digoxin and Kidney-Diseases

Digoxin intoxication occurs frequently and may require treatment with digoxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0.40 L/kg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to 10-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approximately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration. More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological membranes, it can sequester tissue-bound and intracellular digoxin into the extracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity. The pharmacokinetic fate of total digoxin after administration of digoxin-specific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin concentrations, however, is delayed by 12 to 130 hours in patients with renal dysfunction and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concentration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin concentrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time

Topics: Animals; Digoxin; Drug Monitoring; Humans; Immunoglobulin Fab Fragments; Immunoglobulins, Intravenous; Kidney Diseases

The high rates of drug-induced acute renal failure, worsening chronic renal dysfunction and systemic toxicity of renally excreted drugs in the elderly can be minimised by carefully assessing renal function, avoiding potentially nephrotoxic drugs as much as possible and closely monitoring drug concentrations and renal function when they must be used. The co-existence of impaired renal function, degenerative vascular disease or cardiac failure in the elderly substantially increases the risk of renal toxicity. When in doubt about potential nephrotoxicity or an increased risk of systemic toxicity from renally excreted drugs in the elderly, the practitioner should consult the numerous published guidelines.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Aminoglycosides; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Chronic Disease; Contrast Media; Digoxin; Diuretics; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Middle Aged; Risk Factors

Renal parenchymal disease is the most common cause of secondary hypertension, accounting for 2.5% to 5.0% of all cases. Hypertension associated with renal parenchymal disease occurs as a complication of a wide variety of glomerular and interstitial renal diseases and may accelerate the decline in renal function if inadequately controlled. Renal parenchymal hypertension most probably represents the combined interactions of multiple independent mechanisms: potential factors include impaired sodium handling leading to volume expansion, perturbations of the renin-angiotensin system, alterations in endogenous vasodepressor compounds, and possibly increased activity of vasoactive substances. The past several years have witnessed newer insights into both the pathophysiology and the therapeutics of this disorder. The characterization of endothelin and the nitric oxide (NO)-arginine pathway and their roles in biology and medicine has provided additional new insights with regard to the pathogenesis of hypertension in renal parenchymal disease. For example, methylated L-arginine derivatives that possess NO synthase inhibitor capabilities including NG-N-dimethylarginine and N-monomethyl-L-arginine are found in human plasma and in urine. Patients with chronic uremia have impaired elimination of these compounds, and circulating concentrations of these compounds may increase sufficiently to result in inhibition of NO production. Thus, accumulation of endogenous NO synthase inhibitors might contribute to the hypertension of advanced renal failure. Similarly, it has been proposed that increased endothelium-derived endothelin that results from hypertensive injury to vascular endothelium could lead to further vasoconstriction and worsening of hypertension. Additional insight into this fascinating problem must await further biochemical characterization of some of the mediators and a more precise delineation of their pathophysiological role.

Topics: Aldosterone; Animals; Blood Proteins; Cardenolides; Digoxin; Endothelins; Humans; Hypertension; Kallikreins; Kidney; Kidney Diseases; Prostaglandins; Renin-Angiotensin System; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase

It is confirmed by several studies that in normal subjects a substance recognized by antibodies anti digoxin exists. Such a substance can be found at increased concentration in pregnant women, neonates, in liver or kidney diseases. A limited increase in concentration has been also registered in patients with essential hypertension and in normotensive patients with a family history of hypertension. Serum or urines rich in such a substance show an increased capacity of inhibiting in vitro the sodium-potassium pump and therefore in reducing also in vivo the capacity of reabsorption of sodium and with it, of water. The investigators interest for this substance has two main reasons: 1) the interference that such a substance has in dosages of digitalis in therapeutic monitorizing; 2) the possibility that such a substance has an important physiological role in hydroelectrolytic metabolism.

Topics: Adult; Cardenolides; Digoxin; Enzyme Inhibitors; Female; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Liver Diseases; Male; Saponins; Sex Factors

On the assumption that digoxin-like immunoreactivity may represent digitalis-like sodium pump inhibitors in the mammalian body, many investigators have used radioimmunoassay for digoxin to monitor such factors during the past decade. The presence of digoxin-like immunoreactivity has been confirmed by numerous studies using biochemical, immunological or morphological methods. Very recently, ouabain or a very similar substance, which did not cross-react with antidigoxin antibodies, was identified from the human plasma as the long-sought sodium pump inhibitor. However, it is yet to be determined whether sodium pump inhibitory activity in the circulation results from one substance or several. Some researchers still insist on the possible physiological roles of digoxin-like immunoreactivity which may or may not be related to the regulation of sodium pump. These issues are critically reviewed in this article.

Topics: Animals; Blood Proteins; Cardenolides; Cross Reactions; Digoxin; Humans; Hypertension; Kidney Diseases; Ouabain; Radioimmunoassay; Saponins; Sodium-Potassium-Exchanging ATPase

Endogenous factors with biological and immunological activity similar to cardiac glycoside drugs (endogenous digitalis-like factors; EDLF) have been found in several tissues and body fluids of animals and humans. Detectable EDLF concentrations were found in blood and urine extracts of adults (normal healthy controls, hypertensive patients and salt-loaded healthy subjects), while higher levels were generally observed in plasma samples of pregnant women, newborns, and patients with renal insufficiency. The chemical characteristics of this endogenous factor are, at present, unknown, although it has been suggested that EDLF could be a substance with low molecular weight. Experimental studies and theoretical considerations suggest that EDLF, in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, it has been suggested that EDLF is an endogenous modulator of the membrane sodium-potassium pump, and that it could play a role in the regulation of fluids and electrolytes, in the myocardial muscular tone and also in the pathogenesis of hypertension.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Pregnancy; Pregnancy Complications, Cardiovascular; Saponins; Sodium-Potassium-Exchanging ATPase; Water-Electrolyte Balance

Amlodipine, a dihydropyridine calcium antagonist, was synthesized in an attempt to develop a compound with a pharmacokinetic profile characteristic of this class, which would also have an increased oral bioavailability and extended clearance time. A single intravenous dose of 10 mg resulted in an absolute bioavailability of 64% and a calculated elimination half-life of 34 hours. The pharmacokinetic profile of oral doses showed similar changes. These results were significantly different from those seen with most other dihydropyridines (elimination half-life of 3 to 10 hours and absolute bioavailability of 10% to 30%) and nondihydropyridine calcium antagonists (elimination half-life 3 to 6 hours and low absolute bioavailability). With chronic oral dosing of amlodipine once daily for 14 days, support was provided for the linearity of amlodipine's pharmacokinetics and absence of such with chronic oral dosing with verapamil, diltiazem, and nifedipine. In the elderly population, elimination half-life of 5 mg oral doses is significantly prolonged (48 vs 35 hours; p less than 0.025) suggesting decreased oral clearance or increased bioavailability. Comparison of the pharmacokinetics of amlodipine in patients with chronic stable angina pectoris with the profile in healthy volunteers suggested that clearance is not altered in patients with chronic stable angina, steady state being reached 6 to 12 hours after administration of the drug. In patients with cirrhosis, elimination half-life is significantly prolonged (60 vs 34 hours; p less than 0.01) suggesting that there is a greater accumulation of amlodipine in patients with severe liver disease than in individuals with normal hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aging; Amlodipine; Angina Pectoris; Animals; Biological Availability; Calcium Channel Blockers; Cimetidine; Digoxin; Drug Interactions; Half-Life; Humans; Injections, Intravenous; Kidney Diseases; Liver Cirrhosis; Nifedipine

A dualistic function for the natriuretic ATP.inhibiting factor is formulated on the basis of a phenomenon like compensatory renal adaption of residual nephrons: 1. Support of the tubular sodium excretion to the maintenance of homoeostasis of the organism. 2. Inhibition of the forced up vasodilation of the afferent glomerular vessel. It should suggested that the renal vasoconstrictive effect is a part of a protective system for residual nephrons against the pathogenic hyperfiltration and hyperperfusion.

Topics: Animals; Atrial Natriuretic Factor; Blood Proteins; Cardenolides; Digoxin; Glomerular Filtration Rate; Kidney Diseases; Nephrectomy; Nephrons; Saponins; Sodium-Potassium-Exchanging ATPase

Urapidil is a selective alpha 1-adrenoceptor antagonist with central antihypertensive action which is increasingly used in the treatment of hypertension. Urapidil is readily absorbed, is subject to moderate first-pass metabolism and is eliminated primarily as metabolites of much lower antihypertensive activity than the parent drug. The influences of age, renal and hepatic disease on the disposition of urapidil are reviewed. Studies on the relationship between pharmacodynamics and pharmacokinetics show that the optimum use of urapidil in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.

Topics: Adult; Aged; Aged, 80 and over; Aging; Digoxin; Drug Interactions; Half-Life; Humans; Hypertension; Kidney Diseases; Liver Diseases; Male; Middle Aged; Piperazines

Various laboratories have reported endogenous digoxin-like immunoreactive factor(s) (DLIF) in blood from patients in renal failure or liver failure, from newborn infants, and from third-trimester pregnant women. Similar immunoreactivity has been detected in amniotic fluid, in cord blood, and in urine and serum from normal subjects. The factor(s) giving rise to this immunoreactivity cross react with antibodies used in many currently available immunoassays for digoxin, sometimes causing apparent digoxin concentrations exceeding the therapeutic range obtained for exogenous digoxin, with consequent errors in measurement and in subsequent clinical interpretation of digoxin results. Here, I summarize findings in our laboratory and those of others. DLIF evidently exist in three states in serum: tightly protein-bound, weakly protein-bound, and unbound (free). In normal subjects, greater than 90% of the total DLIF in serum is tightly but reversibly bound to serum proteins and is not readily detectable by direct measurement of digoxin in serum with conventional immunoassays. However, there seems to be a redistribution of the more weakly bound and unbound components in patients with renal failure, pregnant women, and newborns. The increased values detected in these groups are ascribable to increased amounts of weakly bound and unbound DLIF rather than to increased total DLIF. Carrier proteins may play a prominent role in the transport of these factors in blood. I discuss the potential physiological and pharmacological implications of detecting endogenous immunoreactive factors that cross react with antibodies to drugs.

