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PubMed1978

The effect of chronic administration of digitoxin on the activity of the myocardial (Na + K)-ATPase in guinea-pigs.

When guinea-pigs were treated for 24 days with digitoxin 0.3 mg/kg s.c., the activity of the (Na + K)-ATPase of the heart muscle increased by about 30% compared to controls, whereas the enzymes prepared from kidney and brain showed no significant alteration in their activity. In animal species treated with digitoxin for 1 to 5 days, no increase of enzyme activity was observed. Only after 10 to 15 days of treatment, a significant increase of the (Na + K)-ATPase activity was noted which increased no further with treatment up to 24 days. There was no significant difference in the kinetic properties of the (Na + K)-ATPase prepared from digitoxin-treated animals compared to those from control animals; the KM-values for ATP remained unchanged, and there was the same dependence of the activity on the K+-concentration and the same sensitivity towards digitoxin. As there appears to be no significant change in the specific properties of the enzyme, the increase in activity may possibly be caused by an increase in the amount of enzyme as a result of an adaptive enzyme regulation.

Adenosine Triphosphatases↗
PubMed1987

Comparison of digitoxin and its major glucuronidated metabolite: inhibition of Na-K-ATPase and reactivity with the radioimmunoassay.

The metabolism of digitoxin is known to occur through several major pathways including oxidation and glucuronidation. Several studies have compared the behavior of the various unconjugated metabolites with respect to reactivity toward Na-K-ATPase and toward the radioimmunoassay (RIA). Other studies with conjugated products synthesized chemically have also been performed. However, the activity of the conjugated products produced in vivo has not been reported and these metabolites are generally assumed to be inactive. In the present studies we have prepared and purified the glucuronide conjugate of digitoxigenin monodigitoxoside formed by rat liver microsomes and determined the activity of this metabolite as measured by inhibition of Na-K-ATPase and by the RIA. The concentration of the conjugated product needed to cause a fifty per cent inhibition of Na-K-ATPase was 5.40 microM compared to 0.68 for digitoxin and 0.08 for digitoxigenin monodigitoxoside. However, the conjugated product had a two-fold greater affinity for the antibody in the RIA procedure than did either digitoxin or digitoxigenin monodigitoxoside. Although these data cannot be extrapolated to the effects of these drugs on cardiac contractility, the results suggest that the contribution of the glucuronide conjugate to the therapeutic or toxic effect of digitoxin may be minimal. This metabolite may, however, lead to inaccurate estimation of blood levels by the RIA.

Animals↗
PubMed1988

Lack of endogenous crossreactivity with three digitoxin radioimmunoassays in adults with renal insufficiency.

The possibility of interference by apparent digitoxin-like immunoreactive substance (DTLIS) with three radioimmunoassays was studied in patients with renal insufficiency. From each of 25 adult patients with renal insufficiency and 25 age-matched and sex-matched control subjects with normal renal function, a single serum sample was obtained and assayed for digitoxin content by three commercially available radioimmunoassays (GammaCoat, Coat-A-Count, and the Wien assay). Although two of the three assays found measurable concentrations, the difference in apparent digitoxin concentrations between the control subjects and those with renal insufficiency was not significant. Assay interference could not be explained on the basis of differences in age, serum creatinine concentration, or weight. The magnitude of DTLIS interference in relation to the digitoxin therapeutic range appears to be small with the radioimmunoassays used in this study.

Acute Kidney Injury↗
PubMed1986

Difference in degree of A-V block and QS2 abbreviation of ouabain digoxin and digitoxin in cats.

Six trained domestic cats received a spectrum of polar to nonpolar cardiac glycosides: ouabain, digoxin or digitoxin with medication free intervals of four weeks. Significant (P less than 0.01) rate reduction (-19 +/- 8%) and prolongation of PR interval (+13 +/- 5%) occurred with ouabain and with digoxin (-18 +/- 5% and +13 +/- 3%) but not with digitoxin (-6 +/- 4% and +6 +/- 5%). However, rate corrected QS2 abbreviation was greater with digitoxin (-13 +/- 3%) than with ouabain (-8 +/- 3%) or digoxin (-10 +/- 5%). The findings indicate that in cats the polar cardiac glycosides ouabain and digoxin produce greater prolongation of A-V conduction while the nonpolar glycoside digitoxin produces greater abbreviation of QS2. Previously this finding was reported by the authors in guinea-pigs and in rabbits and has since been reported in intact rats, dogs, and in man by other authors. Investigators using nonintact subjects have not been able to demonstrate the finding. The differences may have clinical significance and suggest new insight into structural/activity relationships within the cardiac glycoside family.

