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PubMed1976

Studies on digitalis. VI. The effect of heparin on serum protein binding of digitoxin and digoxin.

The aim of the present study was to investigate the nature of the previously reported changes in the serum protein binding of digitoxin and digoxin in uremic patients under treatment with hemodialysis. Kinetic studies on protein binding during hemodialysis showed that the free fraction of digitoxin rose from 2.6% to 6.9% after 5 min of hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from 78.3% to 87.1% during the same period. In vitro hemodialysis experiments showed that such changes occurred only in vivo. Injection of heparin (5,000 IU) to control subjects produced similar kinetic changes in the protein binding of digitoxin and digoxin. Free fatty acids changed in the same way. These results indicate that the heparin-induced release of free fatty acids causes displacement of digitoxin and digoxin from their albumin-binding sites. Patients on hemodialysis have lower serum levels of digitoxin and cardioactive metabolites (mean, 8.9 ng/ml) than control patients (mean, 16.7 ng/ml) (p less than 0.005) on similar doses (mean, 0.085 mg/day). They should be maintained on the same digotoxin doses as uremic and control patients, but serum digitoxin levels should be adjusted to 10 to 15 ng/ml in hemodialysis patients compared to 15 to 25 ng/ml in uremic patients and in patients with normal renal function.

Blood Proteins↗
PubMed1976

Studies on digitalis. VII. Influence of nephrotic syndrome on protein binding, pharmacokinetics, and renal excretion of digitoxin and cardioactive metabolites.

Serum protein binding of digitoxin was lower (p less than 0.05) in 7 patients with nephrotic syndrome (96.2%, SD 1.4) than in 51 control patients (97.3%, SD 0.5). Urine protein binding of digitoxin was 60.1% in the 6 nephrotic patients in whom it was determined. Simultaneous serum and urine measurements of digitoxin and cardioactive metabolites were performed in 5 patients after a single intravenous dose of 0.6 mg digitoxin. A modified 86Rb method was used. Mean T/2 of serum elimation was 4.8 days and 8.1 days in 5 control subjects (p less than 0.05). Serum concentrations 24 hr after the dose were lower in the nephrotic group (p less than 0.0025). The urine concentration T/2 with a mean value of 5.0 days was not significantly different from controls (7.2 days). The cumulative renal exeretion was higher in the nephrotic group (23.2% of dose) than in controls (15.8%) for 8 days. The excretion during one serum T/2 was the same in the two groups. Increased renal excretion thus explains the shortened serum T/2 in nephrotic patients. Preliminary data on the metabolic pattern of digitoxin and cardioactive metabolites in serum and urine suggested that drug metabolism may be changed in patients with nephrotic syndrome. As renal excretion is enhanced, patients with nephrotic syndrome will require higher doses of digitoxin. They should be maintained at lower than usual serum levels of total drug due apparent increased volume of distribution and hypoalbuminemia with consequent increased free drug fraction.

Blood Proteins↗
PubMed1988

A comparative trial of digoxin and digitoxin in the treatment of congestive heart failure.

A randomized, crossover, single-blind study compared the efficacy and dosing accuracy of digoxin and digitoxin in 15 ambulatory patients wth congestive heart failure. Loading doses and maintenance doses were calculated according to published equations that adjust for sex, height, and lean body weight (for digitoxin), plus estimated creatinine clearance (for digoxin). At each 2-week visit, serum drug concentrations were measured and compliance with the prescribed regimen was assessed by tablet count. At the end of each study period, a congestive heart failure (CHF) score was determined in a blinded fashion by the same physician. Patient compliance was unusually high (greater than or equal to 80%) at every visit. Therapeutic concentrations were achieved with digoxin and digitoxin in 5 and 14 patients, respectively (p less than 0.05). During digitoxin therapy, CHF scores were lower than pretreatment values (p less than 0.05). The difference between CHF scores during the digoxin and digitoxin periods did not achieve significance (0.05 less than p less than 0.06). Therapeutic serum concentrations can be achieved more easily and frequently with digitoxin than digoxin without compromising the patient's CHF status.

