Pharmacokinetics of beta-methyldigoxin in subjects with normal and impaired renal function.

Beta-methyldigoxin (beta-MD) was administered orally (0.2 mg) to 24 patients with various degrees of renal function, to investigate its pharmacokinetic characteristics related to renal function. Serum and urine collected until 120 hours after dosing were assayed for beta-MD and digoxin by high-performance liquid chromatography and fluorescence polarization immunoassay method. The steady-state volume of distribution decreased proportionately as creatinine clearance (CLCR) decreased, although steady-state volume of distribution of hemodialysis patients had large interindividual variability, and their mean value was not different from that of patients with normal renal function. Both renal clearance of beta-MD and digoxin were significantly correlated with CLCR (r = .820, P < .001 and r = .822, P < .01, respectively), and the slope of regression line for beta-MD was only 44% that for digoxin. Significantly reduced urinary excretion of total drug (beta-MD plus digoxin) was shown in patients with CLCR below 50 mL/minute/1.48 m2. This study suggests that the dosage modification is not necessary until CLCR decreases to below 50 mL/minute/1.48 m2, but careful attention should be given in the use of beta-MD in patients with CLCR below this value.

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.

Asterixis associated with carbamazepine.

Some antiepileptic drugs, when administered at toxic plasma levels or more rarely at levels within the therapeutic range, induce asterixis. We report the case of a patient with painful syndrome of central origin being treated with carbamazepine, in which asterixis appeared with toxic serum levels. A pharmacologic interference was also observed between carbamazepine and beta-methyldigoxin, which in our patient was being used to treat disease. The blood digoxin levels were inversely proportional to those of carbamazepine. The therapeutic effectiveness of digoxin being sharply reduced when carbamazepine reached toxic levels.

[Serum levels of beta-methyldigoxin and contractile efficiency of the myocardium evaluated with systolic polygraphy and determination of cardiac output]. / Livelli serici di beta-metildigossina ed efficienza contrattile del miocardio valutata con la poligrafia della sistole e con la determinazione della portata cardiaca.

0.3 mg/day betamethyldigoxin was given per os in three daily administrations to 8 healthy subjects, and 8 compensated and 8 decompensated heart patients. Prior to the treatment, and 6 hr after the last administration, blood digoxin values were determined radio-immunologically, together with cardiac output, systolic stroke volume, cardiac index (dilution of indocyanine green), and systolic time intervals, by simultaneous recording of the ECG, carotid pulse, and the phonocardiogram. No significant change in output, stroke volume and cardiac index was noted in the healthy subjects, whereas these parameters were distinctly improved in the decompensated patients. Changes in the systolic intervals after treatment were significant in all cases though there was no significant correlation with the blood digoxin levels reached. In particular, the healthy and compensated subjects displayed a reduction in the corrected electromechanical systole (delta Q-S2), the corrected pre-ejection period (delta PEP), the corrected left ventricular ejection time (delta LVET), and their ratio (PEP/LVET), whereas in the decompensated patients the picture differed to the extent that the LVET increased owing to an augment-systolic stroke volume, the other parameters being reduced. In the healthy subjects, the polygraphic data were normal prior to the treatment, while in the compensated patients delta PEP and the PEP/LVET ratio were enhanced, and the delta LVET was less than in the normal subjects. It is felt that recording of the systolic intervals may be regarded as a sound method, owing to its simplicity and its ability to demonstrate latent cardiac failure before haemodynamic changes appear. Simultaneous determination of serum digoxin and the polygraphic data, therefore, opens the way to the commencement of appropriate, safe and timely management of as yet non-decompensated heart patients.

[Pharmacokinetics of beta-methyldigoxin and beta-acetyldigoxin in patients with cirrhosis of the liver (author's transl)]. / Zur Pharmakokinetik von beta-Methyldigoxin und beta-Acetyldigoxin bei Patienten mit Leberzirrhose.

