digoxin and Uremia

In acutely uremic animals, the contractile force of the heart is consistently increased; such an increase can be dissociated from changes of afterload or catecholaminergic drive. It is associated with diminished sarcolemmal Na,K-ATPase activity in the heart which, in turn, may be related to increased levels of endogenous digitalis-like substances (endigens) that have been postulated to represent a natriuretic factor. In patients with chronic uremia, myocardial contractility is usually normal, but occasionally there may be heart failure unrelated to pre-existing hypertension, coronary heart disease, anemia, fluid overload, or other recognizable factors. So far, the experimental basis for this clinical observation is uncertain. Possible causes for the clinical syndrome include an excess of parathyroid hormone or cardiodepressor substances. There is experimental evidence of impaired cardiac response to beta adrenergic agonists, e.g., decreased isoproterenol-dependent calcium uptake, diminished inotropic and chronotropic responses. In acutely uremic rats, cardiac cyclic AMP levels are high but can be reversed by beta blockers. Heart calcium content is variable and heart weight is constantly increased in acutely uremic rats, despite decreased skeletal muscle mass. The change in heart weight is not related to anemia, to an excess of parathyroid hormone, or to sympathetic activity; its cause remains unknown. Experimental studies to date have shown a variety of abnormalities, but do not provide a uniform concept of the mechanisms or an explanation for the cardiac dysfunction so often observed in patients with uremia.

Topics: Animals; Blood Pressure; Catecholamines; Cats; Digoxin; Disease Models, Animal; Dogs; Heart; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Myocardium; Organ Size; Rats; Uremia

Topics: Acrylates; Blood Urea Nitrogen; Charcoal; Creatinine; Digoxin; Embolism; Female; Gels; Hemoperfusion; Humans; Middle Aged; Poisoning; Renal Dialysis; Uremia; Uric Acid; Water-Electrolyte Balance

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

To test the long-term effect of enalapril maleate treatment on progression of clinical signs of heart disease in dogs with moderate or severe naturally acquired heart failure associated with chronic degenerative mitral valvular disease (mitral regurgitation [MR]) or dilated cardiomyopathy (DCM).. Prospective multicenter study.. 110 dogs enrolled at 15 locations in the United States.. All dogs enrolled in this study were maintained on their randomly allocated treatment regimen until death, treatment failure (deterioration of condition requiring additional medication), or termination of the study. All dogs entered in the study received standard heart failure treatment (furosemide with or without digoxin). Statistical analysis (log-rank test) was performed to compare the distribution of number of days in the study between dogs that received placebo tablets and dogs that received enalapril tablets.. When dogs with MR and DCM were grouped together, mean number of days until treatment failure was significantly different between those receiving enalapril and those given placebo tablets (157.5 and 77.0 days, respectively). For dogs with MR, mean number of days until treatment failure was significantly different between those receiving enalapril and placebo tablets (159.5 and 86.6 days, respectively). Mean number of days until treatment failure among dogs with DCM receiving enalapril and placebo tablets was 142.8 and 56.5, respectively.. Use of enalapril in combination with standard treatment (diuretics with or without digoxin) appears to be beneficial over an extended period, compared with standard treatment alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathy, Dilated; Cardiotonic Agents; Death, Sudden, Cardiac; Digoxin; Disease Progression; Diuretics; Dog Diseases; Dogs; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Furosemide; Heart Failure; Male; Mitral Valve Insufficiency; Prospective Studies; Uremia

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

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

Incidence of cardiovascular disease is more than 20-fold higher in patients with chronic renal failure than in aged-matched individuals with normal renal function. Little is understood about the causes or the mechanism of uremia-induced cardiovascular injury, but the involvement of calpain as a possible mediator has recently been under investigation. Mean calpain activity was found to be 3.4-fold higher in the hearts of uremic rats than in control or spontaneously hypertensive (SHR) rats. In addition, calpain activity was found to be stimulated in myoblasts (Girardi) treated with media enriched with uremic serum compared with cells treated with serum from healthy volunteers. In this study, we assessed the impact of calpain activation in uremia and explored the possibility that calpain might be activated in uremia by endogenous ouabain. Ouabain is known to be elevated in uremia and is strongly associated with left ventricular hypertrophy in essential hypertension.. Calpain activity was measured in situ in human-derived myoblasts treated with low doses of ouabain similar to those concentrations found in uremic patients.. Low concentrations of ouabain (10 nmol/L) caused a highly significant increase in calpain activity, which could be completely inhibited by the simultaneous chelation of intracellular and extracellular Ca2+, and by the chelation of extracellular Ca2+ alone.. Calpain activity can be stimulated by nanomolar concentrations of ouabain due to an influx of extracellular Ca2+. As circulating ouabain is known to be elevated in uremia and strongly associated with LVH remodeling, we hypothesize that endogenous ouabain might be one of the factors that facilitates the remodeling of the left ventricle in patients with renal failure.