Topics: Adult; Animals; Blood Proteins; Cardiovascular Physiological Phenomena; Chemical Phenomena; Chemistry, Physical; Digoxin; Extracellular Space; False Positive Reactions; Female; Fetal Blood; Humans; Immunoassay; Infant, Newborn; Kidney Diseases; Liver Diseases; Pregnancy; Pregnancy Complications, Cardiovascular; Protein Binding; Water-Electrolyte Balance

The calcium entry blockers are used in a wide variety of clinical situations. Coexisting disease states, such as renal or hepatic dysfunction, may require individualized dosing of these agents. The physiologic changes associated with aging may also affect the pharmacokinetic properties of the drugs. If calcium entry blockers are used concurrently with other medications, dosage adjustment or selection of an alternative drug may be needed. Drug interactions between calcium entry blockers and cimetidine, digoxin and quinidine appear to be clinically significant. Individualized dosing in patients who have coexisting disease or who are using other medications is essential to achieve an adequate therapeutic response and avoid adverse effects. Considerations to attain an optimal response in such situations are presented.

Topics: Adult; Age Factors; Aged; Calcium Channel Blockers; Child; Cimetidine; Diabetes Complications; Digoxin; Drug Interactions; Female; Humans; Hypertension; Kidney Diseases; Kinetics; Lactation; Liver Diseases; Middle Aged; Pregnancy; Quinidine; Smoking

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Bile; Biological Transport; Cardiac Glycosides; Contraceptives, Oral, Hormonal; Diazepam; Digoxin; Enterohepatic Circulation; Fluorenes; Half-Life; Hexamethonium Compounds; Humans; Imipramine; Indocyanine Green; Kidney Diseases; Liver Diseases; Molecular Weight; Pharmaceutical Preparations; Spironolactone

When prescribing cardiac glycosides for patients with renal failure, one should consider the different pharmacokinetics of the two most important glycosides, digoxin and digitoxin. Whereas steady state plasma concentrations of digoxin are altered proportionally to renal clearance of creatinine, those of digitoxin remain the same throughout a wide range of renal impairment. The steady state level of both glycosides is partly determined by several clinical factors such as dose, body weight, height, age and serum potassium. However, it is thought that bioavailability, volume of distribution, biotransformation, and total body clearance have the greatest importance for the variability of the plasma glycoside concentrations in patients with normal and with impaired renal function. The bioavailability and biotransformation of digoxin do not vary between healthy subjects and patients with renal insufficiency. As the volume of distribution is smaller in patients with severe renal failure that in normal subjects, the loading dose has to be altered. With decreasing creatinine clearance the total body clearance as well as the renal clearance of digoxin is reduced. On the basis of this assumption maintenance dosage regiments must be adjusted. For digitoxin, the four above-mentioned pharmacokinetic parameters are not altered in patients with renal failure compared to healthy subjects. Moreover, investigations dealing with this problem have suggested an altered protein binding of digitoxin and its metabolites as a possible factor in avoiding accumulation of the drug. However, it is one of the aims of this article to show that a decreased urinary excretion of digitoxin and metabolites is compensated by an increased excretion via the feces. Loading dose and maintenance dose of digitoxin do not have to be adjusted in patients with renal failure.

Topics: Biological Availability; Biotransformation; Digitalis; Digitoxin; Digoxin; Humans; Kidney Diseases; Kinetics; Metabolic Clearance Rate; Plants, Medicinal; Plants, Toxic

Topics: Biotransformation; Cytochrome P-450 Enzyme System; Diazepam; Digitoxin; Digoxin; Drug Interactions; Drug Therapy; Drug Therapy, Combination; Enzyme Induction; Ethanol; Kidney; Kidney Diseases; Liver; Liver Diseases; Nordazepam; Receptors, Drug

The various cardiac glycosides differ significantly in their retention as a result of renal failure. In the case of digoxin, digitoxin, and strophanthin the retention is directly related to the normal renal clearance of these cardiac glycosides: Strophanthin has the highest clearance and the most marked prolongation of pharmacological action in renal failure, whereas digitoxin shows the lowest renal clearance and even in uremic patients a total elimination comparable to normal subjects as a result of increased hepatic clearance; digoxin takes an intermediate position. The quantity of a cardiac glycoside and its metabolites excreted by the kidneys depends, besides the renal clearance, on the plasma concentration which increases considerably during the first days after onset of treatment. From the daily dose approximately 90% of strophanthin, 70% of digoxin, 50% of digitoxin plus metabolites are excreted by normal kidneys under steady-state conditions. The efficiency of hemodialysis in the elimination of cardiac glycosides is low (3-5%) if estimated in relation to a single dose injected before dialysis and high (30-50%) if estimated in relation to the excretory capacity of normal kidneys during a period corresponding to the duration of a dialysis. During hemodialysis the plasma concentration of digoxin decreases as rapidly as in patients with normal renal function. Beside the efficiency of dialysis this finding may be explained by the decrease in the apparent volume of distribution of cardiac glycosides in patients with advanced renal failure; a reduced tissue protein binding seems likely to be the main reason for these changes in chronic renal insufficiency. A reduced volume of distribution and a reduced myocardial sensitivity are the main reasons for a very low predictability of the necessary individual maintenance dose of cardiac glycosides from the creatinine clearance. In patients with advanced renal insufficiency the tolerance to cardiac glycosides is reduced with respect to the daily dose, but it is rather increased in relation to the plasma concentration required to maintain the positive inotropic effect. The combination of hyperkalemia, hypermagnesemia, bypocalcemia and acidosis which is found almost exclusively with chronic renal failure, may explain the reduced myocardial sensitivity. Dosage regimens based on the measurement of creatinine-clearance are of little help in "effective digitalisation". Serial measurements of steady-state plasma concen

Topics: Cardiac Glycosides; Digitoxin; Digoxin; Drug Tolerance; Glomerular Filtration Rate; Humans; Kidney Diseases; Kinetics; Ouabain; Protein Binding; Renal Dialysis; Strophanthins; Uremia

Topics: Biological Availability; Digitalis Glycosides; Digoxin; Humans; Kidney Diseases; Radioimmunoassay

Topics: Blood Specimen Collection; Digitalis Glycosides; Digoxin; Dose-Response Relationship, Drug; Drug Resistance; Heart Diseases; Humans; Kidney Diseases; Radioimmunoassay

Topics: Administration, Oral; Aged; Digitalis Glycosides; Digitoxin; Digoxin; Feces; Heart Atria; Heart Failure; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Kidney Diseases; Liver Diseases; Malabsorption Syndromes; Obesity; Tachycardia; Thyroid Diseases; Tritium; Water-Electrolyte Balance

Topics: Administration, Oral; Animals; Biopharmaceutics; Cats; Digoxin; Guinea Pigs; Half-Life; Heart Diseases; Humans; Kidney; Kidney Diseases; Kinetics; Models, Theoretical; Protein Binding; Radioimmunoassay; Serum Albumin; Solutions; Tablets; Tritium; United Kingdom; United States

Topics: Adenosine Triphosphatases; Arrhythmias, Cardiac; Digitalis Glycosides; Digitoxin; Digoxin; Heart; Heart Failure; Heart Rate; Humans; Kidney Diseases; Kinetics; Lanatosides; Lidocaine; Myocardium; Pacemaker, Artificial; Phenytoin; Potassium; Procainamide; Propranolol; Quinidine; Thyroid Diseases

Topics: Adenosine Triphosphatases; Aged; Arrhythmias, Cardiac; Cell Membrane; Chromatography, Gas; Digitalis Glycosides; Digitoxin; Digoxin; Erythrocytes; Evaluation Studies as Topic; Humans; Kidney Diseases; Potassium; Radioimmunoassay; Radioisotope Dilution Technique; Radioisotopes; Rubidium; Sodium; Tritium

This study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum.. Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials.. In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females.. Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF.. Males and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability.

Topics: Adrenergic beta-Antagonists; Age Distribution; Aged; Aged, 80 and over; Cardiac Resynchronization Therapy; Cardiotonic Agents; Diabetes Mellitus; Digoxin; Female; Heart Failure; Hospitalization; Humans; Hypertension; Kidney Diseases; Logistic Models; Male; Middle Aged; Mortality; Myocardial Ischemia; Phenotype; Prognosis; Proportional Hazards Models; Registries; Severity of Illness Index; Sex Factors; Stroke Volume; Sweden

The present study has been designed to investigate the ameliorative potential of vitamin P, and digoxin in ischemic-reperfusion (I/R)-induced renal injury in isolated rat kidney preparations by using the Langendorff apparatus.. Vitamin P (50 and 100 mg/kg; p.o.) was administered to rats for 5 consecutive days. On the 6th day, isolated kidneys were subjected to 30 min of ischemia followed by 120 min of reperfusion by constant flow (8 ml/min). The total renal effluent was collected at various time intervals (i.e., basal, 0, 15, 30, 45 and 60 min). In addition, urea, creatinine, and creatine kinase (CK) activity were evaluated in the renal effluent, and TBARS, GSH, and Na(+)-K(+)-ATPase activity were evaluated in tissue.. I/R of renal tissue produced a rise in the activity of CK and the levels of urea and creatinine in the renal effluent, as well as in the activity of Na(+)-K(+)-ATPase and levels of TBARS in the tissue. Additionally, it decreased GSH levels when compared with the sham control group. Digoxin served as positive control in the present work. Treatment with vitamin P (100 mg/kg), and digoxin (500 μg/kg) produced a significant (P<0.05) ameliorative effect against the I/R induced changes in biomarkers.. The renoprotective effect of vitamin P is caused by its inhibition of Na(+)-K(+)-ATPase activity, which subsequently results in free radical scavenging and anti-infarct properties. Therefore, this vitamin can be useful in the management of renovascular disorders.

