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PubMed1975

The reactivity of derivatives of digoxin and digitoxin as measured by the Na-K-atpase displacement assay and by radioimmunoassay.

Derivatives of digoxin and digitoxin were measured by the Na-K-ATPase displacement assay and by radioimmunoassay and the data compared with biological potency of these compounds. There was a slightly higher affinity of digoxigenin-bis-digitoxoside as compared with digoxin using digoxin-specific antiserum and considerably less affinity of digoxigenin and dihydrodigoxin than the parent compound in the same system. A similar trend was observed for the derivatives of digitoxin using digoxin-specific antiserum. The recovery on extraction of some of the derivatives of digoxin and digitoxin differed from that of the parent compounds in the ATPase assay. The potency of the derivatives of these drugs in displacing 3H ouabain also differed from the parent compoundmboth the recovery on extraction and the potency for displacing ouabain must be considered in the estimation of the contribution of the derivatives of digoxin or digitoxin to the result of Na-K-ATPase assay. Quantitative information of the metabolites of digoxin and digitoxin in normal and pathological conditions is needed to properly interpret assay data obtained either by radioimmunoassay or by ATPase assay.

Adenosine Triphosphatases↗
PubMed1991

Effects of ouabain and digitoxin on the respiration of chick embryo cardiomyocytes in culture.

The effect of digitoxin (CAS 71-63-6) and ouabain (g-strophantin, CAS 630-60-4) on respiration, morphology and beating activity of cardiomyocytes in culture derived from embryonic chick hearts has been investigated. The drugs were applied in a perfusion system using a protein- and substrate-free perfusion medium (BSS) at two concentration of K+ (5.4 and 4 mmol/l). In either K+ concentration oxygen consumption was 0.13 +/- 0.05 nmol O2 h-1 per 1000 cells. During 3 h of perfusion with BSS oxygen consumption declines only slightly to 79 +/- 15% of the initial value. No relation was found between beating frequency and oxygen consumption. Increase in respiration ranged from 5 to 45% and lasted between 5 and 120 min. At concentrations being inhibitory to the Na+/K(+)-ATPase (greater than or equal to 1 mumol/l) ouabain stimulated respiration by about 20% at 4 mmol/l K+ and 10% at 5.4 mmol/l K+ while digitoxin was effective at 5.4 mmol/l only (a transient increase of 20%). At 0.1 nmol/l, (a concentration below the KD of the high affinity binding site of the Na+/K(+)-ATPase) ouabain caused a long lasting activation of respiration by about 30%, digitoxin induced a transient rise of up to 20% at 5.4 mmol/l K+. At 4 mmol/l K+ digitoxin did not affect respiration while ouabain caused a transient increase. The lowest concentration of ouabain inducing a reproducible activation of oxygen consumption was 0.1 pmol/l. At this concentration digitoxin was no longer effective. At 1 fmol/l respiration was stimulated only occasionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Study of the factors influencing cardiac growth. II. Digitoxin treatment and isoproterenol-induced cardiac hypertrophy in the rat.

Isoproterenol (IPR) administered to rats in a dose of 5 mg/kg for 4 days induces cardiac hypertrophy. The purpose of the present study was to determine the effect of prophylactic + simultaneous digitoxin treatment on the development of IPR-induced cardiac hypertrophy. Digitoxin (1 mg/kg body weight) was given per os, once daily for 6 days prior to IPR administration and continued simultaneously with IPR treatment. To determine myocardial enlargement, wet heart weight, myocardial nucleic acid and protein were measured. Digitoxin treatment induced slight but significant increase in wet ventricle weight and myocardial RNA content (mg/ventricle). At the same time the degree of IPR-induced cardiac hypertrophy in digitoxin-treated and untreated animals was nearly the same. On the basis of these results it can be stated that--unlike the cardiac hypertrophy induced by pressure overload or hypoxia,--the IPR-induced cardiac hypertrophy is not altered by digitoxin administration.

Animals↗
PubMed1986

Study of the factors influencing cardiac growth. III. Digitoxin treatment and thyroxine-induced cardiac hypertrophy in the rat.

