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.

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).

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.

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)

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.

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.

Explanation of the biologically implausible correlation between distribution volume and total body clearance in an open two-compartment model.

The steady-state distribution volume Vss of digoxin decreases with its total body clearance Cltot, which in turn depends on renal function. It is implausible biologically that renal function should influence tissue distribution. The mathematical reason for this discrepancy is the large volume of the central compartment V1 of of 110 l for digoxin obtained by describing the time course of the serum concentrations by an open two-compartment model. With V1 = 17.5 l, Vss is independent of renal function and the regularly observed decrease of V beta with Cltot is explained by the simplification inherent in the one-compartment model used for calculating V beta. A good correlation between kinetic rate constants and biologic data for the exchange of a drug between central and peripheral compartments can be expected only if the volume of the central compartment is close to that of the inulin space. A low volume of the central compartment can be obtained with a multi-compartment model.

Optimizing the lymphocyte transformation test in whole blood. I. Optimum conditions for thymidine incorporation.

The correlation between mitogen concentration and H3-thymidine incorporation can be described mathematically by a sigmoid dose-response curve. Thymidine incorporation/lymphocyte (Ti/Ly) was calculated to facilitate comparison of results. It was highest at a blood dilution of 1:50, lower at 1:10 or 1:250. Ti/Ly obtained with optimum concentrations of PHA was higher than with ConA. Advantages of this optimized method for whole blood over Ficoll-separated mononuclear cells are the higher Ti/Ly, the smaller quantities of blood required and the lower experimental effort.

Optimizing the lymphocyte transformation test in whole blood. II. Kinetics of thymidine incorporation.

From the 2nd day of incubation on, the thymidine incorporation per incubated lymphocyte increased exponentially with time. The duration of the exponential growth phase was inversely correlated with the number of cells. Under optimum conditions the average time for the doubling of thymidine incorporation (Ti) was 15.7 h. Ti after 1 day of incubation was taken as an equivalent for the number of proliferating cells. It was estimated that less than 20% of the incubated lymphocytes are stimulated by PHA under optimum conditions. In Ficoll-separated mononuclear cells, the percentage of cells stimulated by PHA was lower than in whole blood; the proliferation rate was not decreased.

[Comparison of in vitro methods for the determination of the activity of fosfomycin with the efficacy determined in experimentally infected mice (author's transl)]. / Zur Methodik der Aktivitätsbestimmung von Fostomycin in vitro unter Berücksichtigung der Wirkung an der experimentell infizierten Maus.

Effective doses of fosfomycin against 17 strains of bacteria were determined in therapeutic experiments using infected mice. The peak serum levels obtained after administration of these doses were compared with the minimum inhibitory concentrations determined in vitro. Reasonable minimum inhibitory concentrations were obtained only with Mueller-Hinton agar containing glucose-6-phosphate: 1. Correlation of in vivo and in vitro efficacy is much better in comparison with the use of media without glucose-6-phosphate. 2. Minimum inhibitory concentrations below the levels obtained after therapeutic doses were found only in Mueller-Hinton agar containing glucose-6-phosphate. 3. Minimum inhibitory concentrations are better reproducible when determined on solid media than in broth.