Adult↗
PubMed1975

Species differences in plasma binding and tissue uptake of 3H-digitoxin. A comparative study in rats and mice in vivo and in vitro.

The content of cardiac glycosides in plasma and several organs of rats and mice was investigated 30 min and 12 hrs after i.p. administration of 160 mug/kg b.w. 3H-digitoxin. In rat plasma a glycoside concentration of 124.8 and 44.7 ng/ml resp. was found. The corresponding values in the liver were 834.7 and 579.7 ng/g w.w. An opposite liver/plasma distribution was obtained in mice: while in plasma 772.5 and 571.8 ng/ml were recovered, the glycoside concentration in liver was relatively small (284.8 and 235.6 ng/g w.w.). In order to find out the reason for such species differences observed in vivo, liver slices of rats and mice were incubated with 3H-digitoxin in a medium with and without various plasma proteins. The uptake of 3H-digitoxin into liver slices was drastically reduced by adding mouse plasma or albumin to the medium, while rat plasma lowered the uptake far less. These differences are well reflected by binding studies on agargel electrophoresis: only in mouse plasma a binding of 3H-digitoxin could be demonstrated. The binding rate and binding constant analyzed by equilibrium dialysis were higher in mouse than in rat plasma. It is concluded that the lower tissue accumulation in mice compared to rats must be due to the affinity of 3H-digitoxin to mouse plasma albumin. Moreover digitoxin has a higher affinity to the rat than to the mouse liver in the presence of mouse or rat plasma as well as of bovine serum albumin.

Animals↗
PubMed1987

Plasma protein binding of digitoxin and some other drugs in renal disease.

Plasma protein binding of most acidic drugs is decreased in uraemia, whereas the binding of basic drugs is usually unchanged or decreased. Decreased protein binding in patients with renal disease mainly relates to drugs binding to albumin. Digitoxin binds to a specific site on the albumin molecule. Conflicting reports exist on digitoxin-protein binding in patients with renal disease. In ten patients with end-stage renal disease treated with haemodialysis we found only a slightly increased free fraction of digitoxin. A heparin-induced increase of the free fraction of digitoxin during haemodialysis has been reported. However, this increase was caused by the generation of non-esterified fatty acids in vitro. If this in vitro lipolysis was blocked, no increase of free digitoxin could be detected. Alterations of digitoxin-protein binding in uraemic patients during haemodialysis and during the intervals between haemodialysis treatments are small.

Blood Proteins↗
PubMed1993

Lack of a pharmacokinetic interaction between carvedilol and digitoxin or phenprocoumon.

The possibility of a pharmacokinetic interaction between carvedilol and digitoxin (Study I) or phenprocoumon (Study II) has been evaluated in groups of 12 healthy volunteers. The bioavailability (Cmax, tmax, AUC) of digitoxin and phenprocoumon were assessed after a single dose, given once alone and once on day 6 of treatment with carvedilol 25 mg o.d. Cmax, tmax, AUC and Ut of carvedilol and desmethylcarvedilol were also investigated after the fifth dose of carvedilol and after the sixth dose given concomitantly with digitoxin or phenprocoumon. In Study I, the 95% confidence intervals of the ratio test versus the reference findings were; digitoxin Cmax 0.80-1.20, tmax 0.56-1.14, AUC 0.97-1.33, and for carvedilol Cmax 0.81-1.22; tmax 0.66-1.23; AUC 0.91-1.17. Formation of the active metabolite desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by digitoxin. In Study II Cmax and AUC of phenprocoumon were not changed after carvedilol. Cmax of carvedilol was decreased after phenprocoumon. The kinetic parameters of phenprocoumon were Cmax 0.80-1.05, tmax 0.47-2.00, AUC 0.78-1.05, and for carvedilol Cmax 0.59-1.06, tmax 0.71-1.73; AUC 0.80-1.08, respectively. The plasma levels of desmethylcarvedilol and the urinary recovery of carvedilol and desmethylcarvedilol were not influenced by phenprocoumon. The blood pressure and heart rate after carvedilol alone were not affected by concomitant administration of digitoxin or phenprocoumon.

