Absolute bioavailability of carbamazepine after oral administration of a 2% syrup.

Two healthy male volunteers received 10 mg carbamazepine (CBZ) as a 2-h constant-rate intravenous (i.v.) infusion and 100 mg 15N-labeled CBZ as a 2% oral suspension, concomitantly. The two compounds have identical pharmacokinetics. Their respective concentrations in plasma were determined by gas chromatography-mass spectrometry (GC-MS) for 168 h. The comparison of the areas under the plasma curves (AUC) obtained by the two routes of administration, showed the systemic availability of CBZ given as an oral suspension to be equal to its availability when given intravenously. A two-compartment model was estimated: The apparent volume of distribution of CBZ at the steady-state (Vss) was approximately 1 L/kg.

[The percutaneous absorption of diclofenac]. / Die perkutane Resorption von Diclofenac.

The percutaneous absorption of diclofenac diethylammonium 1.16% (w/w) in a combination of emulsion cream and gel (Voltaren Emulgel) and of diclofenac sodium 1% (w/w) in a cream formulation (Voltaren cream) was investigated in guinea-pig, rabbit and man. The percutaneous absorption of diclofenac sodium in guinea-pig was 3 to 6% of the dose when the cream formulation in doses of 320, 100 or 40 mg was applied on 10 cm2 of occluded skin and left in place for 6 h. The transdermal delivery of 14C-labelled diclofenac yielded plateau plasma concentrations of radiotracer from 1.5 h after application until removal of the residual cream. Subsequently the steady state drug depots in the skin and muscle tissue were depleted promptly. During daily administration the steady state levels in the muscle tissue in proximity to the application site were about 3 times higher than in distant muscle tissue. By topical application on knee joints of rabbits diclofenac penetrated into the patellar ligament, the adipose corpus and the synovial fluid. In man the percutaneous absorption was 6% of the dose when the Emulgel formulation was spread by 5 mg/cm2 and left for 12 h on non-occluded skin. The pattern of metabolites of diclofenac in human urine was the same after topical and oral administration. In man, upon daily topical administration of 3 times 2.5 g cream formulation (10 mg/cm2) the diclofenac steady state plasma levels were 20 to 40 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycerol trinitrate (nitroglycerin) plasma concentrations achieved after application of transdermal therapeutic systems to healthy volunteers.

Glycerol trinitrate (nitroglycerin, in the following briefly called GTN) plasma concentrations achieved upon application of a commercial scale produced transdermal therapeutic system containing GTN (TTS-GTN, Nitroderm-TTS) were compared to those induced by 2 TTS-GTN prototypes previously used for clinical trials. Each system was applied to the chest, lateral aspect, of 14 healthy volunteers for 24 h, in a 3-period change-over study. GTN in plasma was determined by gas chromatography-mass spectrometry. The 3 systems released the drug continuously over 24 h. The mean plasma concentrations for all subjects and all sampling times (nmol/l) +/- SE were 0.92 +/- 0.18, 0.80 +/- 0.12 and 0.97 +/- 0.18 for the commercial scale TTS and the 2 other systems, respectively. No significant differences were demonstrated. The mean delivery rate of GTN calculated from the initial and residual contents of the TTS was 6.8 micrograms/min as a mean for the 3 systems. In another study, three different application sites were compared (chest, upper arm and pelvis). The results did not demonstrate significantly different GTN plasma levels. A comparison with published data after intravenous infusion showed a good availability of GTN administered transdermally by means of TTS. Its magnitude seems comparable to that of the intravenous route.

Pre-dosing plasma concentrations and beta-adrenoceptor blocking effects during repeated once daily dosing with 160 mg sustained-release propranolol (Inderal LA) and 16/260 oxprenolol Oros to healthy volunteers.