Topics: Calpain; Cardenolides; Cardiotonic Agents; Cells, Cultured; Digoxin; Enzyme Activation; Humans; Myoblasts, Cardiac; Ouabain; Saponins; Uremia

DanShen is a Chinese medicine that is used to treat cardiovascular disorders. DanShen is moderately to strongly protein bound, mainly to albumin. Because impaired protein binding of albumin-bound drugs in uremia has been reported, we studied protein binding of DanShen by measuring the digoxin-like immunoreactive component of this Chinese medicine. We observed a significantly higher percentage of free fraction of DanShen in uremic sera in vitro. Impaired protein binding of DanShen was also observed in sera from patients with liver disease, who had elevated concentrations of bilirubin. Treating uremic sera with activated charcoal significantly improved the protein binding of DanShen, indicating that uremic compounds are responsible for the impaired protein binding of DanShen. On the other hand, when various amounts of bilirubin were added to aliquots of the normal pool supplemented with DanShen, we observed only a modest displacement of DanShen from the protein-binding sites by bilirubin, indicating that hypoalbuminemia may play a major role in impaired protein binding of DanShen in sera with elevated bilirubin concentrations. We conclude that protein binding of DanShen is lower in uremic sera and in sera with elevated bilirubin concentrations.

Topics: Acetates; Benzenesulfonates; Bilirubin; Blood Proteins; Charcoal; Creatine; Digoxin; Drugs, Chinese Herbal; Fluorescence Polarization Immunoassay; Humans; Hyperbilirubinemia; Phenanthrolines; Protein Binding; Salicylates; Salvia miltiorrhiza; Serum Albumin; Uremia

Substances in the middle molecular weight range have been shown to play a significant pathogenetic role in as diverse disorders as end-stage renal disease and multiple organ failure. To overcome the limitations in the amount removed by hemofilters, new sorbents with a high biocompatibility are actively being developed. Furthermore, biocompatible sorbents by their nonspecific adsorptive behavior could have great impact on detoxification treatment in exogenous intoxications. We performed an in vitro evaluation of a newly developed highly biocompatible sorbent cartridge (Betasorb((R))), examining its adsorptive capacity concerning therapeutic drugs.. Uremic blood spiked with a range of therapeutic drugs was recirculated for 2 h in an in vitro hemoperfusion circuit containing a Betasorb device for hemoperfusion. The drug concentrations before and after the passage of the cartridge were measured, and the total amount removed was calculated.. The sorbent showed effective removal of glycopeptide antibiotics, digoxin, theophylline, phenobarbital, phenytoin, carbamazepine, and valproic acid. Moderate removal could be demonstrated for tacrolimus and cyclosporine A; aminoglycosides were removed to a small extent only.. Betasorb hemoperfusion shows a potent adsorptive capacity concerning therapeutic drugs (except aminoglycosides) and could be of major value in the treatment of intoxications. On the other hand, drug monitoring and possible adjustments are necessary during Betasorb hemoperfusion to maintain the therapeutic ranges of the drugs in blood.

Topics: Adsorption; Anti-Bacterial Agents; Biocompatible Materials; Carbamazepine; Digoxin; Glycopeptides; Hemoperfusion; Humans; Models, Biological; Phenobarbital; Phenytoin; Sorption Detoxification; Theophylline; Uremia; Valproic Acid

We compared digoxin-like (DLIS) and digitoxin-like (DTLIS) immunoreactive substance concentrations for 30 people older than 65 years with those for 25 people younger than 50. None received digoxin or had liver disease, uremia, or volume expansion. We found no DTLIS in any specimen, and only 1 specimen from an elderly person demonstrated a low DLIS concentration. In addition, for 22 non-volume expanded patients (8 younger than 50 years and 14 older than 65) receiving digoxin, the fluorescence polarization (FPIA) and the microparticle enzyme (MEIA) immunoassays revealed comparable serum digoxin concentrations, indicating an insufficient DLIS concentration to interfere with digoxin immunoassay results. Therefore, elderly people who are not volume expanded do not have elevated DLIS or DTLIS concentrations. Furthermore, for patients with liver disease or uremia (18 older than 65 years and 20 younger than 50), the DLIS and DTLIS concentrations were elevated. Finally, for 5 patients with liver disease who received digoxin, serum digoxin concentrations were lower by MEIA and higher by FPIA, indicating the patients had elevated DLIS levels that interfered with the assays. Elevated DLIS and DTLIS concentrations are associated with volume expansion and not age.

Topics: Aged; Aging; Blood Volume; Digitoxin; Digoxin; Female; Fluorescence Polarization; Humans; Immunoenzyme Techniques; Liver Diseases; Male; Middle Aged; Uremia

Little is known about the renal handling of endogenous ouabain-like compound (OLC). The aim of this study was to determine the normal renal clearance of OLC and the effect of mild experimental uremia on plasma OLC and its clearance.. Male Wistar rats were studied 8 weeks after subtotal (5/6th) nephrectomy (n = 8) and compared with a control sham-operated group (n = 8).. Plasma creatinine and OLC were higher in uremic animals compared with controls (creatinine 76+/-5.6 micromol/L v 45+/-9.6 micromol/L, respectively, P < .00005; OLC 195+/-62 pmol/L v 121+/-62 pmol/L, P < .02). Creatinine clearance and OLC clearance were lower in uremic animals compared with controls (creatinine 1.06+/-0.12 mL/min v 1.58+/-0.32 mL/min, respectively, P < .002; OLC 23.6+/-10.4 microL/min v 33.2+/-11.4 microL/min, P < .05). There were no significant differences (all P > .05) between the uremic and control groups in the fractional clearance of OLC (uremic 2.3%+/-1.0% v control 2.2%+/-1.0%), OLC excretion rate (uremic 6.2+/-2.4 pmol/24 h v control 5.0+/-1.1 pmol/24 h) or in the mean systolic blood pressure (BP) (uremic 132+/-13 mm Hg v control 126+/-3 mm Hg). The amount of OLC excreted per unit of functioning nephron mass was 78% higher in uremic animals than in controls. The rate of tubular absorption varied linearly with filtered load, did not differ between groups, and showed no evidence of saturation.. The kidneys are an important excretion route for plasma OLC and moderate but significant increases may occur without inducing hypertension in the short term. The low fractional clearance of OLC is most likely due to tubular absorption and/or catabolism.