In this prospective randomised study 12 patients suffering from cirrhosis of the liver (stable phase) and 12 healthy male volunteers were treated with either 0.3 mg beta-methyldigoxin (Lanitop) or 0.4 mg beta-acetyldigoxin (Novodigal) daily, orally. Every day the total serum digoxin concentrations of the patients and volunteers were measured by radioimmunoassay. Both digoxin and beta-methyldigoxin are measured by this method. In subjects receiving beta-methyldigoxin therapy the ratio of beta-methyldigoxin to digoxin in the serum was determined by liquid chromatography. The digoxin levels in patients with cirrhosis treated with beta-methyldigoxin were statistically significantly higher than in healthy volunteers. In patients with cirrhosis the proportion of serum beta-methyldigoxin averaged 77.7% of the total digoxin concentration, whereas the proportion was only 37.5% in healthy volunteers. With beta-acetyldigoxin there was no statistically significant difference between patients with cirrhosis and healthy volunteers. Alterations in pharmacokinetics may cause the higher total serum digoxin concentrations in cirrhotic patients. The following factors seem to be important: longer elimination half life, changes in distribution volume and reduced renal clearance. There is greater danger of digitalis toxicity in patients with cirrhosis of the liver on standard dosage of beta-methyldigoxin than on standard dosage of beta-acetyldigoxin.

[What value do body weight, age and drug anamnesis have as an index of elevated digoxin level?]. / Welchen Wert haben Körpergewicht, Alter und medikamentöse Anamnese als Indizes eines erhöhten Digoxinspiegels?

A retrospective study of two groups of patients with a different plasma digoxin level (Group A: digoxin greater than or equal to 2 ng/ml, n = 32, Group B: digoxin less than 2 ng/ml, n = 34; total n = 66) showed a significantly lower creatinine clearance (p less than 0.05) in group A. This group also showed a weak correlation between the digoxin level and the length of observation (R = + 0.31, p less than 0.05, n = 29). Furthermore, a weak correlation between digoxin level and the ratio of average daily dosage to creatinine clearance was found for the total sample (R = + 0.30, p less than 0.05, n = 66). Patients treated for less than 7 days and with a higher digoxin level also had a higher dosage and worse renal function (p = 0.05, p = 0.01, respectively). A weak correlation also existed between the digoxin level and creatinine clearance and body weight for the whole sample (R = -0.29, p less than 0.05; R = -0.29, p less than 0.01, respectively; n = 66). The latter correlation was also found within each group. Apart from renal function, the medication taken and body weight seem to be useful variables in predicting impending elevation of the digoxin level. In this study these variables were found to be better suited for the said purpose than the ECG. These conclusions remain to be confirmed by means of a prospective study.

[Maintenance therapy with beta-methyldigoxin in the elderly. A study of 40 patients]. / Terapia di mantenimento con beta metildigossina nell'anziano. Studio su 40 pazienti.

The efficacy of beta methyldigoxin was examined in a group of 40 elderly patients who had been hospitalised due to congested heart decompensation. A good clinical response was obtained in 95.5% of cases with the presence of slight toxic phenomena in 2 cases only (4.5%). The paper underlines the excellent pharmacokinetic pattern of the substance used in the steady state. Steady state digitalemic values were within the acceptable range in 83.76% of cases, whereas underdosage and overdosage phenomena were observed in 6.87% and 9.37% of patients respectively.

[Kinetics of beta-methyl-digoxin in different degrees of renal function (author's transl)]. / Cinética de la beta-metil-digoxina en los diversos grados de funcionalismo renal.

Creatinine clearance was evaluated in individuals with varying degrees of renal function following the administration of beta-methyl-digoxin. From the results of the experiment it can be deduced that significantly increased hematic values and renal clearance values definitely lower than normal appear only in patients of a creatinine clearance of less than 50 ml/min. Furthermore, a positive correlation between creatinine clearance values and beta-methyl-digoxin levels was noticed. This correlation was in proportion to the amount of serum albumin. The degree of distribution of free digitalis and digitalis bound to proteins within the vascular system played an important role in the complex kinetics of digoxin. This relationship is suggested as an indirect index of the proportions of free beta-methyl-digoxin and of beta-methyl-digoxin bound to plasma proteins.

[Analysis of the use of digitalis in a sample of the geriatric population]. / Analiza primjene digitalisa u uzorku gerijatrijske populacije.

