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Biomedical subjects

E Besenfelder

Publications and source records attributed to E Besenfelder.

At least 19 recordsLinked to original sources
PubMed1991

High performance liquid chromatographic determination of Picumast and two active metabolites in plasma using on-line sample preparation.

A method for determining Picumast, an antiallergic drug, in plasma by HPLC and column switching has been developed. The system consisted of two precolumns, an analytical column, three pumps, an autosampler and a fluorescence detector. The precolumns (17 x 4.6 mm i.d.) were packed with LiChroprep RPR (a moderately polar reversed phase) and the analytical column with Nucleosil ODS (RP 18, 5 microns). The columns were connected according to the alternating precolumn technique. The mobile phase consisted of 30% CH3CN/70% 0.05 M KH2PO4, pH 2.5, with a flow gradient. Detection wavelengths were 333 nm for excitation and 383 nm for emission. The retention times of Picumast, M1 and M2 were 12, 3.6 and 4.0 min, respectively. Total run time was 15 min. The limit of detection was 3 ng/mL for M1 and 1 ng/mL for M2 and Picumast using an injection volume of 150 microL. The recoveries vary between 89% and 97% with standard deviations between 2.4 and 3.3%.

Chromatography, High Pressure Liquid↗
PubMed1990

Solid-phase extraction and liquid chromatography of torsemide and metabolites from plasma and urine.

Torsemide is a new diuretic drug with a profile of action similar to that of furosemide. The high potency of torsemide results in low dose therapy and causes problems for the pharmacokinetic study of the drug due to low plasma levels. Described here are methods for the analysis of torsemide and two metabolites in plasma and urine using solid-phase extraction and liquid chromatography. The limits of quantitation are 10 ng/mL for plasma and 20 ng/mL for urine. The relative standard deviations for precision are less than 10% for most analytes at most concentrations in the calibration range. The recoveries from plasma were 94.3, 92.9, and 95.6%, and from urine were 77.5, 66.6, and 76.5% for torsemide and metabolites M1 and M5, respectively. The method was suitable for pharmacokinetic studies. Data from a normal volunteer are presented.

Chromatography, Liquid↗
PubMed1989

Metabolism of picumast after administration of picumast dihydrochloride and antiallergic activity of the main metabolites.

The present experiments were carried out to elucidate the chemical structure and the pharmacological activity of the main metabolites of picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ). The metabolic pathways were identical in animals and man, but there were major quantitative differences. The fraction of the radioactivity in the plasma attributable to the parent compound 0.5 to 3 h after oral administration of picumast dihydrochloride was less than 15% in animals but 95% to 57% in man. Inhibition of the C3-zymosan-induced chemilumiescence of human leucocytes was taken as an indicator of the diminished liberation of mediators and inhibition of the histamine-induced contraction of isolated guinea-pig lung strips as an example for the antagonism of picumast dihydrochloride to mediators of allergic reactions. Stepwise oxidation of the 3-methyl substituent of the coumarin ring to the alcohol and the carbonic acid increased the histaminolytic potency, but decreased the inhibition of chemiluminescence. Another metabolite formed by cleavage of the piperazine-containing side chain was inactive in both tests.

Animals↗
PubMed1989

Pharmacokinetics of picumast after administration of 14C-picumast dihydrochloride in dogs, rats, rabbits and monkeys.

In dogs, rats, monkeys and rabbits, picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ) is eliminated from the plasma by metabolic clearance. Its main metabolic pathway is oxidation of the 3-methyl group of the coumarin ring. After oral administration, the parent compound accounted for less than 15% of the concentration of radioactivity in the plasma. In rats the hydroxylation product M2 was the main metabolite in the plasma; in the other species it was the carbonic acid M1. The hydroxylation of picumast was highly saturable, whereas further oxidation was independent of the dose in dogs and only slightly dose-dependent in rats. Picumast, M1 and M2 are pharmacologically active and potentially toxic. The sum of all three was defined as active compounds. The renal clearance of the active compounds, particularly of picumast, was very low. The terminal half-lives of the active compounds varied between 11 h in rats and 26 h in monkeys. The low plasma concentrations of other metabolites are at least partly due to their renal clearance. In dogs the bioavailability of the parent compound was 14%, the absorption of radioactivity 68%. Of radioactivity injected intravenously 54.8% was recovered from the faeces, 21.8% from the urine. The minimum toxic plasma concentrations of the active compounds were calculated from the minimum toxic dose (MTD) found in chronic or reproduction toxicity studies and the ratio Cl/f of total body clearance/bioavailability determined in the present investigations. The results showed that the differences between the MTDs in dogs and rats and on administration in rats by gavage or in the diet are largely due to differences in total body clearance and bioavailability.

