Search PubMed⌕ Search

Biomedical subjects

N Rietbrock

Publications and source records attributed to N Rietbrock.

At least 145 records · Page 8Linked to original sources
PubMed1977

Canrenoate disposition in dogs. Tissue distribution and elimination.

The metabolism and tissue distribution of intravenously administered C14-canrenoate-potassium (CR-K) was studied at various time intervals in 10 dogs. After a rapid decline of total radioactivity immediately after injection, the elimination in plasma occurred in two distinct phases with half-lives of 6.8 and 23.6 h. Canrenoate was rapidly converted to lipid- and water-soluble metabolites which were separated by thin-layer chromatography. Most tissues showed similar concentrations of total radioactivity as plasma. An accumulation of radioactivity per g wet weight was detected in the adrenal glands and fat tissue as well as in the metabolic and excretory organs but not in the heart. Taking into consideration that skeletal muscle, fat tissue and liver constitute about 64% of the body weight, it is obvious that the main part of total radioactivity was present in these tissues. In contrast to plasma, urine and feces, where various metabolites could be analysed, the bulk of radioactivity in tissues is represented by canrenone. Thus, the estimation of the parent compound and its metabolites in plasma, urine and feces does not allow final conclusions about the active substance in various tissues. Within 72 h 47% of the dose was recovered in urine and 49% in feces.

Animals↗
PubMed1977

Bioavailability of digoxin: some pitfalls and problems.

The bioavailability of tablet formulations averages about 60% for digoxin, 75% for beta-acetyldigoxin, and 75% for beta-methyldigoxin. Bioavailability as a measure of the absolute amount reaching the systemic circulation should be calculated from steady state data. Only in steady state does the retarding effect of absorption disappear which diminishes the p.o./i.v. relation of data. For a screening test bioavailability may be calculated from 24-hour renal excretion values after a single dose, performing absolute and relative studies consecutively in cross-over arrangements. The absorption rate constant of digoxin and its derivatives is approximately 0.7 (h-1) which corresponds to an absorption half life of about 1 hour. The absorption rate constant can be calculated from plasma concentration values as well as from renal excretion rates 1 or 2 hours after dosing.

Biological Availability↗
PubMed1977

Influence of canrenoate-K and cardiac glycosides on their tissue distribution and elimination.

The combination of cardiac glycosides and canrenoate-potassium (CR-K) produces synergistic effects on hemodynamics. On the other hand, CR-K antagonizes digitalis-induced cardiac arrhythmias. Therefore, it was the purpose of this study to determine interactions between these substances, particularly of their myocardial uptake. The additional administration of CR-K leads to significantly higher concentrations of digoxin and ouabain in heart, liver, adrenal gland and spleen. Contrary to this, additional digoxin reduces the concentration of CR-K in the tissue. Particularly obvious is the reduced concentration in the kidney, adrenal gland, pancreas, brain and spleen. The renal excretion of digoxin and ouabain is reduced by the additional administration of CR-K, while digoxin accelerates the CR-K excretion within the first 60 min after application. Metabolic interference was not detected in the combination of cardiac glycosides and CR-K. The mechanisms for the interactions between cardiac glycosides and CR-K during the distribution phase are discussed. The inhomogenous interference of their myocardial uptake makes a common cardiac receptor for the synergistic effect of cardiac glycosides and CR-K rather unlikely. CR-K does not have a suppressant effect on digitalis-induced arrhythmias due to any diminution of the glycoside uptake by myocardial tissue.

Animals↗
PubMed1977

The effect of oral spironolactone and intravenous canrenoate-K on the digoxin radioimmunoassay.

Twenty patients receiving a constant maintenance therapy of digoxin preparations were selected, and daily plasma digoxin concentrations were measured using the clinical assays gammacoat 125I-digoxin radioimmunoassay. A single intravenous dose of canrenoate-K was given to 10 patients, thus producing after 5 min. a rapid rise of plasma digoxin concentrations, which varied from 121.1 to 214.3% of the baseline value (100%). In 3 of these patients, plasma digoxin concentrations were measured serially over a period of 8 hrs. and yielded digoxin levels of 81.5, 112.5 and 122.5% of the baseline value. The other 10 patients received an oral dose of 100 mg spironolactone twice a day, and plasma digoxin determinations were carried out daily. Up to the fifth day, a continuous rise of average digoxin levels was found (on day 5, 181.0%) as long as digoxin and spironolactone were continued. From the sixth to the ninth day of therapy, average mean values remained fairly constant (on days 6-9, 168.9, 173.6, 170.8, 172.5% respectively). Contradictory results have been obtained when the interference of spironolactone, canrenone or canrenoate-K on the radioimmunoassay was studied [1, 2]. This study is a further contribution for evaluating the specifity a commercially available 125J-labeled digoxin kit.