Thyroxine (T4) administered to rats in a dose of 1 mg/kg for 12 days induces cardiac hypertrophy. The purpose of the present study was to determine the effect of prophylactic + simultaneous digitoxin treatments on the development of T4-induced cardiac hypertrophy. Digitoxin (1 mg/kg body weight) was given per os, once daily for 6 days prior to T4 administration and continued simultaneously with T4 treatment. To determine myocardial enlargement, wet heart weight, myocardial nucleic acid and protein were measured. Digitoxin treatment induced a slight increase in wet ventricle weight and a significant elevation of myocardial RNA content (mg/ventricles) and concentration (mg/g). At the same time, the degree of T4-induced cardiac hypertrophy in digitoxin-treated and untreated animals was nearly the same. On the basis of these results it can be stated that--unlike the cardiac hypertrophy induced by pressure overload or hypoxia,--the T4-induced cardiac hypertrophy is not altered by digitoxin administration.

Animals↗
PubMed1989

[Acute digitoxin poisoning].

We report a case of severe digitoxin poisoning with--as to our knowledge--the highest plasma concentration reported so far (376 ng/ml). On admission, the patient suffered from nausea and vomiting. The ECG showed a complete AV-block which was managed temporarily by pacing. Phenytoin was given for ventricular tachycardias. The plasma potassium level was 7.4 mmol/l. The elimination of the digitoxin was enhanced with cholestyramine and hemoperfusion. Because of persisting arrhythmias, hyperkalemia and a very high digitoxin level, purified Fab fragments of digoxin-specific antibodies (cross-reacting with digitoxin) were administered. After a first dose of 480 mg nausea disappeared readily, and with a second dose of 480 mg cardiac rhythm disturbances and hyperkalemia were overcome. There were no adverse reactions to treatment. We confirm the effectiveness of digoxin-specific Fab antibody fragments in life-threatening digitoxin intoxication.

Adult↗
PubMed1981

[Digitoxin plasma concentrations during oral treatment (author's transl)].

In 198 patients, among them 153 with a creatinine clearance of less than 20 ml/min, the relationship between the digitoxin plasma level and retrospective data on daily digitoxin dose, age, body weight and renal function has been evaluated. A multiple regression analysis yielded only a very weak correlation (100 r2 = 13.2%, n = 186), with the digitoxin dose having by far the highest partial coefficient of determination (100 r2 = 11.5%). The partial correlation for the renal function was too small as to be relevant (100 r2 = 0.6%). Owing to the weakness of correlation it is impossible to predict the digitoxin plasma level on the basis of standard clinical data. A single dose in the range of 0.07 to 0.1 mg/day seems to be an appropriate treatment for most patients. Corresponding to a median dose of 0.082 mg digitoxin daily during steady state a median plasma level of 14.6 ng/ml has been calculated.

Age Factors↗
PubMedDate not supplied

Formation of a beta-glucuronidase-resistant glucuronide conjugate of digitoxin by dog liver microsomes.

The aim of these studies was to characterize the glucuronide conjugates of digitoxin and digitoxigenin monodigitoxoside (DMD) produced by liver microsomes from the dog with respect to hydrolysis by beta-glucuronidase and to behavior on HPLC. These results have been compared with studies of conjugates produced by liver microsomes from the rat. Glucuronidation was similar with both substrates with dog microsomes, whereas rat microsomes formed the glucuronide with DMD but not with digitoxin. The DMD glucuronide from both species was completely hydrolyzed by beta-glucuronidase, but no hydrolysis of digitoxin glucuronide was detected. The digitoxin glucuronide was hydrolyzed by a buffer at pH 1.5 but not at pH 10. After acid hydrolysis, the major products appear to be digitoxigenin and DMD glucuronide. These results suggest that glucuronidation of certain drugs by the dog is quite different from that of other species and that the dog may be the only species that possesses a glucuronosyltransferase capable of forming a glucuronide conjugate with digitoxin. The dog also has a glucuronosyltransferase, similar to that in the rat, which is responsible for glucuronidation of DMD. Whether this represents a single glucuronosyltransferase or two different enzymes remains to be elucidated.

