adjustments, we found that 20% fewer patients would have qualified for a dose reduction of amantadine, which would have translated to a higher total cumulative dose delivered.. The use of CG and MDRD provided discordant estimations in over 60% of the elderly patients. While the importance of these equations cannot be questioned, caution should be exercised in situations where they have not been prospectively validated. Therefore, their interchangeable use cannot be advocated in the dosing of medications until further prospective validations are performed.

Topics: Aged; Aged, 80 and over; Algorithms; Amantadine; Asian People; Creatinine; Digoxin; Drug Administration Schedule; Ethnicity; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Male; Models, Theoretical; Retrospective Studies; White People

To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy.. All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 +/- 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200-400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8-4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53-190 days after the administration of clarithromycin.. The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin should be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiotonic Agents; Clarithromycin; Digoxin; Drug Interactions; Female; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Renal Replacement Therapy

Left ventricular hypertrophy commonly complicates chronic renal failure. We have observed that at least one pathway of left ventricular hypertrophy appears to involve signaling through reactive oxygen species (ROS). Green tea is a substance that appears to have substantial antioxidant activity, yet is safe and is currently widely used. We, therefore, studied whether green tea supplementation could attenuate the development of left ventricular hypertrophy in an animal model of chronic renal failure.. Male Sprague-Dawley rats were subjected to sham or remnant kidney surgery and given green tea extract (0.1% and 0.25%) or plain drinking water for the next 4 weeks. Heart weight, body weight, and cardiac Na-K-ATPase activity were measured at the end of this period. To further test our hypothesis, we performed studies in cardiac myocytes isolated from adult male Sprague-Dawley rats. We measured the generation of ROS using the oxidant sensitive dye dichlorofluorescein (DCF) as well as (3H)phenylalanine incorporation following exposure to cardiac glycosides with and without green tea extract.. Administration of green tea extract at 0.25% resulted in attenuation of left ventricular hypertrophy, hypertension, and preserved cardiac Na-K-ATPase activity in rats subjected to remnant kidney surgery (all P < 0.01). In subsequent studies performed in isolated cardiac myocytes, both ouabain and marinobufagenin (MBG) were both found to increase ROS production and (3H)phenylalanine incorporation at concentrations substantially below their inhibitor concentration (IC) 50 for the sodium pump. Addition of green tea extract prevented increases in ROS production as well as (3H)phenylalanine incorporation in these isolated cardiac myocytes.. Green tea extract appears to block the development of cardiac hypertrophy in experimental renal failure. Some of this effect may be related to the attenuation of hypertension, but a direct effect on cardiac myocyte ROS production and growth was also identified. Clinical studies of green tea extract in chronic renal failure patients may be warranted.

Topics: Animals; Blood Pressure; Bufanolides; Cardenolides; Cell Division; Cells, Cultured; Digoxin; Disease Models, Animal; Enzyme Activation; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Myocardium; Myocytes, Cardiac; Nephrectomy; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Rubidium Radioisotopes; Saponins; Sodium-Potassium-Exchanging ATPase; Tea

Hemodialysis (HD) causes rapid volume shifts and circulatory changes. In chronic renal failure (CRF) Na+/K+ATP-ase is depressed, whereas endogenous digoxin-like factor (EDLF) is elevated. Our aim was to characterize HD-induced cardiovascular adaptation and its possible links to Na+/K+ATP-ase and EDLF. Eleven children with CRF on HD (aged 14.7 +/- 3.7 years) and 11 healthy children were investigated for basic circulatory parameters. Thoracic impedance (Zo) and circulatory parameters were monitored by impedance cardiography (ICG) during HD. Erythrocyte Na+/K+ATP-ase and EDLF were measured before and after HD. Up to the loss of 6% of total body weight, Zo rose linearly with fluid removal, above this no further increase occurred. Heart rate and mean arterial pressure (MAP) were inversely related (r = -0.97); MAP rose in the first and decreased in the second part of HD. Systemic vascular resistance paralleled MAP, whereas stroke volume rapidly decreased, but stabilized in the second part of HD. The ratio of preejection period/ventricular ejection time (PEP/VET) correlated positively with HD duration (r = 0.92), suggesting diminished cardiac filling. Cardiac index (CI) remained stable. EDLF was high in uremia accompanied by depressed Na+/K+ATP-ase (P < 0.05 and P < 0.01, respectively). Following HD Na+/K+ATP-ase normalized. Correlation between Na+/K+ATP-ase activity and MAP was linear (r = 0.85). In conclusion, ICG during HD provides detailed information concerning circulatory adaptation resulting in stable CI, suggesting that the dialysis-induced hypovolemia is compensated by the centralization of the blood volume. Changes of Na+/K+ATP-ase indicate that dialyzable blood pressure-regulating substance(s) inhibit(s) the pump. However, lack of further correlation between Na+/K+ATP-ase, EDLF, and cardiovascular parameters indicates the complexity of the regulatory processes.

Topics: Adolescent; Blood Pressure; Cardenolides; Cardiography, Impedance; Child; Digoxin; Female; Heart; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

A sodium pump inhibitor (digitalis-like factor), isolated from the peritoneal dialysate of volume-expanded, hypertensive patients with kidney failure who were treated with this dialysis modality, was further purified and characterized by means of supercritical fluid chromatography, a separation technique whose application to very-low-concentration biomolecules is new. Previous studies suggested that after high-performance liquid chromatography (HPLC) purification, this inhibitor was the only factor correlated with volume status and blood pressure in these patients. When this same HPLC fraction was furthered purified on 2-dimensional supercritical fluid chromatography, a single peak coeluted with [Na,K]ATPase inhibitory activity. When split specimens were used, there was a strict correlation between the peak area, measured by flame ionization detection, and activity (n=10, R=0.98, P=0.00001). Inhibitory activity after supercritical fluid chromatography was still correlated with the degree of volume expansion of donor patients (P=0.01). After HPLC purification, this volume-sensitive inhibitor was chemically labile. With further purification on supercritical fluid chromatography, the active peak was still labile with comparable half-life. Supercritical fluid chromatography coupled with flame ionization detection provided an estimate of the amount of the inhibitor present. Again using split specimens, we determined that the labile digitalis-like factor was approximately 30-fold more effective than ouabain in inhibiting renal [Na,K]ATPase activity and >/=500 times more effective than ouabain in causing vascular smooth muscle contraction. The data suggest that we have purified to homogeneity a labile digitalis-like factor that is readily distinguished from ouabain or bufalin, based on chromatographic characteristics, chemical lability, and a much lower effective concentration for its biological activity.

Topics: Cardenolides; Chromatography, Gas; Chromatography, High Pressure Liquid; Digoxin; Enzyme Inhibitors; Humans; Hypertension; Kidney Failure, Chronic; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase

This prospective study was conducted to compare the predictive performance of fluorescence polarization immunoassay (FPIA, Abbott TDx Digoxin II) and radioimmunoassay (RIA, Kallestad Labs) with combined low-pressure liquid chromatography/RIA (LPLC/RIA) digoxin assay in measuring 15-17 serum digoxin concentrations (SDC) obtained after a single 10 microg/kg intravenous digoxin dose in patients with various degrees of renal function and at different SDC ranges. Eighteen men and women were stratified into 3 age- and gender-matched groups based upon renal function [N = 6 in each, group I (Cl(cr) < 10 mL/min), group II (Cl(cr) = 10-50 mL/min), and group III (Cl(cr) > 50 mL/min)]. Serum digoxin concentrations were measured at time zero; at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hours; and at 2, 3, 4, and 5-7 days after the digoxin dose, using the three different digoxin assays. TDx Digoxin II was unbiased [mean error -0.09 (95% CI -0.19, 0.01)] and RIA biased [mean error -0.29 (95% CI -0.36, -0.21)] to over-predict SDC by 14.2%. In group I patients, the analysis revealed a bias to over-predict SDC by 6.0% for TDx Digoxin II [mean error -0.16 (95% CI -0.29, -0.07)] and an unbiased performance by RIA. In groups II and III, both TDx Digoxin II and RIA showed biased performance, the mean magnitude of bias was low (< 20%). For intermediate SDC range (> 0.5 ng/mL and < or = 3.0 ng/mL), TDx Digoxin II was unbiased in predicting SDC, whereas RIA was biased to under-predict SDC [mean error 0.13 (95% CI 0.10, 0.16)] by 9.9%. The magnitude of bias observed in all cases was less than 20%. Both assays, TDx Digoxin II and RIA, imprecisely measured SDC for all samples combined, different groups and SDC ranges. In all time-paired samples, TDx Digoxin II (FPIA) performed better than the RIA. In conclusion, the magnitude of bias observed with either assay at different groups and SDC ranges was not likely to be clinically relevant. Therefore, either assay may be used to measure SDC in clinical practice.

Topics: Anti-Arrhythmia Agents; Chromatography, Liquid; Digoxin; Drug Monitoring; Female; Fluorescence Polarization Immunoassay; Humans; Kidney; Kidney Failure, Chronic; Male; Predictive Value of Tests; Prospective Studies; Radioimmunoassay; Reagent Kits, Diagnostic

Cardiac involvement rarely occurs in classic hemolytic uremic syndrome (HUS); it is often fatal.. The first patient, a 21-month-old boy, developed classic HUS with acute renal failure. Peritoneal dialysis was performed for 20 days. On the 10th day of dialysis, myocardial infarction occurred, probably related to coronary thrombus. The patient was given heparin and antibiotics because of an unexplained fever. The outcome was favorable despite antero-apical cardiac necrosis, and moderated chronic renal failure. The second patient, a 24-month-old girl, also showed a classic HUS, which required peritoneal dialysis for 10 days. Dilated cardiomyopathy with cardiac failure appeared on the 4th day of dialysis, not related to the volume overload and metabolic consequences of the acute renal failure, such as systemic hypertension or ineffective dialysis. On the 5th day of dialysis neurological involvement appeared. Neurological, cardiac and renal outcome was favorable. The third patient, a 25-month-old girl, developed a classical HUS, requiring peritoneal dialysis for 25 days. No cardiac insult appeared during the acute phase of the disease. After dialysis, the child had chronic renal failure (creatinine clearance: 15 mL/min/1.73 m2). Dilated cardiomyopathy appeared 3 months later, without definite etiology. The outcome was favorable with digoxin treatment.. A cardiac involvement should also be searched for in the acute phase of HUS and several months later.

Topics: Acute Kidney Injury; Cardiac Output, Low; Cardiomyopathy, Dilated; Cardiotonic Agents; Creatinine; Digoxin; Female; Follow-Up Studies; Hemolytic-Uremic Syndrome; Humans; Infant; Kidney Failure, Chronic; Male; Myocardial Infarction; Peritoneal Dialysis; Psychomotor Agitation; Sleep Stages; Treatment Outcome

To report a case of clarithromycin-induced digoxin intoxication.. A 78-year-old white man with ischemic cardiomyopathy and chronic renal insufficiency was admitted 4 days after being prescribed clarithromycin for a suspected episode of bronchitis. He reported weakness, asthenia, and gastrointestinal symptoms; the digoxin serum concentration was measured at 3.89 ng/mL. The patient recovered uneventfully after digoxin and clarithromycin were discontinued.. Erythromycin frequently interacts with other drugs that are also metabolized by the CYP3A4 isoenzyme. However, erythromycin is hypothesized to interact with digoxin by inhibiting Eubacterium lentum, which is a normal inhabitant of the human gut and is responsible for intestinal metabolism of digoxin in 10% of patients. Since clarithromycin shares a comparable antibacterial spectrum with erythromycin, the possibility of a drug interaction with digoxin remains. Only four cases of clarithromycin interacting with digoxin have been reported to date. Clinically, this interaction may have been more obvious because of our patient's moderate renal dysfunction and serum digoxin concentrations in the upper therapeutic range prior to clarithromycin initiation. Other causes for digoxin intoxication could not be identified.. Clarithromycin may inhibit the growth of E. lentum, which can lead to an increase in digoxin bioavailability and blood concentrations in patients in whom this intestinal metabolic pathway is present. Patients at risk include those with renal dysfunction, with serum concentrations in the upper therapeutic range, or with measured digoxin concentrations that are much lower than predicted by pharmacokinetic calculations. For these patients, appropriate therapy includes the selection of an alternative, noninteracting antibiotic or, if this is not possible, a temporary reduction of digoxin dosage.

Topics: Aged; Anti-Arrhythmia Agents; Anti-Bacterial Agents; Blood Pressure; Bronchitis; Cardiomyopathies; Clarithromycin; Digoxin; Drug Interactions; Heart Rate; Humans; Kidney Failure, Chronic; Male

Digoxin intoxication is a serious medical problem, and impairment of renal function is a common risk factor for toxicity. Digoxin specific antibody fragments (Fab) is the most effective treatment available for severe digitalis intoxication. The use of Fab therapy in a patient with renal disease is considered as effective as in patients with normal renal function, although the increased risk of rebound digoxin toxicity mandates a longer period of observation. In patients with kidney failure, neither digoxin nor Fab can be removed efficiently from the systemic circulation by hemodialysis or continuous arteriovenous hemofiltration. Knowledge about the clearance of both compounds by peritoneal dialysis is limited. The authors describe a patient with end stage renal disease who was treated with Fab and peritoneal dialysis for life threatening digoxin intoxication. Like other forms of dialysis, peritoneal dialysis, even when performed in an intensive schedule, is not associated with an enhanced clearance of digoxin.