Topics: Animals; Cardenolides; Creatinine; Digoxin; Enzyme Inhibitors; Hypertension; Male; Rats; Rats, Wistar; Saponins; Severity of Illness Index; Uremia

Digoxin-like immunoreactive substances (DLIS) cross-react with antidigoxin antibody and falsely elevate immunoassay-measured total digoxin concentrations. The fluorescence polarization immunoassay (FPIA) for digoxin showed high cross-reactivity with DLIS, but a new microparticle enzyme immunoassay (MEIA) had low cross-reactivity. The concentration of digoxin in the presence of DLIS was falsely lowered (negative interference) when measured by MEIA. We prepared the following serum pools: 2 normal (no DLIS), 2 from patients with uremia, and 3 from patients with liver disease (high DLIS). No patients received digoxin or digitoxin. When normal pools were supplemented with known concentrations of digoxin, total and free concentrations measured by both assays were comparable, but when liver and uremic pools containing high DLIS were supplemented with digoxin, the measured total digoxin concentrations were lower by MEIA and higher by FPIA. However, by taking advantage of 25% protein binding of digoxin and high protein binding of DLIS, free digoxin levels were not affected by DLIS. In 2 patients receiving digoxin but without volume expansion, total and free digoxin concentrations measured by both assays were comparable; in the 2 volume-expanded patients, only free digoxin concentrations were comparable. Monitoring free digoxin concentration can eliminate negative interference of DLIS in the MEIA for digoxin.

Topics: Cross Reactions; Digoxin; False Positive Reactions; Fluorescence Polarization Immunoassay; Humans; Immunoenzyme Techniques; Liver Diseases; Microspheres; Uremia

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

Digoxinlike immunoreactive substances (DLIS) cross-react with antidigoxin antibodies and falsely elevante total digoxin levels. Cross-reactivity of DLIS with various immunoassays for digoxin has been extensively studied in the past. The digitoxin molecule differs from digoxin by having one extra hydroxyl group in the aglycone ring. Therefore, DLIS may also falsely elevate total digitoxin concentrations. However, in the past, limited studies have shown the presence of digitoxinlike immunoreactive substances (DTLIS) in cord blood and sera of neonates. We compared DLIS and DTLIS concentrations in sera of patients with uremia, liver disease, and hypoalbuminemia. We found measurable DLIS concentrations in 11 of 45 patients by the fluorescence polarization immunoassay (FPIA) for digoxin (range, 0.20-0.89 ng/ml digoxin equivalent). These patients did not receive any digoxin or digitoxin. Using the FPIA, we also found elevated DTLIS concentrations in 10 of these 45 patients (range, 2.88-21.24 ng/ml digitoxin equivalent). Given the narrow therapeutic range of digitoxin (15-30 ng/ml), this cross-reactivity is significant. Elevated concentrations of DTLIS in sera falsely elevated the measured concentrations of digitoxin (positive interference) when known amounts of digitoxin were added to such sera. Interestingly, we found a poor correlation between DLIS and DTLIS concentrations in sera of patients with liver disease and uremia (r = 0.58), with some patients having no measurable DLIS activity but measurable DTLIS activity and vice versa. Digoxin showed only 4-8% cross-reactivity against digitoxin antibody with a wide range of concentration. Some proposed DLIS compounds (nonesterified fatty acids, cholic acid, lysophospholipid, and DHEA-sulfate) did not show any cross-reactivity with the digitoxin assay at a concentrations much higher than the physiologic range. We conclude that DTLIS activity is present in patients with liver disease and uremia, and the correlation between DLIS activity and DTLIS activity is poor. Moreover, some proposed DLIS do not explain the DTLIS activity detected in serum.

Topics: Digitoxin; Digoxin; Fluorescence Polarization Immunoassay; Humans; Liver Diseases; Uremia

Two chronic haemodialyzed patients with digitalis intoxication are reported. One of them took digoxin 0.25 mg three times daily for an unknown period and the other took digitoxin 0.1 mg twice daily for two weeks. The symptoms of intoxication were mainly concealed by uremic syndrome. The diagnosis was established by noticed sinus bradycardia, first- and second-degree atrioventricular block in ECG and the determination of sera levels of glycosides (serum digoxin concentration was 7.36 ng/ml, serum digitoxin concentration was 46.5 ng/ml) in both cases. Considering the probable long elimination period of digitalis and the potentially life-threatening situation the patients were given digoxin-specific antibody (Fab) fragments with potassium replacement therapy. The symptoms disappeared within a few hours after therapy, side effects and rebound toxicity did not develop. In connection with these cases the aim of this report is to publish a method which can reverse the life-threatening digitalis intoxication in patients suffering from renal failure as well. As to the above method, the authors have not found any similar case reports in the Hungarian medical literature.