Animals↗
PubMed1977

Studies on digitalis. VIII. Digitoxin metabolism on a maintenance regimen and after a single dose.

The metabolic pattern of cardioactive and inactive conjugated metabolites of digitoxin on maintenance (9 patients) and after a single 0.6-mg dose (5 patients) was studied in patients with normal renal and hepatic function. Serum samples were obtained 24 hr after the last dose, and urine was collected over 24 hr. The extent of conjugation to glucuronic and sulfuric acid was 35.0% (SD, 17.4) in whole serum and 31.6% (SD, 19.3) in urine samples. Unchanged digitoxin was the main cardioactive substance found both in serum and in urine (89.7% and 87.0%) in the steady-state group. All known cardioactive metabolites were present; digoxin represented less than 1%. All active metabolites were conjugated to glucuronic/sulfuric acid. Serum and urine patterns of metabolites were quite similar, Hydrolysis and conjugation appeared to be more important pathways than hydroxylation. Unchanged digitoxin was the most important cardioactive substance in serum and urine (80.4% and 56.5%) in the single-dose group. Digoxin was the main cardioactive metabolite (12.5% in serum and 25.5% in urine). All active metabolites were conjugated. Hydroxylation, hydrolysis, and conjugation seemed to be equally important. The most important differences between the steady-state and single-dose groups were that in the steady-state group there was significantly more unchanged digitoxin, far less digoxin, and less hydroxylated metabolities than in the single-dose group. Caution is thus necessary when interpreting single-dose data for a drug that is used for maintenance.

Biotransformation↗
PubMed1977

Studies on digitalis. XII. Kinetic pattern of digitoxin metabolism in patients with biliary fistulas.

The metabolic pattern of cardioactive and inactive, conjugated metabolites (a maximum of 24 substances) was studied after a single intravenous dose of 0.6 mg digitoxin in two female patients (aged 72 and 62 yr) with biliary fistulas. Bile and urine were collected every twenty-fourth hour and the 1-, 2-, 4-, 6-, and 8-day samples were analyzed. With the methods used, enzymatic cleavage of conjugation bonds, TLC (thin-layer chromatography), and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. All cardioactive metabolites were present in bile and all were conjugated. Unchanged digitoxin was the main substance excreted. Hydrolyzed and conjugated metabolites formed a greater part of the substances excreted in bile than hydroxylated metabolites. The metabolic pattern in bile did not change much with time. The metabolic pattern in urine showed no close resemblance to that in bile. Hydroxylated, hydrolyzed, and conjugated metabolites were equally predominant in urine. Interruption of the enterohepatic circulation by T tube drainage not only changed the elimination kinetics of digitoxin but also changed the pattern of digitoxin metabolites in urine.

Adult↗
PubMed1985

[Distribution of digoxin, digitoxin and their cardioactive metabolites in human heart and kidney tissue. A postmortem study].

A method was developed for the specific determination of digoxin and digitoxin, as well as their semisynthetic derivatives and dependent cardioactive metabolites, in autopsy samples of heart and kidney. A collective of six patients on long-term treatment with therapeutic doses of beta-acetyldigoxin had a mean myocardial digoxin content of 46.1 +/- 25.0 ng/g (SD); kidney: 50.3 +/- 30.3 ng/g. Digoxigenin bisdigitoxoside represented the second most important metabolite in heart and kidney; digoxigenin monodigitoxoside and digoxigenin follow, respectively. In a collective of seven patients on maintenance treatment with digitoxin, the mean tissue levels were higher but the metabolic pattern was similar (myocardial digitoxin content: 78.9 +/- 38.4 ng/g, renal content: 104.1 +/- 44.1 ng/g). The amount of digoxin formed by hydroxylation under long-term treatment with digitoxin in heart and kidney were approximately 10 ng/g. A case of digoxin intoxication differed both in the tissue content and in the metabolic distribution.

Adult↗
PubMed1975

Inotropic action, myocardial uptake and subcellular distribution of ouabain, digoxin and digitoxin in isolated rat hearts.