Topics: Biological Availability; Bradycardia; Cardiotonic Agents; Digoxin; Drug Monitoring; Electrocardiography; Half-Life; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Tachycardia

1. Digoxin toxicity can result from overdose or iatrogenic causes, especially if renal function is impaired. 2. We present a case of digoxin toxicity presenting with severe bradycardia and hypotension in a 66 year old man with chronic renal failure. Regular haemodialysis had, as predicted, failed to reduce his plasma digoxin concentration. Digoxin specific antibody fragments (Fab) were not readily available and their use was probably inappropriate as they are normally renally eliminated. 3. The patient was successfully treated by two prolonged courses of intestinal dialysis with repeated doses of activated charcoal over 48 and 72 h and totaling 400 g and 600 g, respectively. However, the patient found the activated charcoal extremely unpalatable. 4. Multiple dose activated charcoal intestinal dialysis (MDACID) has been recently advocated for use in a wide range of poisonings. The technique takes advantage of the large surface area of the small intestine to eliminate drugs and metabolites, over several days if necessary. The pharmacokinetics of digoxin toxicity in chronic renal failure make intestinal dialysis an appropriate method of treatment but the realisation of the true potential of this technique awaits a more palatable absorbent or formulation.

Topics: Aged; Anti-Arrhythmia Agents; Antidotes; Charcoal; Dialysis; Digoxin; Humans; Intestinal Mucosa; Kidney Failure, Chronic; Male; Pacemaker, Artificial

Measurement of serum digoxin concentration is recommended as a routine in patients undergoing digoxin therapy because its therapeutic range is narrow. The presence of a high concentration of digoxin-like immunoreactive substances(DLIS) in human serum have been reported in a number of pathophysiological conditions. DLIS which cross-react with anti-digoxin antibodies, can falsely elevate the total digoxin concentration and is troublesome in the therapeutic monitoring of digoxin. The concentrations of serum total digoxin and DLIS in twelve patients of cardiac failure with renal insufficiency were estimated after determination of free digoxin by ultrafiltration with fluorescence polarization immunoassay. In these patients, the free digoxin concentration in serum determined was 0.79 +/- 0.48 (0.46-2.10) nmol.L-1. The total digoxin determined(1.31 +/- 0.80 nmol.L-1) was significantly higher than the calculated total digoxin(1.05 +/- 0.64 nmol.L-1) (P < 0.01), suggesting the presence of elevated DLIS in serum for these patients. The calculated DLIS concentration was 0.27 +/- 0.19(0.07-0.76) nmol.L-1. The results were well consistent with that obtained by recently published method of Dasgupta et al. In conclusion, the approach presented in this paper can estimate the true serum concentrations of digoxin and DLIS in patients of chronic cardiac failure with renal insufficiency.

Topics: Cardenolides; Cardiac Output, Low; Digoxin; Fluorescence Polarization Immunoassay; Humans; Kidney Failure, Chronic; Saponins; Ultrafiltration

The sensitivity of four new digoxin assay methods (on mini-Vidas bioMérieux, with Cedia reagent on Hitachi 911, with Syva Emit 2000 third generation reagent on Cobas-Mira and with Roche digoxin Online reagent on Cobas-Mira) to interference by digoxin like immunoreactive substances (DLIS) was studied in sera from 21 healthy controls, 18 pregnant women (9th month of pregnancy), 26 newborn infants and 42 patients with chronic renal failure undergoing hemodialysis. None of these individuals had been treated with digoxin or others cardiotonic drugs. For each method, results are different according to the population being studied, suggesting that the nature of DLIS is not the same. On the whole, interferences with DLIS seem to be more important in samples from newborn infants (for three methods out of four, the mean concentration of digoxin is significantly different from those observed in control samples). Digoxin assay on mini-Vidas and with Cedia reagent seems to be more sensitive to interference by DLIS, especially in samples from newborn infants and less in samples from pregnant women and patients with chronic renal failure. Online and Emit 2000 reagents seem to be poorly sensitive to interference by DLIS. However, for Emit 2000, the mean concentration of digoxin in samples from newborn infants is significantly different from the one observed in control samples. These results show that testing the sensitivity of new digoxine assay methods to interference by DLIS is very important because it can be a limitation to the use of a reagent independently of its analytical qualities.

Topics: Cardenolides; Digoxin; Drug Interactions; Enzyme Inhibitors; Female; Humans; Immunoassay; Indicators and Reagents; Infant, Newborn; Kidney Failure, Chronic; Pregnancy; Saponins

Compromised renal function predisposes to volume-dependent hypertension. Increased plasma levels of a sodium pump inhibitor as a possible pathogenetic factor have been demonstrated by many investigators in such patients, but efforts to identify the responsible agent have led to many, diverse candidates. Our premise in this study is that candidacy must depend on the satisfaction of rigorous criteria, including a specific action of the agent on the sodium pump. These criteria included reversibility, concentration dependence, receptor mediation, and an action at the appropriate step in the enzyme cycle. These criteria were applied to a potent [Na,K]ATPase inhibitor we have identified in the peritoneal dialysate of patients with chronic renal failure, present only during extracellular fluid volume expansion, the levels of which are correlated with the blood pressure rise that results from excessive NaCl and water intake. In microsomes that contained both [Na,K]ATPase and other ATPases, this candidate inhibited only the Na and K dependent, ouabain-sensitive ATPase. It displaced ouabain from the cardioglycoside binding site and its binding was linked to inhibition. Inhibition was produced by slowing the pump's dephosphorylation step, the exact action of all cardioglycosides. Finally, the candidate cross reacted with a digoxin Fab fragment and this Fab reversed its inhibition of [Na,K]ATPase. Together, these experiments demonstrate that the PD candidate specifically, and reversibly, inhibits the sodium pump via the cardioglycoside binding site, and hence, meets this crucial criterion for candidacy.

Topics: Antineoplastic Agents; Binding Sites; Binding, Competitive; Bufanolides; Cross Reactions; Dialysis Solutions; Digoxin; Enzyme Inhibitors; Humans; Immunoglobulin Fab Fragments; Iodine Radioisotopes; Kidney Failure, Chronic; Lysophosphatidylcholines; Oleic Acid; Ouabain; Peritoneal Dialysis; Peritoneum; Sensitivity and Specificity; Sodium-Potassium-Exchanging ATPase; Strophanthidin

Hyperkalemia resulting from digoxin toxicity is a well-recognized phenomenon. We report a case in which hyperkalemia, bradycardia, and hypotension were unresponsive to standard therapy but appeared to respond to digoxin-specific antibodies (Fab). This case highlights the importance of a high index of suspicion for digoxin toxicity as a potential cause of refractory hyperkalemia.

Topics: Digoxin; Female; Humans; Hyperkalemia; Kidney Failure, Chronic; Middle Aged

Topics: Aged; Aged, 80 and over; Digoxin; Drug Overdose; Female; Heart Failure; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Suicide, Attempted; Ultrafiltration

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

Digoxin and digoxin immune Fab, its antidote, are eliminated renally. However, the disposition of Fab in severe kidney disease is poorly described. Therefore, the disposition of Fab and its relationship to total and free digoxin were studied in five digoxin-toxic patients with end-stage renal disease (n = 4) or severe renal dysfunction (n = 1) with a mean (+/- SD) serum creatinine of 5.9 +/- 1.2 mg/dl (four patients were receiving long-term hemodialysis). Serum was drawn after a clinically neutralizing Fab dose (80 to 160 mg) every 12 to 24 hours for 204 to 327 hours. Fab concentrations were assessed by radioimmunoassay, whereas total digoxin concentrations were assessed with a modified radioimmunoassay or fluorescence polarization immunoassay. The concentration-time profile of Fab appeared to be similar to the concentration-time profile of total digoxin. The mean (+/- SD) half-lives of the alpha and beta disposition phases of Fab were 13 +/- 5 hours and 96 +/- 31 hours, respectively, which were similar to the alpha and beta parameter estimates of total digoxin (14 +/- 4 and 123 +/- 16 hours, respectively). Steady-state volume of distribution and systemic clearance of Fab were 0.29 +/- 0.11 L/kg and 0.057 +/- 0.022 ml/min/kg, respectively. Thus, in comparison to values reported in patients with normal renal function, the elimination of Fab and total digoxin are markedly delayed in patients with end-stage renal disease, which may necessitate prolonged clinical monitoring.

Topics: Aged; Digoxin; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Middle Aged

Digoxin-like immunoreactivity (DLS) and erythrocyte sodium-potassium pump (PSP) activity were measured in a group of 16 patients with chronic renal failure (CRF) before and just after haemodialysis and in a group of 9 healthy persons. Before haemodialysis DLS was present in the blood of most CRF patients, at the mean concentration of 0,14 +/- 0,13 micrograms/l. After haemodialysis DLS concentration decreased to 0,09 +/- 0,09 microgram/l (p less than 0,01). In the control group blood DLS concentration was nondetectable. In the CRF group PSP activity was higher before than after haemodialysis (p less than 0,01; 12,1 +/- 1,8 and 7,6 +/- 1,4 muMol Pi/h/g Hb. PSP activity in the control groups was 10,3 +/- 1,9 muMol Pi/h/g Hb). In the CRF group PSP activity was higher before haemodialysis (p less than 0,05) and lower after haemodialysis (p less than 0.01) than in the control group. Our results confirmed the presence of DLS in the blood of the majority of CRF patients. DLS concentration decreased after haemodialysis but we did not found any parallel increase in PSP activity in these patients. These results did not confirm the hypothesis that DLS might inhibit PSP activity in red blood cells from CRF patients.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Adrenergic beta-Antagonists; Blood Proteins; Calcium Channel Blockers; Cardenolides; Digoxin; Diuretics; Humans; Hypertension; Kidney Failure, Chronic; Prostaglandins; Renal Dialysis; Saponins

In order to characterize the structure of endogenous digitalis-like immunoreactive factor (DLIF), we utilized peritoneal dialysis fluid from patients with chronic renal failure as a source of endogenous digitalis-like immunoreactive factor (DLIF), and subjected it to one-step ion exchange chromatography, followed by one step reverse HPLC. Crude dialysis fluid contained 0.09 ng/ml of DLIF, and using Amberlite XAD-2 chromatography we extracted 110 ng of DLIF from 800 ml of dialysis fluid. By applying this partially purified DLIF to our HPLC system, we discerned three peaks of DLIF activity, with retention times of 34, 58 and 63 minutes. The first peak overlapped the elution profile of ouabain, and the third peak co-eluted precisely with digoxin. The second DLIF peak was not in proximity to any of the digitalis-like markers employed. Thus, our results indicate that DLIF isolated from peritoneal dialysis fluid exists in three distinct forms, one of which resembles ouabain, and one which is identical to digoxin.

Topics: Digoxin; Humans; Kidney Failure, Chronic; Male; Ouabain; Peritoneal Dialysis

The sensitivity of a new homogeneous enzyme immunoassay for the determination of digoxin (CEDIA Digoxin assay) and a fluorescence polarization immunoassay (FPIA) to interference by digoxin-like immunoreactive factors (DLIF) was studied in sera from pregnant women, newborns, patients undergoing hemodialysis and patients with renal insufficiency, but without hemodialysis. None of the patients had been treated with digoxin or digitoxin. Cross-reactivity of DLIF in the CEDIA assay was generally lower than in the FPIA. Data on the distribution DLIF of values and method comparisons showed that sera of the four patient groups reacted in a completely different way in both assays, suggesting that the nature of DLIF in the four groups is not identical. Addition of digoxin to sera of patients not treated with this drug resulted in a reduction of the apparent DLIF concentration in the CEDIA assay and the FPIA. This shows that DLIF interference may be less pronounced in sera of patients undergoing digoxin therapy compared to untreated persons. Although the CEDIA assay is less sensitive to DLIF interference than the FPIA, further efforts are needed to reduce the extent of this interference.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Drug Monitoring; Female; Fetal Blood; Fluorescence Polarization Immunoassay; Humans; Immunoenzyme Techniques; Infant, Newborn; Kidney Failure, Chronic; Pregnancy; Reference Values; Renal Dialysis; Saponins

The TDx digoxin II immunoassay was used in controls and in patients not taking digoxin or any other cardiac glycoside. We report the frequency of interference thought to be caused by digoxin-like factors (DLFs). We found a high incidence of false-positive results in 15 patients with severe hepatic disease (60% false-positive results). In newborn infants we found false-positive results both when their blood was drawn from a peripheral vein (89% false-positive results) and, more strikingly (100% false-positive results), when it was obtained from an umbilical cord vein (p less than 0.001). Compared to a control group, no statistically significant false-positive results were found in patients with mild to moderate chronic renal failure (n = 21) or in pregnant women (n = 15). In patients with chronic renal failure undergoing hemodialysis six of 25 had false-positive results. These results suggest that digoxin levels must be interpreted carefully in patients with chronic liver disease and chronic renal failure and in newborns until new methods that eliminate the interference caused by DLFs become readily available.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; False Negative Reactions; Female; Fetal Blood; Fluorescence Polarization Immunoassay; Humans; Infant, Newborn; Kidney Failure, Chronic; Liver Cirrhosis; Pregnancy; Prospective Studies; Renal Dialysis; Saponins

Endogenous digitalis-like factors (DLF) including those which were immunoreactive with digoxin antibody and those which displaced ouabain from Na,K-ATPase, were isolated from the plasma of a dialysis-dependent male patient not taking digoxin. Plasma was passed through a C18 disposable column, the DLF eluted with methanol and separated by HPLC on a C8 column. Immunoreactive DLF were measured in each 1 ml HPLC fraction using radioimmunoassay (RIA) for digoxin. The immunoreactive peaks were determined and aliquots from each peak analyzed by fast atom bombardment mass spectroscopy (FAB-ms). The compounds in the five major HPLC immunoreactive peaks were identified as: 1) dehydroepiandrosterone glucuronide and tetrahydrocortisone glucuronide; 2) epiandrosterone glucuronide; 3) dehydroepiandrosterone sulfate and androsterone glucuronide; 4) epiandrosterone sulfate and 5) androsterone sulfate and androstanediol glucuronide. These immunoreactive DLF represent 70% of the total plasma immunoreactive DLF of 0.124 micrograms digoxin equivalents/l. Aliquots of the HPLC fractions were also assayed for ability to displace ouabain from Na,K-ATPase. The ouabain displacing DLF gave a very different elution pattern from that obtained by RIA with the major Na,K-ATPase ouabain displacing DLF eluting in the more polar fractions. They remain unidentified.