Topics: Aged; Antidotes; Digoxin; Drug Overdose; Female; Humans; Immunoglobulin Fragments; Potassium; Renal Dialysis; Self Administration; Uremia

The Na(+)-K+ ATPase enzyme plays an essential role in the regulation of cell composition and volume. Enzyme activity itself is regulated by substrate availability and several hormones. In adult uraemic patients red blood cell Na(+)-K+ ATPase activity is decreased. However, it is unknown if children with uraemia exhibit the same phenomenon. Therefore, in the present study we examined whether endogenous digoxin-like factors (EDLF) and physicochemical membrane properties play a role in the regulation of erythrocyte Na(+)-K+ ATPase activity in uraemic children and adolescents. Healthy age-matched children were used as controls. Enzyme activity was measured in detergent-pretreated red blood cells and erythrocyte ghosts. Na(+)-K+ ATPase activity (2204 +/- 538 nmol Pi ml erythrocyte-1 h-1 in detergent pretreated erythrocytes; 204 +/- 56 nmol Pi mg protein-1 h-1 in ghosts) in adolescents with uraemia was lower compared to controls (3245 +/- 362 nmol Pi ml erythrocyte-1 h-1; 266 +/- 37 nmol Pi mg protein-1 h-1, p < 0.001, p < 0.05, respectively). Plasma levels of EDLF were elevated in uraemic patients (0.30 +/- 0.05 versus 0.21 +/- 0.04 ng ml-1, p < 0.01). Furthermore, the membrane lipid component was decreased in patients with uraemia, while the cholesterol/phospholipid ratio and membrane fluidity were similar in both groups. No correlation was found between the decrease in Na(+)-K+ ATPase and the increase in EDLF concentration and altered membrane lipid components. Our results demonstrate, that similar to the findings of adults, the activity of Na(+)-K+ ATPase is diminished in uraemic adolescent patients, and that uraemia-associated elevation in EDLF and altered membrane components do not play a role in the down-regulation of Na(+)-K+ ATPase. Therefore other factors (presence of other inhibitors and/or reduced number of enzyme molecules) should contribute to the lower activity of the Na(+)-K+ pump.

Topics: Adolescent; Adult; Cardenolides; Cholesterol; Digoxin; Down-Regulation; Enzyme Inhibitors; Erythrocyte Membrane; Female; Fluorescence Polarization; Humans; Male; Membrane Lipids; Phospholipids; Saponins; Sodium-Potassium-Exchanging ATPase; Uremia

The enzyme Na+/K(+)-ATPase plays a central role in the regulation of transmembrane ionic transports. According to previous reports its activity decreased in uremic state. The activity of Na+/K(+)-ATPase in detergent pretreated erythrocytes was studied in seven uremic children prior to and following the hemodialysis (HD) session. Additionally, the level of endogenous digoxin like factors in the plasma (EDLF) was determined. Before the HD session the Na+/K(+)-ATPase activity decreased compared to the control value (mean +/- SD: 2078 +/- 527 vs 3245 +/- 362 nmol P/ml RBC/h, p < 0.01). Following HD it became normal (3366 +/- 952 nmol P/ml RBC/h, n.s.). Prior to the HD the EDLF level was higher, while after the HD no difference was noted from the control value (0.29 +/- 0.04, p < 0.05; 0.24 +/- 0.04 n. s. vs control; 0.21 +/- 0.04 ng/ml). Before the HD blood pressure was significantly elevated compared to the control (117 +/- 20/92 +/- 18 vs 95 +/- 2/64 +/- 2 Hgmm, p < 0.05). By the end of the HD it became normal (100 +/- 14/79 +/- 11, n.s.). Although no correlation was found between the EDLF level and Na+/K(+)-ATPase activity, a positive significant correlation was found between the changes of enzyme activity and the changes in the systolic (r = 0.83, p < 0.05) and diastolic (r = 0.82, p < 0.05) blood pressure during the HD. Our results indicate, that in uremic children the Na+/K+ pump is inhibited by a dialysable, blood-pressure regulator substance and so the enzyme activity elevates following the HD session. However, decreased blood pressure activates counterregulatory mechanisms, which-to lower extent-inhibit the activity of the pump.

Topics: Adenosine Triphosphatases; Adolescent; Blood Pressure; Cardenolides; Child; Digoxin; Enzyme Inhibitors; Erythrocytes; Female; Humans; Male; Potassium; Renal Dialysis; Saponins; Sodium; Uremia

To identify factors that regulate the levels of immunoreactive digitalis-like substances (irEDLS) in body fluids, two studies were carried out. Plasma and urine levels of irEDLS were measured in uremic and normal subjects. Extracted material was fractionated (12 fractions) and assayed by digoxin radioimmunoassay. In four fractions, higher levels of irEDLS were found in uremic than in normal plasma. Urine from healthy subjects contained very high levels of irEDLS, but in urine collected from uremic patients irEDLS levels were similar to those in plasma. In another study, eight healthy subjects were given dexamethasone 1 mg orally and tetracosactide [an adrenocorticotropic hormone (ACTH) analogue] 0.25 mg i.v., on separate occasions. Dexamethasone suppressed the plasma and urine levels of cortisol and irEDLS. ACTH increased the levels of cortisol in plasma and urine, and of irEDLS in plasma. Taken together, these results support the hypothesis that irEDLS are of adrenal origin. However, decreased renal clearance, rather than increased production or release, may be the main cause of increased plasma levels of irEDLS in uremia.