Canrenoic Acid↗
PubMed1976

Bioavailability and pharmacokinetics of beta-methyldigoxin after multiple oral and intravenous doses.

To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of beta-methyldigoxin 0.3 mg. After oral or intravenous administration of beta-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.

Administration, Oral↗
PubMed1976

[Influence of antacids on plasma concentration of digoxin in man (author's transl)].

In a cross-over trial the plasma concentrations of digoxin have been studied in nine healthy subjects given oral doses of digoxin alone and simultaneoulsy with magnesium-aluminium-silicate-hydrate and dimagnesium-aluminium-trisilicate. The administration of 0.75 mg digoxin on each of 3 days and 0.375 mg on each of 2 days caused a 17 percent decrease of digoxin plasma level when given simultaneously with 1100 mg magnesium-aluminium-silicate-hydrate (n=4) and a 24 percent increase when given with 1000 mg dimagnesium-aluminium-trisilicate (n=5), respectively. The differences are not significant. The experiments suggested that antacids containing magnesium-aluminium-silicate do not impair the absorption of digoxin in man.

Administration, Oral↗
PubMed1976

Disposition of digitoxin in renal failure.

The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3H-digitoxin. In plasma, the time-course of radioactivity indicated a diminished absorption velocity of tritium compared to that of control subjects already reported and, after reaching of a pseudostate-equilibrium at 24 hr, an exponential decline with a mean half-life of 8.0 days. In urine, smaller amounts of tritiated compounds were eliminated in uremic patients (8.7% of the dose) than in controls (22.5%). The average fecal excretion of digitoxin and its metabolites was not significantly increased. Chloroform extraction and thin-layer chromatography in plasma, urine and feces suggested no qualitative alteration in the metabolism of digitoxin. Calculations of the total body tritium content (body stores) after each 24-hr interval and its pharmacokinetic behavior showed that the elimination of digitoxin is determined by the transfer constant from tissue to plasma. The differences in elimination kinetics of digitoxin and its metabolites of uremic patients and healthy subjects were not significant.

Chromatography, Thin Layer↗
PubMed1976

[Therapeutic equivalence and inequivalence of chemically identical substances using cardiac glycosides for an example (author's transpl)].

The problem of therapeutic equivalence or inequivalence cannot be solved by "ignoring facts and proclaiming opinions". The entire problem is multifarious and is not even clearly arranged although heart glycosides have been used for 200 years in the therapy of cardiac insufficiency. It comprises the physico-chemical properties of the drugs, its preparation and its pharmacolinetic behaviour in the organism. Therapeutic equivalence or inequivalence can primarily only be evaluated in connection with the disease and the symptoms of disease, respectively. Thus, manufacturers, pharmacists and physicians likewise are confronted with the problem. The differences in bioavailability of the individual cardiac glycosides show the necessity for: 1. The number of fixed combinations of heart glycosides should be limited in the interest of drug safety. 2. Only such drugs should be approved whose quantitative and qualitative equivalence has been demonstrated with regard to the monoglycoside. 3. When prescribing digoxin derivatives one should not only observe the bioavailability but take also into account the chemical stability and the pharmacolinetic behaviour.

Animals↗
PubMed1976

[Preoperative digitalization. Measurement of digoxin plasma levels (author's transl)].

In a study of 233 patients from the department of surgery and anesthesiology taking digoxin preparations 64, per cent exhibit digoxin levels in the therapeutic range (0.6--1.5 ng/ml), 19 per cent had subtoxic concentrations ranged from 1.6--2.0 ng/ml and 7 per cent were in the toxic range (greater than 2 ng/ml). In patients treated with digoxin before admission to hospital subtherapeutic levels were most frequent. An average loading dose of digoxin 1 mg or more on one day may result in subtoxic and toxic digoxin levels on the second day, in patients receiving less than 1 mg digoxin daily an increasing frequency of plasma digoxin concentrations of 1.5 ng/ml or higher values was present on the third day. Averaged plasma digoxin concentrations were correlated with daily maintenance dose. There was, however, a wide individual variation in digoxin plasma concentrations. A low incidence of toxic digoxin plasma levels was observed in patients receiving a daily oral maintenance dose of 0.375 mg digoxin (Lanicor). For prophylactic digitalization of patients with normal renal and thyroid function the following schedules or statistical guidlines are proposed: Lanicor (bioavailability 60%): oral loading dose of 0.75 mg over two days, and then daily oral maintenance dose of 0.375 mg; Novodigal (bioavailability 80%): oral loading dose of 0.6 mg over two days and then daily oral maintenance dose of 0.3 mg; Digoxin i.v.: intravenous loading dose of 0.5 (0.4) mg over two days and then 0.25 (0.2) mg daily intravenous maintenance dose. For any patient needing treatment with digitalis glycosides therapy must be individual and dynamic. The reasons for toxic concentrations were frequently attributed to wrong dosage.