Topics: Adult; Androgens; Blood Proteins; Cardenolides; Chromatography, High Pressure Liquid; Digoxin; Hemodialysis, Home; Humans; Kidney Failure, Chronic; Male; Ouabain; Saponins; Sodium-Potassium-Exchanging ATPase; Spectrometry, Mass, Fast Atom Bombardment

During last few years were reports concerning a new endogenous digoxin -like immunologic factor (DLIF) in patients not receiving digitalis. DLIF was stated in pregnant women's blood umbilical and neonatal blood as well as in patients with renal failure or hepatopathy. This phenomenon could be related to hormones changes (pregnancy) as well as alterations of cholesterol, triglycerides, free fatty acids, albumins or total protein level (nephropathy, hepatopathy). DLIF overstated determination of serum digoxin concentration, which in the case of exceptional narrow digoxin therapeutic spectrum as well as its concentration-dependent toxicity became a significant clinical problem. Effect extent of DLIF on serum digoxin level could be also related to applied analytic technics. The aim of the study was to compare two routinely applying analytic methods: polarized immunofluorescence (FPIA-TDx Abbott) with radioimmunological assay (RIA). The study was performed in patients with renal failure to estimate DLIF effect on real serum digoxin concentration as well as on extent and DLIF elimination velocity during dialysis. DLIF occurrence in patients with renal failure not receiving digitalis was experimentally stated using both RIA and FPIA methods. However, RIA revealed DLIF in all cases: before and after dialysis as well as in not dialyzed patients with a concentration above 0.3 ng/ml, when FPIA values were respectively: 0.087; 0.043; 0.078 ng/ml, which was less than 10% of digoxine therapeutic range (0.9-2.0 ng/ml). DLIF lowered in a course of dialysis to FPIA advantage, which was proved by FPIA/RIA ratio decrease nearly of a half of its predialysis value. Pre- and postdialysis values of FPIA/RIA ratio were 0,204 and 0,134 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Diagnostic Errors; Digoxin; Fluorescence Polarization Immunoassay; Humans; Kidney Failure, Chronic; Radioimmunoassay; Renal Dialysis

Verapamil increases the serum-digoxin concentration (SDC) in digoxin treated normals due to a compromised renal and extrarenal clearance. In chronic hemodialysis patients (CHD-patients) treated with digoxin where the renal elimination is diminished, verapamil has been shown to cause substantial increases of SDC with risk of digoxin intoxication. The effect of verapamil treatment on SDC in 8 nearly anephric (Uvol less than 1 l/d) CHD-patients on digoxin treatment was assessed. The patients were continuously treated with verapamil for two periods of two weeks at two dosage levels, 120 mg/d and 240 mg/d, whereafter verapamil was withdrawn. SDC and serum-verapamil were measured weekly. The SDC increased from 1.1 mmol/l to 1.7 mmol/l (p less than 0.05, N = 7) during the first two weeks. Increasing the dose of verapamil to 240 mg/d did not cause a further increment in SDC; on the contrary, the mean SDC decreased. The SDC increments varied between 0 and 200% of baseline values. We conclude that verapamil treatment decreases digoxin clearance in CHD-patients and that the influence of verapamil on SDC in CHD-patients shows great interindividual variation with no close dose dependency and decreases to pretreatment level in 2-3 weeks.

Topics: Adult; Digoxin; Drug Interactions; Humans; Kidney Failure, Chronic; Renal Dialysis; Verapamil

1. Erythrocyte Na+ transport (Na+ pump activity, co-transport, countertransport and passive Na+ efflux) and intracellular Na+ concentration were studied in 10 normal individuals and in 29 uraemic patients on chronic haemodialysis, before and after a haemodialysis session. Eight of them fulfilled the criteria of hypertension. 2. Normotensive patients before haemodialysis were classified in two groups: group 1 (pump-) with decreased erythrocyte Na+ pump activity, and group 2 (normal pump) with normal erythrocyte Na+ pump activity. Group 1 showed, compared with controls, a normal intracellular Na+ concentration and a decreased co-transport, but no difference in either countertransport or passive Na+ efflux. After haemodialysis this difference disappeared. Before haemodialysis, group 2 showed a high intracellular Na+ concentration, but activities of the Na+ transport systems studied were similar to those of controls. After haemodialysis, cell Na+ concentration decreased to a level not significantly different from that of controls. 3. Both before and after haemodialysis, hypertensive patients showed Na+ transport system activities and an intracellular Na+ concentration similar to those of controls. 4. Endogenous digoxin-like immunoreactivity (EDLI) and erythrocyte Na+ transport were studied in five normotensive and five hypertensive patients, before and after haemodialysis. EDLI in plasma was similar in both groups before and after haemodialysis. No correlation was found between EDLI and erythrocyte Na+ pump activity. 5. These results suggest the existence in some dialysed uraemic patients of alterations in erythrocyte Na+ fluxes, which may be corrected by haemodialysis. EDLI and erythrocyte Na+ fluxes do not seem to be markers of secondary hypertension in these patients.

Topics: Adult; Biological Transport; Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Saponins; Sodium; Sodium Channels; Sodium-Potassium-Exchanging ATPase; Uremia

Circulating digitalislike immunoreactive substances (DLIS) may represent a class of volume-sensitive natriuretic factors. Chronic renal failure patients are known to have elevated levels of circulating natriuretic activity and also to have detectable DLIS. Using digoxin radioimmunoassay, DLIS levels were measured in desalted, deproteinized plasma from 15 stable hemodialysis patients. Predialysis DLIS was 109.3 +/- 6.3 pg/mL (digoxin equivalents) and decreased to 97.5 +/- 5.9 pg/mL following dialysis (P less than 0.001). Predialysis DLIS correlated with weight gain from the prior dialysis (P less than 0.01). The degree of extracellular fluid volume expansion predialysis also correlated with predialysis DLIS (P less than 0.01). Postdialysis DLIS also correlated with postdialysis extracellular fluid volume status (P less than 0.01). DLIS levels in dialysis patients were higher than in 50 normal subjects (30.0 +/- 1.2 pg/mL; P less than 0.001). Also, the changes in DLIS with dialysis were paralleled by similar changes in simultaneously measured human alpha-atrial natriuretic peptide (ANP) levels. These results demonstrate that (1) DLIS levels are higher in hemodialysis patients than in normal individuals; (2) with dialysis, DLIS levels increase and decrease in association with extracellular fluid volume expansion and removal, respectively; (3) DLIS levels correlate with the degree of extracellular fluid volume expansion in dialysis patients; and (4) DLIS levels change in parallel with levels of another class of natriuretic factor ANP. These characteristics are consistent with the hypothesis that DLIS represents a volume-sensitive factor.

Topics: Adult; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Extracellular Space; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Radioimmunoassay; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase

Plasma atrial natriuretic peptide (ANP) and digoxin-like immunoreactive substances (DLIS) levels were assayed in 10 patients on intermittent peritoneal dialysis (IPD) before and after a 12 hour dialysis session. Ultrafiltration volumes and blood pressures, pre and post dialysis were recorded. Left atrial diameter (LAD), as determined by M-mode echocardiography was measured prior to and at the end of each dialysis session. Ten age matched patients on hemodialysis (HD) served as controls. Predialysis plasma ANP was significantly higher in HD as compared to IPD patients and dialysis resulted in a significant decrease of plasma ANP in IPD and HD patients (37.9 +/- 28.0 to 23.1 +/- 28.5 and 201.9 +/- 110.7 to 117.0 +/- 75.6 pg/ml, respectively, p less than 0.05). Ultrafiltration volumes in IPD averaged 1840 +/- 645 ml/dialysis. The corresponding decrease in body weight in HD was 2000 +/- 220 g. Total DLIS levels in IPD and HD did not change with dialysis. LAD decrease significantly post dialysis (41.3 +/- 5.0 to 38.6 +/- 5.7 cm, p less than 0.001). Calculated ANP clearance during IPD was 5.6 +/- 3.9 ml/min. Plasma ANP correlated significantly with ultrafiltration volumes and LAD. It thus appears that ANP is sensitive to volume status in dialysed patients. Its dialysance, in IPD, approaches that of other middle molecules. Under the conditions tested ANP does not influence DLIS levels.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Echocardiography; Female; Heart Atria; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Saponins

The elimination of total digoxin after digoxin-specific Fab fragment therapy in a patient in end-stage renal disease is described. Two-component, nonlinear exponential regression of the patient's total digoxin concentration data revealed biphasic elimination: a fast phase with a half-life of 43 h and a slow phase with a half-life of 330 h. Serum total digoxin concentration decreased 20% 12 h after the initiation of Fab fragment therapy. The mean serum concentrations of total digoxin and apparent total digoxin as measured by fluorescence polarization immunoassay during a 520-h period after the initiation of therapy were 18.42 and 14.77 ng/ml, respectively (n = 15). The correlation between the two measurements was good (r = 0.987). The time course of free digoxin concentration obtained after ultrafiltration at 2, 20, or 37 degrees C is also described. The free digoxin concentrations (n = 10) at these temperatures averaged over a 282-h period were 0.35, 0.53, and 0.82 ng/ml, respectively (p less than 0.001, 2 degrees C vs. 37 degrees C).

Topics: Aged; Atrial Fibrillation; Digoxin; Female; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Regression Analysis; Renal Dialysis; Ultrafiltration

In 43 ICU patients undergoing continuous volume constant hemofiltration (CVHF), the pharmacokinetics of 12 drugs were investigated to ensure correct dosage adjustments. Under conditions of CVHF, maximum doses were defined for cefotaxime, ceftazidime, digoxin, digitoxin, imipenem, metronidazole++, netilmicin, phenobarbital, phenytoin, theophylline, tobramycin, and vancomycin. For the estimation of sufficient doses without blood level measurements, sieving coefficients (S) were calculated by a new method. In addition, S was integrated as a CVHF-specific factor into a common equation for drug dose adjustment in patients with renal insufficiency. The regression of dosage received from kinetics on blood-level-independent equation adjustment was r = 0.9923. Since the volumes of distribution in ICU patients are variable, it is suggested that further drug monitoring is necessary for toxic drugs.

Topics: Adult; Aged; Cefotaxime; Ceftazidime; Digitoxin; Digoxin; Hemofiltration; Humans; Imipenem; Kidney Failure, Chronic; Metronidazole; Middle Aged; Netilmicin; Pharmaceutical Preparations; Phenobarbital; Phenytoin; Theophylline; Tobramycin; Vancomycin

Topics: Aged; Digoxin; Humans; Immunoglobulin Fab Fragments; Kidney Failure, Chronic; Male; Renal Dialysis

The pharmacokinetics of digoxin have been studied in eight healthy volunteers, 23 congestive cardiac failure and 10 chronic renal failure patients. The mean serum digoxin concentrations in the volunteers and the congestive cardiac failure patients were significantly different (P less than 0.001) from those in the chronic renal failure patients. The mean half-life of digoxin in the healthy volunteers (37.2 h +/- 8.6 s.d.) was comparable to the widely accepted 40 h for digoxin half-life in normal individuals. Half-life was significantly prolonged in renal failure patients. There was a good inverse correlation, in the three groups, between serum creatinine and creatinine clearance, but the expected close correlation between the renal clearance of digoxin and serum creatinine was not demonstrated, probably because this was an oral study. There was no statistically significant difference in the age and weight in all three groups. There was also no significant difference in all parameters, measured and derived, between the volunteers and the congestive cardiac failure patients. However, when the volunteers and/or the congestive cardiac failure patients were compared with the renal failure patients, there was a significant difference in all parameters except age and weight. Thus, in the absence of renal impairment and hypokalaemia, standard dosages of digoxin can be used in congestive cardiac failure patients, provided symptoms and signs of toxicity are constantly monitored. Therapeutic drug monitoring of digoxin is desirable in view of its low toxicity: therapeutic ratio, and its kinetics should be studied in detail in each community to establish correct dosages to prevent and manage digoxin toxicity.