Topics: Administration, Oral; Blood Proteins; Cardenolides; Cosyntropin; Dexamethasone; Digoxin; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Radioimmunoassay; Saponins; Sodium-Potassium-Exchanging ATPase; Uremia

Digoxin-Like Immunoreactive Factors (DLIF) which cross-react with antidigoxin antibodies are present in elevated concentrations in patients on hemodialysis, uremia, hypertensives, liver failure, pre-eclampsia and premature birth. DLIF may have a potential role as a natriuretic hormone with a speculated low molecular weight (less than 1000). We studied the dialyzability and bindings of DLIF with serum components in hemodialysis patients. We analyzed DLIF concentrations in sera and protein free ultrafiltrates of 31 patients and 22 normal volunteers using a fluorescence polarization assay for digoxin. The DLIF concentrations were expressed as nmol/L Digoxin Equivalent. The gel filtration analysis was done using three different Bio-Gel columns with molecular weight cut-offs of 10,000, 20,000 and 40,000. Molecules with lower molecular weight than cut-off were absorbed in the column. Only 3 out of 22 normal volunteers (13.6%) showed measurable DLIF. However 23 out of 31 patients (74.2%) showed measurable DLIF. The concentrations of DLIF were significantly higher in patients with renal failure on hemodialysis (P less than 0.05) by both chi-squared and Fisher's exact test. We observed no statistically significant difference in the concentrations of DLIF in pre and post-dialysis sera, indicating that DLIF were not filtered during hemodialysis. We observed no DLIF activity in the protein free ultrafiltrates of any DLIF positive sera (patients and normal volunteers), indicating that unlike digoxin (where we observed 70-80% of total digoxin concentrations in ultrafiltrates), DLIF were strongly bound to serum components. With Bio-Gel filtration experiments (five different serum pools), we recovered all DLIF activities in the fraction equivalent to the void volume of the column with Bio-Gel P6 and P10 columns, indicating that DLIF were almost completely bound to serum components with molecular weight greater than 20,000. On the other hand, we recovered no DLIF activities in the void volume when the same serum pools were passed through the Bio-Gel P30 column, indicating that DLIF were strongly bound to serum macromolecules with molecular weight less than 40,000. In sharp contrast, when serum containing digoxin was subjected to the same series of experiments, we recovered only 20-30% of digoxin concentrations in void volume with all three columns as expected since digoxin is only 25% bound to albumin (MW 67,000).

Topics: Blood Proteins; Cardenolides; Chi-Square Distribution; Chromatography, Gel; Digoxin; Humans; Macromolecular Substances; Protein Binding; Renal Dialysis; Saponins; Serum Albumin; Uremia

Patients with essential hypertension have 3.2 fold and patients with chronic uraemia 11.7 fold higher serum concentrations of endogenous digitalis-like activity than normotensives (76.3 +/- 9.3 nM). Upon haemodialysis this serum activity drops to almost normal values. A low molecular factor could be partially purified from 4000 l haemofiltrate.

Topics: Aged; Blood Proteins; Cardenolides; Chromatography; Chronic Disease; Digoxin; Female; Humans; Hypertension; Male; Middle Aged; Saponins; Sodium; Sodium-Potassium-Exchanging ATPase; Uremia

Digoxin concentrations in serum samples were measured before and after hemodialysis of 31 uremic patients (pts) who either never took digoxin or who had not taken digoxin for at least 1 year. False positive digoxin was found in 22 of 31 patients (71%) before hemodialysis and in 14 of 31 patients (45%) after hemodialysis. The concentrations ranged from 0.1 to 0.5 nmol/L, mean value was 0.20 +/- 0.16 before hemodialysis and after hemodialysis ranged 0.1 to 0.4 nmol/L mean value was 0.11 +/- 0.14 nmol/L. The difference before and after hemodialysis is statistically significant. Some of the patients had a constant value before and after hemodialysis. None had a higher value after hemodialysis than they did before. Eight patients, who had positive serum digoxin before hemodialysis with concentrations up to 0.5 nmol/L, became negative after hemodialysis. Our results indicate that a digoxinlike substance in uremic serum could be at least partly dialyzable.

Topics: Adolescent; Adult; Digoxin; Female; Humans; Male; Middle Aged; Renal Dialysis; Uremia

Digoxin-like immunoreactive substance (DLIS) was measured in 34 samples obtained from subjects not receiving digoxin: 10 uremic, 10 third trimester pregnancy, seven cord blood and seven normal. DLIS concentration was measured by four commercial polyclonal radioimmunoassay (RIA) systems: Clinical Assay (CA), Corning Immophase (CI), Diagnostic Products Double Antibody (DP), Kallestad Quantitope (KK), a monoclonal antibody (MA) assay and a Fluorescence Polarization Immunoassay (FPIA). In general, the cord blood samples were richer in DLIS. Digoxin immunoassays, MA and DP showed minimal interference by DLIS in all samples, whereas FPIA and CA exhibited the maximal cross-reactivity with DLIS. In cord blood samples, mean +/- SD DLIS concentration ranged from 0.41 +/- 0.13 (by CA) to 0.034 +/- 0.02 ng ml-1 as measured by MA assay. In uremics, the mean DLIS concentration was below the detection limit of all RIA assays. The FPIA method showed a higher degree of cross-reactivity to DLIS, especially in the cord and pregnancy samples (0.42 +/- 0.13 and 0.4 +/- 0.14 ng ml-1, respectively). DLIS in uremics was below the FPIA detection limit of 0.2 ng ml-1. Overall, the degree of interference by DLIS in decreasing order was FPIA greater than CA greater than CI greater than or equal to KQ greater than DP greater than or equal to MA. The cord blood samples were re-analysed by FPIA (Digoxin-II assay) 4 months later, resulting in 2-4-fold higher DLIS concentrations for these samples. This appears to be due to the substitution of 5-sulphosalicylic acid as a protein precipitating reagent and this effect may have been accentuated by freeze-thaw cycles.