In experiments on isolated, electrically driven (240/min) rat hearts, perfused via the aorta at a constant flow (3.8 ml/min), the pharmacologically effective concentration range, the myocardial uptake and the subcellular distribution of three cardiac glycosides (digitoxin, digoxin, ouabain) were determined. The following results were obtained: 1. The effective range varied depending on the cardiac glycoside tested: With digoxin and ouabain very similar results were found- the positive inotropic concentration ranges being within 8x10(-6)M and 6x10(-5)M, the maximum positive inotropic effects attainable being about 100% and the concentration for half maximum effects (ED-50) being 2.4x10(-5)M and 2.3x10(-5)M, respectively. With digitoxin the inotropic concentration range was found to be within 3.6x10(-6)M and 2.4x10(-5)M with a maximum inotropic effect attainable of about 50% only and an ED-50 of 9.5x10(-6)M. The analysis of the time course of the inotropic action revealed extremely short half times for all cardiac glycosides studied (between 48 and 54 sec). 2. The myocardial uptake correlated with the physicochemical behaviour of the three cardiac glycosides studied and was found-depending on the perfusion time (5 to 60 min)-to be in the range of 23 and 36 (ouabain), 66 and 98 (digoxin) and 169 and 264 (digitoxin) nmoles/g wet weight. The respective computed half times for these uptake processes were 2.5 min (digoxin, ouabain) and 3.4 min )digitoxin). 3. Regarding the subcellular distribution an accumulation exceeding an "unspecific" binding (non-perfused hearts) was found mainly in the nuclear-membrane fraction. On the basis of these results (very short half times of either the pharmacological action and the cardiac uptake) the site of action of cardiac glycosides in the rat heart is supposed to be located at the surface membrane of the heart muscle cells. Furthermore, the above results are discussed with respect to those obtained in digitalis-sensitive species.

Animals↗
PubMed1982

Phenobarbital-digitoxin interaction in the guinea pig liver.

The influence of phenobarbital pretreatment on liver concentration of digitoxin and its metabolites was studied in guinea-pigs after i.p. administration of the cardiac glycoside. During the first hour an increase in liver uptake was observed in pretreated animals. The differences detected in the hepatic subcellular distribution do not seem to explain the higher concentrations found in the liver of phenobarbital pretreated animals. About 80% of the liver radioactivity was found in the supernatants. Inhibition of digitoxin biotransformation by phenobarbital was demonstrated by chromatographic analysis of the organic soluble compounds present in the supernatants. The possible binding of digitoxin and its metabolites to soluble proteins of liver cytosol was excluded by thin-layer gel filtration. The decrease in digitoxin biotransformation seems to be the reason for the increase in liver uptake and for the decrease in bile concentrations, observed in phenobarbital pretreated animals.

Animals↗
PubMed2001

P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin.

Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Effect of physical activity on serum concentrations of digoxin and digitoxin.

OBJECTIVE: To study the influence of moderate physical activity on serum concentrations of digoxin, digitoxin and albumin. METHODS: Blood samples were drawn from 10 consecutive mobile patients on digoxin and 12 patients on digitoxin therapy before and following a 10-min walking period. Digitalis serum concentrations were determined by radioimmunoassay, and albumin serum concentrations by laser nephelometry. RESULTS: Following physical activity, digoxin serum concentrations dropped immediately to 79% of baseline values and remained significantly decreased for 20 min. Digitoxin concentrations did not change significantly. CONCLUSION: In contrast to digoxin, the effect of physical activity the serum concentration of digitoxin can be disregarded.

Adult↗
PubMed1983

Effects of arrhythmia-producing concentrations of digitoxin on mechanical performance of cat myocardium.