Topics: Adolescent; Adult; Aged; Digoxin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nigeria; Reference Values

Topics: Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase

To elucidate further the possible role of atrial natriuretic peptide (ANP) and hypothetical natriuretic hormone (NH) in volume and BP regulation in chronic renal failure (CRF) we measured plasma ANP, digitalis-like substances (DLS) and Na+-K+-ATPase activity (using 86Rb influx into RBC) in 9 patients with CRF before and after hemodialysis. Volume expansion between consecutive dialyses led in all patients to the elevation of plasma ANP (83.4 +/- 14.2 pmol/l) reaching in some overhydrated subjects and/or patients with concomitant cardiac insufficiency concentration greater than 150 pmol/l. Reduced 86Rb influx into RBC before hemodialysis (37.7 +/- 4.9% of controls) was accompanied by higher DLS concentrations (201 +/- 32 pmol/l). Ultrafiltration during hemodialysis with ECFV reduction lowered both ANP and DLS concentrations to 28.1 +/- 9.4 pmol/l and to 151 +/- 23 pmol/l, respectively, and abolished partly the inhibition of Na+-K+-ATPase activity (64.9 +/- 7.6% of controls). These changes corresponded to the degree of ECFV alteration. Our results suggest that both natriuretic principles are activated during ECFV expansion in CRF, probably as a corrective mechanism, with a tendency to normalize when ECFV is reduced during hemodialysis.

Topics: Adult; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Female; Humans; Kidney Failure, Chronic; Male; Natriuretic Agents; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase

The pharmacokinetics of ibopamine was studied after single dose and after single and multiple dosing. The studies after single dose were conducted in normal subjects (NS) and in patients with congestive heart failure (CHF) of NYHA functional classes II, III and IV, in patients with chronic renal impairment (CRI), with hepatic cirrhosis (HC) and in elderly patients. Furthermore, ibopamine-quinidine pharmacokinetic interaction and the effects of food on plasma kinetics were evaluated in NS. The studies after single and multiple dosing were conducted in CHF patients. The effects were also studied of chronic oral ibopamine treatment on the pharmacokinetics of digoxin after chronic oral dosing and of treatment with digoxin on ibopamine pharmacokinetics. Ibopamine appears to be rapidly and extensively absorbed, quickly hydrolyzed to epinine and then excreted mainly through the kidneys either after being sulpho-conjugated or oxidized to homovanillic acid and 3,4-dihydroxyphenylacetic acid. Epinine is thought to be the therapeutically active moiety of the drug. In patients with CHF epinine pharmacokinetics does not depend on the NYHA functional class, and it falls within the same area as that in NS; the pharmacokinetics of epinine does not vary during the repeated administration of the drug for one month. In patients with CHF the pharmacokinetic data do not suggest the need to adjust the dose according to the NYHA functional class. In patients with CRI the pharmacokinetics of epinine does not vary with the degree of renal impairment. In HC patients AUC and Cmax of epinine seem to be higher than in NS; in these patients a higher amount of epinine is excreted into urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Absorption; Administration, Oral; Adult; Aged; Aged, 80 and over; Biological Availability; Chemical Phenomena; Chemistry; Deoxyepinephrine; Digoxin; Dopamine; Dopamine Agents; Drug Interactions; Female; Food; Heart Failure; Humans; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Quinidine; Vasodilator Agents

In patients on peritoneal dialysis drug movement across the peritoneum depends on the physiology of the peritoneal membrane, the physiochemical properties of the drug, the dialysis regimen and the basic pharmacokinetic properties of the particular pharmacon. Besides the low dialysate flow rate in continuous ambulatory peritoneal dialysis (CAPD), the latter point-drug kinetics-is thought to be of major importance for the influence of CAPD on drug kinetics. The eliminative potency of CAPD for drugs is limited due to the low dialysate outflow rate, an unfavorable ratio of the dialysate to the body volumes of distribution, the usually low ratio of the peritoneal to body clearance and the effect of drug protein binding. With intraperitoneal application, the drug appears rapidly in the circulation. This again results from the large differences in the volumes of the body to the peritoneal compartments, leading to a high concentration gradient across the peritoneal membrane. Thus a rapid disappearance of a pharmacon from the peritoneal cavity following intraperitoneal application combined with an insufficient drug elimination by CAPD may be explained by basic pharmacokinetic considerations. Unidirectional peritoneal transport of a particular drug has so far not been demonstrated.

Topics: Administration, Oral; Ceftriaxone; Cimetidine; Digoxin; Humans; Injections, Intravenous; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Tobramycin

The endogenous digoxin-like substance seems to play an important role in the aetiology and pathogenesis of essential and secondary hypertension. Immunoreactive digoxin-like substance was determined in 52 subjects: 17 healthy ones, 15 patients with essential hypertension, 10 cases of chronic renal failure and 10 patients with acromegaly. The substance was not found in healthy subjects, in acromegaly and essential hypertension. In chronic renal failure detectable concentrations of the substance were observed but they showed no correlation with the creatinine level and other clinical data.

Topics: Acromegaly; Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Reference Values; Saponins

Plasma digitalis-like factors (DLF), dehydroepiandrosterone sulfate (DHEAS) and cortisol were assayed in 20 healthy subjects, 22 dialysis dependent subjects and 30 patients with kidney transplants. DLF were assayed on plasma extracts by digoxin radioimmunoassay (RIA), and by Na,K-ATPase inhibition and [3H]-ouabain displacement using hogbrain Na,K-ATPase. Values for the 3 methods strongly intercorrelated (r = 0.99, p less than .001). Mean values for plasma DLF, assayed by all three methods, were significantly greater in dialysis dependent subjects, than in healthy subjects (p less than .0001). Mean plasma DLF values measured by digoxin RIA in renal transplant recipients, were significantly lower than in dialysis dependent subjects (p less than 0.0001) and higher than in healthy subjects. Plasma DLF values correlated inversely with creatinine clearance (p less than 0.01). Plasma DHEAS levels were significantly lower and contributed substantially less to digoxin antibody reactivity and ouabain displacement in dialysis subjects and in renal transplants compared with healthy subjects. There was no change in plasma immunoreactive DLF, DHEAS or cortisol measured before and after dialysis. DHEAS is a major digoxin like immunoreactive DLF and a minor Na,K-ATPase inhibitor in healthy subjects but makes only a minor contribution to DLF in dialysis and transplant subjects. We found the assays involving Na,K-ATPase inhibition and [3H]-ouabain displacement from Na,K-ATPase to be more sensitive for plasma DLF than the digoxin RIA, but because of the strong correlation between the methods, we suggest the RIA on plasma extracts can be used as a screening procedure.

Topics: Adult; Blood Proteins; Cardenolides; Dehydroepiandrosterone; Digoxin; Female; Humans; Hydrocortisone; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Ouabain; Radioimmunoassay; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Adolescent; Child; Child, Preschool; Digoxin; False Positive Reactions; Female; Humans; Kidney Failure, Chronic; Male; Renal Dialysis

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

Topics: Blood Proteins; Cardenolides; Chromatography, Gel; Digoxin; Female; Humans; Immunoenzyme Techniques; Infant, Newborn; Kidney Failure, Chronic; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Reference Values; Saponins

Topics: Blood Proteins; Cardenolides; Digoxin; False Positive Reactions; Female; Humans; Kidney Failure, Chronic; Pregnancy; Radioimmunoassay; Saponins

The hypothesis that endogenous digitalis-like compounds might participate in body sodium and water homeostasis have led us to investigate the presence in plasma of compounds interacting with digoxin antibodies in man and rats. The apparent levels of digoxin-equivalents in plasma of control subjects (n = 21) and patients with essential hypertension (n = 48) or end-stage renal failure (n = 13) were 24.7 +/- 3.2, 34.4 +/- 4.4 and 98.7 +/- 17.4 pg/ml, p less than 0.05 and p less than 0.01 respectively. Positive correlations were observed between systolic and diastolic blood pressure and the apparent immunoreactivity of plasma. No relationship was found with the renal Na+ excretion or the plasma renin activity. The apparent digoxin-like immunoreactivity of the plasma was correlated with its ability to inhibit ouabain binding to the erythrocyte Na+ pump and to reduce the renal Na+,K+-ATPase activity. In rats with experimental hypertension, the plasma cross-reactivity with antidigoxin antibodies was also enhanced when compared to control rats (71.6 +/- 10.2 pg/ml, n = 12 and 57.3 +/- 5.0 pg/ml, n = 33 in Na+ loaded rats and in rats with reduced renal mass respectively compared to 43.4 +/- 3.7 pg/ml, n = 36, p less than 0.05). In spontaneously hypertensive rats (SHR), the apparent levels of digoxin- equivalents were higher than that of age-matched WKY normotensive rats. This increase was already present in prehypertensive SHR (3 week-old) (105.8 +/- 12.4 vs 40.0 +/- 6.5 pg/ml, n = 9 and 8, p less than 0.001) and persisted after hypertension has developed (134 +/- 12.6 vs 85 +/- 7.9 pg/ml, n = 7 and 8, p less than 0.005 in 30 week-old rats). The apparent affinity of the erythrocyte Na+,K+ cotransport for intracellular Na+ and the maximal rate of the Na+ pump were correlated with the plasma digoxin-like levels. These results confirm the presence in plasma of compounds possessing some of the functional and structural properties of cardioactive steroids, associated with a rise in blood pressure.

Topics: Adult; Aged; Animals; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Rats; Rats, Inbred SHR; Saponins

Topics: Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Radioimmunoassay; Renal Dialysis

Digoxin-like immunoreactive substance(s) (DLIS) in the sera of patients with renal insufficiency may confound attempts to monitor serum digoxin levels. We investigated whether DLIS would affect the radioimmunoassay (RIA) for digitoxin. DLIS was detected by RIA in 9 of 38 chronic hemodialysis patients and in none of 25 healthy controls. Digitoxin levels were not elevated in either the control or dialysis group, and false-positive results for digitoxin by RIA were not obtained in any patient with DLIS. It is concluded that DLIS does not interfere with the digitoxin RIA, nor are digitoxin levels spuriously elevated in chronic hemodialysis patients. Digitoxin may be a preferable preparation for digitalis-dependent dialysis patients with DLIS.

Topics: Digitoxin; Digoxin; False Positive Reactions; Humans; Kidney Failure, Chronic; Radioimmunoassay; Renal Dialysis

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Humans; Infant; Infant, Newborn; Kidney Failure, Chronic; Radioimmunoassay; Saponins

By measuring in vitro the effect of deproteinized plasma on canine kidney Na+K+-ATPase activity, evidence was sought for the presence of a circulating inhibitor of the enzyme in 31 patients with end-stage renal failure, 10 patients treated with digoxin, and 22 patients with untreated essential hypertension. In the renal failure group, mean Na+K+-ATPase activity with plasma samples taken just before a regular haemodialysis was 88% of that obtained with plasma from a normotensive control group (P less than 0.001). In digoxin-treated patients, the result was 94% of that obtained in control subjects (P less than 0.005). There was no significant difference in mean Na+K+-ATPase activity with plasma, between the hypertensive and control groups, or between age- and sex-matched subsets of these groups. The hypertensive group did not differ significantly from the control group in plasma renin activity or erythrocyte Na+ concentration. It was concluded that a circulating digitalis-like sodium-pump inhibitor was readily detectable in volume-expanded renal failure, but not in normal-renin essential hypertension.