Plasma drug concentrations and attenuations in sub-maximal exercise tachycardia were measured in six healthy subjects 24 h after the third and fourth doses of Inderal LA and 16/260 oxprenolol Oros administered once daily. Both drugs significantly reduced exercise heart rates relative to the placebo response, at both observation times. The mean percentage reductions on the third and fourth days were, respectively, 15.7 and 11.6% for Inderal LA compared with 18.1 and 12.2% for 16/260 oxprenolol Oros. The differences between formulations were not statistically significant. The mean plasma concentrations at 24 h on the third and fourth day were 119 and 101 ng/g for oxprenolol and 16.2 and 15.8 ng/g for propranolol.

Concentration-effect relationship of oxprenolol in healthy volunteers: a retrospective analysis.

A mathematical model describing the relationship between plasma concentrations of oxprenolol and submaximal-exercise heart rates has been developed on the basis of data available from 34 healthy volunteers. This relationship, which is exponential in type, is consistent with the 'law of diminishing returns', and is independent of the pharmaceutical formulations used; it appears to be established instantaneously, and is not modified by repeated drug administration over 8 days. At oxprenolol concentrations of 190-250 ng/ml, between half and three-quarters of the subjects investigated reached 90% of their estimated maximum levels of beta-adrenoceptor blockade.

Gastrointestinal transit of Oros drug delivery systems in healthy volunteers: a short report.

Transit times for oxprenolol and metoprolol Oros drug delivery systems through the gastrointestinal tract have been measured in 35 individuals in six separate studies. A total of 45 systems were recovered in a median time of 27.4 h; individual transit times varied from 5.1 to 58.3 h. The residual amount of drug in recovered systems was inversely related to transit time and corresponded closely with the amount estimated from in vitro dissolution profiles.

Osmotically controlled-delivery of metoprolol in man: in vivo performance of Oros systems with different durations of drug release.

In vivo absorption from 19/190 and 19/285 metoprolol Oros drug delivery systems has been assessed by measuring plasma drug concentrations after single administration of the systems to six healthy volunteers. The initial in vitro release rate for both Oros preparations was 19 mg/h but they contained 190 or 285 mg of metoprolol fumarate. The plasma concentration-time profiles for both Oros dosage forms were consistent with an extended duration of release and absorption from the gastrointestinal tract. Analysis of the plasma level data indicated that the rate and duration of in vivo absorption closely mirrored the in vitro release behaviour of the 19/190 and 19/285 systems, but the in vivo profiles showed a 1-2 h initial delay. The administration of the 19/190 system on two occasions to the same six volunteers indicated that in vivo release of drug from this Oros preparation was reproducible.

New metabolites of sulfinpyrazone in man.

The disposition and metabolism of sulfinpyrazone have been studied after oral administration of 100 mg 14C-labelled drug to two male volunteers. The results confirmed earlier observations on the kinetics and biotransformation of the drug in man. Additionally, four new metabolites were identified and quantified, i.e., the sulfide analogue G 25 671 of sulfinpyrazone (Anturano), the p-hydroxy-sulfide G 33 378, the p-hydroxy-sulfone CGP 17 385 and the C(4)-glucuronide of the sulfide. In plasma, the area under the concentration-time curve (0--24 h) of sulfinpyrazone was, on an average, 61.7% of that of total 14C-substances. The AUC-value for the sulfide and the sulfone corresponded to 13.4 and 6.0%, respectively. The other, specifically measured plasma metabolites (p-hydroxy-sulfin-pyrazone, p-hydroxy-sulfide, p-hydroxy-sulfone and 4-hydroxy-sulfinpyrazone) accounted for only 1.6% or less of total AUC. Almost no sulfide was excreted in the urine. The compound was transformed to its C(4)-glucuronide, a reaction common to drugs of the dioxo-pyrazolidine series. The appearance of the sulfide in plasma may be clinically important, since this metabolite shows a strong inhibitory effect on platelet aggregation in various in vitro experimental systems.

Percutaneous absorption of chlorquinaldol (Sterosan).

