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PubMed2000

Severe thrombocytopenia caused by digitoxin intoxication in a patient with heart failure associated with Sjögren's syndrome.

Congestive heart failure (CHF) related to Sjögren's syndrome is extremely rare. This report concerns a patient who presented with CHF and severe thrombocytopenia (5,000/microl). Serum concentrations of K, Mg and digitoxin were 3.2mmol/L, 1.4mg/L and 57.2ng/ml, respectively. Digitoxin intoxication was evident, seemingly evoked by hypokalemia, hypomagnesemia, hepatorenal dysfunction and hypothyroidism. The severe thrombocytopenia was considered to have been caused by this intoxication, as it disappeared soon after the digitoxin was discontinued and potassium was supplemented.

Cardiotonic Agents↗
PubMed2000

Chronic hypertension induced by ouabain but not digoxin in the rat: antihypertensive effect of digoxin and digitoxin.

Elevated circulating levels of an endogenous ouabain (EO) have been associated with essential hypertension. To investigate structure-activity relationships relevant to blood pressure, we infused either ouabain, ouabagenin, digoxin or digitoxin at 30 microg/kg/day in normal Sprague Dawley rats. After five weeks, the ouabain and ouabagenin infused rats were hypertensive, whereas blood pressures declined below their vehicle controls in rats infused with digoxin or digitoxin. In a second study, mean blood pressures were 118.5+/-1.7 mmHg in rats infused with ouabain (15 microg/kg/day) on day 35 vs. 98.3+/-1.8 and 100.3+/-1.1 mmHg in the digoxin (30 microg/kg/day) and vehicle infused groups (both p<0.005 vs. ouabain), respectively. Plasma and kidney levels of ouabain immunoreactivity were increased 4-8 fold in ouabain infused rats while blood pressure and plasma levels of ouabain returned to normal one week following discontinuation of the steroid infusion. In rats with ouabain-dependent hypertension, secondary infusions of digoxin or digitoxin (30 microg/kg/day) normalized blood pressure even though circulating ouabain remained elevated. In digoxin infused rats, neither blood pressure nor kidney digoxin immunoreactivity was raised whereas plasma digoxin was increased. Collectively, the results show that the hemodynamic effects of these sodium pump inhibitors differ dramatically during prolonged administration and that tissue rather than circulating levels of these agents appear to better explain their effects on blood pressure. These studies suggest that sodium pump inhibition is not the exclusive mediator of the hemodynamic effects of these cardiac glycosides and demonstrate the presence of structure-specific mechanisms that regulate their tissue levels and effects on long-term blood pressure.

Aldosterone↗
PubMed1979

[Determination of serum digitoxin by means of a solid-phase enzyme-linked immunosorbent assay (author's transl)].

A solid-phase ELISA-technique for clinical applications is described. It requires little apparatus other than a photometer and allows the rapid determination of serum digitoxin levels. It differs from the original technique only in the sample volume being smaller and a digitoxin calibration curve being required. Concurrent assays by a reference method (86Rb-erythrocyte assay) gave results in excellent agreement with the values obtained by the modified ELISA-technique on samples from patients under long-term therapy with digitoxin (r = 0.95).

Digitoxin↗
PubMed1975

Pharmacodynamic distinctions between ouabain, digoxin and digitoxin.

Current pharmacologic texts recognize no significant pharmacodynamic differences between the various cardiac glycosides. To reconsider this concept, a special recording device was constructed so that electrocardiograms and phonocardiograms could be obtained in small mammals without anesthesia or premedication, and a spectrum of cardiac glycosides was studied. Utilizing guinea-pigs, cardiac rate reduction of 20% was sought and achieved with 0.07 mg/kg ouabain, 0.34 mg/kg digoxin and 1.12 mg/kg digitoxin. With comparable rate reduction, digitoxin produced significantly greater shortening of electro-mechanical systole than did ouabain or digoxin (P less than 0.05). Other authors have shown that cardiac glycosides produce slowing of cardiac rate prior to onset of positive inotropic effect. Therefore it is probable that for a given amount of vagal effect (sinoatrial slowing) digitoxin possesses greater positive inotropic effect (abbreviation of electromechanical systole) in guinea-pigs than do ouabain or digoxin. A review of the literature suggests that the same holds true for humans.