Topics: Animals; Creatine Kinase; Creatinine; Digoxin; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Glutathione; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Rutin; Sodium-Potassium-Exchanging ATPase; Thiobarbituric Acid Reactive Substances; Time Factors; Urea

Management of systolic heart failure can be particularly challenging in patients with chronic kidney disease, especially those who are not yet receiving dialysis. Few clinical trials have been performed in this particular population, so management is directed by evidence from studies of patients with limited or no renal impairment. Their heightened risk for many treatment complications mandates additional considerations regarding drug selection, dosing, and monitoring. Subspecialty consultation is driven by patient instability or disease progression, intolerance of standard treatment, or need for device placement.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Digoxin; Heart Failure; Humans; Hyperkalemia; Kidney Diseases; Mineralocorticoid Receptor Antagonists

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

Acute heart failure syndromes, commonly recognized as de novo heart failure or acute decompensated chronic heart failure (ADHF), are characterized by a rapid onset or change in signs and symptoms of heart failure requiring urgent treatment. Coexisting renal dysfunction is associated with poor prognosis in these patients. We sought to determine whether renal impairment in particular and other admission factors in general predict long-term mortality after hospitalization for ADHF.. We studied 128 patients (age 63 + or - 12 years, 76% male) in NYHA class 2.6 + or - 0.7 with a left ventricular ejection fraction (LVEF) < or = 39%, hospitalized due to ADHF. Mortality rates (per 100 person-years) were 21.9 at 12 months and 12.0 at 60 months. We found that admission serum creatinine level was the best predictor of mortality after 1 (P < 0.001, log-transformed due to skewed distribution) and 5 years (P = 0.001), followed by creatinine clearance, the use of loop diuretics, and digoxin. Moreover, higher NYHA class, decreased body mass index (BMI) and increased levels of urea predicted 1 and 5 years mortality on univariate analysis. In the multivariate analysis, creatinine, NYHA class, and LVEF emerged as independent predictors of mortality after 1 year, whereas BMI and the use of diuretics did not reach significance (joint chi(2) = 29.40, P < 0.001). After 5 years, creatinine and NYHA class independently predicted all-cause mortality (joint chi(2) = 22.71, P < 0.001), but BMI and age did not remain significant.. Admission creatinine level strongly predicts medium- and long-term mortality after hospitalization in patients with ADHF, and serves as a cheap and fast clinical marker to identify patients at risk of death.

Topics: Aged; Body Mass Index; Cardiotonic Agents; Confidence Intervals; Creatinine; Digoxin; Female; Germany; Heart Failure; Humans; Kaplan-Meier Estimate; Kidney Diseases; Linear Models; Male; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Risk Factors; Sodium Potassium Chloride Symporter Inhibitors; Statistics as Topic; Stroke Volume; Treatment Outcome; Ventricular Function, Left

The aim of this study was to compare the estimated glomerular filtration rate (GFR) using the Cockcroft-Gault and the 4-, 5-, and 6-variable Modification of Diet in Renal Disease (MDRD) formulas for digoxin dose adjustment.. Steady-state serum digoxin concentrations were determined in 100 patients with heart failure and normal to severely impaired renal function. Total clearance (CL) and predicted average concentrations of digoxin were calculated using general pharmacokinetic principles.. The mean+/-SEM (median) estimated GFR values were 48.9+/-2.8 (46.5) mL/min/1.73 m(2) using the Cockcroft-Gault formula, 61.4+/-3.6 (56.4) mL/min/1.73 m(2) using the MDRD4 formula, 56.8+/-3.3 (52.1) mL/min/1.73 m(2) using the MDRD5 formula, and 53.3+/-3.0 (48.7) mL/min/1.73 m(2) using the MDRD6 formula, with high correlation coefficients between the estimates (r > or = 0.928, P < 0.001). Significant correlations were found between the digoxin total CL and estimated GFR by the Cockcroft-Gault (r = 0.649, P < 0.001), MDRD4 (r = 0.634, P <0.001), MDRD5 (r = 0.635, P < 0.001), and MDRD6 (r = 0.652, P < 0.001) formulas. A significant negative correlation of the digoxin total CL/GFR ratio with estimated GFR was obtained (r = -0.356, P < 0.001), with a high variability for this ratio for GFR lower than 60 mL/min. Analogous correlation coefficients were found between the obtained and predicted digoxin concentrations calculated using the estimated GFR by the Cockcroft-Gault (r = 0.628, P < 0.001), MDRD4 (r = 0.642, P < 0.001), MDRD5 (r = 0.650, P < 0.001), and MDRD6 (r = 0.665, P < 0.001) formulas, with a wide dispersion between the values in all cases.. For GFR lower than 60 mL/min, the high interindividual variation of the digoxin total CL found among patients with similar renal function is an important limiting factor in the prediction of digoxin dosage regimens.

Topics: Adult; Aged; Aged, 80 and over; Cardiotonic Agents; Digoxin; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Diseases; Male; Middle Aged

Heralded as the oldest known cardiovascular drug, digoxin remains widely used today in the face of increasing rates in heart failure and atrial fibrillation despite the emergence of newer medications. Its hemodynamic, neurohormonal and electrophysiologic actions make it a suitable adjunctive, evidence-based therapy for the above conditions. Its narrow therapeutic index and its toxicity, however, have become more relevant as aging, comorbid diseases, and polypharmacy make more patients vulnerable. Because signs and symptoms of digoxin toxicity are mostly nonspecific, a high index of suspicion is crucial for early recognition and appropriate management.

Topics: Aging; Atrial Fibrillation; Cardiotonic Agents; Contraindications; Digoxin; Drug Interactions; Heart Failure; Humans; Kidney Diseases

The association between higher New York Heart Association (NYHA) class and outcomes in patients with heart failure and preserved systolic function is not well known.. We performed a retrospective follow-up study of 988 patients with heart failure with ejection fraction > 45% who participated in the DIG trial. Using Cox proportional hazard models, we estimated risks and all-cause mortality, heart failure mortality, all-cause hospitalization, and hospitalization due to worsening heart failure during a median follow-up of 38.5 months.. Patients had a median age of 68 years; 41.2% were women and 13.9%, nonwhites. Overall, 23.4% of patients died, and 19.9% were hospitalized because of worsening heart failure. Proportion of patients with NYHA classes I, II, III, and IV were 19.9%, 58.0%, 20.9%, and 1.2%, respectively, and 14.7%, 21.1%, 35.9%, and 58.3%, respectively, died of all causes (P < .001 for trend). Respective rates for heart failure-related hospitalizations were 14.2%, 17.1%, 32.5%, and 33.3% (P < .001 for trend). Compared with NYHA class I patients, adjusted hazard ratios (HRs) for all-cause mortality for class II, III, and IV patients were 1.54 (95% CI 1.02-2.32, P = .042), 2.56 (95% CI 1.64-24.01, P < .001), and 8.46 (95% CI 3.57-20.03, P < .001), respectively. Respective adjusted HRs (95% CI) for hospitalization due to heart failure for class II, III, and IV patients were 1.16 (0.76-1.77) (P = .502), 2.27 (1.45-3.56) (P < .001), and 3.71 (1.25-11.02) (P = 018). New York Heart Association classes II through IV were also associated with higher risk of all-cause hospitalization.. Higher NYHA classes were associated with poorer outcomes in patients with heart failure and preserved systolic function.

Topics: Aged; Cardiotonic Agents; Cause of Death; Diabetes Complications; Digoxin; Female; Heart Failure; Hospitalization; Humans; Kidney Diseases; Male; Proportional Hazards Models; Randomized Controlled Trials as Topic; Retrospective Studies; Severity of Illness Index; Statistics, Nonparametric; Stroke Volume

Topics: Digoxin; Drug Interactions; Female; Humans; Kidney Diseases; Selective Serotonin Reuptake Inhibitors

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

Topics: Adult; Antibodies, Monoclonal; Calibration; Digoxin; Female; Humans; Immunoassay; Kidney Diseases; Liver Diseases; Pregnancy

Although there is renewed enthusiasm for the use of digoxin in patients with heart failure, current dosing guidelines are based on a nomogram published in 1974. We studied the incidence of and risk factors for elevated digoxin levels in patients admitted to a community hospital, and compared their dosage regimens to published guidelines.. We reviewed the charts of all patients who had serum digoxin levels greater than 2.4 ng/mL during a 6-month period. We collected demographic and clinical data, indications for digoxin use, digoxin dosage, concurrent medications, laboratory data, and clinical and electrocardiographic features of digoxin toxicity.. Of the 1,433 patients with digoxin assays, 115 (8%) patients had elevated levels. Of the 82 patients with complete records and correctly timed digoxin levels, 59 (72%) had electrocardiographic or clinical features of digoxin toxicity. Patients with serum digoxin levels >2.4 ng/mL were slightly older (78 +/- 8 versus 73 +/- 9 years of age; P = 0.12) and had greater serum creatinine levels (3.1 +/- 7.3 versus 1.4 +/- 0.3 mg/dL; P = 0.01) than those with levels < or =2.4 ng/mL. Forty-seven patients had elevated digoxin levels on admission, including 21 patients admitted for digoxin toxicity. Impaired or worsening renal function contributed to high levels in 37 patients, and a drug interaction was a contributory factor in 10 cases. Twenty (43%) of these patients were taking the recommended maintenance dose based on the scheme employed in the Digitalis Investigation Group study. Thirty-five patients developed high digoxin levels while in hospital. In 26 patients, this followed a loading dose of digoxin for the control of rapid atrial fibrillation. Impaired renal function was implicated in all of these patients. Despite the elevated digoxin level, rate control was achieved in only 11 patients of these patients.. Elevated digoxin levels and clinical toxicity remains a common adverse drug reaction. Elderly patients, particularly those with impaired renal function and low body weights, are at the greatest risk. As published digoxin nomograms often result in toxicity, clinical variables need to be monitored. In patients with congestive heart failure and normal sinus rhythm the potential benefit of digoxin is small; thus, patients should receive a dose that minimizes the risk of toxicity. For patients with new onset atrial fibrillation, other agents may be preferable for rate control.