Digitalis toxicity in vivo generally is recognized by the appearance of cardiac arrhythmias but in vitro by a decline in myocardial performance. To determine whether concentrations of digitoxin producing cardiac arrhythmias in intact animals also produce a decline in myocardial performance directly, three groups of adult cats were studied. One received digitoxin daily until arrhythmias developed (toxic group), the second sufficient digitoxin to produce an inotropic effect without arrhythmias (nontoxic group), and the third was untreated. Peak isometric force and maximal dF/dt of isolated right ventricular papillary muscles were significantly greater in nontoxic muscles (3.9 +/- 0.4 gm/mm2 and 21.3 +/- 1.7 gm/mm2 . sec-1). Values in toxic muscles were similar to untreated ones (2.8 +/- -.6 gm/mm2 and 19.0 +/- 3.2 gm/mm2 . sec-1). Acetylstrophanthidin (2 X 10(-8) M) resulted in an increase in peak force and max dF/dt in nontoxic muscles, whereas myocardial performance changed minimally in untreated muscles and declined in 8 of 10 toxic muscles. We conclude that electrical and mechanical toxicity induced by digitoxin frequently coexist.

Animals↗
PubMed1986

Bioavailability and elimination of digitoxin in patients with hepatorenal insufficiency.

Following administration of digitoxin, 1 mg intravenously, the pharmacokinetics of this glycoside were studied in eight healthy volunteers and in eight patients with hepatorenal insufficiency (mean creatinine clearance 19.6 +/- 2.9 ml/min; antipyrine clearance 25.6 +/- 3.2 ml/min; means +/- SEM). Liver cirrhosis of the patients was confirmed by liver biopsy. Plasma protein binding of digitoxin (means +/- SEM) was 95.1 +/- 0.7% in the patients and 95.6 +/- 1.2% in the volunteers (NS). Total body clearance of digitoxin was 0.0530 +/- 0.0040 ml/min/kg of body weight in the patients and 0.0547 +/- 0.0043 ml/min/kg of body weight in the healthy subjects (NS). When elimination half-lives of the patients and the volunteers were compared, there was also no significant difference (7.0 +/- 0.77 days in the patient group and 7.8 +/- 0.8 days in the volunteers). Our data concerning digitoxin kinetics in patients with hepatorenal insufficiency do not indicate an accumulation of the drug in these patients.

Adult↗
PubMed1975

Pharmacokinetics of digoxin and digitoxin in patients undergoing hemodialysis.

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

Adult↗
PubMed1998

Neutralization of cardiac toxins oleandrin, oleandrigenin, bufalin, and cinobufotalin by digibind: monitoring the effect by measuring free digitoxin concentrations.

Oleandrin plant poisoning is common in children and the plant extract is used in Chinese medicines. The toxicity is due to oleandrin and the deglycosylated metabolite oleandrigenin. Bufalin and cinobufotalin (toad cardiac toxins) are also widely used in Chinese medicines like Chan SU, and Lu-Shen -WU. Severe toxicity from bufalin after consumption of toad soup has been reported. Taking advantage of structural similarities of these toxins with digitoxin, we demonstrated that these compounds can be rapidly detected in blood by the fluorescence polarization immunoassay for digitoxin. The cross reactivities of these compounds with digoxin assay were much lower. For example, when a drug free serum was supplemented with 10 microg/ml of oleandrin, we observed 127.7 ng/ml of digitoxin equivalent but only 2.4 ng/ml of digoxin equivalent concentration. Digibind neutralized all cardiac toxins studied as evidenced by significant fall of free concentrations. When aliquots of serum pool containing 50.0 microg/ml of oleandrin were supplemented with 0, 10.0, 25.0, 50.0, 100, and 200 microg/ml of digibind, the mean free concentrations were 30.6, 23.3, 16.0, 10.7, 7.8 and 5.5 microg/ml respectively. Similarly, with 50.0 microg/ml of oleandrigenin (total concentration: 36.2 ng/ml), the free concentration was 14.5 ng/ml digitoxin equivalent in the absence of digibind and 5.4 ng/ml in the presence of 200 microg/ml of digibind. In another specimen containing 500 ng/ml bufalin (total concentration: 156.9 ng/ml), the free concentration was 8.6 ng/ml in the absence of digibind and none detected in the presence of 100.0 microg/ml digibind. Because such neutralization may also occur in vivo, digibind may be useful in treating patients exposed to these toxins.

Bufanolides↗