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PubMed2003

Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and beta-methyldigoxin in rats.

Digoxin and beta-methyldigoxin were evaluated pharmacokinetically in terms of P-glycoprotein (P-gp)-mediated drug interactions in rats. Evaluation was made by measuring the effects of a potent P-gp inhibitor (verapamil, cyclosporin A) on in vitro efflux transport of these compounds across the everted small intestine, on in situ absorption from the small intestine, and on in vivo total plasma clearance (CL(total)) as well as biliary and urinary excretions after intravenous administration. Both the intestinal efflux transport and absorption of beta-methyldigoxin were approximately 1.5-fold greater than those of digoxin, probably due to its higher lipophilicity. Addition of verapamil (300 microM) significantly decreased the intestinal efflux transport and increased the intestinal absorption of digoxin. In contrast, the influence of verapamil on beta-methyldigoxin was small. Intravenous cyclosporin A (30 mg/kg) significantly decreased in vivo CL(total) and biliary excretion of digoxin, but affected little on beta-methyldigoxin clearances. These results suggest that P-gp-mediated drug interactions can easily occur in digoxin, but hardly in beta-methyldigoxin. These findings may give a clue in selecting these digitalis compounds in clinical use, towards escape from P-gp-mediated drug interactions or reduction of interindividual variations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Role of organic anion transporting polypeptide 2 in pharmacokinetics of digoxin and beta-methyldigoxin in rats.

Recently, we found that potent P-glycoprotein (P-gp) inhibitors, such as verapamil and cyclosporin A, markedly modulated the pharmacokinetics of digoxin in rats, whereas they did not affect beta-methyldigoxin pharmacokinetics significantly. Digoxin is also a substrate of rat organic anion transporting polypeptide 2 (Oatp2). Here, we compared the magnitude of Oatp2-mediated drug interaction of digoxin and beta-methyldigoxin using amiodarone as an Oatp2 inhibitor in rats. Amiodarone (20 mg/kg) given intravenously significantly increased plasma levels and decreased biliary excretion, liver distribution, and intestinal distribution of digoxin administered intravenously at a dose of 10 mug/kg. Amiodarone also significantly decreased biliary excretion and liver distribution of beta-methyldigoxin, but the change in plasma levels of beta-methyldigoxin was quite small. These findings may give a clue in selecting these cardiac glycosides in clinical pharmacotherapy for patients receiving multiple drugs towards escape from Oatp2-mediated drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Evaluation of cardiac activity and pharmacokinetic analysis of 3H-adriamycin in patients pretreated with beta-methyldigoxin.

The consequences at the cardiac level of adriamycin treatment alone or in association with the cardiac glycoside beta-methyldigoxin, were evaluated with reference to the PEP/LVET ratio, heart rate, and minimum blood pressure. The variation usually seen in the PEP/LVET ratio when adriamycin is administered alone was not observed when pretreatment with beta-methyldigoxin was also given. A similar situation is found with variations in blood pressure and heart rate. From a pharmacokinetic point of view, this treatment scheme does not seem to affect the general behavior of the antibiotic.

Adult↗
PubMed1989

Serum digoxin and beta-methyldigoxin in elderly patients on hospital admission: correlation with home compliance and clinical variables.

Serum digoxin and beta-methyldigoxin (BMD) were measured in 165 elderly patients (age greater than 60 years) admitted to hospital, of whom 109 had been treated at home with digoxin and 56 with BMD. The mean BMD level was significantly lower than that of digoxin (1.1 vs. 1.4 ng/ml). Creatinine clearance and daily dose were the variables most strongly associated with digoxin level, and the prescribed dose and serum albumin were the best predictors of the BMD concentration. Compliance was assessed by a compliance index (CI), namely the ratio of the measured glycoside concentration, corrected for creatinine clearance, over the expected steady-state dose, calculated from a hospitalized reference group. Compliant individuals in both treatment groups, i.e. those with a CI greater than the median value, were characterized by a lower daily dose and dosage frequency. Toxicity, whether clinical or electrocardiographic, was present in 9% of the patients and was associated only with a significantly higher mean serum level of the drug.