Animals↗
PubMed1979

Effect of phenobarbital pretreatment on digitoxin toxicity and biotransformation in guinea-pigs.

Pretreatment with phenobarbital enhanced digitoxin toxicity in guinea-pigs. In both male and female animals the LD50 was reduced by one half as compared to control animals. Plasma and bile concentrations were determined at 15, 30, 60 and 120 min after intraperitoneal administration of 3H digitoxin. Plasma from pretreated guinea-pigs always presented higher concentrations of non-metabolized digitoxin and lower amounts of water soluble metabolites than control animals. If these compounds are less active than the parent drug, the increased toxicity of digitoxin after pretreatment with the enzymatic inducer may be explained by inhibition of detoxication.

Animals↗
PubMed1983

[Ventricle function in low-dose digitoxin in patients with chronic heart failure (stage II/III)].

Using one- and two-dimensional echocardiographic parameters, left ventricular function and dimensions were investigated in 11 patients with chronic heart failure (NYHA stages II-III) and in 10 normal subjects after administration of low-dose digitoxin (0.07 mg). Tests were performed before the begin of therapy, on the 3rd day following rapid saturation, and on the 15th day under maintenance therapy. There was no significant decrease either of heart volume as assessed by X-ray or of enddiastolic volume measured echocardiographically. However--predominantly in patients--a marked decrease in endsystolic diameter (p less than 0.01) and an increase in posterior wall motion amplitude (p less than 0.05) was observed resulting in increased stroke volume, shortening fraction (p less than 0.001). Early diastolic left ventricular filling speed also increased significantly in both groups (p less than 0.01). Changes in these parameters were more pronounced in patients than in normal subjects. In both groups the effects were achieved soon after rapid saturation, increasing slightly during the period of chronic administration of low-dose digitoxin. Parallel to the changes in echocardiographic parameters, a noticeable clinical improvement occurred among patients. No side effects were observed as serum digitoxin levels were in the therapeutic range. It may be concluded that low-dose digitoxin can be employed to increase cardiac contractility in patients with heart failure.

Adult↗
PubMed1982

[Digitoxin poisoning: reversing ventricular fibrillation with Fab fragments of anti-digoxin antibody].

Purified Fab fragments of ovine anti-digoxin antibodies (Wellcome Foundation) were used to treat a patient who attempted suicide by absorbing 10 mg of digitoxin (serum concentration 265 micrograms/l). The poor prognosis, as assessed clinically and from serum potassium levels (7.5 mEq/l), seemed to warrant such a treatment. The weak (6.85%) cross-reactivity elicited in vitro between the anti-digoxin antibodies and digitoxin was compensated by increasing the doses, but improvement was observed with 3.6 g, i.e. about half the effective dosage initially considered. The criteria of effectiveness were clinical, electrocardiographic (reversal of the ventricular fibrillation), biochemical (simultaneous and opposite changes in extra- and intracellular potassium levels, suggesting that ATPase inhibition by digitalis is a reversible process) and toxicological: there was an increase in digitoxin serum levels suggesting displacement of the drug from tissue sites to plasma and other extracellular compartments where the Fab fragments are distributed, and Fab-bound digitoxin appeared fairly rapidly in the urine, which suggested shunting of the normal hepatic metabolic pathway.

Aged↗
PubMed1993

[Digitoxin-induced thrombocytopenia].

A 82-year-old woman was admitted to hospital because of heart failure, vomiting, and pain in the right upper abdomen. During the past three months she had received treatment with 0.07 mg digitoxin twice daily. The ECG showed sinus bradycardia with intermittent complete sinoatrial block. On the basis of the history, clinical presentation and ECG findings digitalis intoxication was suspected. Digitoxin level was 65.23 ng/ml--far beyond the therapeutic range. Laboratory examinations revealed a marked thrombocytopenia (25,000/microliters). The patient was placed on cholestyramine (4g three times daily) to accelerate intestinal excretion of digitoxin. As there were no life-threatening complications there was no indication for treatment with digitalis-specific antibodies. On the 6th day after discontinuation of digitoxin treatment the platelet count showed a marked rise and returned to normal values as from the 12th day.

Aged↗
PubMed1996

[Digitoxin Reference Standard (Control 951) of the National Institute of Health Sciences].