Absorption↗
PubMed1989

Pharmacokinetics of picumast dihydrochloride and its active metabolites M1 and M2 in humans.

The pharmacokinetics of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and the pharmacodynamically active metabolites M1 and M2 as well as the absolute bioavailability of picumast dihydrochloride have been studied in healthy volunteers after oral administration of the drug in doses which were considerably higher than therapeutically used. After intravenous administration of 10 mg picumast dihydrochloride a peak concentration of 182 ng/ml was achieved at the end of the 1 h infusion. Picumast dihydrochloride was extensively distributed to the tissues (Vz = 130 l) and almost exclusively eliminated by hepatic metabolism (total clearance 95 ml/min, amount of unchanged compound excreted in urine below detection limit). Median elimination half-life was 16.5 h. The absolute bioavailability reached 57%. The relative bioavailability of picumast dihydrochloride was 20% higher after a meal. After a 20 mg oral dose maximum concentrations between 129 and 284 ng/ml were achieved within 1.3 h. The elimination half-life ranged from 10-26 h. No difference existed between oral (14.5 h) and intravenous administration. The metabolites M1 and M2 in human plasma peaked at 3.4 and 4 h. With 41 h (M1) and 34 h (M2) they exhibited longer half-lives than the parent compound. So under steady state conditions the average plasma concentration of these metabolites amounted to about 68% and 40%, resp., of the unchanged drug as calculated by the ratio of the total areas. The total amount of metabolites M1 and M2 recovered in urine was 6.88% of the oral dose administered, i.e. 6.8% M1 and 0.08% M2. The renal clearance was determined as 28 and 0.5 ml/min for M1 and M2, resp.

Administration, Oral↗
PubMed1989

Study of potential kinetic interactions of picumast dihydrochloride and theophylline in vitro and after oral administration in man.

The kinetic interaction of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and theophylline has been studied in vitro (displacement from protein binding) and in vivo in healthy male non-smokers after oral administration. In a randomized, three-way cross-over study, 12 subjects received at weekly intervals either separated or combined single doses of picumast dihydrochloride (10 mg) and theophylline (7 mg/kg b.w.) Picumast and its metabolites were analysed in plasma and urine up to 24 h and theophylline was assayed in plasma during the same time. Theophylline pharmacokinetic parameters like time to peak concentration, peak concentration, elimination half-life, area under the plasma concentration-time curve and oral clearance were not changed after a concomitant dose of picumast dihydrochloride. The combination of theophylline and picumast dihydrochloride revealed no significant changes in the picumast pharmacokinetic parameters t1/2, tmax and CLR. However, Cmax and AUC0-24 decreased significantly by 11% and 7%, resp. Additional theophylline administration significantly increased peak concentration of the intermediate active metabolite M2 by 23% from 7 to 8.6 ng/ml. The absorptive parameters, i.e. time to peak and peak concentration of M1 as well as the AUC calculated from 0-24 h and the renal clearance did not differ in single or combined picumast dihydrochloride administration. A supplementary in vitro study showed no change in plasma protein binding of picumast (100 ng/ml) in the presence of theophylline (20 micrograms/ml) and vice versa. In all volunteers picumast dihydrochloride proved to be safe and well tolerated and treatment was not negatively influenced by theophylline co-administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Pharmacokinetics of picumast dihydrochloride in patients with liver cirrhosis.