Animals↗
PubMed1975

[Pharmacokinetics and action of digitoxin and ouabain in the isolated hearts of guinea pigs and rats].

Isolated guinea pig and rat hearts were perfused with 3H-digitoxin and 3H-ouabain. After varying perfusion periods (3-90 min) the glycoside content in the tissue was determined. With digitoxin the tissue/medium-ratio at equilibrium was found to be 14 in guinea pigs and 8 in rats, with ouabain the corresponding values were 2 and 1. In further experiments the efflux of radioactivity from isolated perfused hearts preloaded with 3H-glycosides was measured in 3 min intervals. A compartmental analysis was carried out. The efflux could be described by the sum of two exponentials indicating the existence of two compartments. The half lives of compartment 1 (2.1-4.0 min) and those of compartment 2 (16.8-20.6 min) were similar with both glycosides and both species. The development and decline of the positive inotropic effect in guinea pig hearts exhibited a time course similar to that of the glycoside content in compartment 1: the time for reaching the half maximum effect was 3-4 min with ouabain and 5-6 min with digitoxin. It is suggested that compartment 1 represents the site of the positive inotropic action of cardiac glycosides.

Animals↗
PubMed2006

A novel LC-IDMS/MS method for the determination of the cardiac glycosides digoxin and digitoxin using caesium adducts.

This article describes an essential improvement of the published candidate reference measurement procedure for digoxin and digitoxin and compares it with the original method. The novelty of the method lies in the measurement of the caesium (Cs+) ion as product ion in the multiple reaction monitoring mode (MRM) with potentially improved analytical specificity whilst retaining a comparable accuracy and precision at therapeutic levels. The original measurement procedure used the single-ion mode (SIM). The dissociation of the Cs+ adducts in MRM leads to the formation of Cs+ ions as main charged product in high yield. The present method results in a product ion signal intensity in MRM for digoxin and digitoxin of up to 80% of the precursor ion signal intensity in SIM. The precision, expressed as the coefficient of variation of the new method for digoxin was 3.18% (SIM) and 2.28% (MRM) at a concentration of 0.66 microg/l and 1.26% (SIM) or 1.65% (MRM) at 2.0 microg/l. The corresponding data for digitoxin were 1.21% (SIM) and 1.62% (MRM) at 24 microg/l and 1.46% (SIM) and 1.13% (MRM) at 42 microg/l.

Cesium↗
PubMed1991

Repeated doses of activated charcoal and cholestyramine for digitoxin overdose: pharmacokinetic data and urinary elimination.

A 48-year-old man chronically treated with digitoxin and verapamil for prevention of atrial fibrillation voluntarily ingested 2.2 mg of digitoxin. Serum digitoxin concentrations and the urinary elimination of the drug were followed over a 12-day period. Urinary data indicate that a large percentage (50%) of the drug was eliminated renally despite administration of multiple doses of activated charcoal, cholestyramine and hyperosmotic laxatives. The possible interaction with two other drugs, heparin and verapamil, is also discussed.

Charcoal↗
PubMed1988

Combined intoxication with digitoxin and verapamil. The possible inhibition of sensitisation to digitalis-specific antiserum by toxic drug concentrations.

The clinical course in a patient with a combined intoxication with digitoxin (maximal serum level 357 nmol/l) and verapamil is described. The patient received two injections of digitalis-specific antiserum. No adverse reactions to the therapy was seen, and the antiserum markedly shortened the plasma half-life of digitoxin. In vitro studies indicate that digitoxin in concentrations seen during the intoxication may have an immunosuppressive effect, thereby reducing the risk of sensitisation to the antiserum.