Topics: Antibodies; Antibodies, Monoclonal; Blood Proteins; Cardenolides; Cross Reactions; Digoxin; Female; Fetal Blood; Fluorescence Polarization Immunoassay; Humans; Infant, Newborn; Pregnancy; Pregnancy Trimester, Third; Radioimmunoassay; Saponins; Uremia

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

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

We have evaluated in 26 uremic patients [21 on hemodialysis, 5 on continuous ambulatory peritoneal dialysis (CAPD)], 11 normotensive, and 15 hypertensive (MAP greater than 110 mm Hg) patients the following properties: a) erythrocyte (RBC) Na concentration [Nai] and ouabain-sensitive and -resistant Na effluxes; b) the effect of uremic sera on ouabain-sensitive Na efflux in normal RBC; c) serum digoxin-like immunoreactivity; d) cardiac index and total peripheral resistance. In 19 healthy subjects a) and c) were also evaluated. RBC Na,K pump activity was lower in uremic patients than in normal subjects (P less than 0.0005), and lower in hypertensive (P less than 0.02) than in normotensive patients. Serum from uremic patients inhibited ouabain-sensitive Na efflux in normal RBC, the inhibition being correlated with both the rate constant for ouabain-sensitive Na efflux (r = -0.67; P less than 0.005) and [Nai] (r = 0.43; P less than 0.05) of RBC of patients from whom the serum was obtained. Inhibition of ouabain-sensitive Na efflux was significantly higher with serum from hypertensive than from normotensive patients (P less than 0.05). Serum digoxin-like immunoreactivity was present in all uremic patients (0.402 +/- 0.054 ng/ml in normotensive and 0.428 +/- 0.040 ng/ml in hypertensive, P = ns), while it was not detectable in normal subjects. Hypertensive patients had peripheral resistance significantly higher than normotensive (P less than 0.05), while cardiac index was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Proteins; Cardenolides; Digoxin; Erythrocytes; Female; Humans; Hypertension, Renal; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Saponins; Sodium Channels; Sodium-Potassium-Exchanging ATPase; Uremia; Vascular Resistance

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

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

Topics: Adult; Aged; Digoxin; False Positive Reactions; Fluorescence Polarization; Fluorescent Antibody Technique; Humans; Middle Aged; Radioimmunoassay; Uremia

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

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

In a review of the records of 81 patients with the discharge diagnosis of digitalis toxicity, I found a preponderance of very old patients, many of whom had anorexia, nausea, and prerenal azotemia. Arrhythmias were common (93%) and reflected enhanced automaticity, enhanced AV block, or both. Atrial fibrillation with complete heart block and a regular junctional rhythm should particularly elicit suspicion of digitalis toxicity. Atrial tachycardia with block is less specific and less frequent.

Topics: Adult; Age Factors; Aged; Anorexia; Arrhythmias, Cardiac; Atrial Fibrillation; Digitalis; Digoxin; Heart Atria; Heart Block; Humans; Middle Aged; Nausea; Plants, Medicinal; Plants, Toxic; Radioimmunoassay; Tachycardia; Uremia

Topics: Digoxin; Fluorescence Polarization; Humans; Middle Aged; Radioimmunoassay; Uremia

In patients with chronic uremia we have previously demonstrated a significant inhibition of the Na-K-ATPase enzyme which represents the specific receptor protein for cardiac glycosides. Since an endogenous inhibitor of this enzyme was previously shown to react with a digoxin antibody, in the present study we determined digoxin-like immunoreacting activity(ies) (DLIA) by a radioimmunoassay in 15 nondialyzed patients with chronic renal failure. In native serum, DLIA ranged from 0 to 1.70 ng/ml and was unrelated to the degree of renal failure. After gel filtration of serum, DLIA exclusively eluted in the small molecular weight salt (FIII) and post-salt (FIV) fractions and averaged 0.22 +/- 0.04 and 0.20 +/- 0.05 ng/ml in fractions III and IV, respectively. Total activities ranged from 0.11 to 0.88 ng/ml with a mean of 0.42 +/- 0.06 ng/ml and closely correlated with the degree of renal impairment (p less than 0.001). The results confirm the presence of small molecular weight digoxin-like immunoreacting substance(s) in uremic serum. The variable activities in native serum and the lack of correlation between the degree of renal failure and DLIA in serum fraction IV previously shown to possess the Na-K-ATPase-inhibiting activity, however, indicate that DLIA may not reflect specifically the endogenous sodium pump inhibitor and that unspecific binding to this digoxin antibody of uremic toxins or other endogenous compounds, such as steroids other than aldosterone, may have occurred.