Aged↗
PubMed1981

Clinical implications of serum digoxin concentrations.

Factors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=-0.36, p less than 0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS durations, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.

Acetyldigoxins↗
PubMed1987

[Determinants of plasma digoxin and digitoxin concentrations in elderly patients. A multivariate analysis].

In 1063 patients (greater than or equal to 60 years, 531 men, 532 women) the plasma concentration during digitalis maintenance therapy (metildigoxin, n = 356, beta-acetyldigoxin, n = 359, and digitoxin, n = 348) was determined and related to sex, age, body weight, serum potassium, renal function and the prescribed daily maintenance dose. Classification of treatment groups according to renal function (Crea less than or equal to 1.3 mg/dl parallel greater than 1.3 mg/dl) did not show any difference of the mean maintenance doses. In multiple linear regression analyses only a weak relationship between plasma digitalis concentration and the studied variables was found, which could be equally attributed to dose, creatinine and serum potassium in the digoxin derivative groups, whereas for digitoxin only body weight had a significant effect on the plasma concentration. During a maintenance dose of 0.07 or 0.1 mg/die which was given to 87% of patients in the digitoxin group, 70% were found to have plasma levels within the therapeutic range.

Acetyldigoxins↗
PubMed1982

[The influence of systemic digitalis application on intraocular pressure].

The intraocular pressure (IOP) of ten healthy subjects was measured before and after a 2-week systemic application of beta-methyldigoxin. The drug led to a highly significant decrease of IOP of on the average 2 mm Hg. The decrease was independent of the blood concentration of glycoside - at least within the therapeutic range. There was a positive correlation between IOP before digoxin application and the subsequent IOP decrease. The rate of outflow increased, but not significantly. Implications for the therapy of glaucoma are briefly discussed.

Adult↗
PubMed1979

[Forensic aspects of digoxin-poisoning: toxicological and morphological findings (author's transl)].

Case report. A 82 year old woman died 80 min after accidental ingestion of 5 mg beta-methyl-digoxin. The autopsy and the histological examination revealed non-specific alterations due to shock and preexisting coronary heart disease. Digoxin levels in various fluids and tissues were estimated by radioimmunoassay: bloodplasma 20--25 ng/ml, liquor 10--13 ng/ml, liver 100--110 ng/g, kidney 130--145 ng/g; the gastric fluid contained 0,6 mg. Forensic aspects of glycosid-intoxication, especially of the varying concentrations in different tissues, are discussed.

Aged↗
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↗
PubMed1987

Amplification of serotonin-induced contractions of isolated porcine coronary arteries after pretreatment with therapeutic doses of beta-methyldigoxin.

The present experiments demonstrate that after pretreatment of isolated porcine coronary arteries with therapeutic (2.5 X 10(-9) M) was well as with toxic (10(-6) M) doses of beta-methyldigoxin the serotonin-induced contractions were significantly amplified. Since serotonin released from destroyed thrombocytes may be one of the triggering factors eliciting coronary spasms, caution must be taken in the use of digitalis in coronary disease of spastic origin.

Animals↗
PubMed1988

Micro high-performance liquid chromatographic determination of cardiac glycosides in beta-methyldigoxin and digoxin tablets.

A micro high-performance liquid chromatographic (micro-HPLC) method has been developed for the assay of beta-methyldigoxin and digoxin tablets. Quantitation of cardiac glycosides in tablets was carried out by the incorporation of dexamethasone as an internal standard. The procedure consisted of disintegration of tablets, extraction with acetone-ethanol (9:1) and injection for micro-HPLC on an ODS micro column, using acetonitrile-water (28:72) for beta-methyldigoxin tablets and methanol-water (1:1) for digoxin tablets; the effluent was monitored by UV detection at 220 nm. The average values of the contents in beta-methyldigoxin and digoxin tablets were 99.6 and 100.2% of the labelled amounts, respectively. The proposed method is sufficiently precise and sensitive to examine the content uniformity of tablets.