Adult↗
PubMed1977

Studies on digitalis. XIII. A prospective study of 649 patients on maintenance treatment with digitoxin.

In a prospective study of digitalis intoxication in 649 patients on maintenance treatment with digitoxin a low incidence of digitalis toxicity was found, namely, 5.8 per cent. This is mainly due to a more careful use to digitalis glycosides. It is especially important to reduce the dose of digitoxin in the liver and partly excreted metabolized in the liver and partly excreted through the kidneys as metabolities. Serum half-time of digitoxin is shortened in patients with impaired renal function. Patients with reduced renal function may be treated with digitoxin in the same doses as individuals with normal renal function. This is in contrast to patients treated with digoxin. Digitoxin should therefore be the cardiac glycoside of choice in treatment of patients with renal failure. Digitoxin is further rapidly eliminated in patients with reduced liver function in spite of its extensive hepatic metabolism. In this study extracardia symptoms were found equally often as cardiac signs of toxicity. Patients intoxicated usually had several symptoms and signs of toxicity at the same time. The specificity of commonly used symptoms and signs a digitalis intoxication is very low. In this study atrial tachycardia with block, which has been considered to be an important cardiotoxic arrhythmia, very seldom was found in digitalis intoxication. There is an overlap in digitalis serum concentration between toxic and nontoxic patients. The diagnosis of toxicity was made on clinical grounds. Most of the intoxicated patients had high serum concentrations, but some had concentrations in the normal or low range. Apart from being a guide to the diagnosis of digitalis intoxication, serum digitalis levels may further be a guide to underdigitalization of cardiac patients, especially patients in sinus rhythm.

Age Factors↗
PubMed1985

Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure.

The effect of therapeutic doses of digitalis in modifying neural activity has been the subject of considerable controversy. In earlier studies we reported an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. Heart failure was associated with an increase in serotonin in five nuclei: the mammillary; bodies, ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the ventromedial and the centralis superior.+2

Animals↗
PubMed1985

Effect of heparin on digitoxin protein binding.

Reduction of digitoxin binding to plasma proteins after heparin has been reported. Our aim was to determine whether this reduction is an in vivo effect or occurs only after blood collection as a result of heparin-induced lipolysis that increases levels of nonesterified fatty acids in vitro. The effect of heparin on digitoxin protein binding was studied in 10 patients undergoing hemodialysis receiving digitoxin maintenance therapy. Digitoxin free fraction increased after heparin, from 2.5% +/- 0.7% to 4.4% +/- 1.1%, but after inhibition of in vitro lipolysis with diethyl p-nitrophenyl phosphate (2mM), a potent lipase inhibitor, there was no increase in the free fraction (2.3% +/- 0.4% before heparin and 2.4% +/- 0.5% after heparin). Digitoxin salivary levels were also unchanged (0.41 +/- 0.08 ng/ml before heparin and 0.41 +/- 0.08 ng/ml after heparin [n = 8]). These data indicate that the binding of digitoxin to plasma proteins in vivo is not altered by heparin. The reduced binding reported elsewhere was a result of heparin-induced in vitro lipolysis.

Aged↗
PubMed1992

[Thrombocytopenia in digitoxin poisoning].

Because she felt unwell, an 80-year-old woman who was receiving treatment with digitoxin (0.07 mg daily) raised the dose on her own initiative to twice or three times the previous level. She then experienced faintness, visual abnormalities and bradyarrhythmia (rate about 40/min). The ECG showed 2 degrees AV block. The digitoxin level was 70.8 ng/ml--far above the upper limit of the therapeutic range (7.5-25 ng/ml). One striking abnormality was thrombocytopenia (33,000/microliters), though the white and red cell counts were normal. Petechiae were not present and there was no evidence of internal bleeding. As the AV block had not produced any critical fall in ventricular rate, there was no need to start treatment with digitalis-binding antibody fragments (Fab fragments). Instead, the patient was given cholestyramine 4 g three times daily with the aim of interrupting the enterohepatic circulation of digitoxin. From then on the rise in platelet count paralleled the fall in digitoxin level. Seven days after discontinuing digitoxin the platelet count reentered the normal range (147,000/microliters). However, the digitoxin level (39.5 mg/ml) was still well above the therapeutic range.

