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.

Measurement of beta-methyldigoxin level in serum from patients by enzyme immunoassay using novel specific antiserum with a phenyl boric acid column.

The authors compared serum beta-methyldigoxin (MDx) levels in digitalized patients by enzyme immunoassay (EIA) using anti-MDx 3'-hemisuccinate BSA antiserum (antiserum-I) with commercial antidigoxin antiserum (antiserum-II). The usefulness of a phenyl boric acid (PBA) column for pretreatment of the serum samples was also investigated. The assay using antiserum-I demonstrated good accuracy and precision in the concentration range of 0.5 to 5 ng/mL. When the specificities of antiserum-I and antiserum-II were assessed by cross-reactivity studies with various related compounds, antiserum-I was much more specific for MDx antiserum-II. Using a phenyl boric acid (PBA) column, MDx, and digoxigenin, which exhibits a negligible cross-reactivity, were separated from serum, including MDx and its metabolites. The recovery tests of MDx using antiserum-I with a PBA column in human serum were satisfactory and no interference of metabolites of MDx was observed. Mean MDx concentrations in serum samples (n = 30) from digitalized patients by EIA using antiserum-I with PBA column, antiserum-I, and antiserum-II were 1.06, 1.30, and 1.74 ng/mL, respectively. These results indicate that our EIA system using antiserum-I with a PBA column for pretreatment of serum samples is useful to more precisely measure the unchanged type of MDx in patients.

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.

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.

[Effect of the in vivo administration of beta-methyldigoxin on the Na, K-ATPase measured in different tissues of guinea pigs]. / Effecto de la beta-metil digoxina, administrada in vivo, sobre la actividad de la Na,K-ATPasa de diferentes tejidos de acure.

We measured the activity of the Na,K ATPase, Mg dependent and inhibited by ouabain, in microsomal fractions obtained from guinea pig myocardium and kidney, as weel as red cell ghosts. A group of animal was treated with beta-methyl digoxin (0.2 mg intraperitoneally) about one hour before obtaining the tissues. The control group received no medication. The plasma of both group, control and treated, had similar potassium concentrations (4.3 +/- 0.87 mM and 4.3 +/- 0.66 mM, respectively). The plasma digoxin concentrations from treated animals was always high (76.4 +/- 34.1 ng/ml). The Na,K-ATPase activity in the microsomal fraction from treated animals decreased by 28.7% in myocardium and by 27.7% in red cell ghosts, in comparison to the enzime activity measured in control animals. On the other hand, the Na/K activity obtained in kidney microsomal fraction did not change with treatment. We then measured the Na,K-ATPase activity in the red cell ghosts and microsomal fractions obtained from myocardium and kidney of untreated Guinea pigs. Adding digoxin in vitro (1 x 10(-9) M to 1 x 10(-3) M) we obtained, in myocardial fractions, a 50% maximal inhibition; the digoxin concentration causing half maximal effect (DI50) was 7 x 10(-5) M. In the kidney microsomal fraction we measured a 66% maximal inhibition of the enzime activity and DI50 was 2 x 10(-6) M. For red cell ghosts the maximal enzime inhibition was 34% and the DI50 was 1 x 10(-5) M. In conclusion, in the Guinea pig, the acute in vivo administration of beta-methyl digoxin causes a parallel inhibition of the Na,K-ATPase from myocardial fractions and red cell ghosts. We measured no significant change in the kidney microsomal fractions. We propose the determination of red cell Na,K-ATPase activity as possible indicator of digitalis effect on humans treated with these drugs.

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.

[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.

[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.

[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.

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.

[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.

[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.

[Pharmacological and clinical research on the interaction of digitalis and amiodarone in heart disease patients with varying degrees of cardiac insufficiency]. / Ricerca farmacologico-clinica sull'interazione digitale-amiodarone in pazienti cardiopatici con insufficienza cardiaca di vario grado.

The increasing use of amiodarone as antiarrhythmic drug has raised the possibilities of dangerous effects from amiodarone-digitalis interaction. We have studied twelve patients who were taking digitalis and to whom amiodarone was administered because of arrhythmias. We found a 75,42% increase of digitalis plasma levels (p less than 0,001) in the early days of amiodarone therapy, and a 52,1% increase (p less than 0,001) in the medium term. An inverse correlation was found (r = -0,65; p less than 0,05) between the plasma levels of digitalis during the steady-state control period and during the following 2-to-6 months evaluation. Acute episodes of cardiac failure caused in our patients an abrupt increase of digitalis plasma levels: in three patients digitalis toxicity occurred. Based on our experience, we recommend that the dose of digitalis be halved when the two drugs are given together in patients with various degree of cardiac failure; moreover digitalis plasma levels should be frequently monitored in these patients. On the other hand digitalis administered according to age, sex, weight, kidney function, together with amiodarone, can be given at full dosage in patients without cardiac failure.

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.