[Possibility of using saliva for therapeutic monitoring of digoxin]. / Mozliwosc zastosowania sliny do terapii monitorowanej digoksyny.

Digoxin in salvia and blood serum of 24 patients obtained Bemecor was determined by the method of FPIA (IMx-ABBOT). Mixed saliva was collected by three different types of Salivette (Sarstedt) given in order: normal Salivette with cotton wool swab, Slivette with polyester wool and Salivette with citric acid as a stimulator. It was found, that the correletio between the digoxin concentrations in saliva and serum and saliva/serum rations depended on the type of Salivette. The highest correlation was obtained with the Salivette with polyester wool (r = 0.892), but low concentrations of this drug in serum were good reflected in all samples of saliva, independent on kind of Salivette.

Influence of food on the absorption of beta-methyldigoxin.

Nine healthy subjects received 0.2 mg of beta-methyldigoxin (beta-MD) orally in the fasting state, 30 minutes after and before a standard breakfast. The time-to-peak serum glycoside concentration was delayed and the peak concentration was lower in the postprandial state compared with the other regimens (P less than .01). The absorption rate constant was significantly reduced when beta-MD was given after a meal (1.55 +/- 1.75 hr-1) than before a meal (5.54 +/- 2.16 hr-1) and in the fasting state (5.22 +/- 3.06 hr-1)(P less than .01). Although the area under the serum glycoside concentration-time curve and the cumulative urinary excretion (CUE) of beta-MD, digoxin, and total drug (beta-MD plus digoxin) was not significantly different between three regimens, the CUE infinity tended to be smaller in the postprandial state compared with before a meal. The results indicate that the timing of drug administration in relation to a meal is an important factor leading to the fluctuations of serum glycoside concentration after oral beta-MD, which might be of some clinical importance.

Variances in pharmacokinetic parameters due to assay methods for beta-methyldigoxin.

A digoxin radioimmunoassay (RIA) or fluorescence polarization immunoassay (FPIA) kit is frequently used in routine therapeutic drug monitoring (TDM) of beta-methyldigoxin (MD) by applying a calibration curve made using the corresponding digoxin calibrators. The variances in the plasma levels (61 samples) and pharmacokinetics (5 patients) due to these two different assay methods for MD were examined in our patients with congestive heart failure. Although the plasma levels of MD measured by these methods were well correlated (r = 0.956, p less than 0.001) to each other over a wide range, RIA showed significantly lower values (p less than 0.01) in the subtherapeutic range (less than 0.80 ng/ml), but significantly higher values (p less than 0.002) in the therapeutic and toxic ranges (0.80-2.00 and 2.00 less than ng/ml), respectively than FPIA. This trend occurred with increasing concentrations. When MD samples, spiked in normal human plasma, were analyzed by these methods, RIA showed almost true MD values and gave larger values than FPIA with a mean ratio of FPIA to RIA of 0.83. In contrast, normal plasma samples, each spiked with a MD metabolite such as digoxigenin-bisdigitoxide or digoxigenin-monodigitoxide, showed higher values by 10 to 22% in FPIA. These observations are in good agreement with the findings obtained in a pharmacokinetic study that RIA gave significantly higher levels than FPIA, only in the early stage after MD administration, resulting in a smaller total volume of distribution and a larger beta value in the elimination phase, as compared with FPIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the onset of beta-methyl-digoxin action by potentiation of the adenosine response in guinea pigs.

The onset of beta-methyl-digoxin action was investigated by the potentiation of the adenosine response in guinea pigs and rats, and compared with that of digoxin and dipyridamole. A number of i.v. infusions of adenosine were given to determine the mean control adenosine response and its 95% confidence limits. After oral administration of the drugs, successive infusions of adenosine were continued until a drug-induced potentiation of the adenosine response was observed. The time of appearance of the potentiated adenosine response was marked as the onset of action of the drugs. The onset of action in guinea pigs was 9 to 12 min for 0.2 to 0.4 mg/kg of beta-methyl-digoxin, 90 to 100 min for 0.2 mg/kg of digoxin and 25 min for 5 mg/kg of dipyridamole. The maximal potentiation was 48.8 to 53.8% at 18 to 21 min for beta-methyl-digoxin, 74.5% at 130 min for digoxin and 74.8% at 80 min for dipyridamole. Adenosine infused i.v. into rats produced heart block, as in guinea pigs. However, in rats, the adenosine response was not potentiated by beta-methyl-digoxin and digoxin. Dipyridamole at a dose as high as 200 mg/kg produced 25.8% potentiation at 36 min after oral administration to rats.

