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Biomedical subjects

W Schaumann

Publications and source records attributed to W Schaumann.

At least 19 recordsLinked to original sources
PubMed1992

Receptor kinetics and concentration-effect relation of cardiac glycosides.

Therapeutic and toxic actions of cardiac glycosides are attributed to an inhibition of Na, K-ATPase. The therapeutically relevant range is between 25% and 50% inhibition. There is a good correlation between the average steady state serum concentration of glycosides and their therapeutic action. However, therapeutic and toxic effects set in with a latency and therefore do not follow the daily variations in glycoside concentration. Although the effect follows the average serum concentrations, only the minimal concentration is measured. In principle this is only adequate if the ratio of average/minimal concentration is constant. A model calculation showed that with a constant average steady state concentration an increase in the distribution volume or a decrease in total body clearance with corresponding reduction of the daily dose lead to an increase of the minimal concentrations of 5-7%. This means a corresponding underestimation of the average concentration from the minimum concentration. However, the deviations are too small to be of clinical relevance.

Cardiac Glycosides↗
PubMed1991

Picumast dihydrochloride (Auteral), a new anti-allergic inhibitor of mediator release and action.

Picumast dihydrochloride (PDH), (3,4-dimethyl-7-[4-chlorobenzyl) piperazine-1-yl]propoxycoumarin dihydrochloride) is a prophylactically active anti-allergic compound which combines inhibition of mediator release and action. The activity profile of PDH differs clearly from that of known prophylactic anti-allergic drugs such as DSCG and ketotifen. Other inhibitory actions of PDH in addition to its H1-antagonism (and that of its metabolites M2 and M1) may be the cause of the suppression of immediate and late phase allergic reactions in animals as well as allergic rhinitis and bronchial responsiveness and symptom scores in asthmatic patients.

Anaphylaxis↗
PubMed1989

Digitalis intoxication and treatment with digoxin antibody fragments in renal failure.

Severe digitalis intoxication today is preferentially treated by intravenous infusion of Fab fragments of digoxin antibodies (Digitalis Antidot BM). The kinetics of Fab fragments in the circulation are well known when kidney function is normal or slightly impaired. There are no data available, however, in complete renal failure. We observed a patient with life-threatening digitalis intoxication (serum digoxin, 3.7 ng/ml) and anuria, who was treated successfully by 160 mg Fab fragments i.v. Serum digoxin and Fab fragment concentrations could be followed for 229 h. The extrarenal clearance of Fab fragments was lower (5.6 ml/min) than in patients with normal kidney function (10.9 ml/min). This finding suggests that lower doses than usual might be sufficient for treating patients with severe digitalis intoxication and renal failure.

Acute Kidney Injury↗
PubMed1989

Antiallergic activity of picumast dihydrochloride in several animal species.

Picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) was compared with cromoglycate, ketotifen and mepyramine as an inhibitor of allergic and anaphylactoid reactions. 1. In guinea-pigs, pretreatment with picumast dihydrochloride given intravenously, orally or by inhalation prevented bronchospasm induced by antigen or histamine. The fraction of the bronchospasm remaining after mepyramine pretreatment was further reduced by picumast dihydrochloride. 2. Systemic administration of picumast dihydrochloride inhibited antigen-induced conjunctivitis, whereas mepyramine and ketotifen were inactive. 3. Intravenous and oral pretreatment with picumast dihydrochloride inhibited the antigen-induced mast cell degranulation in rat mesentery. The effective doses of cromoglycate given intravenously were twice as high as those of picumast dihydrochloride. Picumast dihydrochloride did not inhibit antigen-induced bronchoconstriction in rats. 4. The cutaneous reaction induced with Ascaris antigen in atopic monkeys was insensitive to the antihistaminic action of ketotifen, whereas it was inhibited by low doses of picumast dihydrochloride. Both compounds suppressed skin reactions induced by histamine. 5. Picumast dihydrochloride decreased IgE production in atopic high responder mice. It did not prevent autoimmune nephritis in NZB/W mice. 6. In rats, picumast dihydrochloride did not reduce cotton pellet granuloma, nor adjuvant arthritis. The inhibition of carrageenin oedema is presumably due to its anti-oedematous properties rather than to an antiproliferative activity. In conclusion, the inhibition of allergic and anaphylactoid reactions by picumast dihydrochloride can be attributed to a combined inhibition of liberation and action of histamine and other mediators.