Aged↗
PubMed1984

[Digitoxin blood picture and renal elimination in long-term therapy with aluminum-magnesium hydroxide gel].

In ten patients in heart failure for which they were on long-term administration of digitoxin, the influence of aluminium-magnesium hydroxide gel (Maaloxan) on steady-state digitoxin plasma concentration and renal glycoside excretion was studied. Compared with control values before antacid medication (13.6 +/- 4.4 ng/ml), the administration of 20 ml aluminium-magnesium hydroxide gel three or four times daily for several weeks caused no significant change in digitoxin plasma levels (15.1 +/- 4.9 ng/ml). Daily renal glycoside excretion, as a further measure of bioavailability of digitoxin, was also unchanged by the antacid. Therapeutic plasma concentrations of digitoxin are not influenced by antacids which contain aluminium-magnesium hydroxide, at least not if the antacid is taken 1-2 hours after the digitoxin dose.

Aged↗
PubMed1983

[Digitoxin in hepatorenal insufficiency].

Serum digitoxin levels were measured during maintenance treatment with digitoxin, 0.1 mg daily i.v., in 12 patients under intensive postoperative care who had hepatorenal failure resulting from multiple organ failure. Thirteen patients in intensive care with comparable basic diseases served as controls; they had developed predominantly renal failure. Serum digitoxin levels in the two groups were no different and remained within therapeutic range during the total period of observation of 8-40 days. During this time toxic serum digitoxin levels were measured in 2.9% of patients in renal failure and 2.7% of patients with hepatorenal failure. The pathogenesis of the liver failure and the severity of the underlying disease did not influence serum digitoxin levels. Digitoxin was tolerated similarly in the two patient groups.

Adult↗
PubMed1991

Digitoxin-associated mortality in acute myocardial infarction.

The use of digitalis in patients who have sustained an acute myocardial infarction has been controversial. A number of reports have suggested that the use of the glucoside actually can increase mortality. In all previous reports, digoxin has been the glucoside in use. In 620 patients admitted to Hamar Hospital from January 1, 1982 to December 31, 1984 with an acute myocardial infarction, 159 were using digitoxin at entry. Their survival until January 1, 1985 was compared with the rest of the population, not using digitoxin. The patients on digitoxin had a significantly higher mortality than those who were not, with a relative risk ratio of 2.33. However, major differences in baseline risk factors existed, and a multivariate Cox regression analysis was employed to adjust for the inequalities in baseline covariates. Only variables available at the entry of the index infarction were used for adjustment. Serum sodium, serum creatinine, age and no smoking were identified in a backward selection procedure as independently influencing mortality. By adjusting for these variables the relative risk ratio was reduced to 1.41, but digitoxin still exerted a significant influence on mortality. It is concluded that the results obtained with the use of digitoxin during a myocardial infarction is similar to previous reports with digoxin. Most of the excess mortality in the digitoxin group can be accounted for by inequalities in baseline characteristics. However, the possibility that a small excess in mortality is due to the digitalis glucoside cannot be excluded.

Aged↗
PubMed1993

Effect of fat substitutes, sucrose polyester and tricarballylate triester, on digitoxin absorption in the rat.

The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on [3H]digitoxin intestinal absorption was studied in the rat using a small intestine in-situ perfusion technique. The effect of SPE and TCTE was compared with that of sunflower oil, oleic acid, and saline. After 120 min perfusion, 5% SPE emulsion significantly reduced (P < 0.001) digitoxin absorption compared with all other treated groups. Five per cent TCTE emulsion had a less marked effect than SPE (P = 0.0002) and did not differ from sunflower oil. No difference was found between saline and 5% oleate emulsion, which did not reduce digitoxin absorption compared with other treated groups (P < 0.02). When taurocholic acid and lipase were added, results for the saline-, TCTE-, and SPE-treated groups were similar to those above, but the sunflower oil-treated group showed significantly enhanced (P < 0.01) digitoxin absorption. Thin-layer chromatography of the lipid phases showed hydrolysis of sunflower oil in the presence of taurocholic acid and lipase, but not of TCTE or SPE. The inhibitory effect of the non-absorbable fat substitutes on digitoxin absorption could be related to drug sequestration by the persistent oil phase constituted by the undigested and then unabsorbed fat substitutes. That part of digitoxin dissolved in the undigested oil phase is consequently unavailable for intestinal absorption.