Topics: Adult; Aged; Antigen-Antibody Reactions; Chromatography, Gel; Chronic Disease; Digoxin; Female; Humans; Male; Middle Aged; Uremia

Topics: Digoxin; Drug Interactions; Female; Humans; Middle Aged; Renal Dialysis; Uremia; Verapamil

Topics: Digoxin; Drug Interactions; Female; Humans; Kinetics; Middle Aged; Renal Dialysis; Uremia; Verapamil

Topics: Digitalis Glycosides; Digitoxin; Digoxin; Heart Failure; Humans; Kinetics; Myocardial Contraction; Sodium-Potassium-Exchanging ATPase; Uremia

Topics: Digoxin; Fetal Blood; Fluorescence Polarization; Humans; Infant, Newborn; Radioimmunoassay; Reagent Kits, Diagnostic; Uremia

Topics: Acute Kidney Injury; Cross Reactions; Digoxin; Humans; Immunoassay; Kinetics; Male; Middle Aged; Uremia

The influence of haemolysis, uraemia and hyperbilirubinaemia on the radioimmunoassay for both digoxin and insulin has been investigated for five separation techniques (dextran/charcoal; coated tube; polyethyleneglycol 4000; sodium sulphite; double antibody). Recoveries, and intra- and interassay precision were calculated. It was demonstrated that even in serum samples with a rather high degree of haemolysis (haemoglobin up to 50 g/l)digoxin can be measured by using each of the five separation techniques without any significant interference. Visible haemolysis (haemoglobin above 200 mg/l) leads either to disturbance or to a complete failure of insulin radioimmunoassays with all separation techniques. This effect can be largely neutralized, and precision improved, by using N-ethylmaleimide. With the exception of the coated tube separation technique the intraassay precision has a CV of less than 10%, and the interassay CV is between 10 and 20%. Elevated urea concentrations interfered in the digoxin radioimmunoassay only when the coated tube technique was used. The insulin radioimmunoassay, however was affected by high urea when either the double antibody or the coated tube technique was used. Here the intraassay precision also has a coefficient of variation less than 10%, the interassay CV lying between 10 and 20%. Bilirubin influenced the digoxin test when the sodium sulphite separation was used, and it affected the insulin determinations with polyethyleneglycol 4000 and sodium sulphite. The intra- and interassay precision were however also around 10% and between 10 and 20% respectively. Compared with the interassay precision of 15% CV for digoxin and 13% for insulin for a pool-serum from blood donors, the decrease of interassay precision caused by haemolysis, uraemia and hyperbilirubinaemia was insignificant.

Topics: Animals; Bilirubin; Digoxin; Ethylmaleimide; Guinea Pigs; Hemolysis; Humans; Insulin; Rabbits; Radioimmunoassay; Urea; Uremia

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

We studied the interference of the sample matrix on digoxin radioimmunoassays using four commercial kits. Plasma samples from non-digitalized patients of the following categories were assayed: uncomplicated essential hypertension treated with spironolactone, uremia, and acute myocardial infarction (AMI). Digoxin 2.50 nmol/L was added to all samples. Digoxin in plasma from patients on spironolactone was overestimated by two of the kits (means 2.77 and 2.68 nmol/L, respectively; p less than 0.01) and underestimated in samples from uremic patients by one kit (2.32 nmol/L; p less than 0.01). The digoxin content of AMI plasma was overestimated by one kit (2.62 nmol/L; p less than 0.05). Significant differences were found between radioimmunoassays when estimating digoxin concentration in the same category of patient and within individual methods used for different categories. Precision expressed as 95% confidence intervals ranged from 0.43 to 0.80 nmol/L for the kits. Thus, deviations in recorded digoxin concentrations from the true values found, but were of secondary importance because of the relatively low precision of the assays.

Topics: Digoxin; False Positive Reactions; Humans; Hypertension; Myocardial Infarction; Radioimmunoassay; Reagent Kits, Diagnostic; Spironolactone; Uremia

Toxicity to digoxin was monitored in 437 consecutive recipients in a comprehensive drug surveillance programme, Adverse reactions developed in 19.5% and, in contrast to previous reports, were generally of a relatively benign nature. There were no drug-related deaths, but patients with adverse reactions spent longer in hospital. Low body weight, impaired renal function, old age and concurrent use of diuretics individually did not increase the risk of toxicity. This was attributed to improvements in the prescribing of digoxin. There was a highly significant excess of gastrointestinal reactions in women, which tended to occur early in the course of therapy. This susceptibility is not widely recognized. The use of loading doses may have caused many early reactions and it is suggested that this practice cold be abandoned in all but the most urgent cases.

Topics: Age Factors; Aged; Arrhythmias, Cardiac; Digoxin; Diuretics; Drug Administration Schedule; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Potassium; Sex Factors; Time Factors; Uremia

Topics: Animals; Chronic Disease; Digoxin; Intestinal Absorption; Male; Rats; Uremia

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

The purpose of this study was to evaluate the metabolism and rate of elimination of digoxigenin bisdigitoxoside (bis) before and during chronic azotemia in dogs. Bis was eliminated primarily by nonrenal mechanisms. The half-life of bis was 18.5 hr, compared to 31.6 hr for digoxin, and was not significantly increased in azotemic dogs. The oral bioavailability of bis in azotemic dogs relative to an intravenous dose was approximately 46%.

Topics: Animals; Biological Availability; Digoxigenin; Digoxin; Dogs; Half-Life; Kinetics; Male; Uremia

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

Topics: Aged; Arrhythmias, Cardiac; Bethanidine; Digoxin; Drug-Related Side Effects and Adverse Reactions; Female; Furosemide; Humans; Hyperkalemia; Hypotension, Orthostatic; Male; Middle Aged; Spironolactone; Uremia

The results of parallel determinations of digoxin in the sera of non selected patients (n = 104) by enzyme immunoassay (EMIT-EIA) and radioimmunoassay (J-125 labeled RIA) were compared with each other. The determinations revealed considerably different concentrations; the values determined by EIA were statistical lower (for EIA 1.09 +/- 0.99 ng/ml, for RIA 1.34 +/- 1.01 ng/ml, p less than 0.01). In sera with hemolysis and in sera of patients with hyperlipidemia and uremia false-negative results were found by EIA. After elimination of these sera an exact concordation of the values of both the methods was obtained (for EIA 1.12 +/- 1.01 ng/ml, for RIA 1.12 +/- 1.02 ng/ml, r = 0.95).

