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.
Bioavailability of acetylated derivatives of digoxin tablets have been studied in healthy subjects after a single oral and intravenous dose as well as during maintenance therapy. alpha-acetyldigoxin shows a lower bioavailability than beta-acetyldigoxin even if the alpha-acetylated derivative is incorporated in a matrix of aerosil (SiO2). Moreover, beta-acetyldigoxin can be transferred to alpha-acetyldigoxin in alkaline solutions. This isomerisation leads to a decrease of the bioavailability of such fixed preparations which contain beta-acetyldigoxin and the hygroscopic salts of potassium-magnesium-aspartate. A prevention of the isomerisation is attained by isolating beta-acetyldigoxin from potassium-magnesium-aspartate. The bioavailability of a such new formulation is comparable to that of beta-acetyldigoxin alone. The experiments show the bioavailability of acetylated derivatives of digoxin to be influenced by the physico-chemical properties of a drug and its preparation.
The PARAGON Investigators* Background-Unstable angina and non-Q-wave myocardial infarction involve coronary arterial plaque rupture, platelet activation, and thrombus formation. This study tested the benefit of different doses of lamifiban (a platelet IIb/IIIa antagonist) alone and in combination with heparin in patients with these conditions to select the most promising lamifiban regimen for subsequent evaluation. Methods and Results-At 273 hospitals in 20 countries, 2282 patients were randomly assigned to lamifiban (2ϫ2 factorial design: low-dose [1 g/min] with and without heparin versus high-dose [5 g/min] with and without heparin) or to standard therapy (placebo and heparin). All patients received aspirin. The composite primary end point of death or nonfatal myocardial infarction at 30 days occurred in 11.7% of those receiving standard therapy, 10.6% receiving low-dose lamifiban, and 12.0% receiving high-dose lamifiban (Pϭ0.668). By 6 months, this composite was lowest for those assigned to low-dose lamifiban (Pϭ0.027) and intermediate for those assigned to high-dose lamifiban (Pϭ0.450) compared with control (13.7%, 16.4%, and 17.9%, respectively). Compared with control, the combination of high-dose lamifiban and heparin resulted in more intermediate or major bleeding (12.1% versus 5.5%; Pϭ0.002) and a similar rate of ischemic events. Conversely, low-dose lamifiban and heparin yielded similar bleeding rates as in the control group but fewer ischemic events at 6 months (12.6% versus 17.9%; Pϭ0.025). Conclusions-In unstable angina and non-Q-wave infarction, platelet IIb/IIIa antagonism with lamifiban reduces adverse ischemic events at 6 months beyond that of aspirin and heparin therapy. The role of conjunctive heparin remains uncertain but appears more favorable with low-dose IIb/IIIa antagonism. Larger-scale study is needed to more reliably estimate these effects. (Circulation. 1998;97:2386-2395.)
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