Administration, Oral↗
PubMed1975

Excretion of methylproscillaridin in patients with a biliary fistula.

Four patients with a biliary fistula received 0.5 mg 3H-methylproscillaridin as a single oral dose. 55% of the dose was excreted in bile, 16% in urine and 3% in faeces. More than 60% of the radioactivity excreted in bile and urine appeared within the first 24 hours. 78% of the radioactivity in bile consisted of CHCl3-insoluble metabolites of methylproscillaridin, incubation of which with beta-glucuronidase led to splitting off glucuronic acid from almost 80%. Methylproscillaridin can be regarded as the principal conjugated compound. TLC-separation of CHCl3-soluble compounds from bile showed identical running of radioactivity with methylproscillaridin, proscillaridin and scillarenin and three unknown metabolites P1, P2, and P3. In urine the CHCl3-soluble fraction averaged 16% to 34% of the total amount and was identified as methylproscillaridin, proscillaridin, scillarenin, P2 and P3. The relative composition of the total radioactivity in faeces amounted to 77% methylproscillardidin, 4% scillarenin and 12% polar metabolites.

Aged↗
PubMed1975

Disposition of beta-methyldigoxin in man.

The time course of radioactivity in plasma and the excretion in urine and faeces over 7 days were determined in 12 healthy subjects after single oral and intravenous doses of a solution of 3H-beta-methyldigoxin. 62.2 +/- 2.1 and 29.0 +/- 5.2 per cent of the dose were excreted in urine and faeces, respectively, within 7 days of intravenous administration, compared with 55.2 +/- 2.8 and 28.6 +/- 5.7 per cent after oral administration. This indicates almost complete absorption of the glycoside when given in solution. 12 hours after its administration a pseudo-distribution equilibrium was reached and the average half life of tritiated compounds was 1.3 days. By 48 - 96 hours after treatment the average half life was 2.8 days. O-demethylation was revealed as the main metabolic degradation step in man. The rate of Demethylation was higher after oral than i.v. administration. Thus, only 31% of the radioactivity excreted in the urine consisted of unchanged beta-methyl-digoxin after oral administration compared to 51% after i.v. dosing. Only traces of bis- and monoglycosides were excreted in urine, but there were considerable amounts in faeces, where they accounted for more than 35% of the total excretion. Up to 40% of the radioactivity in plasma and urine consisted of polar conjugates during the first 12 hours after administration of beta-methyldigoxin. The mono- and bisglycosides were identified as the main products of conjugation. During the 7 days approximately 15% of the administered dose was metabolized by splitting off glycosidic bonds and conjugation to polar compounds.

Administration, Oral↗
PubMed1975

Metabolism and excretion of methylproscillaridin by man.

0.5 mg 3H-proscillaridin-4-methylether was administered orally to 5 healthy males. Maximum plasma levels of total radioactivity were reached after one to two hours. In two subjects a second peak was observed between 6 and 12 hours. The plasma half life of total radioactivity was 51 hours. 20% and 56% respectively of the dose were eliminated in urine and faeces during the following 7 days. 55% of the total radioactivity in plasma, 80% in urine and 20% in faeces consisted of CHC13-insoluble compounds. 50-60% of the latter in plasma and urine could be hydrolysed by beta-glucuronidase. More than 90% of the split products were identified as conjugates of methylproscillaridin. TLC-separation of the CHC13-soluble fractions of plasma and urine yielded two unidentified metabolites, P2 and P3, as the main compounds, besides methylproscillaridin, proscillaridin and scillarenin. In faeces more than 90% of the non-polar fraction was identified as methylproscillaridin. Shortly after administration of 3H-methylproscillaridin, the radioactivity in plasma consisted mainly of CHC13-insoluble conjugates and of the metabolite P2.

Adult↗