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5 mg folic acid were administered in two sessions to 9 female and 8 male healthy subjects within a balanced 2-way crossover trial either as one Folsan tablet (CAS 59-30-3, test preparation A) or as 2.5 ml of an injection solution (Folsan 2, reference preparation B). Folic acid was determined in serum and urine collected in fractions over 12 h after administration by means of a radioassay. Before each session a saturation period of 9 days duration was performed by administering 1 tablet per day containing 5 mg folic acid followed by a 4-day wash-out period. The mean predose serum level of folic acid amounted to 17.9 +/- 5.62 ng/ml before the oral and 18.2 +/- 5.73 ng/ml before the intravenous administration. The post dose serum levels were corrected with the individual predose levels. After oral administration of test preparation. A a mean peak serum concentration of 243 +/- 33.0 ng/ml (Cmax) was obtained after 2.24 +/- 0.85 h (tmax). The mean area under the corrected serum level time curve was determined with 1160 +/- 177 ng x h/ml (AUC(0-12)). 6 min after intravenous administration serum levels ranged from 559 to 1490 ng/ml. Following correction with the individual predose levels the mean area under the curve amounted to 1550 +/- 249 ng x h/ml. The individual bioavailability ratios of AUC(0-12) (A versus B) varied between 49.3% and 96.7%. The mean absolute bioavailability of folic acid was 76.2% +/- 13.8% (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and the relative bioavailability of iron and of folic acid was investigated in a randomized, balanced 2-way cross-over study with 14 healthy male participants. The drugs were given in a combined preparation dragée (Ferro-Folsan) containing 100 mg of ferrous-II-sulfate x 1.5 H2O (CAS 13463-43-9) and 0.85 mg of folic acid (CAS 59-30-3). Other established preparations were used as reference drugs. All subjects had a normal iron body level and were brought to a saturated folic acid level prior to the investigation. After administration of 2 dragées of the test medication and determination of serum iron level until 9 h p.a., a relative bioavailability of 64%, compared to an equal dose of a ferrous-II-sulfate-ascorbic acid reference solution, was calculated. From the serum folate AUC (0-9 h) the relative bioavailability was evaluated with 97% for the oral formulation compared to the i.m. administration. The ratio of the cumulative renal folate excretion in the 0-9 h interval amounted to 76% for the oral compared to the i.m. administration. However, in order to understand this differing result it should be kept in mind that during the first hours following parenteral administration a greater amount of the unchanged compound is renally excreted than after oral dosing. This is presumably based upon the different rate of absorption following both administrations with a steeper absorption phase following the parenteral dose.

Bioavailability of Folic Acid Following Intramuscular and Intravenous Administration to Healthy Volunteers 2 mg folic acid (Folsan 2, CAS 59-30-3) were either i.m. or i.v. administered as injection solution to 15 male healthy subjects within an open balanced two-way crossover study. The concentration-time profile of folic acid was determined up to 12 h p.a. in serum and urine using a radioassay. Each change-over phase included a 9 days lasting saturation phase with once-per-day oral administration of a tablet containing 5 mg folic acid. Saturation was performed in order to guarantee filled-up endogenous folate storage compartments in the body of the subjects. After a four-day wash-out phase the subjects were confined and the basic serum level and basic renal 0-12 h folate excretion determined. On the following morning the respective dose of 2 mg folic acid was either i.m. or i.v. applied to the subjects (treatment day 14). 11 (i.m.) and 15 (i.v.) venous blood specimens were drawn up to 12 h p.a. and urine collected following the same schedule as the day before in 4 different fractions. The mean predose level of folic acid in serum was 13.2 +/- 4.85 ng/ml before the i.m. administration and 13.3 +/- 5.59 ng/ml before i.v. administration. The serum concentration data following the respective single administrations were corrected by subtraction of the individual predose values. After 0.50 +/- 0.19 h (mean tmax) the folate serum level increased by 101 +/- 27.2 ng/ml after the i.m. dose. Serum concentration decreased in the following 6-8 h approximately to the predose values.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetic profile of azapropazone (Prolixan), sodium salt of 5-dimethylamino-9,5-dimethylamine-9-methyl-5-propyl-1H-pyrazolol[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione, was established. Six healthy, adult volunteers received a single dose of either 600 mg or 1200 mg azapropazone as sodium salt intravenously. The drug was selectively separated from its metabolites and other plasmatic compounds and it was quantified by measurement of extinction at 254 nm. The kinetic parameters of azapropazone were independent of the applied dose (600 mg and 1200 mg): Biological half-life (t0.5): 16.8 +/- 2.95 h and 17.2 +/- 3.0 h; Total clearance (Cltot): 10.2 +/- 2.1 ml min-1 (both doses); Central volume of distribution (Vc): 3.7 +/- 0.71 and 3.9 +/- 0.91; Apparent volume of distribution (Vd): 12.5 +/- 2.91 and 14.4 +/- 2.41. Initial serum concentrations were 170 +/- 41.5 micrograms ml-1 and 326.3 +/- 84.5 micrograms ml-1, determined by extrapolation (C0 at time t0). The areas under the plasma concentration curves (AUC0 infinity) were calculated to amount 1052.5 +/- 217.4 micrograms ml-1h-1 and 2078.4 +/- 515.9 micrograms ml-1h-1. Three rate constants associated with the elimination of the drug could be calculated.