Topics: Digoxin; False Negative Reactions; Glucosephosphate Dehydrogenase; Hemolysis; Humans; Hyperlipidemias; Immunoenzyme Techniques; Radioimmunoassay; Uremia

The purpose of this study was to evaluate the disposition kinetics of digoxin after the administration of a single intravenous dose to the same dogs before and during azotemia. The digoxin plasma concentration-time data were fitted to a multicompartment model using nonlinear regression analysis. During azotemia, the biological half-life of digoxin was prolonged in six of seven dogs, while digoxin renal clearance, body clearance and apparent volume of distribution were significantly decreased. There was a corresponding increase in the apparent volume of the "central" compartment of digoxin. Approximately 45% of a digoxin dose was excreted by the kidney in these animals indicating a substantial nonrenal component to digoxin elimination in the dog. This nonrenal elimination did not change during azotemia, despite a decrease in renal clearance by 61%.

Topics: Animals; Creatinine; Digoxin; Dogs; Kinetics; Male; Uremia

Immunoreactive parathyroid hormone (iPTH) was measured in the serum and filtrate before, during and after hemofiltration. iPTH regularly declines during hemofiltration; one patient, investigated for a longer period, showed a normalization of iPTH serum level with this treatment. The iPTH values found in the hemofiltrate were remarkably high, a finding that could be explained by non-specific effects, by the occurrence of hormone fragments or by an increased secretion rate. At any rate, the results suggest a filtration of parathyroid hormone and/or hormone fragments. On the other hand, it was impossible to detect any 25-OH-vitamin D in the hemofiltrate. Finally, digoxin could be found in the filtrate, but only in very low concentrations.

Topics: Digoxin; Humans; Hydroxycholecalciferols; Parathyroid Hormone; Renal Dialysis; Ultrafiltration; Uremia

The aim of the present investigation is to study digitoxin and digoxin protein binding in patients with normal renal and hepatic function, in patients with uremia, and in patients under treatment with hemodialysis for renal failure. The binding of digitoxin and cardioactive metabolites to serum proteins was studied using equilibrium dialysis (an in vitro chemical assay) alone and in combination with a modified 86Rb method. The following values for protein binding were found: DT-3 (digitoxin), 95.7%; DT-2 (digitoxigenin-bis-digitoxoside), 96.5%; DT-1 (digitoxigenin-mono-digitoxoside), 98.7%; DT-0 (digitoxigenin), 92.7%; DG-3 (digoxin), 21.2%; DG-2 (digoxigenin-bis-digitoxoside), 16.3%; DG-1 (digoxigenin-mono-digitoxoside), 18.5%; and DG-0 (digoxigenin), 13.3%. In vitro addition of procainamide, phenytoin, heparin, and rifampicillin did not influence the in vitro binding of digitoxin. Protein binding of digitoxin showed small individual variations in patients with normal renal and hepatic function. Uremia per se did not influence the in vitro binding of digitoxin. There were marked changes in digitoxin and digoxin protein binding during an 8-hr hemodialysis, digitoxin binding decreasing from 97.1% to 93.7% (p less than 0.0025) and digoxin binding from 23.5% to 15.4% (p less than 0.05). In the uremic patient the metabolic pattern of digitoxin tended toward a decrease in protein-bound metabolites.

Topics: Blood Proteins; Digitoxin; Digoxin; Drug Interactions; Heparin; Humans; Kidney; Kidney Transplantation; Liver; Phenytoin; Procainamide; Protein Binding; Renal Dialysis; Rifampin; Transplantation, Homologous; Uremia

Topics: Adult; Age Factors; Aged; Creatinine; Digoxin; Electrocardiography; Female; Heart Failure; Humans; Kidney; Male; Middle Aged; Uremia

Topics: Digitoxin; Digoxin; Heart Diseases; Humans; Magnesium; Poisoning; Radioimmunoassay; Spectrum Analysis; Uremia

Topics: Blood Proteins; Cardiac Glycosides; Digitoxin; Digoxin; Humans; Membranes, Artificial; Ouabain; Protein Binding; Renal Dialysis; Strophanthins; Tritium; Uremia

Topics: Digoxin; Humans; Uremia

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

Topics: Animals; Bilirubin; Blood Proteins; Digoxin; Drug Stability; Hemolysis; Humans; Immune Sera; Iodine Isotopes; Luminescent Measurements; Methods; Protein Binding; Rabbits; Radioimmunoassay; Serum Albumin; Succinates; Temperature; Time Factors; Tritium; Uremia

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

Topics: Acute Kidney Injury; Adult; Aged; Digoxin; Female; Heart Failure; Humans; Male; Middle Aged; Renal Dialysis; Strophanthins; Tritium; Uremia

Topics: Adenine Nucleotides; Animals; Digoxin; Glucose; Guinea Pigs; Lactates; Myocardium; Phosphates; Phosphocreatine; Poisoning; Rats; Uremia; Ureter

Topics: Aged; Arrhythmias, Cardiac; Atrial Fibrillation; Atropine; Bradycardia; Cardiac Complexes, Premature; Digoxin; Drug Hypersensitivity; Dyspnea; Heart Rate; Humans; Male; Middle Aged; Propranolol; Tachycardia; Uremia