Airway Resistance↗
PubMed1989

Metabolism of picumast after administration of picumast dihydrochloride and antiallergic activity of the main metabolites.

The present experiments were carried out to elucidate the chemical structure and the pharmacological activity of the main metabolites of picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ). The metabolic pathways were identical in animals and man, but there were major quantitative differences. The fraction of the radioactivity in the plasma attributable to the parent compound 0.5 to 3 h after oral administration of picumast dihydrochloride was less than 15% in animals but 95% to 57% in man. Inhibition of the C3-zymosan-induced chemilumiescence of human leucocytes was taken as an indicator of the diminished liberation of mediators and inhibition of the histamine-induced contraction of isolated guinea-pig lung strips as an example for the antagonism of picumast dihydrochloride to mediators of allergic reactions. Stepwise oxidation of the 3-methyl substituent of the coumarin ring to the alcohol and the carbonic acid increased the histaminolytic potency, but decreased the inhibition of chemiluminescence. Another metabolite formed by cleavage of the piperazine-containing side chain was inactive in both tests.

Animals↗
PubMed1989

Pharmacokinetics of picumast after administration of 14C-picumast dihydrochloride in dogs, rats, rabbits and monkeys.

In dogs, rats, monkeys and rabbits, picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ) is eliminated from the plasma by metabolic clearance. Its main metabolic pathway is oxidation of the 3-methyl group of the coumarin ring. After oral administration, the parent compound accounted for less than 15% of the concentration of radioactivity in the plasma. In rats the hydroxylation product M2 was the main metabolite in the plasma; in the other species it was the carbonic acid M1. The hydroxylation of picumast was highly saturable, whereas further oxidation was independent of the dose in dogs and only slightly dose-dependent in rats. Picumast, M1 and M2 are pharmacologically active and potentially toxic. The sum of all three was defined as active compounds. The renal clearance of the active compounds, particularly of picumast, was very low. The terminal half-lives of the active compounds varied between 11 h in rats and 26 h in monkeys. The low plasma concentrations of other metabolites are at least partly due to their renal clearance. In dogs the bioavailability of the parent compound was 14%, the absorption of radioactivity 68%. Of radioactivity injected intravenously 54.8% was recovered from the faeces, 21.8% from the urine. The minimum toxic plasma concentrations of the active compounds were calculated from the minimum toxic dose (MTD) found in chronic or reproduction toxicity studies and the ratio Cl/f of total body clearance/bioavailability determined in the present investigations. The results showed that the differences between the MTDs in dogs and rats and on administration in rats by gavage or in the diet are largely due to differences in total body clearance and bioavailability.

Absorption↗
PubMed1989

Pharmacokinetics of isosorbide dinitrate and isosorbide-5-mononitrate.

Short-acting nitrates like glyceryl trinitrate are most suitable for interrupting attacks of angina pectoris, long-acting nitrates for their prophylaxis. A salient feature of drugs used in prophylaxis is a long duration of action. Among many organic nitrates developed for this purpose, ISDN became the most prominent. ISDN is metabolized to isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) which are pharmacologically active. Since denitration is practically the only way of elimination, the denitration rate of the compounds is proportional to their total body clearance, which is 3.2 l/min for ISDN, 0.371 l/min for IS-2-MN and 0.124 l/min for IS-5-MN. Their terminal elimination half-life is 63, 108 and 264 min respectively. These figures are the weighted means from studies with intravenous administration. Several authors determined the AUCs of ISDN and its mononitrates after administration of ISDN. From the AUCs and the respective total body clearances, the amounts of ISDN were calculated which enter the systemic circulation intact, and those of the mononitrates formed by denitration of ISDN. After intravenous administration of ISDN, 62% were metabolized to IS-5-MN, 24% to IS-2-MN. The remaining 14% must be eliminated by other routes. After oral administration as plain tablets, 26% of the ISDN enter the systemic circulation intact. Forty-seven percent of the dose are metabolized to IS-5-MN during absorption, 17% after absorption. The figures for IS-2-MN are 14% and 5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1988

Animal experiments for estimating the radiation exposure of human subjects by radioactive drugs.