Changes in metildigoxin pharmacokinetics in cirrhosis of the liver: a comparison with beta-acetyldigoxin.

In a prospective randomized study 12 patients suffering from cirrhosis of the liver (stable phase) and 12 healthy volunteers were treated daily with either 0.3 mg metildigoxin (Lanitop) or 0.4 mg beta-acetyldigoxin (Novodigal) 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 patients receiving metildigoxin therapy the ratio of beta-methyldigoxin/digoxin in the serum was determined by HPLC. The digoxin levels in patients with cirrhosis treated with metildigoxin 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. The higher total serum-digoxin levels in patients with cirrhosis of the liver after moderate saturation with metildigoxin are caused by reduced demethylation of beta-methyldigoxin to digoxin due to impaired liver function. A comparison with healthy volunteers showed that the reduced hepatic metabolism in the cirrhotic patients caused changes in the pharmacokinetics: a reduced metildigoxin clearance and a smaller distribution volume were found. According to our findings there is more danger of digitalis toxicity in patients with cirrhosis of the liver on a standard dosage of metildigoxin than on a standard dosage of beta-acetyldigoxin.

Relationship between myocardial uptake and actions in heart failure of methyldigoxin.

1 Problems have been encountered in recent years in confirming useful benefit to patients with heart failure and sinus rhythm from acute exposure to digitalis glycosides, though effectiveness of these preparations upon cardiac contractile performance is indisputable. Undesired effects such as those upon systemic vascular resistance have been invoked to explain this. 2 Detailed haemodynamic responses have been studied by cardiac catheterisation in nine such patients for 30 min after intravenous methyldigoxin infusion. Myocardial glycoside uptake was simultaneously assessed. 3 Methyldigoxin uptake by the heart was rapid, passing its peak within 20 min, and was followed by substantial elution. 4 A small progressive and significant increase in cardiac output was observed, though left ventricular filling pressures were not significantly reduced after methyldigoxin. Cardiac contractile function as assessed by left ventricular maximum dP/dt, measured in six patients, showed consistent improvement.

[Bioavailability of digoxin and beta-methyl-digoxin in patients with liver and gastro-intestinal diseases ]. / Biologische Verfügbarkeit von Digoxin und Beta-Methyldigoxin bei Hepatopathien und Magen-Darm-Erkrankungen.

The bioavailability of digoxin and beta-methyl-digoxin (BMD) was tested with a single dose on the grounds of peak serum concentration, tmax, area under the serum concentration-time curve and the cumulative 24 hour urinary excretion on one group of patients with liver disease (n = 20) and one with gastrointestinal disease (n = 10). Despite the smaller dose (0.5 mg BMD against 0.75 mg digoxin), peak serum concentration was significantly higher with BMD in both groups and was also reached earlier than with digoxin. The extent of absorption was also higher in both groups with BMD than with digoxin. A comparison of the results on hand with the results obtained in corresponding tests on healthy persons showed no significant differences with BMD. The excellent bioavailability of BMD was therefore also proved on patients with gastrointestinal diseases, whereas with digoxin the absorption in these patients was retarded, compared with healthy persons, but the extent of absorption was not reduced either. In gastrointestinal diseases with unknown conditions of absorption, the better bioavailability of BMD is probably of advantage, when compared with digoxin. According to medical literature, t/2 of BMD may be prolonged in liver diseases, so that in such cases the dose of BMD has to be adjusted or the use of digoxin is recommended.

Pharmacokinetics of metildigoxin and digoxin in geriatric patients with normal and elevated serum creatinine levels.

