Elimination of 16-acetyl-gitoxin in patients suffering from impaired liver function.

In ten patients suffering from moderate to severe disturbances of liver function (hepatic cirrhosis, carcinomatous metastases of the liver) the elimination of 16-acetyl-gitoxin from plasma was measured after a single oral dose of 1.2 mg pengitoxin. In 9 of 10 patients the mean half-life amounted to 67.3 h (SD 14.2 h). In one patient with carcinomatous infiltration of the liver and concomitant cirrhosis, the half-life was prolonged to 165.3 h. The results point to an unchanged elimination of 16-acetyl-gitoxin in patients suffering from liver cirrhosis.

Dose-dependent shortening of systolic time intervals after intake of pengitoxin.

The systolic time intervals (STI) corrected for changes in the heart rate, electromechanical systole (QS2c) and left ventricular ejection time (LVETc), and the ECG-derived PQ-time and QT-interval were measured in five female and four male healthy subjects. Each volunteer took 0.15, 0.30, 0.45, 0.60, 0.75 or 0.90 mg pengitoxin over six days, with a glycoside-free interval of two or three weeks between two doses. The glycoside plasma level was measured radioimmunologically. Linear correlations were found between the shortening of QS2, LVET, and QT (delta QS2c, delta LVETc, delta QTc) and the plasma level of 16-acetyl-gitoxin. The PQ-time showed a flat dose-dependent increase. The shortening of STI observed after therapeutic and subtoxic doses of pengitoxin was in accordance with that after intake of digitoxin and digoxin in corresponding doses. The efficacy of pengitoxin estimated by shortening of STI justifies the administration of daily maintenance doses between 0.30 and 0.45 mg.

On the pharmacokinetics of 16-acetyl-gitoxin and its bioavailability from pengitoxin-containing tablet formulations.

In six volunteers the pharmacokinetics of 16-acetyl-gitoxin (16AG, 0.5 mg) administered intravenously (A1) and as an oral solution (A2) and of pengitoxin (PAG, 0.6 mg) administered intravenously (A3) was evaluated. In six volunteers the bioavailability of 16AG from two PAG tablet formulations (1.2 mg) (B2, B3) was measured by comparison with the absorption after administration of a pengitoxin solution (1.2 mg) (B1). In both studies the test was performed using a crossover design. After a single i.v. injection of equimolar doses, 16AG and PAG showed similar mean kinetic parameters: t1/2 = 51.6 hr (16AG) and 60.8 hr (PAG), CL = 11.7 ml min-1 (16AG) and 12.7 ml min-1 (PAG), CLR = 4.1 ml min-1 (16AG) and 4.2 ml min-1 (PAG). The 16AG was absorbed from solution with a mean half-life of 0.2 hr to an extent of 98.6%. The mean urinary excretion/Ae (0,4)/of 16AG amounted to 24.6% (A1), 20.8% (A2) and 28.1% (A3). On the basis of AUC values, the mean bioavailability of PAG from either tablet formulation amounted to 79.6% (B2) and 89.6% (B3). The pharmacokinetic parameters of 16AG (PAG) are closer to those of digitoxin than those of digoxin. In general, 16AG is characterized as a digitoxin with a digoxin-like elimination half-life.

[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.

[The effect of cardiac glycosides on the visual system of man measured with cortical evoked potentials]. / Die Wirkung von Herzglykosiden auf das visuelle System des Menschen, gemessen mit kortikal evozierten Potentialen.

The effect of beta-acetyldigoxin (Novodigal) on color vision in normal, healthy subjects was studied using cortical evoked potentials. Initial results indicate a significant latency increase of one component of the visual evoked potential (VEP) and a dose dependency following a change of color from blue to red. The Farnsworth-Munsell-100-Hue test, however, showed no significant changes in color vision. It is postulated that the VEP is an even more sensitive measurement of color vision than subjective tests are.

[Pharmacokinetic and cardiac efficacy of beta-acetyldigoxin and digitoxin in combination therapy with diltiazem]. / Pharmakokinetik und kardiale Wirksamkeit von beta-Acetyldigoxin und Digitoxin unter einer Kombinationstherapie mit Diltiazem.