The raw material of digitoxin was tested for preparation of the "Digitoxin Reference Standard (Control 951)". Analytical data obtained were as follows: loss on drying, 0.0%; infrared spectrum, the same as that of the JP Digitoxin Reference Standard (Control 845); thin-layer chromatography, no impurity was detected; high-performance liquid chromatography (HPLC), two kinds of impurities were detected and the total amount was estimated to be 0.16 +/- 0.01% (n = 3); assay, 99.0% by HPLC. Based on the above results, the raw material was authorized as the JP Digitoxin Reference Standard (Control 951).

Chemical Phenomena↗
PubMed1977

Studies on digitalis. IX. Some kinetic aspects of digitoxin metabolism.

The metabolic pattern of cardioactive and inactive conjugated metabolites (a maximum of 24 substances) was studied in one female and one male after a single dose of 0.6 mg digitoxin intravenously. Serum samples were obtained after 24 hr, and 24-hr urine was collected after 1, 2, 4, 6, and 8 days. With the methods used, enzymatic cleavage of conjugated bonds, thin-layer chromatography (TLC) separation, and a modified 86Rb method, the products of hydroxylation, hydrolysis, and conjugation could be separated. The Kendall rank correlation coefficient was used to compare the results from Subjects 1 and 2. Conjugation was the most rapid process, followed by hydrolysis and hydroxylation. Metabolism was progressive, leading to an increase in metabolites resulting from several enzymatic processes with time. Unchanged digitoxin reached minimum values on the fourth and sixth days and increased again on the eighth day. This indicated a continuous release of digitoxin from tissue stores and the enterohepatic circulation.

Adult↗
PubMed1976

Dissolution characteristics and oral absorption of digitoxin and digoxin coprecipitates.

A marked increase in the dissolution rates od digitoxin and digoxin was attained by dispersing the drugs in two inert solid carriers, poloxamer 188 and deoxycholic acid. The 1 and 10% (w/w) drug-carrier solid dispersions were prepared by the solvent method. The former dissolved significantly faster than the latter. The oral administration of 10% (w/w) digitoxin-carrier coprecipitates to mice significantly increased toxicity. This observed increase is attributed to an increase in the rate and, possibly, the extent of oral absorption of the drug. Although a 10% coprecipitate of digoxin in both carriers showed an increase in the dissolution rate, no increase in oral toxicity was observed. X-ray diffraction patterns indicated that both digitoxin and deoxycholic acid undergo crystalline modifications due to treatment by the solvent, but the exact nature of the drug-carrier solid dispersions was not revealed.

Animals↗
PubMed1982

High-performance liquid chromatographic analysis of digitoxin formulations.

A rapid, selective, and simple high-performance liquid chromatographic assay for digitoxin formulations is described. The method utilizes a conventional octadecyl-bonded phase column with detection at 220 nm. The isocratic solvent system resolves digitoxin from its potential degradation products and provides an accurate assay for tablet and injectable formulations with a relative standard deviation of 1.4 and 3.3%, respectively. The method is sufficiently sensitive to monitor content uniformity of tablets and the minimum quantifiable amount of digitoxin was determined to be 20 ng. The total chromatograph time was approximately 15 min.

Chromatography, High Pressure Liquid↗
PubMed1984

Positive inotropic effects of digitoxin- and digoxin-glucuronide in human isolated ventricular heart muscle preparations.

The effect on force of contraction of human isolated ventricular heart muscle preparations was studied with the 16'-glucuronides of digitoxin (dt-gluc) and digoxin (dg-gluc). The parent compounds digitoxin (dt) and digoxin (dg) were studied for comparison and all compounds were also investigated in guinea-pig isolated papillary muscles. All compounds increased myocardial force of contraction in human preparations in a concentration-dependent manner. The positive inotropic effect of dt-gluc and dg-gluc began at 0.1 mumol 1(-1) and was maximal at 1 mumol 1(-1). The metabolites were slightly less potent but, on the other hand, slightly more effective than the parent compounds dt and dg. The positive inotropic effects of all compounds peaked after about 60 minutes. In contrast, the decline of the positive inotropic effect upon washing was about twice as fast in the case of the hydrophilic metabolites. Similar results were obtained in guinea-pig papillary muscles. It is concluded that the glucuronides of digitoxin and digoxin are biologically active in the human heart. This may be of clinical importance with respect to the positive inotropic action and the plasma level determination of the cardiac glycosides.

Animals↗
PubMed1986

Effect of oral high-dose progestins on the disposition of antipyrine, digitoxin, and warfarin in patients with advanced breast cancer.