In a randomized parallel group design the pharmacokinetics of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarine++ + dihydrochloride) and its active metabolites M1 and M2 were studied after intravenous or oral administration of a single dose of 10 mg picumast dihydrochloride in two groups of 8 patients with liver cirrhosis. After intravenous administration, the terminal half-life of 65 h was about 4 times longer than in healthy subjects although the total body clearance of 87 ml/min was only 7.4% lower. The 3.6-fold increase in the steady-state volume of distribution (351 l) may be due to a higher uptake by the liver and other tissues and/or to a slower re-diffusion from these tissues into the circulation. Only negligible amounts of picumast dihydrochloride appeared in the urine. Picumast dihydrochloride is almost exclusively eliminated by hepatic metabolism. After oral administration peak concentrations were reached at 1.4 h; plasma elimination half-life was considerably longer (107 h), however, without being significantly different from i.v. administration. The two patient groups differed with respect to their drug metabolizing capacity, therefore the absolute biovailability could not be established. The maximum concentration of the metabolites was reached 1.4 to 3.4 h later than Cmax of the parent drug. As compared to healthy subjects the clearance of the metabolites appeared to the reduced to a greater extent than that of the parent compound, so that under steady-state conditions in patients with liver disease these active metabolites will contribute more to the overall therapeutic effect than in normal individuals. 10.4% to 12.8% of the dose were recovered from the urine als M1.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

Pharmacokinetics and metabolism of torasemide in man.

Torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3- sulfonyl)urea) is a potent new loop diuretic. The pharmacokinetics, absolute bioavailability and metabolic disposition of torasemide have been studied after administration of a standard-release tablet to healthy volunteers. According to a latin square design 9 subjects received in random order single doses of either 20 mg i.v. over 1 h or 20 or 40 mg p.o. On each of the three occasions, torasemide and its metabolites were analysed in plasma and urine up to 24 h. From the results of urinary excretion and plasma AUC, the availability of torasemide from the tablet was 80% to 90%, i.e. nearly complete. The kinetics were linear with dose. The time of peak was reached at 1 h, the elimination half-life varied from 3 h to 4 h. None of the metabolites M1, M3 or M5 found in plasma exhibited a longer half-life. Only a quarter of the low systemic clearance of torasemide (41 ml/min) was accounted for by renal clearance. The distribution volume of 15.5 l was in the order of the extracellular fluid volume. The total amount of torasemide and metabolites recovered in urine was 83%, i.e. 25% torasemide, 11% M1, 3% M3 (both active), and 44% M5 (inactive). Therefore, M1 and M3 probably contribute to the diuretic action of torasemide. Since the renal clearances of the metabolites exceeded that of the parent drug, renal impairment may change their elimination kinetics.

Adult↗
PubMed1987

Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats.

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a cytotoxic thioether phospholipid analogue that recently has entered phase I trials in cancer patients. The objective of this study was to evaluate the pharmacokinetics of this compound in female rats after administration of a single oral dose (15 mg/kg body weight [bw] ). Furthermore, BM 41.440 serum concentrations were determined under a daily oral treatment of up to 13 weeks. Blood samples were obtained via permanent catheters from the femoral arteries before and after drug administration for a total of 120 hr. Urine was collected in 24 hr-intervals for 120 hr; the volume was measured, and aliquots were stored at -20 C until analytical determination of the thioether derivative. BM 41.440 was assayed in serum and urine by means of a specific, newly developed reverse-phase high pressure liquid chromatography technique. Mean maximum serum concentrations (1.7 micrograms/ml, n = 4 animals) were attained after seven hr. A terminal half-life of ca. 27 hr was calculated from the rate constant for the terminal elimination phase (lambda z approximately 0.026/hr). The mean serum BM 41.440 concentration-time-area-under-the-curve was 52.9 mg X hr/l. The ratio of total body clearance to absorption fraction was 4.7 ml/min X kg bw. Only a small amount of the drug was found in the urine. The quantity excreted in the urine during a 24 hr-interval never exceeded 1.5% of the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

The determination of torasemide and metabolites in plasma by high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of torasemide and two active metabolites is described. The assay uses a reversed-phase gradient system and UV-detection. Sample preparation includes deproteinisation and liquid-solid extraction incorporating an internal standard. Data on recovery, detection limits, precision and accuracy are presented. The presence of an unidentified metabolite also is reported.

Journal Article↗
PubMed1982

Quinidine-digoxin interaction: evidence for involvement of an extrarenal mechanism.