Animals↗
PubMed1987

Digoxin-like immunoreactive substance in chronic hemodialysis patients: effect on digitoxin radioimmunoassay.

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

Digitoxin↗
PubMed1975

Serum digitoxin concentrations in infants and children.

Serum digitoxin levels were measured in 18 infants (under two years) and in 23 children (aged 2-13 years) receiving maintenance therapy. Digitalization was carried out because of heart failure in 17 infants and 13 children and for control of dysrhythmia in one infant and 10 children. Mean maintenance dosage for infants was 0.0042 plus or minus 0.0008 (sd) mg/kg/day and for children was 0.0031 plus or minus 0.0012 mg/kg/day. The mean serum digitoxin level was not significantly different in infants (30 plus or minus 10 ng/ml, range 14-58) from that found for children (34 plus or minus 11 ng/ml, range 19-61). Both values were significantly different (P smaller than 0.001) from those determined in this laboratory for adults (mean 24 plus or minus 7 ng/ml, range 5-39). In four infants with electrocardiographic or other evidence of toxicity, the mean serum level was 71 plus or minus 2 ng/ml (range 68-72), and in four children with electrocardiographic or other evidence of toxicity, the mean serum level for digitoxin was 72 plus or minus 14 ng/ml (range 53-84). The data suggest that infants and children tolerate a higher serum digitoxin concentration without any evidence of toxicity and may require more digitoxin (mg/kg) for therapeutic effect than do adults. Serum digitoxin levels may serve as an important guide in determining the adequacy of digitalization and in the recognition and management of digitalis toxicity.

Adolescent↗
PubMed1994

Preparation and antigenic properties of digitoxin-bovine serum albumin conjugates linked at the digitoxose C-3' and C-3" positions.

In order to obtain specific antisera to digitoxin, four new types of hapten-bovine serum albumin (BSA) conjugates were synthesized from digitoxin. The haptens were linked to the carrier protein through hemisuccinate and hemisuccinylglycine bridges at the C-3' and C-3" positions in the digitoxose chain. The antisera were prepared by immunizing rabbits with each digitoxin-BSA conjugate and the properties of the antisera were investigated by RIA with 3H-labeled digitoxin. Among these antisera, the antiserum raised against digitoxin 3'-hemisuccinate-BSA conjugate possessed high specificity for digitoxin, exhibiting only minor cross-reactions with digitoxigenin bisdigitoxoside (4.0%), dihydrodigitoxin (2.8%), digoxin (2.4%), digitoxigenin monodigitoxoside (0.23%) and digitoxigenin (< 0.05%).

Animals↗
PubMed1986

Clinical evaluation of a new digitoxin enzyme-immunoassay.

A solid-phase enzyme-immunoassay for the determination of the digitoxin concentration in human serum (Enzymun-Test Digitoxin) was developed, and subsequently evaluated in seven laboratories. The test is based on the competition principle. Polystyrene tubes coated with anti-digitoxin antibodies (from sheep) were used as the solid phase. In the concentration range 10-40 micrograms/l, the coefficient of variation for the majority of laboratories was between 2 and 7%. The day-to-day precision only slightly differed from the within-run precision. The measuring range was between 4 and 60 micrograms/l. Enzymun-Test Digitoxin showed good agreement with three known methods for digitoxin determination. No influence on the values was observed in lipaemic, uraemic and icteric samples, dysproteinaemia sera and in the presence of various digoxin derivatives. The new enzyme-immunoassay permits the practical and reliable determination of serum digitoxin and is suited for use in routine analysis.

Cross Reactions↗