The influence of two progestins, medroxyprogesterone acetate (MPA) and megestrol acetate (MA), given orally in high doses, on the pharmacokinetics of antipyrine, digitoxin, and warfarin were studied in patients with advanced breast cancer. Antipyrine and warfarin were given as a single test dose before and after 5 weeks of progestin treatment. The pharmacokinetics of digitoxin was investigated at steady state in patients receiving this drug therapeutically before and during treatment with progestins. Small changes in clearance rates for antipyrine, warfarin, and digitoxin were found. A minor decrease observed in warfarin clearance however may be of clinical importance. Half-lives decreased by 13% for antipyrine and increased by 71% for warfarin. High-dose progestins given orally do not seem to have a major influence on drug metabolism, probably reflecting a minor effect on drug and steroid-metabolizing microsomal mono-oxygenases in the liver.

Administration, Oral↗
PubMed1991

A comparison of the effects of digoxin and digitoxin on systolic time intervals and colour vision.

Animal studies suggest that for the same inotropism hydrophilic cardiac glycosides produce greater depression of atrioventricular (AV) conduction than lipophilic ones. This has been explained on the basis of a greater vagomimetic effect with hydrophilic agents and a greater sympathomimetic effect with lipophilic agents. In this randomized, cross-over study we investigated the effects of placebo, digoxin (relatively hydrophilic), and digitoxin (relatively lipophilic) in twelve healthy volunteers. For both drugs steady-state serum concentrations in the mid-therapeutic range were achieved. Both drugs produced the same positive inotropic effect as measured by systolic time intervals (QS2c). There was a trend for digoxin to have a greater effect on AV conduction than digitoxin. After atropine or propranolol there was no difference between the effect of the two cardiac glycosides on AV conduction. No significant effects on colour vision were seen. We conclude that, there do not seem to be pharmacodynamic differences between digoxin and digitoxin at mid-therapeutic serum concentrations.

Adult↗
PubMed1975

Influence of spironolactone pretreatment on pharmacokinetics and metabolism of digitoxin in rats.

The influence of pretreatment with spironolactone (84 mg/kg at 3 days, twice per day) on the tritium levels in plasma, urine and feces of female SD-rats (n=9) was investigated at various time periods after oral administration of 25mug/kg -3H-digitoxin. In plasma, the concentrations of total radioactivity are reduced in pretreated animals to about 20% of tritium levels in control rats, while the half-life of radioactivity in both groups is almost identical, 2.9 days in pretreated rats and 2.8 days in controls. The lower plasma levels of tritium in pretreated rats coincide with a six-fold decrease in the urinary -3H-elimination and a corresponding increase in the fecal excretion. This is due to a higher biliary clearance of tritiated products in the early phase of elimination. The separation of the excretion products by TLC shows that spironolactone pretreatment enhances the splitting of the glycosidic bonds of digitoxin. The amount of digitoxigenin-bis-digitoxoside and of digitoxigenin-mono-digitoxoside excreted in urine and feces within 96 hrs is four and ten times greater than that recovered in control animals, respectively. The formation of the hydroxylation products digoxin and digoxigenin-bis-digitoxoside is decreased from 50% of the total excreted radioactivity in control to 15% in pretreated rats. The conjugation reactions with glucuronic and sulfuric acid are increased after pretreatment with spironolactone. Thus, the effect of spironolactone on digitoxin kinetics is apparently related to an enhancement of the hepatic excretory mechanism as well as to an enhanced metabolism.

Animals↗
PubMed1976

Metabolism of digitoxin in man and its modification by spironolactone.

The effect of spironolactone on the metabolism of intravenously administered 3H-digitoxin (80 muCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79% was unaltered drug and 12% consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (less than 2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p less than 0.05). In addition spironolactone caused a 20 ( reduction in the half-life of serum radioactivity (p less than 0.01) and a 16 % reduction in the volume of distribution (p less than 0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.

Aged↗
PubMed1985

Effects of digoxin and acetyl-digitoxin on basal and CO2-stimulated ventilation.

Eight healthy volunteers were studied to ascertain the effect of digoxin and the relatively more lipophylic cardiac glycoside, acetyl-digitoxin on ventilation. Baseline ventilation as well as the response to the inspiration of 2.2% and 4.8% carbon dioxide were assessed. Digoxin produced a depression of minute volume and oxygen consumption whereas acetyl-digitoxin produced the opposite effect. This could be the result of a relatively greater vagomimetic effect with digoxin and a greater symphatomimetic effect with acetyl-digitoxin. These findings might have clinical implications in cardiac patients who have pulmonary disease.

Acetyldigitoxins↗