The influence of quinidine 750mg per day for one week on serum digoxin concentration (SDC) was evaluated in digitalized anuric patients on chronic haemodialysis. During quinidine administration the SDC increased markedly, from 0.84 +/- 0.37 to 1.58 +/- 0.72 ng/ml (p less than 0.01), a comparable effect ot that reported previously in patients with normal renal function. Neither in vitro nor in vivo did quinidine alter the serum protein binding of digoxin. The increase in SDC in anuric patients indicates a decrease in the extrarenal clearance of digoxin, which means that mechanisms other than of renal origin are also involved in the interaction of quinidine and digoxin. There was great interindividual variability in the extent of the quinidine-induced rise in SDC. Regardless of the state of renal function, careful monitoring of digitalized patients seems mandatory once quinidine treatment is initiated.

Anuria↗
PubMed1981

[Investigation of the viability of radioactively labelled bacteria after adsorption on activated charcoal (author's transl)].

A method for radioactive labelling of bacteria is described. [35S]-L-methionine labelled Staphylococcus aureus and Escherichia coli used as model microorganisms were adsorbed onto the surface of acrylhydrogel coated charcoal. On the average 33% of S. aureus and 10% of E. coli supplied were bound. In both cases most of the pathogens (75-90%) could be desorbed by intensive washing, but about 3% of the bacteria provided remained fixed to the surface of the charcoal. Of these remaining bacteria 50% (in the case of S. aureus) or 1% (in the case of E. coli) could be detected in subsequent cultures. These experiments demonstrate that a modified technique of haemoperfusion may be useful in the diagnosis of septicaemia. Haemoperfusion charcoal in an extracorporal circulation of a patient serves as a matrix for adsorption of microorganisms from the circulating blood. This leads to an "in vivo" enrichment of circulating pathogens which may be cultured, identified and their antibiotic sensitivity tested in the usual manner. Thus, this procedure may provide a new diagnostic tool in the diagnosis of septicaemia (9).

Adsorption↗
PubMed1980

Enzymatic inhibition assay for fluorometric determination of allopurinol and oxipurinol in serum and urine.

An enzymatic inhibition assay for the xanthine oxidase (XOD) inhibitors allopurinol and oxipurinol is described. 2-Amino-4-hydroxypteridine is used as sensitive fluorogenic substrate, which is oxidized to highly fluorescent isoxanthopterin by XOD. Increasing concentrations of allopurinol (Ap) or oxipurinol (Ox) prevent conversion of 2-amino-4-hydroxypterdine to isoxanthopterin. Assay conditions of XOD-inhibition are different for Ap and Ox. In the presence of xanthine both Ap and Ox inhibit XOD to the same degree; absence of xanthine results in inactivation by Ap only. Thus rapid and convenient determination of Ap and Ox is possible without prior separation of the substances. The limit of detection is about 0.5 nmol/ml (50 micrograms/ml) in serum and 25 nmol/ml (2.5 micrograms/ml) in urine.

Allopurinol↗
PubMed1978

Clinical and pharmacological investigations of the new saluretic azosemid.

Ple 1053 (Azosemid) is a diuretic which resembles furosemide chemically and in its mode of action. When administered intravenously, Ple 1053 was approximately 5 times more potent on a weight basis than furosemide, its dose-response relationship was closer and the slope was steeper. After oral administration Ple 1053 and furosemide were approximately equal in potency. However, the effect of Azosemid in healthy subjects was relatively prolonged and abrupt peaks did not occur.

Administration, Oral↗
PubMed1975

On the bound state of alkali cations in subcellular preparations of rat liver.

Gel filtration and ion-specific electrodes were used together with atomic absorption spectrophotometry in a search for substances in rat liver which are capable of binding alkali cations. In the cytosol, a material which binds K specifically and reduces the ion activity of potassium can be detected. The binding material, which may be destroyed by alpha-chymotrypsin, has been purified about 100-fold. Its molecular weight is around 5 x 10(3). 1 muval K becomes bound per 20-40 amino acid residues; the total binding capacity may amount to 10-15% binding of the K in rat-liver cytoplasm. Washed nuclear residues, consisting mainly of chromatin, are capable of binding Na in a cation-specific mode. DNA and RNA are ruled out as binding material, so it is assumed to consist of protein, and would then contain about 20 amino acid residues per Na. The cation-binding processes are discussed with regard to nucleo-cytoplasmic sequestration of Na and K, with consequences for the cellular chemi-osmotic gradients, and for the regulation of gene activity in the nucleus.

Animals↗