Topics: Age Factors; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Atrial Fibrillation; Chi-Square Distribution; Creatinine; Digoxin; Drug Interactions; Drug Monitoring; Electrocardiography; Female; Heart Failure; Hospitalization; Humans; Kidney Diseases; Male; Risk Factors

Endogenous digoxin-like immunoreactive factors (DLIF) can interfere with some digoxin immunoassays. We looked for similar interference, called digitoxin-like immunoreactive factors (DTLIF) in two digitoxin immunoassays: A new chemiluminescent assay (CLIA), processed on the automated random access immunoassay system ACS:180, and a fluorescent polarization assay (FPIA), processed on the semiautomated TDx batch analyzer. One hundred thirty-seven samples of sera were tested from nondigitalized pregnant women, patients with liver or kidney diseases, and cord blood. The CLIA digitoxin assay uses a murine monoclonal antibody and requires no sample pretreatment; the FPIA digitoxin assay uses a polyclonal rabbit antibody and requires sample precipitation. Both assays have a similar dynamic range and sensitivity and give comparable results with commercial controls and external quality control survey samples. Although the CLIA detected no digitoxin in any sample tested, the FPIA showed apparent digitoxin concentrations of more than 2.0 ng/ml for 100% and 44% among cord blood and liver disease specimens, respectively. The highest DTLIF concentration was found in serum from a patient with liver disease (18.1 ng/ml). When spiked with 32 ng/ml digitoxin, six of the samples containing DTLIF generated FPIA digitoxin values of 6% to 27.5% more than the expected digitoxin levels. Two specimens with no detectable DTLIF activity were run as controls, and when spiked with digitoxin, showed target digitoxin concentrations in the FPIA. The CLIA recovered near the target digitoxin values (32 ng/ml) in all spiked samples. It was concluded that the polyclonal FPIA digitoxin assay may give discordant digitoxin concentrations in some patient groups because of interference from digitoxin-like immunoreactive factors. The CLIA digitoxin assay is not affected by DTLIF interference.

Topics: Antibodies, Monoclonal; Cardenolides; Digitoxin; Digoxin; Female; Fetal Blood; Fluorescence Polarization; Fluorescence Polarization Immunoassay; Humans; Immunoassay; Kidney Diseases; Liver Diseases; Luminescent Measurements; Pregnancy; Saponins; Sensitivity and Specificity; Uremia

A comparison of the results of a newly developed fluorescence-derivatization/HPLC method and a commercial immunoassay method (ACA, Dupont) for the measurement of serum digoxin concentrations in patients indicates that (1) the results from the ACA method agree well with those from the HPLC method in patients with cardiovascular disease but without renal, diabetic, and liver disease, (2) serum digoxin concentrations determined by the ACA method are overestimated in patients with renal, diabetic, or liver disease, and (3) the steady-state serum concentrations of hydrolyzed and reduced metabolites are relatively insignificant in patients receiving digoxin therapy, including patients with renal failure. The excellent reproducibility of the HPLC and immunoassay methods (coefficient of variation < 9.0%), together with the demonstrated specificity of the HPLC method with respect to potential interference from digoxin metabolites, endogenous digoxin-like immunoactive substances, and coadministered drugs and their metabolites, allows quantitation of the degree of interference in digoxin immunoassays under actual therapeutic drug monitoring conditions. Clinically significant interferences (0.3 to 1.1 ng/ml) with immunoassay determination were found in the majority of patients in all three diseases studied.

Topics: Adult; Aged; Cardiotonic Agents; Chromatography, High Pressure Liquid; Diabetes Mellitus; Digoxin; Female; Fluorescence; Humans; Immunoassay; Kidney Diseases; Liver Diseases; Male; Middle Aged

Performance characteristics of the Abbott nonpretreatment AxSYM Digoxin II assay were evaluated for quantification of digoxin at four independent sites. Correlation of digoxin measurements with the Abbott pretreatment AxSYM, Baxter Stratus II, Abbott TDx/ TDxFLx II, Abbott IMx, Emit 2000, and Beckman Synchron CX digoxin assays showed acceptable agreement, as indicated by: slope values > 0.84, r > 0.90, y-intercepts for all comparisons at or below the assay detection limit, and Sy/x ranging between 7.5% and 15.4% of the average digoxin value. Susceptibility to interference from digoxin-like immunoreactive factors (DLIFs) was examined in 233 samples from renal patients, liver disease patients, cord blood, and third-trimester pregnancies; the AxSYM Digoxin II assay demonstrated the least DLIFs interference. DLIF susceptibility for four of the methods was significantly greater (P < 0.05) than in the AxSYM Digoxin II assay; susceptibilities of the Stratus II and Emit 2000 methods were similar to the AxSYM Digoxin II assay.

Topics: Autoanalysis; Automation; Digoxin; False Positive Reactions; Female; Fetal Blood; Humans; Immunoassay; Immunoenzyme Techniques; Indicators and Reagents; Kidney Diseases; Liver Diseases; Pregnancy; Pregnancy Trimester, First; Regression Analysis; Reproducibility of Results

Comparison of a new monoclonal digoxin assay with three polyclonal digoxin assays for their cross-reactivity to digoxin-like immunoreactive factors (DLIF) and digoxin metabolites.. Sixty-six nondigitalized patient samples from 5 different groups: neonates, women in 3rd trimester pregnancy, and patients with liver or renal diseases, or undergoing organ transplants, and 139 samples from digoxin-treated patients of 4 categories (hospital sick, liver, renal, and outpatients) were compared in 4 different digoxin assays: (a) ACS Digoxin (ACS) developed for the automated chemiluminescent Ciba Corning ACS 180 system, (b) Baxter Stratus (Stratus, a fluoroimmunoassay), (c) Ciba-Corning Magic (Magic, a radioimmunoassay), and (d) an in-house radioimmunoassay (RIA). The ACS and RIA were also compared for their cross-reactivity to four principal digoxin metabolites.. Among the nondigitalized specimens, no significant DLIF interference was found for all 4 assays among the pregnant women or liver and transplant patients. However, the neonates registered high DLIF interference with Magic and RIA, but none for ACS or Stratus. DLIF interference in renal samples was highest in the Magic assay and lowest in RIA. Among the specimens with digoxin, a higher number of discrepant samples were found from the sick patients than from outpatients. In 75% of such discrepant samples, the ACS result was less than other assay results, suggesting DLIF as the probable cause. The two assays differed most in their cross-reactivity to the deglycated metabolites, digoxigenin and its mono-digitoxoside.

Topics: Adult; Antibodies, Monoclonal; Cross Reactions; Digoxin; Female; Fluoroimmunoassay; Humans; Immunoassay; Infant, Newborn; Kidney Diseases; Liver Diseases; Luminescent Measurements; Male; Organ Transplantation; Pregnancy; Radioimmunoassay; Sensitivity and Specificity

Five immunoassays for the determination of digoxin have been evaluated (Digoxin II, Abbott; Cedia Digoxin XL, Microgenics; Coat-a-Count Digoxin, Diagnostic Procedure Corporation, DPC; "On-line" Digoxin, Roche Diagnostic Systems; EMIT 2000 Digoxin, Syva). Four of them required no sample pre-treatment. The methods included a radioimmunoassay, fluoroimmunoassay, two enzyme-immunoassays and a turbidimetric immunoassay: the last three mentioned were adapted to the Cobas Mira Plus. The intra- and inter-assay precision was lower than 9%, except for Microgenics. The calibration stability fluctuated from 120 days for Abbott to 27 days for the Roche test, 7 days for the Syva assay and 2 days for Microgenics. The DPC test was not assayed for calibration stability. The interference from "digoxin-like immunoreactive factor(s)" differed according to the assay. The highest interference was seen with Abbott and Microgenics, and the lowest with the DPC test. The comparison among all the methods offered values of "r" higher than 0.95 except Microgenics and Syva assays where "r" was 0.896. The results obtained with Roche and Microgenics were higher than 12% of the remaining assays.