Aged↗
PubMed1977

[Modification-possibility of the enterohepatic circulation of digitoxin in man].

Tritiated digitoxin (0.25 mg) was i.v. administered to a control group of 5 patients as well as to 5 patients with a T-tube quantitatively draining the bile fluid. During the initial 24 h after injection, 10% of the dose administered, on the second and third days 5 and 3,5%, respectively, were biliarily excreted. The amount biliarily excreted did not influence the course of the blood level as compared to the controls. Also charcoal given perorally in a sufficient amount (50 g) did not affect the blood level of radioactive digitoxin and/or its metabolites. As obtained from in vitro experiments the absorptive potency of cholestipole and cholestyramine for digitoxin and its metabolites in human bile fluid is similar to that of charcoal.

Cholestyramine Resin↗
PubMed1979

[The effect of thyroid hormone on the absorption of L-proline, chloramphenicol and digitoxin].

Using the method of the perfused small intestine preparation in situ, the influence of triiodothyronine on the absorption was investigated. The absorptions of L-proline and digitoxin were disturbed by the thyroid hormone in different ways, in contrast to chloramphenicol, where it is unaltered. The effects of triiodothyronine on the absorption of these substances are dose dependently different. Obviously the thyroid hormone can influence the absorption of proline and digitoxin in both ways, increase or decrease. The behaviour of digitoxin different from that of chloramphenicol points to this drug making use of active mechanisms concerned in the absorption.

Animals↗
PubMed1984

Use of cholestyramine in three patients with beta-acetyldigoxin, beta-methyldigoxin and digitoxin intoxication.

The effect of cholestyramine (8 g every 6 h by oral administration) on glycoside plasma concentrations of three patients with suicidal and accidental digitalis intoxications were studied. During treatment with cholestyramine the plasma concentrations of beta-acetyldigoxin and beta-methyldigoxin declined with half-lives of 20.4 or 30.0 h. These values are significantly shorter than the therapeutic half-lives reported in the literature. The digitoxin plasma concentration decreased with a half-life of 74.5 h during the first 2 days. When the digitoxin plasma level dropped under 40 ng/ml, the half-life increased, similar to the half-life without cholestyramine administration. From these case reports cholestyramine seems to be helpful in managing intoxications with digoxin derivates as well as with digitoxin.

Acetyldigoxins↗
PubMed1983

Stability of digitoxin tablets submitted by U.S. hospitals.

The stability of digitoxin tablets that had been stored in hospital pharmacies across the United States was studied. Through a voluntary FDA drug stability program, all hospital pharmacies in the United States were asked in October 1981 to complete a response card indicating information about the digitoxin products they had in stock. Based on the responses, FDA selected 25 samples (representing seven manufacturers) from pharmacies that represented an adequate cross section of the country. These samples were analyzed for content uniformity, strength, dissolution, identification, and other digitoxosides. Of the 25 samples, 19 lots were represented, including 11, 6, 1, and 1 lots of 0.1-mg, 0.2-mg, 0.15-mg and 0.05-mg tablets, respectively. Samples from two lots failed to meet USP requirements for strength, content uniformity, and dissolution; samples from four lots failed to meet the requirements for dissolution only. All six defective lots did not show an expiration date, indicating that they were manufactured before 1975. Digitoxin tablet products still within the expiration date showed no evidence of degradation after storage under actual marketplace conditions.

Cardiac Glycosides↗
PubMed1984

Relationship between renal clearance, protein binding and urine flow for digitoxin, a compound of low clearance in the isolated perfused rat kidney.

An isolated perfused rat kidney preparation is described which allows the relationship between protein binding and renal clearance to be studied in a quantitative manner. The influence of unbound fraction of drug in the perfusate, urine pH and urine flow upon the renal clearance of digitoxin is examined. Renal clearance and unbound fraction were found to be related linearly. Urine pH did not influence digitoxin renal clearance but urine flow did, in a nonlinear manner. A simple physiologically based model of renal clearance is developed which predicts the influence of urine flow and protein binding upon digitoxin clearance in this preparation.