Rationality of digitalis use in 20 elderly patients in long term-care institution was analysed using the method of correlation of the past medical history, clinical examination and basic laboratory findings. After consultation of clinical pharmacologist, general practitioner and medical biochemist it was possible to stop the digoxin therapy in 6 (30%) of the patients. Four (20%) patients were hypersaturated with digoxin. Lack of indication was the reason for stopping the digitalis in one of them. Therapy was modified in 3 patients. Use of digitalis was rational in 10 (50%) of the patients. The results suggest that digitalis was prescribed too often in this sample of the elderly patients.

Free and total digoxin in serum during treatment of acute digoxin poisoning with Fab fragments: case study.

A woman ingested 10 mg of methyldigoxin in a suicide attempt and presented 19 hours after ingestion with clinical signs of glycoside intoxication. Her serum level of digoxin was 7.4 ng/mL, and antidotal therapy with Fab antibody fragments was started. The manufacturer's recommended dosing scheme was modified, with 80 mg Fab administered intravenously within 15 minutes followed by a continuous infusion at 30 mg/h. Total serum concentration of digoxin increased markedly within minutes after Fab therapy was started, while the level of free digoxin immediately decreased into the nontoxic range without recrudescent toxic effects of digoxin. The cumulative amounts of free and bound digoxin that were excreted in urine within 30 hours after ingestion were 900 microg and 1600 microg, respectively. Half-life of bound digoxin in urine was 9.9 hours; mean rate of clearance of bound digoxin in the urine was 7.0 mL/min. On the basis of these kinetic data, a smaller initial bolus dose of Fab followed by a continuous infusion may be a more tailored, cost-effective, and relatively safe therapy for patients who have overdosed on cardiac glycosides.

[Tissue concentrations of beta-methyl-digoxin in children]. / Concentraciones tisulares de beta-metil-digoxina en el niño.

Beta-methyl-digoxin concentrations in adipose, skeletal muscle and myocardial tissues, were studied in 8 patients undergoing by-pass surgery because of congenital heart disease. Correlation between doses/kg, plasmatic and tissue concentrations were analysed. We found statistically correlation between doses/kg and plasmatic concentrations; doses/kg and skeletal muscle concentrations (p less than 0.01); plasmatic and skeletal muscle concentrations (p less than 0.05). Concentrations was significantly greater in myocardial than adipose tissue before extracorporeal circulation (p less than 0.01); and significantly greater than adipose (p less than 0.01) and skeletal muscle (p less than 0.05) tissues after extracorporeal circulation. Extracorporeal circulation lessens adipose and skeletal muscle concentrations, but increases myocardial concentrations significantly (p less than 0.05). It is concluded, that the behaviour of beta-methyl-digoxin, in relation with tissue concentrations, is similar to digoxin.

[Individual glycoside therapy using serum concentration determination in heart insufficiency of horses]. / Individuelle Glykosidtherapie mittels Serumkonzentrationbestimmung bei der Herzinsuffizienz des Pferdes.

23 horses and one donkey with congestive heart failure are treated with a standardized methyldigoxin dose (0.0032 mg/kg of body weight). The therapy is controlled by the serum concentration of the cardiac glycoside. 4 horses have a higher and 13 horses a lower serum concentration as necessary for therapeutic approach. The influence of additional diseases and medications is demonstrated. Finally a rule for the evaluation of the individual therapeutic glycoside-dose is given.

Establishment of enzyme immunoassay for measuring beta-methyldigoxin levels in human serum by specific antiserum.

We investigated the specificity of obtained antisera to beta-methyldigoxin by the enzyme immunoassay. Three types of hapten-bovine serum albumin (BSA) conjugates were synthesized to obtain high specific antisera to beta-methyldigoxin. The haptens were linked to the carrier protein through hemisuccinate at C-3' and C-3'' positions in the digitoxose chain and at C-12 position in the aglycone. Anti-beta-methyldigoxin 3'-hemisuccinate-BSA antiserum showed a low detection limit (0.2 ng/ml) and possessed high specificity for beta-methyldigoxin, exhibiting low cross-reactions with digoxigenin bisdigitoxoside (8.3%), dihydrodigoxin (4.8%), digitoxin (1.5%), and digoxigenin monodigitoxoside (0.95%), except for cross-reaction with digoxin (43%). Compared with commercial antidigoxin antiserum, clinically used to monitor beta-methyldigoxin concentration in human serum, cross-reaction data of anti-beta-methyldigoxin 3'-hemisuccinate-BSA antiserum showed higher specificity for beta-methyldigoxin. The intra-assay and inter-assay variations using this antiserum were less than 6.9% and 8.1%, respectively. The recovery tests were good, within the range of 96.2-104.3%. Phenyl boric acid (PBA) column treatment was effective to rapidly and selectively separate beta-methyldigoxin from the mixture of beta-methyldigoxin and its metabolites in human serum. The recovery tests of beta-methyldigoxin with PBA column in human serum were about 110% and interference of metabolites of beta-methyldigoxin was negligible. These results suggest that anti-beta-methyldigoxin 3'-hemisuccinate-BSA antiserum and PBA column treatment are useful to more precisely monitor the unchanged type of beta-methyldigoxin concentration in human serum.