The pharmacokinetics of digoxin and metildigoxin were investigated in geriatric patients on maintenance treatment. Minimum serum glycoside concentrations were determined on 3 consecutive days, and the elimination rate over a withdrawal period of 4 to 6 days was studied. In patients with serum creatinine levels of less than or equal to 1.3 mg/dl, the oral standard dose D1) of digoxin necessary for a minimum serum concentration of 1.0ng/ml was 1.4 times higher than that of metildigoxin. There was no significant difference in the elimination rate of both glycosides. The pharmacokinetics of metildigoxin were further investigated in patients with elevated serum creatinine levels. The standard dose was best correlated with the creatinine clearance, calculated from the serum creatinine, age, weight and sex of the patients. The apparent volume of distribution of metildigoxin decreased with the drug's total body clearance.

[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.

Extrarenal clearance, distribution volume, and elimination rate of digoxin and metildigoxin in anuric patients.

The pharmacokinetics of 3H-labeled digoxin and metildigoxin were compared in six anuric patients. The following means +/- s.e.m. were obtained: extrarenal clearance of digoxin, 43.3 +/- 5.4 ml/min, of metildigoxin, 30.3 +/- 2.9 ml/min; distribution volume of digoxin, 315 +/- 29 1, of metildigoxin, 258 +/- 22 1; rate constant for elimination of digoxin, 0.0086 +/- 0.0013 h-1, of metildogixon, 0.0071 +/- 0.0007 h-1. The elimination rates correspond to half-lives of 80 h for digoxin and of 97 h for metildigoxin. From our investigations and published data a weighed mean of 47 ml/min was calculated for the extrarenal clearance of metildigoxin. This is not significantly different from the mean extrarenal clearance of 40 ml/min reported for digoxin. A total body clearance of 40 ml/min and a daily intravenous dose of 0.1 mg correspond to an average steady-state glycoside concentration of 1.74 ng/ml.

Digoxin concentration in cerebrospinal fluid-a study carried out after 9 days of treatment of beta-methyldigoxin or beta-acetyldigoxin.

Two groups of seven healthy volunteers were treated for 9 days with either 0.3 mg beta-methyldigoxin or 0.4 mg beta-acetyldigoxin daily, applied orally. On the 10th day, digoxin concentrations in plasma and cerebrospinal fluid (CSF) were determined by radioimmunoassay. After therapy with beta-methyldigoxin the plasma/CSF digoxin concentration ratio was 3.7:1; after therapy with beta-acetyldigoxin it was 3.2:1. There was no significant difference in the plasma/CSF digoxin concentration ratio after 9 days of treatment with equipotent doses of beta-methyldigoxin and beta-acetyldigoxin.

Evaluation of medigoxin in outpatients.

We compared our ability to predict the dose of medigoxin and of digoxin required to achieve a fixed serum concentration (the dose requirement) in 33 outpatients. Preliminary work supported the assumptions that the steady state glycoside concentration achieved was proportional to the daily dose given to an individual, and that the bioavailability of the different tablet presentations was similar for either glycoside. We were not able to predict the dose requirement from patient characteristics with any more certainty for medigoxin than for digoxin. Not only the between-patient variability in dose requirement, but also the within-patient variability, was similar for the two glycosides. However the digoxin used had a dissolution rate of over 90% in 1 h. When comparing medigoxin with digoxin of lower, or more variable dissolution rate, medigoxin may be preferable.

Comparative pharmacokinetics and pharmacodynamics of cardiac glycosides.

1 The pharmacokinetics and pharmacodynamics of ouabain, digoxinn and beta-methyl digoxin (medigoxin) have been investigated in a crossover study in four normal healthy volunteers. 2 Pharmacokinetics were studied using [3H]-labelled glycosides and the shortening of the left ventricular ejection time (LVET) was used as a measure of the effect of the drugs. A graded exercise protocol was used to correct for the effects of heart rate on LVET. 3 In three of the four subjects, both digoxin and beta-methyl digoxin produced a shortening in the LVET, but no such change could be detected with ouabain in any of the four subjects. 4 There was a good linear correlation between the shortening of the LVET and the amounts of digoxin or beta-methyl digoxin present in the body tissues. 5 One subject who showed no drug-related LVET shortening had greatly enhanced clearances of all three drugs studied.

[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.