Topics: Digoxin; Female; Fetal Blood; Humans; Immunoassay; Infant, Newborn; Kidney Diseases; Liver Diseases; Pregnancy; Reagent Kits, Diagnostic

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cardiotonic Agents; Digoxin; Diphosphonates; Dose-Response Relationship, Drug; Drug Interactions; Female; Half-Life; Humans; Kidney Diseases; Male; Middle Aged; Osteitis Deformans

Topics: Antibody Specificity; Blood Proteins; Cardenolides; Digitoxin; Digoxin; Female; Fetal Blood; Humans; Immune Sera; Kidney Diseases; Liver Diseases; Pregnancy; Saponins

To characterize the disposition of total and free serum digoxin following the administration of digoxin Fab antibody in patients with varying degrees of renal function.. Observational study of pharmacokinetics and pharmacodynamics.. Critical care and telemetry units of two university-affiliated teaching institutions, Hartford Hospital and Henry Ford Hospital.. Fourteen digoxin-intoxicated patients (baseline total digoxin > 3.2 nmol/mL) with mean (+/- SD) serum creatinine of 380.1 +/- 212.2 mumol/L who received digoxin Fab antibody therapy.. Serum was drawn every 12 to 24 hours for 80 to 327 hours after Fab administration. Total and free digoxin were assayed in serum by fluorescence polarization immunoassay or modified immunofluorometric assay.. Before Fab was administered, total digoxin ranged from 3.5 to 10.5 nmol/mL. After treatment with Fab, total digoxin increased rapidly to a mean (+/- SD) maximum of 51.8 +/- 22.7 nmol/mL and decreased to 7.2 +/- 4.7 nmol/mL at the last measurement. Total digoxin was eliminated in a two-phase fashion. The half-life of the initial phase of total digoxin decline was 11.6 +/- 4.1 hours, and the half-life of the second or terminal elimination phase was 118 +/- 57 hours. Free digoxin levels decreased rapidly following Fab therapy, to a mean nadir of 0.6 +/- 1.1 nmol/mL, but rebounded to a mean maximum free digoxin concentration of 1.7 +/- 1.3 nmol/mL in 77 +/- 46 hours. The time to maximum free digoxin rebound occurred later in patients with end-stage renal disease (n = 4) compared with other patients (127 +/- 40 hours compared with 55 +/- 28 hours).. Elimination of digoxin following Fab therapy is prolonged in digoxin-toxic patients with renal dysfunction. In addition, rebound of free digoxin is delayed in anephric patients. Monitoring free digoxin following the administration of Fab may be of value in selected patients to guide additional Fab dosing, confirm possible rebound toxicity, or guide the reinitiation of digoxin therapy.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Digoxin; Humans; Immunoglobulin Fab Fragments; Kidney Diseases; Middle Aged; Protein Binding

Beta-methyldigoxin (beta-MD) was administered orally (0.2 mg) to 24 patients with various degrees of renal function, to investigate its pharmacokinetic characteristics related to renal function. Serum and urine collected until 120 hours after dosing were assayed for beta-MD and digoxin by high-performance liquid chromatography and fluorescence polarization immunoassay method. The steady-state volume of distribution decreased proportionately as creatinine clearance (CLCR) decreased, although steady-state volume of distribution of hemodialysis patients had large interindividual variability, and their mean value was not different from that of patients with normal renal function. Both renal clearance of beta-MD and digoxin were significantly correlated with CLCR (r = .820, P < .001 and r = .822, P < .01, respectively), and the slope of regression line for beta-MD was only 44% that for digoxin. Significantly reduced urinary excretion of total drug (beta-MD plus digoxin) was shown in patients with CLCR below 50 mL/minute/1.48 m2. This study suggests that the dosage modification is not necessary until CLCR decreases to below 50 mL/minute/1.48 m2, but careful attention should be given in the use of beta-MD in patients with CLCR below this value.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Digoxin; Female; Hospitals, University; Humans; Kidney; Kidney Diseases; Male; Medigoxin; Middle Aged

Measurement of serum endogenous digitalis-like factor (EDF) concentration was carried out in 58 patients with renal impairment with radioimmunoassay. The results showed that serum EDF concentration in patients with renal impairment was markedly higher than that of normal cases. The serum EDF concentration was significantly elevated with decrease of renal function and was positively correlated with the levels of BUN and blood creatinine. The serum EDF concentration in patients with primary and secondary renal impairment was of no difference. It was found that the difference between patients with and without hypertension was statistically significant. The serum EDF concentrations were markedly decreased after hemodialysis but still higher than those of normal cases.

Topics: Adult; Aged; Blood Proteins; Blood Urea Nitrogen; Cardenolides; Creatinine; Digoxin; Female; Glomerulonephritis; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Aged; Aging; Captopril; Digoxin; Furosemide; Heart Failure; Humans; Hypertension; Kidney Diseases; Lung Diseases, Obstructive; Male

Some pharmacokinetic and pharmacodynamic interactions between digoxin and gentamicin were studied in experiments on rabbits, guinea-pigs and cats. An increase of digoxin serum levels and changes in some basic pharmacokinetic parameters of digoxin (t1/2 alpha, t1/2 beta, AUC, AL) were established in gentamicin-pretreated rabbits, the changes being dependent on the dose and schedule of administration. Most pronounced were the changes in digoxin kinetics during simultaneous 5-day treatment with digoxin (0.035 mg/kg i. p.) and nontoxic doses (10 and 2 mg/kg) of gentamicin. The toxicity of digoxin in guinea-pigs, assessed by lethal doses of digoxin, was increased only after the highest dose of gentamicin (100 mg/kg), while after nontoxic or close to therapeutic doses (10 and 2 mg/kg) of gentamicin the digoxin toxicity was not changed or was even decreased. Digoxin decreased the nerve-muscle blocking effect of gentamicin on cat ischiadicus-gastrocnemius preparation. The possible mechanisms involved are discussed.

Topics: Animals; Calcium; Chinchilla; Digoxin; Drug Interactions; Gentamicins; Iodine Radioisotopes; Kidney Diseases; Male; Rabbits; Radioimmunoassay; Sodium-Potassium-Exchanging ATPase

Increased levels of a circulating digoxin-like factor (DLF) occur in a number of physiologic states in which sodium homeostasis is altered, and may contribute to the pathogenesis of hypertension. We exploited the different affinities for DLF of seven antisera directed at digoxin to develop an immunochemical profile, and then employed this index to address two questions: does the same DLF species exist in several conditions associated with increased DLF levels, including pregnancy, renal failure, hepatic failure, and neonatal cord blood? Will this approach prove useful in assessing candidates proposed to be DLF? An identical profile was identified in serum from pregnant women and patients with renal or hepatic failure, and a highly significant correlation existed between DLF levels measured with antisera of high and intermediate affinity in 42 subjects with increased levels (r = 0.93; P less than .001). In patients with renal failure, when endogenous DLF levels were too low to assess the profile, concentration of the serum resulted in measurable DLF levels that had an identical profile. The profile was somewhat altered in umbilical cord blood, perhaps reflecting an influence of increased steroid hormone levels. Among agents suggested as candidates for DLF, neither lysophosphatidylcholine nor ouabain showed a profile resembling DLF. Progesterone, 17-OH-progesterone, and bufalin, on the other hand, did show substantial similarity, perhaps providing a clue to the structure of DLF. The normal plasma levels of progesterone and 17-OH-progesterone are 100- to 1000-fold too low to be candidates for DLF and bufalin was sufficiently dissimilar not to be a candidate. DLF in at least three different patient populations probably represents identical chemical species.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antibodies; Antibody Affinity; Antibody Specificity; Blood Proteins; Bufanolides; Cardenolides; Digoxin; Female; Fetal Blood; Humans; Kidney Diseases; Liver Diseases; Pregnancy; Progesterone; Radioimmunoassay; Saponins

The molecular structure is one of the keypoints that govern both the extent of extracardiac action of cardiac glycosides and their different kinetics. The apolar, fat soluble digitoxin is very well absorbed from the intestine, its onset of action is slow, binds to a high degree to albumin and undergoes enterohepatic recirculation which accounts for a long elimination half time and stability of plasmatic levels. Digitoxin is largely excreted via gastrointestinal tract. The absorption of digoxin is less reliable, onset of action occurs earlier and the binding to albumin is considerably less than that of digitoxin. The drawback, however small, of digoxin lies in a lower stability of plasma levels and prevailing renal excretion. The molecule of strophatin is highly polar, its absorption from the intestine negligible and can be administered only intravenously. The onset of action is prompt, elimination half time short and about half the injected amount is excreted extrarenally.

Topics: Cardiac Glycosides; Digitoxin; Digoxin; Gastrointestinal Diseases; Humans; Kidney Diseases; Strophanthins; Thyroid Diseases

Digoxin-like immunoreactive substances are an endogenous group of compounds that cross-react in conventional immunoassays for digoxin. Plasma digoxin-like immunoreactive substance concentrations were estimated using the Abbott TDxll fluorescence polarisation immunoassay kit for digoxin. Digoxin-like immunoreactive substances were measured in one hundred consecutive Intensive Care Unit (ICU) patients who were not treated with digoxin. One hundred healthy blood donors were used as controls. Thirty of the ICU patients had plasma digoxin-like immunoreactive substance concentrations greater than or equal to the greatest value found in the control group (0.22 nmol/l). In the ICU group the median value was 0.17 nmol/l and the range zero to 1.69 nmol/l. In the control group the median was less than the limit of detection of the assay, and the range zero to 0.22 nmol/l. Sixteen ICU patients had coexisting renal and hepatic dysfunction and this group had a median digoxin-like immunoreactive substance concentration of 0.21 nmol/l (range zero to 1.69 nmol/l), while 38 patients with hepatic dysfunction and normal renal function had a median concentration of 0.17 nmol/l (range zero to 0.77 nmol/l). In contrast four patients with renal dysfunction only had a median concentration of 0.05 nmol/l (range zero to 0.34 nmol/l). The remaining forty-two patients had neither hepatic nor renal dysfunction and this group had a median concentration of 0.15 nmol/l (range zero to 0.36 nmol/l). This study has identified the critically ill as a group of patients who exhibit measurable plasma digoxin-like immunoreactive substances using the most commonly used kit for analysis of digoxin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Proteins; Cardenolides; Critical Care; Digoxin; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Reagent Kits, Diagnostic; Saponins; Sodium-Potassium-Exchanging ATPase

This report demonstrates the questionable usefulness of monitoring digoxin concentrations using the available immunoassays in some clinical situations. The patient reported here showed three characteristics (being a neonate with hepatic and renal impairment) that are associated with the presence of digoxin-like immunoreactive substances. The patient's serum digoxin concentration continued to rise to a peak of 43.7 nmol/L (34.1 ng/mL), 19 days after administration of the drug was discontinued.