Cardiac Glycosides↗
PubMed1984

On the mechanism by which caffeine abolishes the fast rhythms induced by cardiotonic steroids.

The abolition by caffeine of the arrhythmias induced by cardiotonic steroids was studied in canine Purkinje and ventricular muscle fibers and in guinea pig ventricular muscle perfused in vitro. Both the electrical and mechanical activity were recorded. The following results were obtained: (1) Caffeine (9 mM) quickly abolished the arrhythmias induced by strophanthidin (10(-6)M) in Purkinje fibers by inducing quiescence at a depolarized level; (2) A lower concentration of caffeine (3 mM) hastened the appearance of the arrhythmias by favoring the onset of spontaneous activity at a depolarized level but abolished the oscillatory potential at lower strophanthidin concentrations (2-5 X 10(-7)M); (3) Caffeine (9-10 mM) abolished the oscillatory potentials and after-contractions induced by cardiotonic steroids in ventricular muscle fibers; (4) Caffeine prevented the induction of oscillatory potentials and of arrhythmias by cardiotonic steroids; (5) In the presence of cardiotonic steroids and norepinephrine, the oscillatory potentials can induce fast discharge in myocardial fibers which is eliminated by caffeine; (6) High calcium and norepinephrine (singly or together) induce oscillatory potentials and after-contractions which are abolished by caffeine; (7) The elimination of the oscillatory potentials by caffeine in myocardial fibers is associated with the development of contracture. It is concluded that caffeine eliminates cardiac steroid-induced arrhythmias by quickly depolarizing Purkinje fibers and by eliminating the oscillatory potentials in myocardial fibers and (at suitable concentrations) also in Purkinje fibers.

Action Potentials↗
PubMed1977

[Quantitative EEG analysis of the effects of carbocromen, pentetrazole, beta-methyldigoxin, and strophantin-K in normal human volunteers (author's transl)].

With EEG-interval analysis we studied the influence on C.N.S. of some drugs normally used for cardiovascular diseases: carbochromen, pentetrazole, beta-methyldigoxin and Strophantin-K. All investigated drugs induced activation of alpha-waves, especially in frontal areas with primary small alpha-activity. Dominant alpha-frequency was accelerated. These results confirm the direct and stimulating effects of these drugs on C.N.S. in therapeutic doses. Alpha-acceleration may not only indicate psychostimulation but also indicate epileptogenic effects. All these drugs may provoke epileptic seizures in toxic doses.

Adult↗
PubMed1995

[Percutaneous extracorporeal circulation in cardiogenic shock caused by combined poisoning with methyldigoxin, nifedipine and indapamide].

HISTORY AND FINDINGS: A 38-year-old man with endogenous depression was found comatose and with gasping respiration. Empty packets of tablets pointed to poisoning with methyldigoxin, nifedipine and indapamide. Pupils reacted slowly to light and no peripheral blood pressure could be measured. TREATMENT AND COURSE: Routine resuscitation measures (intubation, mechanical ventilation, external cardiac massage and drugs) were undertaken during transport to hospital where, in addition to further symptomatic treatment, digoxin antibodies were administered, but without noticeable effect. Percutaneous cardiopulmonary bypass was therefore undertaken. It achieved a cardiac output of 3.2l and a systolic pressure of 80 mm Hg: a stable rhythm and circulation were obtained within 15 hours indicating that electromechanical uncoupling had for the time being been overcome. The EEG suggested a midbrain syndrome. After another 18 hours of mechanical ventilation and symptomatic treatment asystole suddenly occurred. Renewed resuscitation procedures were not undertaken because of the very poor neurological state and prognosis. CONCLUSION: Although haemodynamic stabilization was only temporarily achieved and the patient's death could not be prevented because of adverse pretreatment conditions, the application of percutaneously implantable, transportable heart-lung machine appears to be justified in cases of intoxication with cardio- and vasodepressive substances.

Adult↗