The kinetics of mofebutazone in the plasma and in the synovial fluid was investigated in a pharmacokinetic study. To this purpose 7 volunteers and 36 patients were injected with one ampule Mofesal (650 mg mofebutazone sodium) i.m. The determination of mofebutazone in the plasma and in the synovial fluid was carried out by means of high performance liquid chromatography. The kinetics in the plasma and in the synovial fluid showed a dissociated course of development. Maximum concentrations of the active substance were reached after 1.4h in the plasma and after approx. 2 h in the synovial fluid. While mofebutazone in the plasma is eliminated with a half life time of 1.9 h, the half life time in the synovial fluid amounted to 7.7 h. According to pharmacokinetic simulation calculations no accumulation in the plasma occurred even after the administration of 1 ampule Mofesal three times daily, on the other hand a steady state is presumably reached in the synovia after 4-5 injections. On the basis of this study we regard it once again as essential that the kinetics in the synovial fluid should without doubt be preferred to the kinetics in the plasma for the calculation of a dosage schedule for non-steroidal antiphlogistics.

The rate and extent of allopurinol absorption was studied following its oral ingestion in a "high frequency capsule" which allows the evaluation of the sites of drug absorption. If allopurinol is liberated in the duodenum or upper jejunum its absorption is fast and complete while its liberation in the lower jejunum results in a slow and incomplete absorption. A capacity limited absorption process for allopurinol, suggested from the results of a study on the allopurinol bioavailability from different formulations, could not be proved in the range of single doses between 200 and 600 mg resp. 2.2 to 12.8 mg/kg. AUC- and Cp-values of allopurinol and oxipurinol correspond to the calculated figures in relation to the different doses/kg.

To further elucidate the distribution and differentiation of mofebutazone in comparison to phenylbutazone, 6 rats received 200 mg/kg 4-14C-mofebutazone corresponding to approx. 27 microCi/animal. 2 animals were sacrificed each time after 45 min, 6 h and 24 h. The 4-14C-plasma level was determined at the corresponding test periods and the radioactivity eliminated within 24 h in the urine was also determined. In addition autoradiograms of the whole animal were prepared for each animal. According to this study 4-14C-mofebutazone is distributed mainly in the metabolisation and elimination organs, a moderate activity was to be found under the skin and muscle tissue, but none, however, in the central nervous system and the bone marrow. Nearly 81% of the substance was eliminated after 24 h and with exception the colon the corresponding autoradiograms were practically free of activity. Because of the short half-life time and the rapid elimination mofebutazone does not lead to any accumulation.

The difference between mofebutazone and phenylbutazone is shown by means of toxicological, pharmacological and pharmacokinetic studies as well as by the protein binding. In spite of a certain chemical similarity both substances differ distinctly. Mofebutazone is approx. 5-6 times less toxic than phenylbutazone but its analgesic and antiphlogistic effects are weaker than those of phenylbutazone. The half life time of mofebutazone of 1.9 h is considerably shorter than that of phenylbutazone (54-99 h). Mofebutazone, in contrast to phenylbutazone, is mainly glucuronidised and to 94% eliminated within 24 h, phenylbutazone on the other hand to only 88% within 21 days. In spite of a high plasma protein binding quota of 99%, mofebutazone is classed among those substances with a medium binding potential. Conclusions may only be drawn with great reservation with regard to a category of substances from the effect and side effects of one substance on the basis of the present studies.

The effects on platelet function of a four-week administration of aspirin at a low dosage (100 mg daily) were compared in two groups, 14 healthy young volunteers and 14 patients with coronary heart disease. In both groups there occurred a clear inhibition of platelet aggregation with collagen (1 and 5 micrograms/l) and arachidonic acid (1 mmol/l) during the aspirin period. The inhibitory effect reached its maximum after three days, remaining at maximum for the remainder of the four weeks. Platelet functions returned to normal within eight days of discontinuing aspirin. The inhibitory effects went together with a definite in-vitro decrease in thromboxane synthesis. In both groups there was no change in aggregation velocity with adenosine diphosphate (ADP) as aggregation-inducing substance, while the frequency of irreversible aggregation decreased with submaximal concentrations of ADP (0.5 and 1.0 mumol/l). The results indicate that low-dose aspirin causes a definite inhibition of platelet function, in a similar manner, in both healthy subjects and patients with coronary heart disease.

20 patients with an average age of 73.3 years suffering from left cardiac insufficiency in stage II to III of the NYHA, who could not be recompensated alone by means of digitalisation, received additionally the diuretic combination furosemide-retard (30 mg)/triamterene (50 mg) for 2 to 3 weeks. Subjective side effects were not observed. The laboratory parameters did not show any substantial changes. A short increase of uric acid and serum creatinine in the older patients returned to normal spontaneously. A decreased potassium level returned to normal; a hyperkaliemia was not observed. The repeated administration of the combination did not lead to any accumulation; only a balanced concentration at a low level appeared. The urine elimination, the decrease in body weight, the regression of the lung congestion and the size of the heart were statistically significant.