The percutaneous absorption of chlorquinaldol from three different preparations for skin treatment (Sterosan-hydrocortison ointment and cream, Sterosan ointment) was evaluated by measuring the cumulative urinary excretion of chlorquinaldol and was compared to that found after an equivalent oral dose. In the blood the concentrations were below the detection limit of the analytical procedure, i.e., smaller than 0.02 microgram/ml. The study was carried out in 3 healthy volunteers using a four-period change-over design. The topical preparations were applied under occlusive dressings. Following epicutaneous application of the three topicals in quantities containing 30 mg chlorquinaldol each, the mean urinary excretion of the drug amounted to 11.1 +/- 6.6, 19.5 +/- 3.5 and 13.0 +/- 2.5% of the applied dose. When the same dose of chlorquinaldol was administered orally, 67.6 +/- 9.5% of the dose was excreted in the urine. Taking the urinary elimination as the minimal amount of drug absorbed, the extent of percutaneous absorption from the three dermatological preparations varied between 4.2 and 23.5% of the applied dose. There was no difference in the pattern of urinary excretion products among the three topicals and the oral formulation. The bulk of chlorquinaldol (mean 98.0 +/- 0.1%) was excreted as sulfate (mean 1.3 +/- 0.3%) or unchanged drug (mean 0.8 +/- 0.1%).

Percutaneous absorption of clioquinol (Vioform).

The percutaneous absorption of clioquinol from three different preparations for skin treatment (Vioform cream, Locacorten-Vioform cream and Vioform-Hydrocortisone cream) was evaluated. After topical dosages corresponding to 30 mg clioquinol, concentrations in the blood were below the detection limit of the analytical procedure, i.e., smaller than 0.02 micrograms/ml; therefore the percutaneous absorption was evaluated by measuring cumulative urinary excretion of clioquinol and was compared to that found after an equivalent oral dose. The study was carried out in 4 healthy volunteers. The topical preparations were applied under occlusive dressings. Following epicutaneous application of the three topicals in quantities containing 30 mg clioquinol each, the urinary excretion of the drug was between 1.2 and 3.6% of the applied dose. When the same dose of clioquinol was administered orally to two volunteers, 52.4 and 92.9% of the dose was excreted in the urine. Taking the urinary elimination as the minimal amount of drug absorbed, the extent of percutaneous absorption from the three dermatological preparations amounted to 1.2-3.6% of the applied dose. There was no difference in the pattern of urinary excretion products among the three topicals and the oral formulation. The bulk of clioquinol was excreted as glucuronide (mean: 96 +/- 3%) and only a small fraction was excreted as sulfate (mean: 3.8 +/- 3%). A small amount of free clioquinol (1.1%) was measured in 1 subject only after the oral dose.

[Systolic prolapse ("ballooning") of the mitral valves with secondary atrial septal defect: a still not much known combination]. / Systolischer Prolaps ("Ballooning") der Mitralklappen mit Vorhofseptumdefekt vom Sekundum-TYP: Eine noch wenig bekannate Kombination

Two case with the combination of a ballooning mitral valve and a secundum type ASD are described. The possibility of correct identification of the two anomalies by using relatively simple noninvasive methods is emphasized. Furthermore, a short review of the etiology of the clinical "mid systolic click/late systolic murmur" syndrome is given and the evidence for and against the existence of a true congenital combination of the two abovementioned defects is discussed.

[Clinical aspects and hemodynamics of idiopathic dilatation of pulmonary artery]. / Klinik und Hämodynamik der idiopathischen Dilatation der Arteria pulmonalis

1. The following clinical findings were seen with increased frequency in patients with idiopathic pulmonary artery dilatation: pulmonary ejection click, systolic ejection murmur in the pulmonic area and abnormally wide splitting of second heart sound. 2. Hemodynamically these patients present often a pressure gradient on the pulmonic valve of minor degree and a slightly elevated cardiac index. A congenitally increased elasticity of the tissue of the common pulmonary artery has to be considered as the possible etiology of this lesion. 3. The diagnosis of idiopathic dilatation of the pulmonary artery can be established by non invasive methods, excluding pulmonary valvular stenosis, pulmonary hypertension and left-to-right shunts.