[Digitalization without saturation dose using methyldigoxin. Experiences with 29 patients]. / Digitalisierung ohne Sättigungsdosis mit Methyldigoxin. Erfahrungen an 29 Patienten.

The indications and performance of oral digitalization without saturation dose are evaluated on the basis of clinical parameters and plasma digitalis levels. A group of patients with evident cardiac insufficiency received a daily maintenance dosage of digitalis (2 tablets of 0.1 mg methyldigoxin) from the outset. After 7, 15 and 30 days the plasma concentration of methyldigoxin was measured. Objective and subjective signs of cardiac insufficiency were noted. In 28 of 29 patients the therapeutic plasma level (0.8-2.0 ng/ml) was achieved with a mean plasma digitalis concentration of 1.47 +/- 0.4 ng/ml. A clinical improvement was observed in 18 patients. On the 15th and 30th day of treatment the mean plasma level of methyldigoxin showed no significant difference: X15 = 1.51 +/- 0.57 ng/ml and X30 = 1.40 +/- 0.46 ng/ml. The measured plasma values were not influenced by the patient's weight or age. In 6 patients with renal insufficiency a clear correlation between the plasma level of methyldigoxin and the creatinine level was observed. The evaluation of ECG signs showed only minimal alterations of conduction and repolarisation. On the basis of these results conclusions are drawn with regard to the clinical value and use of this therapy.

[Influence of the gastric acidity on the digoxinemia. Comparison between digoxin and beta-methyldigoxin (author's transl)]. / L'influenza dell'acidita' gastrica sulla digossinemia. Confronto fra diagnossina e beta-metildigossina.

In a medium term study, carried out according to a random cross-over schema, the Authors have evaluated the influence of gastric acidity on the digoxinemia, after the administration of digoxin (0.375 mg/day) and beta-methyldigoxin (0.25 mg/day) from the same batches. The results confirmed the effect of the gastric acidity on cardiac glycosides and an higher stability of beta-methyldigoxin than digoxin. These data suggest that digoxin, particularly in patients with gastric hypoacidity, must be used cautiously, because we can reach decidedly dangerous haematic levels, with a mean deviation of the values from the normal subjects of 89%, in comparison with 18% in the beta-methyldigoxin treated patients.

[Biological availability of digoxin and beta-methyl-digoxin administered in the fasting state or after meals]. / Biologische Verfügbarkeit von Digoxin und beta-Methyl-Digoxin bei nüchterner und postprandialer Einnahme.

Ten healthy volunteers were given 0.75 mg digoxin and 0.5 mg beta-methyl-digoxin (BMD) in tablet form in the fasting state or after breakfast. Serum concentrations and 24-hour urine excretion of glycoside were measured by radioimmunoassay. Neither the mean area under the serum concentration curve nor the mean cumulative urinary excretion was significantly changed by postprandial administration. Peak serum concentrations were higher when the subjects took the tablets while fasting than when they took them postprandially, but the difference was significant only for BMD. After BMD in the fed state the peak serum concentration was reached earlier and with less variation than after digoxin, but -- as after administration in the fasting state -- the differences were not significant. The peak serum concentration and the time when it is achieved are, as parameters for the rate of absorption, only of secondary importance for treatment with cardiac glycosides in medical practice. They suggest faster absorption of BMD compared with digoxin. Both the glycosides can be given equally well before, during or after food, a fact which facilitates prescription.