Topics: Adult; Digoxin; Female; Humans; Hypertension; Ion Channels; Kidney Failure, Chronic; Male; Middle Aged; Osmolar Concentration; Sodium; Sodium-Potassium-Exchanging ATPase; Uremia

Endogenous digitalis-like factors have been implicated in the adaptations that accompany renal insufficiency and in the pathogenesis of hypertension. We recently described several fractions of normal human plasma that inhibit NaK-ATPase and exhibit apparent digoxin-like immunoreactivity. To determine if hypertension and/or renal insufficiency affect plasma levels of these factors, we examined four patient groups: normotensive controls; hypertensive subjects with normal renal function; hypertensives with moderate renal insufficiency; and chronic dialysis patients. Plasma levels of digoxin-like immunoreactivity and NaK-ATPase inhibitory activity were significantly increased in hypertensive patients with mild renal failure (7.6 +/- 1.1 ouabain equivalents, mean +/- SEM, N = 21 vs 4.1 +/- 1.1 in normotensive controls, N = 20, P less than 0.05). NaK-ATPase inhibitory activity tended to be higher in patients with primary hypertension and normal renal function (5.5 +/- 0.7 ouabain equivalents, P less than 0.07); in dialysis patients, it was not different from controls. There was no correlation between NaK-ATPase inhibitory activity and blood pressure in any group. There was a significant rise in plasma NaK-ATPase inhibitory activity during dialysis (+ 1.8 +/- 0.7 ouabain equivalents, N = 22, P less than 0.03). As we have found that NaK-ATPase inhibitory activity in the plasma of normal humans can be separated into three distinct fractions, EI1, EI2, and EI3, we analyzed the plasma of 10 dialysis patients further. The increase in NaK-ATPase inhibitory activity could be attributed to fractions EI1 and EI3. These results suggest that plasma NaK-ATPase inhibitors increase with chronic renal insufficiency, but not hypertension alone. Although hemodialysis may acutely raise plasma levels, long-term dialysis returns them to the normal range.

Topics: Adult; Aged; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase

Immunoassay techniques have been widely used for therapeutic drug monitoring, but lack of antibody specificity can lead to measurement of erroneous drug concentrations due to cross-reactivity with other drugs, metabolites, or endogenous substances, particularly in patients with excretory organ compromise such as renal dysfunction. The Abbott TDx system, a popular automated immunoassay method for therapeutic drug monitoring, was used to measure apparent serum concentrations of carbamazepine, digoxin, gentamicin, lidocaine, phenobarbital, phenytoin, quinidine, valproic acid, and vancomycin in patients with renal failure who were not receiving these drugs. Endogenous substances and other concomitantly administered drugs did not lead to spuriously elevated drug levels, and a previous report of cross-reactive digoxin-like substances was not confirmed. Pooled plasma samples from the patients were spiked with digoxin or phenytoin, each at two concentrations, and the samples were assayed for the drug concentration using the TDx system. No falsely elevated values were found. This work suggests that the TDx system may be better suited for the measurement of these drugs in patients with renal failure than some other immunoassay methods.

Topics: Carbamazepine; Cross Reactions; Digoxin; Gentamicins; Humans; Immunoassay; Kidney Failure, Chronic; Lidocaine; Monitoring, Physiologic; Pharmaceutical Preparations; Phenobarbital; Phenytoin; Quinidine; Valproic Acid; Vancomycin

Topics: Adult; Aged; Digoxin; Female; Humans; Immunoassay; Kidney Failure, Chronic; Liver Diseases; Male; Middle Aged; Radioimmunoassay

We have studied three circumstances that have been reported to make interpretation of the serum digoxin concentration difficult in patients with renal failure: increased biotransformation; endogenous digitalis-like factors (DLF); and sudden, unexpected increases in serum digoxin values, even after the discontinuation of digoxin. Biotransformation, as estimated by the percent true digoxin in serum, was comparable in patients with renal failure who were dependent on dialysis and in control subjects (76% vs. 73%). Certain commercial immunoassays did not, or rarely, gave values for DLF of clinical significance (greater than 0.2 ng/ml digoxin equivalents) in patients with a wide range of renal dysfunction who were not receiving digoxin. With a sensitive method, values for DLF did not exceed 0.23 ng/ml in 22 dialysis patients dependent on dialysis, but were significantly increased in comparison with values in control subjects. The case histories of two patients with renal failure, acute illness, and sudden unexpected marked increases in serum digoxin concentrations are presented and possible explanations are discussed.

Topics: Adult; Aged; Biotransformation; Chromatography, High Pressure Liquid; Creatinine; Digoxin; Female; Humans; Kidney Failure, Chronic; Liver Function Tests; Male; Middle Aged; Peritoneal Dialysis; Radioimmunoassay

In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations after the oral administration of rubidium chloride. In this paper we describe our findings in 22 patients with untreated essential hypertension, compared with the findings in 22 carefully matched control subjects. Our findings in patients receiving short-term digoxin therapy and in patients with chronic renal failure are also included for comparison. Whereas the findings in patients receiving digoxin and in patients with chronic renal failure are compatible with a widespread reduction in sodium, potassium-ATPase activity in vivo, the findings in patients with untreated essential hypertension are not. Further analysis of the data and a similar study of the disposition of 42K after the intravenous administration of 42KCl suggest that in vivo net cation transport is enhanced in the erythrocytes of patients with untreated essential hypertension.

Topics: Adult; Aged; Biological Transport; Digoxin; Erythrocytes; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Rubidium

Topics: Acute Kidney Injury; Adolescent; Adult; Digoxin; False Positive Reactions; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Adolescent; Adult; Aged; Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Radioimmunoassay; Renal Dialysis

Digoxin-like substance (DLS) is detected in pregnant women near term, newborns, and in patients with renal failure using RIAs for digoxin. We made "digoxin" measurements in such patients using three digoxin RIA kits (Nuclear Medical Laboratories (N), Clinical Assays (C), and Corning Magic (M]. At term mother DLS (micrograms/l digoxin) was 0-0.19 (N), 0.09-0.24 (C), 0.07-0.24 (M); cord blood DLS was 0.35-0.75 (N), 0.46-0.90 (C), 0.42-0.90 (M); infant DLS was 0.5-1.1 (N), 0.28-0.98 (C) and was not measured by M. DLS was detected at term in mothers and was essentially undetectable by 24 hr postdelivery. Cord levels fell in eight of ten infants to significantly lower levels by the second day of life. DLS in renal hemodialysis patients not receiving digoxin was 0.04-0.41 (N), 0.01-0.34 (C), 0.03-0.40 (M). While postdialysis levels by N tended to be lower than predialysis, they rose by C and M. Dilutions of cord blood yielded similar results by N, nonlinear decreases by C, and more nearly parallel decreases by M. In renal failure patients, dilutions yielded similar results by N and marked nonparallel results by M. Digoxin results obtained with immunoassays may be inaccurate in these patient populations. Digoxin immunoassays must be individually characterized as to the expected results.

Topics: Digoxin; Female; Fetal Blood; Humans; Infant, Newborn; Kidney Failure, Chronic; Pregnancy; Radioimmunoassay; Reagent Kits, Diagnostic

A digoxin-like immunoreactive substance (DLIS) has been described in the sera of patients with renal impairment. To further investigate this problem, we measured digoxin in 50 patients with elevated serum creatinine using 4 commercial digoxin immunoassay kits (3 radioimmunoassay methods and 1 fluorescence polarization immunoassay technique). Ten of the patients were receiving digoxin therapeutically, while the remainder were not receiving the drug. Two of the radioimmunoassay kits detected low amounts of DLIS in 23% of the subjects not receiving digoxin, the highest level being 0.5 nmol/l. No DLIS was detected by the other radioimmunoassay kit or by the fluorescence polarization technique. The majority of renal patients receiving digoxin had similar results by all 4 methods, although 2 patients differed by 0.6 nmol/l as measured by 2 of the radioimmunoassay kits. We conclude that the extent of interference by DLIS in digoxin immunoassays in patients with renal impairment is not as great as has been previously reported.

Topics: Blood Proteins; Cardenolides; Digoxin; Fluorescence Polarization; Humans; Immunoassay; Kidney Failure, Chronic; Predictive Value of Tests; Radioimmunoassay; Reagent Kits, Diagnostic; Saponins

Topics: Digoxin; Humans; Kidney Failure, Chronic

We have previously shown that a natriuretic factor which is present in a small molecular weight fraction (IV) of serum and urine from salt loaded animals and healthy subjects, respectively, inhibits the Na-K-ATPase enzyme in vitro and also binds to a specific digoxin antibody. In the present study digoxin-like immunoreacting activity (DLIA) was therefore determined in the serum of healthy volunteers during low (35 nmol/day) and high (greater than 400 mmol/day) sodium intake and of patients with chronic renal failure and serum creatinine concentrations ranging from 127 to 757 mumol/l. DLIA was determined with a radioimmunoassay for digoxin in native serum and in the salt (III) and post-salt (IV) serum fractions eluted from a Sephadex G-25 column. DLIA in native serum of healthy subjects was less than 0.125 ng/ml. After gel filtration DLIA eluted exclusively in the small molecular weight salt (F III) and post-salt (F IV) fractions. Whereas DLIA increased in F III and decreased in F IV, total DLIA in F III + IV slightly increased from 0.37 +/- 0.03 to 0.49 +/- 0.05 ng/ml (p less than 0.01) with the change from low to high sodium intake. DLIA in native serum of uremic patients ranged from 0 to 1.70 ng/ml and was detectable consistently only in patients with serum creatinine concentrations above 250 mumol/l. DLIA in F III which averaged 0.22 +/- 0.04 ng/ml and total activity which ranged from 0.11 to 0.88 ng/ml closely correlated with the degree of renal impairment (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Chromatography, Gel; Creatinine; Diet, Sodium-Restricted; Digoxin; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Radioimmunoassay; Sodium; Sodium-Potassium-Exchanging ATPase

Cardiac dysfunction is common in patients with terminal renal failure. However, no consensus has been reached with respect to the indications for digitalis therapy. Depression of myocardial contractility may occur as a result of circulating toxic factors, parathyroid hormone, and altered catecholaminergic responsiveness. On the other hand, paradoxical positive inotropic effects have been observed possibly as a result of a circulating natriuretic factor (an endogenous digitalis analogue) which inhibits Na,K-ATP'ase. Pharmacokinetics and pharmacodynamics of digitalis steroids are altered in uremia. Elimination half-lives of strophanthin and digoxin are prolonged, whereas the elimination half-life of digitoxin is unchanged. Altered protein binding and volume of distribution have been noted. Despite its long elimination half-life, most nephrologists favor administration of digitoxin because of its insensitivity to changes in renal function.

Topics: Animals; Biological Availability; Blood; Blood Proteins; Cardenolides; Cardiomyopathies; Cats; Digitalis; Digitoxin; Digoxin; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Kidney Failure, Chronic; Kinetics; Metabolic Clearance Rate; Myocardial Contraction; Peritoneal Dialysis, Continuous Ambulatory; Plants, Medicinal; Plants, Toxic; Rabbits; Rana temporaria; Rats; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase; Stimulation, Chemical; Ultrafiltration; Uremia

Between January 1981 and April 1984, excessive serum concentrations of digoxin (5 ng/ml or higher) were recorded in 47 children, aged 2 days to 16 years. In 10 patients, the high concentrations were measured 9.25 to 48 hours after death and were significantly higher than antemortem levels in all cases (8.3 +/- 2.4 (+/- standard deviation) postmortem vs 3.3 +/- 1.5 antemortem, less than 0.0001). In 15 patients (40.5% of the living patients) serum concentrations of 5 ng/ml or higher reflected sampling errors; drug levels were monitored too closely to the administration of a dose. None of these children had toxic manifestations of digoxin. In 10 patients, the excessive concentrations were associated with renal failure and a prolonged elimination half-life (T1/2) of digoxin; in 3 of these patients, there were signs of digoxin toxicity. Six cases were caused by digoxin overdose (accidental ingestions, pharmacy error and a suicide attempt). In 6 additional cases, the existence of an endogenous digoxin-like substance (EDLS) was shown to contribute to the excessive levels of the drug. One case could be attributed to digoxin-amiodarone interaction. In 10 of 37 living patients, digoxin toxicity was diagnosed. After excluding the 15 sampling errors and 6 cases with EDLS, this represents 63% of the cases. There was a good correlation between digoxin elimination T1/2 and serum creatine concentrations (r = 0.71, p less than 0.01). The above observations suggest that excessive serum concentrations of digoxin may not necessarily reflect potentially toxic levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Amiodarone; Blood Proteins; Cardenolides; Digoxin; Drug Interactions; Female; Half-Life; Humans; Infant; Infant, Newborn; Kidney Failure, Chronic; Male; Saponins

Endogenous digoxin-like immunoactivity has been detected in the blood of adult patients in renal failure, newborn infants, and pregnant women in the third trimester. Blood levels of this activity increase in pregnant women as gestation progresses, and preliminary data suggest that the activity is increased in hypertensive pregnant women relative to normotensive pregnant women. Similar immunoactivity has also been detected in amniotic fluid and in the urine and serum of normal healthy subjects. The factors giving rise to this immunoactivity cross-react with antibodies used in many commercially available immunoassays for digoxin. The immunoactive factor isolated from human subjects is water soluble and exists tightly but reversibly bound to proteins in serum. The extent of this protein binding is altered in the clinical conditions studied relative to normal adults. This altered protein binding accounts for the detection of this factor by many of the commercially used immunoassays for digoxin. In this article I summarize recent findings related to detecting this activity in the blood of several clinical populations where the accurate measurement of digoxin may be compromised. I also summarize the preliminary isolation and characterization of the factor responsible for this immunoactivity.