The effect of diltiazem (D) on the pharmacokinetics and pharmacodynamics of beta-acetyldigoxin (AD; n = 12) and digitoxin (DGT; n = 10) was studied in 22 patients with cardiac insufficiency stages II-III by the New York Heart Association. Glycoside plasma concentration and renal excretion as well as electrocardiogram [heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QTc), mean amplitude of T-waves in leads V2 to V6 (TV2-6)] and systole time intervals [total electromechanical systole index (QS21), left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), PEP/LVET ratio] were recorded repeatedly before and during co-administration of 180 mg/day D. In eight patients digoxin plasma levels increased continuously during additional D administration. After reaching a new steady state at 0.93 +/- 0.35 ng/ml digoxin concentrations were at an average 43% higher than before D administration (0.65 +/- 0.27 ng/ml) with a simultaneous increase in renal glycoside excretion. The other four patients showed neither changes in digoxin concentrations in plasma nor in renal glycoside excretion. Only half the patients treated with DGT and D revealed an increase in DGT plasma levels of 21.4%. Daily renal glycoside excretion was not altered by D administration. In accordance to the increasing AD plasma concentration, PQ-interval was prolonged and T-wave flattening was intensified, whereas the systolic time intervals after concomitant treatment of AD and D did not differ from those after AD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of laxative measures on the serum concentration of digoxin in the human]. / Einfluss von abführmassnahmen auf die Serumkonzentration von Digoxin beim Menschen.

Plasma digoxin levels were measured in patients on laxatives during the initial phase and during the steady state of digoxin intake. Plasma digoxin levels were significantly lower during intake of laxatives. Reduced intestinal resorption may be due to accelerated passage through the intestinal tract and to alteration of distribution volumes.

[Effect of a fiber-rich diet on digoxin resorption]. / Der Einfluss einer ballaststoffreichen Kost auf die Digoxin-Resorption.

In five female healthy volunteers the influence of dietary fiber (wheat bran or carob seed flour) on absorption of digoxin was investigated. Five minutes after ingestion of a formula diet alone or in combination with wheat bran or carob seed flour 0,8 mg beta-acetyldigoxin was given per os. The plasmaconcentration-time curve over eight hours, the area under curve and the cumulative urinary excretion were not changed significantly. It was concluded that there is no influence of dietary fiber on rate or degree of digoxin-absorption.

Differences in color vision impairment caused by digoxin, digitoxin, or pengitoxin.

Color discrimination ability of 53 patients with congestive heart failure and 32 healthy volunteers treated with digoxin, digitoxin, or pengitoxin was determined with the Farnworth's Munsell 100 hue test. The patients had been treated with digitalis glycosides for several months prior to color vision testing. The volunteers received glycosides until a steady-state plasma concentration was reached. Glycoside plasma levels were measured by radioimmunoassay on the 3 days prior to color vision testing. The total error scores, indices of color discrimination, increased with the glycoside plasma levels. Subjects treated with digitoxin or pengitoxin exhibited no marked elevation in total error score at therapeutic concentrations, whereas 17 of 28 subjects with therapeutic digoxin plasma concentrations (less than 2.0 ng/ml) showed disturbed color discrimination. At toxic plasma levels all 5 digoxin-treated subjects, 7 of 13 digitoxin-treated subjects, and 3 of 8 pengitoxin-treated subjects showed impairment of color discrimination. The greater tendency of digoxin to impair color vision in comparison with digitoxin and pengitoxin may be related to a higher uptake or different distribution in the retina.

[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.

Direct radioimmunoassay for the determination of 16-acetyl-gitoxin in serum.

A simple and reliable radioimmunoassay procedure for the specific determination of 16-acetyl-gitoxin, the main cardioactive metabolite of penta-acetyl-gitoxin, in serum is described. Antisera raised against 15-acetyl-gitoxin-bovine serum albumin conjugates proved to be highly specific, thus permitting direct analysis of serum. The assay is capable of detecting 0.4 ng of 16-acetyl-gitoxin. This covers the therapeutic and toxic range when 0.1 ml serum is analyzed. A single worker can assay about 100 serum samples per day in triplicate.