Animals↗
PubMed1983

Interaction of rifampin and digitoxin.

In a patient who had been receiving digitoxin therapy, the serum digitoxin level decreased markedly when rifampin was added to the therapeutic regimen. The serum digitoxin level returned to the pretreatment level when rifampin therapy was discontinued.

Aged↗
PubMed1982

Fluoroimmunoassay of digitoxin in serum.

This fluoroimmunoassay for digitoxin in serum involves use of a sheep antiserum to digitoxin coupled to magnetizable solid-phase particles and fluorescein-labeled 3-O-succinyl digitoxigenin as tracer. Sodium salicylate blocks binding of the drug by binding proteins, and endogenous fluorophores and other interfering components in serum samples are reliably and completely removed at the separation and wash steps, which are facilitated by magnetic sedimentation. The method is sufficiently sensitive, precise, and specific for application to routine monitoring of digitoxin therapy, and results correlate closely (r = 0.992) with those of an established radioimmunoassay.

Digitoxin↗
PubMed1982

Digitoxin metabolism by rat, mouse, and rabbit: NADPH requirement and spironolactone effect.

Digitoxin metabolism in rat, mouse, and rabbit liver homogenates was compared. The rabbit metabolized the compound most extensively, yielding digitoxigenin as major hydrolysis product. Rat and mouse both produced digitoxigenin bisdigitoxoside as major product. Metabolite formation was enhanced by NADPH in all three species. Spironolactone induced the hydrolysis of digitoxin in the rat, but had no effect in the mouse or rabbit. The mechanism of the protective effect of spironolactone in the mouse does not involve induction of digitoxin hydrolysis; in the rabbit, rapid inactivation of spironolactone accounts for the lack of induction.

Animals↗
PubMed1980

Uptake and pharmacological effect of gitoxin and gitaloxin in rat and guinea-pig perfused hearts. Comparison with digitoxin and digoxin.

Rat and guinea-pig hearts were perfused with gitoxin and gitaloxin at various concentrations. Simultaneously, the amplitude of myocardial contractions was recorded. In the case of guinea-pig, digoxin and digitoxin were studied, too. After perfusion, the amount of cardiac glycoside taken up by each heart was determined. The uptakes of gitoxin and gitaloxin by rat hearts were similar and directly proportional to the glycoside concentration in the perfusion medium. In guinea-pig hearts, the sequence in binding amount of digoxin less than gitaloxin less than gitoxin less than or equal to digitoxin. The positive inotropic effects of the four glycosides in guinea-pig hearts were similar; the toxicity, however, increased in the sequence: gitoxin less than gitaloxin congruent to digoxin less than digitoxin. Briefly, gitoxin is bound to the guinea-pig heart muscle much more than its positional isomer, digoxin; though it shows a similar positive inotropic effect on guinea-pig hearts, gitoxin appears to be markedly less toxic than the three other glycosides.

Animals↗
PubMed1994

Ouabain and digitoxin as modulators of chick embryo cardiomyocyte energy metabolism.

The effects of 0.1 nmol/l ouabain (CAS 630-60-4) and digitoxin (CAS 71-63-6) on oxygen consumption rate (OCR) and the contractility of cultured chick embryo cardiomyocytes were investigated using a perfusion system which allowed microscopic observation during the experiment. contractility was assessed by a novel image analysis procedure. During substrate free perfusion the OCR was increased on application of 0.1 nmol/l ouabain or digitoxin for 60 min, whilst contractility was not affected. Digitoxin (0.1 nmol/l) elicited no change in the OCR in the presence of glucose, pyruvic acid, lactic acid and caprylic acid. Ouabain (0.1 nmol/l) did not affect the OCR or contractility in the presence of glucose, pyruvic acid and lactic acid, however together with caprylic acid the OCR was increased significantly. These results demonstrate a hitherto unknown stimulation of fatty acid utilization by low concentrations of ouabain.

Animals↗