Topics: Adult; Blood Proteins; Cardenolides; Creatinine; Cross Reactions; Digoxin; Female; Hot Temperature; Humans; Infant, Newborn; Kidney Failure, Chronic; Methods; Molecular Weight; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Reagent Kits, Diagnostic; Saponins; Ultrafiltration

Topics: Creatinine; Digoxin; Humans; Kidney Failure, Chronic; Methods; Renal Dialysis

We describe the occurrence of hyperkalemia in a stable hemodialysis patient who developed digoxin toxicity. The patient had been receiving digoxin for 2 years. His maintenance digoxin dose was increased from 0.125 to 0.25 mg three times a week, which resulted in a toxic serum level of 4.9 ng/mL (therapeutic range is 0.8 to 2.0 ng/mL). As a consequence of the digoxin toxicity, he became hyperkalemic (7.8 mEq/L), and this value returned to normal only after the digoxin level was lowered by a combination of oral charcoal and dialysis. This study shows how readily hyperkalemia can occur in an anephric patient manifesting digoxin toxicity. Thus, potentially lethal hyperkalemia can occur in hemodialysis patients who ingest therapeutic quantities of digoxin. Digoxin toxicity should be added to the differential diagnosis of hyperkalemia in patients with renal failure. This can occur despite the absence of a history of massive ingestion of a cardiac glycoside.

Topics: Aged; Digoxin; Dose-Response Relationship, Drug; Humans; Hyperkalemia; Kidney Failure, Chronic; Male; Propranolol; Renal Dialysis

This method for assaying digoxin in serum with improved specificity combines small-column extraction of serum, "high-performance" liquid chromatography, and RIA of the eluted fractions. Analytical recoveries of 1.0, 0.5, and 0.1 microgram/L standards were 95%, 93%, and 84%, respectively. The CVs for duplicates and replicates of sera with values of 0.5 to 1 microgram/L were 4 to 6%. Fifty-nine sera from 50 patients receiving digoxin were so studied. All digoxin metabolites appear to cross react with antibody to digoxin to various degrees. The most polar metabolites were quantitatively the most important, their average cross reactivity being 33%. For eight patients the value for digoxin by the present method was less than 60% of the RIA value. Sera from nine patients not taking digoxin but with falsely high digoxin values were also studied by the present method. The digoxin peak was well resolved from those for (a) digoxin metabolites (except dihydrodigoxin), (b) digitalis-like factors in neonates and in patients with renal failure or combined hepatic and renal failure, and (c) two cross reacting drugs and their metabolites.

Topics: Adult; Chromatography, High Pressure Liquid; Cross Reactions; Digoxin; False Positive Reactions; Fetal Blood; Humans; Infant, Newborn; Kidney Failure, Chronic; Liver Diseases; Radioimmunoassay; Renal Dialysis

We have reported the presence of endogenous digoxin-like immunoreactivity in the bloods of patients in renal failure, of newborn infants, and of third-trimester pregnant women. Similar reactivity has also been detected in amniotic fluids and in the urine and serum of normal healthy subjects. The substance(s) giving rise to this immunoactivity cross-react with the antibodies used in many commercially available immunoassays for digoxin. In this brief review I summarize the findings of our laboratory in detecting this activity in the bloods of several clinical populations where the accurate measurement of digoxin may be compromised. Present data suggests the substance or group of substances being detected by these immunoassays are not one or a combination of elevated steroids or polypeptides commonly observed in these same clinical conditions. Some preliminary information on the physical characterization of this activity is also presented.

Topics: Digoxin; Female; Half-Life; Humans; Immunoassay; Infant, Newborn; Kidney Failure, Chronic; Pregnancy; Pregnancy Trimester, Third; Reference Values; Renal Dialysis

In order to study cation transport in vivo the changes in plasma and red cell rubidium concentrations were measured following an oral load of rubidium chloride. Eight patients receiving short-term digoxin therapy, 10 patients with chronic renal failure and 22 patients with untreated essential hypertension were studied, and the findings were compared with those in healthy control subjects matched for age, sex, race, obesity index, and plasma and red cell potassium concentrations. In patients receiving short-term digoxin therapy, and in patients with chronic renal failure, the increases in plasma rubidium concentrations after the oral load of rubidium chloride were significantly enhanced and the increases in red cell rubidium concentrations were significantly attenuated. These findings are consistent with a generalized reduction in Na+, K+-ATPase activity in vivo. In contrast, in patients with untreated essential hypertension the increases in both plasma and red cell rubidium concentrations following the oral load were significantly enhanced. These data do not support the hypothesis that essential hypertension is associated with reduced Na+, K+-ATPase activity in vivo, at least in the red cell.

Topics: Adult; Aged; Biological Transport; Cations; Chlorides; Digoxin; Erythrocytes; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Rubidium; Sodium-Potassium-Exchanging ATPase; Time Factors

Serum digoxin and metabolites were assayed in plasma and urine by HPLC in 10 dialysis-dependent patients with end-stage renal failure (group I) and in five patients with comparatively normal renal function (group II) after ingestion of 150 muCi 3H-digoxin-12 alpha. Thirteen patients were on maintenance digoxin therapy and were at steady state. Metabolites found regularly but usually in small amounts, were 3 beta-digoxigenin and its mono- and bis-digitoxosides, and 3-keto and 3 alpha(epi)-digoxigenin. Quantitatively the most abundant metabolites were polar and averaged 26% (7 to 76) of the radioactivity in plasma 6 hr after drug, and 60% (11 to 88) for digoxin for all 15 patients. Neither values between group I and II for the polar metabolites nor digoxin differed significantly. The metabolites reacted with antibody to digoxin to varying degrees and may make up an important component of the serum digoxin concentration when determined by standard radioimmunoassay. In some patients, digoxin undergoes extensive biotransformation, mainly, we suggest by hydrolysis, oxidation, epimerization, and conjugation to polar end-metabolites.

Topics: Administration, Oral; Adult; Aged; Biological Availability; Biotransformation; Chromatography, High Pressure Liquid; Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Radioimmunoassay; Tritium

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Digoxin; Fluorescence Polarization; Humans; Immunoassay; Kidney Failure, Chronic; Middle Aged

In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations following an oral load of rubidium chloride. The changes in plasma rubidium concentration are related to the distribution of rubidium to all the body tissues and the changes in intra-erythrocytic rubidium concentrations provide an example of rubidium uptake by one particular tissue. In eight healthy volunteers pretreatment with a loading dose of digoxin (20 micrograms/kg) enhanced the rise in plasma rubidium concentrations and attenuated the rise in intra-erythrocytic rubidium concentrations after the oral load of rubidium chloride. Ten patients with chronic renal failure, compared with a well-matched control group, were found to have changes similar to, but more marked than, those caused by digoxin, i.e. a much greater rise in plasma rubidium concentrations and a much smaller rise in intra-erythrocytic rubidium concentrations, after the oral load of rubidium chloride. These findings are consistent with wide-spread reduction in Na+, K+-ATPase activity in subjects who have taken a loading dose of digoxin and patients with chronic renal failure. They are, therefore, consistent with the findings of previous studies in vitro and show that it is possible to demonstrate changes in cation transport in vivo.

Topics: Adult; Biological Transport, Active; Chlorides; Digoxin; Erythrocytes; Female; Humans; Kidney Failure, Chronic; Male; Methods; Middle Aged; Rubidium; Time Factors

Digoxin doses required to maintain therapeutic serum concentrations rose substantially in two patients dependent on dialysis with the commencement of rifampin therapy. When rifampin was discontinued, doses fell to requirements before rifampin. Serum digoxin concentration may fall to ineffective levels with rifampin therapy and rise to potentially toxic levels when rifampin is discontinued.

Topics: Digoxin; Drug Administration Schedule; Drug Interactions; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Rifampin

The authors have estimated the effect of hemodialysis on the pharmacokinetics of digoxin instilled intravenously to patients with the terminal stage of chronic renal insufficiency. It has been shown that dialysis was associated with an almost double increase in the clearance constant of digoxin due to its additional elimination through the membrane of the dialyzer. Over five h of dialysis the body excretes 12.5% of the administered dose of digoxin which is only 3.8% more (by 19 micrograms) than the average amount eliminated without dialysis. The contribution of dialysis to the elimination of digoxin is insignificant and, therefore, the regimen of its administration on days when dialysis is performed should be left unchanged.

Topics: Adult; Digoxin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Kinetics; Male; Metabolic Clearance Rate; Renal Dialysis; Time Factors

Topics: Adult; Creatinine; Digoxin; Heart Diseases; Humans; Kidney Failure, Chronic; Kinetics

Topics: Acute Kidney Injury; Adult; Aged; Arrhythmias, Cardiac; Diabetes Mellitus; Digoxin; Female; Half-Life; Hemoperfusion; Humans; Hypotension; Kidney Failure, Chronic; Male; Middle Aged; Polystyrenes; Polyvinyls; Renal Dialysis

For digoxin analyses blood and skeletal muscle samples were taken from seven digoxin-treated patients with chronic renal failure. The ratio between skeletal muscle and serum digoxin concentration in the patients with renal failure was not significantly different from the ratios in two control groups consisting of subjects with normal renal function. In the group of patients with renal failure there was no relationship between the glomerular filtration rate and muscle digoxin binding (specific plus unspecific). The present study does not indicate reduced skeletal muscle digoxin binding in patients with chronic renal failure.

Topics: Adult; Aged; Calcium; Creatinine; Digoxin; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Muscles; Potassium; Sodium

The peritoneal elimination of digoxin during C.A.P.D. was studied in five patients. The plasma half life of digoxin varied from 54 hours to 141 hours. Only 7 to 24 micrograms was eliminated via the peritoneal route during 3 to 4 days C.A.P.D. treatment. The total urinary elimination during the same period ranged from 11 to 57 micrograms. It is concluded that adjustment of dose is not necessary when starting C.A.P.D.

Topics: Aged; Digoxin; Female; Humans; Kidney Failure, Chronic; Kinetics; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Radioimmunoassay

Topics: Digitoxin; Digoxin; Female; Humans; Hydroxylation; Kidney Failure, Chronic; Male; Protein Binding; Radioimmunoassay

We evaluated the effect of quinidine on digoxin pharmacokinetic in six patients with severe renal failure. Quinidine reduced the total body clearance of digoxin from 1.87 to 1.06 l/hour (p less than 0.001), and prolonged the digoxin half-life of elimination from 5.20 to 9.61 days (p less than 0.01). The digoxin volume of distribution was unchanged. Renal clearance of digoxin was negligible; thus, the decrease in total body clearance was due to a decrease in the nonrenal clearance of digoxin. The mean trough serum concentrations of quinidine ranged from 1.0 to 3.0 micrograms/ml. We conclude that in patients with chronic renal failure, the dose of digoxin should be decreased by 50% if quinidine therapy is initiated.

Topics: Adult; Digoxin; Drug Interactions; Female; Half-Life; Humans; Kidney Failure, Chronic; Male; Middle Aged; Quinidine

Topics: Adrenergic beta-Antagonists; Digitalis Glycosides; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Heart Failure; Humans; Hyperthyroidism; Kidney Failure, Chronic; Liver Diseases; Quinidine

Na+,K+-ATPase activity was assessed indirectly in three groups of subjects of differing age, and in a group of patients with renal failure, by measuring the 86-rubidium uptake in the patients' own erythrocytes. The inhibiting action of digoxin on this activity was also measured in vitro. Erythrocyte 86Rb uptake was found to be lower in the elderly as was the calculated volume of distribution of digoxin. Sensitivity to the inhibiting action of digoxin increased with age. In the renal failure group 86Rb uptake was diminished and the sensitivity to digoxin was variable. This suggested that Na+,K+-ATPase activity could be one determinant of the volume of distribution of digoxin and that quantitative and qualitative changes of this enzyme could explain features of the pharmacokinetics of digoxin in renal failure and in old age.

Topics: Adult; Age Factors; Aged; Digoxin; Erythrocytes; Humans; Kidney Failure, Chronic; Middle Aged; Radioisotopes; Rubidium; Sodium-Potassium-Exchanging ATPase

Topics: Adolescent; Adult; Aged; Aging; Biological Transport, Active; Digoxin; Erythrocytes; Female; Humans; Hyperthyroidism; Kidney Failure, Chronic; Male; Middle Aged; Ouabain; Sodium; Sodium-Potassium-Exchanging ATPase

Topics: Adult; Digoxin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoenzyme Techniques; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Digoxin; Humans; Kidney Failure, Chronic; Male; Renal Dialysis

Topics: Digitoxin; Digoxin; Dose-Response Relationship, Drug; Glycosides; Heart Failure; Humans; Kidney Failure, Chronic; Metabolic Clearance Rate; Proscillaridin; Strophanthins; Uremia

Topics: Aged; Digitoxin; Digoxin; Humans; Kidney Diseases; Kidney Failure, Chronic; Liver Diseases

Investigations were performed in order to study whether or not quinidine would exert similar effects on the serum digoxin concentration in patients with renal failure as in normal subjects. Fourteen out of fifteen patients showed a significant increase of the serum digoxin level after four days of quinidine application. This indicates, that the quinidine effect is not solely caused by a decrease of the renal digoxin clearance, although nine patients, not being hemodialysed, revealed a correlation between their creatinine clearance and the rise of the serum digoxin concentration after quinidine. As however, the patients on hemodialysis did not show higher digoxin levels than those treated conservatively, it is suggested that the degree of the uremic intoxication might be responsible for the observed correlation.