The radiation exposure of human subjects is extrapolated from the elimination rate of radioactivity from the plasma and a single determination of the tissue distribution of radioactivity in rats. With an interval of 3-4 half-lives between administration and determination, the radiation exposure of an organ is underestimated only if the elimination rate from the organ is 5.5-12.9 times lower than from the plasma. Determining the elimination rate from the relevant organs is recommendable only if the radiation exposure calculated for the commonly used dose of 100 microCi per volunteer approaches the official yearly limit.

Animals↗
PubMed1987

Pharmacodynamics, pharmacokinetics and metabolism of digitoxin and derivatives in cats.

Derivatives of dihydro-digitoxin (DHD) were studied in the search for a glycoside with a primarily extrarenal clearance and a faster elimination rate than digitoxin. The positive inotropic doses of the derivatives of DHD were higher than those of digitoxin and digoxin. There was no significant difference in the therapeutic margin. After injection of 3H-digoxin in unaesthetized cats, no metabolites were found in the serum which did not bind with the antibody used for the RIA. After injection of 3H-digitoxin and its derivatives, the radioactivity was cleared from the serum at a much lower rate than the concentrations assayed by RIA. The metabolites which did not bind to the digitoxin antibody were hydrophilic and had a low protein binding. Digitoxin-bisdigitoxoside (Dt-2) determined by RIA rapidly disappeared from the serum. The radioactivity remaining after 24 h was eliminated with a half-life of 219 h. Ten min after injection of DHD the serum contained no unchanged DHD, but 36% digitoxin suggesting that the reduction of digitoxin to DHD is reversible and that the conversion of DHD to Dt-2 is the rate limiting step in the metabolism of digitoxin. The total body clearance of digitoxin, its metabolites and derivatives determined by RIA increased in the order DHD-oxime less than or equal to digitoxin less than DHD less than or equal to DHD-acetyloxime less than DHD-methyloxime. The clearance and the elimination rate of DHD-methyloxime were significantly higher than those of digitoxin (P = 0.05).

Animals↗
PubMed1986

Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication.

17 patients with severe digoxin intoxication were successfully treated with 320 to 480 mg Fab fragments of digoxin-specific IgG from sheep. The infusion period ranged between 0.5 and 7 h. Serum and urine concentrations of digoxin bound to Fab fragments, and in 11 cases unbound Fab fragments in serum, were determined during and after the infusion. The renal clearance of bound digoxin and therefore of the antibody was 13.6 ml/min. The median extrarenal clearance of the Fab fragments was 10.9 ml/min. The half-life of the serum concentrations starting at 12 h was 14.3 h, and the value was increased to 25.4 h when regression began at 24 h; the corresponding apparent distribution volumes were 25.9 and 541. These figures exceed the volume of the extracellular space and suggest intracellular penetration of the Fab fragments. The dosage of the antibody should be sufficiently high to bind digoxin in the most severe cases of poisoning. The maximum serum concentrations of bound antibody were 30 mg/l after 3 h and 20 mg/l after 5 h. A loading dose of 160 mg followed by an infusion of 0.5 mg/min was sufficient to absorb digoxin re-diffusing into the serum during the first 8 h. In some cases free digoxin reappeared in the serum 8-12 h after beginning the treatment. This might be prevented by infusing a further ampoule at a rate of 0.1 mg/min or less.

Adolescent↗
PubMed1985

Increase in the cardiotonic action and in the therapeutic margin of digoxin by the adrenergic beta-stimulant doxaminol in cats.

The interaction between digoxin and the beta-sympathomimetic drug doxaminol was investigated in cats with acute heart failure induced by pentobarbital sodium. Doxaminol, 50 micrograms/kg X min, infused for 60 min caused a dose-dependent rise in dp/dtmax with little increase in heart rate. The maximum increase of 4.3 mHg/s was obtained after about 37 min. Digoxin, 10 micrograms/kg X min, and the combination of both drugs were infused until cardiac arrest. The maximum increase of dp/dtmax was observed after 29 min in both experiments; it was 5.7 mHg/s with digoxin alone and 7.3 mHg/s with the combination (p = 0.025). The combined infusion of epinephrine (0.3 micrograms/kg X min) plus digoxin (10 micrograms/kg X min) caused a maximal increase of dp/dtmax by 7.9 mHg/s. The cardiotoxic dose of digoxin was markedly reduced by epinephrine, not by doxaminol. The relevance of this difference to man cannot be assessed definitely because the ECG changes produced by digoxin in cats are different from those seen in man.