Topics: Digoxin; Humans; Infant, Newborn; Kidney Diseases; Liver Diseases; Male

1. This study compared the analysis of digoxin using a high-performance liquid chromatographic post-column derivatization (HPLC-PC) assay and the TDx fluorescence polarization immunoassay (FPIA). 2. Serum obtained from 15 digitalized patients showed higher mean digoxin levels with the FPIA method as compared to the HPLC-PC procedure such that the mean HPLC-PC/FPIA ratio was 0.91 +/- 0.14 (mean +/- SD). Demonstrated cross-reactivity of digoxin metabolites with the FPIA is probably responsible for this observation. 3. Cross-reactivity of the immunoassay towards endogenous material present in serum samples from certain patient groups was an even greater problem, with apparent 'digoxin' serum concentrations in untreated hepatic failure patients being within the therapeutic range for digoxin. 4. The HPLC-PC method did not suffer from such interference and would therefore provide more accurate values for patients where high levels of interference could contribute to false digoxin levels.

Topics: Chromatography, High Pressure Liquid; Digoxin; False Positive Reactions; Fetal Blood; Fluorescence Polarization; Humans; Immunoassay; Kidney Diseases; Liver Diseases

We assessed the role of circulating digitalis-like substance(s) on the blood pressure regulation in patients with essential hypertension, cardiac diseases, diabetes mellitus and renal diseases by measuring digoxin-like immunoreactivity (DLI). Plasma DLI concentrations tended to correlate with blood pressure in all patient groups. Plasma DLI correlated to plasma aldosterone concentration in patients with essential hypertension, which suggested close interrelationship between DLI and electrolytes metabolism with adrenal steroids. Serum immunoreactive insulin (IRI) levels significantly correlated with blood pressure. Because plasma DLI levels correlated with serum IRI, increased levels of insulin could have induced sodium retention leading to increased DLI levels. Digitalis-like substance, but not insulin, would have directly increased blood pressure in patients with abnormal glucose tolerance. Plasma DLI levels significantly correlated with the severity of renal insufficiency in patients with renal diseases. Plasma DLI highly correlated with amounts of plasma proteins, particularly with albumin, which would be due to the binding of DLI with albumin in plasma. Because the level of non-binding DLI is extremely low when assayed with a digoxin-radioimmunoassay, it was impossible to assess the level of a free-form of DLI, i.e., active DLI. That could be a reason why the correlation between the DLI and the other parameters was not highly significant. Collectively, these findings suggest that the DLI is one of the major determinants of blood pressure rises, regardless of any cause.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Cardenolides; Diabetes Mellitus; Digoxin; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Obesity; Saponins

Topics: Adult; Age Factors; Arrhythmias, Cardiac; Biological Availability; Digoxin; Dosage Forms; Drug Interactions; Eating; Female; Humans; Infant, Newborn; Kidney Diseases; Male; Obesity; Pregnancy; Radioimmunoassay; Specimen Handling

New method for measuring plasma and urinary Na-K-ATPase inhibitor (ATPI) was developed. Plasma and urine were extracted with reversed phase cartridge column and sample was reconstituted by assay buffer. Na-K-ATPase inhibitory activity of sample was monitored by continuously recording the absorbance of NADH at 340 nm, which coupled to the dephosphorylation of ATP. Ouabain was used for standards of Na-K-ATPase inhibition and this standard showed good linearity ranged 5-100 nmol/ml. Using this new method, P-ATPI and U-ATPI were quantitatively evaluated and paradoxical Na-K-ATPase stimulating phenomenon which observed in conventional method (Hamlyn et al) was diminished. Adopting of this new method for measuring plasma(P-) and urinary(U-)ATPI, and radioimmunoassay for P- and U-digitalis-like substance(DLS)--using crossreactivity to anti digoxin antibody--, these substances were estimated in patients with essential hypertension (EHT), chronic heart failure(CHF), primary and idiopathic hyperaldosteronism(HA), hyperthyroidism(BA) and chronic renal failure(CRF). In EHT, U-DLS, P-DLS, U-ATPI, P-ATPI were significantly higher than those of control(C). In CHF and BA, U-DLS and -ATPI were also significantly higher than those of C. In HA, U-ATPI, DLS distributed in wide range, and a few patients showed high levels of U-DLS and -ATPI. In CRF, P-DLS and -ATPI levels were significantly higher than those of C in prehemodialytic state but P-ATPI was significantly decreased after hemodialysis. From these results it is suggested that 1) DLS and ATPI might contribute to the etiology of hypertension. 2) Volume expansion stimulates the secretion of DLS and ATPI. 3) Stimulatory effect of volume expansion and inhibitory effect of mineralocorticoid may be responsible for wide distribution of these factors in HA. 4) DLS and ATPI are not the same substances.

Topics: Adult; Blood Proteins; Cardenolides; Cardiovascular Diseases; Digoxin; Female; Humans; Hyperaldosteronism; Hypertension; Hyperthyroidism; Kidney Diseases; Male; Middle Aged; Saponins; Sodium-Potassium-Exchanging ATPase

In order to investigate a new possibility for artificial blood with oxygen-carrying capability to be applied to other than mere supplementation, normothermic whole body rinse-out in which artificial blood deriving from perfluorochemical emulsion, Fluosol-DA 20% (Green Cross Co., Ltd., Osaka, Japan) or stabilized hemoglobin solution, (pyridoxylated hemoglobin)-(polyoxyethylene) conjugate solution (Ajinomoto Co., Ltd., Tokyo, Japan) were used as rinsing fluid for a blood purification experiment. Replacement either with approximately 150 ml/kg of Fluosol-DA or stabilized hemoglobin solution showed effective removal of digoxin at a reduction rate of 96.3% or 92.2%, respectively. However, when Fluosol-DA was used, a certain amount of perfluorochemical should be retrieved by centrifugation to avoid a possible toxic effect on the reticulo-endothelial system. Even though 3 out of 6, and 3 out of 8 dogs, respectively, survived for a long period after the procedure, the experimental dogs were very susceptible to infection.

Topics: Animals; Blood Coagulation Disorders; Blood Substitutes; Chemical and Drug Induced Liver Injury; Digoxin; Dogs; Drug Combinations; Exchange Transfusion, Whole Blood; Fluorocarbons; Hematocrit; Hemoglobins; Hydroxyethyl Starch Derivatives; Kidney Diseases; Polyethylene Glycols; Solutions

In an attempt to confirm the presence of endogenous substances with cardiac glycoside-like activity, the biological and immunological cardiac glycoside-like activity was measured by a sensitive solid-phase radioimmunological assay (RIA), two radioreceptor assays (RRA), and a 86Rb uptake method in normal subjects and in some pathophysiological conditions characterized by sodium retention and volume expansion. Significant concentrations of digoxin-like immunoreactive substances (DLIS) were measured in plasma (or serum) of normal subjects while significantly higher levels were found in pregnant women, newborns and in patients with renal impairment, and in some with essential hypertension. Concentrations in urine of normal adults or newborns were several times higher than in plasma. The results obtained by RIA correlated with those obtained by RRA and 86Rb uptake methods. In 88 normal subjects, DLIS excretion rates (overnight urine collection) in men were significantly higher than in women (68.6 +/- 23.6 pg/min vs 50.9 +/- 21.0 pg/min, p less than 0.01). The DLIS excretion rates correlated with creatinine, Na and K urinary excretion rates, and also with the subjects' body weight, height, body mass index, and systolic blood pressure. These findings confirm the presence of endogenous substances with immunological and biological activity similar to cardiac glycosides in human body fluids and also confirm the hypothesis that these endogenous factors may be involved in fluid and electrolyte regulation in man. In addition, the present data indicate that urinary excretion of DLIS is dependent on body mass and renal glomerular filtration.

Topics: Adult; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Hypertension; Infant, Newborn; Kidney Diseases; Male; Pregnancy; Radioimmunoassay; Saponins

In 11 of 15 profoundly sick, digitalized infants and children, elevation in serum digoxin concentration could be detected long after cessation of therapy. This phenomenon concurred with a rapid deterioration of renal function. Because death of a digitalized child may be attributed to the glycoside itself, it is important to recognize that elevation in serum concentration to a potentially toxic level is a common pathophysiologic pattern.

Topics: Child; Child, Preschool; Digoxin; Female; Heart Defects, Congenital; Hemolytic-Uremic Syndrome; Humans; Infant; Infant, Newborn; Kidney Diseases; Male; Prospective Studies

The effect of renal and/or hepatic dysfunction, and of concomitant spironolactone therapy, on seven commercial digoxin assays was evaluated in 45 patients taking both these drugs, and a comparison made with the digoxin concentrations measured using the same assays in 30 patients taking digoxin in the absence of spironolactone. The study showed that increasing renal dysfunction resulted in increasing inaccuracy in assay results with the methods tested. The influence of concomitant spironolactone was to produce a further distortion, which was shown to be additive in patients with impaired renal and/or liver function. The results highlight the unresolved specificity problems which persist in many, if not all, of the immunoassays currently offered to clinical laboratories which, if not recognised, could significantly influence digoxin therapy and patient management.