Topics: Acetyldigoxins; Adult; Aged; Creatinine; Digoxin; Drug Interactions; Electrocardiography; Female; Heart Diseases; Humans; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Quinidine; Renal Dialysis

1. We have examined the inter-relationships between erythrocyte sodium content and sodium transport in a group of healthy subjects and in groups of patients with disorders known to change the sodium content of erythrocytes. 2. In the healthy subjects the sodium content of erythrocytes was inversely related to both the permeability of the erythrocyte membrane to sodium (as measured by the unidirectional, ouabain-sensitive, sodium efflux) and the total activity of the sodium pumps (as measured by the rate constant of ouabain-sensitive sodium efflux). There was a correlation between the total activity of the sodium pumps and the membrane permeability to sodium. 3. Changes in the erythrocyte sodium content were due to a decrease in the activity of the sodium pumps (as in hypokalaemia and digoxin treatment), or a decrease in the permeability of the erythrocyte membrane to sodium (as in chronic renal failure) or a reduction of both the membrane permeability and the number of sodium pumps (as in hyperthyroidism or elderly patients). 4. One interpretation of the results in the healthy subjects is that there are two components of sodium influx; one associated with the sodium pumps in what we have called 'membrane-units' and the other determined by the ground permeability of the membrane. 5. On the basis of this model we suggest that in the geriatric and hyperthyroid patients there is a reduction in the number of 'membrane-units', that in hypokalaemia and during digoxin treatment there is inhibition of the sodium-pump component of the 'membrane-units' and that in chronic renal failure there is a decrease in the permeability of the membrane to sodium.

Topics: Adult; Age Factors; Aged; Biological Transport, Active; Digoxin; Erythrocytes; Female; Humans; Hyperthyroidism; Hypokalemia; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Ouabain; Sodium

Topics: Aged; Digoxin; Heart Failure; Humans; Hypertension; Hypertension, Renal; Kidney Failure, Chronic

Topics: Adult; Aged; Digoxin; Diuretics; Drug Interactions; Female; Heart Diseases; Humans; Kidney Failure, Chronic; Male; Medigoxin; Middle Aged; Radioimmunoassay; Renal Dialysis; Uremia

1 Twenty-two dialysis dependent patients received an intravenous loading dose of digoxin of 10 microgram/kg and the mean +/- s.d. serum digoxin concentration 24 h later was 1.5 ng/ml +/- 0.4 (range 0.8--2.1 ng/ml). No evidence of toxicity was observed. 2 The average apparent volume of distribution of digoxin in dialysis dependent patients was found to be reduced by about one third compared with that reported for individuals with normal renal function, but there was great variation. 3 An appropriate intravenous loading dose of digoxin in most patients with advanced renal failure is 10 microgram/kg.

Topics: Acute Kidney Injury; Adult; Aged; Digoxin; Electrolytes; Half-Life; Humans; Kidney Failure, Chronic; Male; Middle Aged; Time Factors

The responses in the left ventricular systolic time intervals following digoxin administration (0.5 mg i.v.) were studied in 11 patients with chronic renal failure and hypertension. The control group comprised 11 patients with mild essential hypertension. There were no clinical signs of congestive heart failure in any of the patients. Before digoxin administration total electromechanical systole (QS2), the pre-ejection period (PEP) and the PEP/LVET ratio were greater, while the left ventricular ejection time (LVET) was shorter than in the control group (P < 0.001). In patients with chronic renal failure digoxin administration induced a reduction in QS2, PEP and PEP/LVET ratio and a prolongation of LVET (P < 0.001). These data suggest latent heart failure in the group of patients studied with chronic renal failure. It seems to be advisable to use digitalis preparations in patients with chronic renal failure despite the absence of clinical signs of heart failure.

Topics: Adult; Blood Pressure; Digoxin; Female; Heart Failure; Heart Ventricles; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Contraction; Systole

Topics: Digitalis Glycosides; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Uremia

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

Topics: Digoxin; Humans; Kidney Failure, Chronic; Radioimmunoassay; Renal Dialysis

Topics: Adult; Aged; Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Glycoside toxicity, a common and potentially fatal complication among patients taking digoxin, is treated basically by managing cardiac arrythmias until the patient can excrete enough drug to decrease the intoxication. Patients with renal failure, however, are particularly difficult to manage. We describe a case of advanced digoxin toxicity in an elderly man with severe renal failure, treated with a charcoal hemoperfusion device.

Topics: Aged; Arrhythmias, Cardiac; Charcoal; Digoxin; Half-Life; Heart Failure; Hemoperfusion; Humans; Kidney Failure, Chronic; Male

Topics: Aged; Biological Availability; Digoxin; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Middle Aged

A digitoxic patient with severe renal failure underwent two hemoperfusion treatments with Amberlite XAD-4 resin. Digoxin clearances calculated from plasma flow rates and plasma digoxin concentrations, as well as from the amount of digoxin eluted from the used columns, were superior to those previously described for peritoneal dialysis, hemodialysis and charcoal hemoperfusion. There was a temporary improvement in the patient's life-threatening digitoxic cardiac rhythm with the first hemoperfusion, and a permanent improvement after the second hemoperfusion. It is submitted that hemoperfusion with this resin may significantly lessen manifestations of digoxin poisoning and may hasten digoxin elimination in digitoxic patients with renal failure.

Topics: Aged; Blood Flow Velocity; Digoxin; Heart Block; Hemoperfusion; Humans; Ion Exchange Resins; Kidney Failure, Chronic; Male; Polystyrenes; Polyvinyls

Topics: Adult; Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged

A 72-year-old man with coronary heart disease and renal failure required hospitalization because of digoxin intoxication with severe arrhythmias and generalised heart failure. The intoxication was successfully treated and sinus rhythm rapidly restored after administration of heterologous digoxin-specific F(ab')2 antibody fragments. There were no side-effects and the heart failure improved after treatment.

Topics: Aged; Animals; Antibodies; Coronary Disease; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Male; Sheep

The purpose of this study was to determine if there is a linear relationship between oral doses of digoxin and various measurements of steady-state digoxin plasma concentration and urinary excretion in patients with wide range of renal function. Ten patients (mean age 58 years) with creatinine clearances greater than 50 ml/min/1.73 m2 BSA (mean creatinine clearance 80 ml/min/1.73 m2 BSA) and nine patients mean age 61 years) with creatinine clearances less than 50 ml/min/1.73 m2 BSA (mean creatinine clearance 20 ml/min/1.73 m2 BSA) were given digoxin tablets orally at two or three different dose levels (dose range 0.0313--0.5 mg/day). After a dosing period equal to at least five half-lives, three to four consecutive daily digoxin plasma concentrations were determined. Plasma concentrations and urinary digoxin excretion were measured during one 24-hour dosing interval at each dose level. Digoxin plasma and urine concentrations were determined in triplicate using radioimmunoassay. Individual patient plots provided evidence of linearity for: digoxin 24-hour steady-state plasma concentration vs dose; digoxin 24-hour cumulative urinary excretion versus dose; and area under the digoxin plasma concentration-time curve during a 24-hour dosing interval vs dose. Absolute values for these various parameters indicated substantial interpatient variation probably due to patient differences in both digoxin absorption and digoxin total body clearance. These results indicate that there is a linear relationship between digoxin plasma concentration and dose in patients with normal and decreased renal function. This linearity is support for dose-independent pharmacokinetics of digoxin in man. We conclude from these data that a change in digoxin dose should result in a proportional change in digoxin plasma concentration over the dose range examined.

Topics: Administration, Oral; Adult; Aged; Atrial Fibrillation; Digoxin; Dose-Response Relationship, Drug; Female; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Tablets; Time Factors

Digoxin dosage regimens for patients on chronic intermittent hemodialysis (CIH) were calculated from pharmacokinetic data of digoxin in these patients between the during hemodialyses. Especially when a maximal digitalisation is not necessary an administration of 0.125 mg digoxin only on days without hemodialysis will be adequate. The regimens should be considered as a suitable starting-point in therapy as individual differences in bioavailability, apparent volume of distribution. clearance and sensitivity may necessitate an individual correction. The place of hemodialysis in the management of severe intoxications will also be discussed. Besides, it is advised to use digoxin instead of digitoxin in patients on CIH.

Topics: Digitoxin; Digoxin; Humans; Kidney Failure, Chronic; Kinetics; Renal Dialysis

Removal of digoxin by hemoperfusion over Amberlite XAD-4 was determined in a functionally anephric patient. During four hours of hemoperfusion, 50.45 microgram of digoxin were removed by the column and serum digoxin concentrations decreased by 0.2 ng/ml after the post-hemoperfusion reequilibration was complete.

Topics: Digoxin; Heart Failure; Hemoperfusion; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polystyrenes; Polyvinyls; Resins, Synthetic; Tissue Distribution

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

The effect of an i.v. injection of 25 mg heparin on the plasma digoxin level was studied in ten patients on chronic intermittent hemodialysis. Six patients did not show a significant change in the plasma digoxin level of more than 0.1 ng/ml. An increase up to 0.4 ng/ml was observed in four patients. The consequences with regard to digoxin assay and clinical effects are discussed.

Topics: Digoxin; Drug Interactions; Fatty Acids, Nonesterified; Heparin; Humans; Kidney Failure, Chronic; Kinetics; Triglycerides

Topics: Creatinine; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Medigoxin

Consideration of the interactions of drugs and dialysis must include an understanding of the mechanisms of transport during dialysis, i.e., diffusion, ultrafiltration and membrane-protein binding effects. Clearance is a function of molecular size, blood and dialysate flow, membrane area and permeability, and dialyzer support geometry. Protein binding and hematocrit decrease the in vivo clearances in comparison to those measured in vitro with aqueous solutions. The effect on the serum half-life is also determined by the distribution space and clearance by other routes. Other factors such as metabolic alterations of dialysis can affect pharmacologic activity, and the clinical response is the end product of many determinants. Numerous drugs are effectively removed by hemodialysis or at a slower rate by peritoneal dialysis, which occasionally allows considerable influx. The influence of intestinal contents on elimination rates by peritoneal dialysis is unknown. Peritoneal dialysis can be influenced considerably by vasoactive drugs.

Topics: Animals; Barbiturates; Capillary Permeability; Digoxin; Half-Life; Humans; Kidney Failure, Chronic; Metabolic Clearance Rate; Peritoneal Dialysis; Pharmaceutical Preparations; Poisoning; Potassium; Protein Binding; Renal Dialysis

The purpose of pharmacokinetics of cardiac glycosides is to study the time courses of glycosides in biological fluids, tissues and excreta. The extent of accumulation of a given dose at uniform time intervals depends only from the overall elimination rate constant. By knowing the elimination rate constant the extent to which a cardiac glycoside would accumulate in the body following a fixed dosing regimen can be calculated. The higher accumulation in the central nervous system requires a much longer time. Therefore it may be assumed that the brain is a deep compartment for cardiac glycosides and this compartment cannot be detected by analysis of plasma glycoside concentrations. Central side effects of cardiac glycosides may occur at therapeutic plasma levels. In renal disease a lower maintenance dose of digoxin and methyldigoxin should be administered or the same dose less frequently. Digitoxin does not accumulate in patients with renal failure or in anuria since the extrarenal elimination of digitoxin is much higher compared to digoxin and methyldigoxin.