Animals↗
PubMed1977

Serum glycoside concentrations after single or repeated intravenous doses of beta-methyl-digoxin and digoxin.

The aim of the present investigation was to estimate the ratio of the intravenous doses of beta-methyl-digoxin and digoxin required to produce identical serum glycoside concentrations in man. 20 patients on intravenous maintenance therapy were changed from beta-methyl-digoxin to the identical dose of digoxin or vice versa. Each drug was given for 7 days. Serum concentrations 13% higher were found during administraton of beta-methyl-digoxin. Assuming a half life of 60 h after withdrawal, the dose of digoxin producing the same minimum serum concentration was estimated to be 1.16 times higher than that of beta-methyl-digoxin. 18 healthy volunteers received 0.4 mg beta-methyl- digoxin, and 23 the same dose of digoxin, as an intravenous infusion over 2 h. The serum concentrations and urinary glycoside excretion were measured over a period of 32 hrs. During the first hour after the infusion the serum concentration of digoxin declined more rapidly than that of beeta-methyl-digoxin. Thereafter, the ratio of the serum concentrtions did not change appreciably up to the end of the investigation. The area under the serum concentration/time curve was about 13% greater for beta-methyl-digoxin than for digoxin; this difference was not significant. The average renal clearance was 96 +- 9 ml for beta-methyl-digoxin, 151 +- 13 ml for digoxin. Since the total body clearance of digoxin is only about 1.16 times higher than that of beta-methyl-digoxin, the lower renal clearance of beta-methyl-digoxin must partly be compensated by higher extrarenal clearance. From the ratios of the areas under the serum concentration/time curves after single doses of beta-methyl-digoxin and digoxin, and the minimum serum concentrations during maintenance therapy, it was concluded that the dose of digoxin to produce the same average serum concentrations would be about 1.15 times higher than that of beta-methyl-dogoxin. In comparison wtih the large variations in individual dosage of digoxin and beta-methyl-digoxin, this difference is too small to be of practical importance.

Aged↗
PubMed1976

Absorption of beta-methyl-digoxin determined after a single dose and under steady state conditions.

Single doses of beta-methyl-digoxin 0.4 mg were given to groups of 17-18 healthy volunteers as an intravenous infusion lasting 2 hours, or orally as Lanitop Liquidum or Lanitop tablets. The serum glycoside concentration and urinary glycoside excretion were measured over 8 and 32 h. The absolute bioavailability from the oral preparations in comparison with the infusion was lower for the first 8 h than for the entire 32 h of the investigation; the relative bioavailability from tablets was the same as from the solution for both periods. For both periods the area under the serum concentration/time curve and the urinary glycoside excretion were significantly lower after administration of the tablets than after intravenous infusion. Taking the average of both parameters, the absolute bioavailability of beta-methyl-digoxin was about 80% from the solution and about 70% from the tablets. In 18 patients undergoing intravenous or oral therapy with beta-methyl-digoxin steady state glycoside concentration were compared in a cross-over study of intravenous maintenance therapy with Lanitop ampoules or oral treatment with Lanitop tablets. For a standard daily dose of 0.2 mg beta-methyl-digoxin the serum concentrations were 1.35 +/- 0.10 ng/ml during both intravenous and oral administration. The intra-individual variation in glycoside concentration after changing from intravenous to oral maintenance therapy, or vice versa, was about the same as during continued intravenous or oral administration. It is concluded that the rate of rise of serum concentration after a single dose may be a useful indicator of the rate of absorption, but that the area under the serum concentration/time curve and the urinary glycoside excretion up to 32 h are unsuitable for determining equivalent doses of different formulations or routes of administration of digitalis glycosides.

Administration, Oral↗