Topics: Aged; Aged, 80 and over; Digoxin; Female; Humans; Immunoassay; Kidney Diseases; Liver Diseases; Male; Middle Aged; Spironolactone

Topics: Adolescent; Adult; Aged; Blood Proteins; Cardenolides; Digoxin; Europium; False Positive Reactions; Female; Humans; Immunoassay; Kidney Diseases; Male; Middle Aged; Saponins; Spectrometry, Fluorescence

Use of immunoassays that do not detect endogenous digoxin-like immunoreactive factors (DLIF) in serum significantly improves the between-assay correlation of digoxin results for patients. We investigated five different immunoassay methods (Abbott, Clinical Assays, Corning, Du Pont, and Syva), measuring digoxin by all five assays in sera from 38 patients in renal failure and in 40 patients with normal renal function, all taking digoxin. The mean standard error of the estimate (Sy X x) of digoxin results (compared for all five assays) were significantly lower for patients with normal renal function than for patients in renal failure (0.148 vs 0.293 microgram/L, P less than 0.001). Assays previously shown (Clin Chem 1987;33:401) to be the least sensitive to DLIF (Syva and Corning) gave the lowest mean scatter about the regression (Sy X x = 0.192 microgram/L, renal failure; 0.114 microgram/L, normal renal function) for all 10 assay correlations. Evidently, discrepancies between digoxin values as measured by different immunoassay kits for patients with renal disease can be attributed to DLIF. Moreover, because inaccurate digoxin results attributed to DLIF may not be limited exclusively to groups of patients with known increased concentrations of DLIF, the possibility of "latent" DLIF interference may be a problem in many other human subjects.

Topics: Blood Proteins; Cardenolides; Digoxin; Humans; Immunoassay; Kidney Diseases; Regression Analysis; Saponins

Topics: Blood Proteins; Cardenolides; Digoxin; Humans; Immunoassay; Kidney Diseases; Saponins

The effect of encainide administration on steady-state plasma digoxin levels was evaluated in 17 patients receiving stable doses of digoxin. A paired t test, comparing plasma digoxin levels (mean +/- standard error) before encainide therapy (1.05 +/- 0.14 ng/ml) and after 2 weeks of encainide, 100 mg/day (1.03 +/- 0.11 ng/ml) or 200 mg/day (1.2 +/- 0.2 ng/ml), indicates no significant (p greater than 0.05) change in digoxin levels. These results were confirmed in a second study of 10 patients with severe congestive heart failure. Also, no difference in efficacy of either drug was observed and changes in dosing of digoxin were not required. Plasma concentrations of encainide and its 2 major metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide, significantly increased by 31.6%, 43.1% and 35.6% after concomitant cimetidine administration in 13 healthy adult men receiving 75 mg/day of encainide. However, a retrospective evaluation of 33 patients receiving both drugs did not reveal any clinically significant interactions. Retrospective evaluation of patients enrolled in clinical studies who received concomitant digoxin (268), antiarrhythmics (118), anticoagulants (78), antidiabetics (40), antipsychotics (23), beta blockers (88), calcium-channel blockers (24) or diuretics (229) did not reveal any clinically significant interactions with encainide. Similarly, in vitro protein binding studies did not reveal any clinically significant interactions with encainide or its major metabolites. Six patients with moderate to severe renal impairment (creatinine clearance 10 to 38 ml/min) received 25 mg of encainide, 3 times/day, for 7 doses. Plasma encainide, ODE and 3-methoxy-O-demethyl concentrations were similar to those observed in normal subjects who had received twice the dose of encainide, and steady-state apparent oral clearance of encainide was reduced by 66% with renal impairment. Based on these data it is recommended that in patients with moderate to severe renal impairment encainide be initiated at one-third the normal dose, or 25 mg once a day. Doses may be elevated in small increments at 1-week intervals if needed for efficacy. The effect of hepatic impairment on the pharmacokinetics of encainide was studied in 7 patients with clinically documented cirrhosis. Compared with normal subjects studied using a similar protocol, the plasma concentrations of encainide were elevated significantly due to a 6-fold decrease in oral clearance. Howeve

Topics: Adrenergic beta-Antagonists; Adult; Amiodarone; Anilides; Anti-Arrhythmia Agents; Anticoagulants; Antipsychotic Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Cimetidine; Digoxin; Diuretics; Drug Interactions; Encainide; Humans; Hypoglycemic Agents; Kidney Diseases; Liver Diseases; Middle Aged; Prospective Studies; Protein Binding; Retrospective Studies

Topics: Blood Proteins; Cardenolides; Digoxin; Fetal Blood; Humans; Kidney Diseases; Liver Diseases; Saponins

The Amersham Amerlex Radio-immunoassay was used to detect 'digoxin-like' substance in the sera of 37 elderly subjects, nine with renal impairment, 14 with hepatobiliary disease and 14 over-65-years-old controls with no renal or hepatic impairment. In the patients with hepatobiliary disease, digoxin-like substance was detected in 11 out of 14, the level being closely correlated with serum bilirubin (P less than 5.5 X 10(-10)) and significantly but less closely with serum alkaline phosphatase activity (P less than 10(-3)). While serum digoxin-like substance was detectable in seven out of nine patients with renal impairment, there was no correlation between the degree of renal impairment as reflected by blood urea and serum creatinine and serum digoxin-like activity. We suggest that in elderly subjects with renal impairment or hepatobiliary disease these findings should be borne in mind especially when considering digoxin toxicity.

Topics: Aged; Biliary Tract Diseases; Bilirubin; Digoxin; Humans; Kidney Diseases; Liver Diseases; Reference Values

The effect of renal function and digoxin use in adult patients on interference from digoxin-like immunoreactive substances (DLIS) with three digoxin immunoassays was studied. Hospital patients entered into the study were categorized into the following groups according to renal function: group I (serum creatinine less than 1.5 mg/dL), group II (serum creatinine 1.5-2.5 mg/dL), group III (serum creatinine greater than 2.5 mg/dL, not on hemodialysis), and group IV (serum creatinine greater than 2.5 mg/dL, on maintenance hemodialysis). Medical records were reviewed to determine whether or not patients were receiving digoxin. Excess sera for analysis of serum digoxin concentrations (SDCs) was collected from routine laboratory tests. Serum samples were assayed singly by fluorescence polarization immunoassay (FPIA, Digoxin I, Abbott), radioimmunoassay (RIA, Micromedic), and affinity-column-mediated immunoassay (ACMIA, aca, E.I. du Pont). Correlation of SDCs obtained by RIA and ACMIA with FPIA results was determined using linear-regression analysis. A total of 177 patients met the study criteria; 98 were receiving digoxin. In patients on digoxin, SDCs by RIA were significantly higher than those obtained by FPIA in group II and III patients. SDCs obtained by ACMIA correlated well with and were not significantly different from those obtained by FPIA in any of the patient groups. Maximum differences and mean absolute differences in SDCs obtained by RIA were greater than those for ACMIA when compared with FPIA values in all patient groups. Over 40% of patients with renal dysfunction not on digoxin had false-positive SDCs by RIA; the highest of these values was seen in groups II and III.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Blood Proteins; Cardenolides; Digoxin; Fluorescence Polarization; Humans; Immunoassay; Kidney; Kidney Diseases; Middle Aged; Radioimmunoassay; Saponins

Topics: Adult; Aged; Digoxin; Female; Humans; Immunoassay; Kidney Diseases; Male; Middle Aged

Topics: Digoxin; Humans; Kidney Diseases; Radioimmunoassay

Digoxin concentrations were measured in serum samples from 102 patients with renal impairment who were receiving digoxin therapy. Many patients had values that differed widely on several currently available immunoassays, with differences as great as 2.9 ng/mL. In contrast, patients with normal renal function who were receiving digoxin had few discrepant results, with the largest difference being 0.5 ng/mL. We also assayed serum samples from 54 patients with renal impairment not on digoxin therapy and found that more than 60% of these digoxin-free patients had false-positive digoxin values on most assays. Our data suggest that a substance with digoxin-like immunoactivity is present in many patients with renal insufficiency. This substance may seriously compromise the accuracy and interpretation of digoxin concentration measurements.

Topics: Creatinine; Cross Reactions; Digoxin; False Positive Reactions; Humans; Kidney Diseases; Radioimmunoassay

17 patients on maintenance hemodialysis were monitored for cardiac arrhythmias using ambulatory electrocardiographic recording. Atrioventricular dissociation was found in a patient with an elevated serum digoxin concentration, intradialytic supraventricular tachycardia had been present in a second patient during acute uremic pericarditis prior to the study. Ventricular premature beats (VPB) were absent or of low grade (occasional/uniform) in 14 patients and did not increase on dialysis. 3 patients had potentially dangerous VPB of higher grades (multiform, salvos or R on T) which occurred on or after dialysis in 2. 2 of these 3 patients were overdigitalized, and 2 had severe cardiac disease (amyloid, old myocardial infarction). Several other risk factors (age, hypertension, cardiac hypertrophy, smoking, hyperlipidemia, electrolyte changes) did not seem to be of importance for VPB. In these patients on maintenance hemodialysis, potentially dangerous VPB were rare and occurred mainly during or after dialysis in patients with preexisting heart disease and/or digitalization.