Topics: Biological Availability; Cardiac Glycosides; Central Nervous System; Digoxin; Humans; Kidney Failure, Chronic; Kinetics

In 1164 cases clinical and electrocardiographical findings were correlated with serum digoxin concentrations (SDC). The diagnosis of digitalis intoxication was based on rhythm disturbances which disappeared on withdrawel of the drug. The mean SDC for patients with digitalis-induced arrhythmias was 3.07 ng/ml compared to 1.02 ng/ml for patients with normal Ecg's and 1.01 ng/ml for patients with rhythm disturbances of other origin. Taking 2.0 ng/ml as the lower limit of digitalis intoxication a more than 85% coincidence was found between the diagnosis based on serial Ecg's and on SDC levels. No signs of cardiac toxicity were found in patients with SDC's less than 1.6 ng/ml, some patients, however, showed normal Ecg's despite SDC's up to 4.5 ng/ml. Patients with SDC's greater than 1.9 ng/ml and normal Ecg's were significantly younger than patients with digitalis-induced arrhythmias at comparable SDC's. Although no definite diagnosis of cardiac toxicity could be established in 327 cases, the clinical data of patients with SDC's of 2.0 ng/ml and greater resemble closely those with digitalis-induced arrhythmias while patients with SDC's less than 2.0 ng/ml showed close resemblance to patients with no cardiac evidence of toxicity with regard to: mean age, kidney function, mean digoxin dosage and mean body weight. Patients with elevated SDC's showed a 45% incidence of severely impaired kidney function in contrast to 28% of the patients with SDC's less than 2.0 ng/ml. Even in patients with normal kidney function the correlation between the orally administered digoxin dosage and SDC levels was poor. The correlation was significantly better when dogoxin was administered intravenously. Therefore knowing the amount of digoxin taken (according to the patient's statement) seems of little benefit in the evaluation of digitalis toxicity. In patients with digitalis-induced arrhythmias mean age and mean body weight were significantly lower, mean creatinine concentration and the incidence of severe cardiac insufficency and of typical ST-T-changes were significantly higher. There was no significant difference in mean potassium concentration and incidence of coronary artery disease compared to nontoxic patients. Compared to patients with cardiac arrhythmias of other origin there were no significant differences in mean age, mean potassium and creatinine concentrations and cardiac insufficiency while the incidence of coronary artery disease was significantly higher among patien

Topics: Arrhythmias, Cardiac; Creatinine; Digoxin; Electrocardiography; Heart Failure; Humans; Kidney Failure, Chronic; Potassium

Pharmacokinetics of digoxin was studied in 9 patients during hemodialysis. All patients were treated with a short-dialysis schedule, using Gambro Lundia Major dialysers for 5 patients and Gambro Lundia Nova dialysers for 4 patients. Clearances of the dialysers and half-lives were calculated from plasma digoxin levels in blood samples taken simultaneously from arterial and venous blood lines during hemodialysis. The mean clearances of the Major and Nova were 28.3 and 21.8 ml/min respectively. During hemodialysis the mean plasma half-life was 13.8 hours with the Major and 19.1 hours with the Nova. The mean net lowering effect of hemodialysis on the plasma concentration decay line was 9.5 and 6.5% for the Major and Nova respectively. Post-dialysis plasma concentration data suggest that the rate at which digoxin returns to plasma from body tissues is the rate-controlling factor in the elimination of digoxin by the artificial kidney.

Topics: Digoxin; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Metabolic Clearance Rate; Renal Dialysis; Time Factors

Topics: Adult; Aged; Creatinine; Digoxin; Female; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Renal Dialysis

Topics: Adolescent; Adult; Digoxin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Adult; Aged; Digoxin; Female; Heart Diseases; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged

Digoxin is excreted primarily in the urine as the unchanged glycoside: 60-80% can be recovered from the urine in 7 days after a single intravenous dose in the human subject. Definition of the role of the kidney in digoxin excretion, turnover and metabolism was studied in 57 patients with renal disease, transplant candidates and/or donors and recipients of renal transplants. A single dose of 3H digoxin was given to the subjects, frequent serum samples were obtained and all urine and stools were saved for 7 days. All specimens were extracted with chloroform and digoxin, and its metabolites were separated by column chromatography. Results reveal that the serum T1/2 and the dominant T1/2 of digoxin are prolonged in renal disease in direct proportion to the reduction in creatinine clearance (r = 0.833). The blood urea nitrogen (BUN) is also related to digoxin clearance (r = 0.742). The higher the BUN, the less digoxin excreted in the urine. Anephric patients excrete more digoxin in stool, but this does not compensate for the lack of renal excretion. Transplanted kidneys excrete digoxin in proportion to renal functional capacity, as do patients who have experienced unilateral nephrectomy. Peritoneal or hemodialysis is not effective in removing digoxin from the human subject and may lead to digitalis intoxication if K+ is allowed to fall to critical levels. Digoxin excretion is not volume related, as patients with nephritogenic diabetes insipidus excrete the drug normally with urine volumes of 12 liters a day. Digoxin doses in renal insufficiency should be dictated by knowledge of renal functional ability of the kidneys and after "normal" loading doses, and maintenance doses should be 1/4 to 1/2 those usually administered.

Topics: Adult; Aged; Blood Urea Nitrogen; Creatine; Digoxin; Female; Half-Life; Heart Failure; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Kinetics; Male; Middle Aged; Nephrectomy; Peritoneal Dialysis; Renal Dialysis; Tissue Donors; Transplantation, Homologous

Seventy-six patients with clinical and ECG evidence of digitalis toxicity and serum-digoxin concentrations over 2.5 ng/ml were investigated for possible correlation between certain ECG changes and the level of serum digoxin, but no correlation was found. However, radioimmunological determination of digoxin level proved to be a reliable means of deciding whether abnormalities of impulse formation or conduction were due to digitalis. In only one case (during haemodialysis) was there a fall in potassium level below normal, with signs of digitalis toxicity electrocardiographically. In five other patients with serum digoxin levels above 6 ng/ml high potassium values were found. Caution in the administration of potassium is advised: it should be given only if it is demonstrated to be below normal. Fifty-one of the patients had impaired renal function.

Topics: Aged; Arrhythmias, Cardiac; Digitalis Glycosides; Digoxin; Electrocardiography; Female; Humans; Hypokalemia; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Radioimmunoassay; Renal Dialysis

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population. Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dialyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin. When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (plus or minus SE) of 0.84 plus or minus 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 plus or minus 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the parmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.

Topics: Adult; Digitoxin; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Kinetics; Middle Aged; Renal Dialysis

Six commercially available kits for radioimmunoassay of digoxin were compared. When serum from patients with chronic renal failure on maintenance digoxin therapy was analysed, important discrepancies in the results obtained with the 6 kits were found in some of these patients. However, recovery of digoxin added to serum of a healthy volunteer, was within acceptable limits and comparable for the 6 kits. In patients with renal failure not taking digoxin but several other medications, digoxin estimations gave results close to zero. The affinity of the antibodies for some metabolites of digoxin was also assessed: important differences between the kits were found.

Topics: Adult; Aged; Digoxin; Evaluation Studies as Topic; Humans; Kidney Diseases; Kidney Failure, Chronic; Methods; Middle Aged; Radioimmunoassay

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2-compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady-state volumes of distribution (V-ss-D equals 195 to 489 liters/1.73 m-minus2) and t1/2beta values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant V-ss-D and a rigorous relationship between t1/2beta and creatinine clearance (Cl-CR). Body clearance (Cl-B) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between Cl-B and renal clearance of digoxin or Cl-CR was found and was used to develop a model-independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady-state serum concentrations of digoxin (C-ss-p) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of C-ss-p is obtained by use of digoxin renal and body clearances. Variability in the digoxin:creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.

Topics: Adult; Aged; Creatinine; Digoxin; Half-Life; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kinetics; Metabolic Clearance Rate; Middle Aged; Protein Binding; Radioimmunoassay

The authors used radioimmunity to study blood digoxin behaviour in patients with normal renal function and with variable BUN. The computerized and mathematically considered data showed that digitalic intoxication occurs with higher digoxin blood levels in patients with renal failure than in normal renal function cases. In the first case, moreover, it occurs sooner than in the second one, and the total digoxin dose is smaller than in normal patients. We have found that the large range of digosin blood levels is vital in deciding the therapeutic and toxic dose; that may be done, for most cases, following the estimate of the theoretical saturation dose using our method.

Topics: Aged; Arrhythmias, Cardiac; Digoxin; Female; Heart Block; Heart Failure; Humans; Kidney Failure, Chronic; Male; Middle Aged; Radioimmunoassay

The radioimmunoassay of digoxin is one of the most important services of the nuclear medicine laboratory. Precision and accuracy in the performance of the test are especially critical. A number of commerical kits are available and reliable. Pitfalls to be avoided includelimited availability or delay in performance of the assay; failure to consider senitizing factors; drawing the blood sample too soon after a digoxin dose; failure to consider desensitizing factors; forgetting that renal function is a major determinant of blood and tissue digoxin levels; assuming patient compliance and uniform intestinal absorption (bioavailiability with all digoxin preparations in all patients; attempting to interpret digoxin levels without the necessary clinical information; and failure to deliver the result to the proper person. If one avoids these pitfalls, and important service will be rendered in the evaluation of the patient requiring digitalis therapy.

Topics: Administration, Oral; Aged; Biopharmaceutics; Calcium; Digoxin; Drug Interactions; Female; Heart Diseases; Humans; Hypothyroidism; Hypoxia; Kidney Failure, Chronic; Magnesium; Male; Middle Aged; Potassium; Procainamide; Propranolol; Quinidine; Radioimmunoassay

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

Plasma digoxin and digitoxin determination has proven to have an important bearing, particularly in patients with renal failure. It permits early detection of digitalis intoxication in the absence of marked clinical and ECG evidence, and adjustment of dosage accordingly. Also, in patent intoxication it makes it possible to select the right moment for resumption of therapy. To illustrate the importance of the method some cases are cited involving plasma digoxin and digitoxin determination.

Topics: Acute Kidney Injury; Bradycardia; Creatinine; Digitalis Glycosides; Digitoxin; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic

Topics: Arrhythmias, Cardiac; Digitalis Glycosides; Digoxin; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Potassium; Renal Dialysis; Time Factors

Topics: Administration, Oral; Aged; Arrhythmias, Cardiac; Digitalis Glycosides; Digitoxin; Digoxin; Heart Block; Heart Diseases; Heart Failure; Humans; Hyperthyroidism; Injections, Intravenous; Kidney Failure, Chronic; Middle Aged; Obesity; Ventricular Fibrillation

Topics: Adolescent; Creatinine; Digoxin; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Kinetics; Metabolic Clearance Rate; Radioimmunoassay

Topics: Digoxin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Kidneys, Artificial; Male; Radioimmunoassay; Renal Dialysis

Topics: Adult; Digoxin; Female; Humans; Kidney; Kidney Failure, Chronic; Male

Topics: Digoxin; Humans; Kidney; Kidney Failure, Chronic; Radioimmunoassay

Topics: Adult; Aged; Creatinine; Digoxin; Female; Glomerular Filtration Rate; Half-Life; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Regression Analysis; Statistics as Topic; Tritium; Weights and Measures

Topics: Aged; Atrial Fibrillation; Creatinine; Digoxin; Dose-Response Relationship, Drug; Electrocardiography; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Radioimmunoassay; Urea

Topics: Administration, Oral; Coronary Disease; Digoxin; Electrocardiography; Female; Heart Failure; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Myocardial Infarction; Phenytoin; Tachycardia

Topics: Computers, Analog; Digoxin; Heart Rate; Humans; Kidney; Kidney Failure, Chronic; Kinetics; Models, Theoretical; Time Factors

Topics: Aged; Blood Urea Nitrogen; Calcium; Coronary Disease; Creatinine; Digitalis Glycosides; Digitoxin; Digoxin; Electrocardiography; Evaluation Studies as Topic; Heart Failure; Heart Valve Diseases; Humans; Kidney Failure, Chronic; Middle Aged; Myocardial Infarction; Photometry; Potassium; Radioimmunoassay; Saliva; Specimen Handling; Spectrophotometry, Atomic

Topics: Adult; Aminohippuric Acids; Arrhythmias, Cardiac; Creatinine; Digitalis Glycosides; Digoxin; Electrocardiography; Glomerular Filtration Rate; Humans; Inulin; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Metabolic Clearance Rate; Middle Aged; Radioimmunoassay; Tritium

Topics: Aged; Aminosalicylic Acids; Arrhythmias, Cardiac; Arteriosclerosis; Cerebrovascular Disorders; Coronary Disease; Digoxin; Electrocardiography; Furosemide; Heart Conduction System; Humans; Hypertension; Isoniazid; Kidney Failure, Chronic; Lung Diseases, Obstructive; Middle Aged; Myocardial Infarction; Phenytoin

Topics: Aged; Arteriosclerosis; Coronary Disease; Creatinine; Diabetes Complications; Digoxin; Gout; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Time Factors

Topics: Aged; Dehydration; Digoxin; Drug-Related Side Effects and Adverse Reactions; Furosemide; Guanethidine; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Pharmaceutical Preparations; Tetracycline; Uremia

Topics: Administration, Oral; Digitalis Glycosides; Digoxin; Heart Failure; Humans; Kidney Failure, Chronic; Pacemaker, Artificial; Radioimmunoassay

Topics: Digoxin; Drug-Related Side Effects and Adverse Reactions; Humans; Kidney Failure, Chronic

Topics: Digitoxin; Digoxin; Drug Tolerance; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis; Strophanthins; Uremia

Topics: Adult; Digoxin; Female; Humans; Intestine, Small; Kidney Failure, Chronic; Kidneys, Artificial; Male; Middle Aged; Myocardium; Peritoneal Dialysis; Tritium

Topics: Cardanolides; Cardiac Glycosides; Digitoxin; Digoxin; Humans; Kidney; Kidney Failure, Chronic; Ouabain; Pyrans; Strophanthins; Time Factors; Tritium

Topics: Cell Membrane Permeability; Digoxin; Humans; In Vitro Techniques; Kidney Failure, Chronic; Peritoneal Dialysis; Protein Binding; Renal Dialysis; Time Factors; Tritium

Topics: Adult; Aged; Diabetes Mellitus; Digoxin; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Tritium

Topics: Acute Kidney Injury; Adult; Animals; Bile; Chromatography, Paper; Digoxin; Humans; Intestinal Mucosa; Kidney Failure, Chronic; Liver; Middle Aged; Myocardium; Nephrectomy; Organ Size; Tritium; Ureteral Obstruction