Pharmacokinetics and pharmacodynamics of emepronium bromide (Cetiprin) after intravenous administration in man.

Intravenous doses of 1, 5, 10 and 15 mg of emepronium bromide were given to three healthy volunteers. Emepronium serum concentration declined in a triexponential manner with half-lives between 2.2-3.0 min., 1.0-1.6 hours and 5.1-13 hours, respectively. The initial dilution space (volume of the central compartment) varied between 4.1-7.5 l. The area under the serum concentration time curve increased linearly with dose, indicating constancy of total serum clearance (range: 24-38 l/hr) with dose. The renal clearance of emepronium varied with serum concentration; secretion in addition to glomerular filtration was evident. Tubular secretion of emepronium was half-saturated at serum concentrations of approximately 50 nmol/l. No obvious drug-related effect on blood pressure was noted, whereas salivary secretion decreased and heart rate increased with 10-15% at emepronium serum concentrations of about 200 nmol/l. ECG recordings were without abnormalities after slow intravenous injections of emepronium bromide in doses of up to 15 mg. Since no adverse effects were noted, intravenous administration of emepronium bromide may be an alternative in situations where the drug is now used intramuscularly e.g. severe tenesmus in the urinary bladder.

Development of an oral formulation of omeprazole.

Omeprazole has a low water solubility and is chemically labile in an acid environment. In the formulation of an oral dosage form of omeprazole the possibilities of dissolution rate limited absorption and preabsorption degradation must be kept in mind. A water suspension of omeprazole was tested in a pilot bioavailability study. The suspension was given to six healthy, fasting volunteers on two occasions--together with sodium bicarbonate solution and together with the same volume of water. When the suspension was given with water the bioavailability was reduced by about 50% owing to preabsorption degradation. In another bioavailability study the slowest of three granule formulations with differing in vitro dissolution rates showed a reduced extent of absorption. A controlled-release pellet formulation (enteric-coated) was formulated and tested in a series of bioavailability studies. A single dose given with food resulted in a delayed absorption and possibly lower bioavailability than under fasting conditions. When the granules were given on an empty stomach before the morning meal the length of time between dosage and meal was of no importance. Concomitant administration of a liquid antacid had no influence on the bioavailability of omeprazole.

Determination of tranexamic acid (AMCA) and fibrin/fibrinogen degradation products in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage.

Six patients with recently ruptured intracranial aneurysms were treated preoperatively with tranexamic acid (AMCA). Two patients received 6 g daily in i.v. infusion, two had 6 g daily by i.v. injection, and two patients were given AMCA 9 g daily by mouth during the first week after bleeding. Serial assays of AMCA and fibrin/fibrinogen degradation products (FDP) in cerebrospinal fluid (CSF) were performed during 6--13 days after the initial subarachnoid haemorrhage (SAH). Judged from the decline in CSF-FDP, an assumed therapeutic level of greater than or equal to 1 mg/l of AMCA in CSF was reached within 24--36 hours after the first dose when the drug was administered intravenously and within 48 hours when the drug was given orally.

Pharmacokinetics and bioavailability of tranexamic acid.

Tranexamic acid 1 g was given intravenously to three healthy volunteers. Plasma concentrations decayed in three monoexponential phases. Most elimination took place during the first eight hours, giving an apparent elimination half-life of approximately two hours. Plasma clearance ranged between 110-116 ml/min. The urinary recovery of tranexamic acid exceeded 95% of the dose. Ten healthy volunteers were given tranexamic acid 2 g orally on an empty stomach, and together with a meal. Food had no influence on the absorption of tranexamic acid, as judged by comparison of the peak plasma concentration, the time required to reach the peak, the AUC from zero to six hours, and the urinary excretion data. The oral bioavailability of tranexamic acid, calculated from 24 h urinary excretion after oral and intravenous administration, was 34% of the dose.

Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia.

Oral treatment of pernicious anaemia patients with 1 mg cyanocobalamin daily has been shown before to be as effective as conventional injection therapy. The result of this study indicates that oral treatment also keeps the vitamin B12 body stores adequately filled, a confirmation of earlier results obtained in another way.

Comparative bioavailability of oral dosage forms of oxazepam--correlation with in vitro dissolution rate.

Four oxazepam tablet preparations and a suspension of micronized oxazepam in water were given to healthy, fasting volunteers in a comparative bioavailability study using a partial cross-over design. Urinary recovery (0-72 hours) was used as a measure of extent of absorption. Peak serum concentration was used as a measure of rate of absorption. The three dosage forms having the highest dissolution rate in vitro were absorbed to the same extent, while slower dissolving tablets were not as fully absorbed. Peak serum concentration correlated linearly with in vitro dissolution rate. Single oral doses of oxazepam tablets containing 10, 15 and 25 mg showed equal rates and extents of absorption and produced serum concentrations linearly correlated with dose.

Disposition of three benzodiazepines after single oral administration in man.

Three benzodiazepines in equipotent doses: oxazepam 15 mg, dipotassium chlorazepate 10 mg and diazepam 5 mg, were administered in single, oral doses to seven healthy volunteers in a three-way cross-over study. The serum concentrations of oxazepam, N-desmethyldiazepam and diazepam were followed for 72 hours by gas chromatography and electron capture detection. The absorption of diazepam was most rapid and the mean time required to reach peak serum concentration was 45 minutes, followed by N-desmethyldiazepam 80 minutes and oxazepam 114 minutes. The serum concentration decay curves were biphasic with terminal mean half-lives of 48, 62 and 11 hours for diazepam, N-desmethyldiazepam and oxazepam, respectively. The mean and individual serum concentration time data were fitted to a two-compartment open model with first order absorption using a non linear least square program. The mean serum data fitted the model well. The same rank order was obtained with mean absorption half-lives as when comparing mean peak times while slightly shorter terminal half-lives were obtained in the curve fitting of mean serum data. Due to irregularities in the serum concentration time curves only five out of the 21 sets of individual data could satisfy the convergence criterion. The obtained parameters in the curve fitting were also accompanied with very large asymptotic standard deviations.