Topics: Arrhythmias, Cardiac; Chronic Disease; Digoxin; Electrocardiography; Female; Glomerulonephritis; Humans; Hyperlipidemias; Hypertension; Kidney Diseases; Male; Middle Aged; Phenacetin; Polycystic Kidney Diseases; Renal Dialysis; Risk

Quinidine has been reported to reduce clearance and the distribution volume of digoxin. Data are presented indicating that serum digoxin concentration (SDC) is increased throughout the coadministration of quinidine. This strongly suggests that the quinidine-induced reduction of digoxin clearance is the main mechanism underlying this drug interaction. It has been suggested that beside renal clearance quinidine also reduces non-renal clearance of digoxin. Direct evidence is provided by a study in patients with impaired renal function. Irrespective of the degree of renal impairment, quinidine increases SDC to about the same amount as found in patients with normal renal function. Since quinidine does not interfere with plasma protein binding of digoxin, this implies a decrease in non-renal clearance. In all patient groups the incidence of this drug interaction is rather high; however, pronounced interindividual differences occur as regards the extent of the increase in SDC. Regardless of the state of renal function careful monitoring of digitalized patients is mandatory once quinidine therapy is initiated. Since it may take a week or more until a new steady state is established in patients with impaired renal function, this period of close monitoring should be extended correspondingly.

Topics: Blood Proteins; Digoxin; Drug Interactions; Drug Therapy, Combination; Humans; Kidney Diseases; Metabolic Clearance Rate; Protein Binding; Quinidine

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

Topics: Adult; Aged; Digoxin; Female; Humans; Kidney Diseases; Male; Middle Aged; Radioimmunoassay

Topics: Anti-Inflammatory Agents; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Humans; Kidney Diseases; Liver Diseases

Topics: Chemical Phenomena; Chemistry; Digitalis; Digitoxin; Digoxin; Drug Interactions; Humans; Kidney Diseases; Kinetics; Liver Diseases; Plants, Medicinal; Plants, Toxic

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

Topics: Adolescent; Adult; Aged; Digoxin; Female; Heart Diseases; Humans; Kidney Diseases; Male; Middle Aged

Using high-performance liquid chromatography (HPLC) to separate digoxin from its metabolites digoxigenin, digoxigenin-bis-digitoxoside, and digoxigenin-mono-digitoxoside with subsequent quantitation by 125I radioimmunoassay (RIA), we examined the plasma of patients on long-term oral digoxin therapy. Digoxin was also measured by RIA without prior HPLC separation. Nine patients requiring maintenance dialysis and 9 subjects with lesser degrees of renal impairment were studied. Trace amounts of 1 or more of the digoxin metabolites were found in the plasma of all dialysis patients while subjects with lesser degrees of renal failure had either none or only 1 metabolite in trace amounts. The ratio of HPLC digoxin without HPLC was 0.83 +/- 0.12 (SD) in renal failure patients and 1.06 +/- 0.09 in subjects with renal function (p less than 0.01). RIA overestimates the amount of digoxin in plasma of renal failure patients and in them from 6% to 42% of plasma digoxin, as determined by conventional 125I RIA, may represent compounds other than digoxin.

Topics: Chromatography, High Pressure Liquid; Digoxigenin; Digoxin; Humans; Kidney Diseases; Radioimmunoassay; Renal Dialysis; Time Factors

Topics: Digitoxin; Digoxin; Dose-Response Relationship, Drug; Half-Life; Heart Failure; Humans; Intestinal Absorption; Kidney Diseases; Protein Binding

Topics: Arrhythmias, Cardiac; Digoxin; Humans; Kidney Diseases; Radioimmunoassay

Topics: Adult; Antihypertensive Agents; Cardiomegaly; Digoxin; Drug Therapy, Combination; Female; Furosemide; Humans; Hydralazine; Hypertension, Malignant; Hypertension, Renal; Kidney Diseases; Methyldopa; Minoxidil; Propranolol; Scleroderma, Systemic; Time Factors

Topics: Adult; Age Factors; Aged; Arrhythmias, Cardiac; Creatinine; Digitalis Glycosides; Digoxin; Female; Hospitalization; Humans; Kidney Diseases; Male; Middle Aged; Potassium; Prospective Studies

Creatinine clearance was evaluated in individuals with varying degrees of renal function following the administration of beta-methyl-digoxin. From the results of the experiment it can be deduced that significantly increased hematic values and renal clearance values definitely lower than normal appear only in patients of a creatinine clearance of less than 50 ml/min. Furthermore, a positive correlation between creatinine clearance values and beta-methyl-digoxin levels was noticed. This correlation was in proportion to the amount of serum albumin. The degree of distribution of free digitalis and digitalis bound to proteins within the vascular system played an important role in the complex kinetics of digoxin. This relationship is suggested as an indirect index of the proportions of free beta-methyl-digoxin and of beta-methyl-digoxin bound to plasma proteins.

Topics: Creatinine; Digoxin; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Medigoxin; Protein Binding; Time Factors

Six subjects with normal renal function (NRF) and 6 patients with minimal renal function (MRF) on 3 times weekly hemodialysis received 150 muCi3H-digoxin-12 alpha orally. Serial urine collections were made for five days or more. Digoxin and metabolites were separated using diethylaminoethyl Sephadex LH-20 column chromatography. Mean cumulative percentages of the ingested radioactivity excreted over five days in NRF and MRF groups were: digoin, 54.5% and 14.7%; bis-digitoxoside of digoxigenin, 2.0% and 0.59%; mono-digitoxoside, 0.8% and 0.19%; digoxigenin, 0.25% and 0.03%; and dihydrodigoxin, 0.3% and 0.03%. Half-lives based on the mean rates of disappearance from urine comparing NRF and MRF groups were: for digoxin 40 hr and 120 hr; for bis-digitoxoside, 11.5 hr and 46 hr; for mono-digitoxoside, 8.5 hr and 12 hr; for digoxigenin, 2 hr and 7.5 hr; and for dihydrodigoxin, 1.2 hr and 7.0 hr. Considering the relationships of the five-day cumulative excretion and half-lives of digoxin and metabolites in the NRF and MRF groups, it appears unlikely that there is a major alteration in the biotransformation of digoxin in advanced renal failure when there appears to be a shift from renal to slower biliary excretion.

Topics: Adult; Aged; Bile; Biotransformation; Chromatography, Ion Exchange; Digoxin; Female; Half-Life; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Time Factors

We examined digoxin-prescribing in 47,000 prescriptions written predominantly by physicians in a large family medicine practice. Two hundred fifty-four patients received 511 digoxin prescriptions. Dose adjustments for age (16% decrease in patients older than 64 years), for renal disease (33% decrease), and for atrial fibrillation (39% increase) followed good prescribing practices. Appropriately lower loading doses were used for digitalization. However, despite continuing concern over the bioavailability of generic digoxin tablets, less than 40% of digoxin prescriptions in this study were written for the innovator's brand-name product (Lanoxin).

Topics: Adult; Age Factors; Aged; Atrial Fibrillation; Digoxin; Female; Humans; Kidney Diseases; Male; Middle Aged; Therapeutic Equivalency

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

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

Topics: Biological Availability; Digoxin; Humans; Kidney; Kidney Diseases; Myocardium; Prospective Studies; Radioimmunoassay

Topics: Absorption; Cardiac Glycosides; Digitoxin; Digoxin; Humans; Kidney; Kidney Diseases; Liver; Proscillaridin; Strophanthins

Topics: Adolescent; Adult; Aged; Animals; Digoxin; Dogs; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Rabbits; Radioimmunoassay

Topics: Adolescent; Adult; Aged; Creatinine; Digoxin; Female; Heart Failure; Humans; Kidney Diseases; Male; Middle Aged

Topics: Biological Availability; Cardiac Glycosides; Creatinine; Deslanoside; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Humans; Hypokalemia; Kidney Diseases; Liver Diseases; Malabsorption Syndromes; Obesity; Ouabain; Thyroid Diseases

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

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

Topics: Adult; Digitoxin; Digoxin; Heart Failure; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Renal Dialysis

Topics: Digoxin; Dose-Response Relationship, Drug; Humans; Kidney; Kidney Diseases; Mathematics; Time Factors

Topics: Adenosine Triphosphatases; Adolescent; Adult; Age Factors; Animals; Calcium; Cell Membrane; Child; Child, Preschool; Digitalis; Digitalis Glycosides; Digoxin; Heart Failure; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Kidney Diseases; Myocardium; Ouabain; Plants, Medicinal; Plants, Toxic; Sodium; Tritium

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

Topics: Digitoxin; Digoxin; Humans; Kidney Diseases

Topics: Administration, Oral; Age Factors; Arrhythmias, Cardiac; Digoxin; Humans; Kidney Diseases; Middle Aged; Time Factors

Topics: Aminohippuric Acids; Creatinine; Digoxin; Glomerular Filtration Rate; Humans; Inulin; Kidney Diseases; Kidney Function Tests; Radioimmunoassay

Topics: Digoxin; Heart Diseases; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Middle Aged; Tritium

Topics: Creatinine; Digoxin; Half-Life; Humans; Kidney Diseases; Kidney Function Tests; Mathematics; Tritium

Topics: Adult; Cardiovascular Diseases; Child; Digoxin; Female; Humans; Kidney Diseases; Male; Prospective Studies; Radioimmunoassay; Renal Dialysis; Retrospective Studies

Topics: Digoxin; Heart Diseases; Humans; Kidney Diseases

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

Topics: Adolescent; Adult; Blood; Collagen Diseases; Digoxin; Feces; Female; Glomerulonephritis; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Kidneys, Artificial; Male; Middle Aged; Polycystic Kidney Diseases; Pyelonephritis; Tritium; Urine

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Child; Child, Preschool; Digitalis Glycosides; Digoxin; Female; Heart Block; Humans; Infant; Infant, Newborn; Kidney Diseases; Male; Middle Aged; Potassium; Pulmonary Heart Disease; Tachycardia; Tachycardia, Paroxysmal