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G Blaschke

Publications and source records attributed to G Blaschke.

At least 91 records · Page 5Linked to original sources
PubMed1997

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites.

To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m2 Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUCTrofo:AUCIfo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC(Ifo):AUC(Cyclo) 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechlorethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy.

Adolescent↗
PubMed1997

Antibody-mediated clean-up of blood for simultaneous HPLC determination of morphine and morphine glucuronides.

For the interpretation of the concentration of morphine in blood samples of heroin consumers information about the concentration of the analgesic active morphine metabolite morphine-6-glucuronide is very important. Thus a simple but specific clean-up procedure based on immuno-affinity chromatography is presented for the extraction of morphine, morphine-3-glucuronide and morphine-6-glucuronide from whole blood in cases of fatal heroin overdose. The preparation of the immunoabsorber by immobilization of antibodies against morphine-3-BSA and morphine-6-KLH with carbonyldiimidazole-activated trisacrylgel is described. The separation of the extracts is achieved by HPLC using native fluorescence detection. The limits of detection for this method are 10ng for morphine and morphine glucuronides/g blood. The results for the concentration of morphine and morphine glucuronides in blood from seven cases of heroin overdose are presented. By calculating the quotients for the concentrations of morphine-6-glucuronide/morphine the time elapsed since the last intake of heroin is estimated.

Antibodies↗
PubMed1997

Selected applications of capillaries with dynamic or permanent anodal electroosmotic flow in chiral separations by capillary electrophoresis.

The techniques for a dynamic and permanent reversal of the electroosmotic flow (EOF) were used for the reversal of the enantiomer migration order (EMO) of neutral and cationic analytes in chiral capillary electrophoresis (CE). Native beta-Cd and an anionic CD derivative, CM-beta-CD were used in both, bare silica- and positively coated capillaries. Advantages and disadvantages of a dynamic and permanent modification of the capillary inner surface are briefly discussed.

Benzoin↗
PubMed1997

Enantioselective biotransformation of the chiral antihistaminic drug dimethindene in humans and rats.

The biotransformation of dimethindene (CAS 5636-83-9, dimethindene maleate, CAS 3614-69-5) after oral administration was determined in urine using an HPLC gradient method. Besides the phase I metabolites the conjugates of the hydroxylated metabolites with glucuronic and/or sulfuric acid were quantitatively determined after enzymatic deconjugation. The cumulative excretion of 6-hydroxydimethindene and 6-hydroxy-N-demethyldimethindene in human urine after hydrolysis of the conjugates ranged from 18 to 23% of the administered dose, independent of the amount of the dose applied. The results indicate that conjugated 6-hydroxydimethindene is the main metabolite of dimethindene. Increasing doses of 5 to 20 mg dimethindene maleate did not affect the relative amount of the excreted metabolites but changed the ratio of 6-hydroxydimethindene to 6-hydroxy-N-demethyldimethindene from 3:1 to 1:1. In rats about 4 to 8% of the administered dose of dimethindene was excreted as dimethindene-N-oxide which is the main metabolite in rat urine. After administration of R-(-)-dimethindene the elimination of all metabolites was 2 to 3 fold higher compared to the administration of the S-(+)-enantiomer. By chiral HPLC, in 10 human volunteers a stereoselective elimination of N-demethyl-dimethindene after oral administration of racemic dimethindene with the predominant excretion of the R-(-)-enantiomer was observed.

Adult↗
PubMed1996

Simultaneous determination of all-trans-, 13-cis- and 9-cis-retinoic acid, their 4-oxo metabolites and all-trans-retinol in human plasma by high-performance liquid chromatography.

All-trans-retinoic acid (all-trans-RA) and 13-cis-retinoic acid (13-cis-RA), due to their effects on cell differentiation, proliferation and angiogenesis, improved treatment results in some malignancies. Pharmacokinetic studies of all-trans-RA and 13-cis-RA along with monitoring of retinoic acid metabolites may help to optimize retinoic acid therapy and to develop new effective strategies for the use of retinoic acids in cancer treatment. Therefore, we developed a HPLC method for the simultaneous determination in human plasma of the physiologically important retinoic acid isomers, all-trans-, 13-cis- and 9-cis-retinoic acid, their 4-oxo metabolites, 13-cis-4-oxoretinoic acid (13-cis-4-oxo-RA) and all-trans-4-oxoretinoic acid (all-trans-4-oxo-RA), and Vitamin A (all-trans-retinol). Analysis was performed on a silica gel column with UV detection at 350 nm using a binary multistep gradient composed of n-hexane, 2-propanol and glacial acetic acid. For liquid-liquid extraction a mixture of n-hexane, dichloromethane and 2-propanol was used. The limits of detection were 0.5 ng/ml for retinoic acids and 10 ng/ml for all-trans-retinol. The method showed good reproducibility for all components (within-day C.V.: 3.02-11.70%; day-to-day C.V.: 0.01-11.34%). Furthermore, 9-cis-4-oxoretinoic acid (9-cis-4-oxo-RA) is separated from all-trans-4-oxo-RA and 13-cis-4-oxo-RA. In case of clinical use of 9-cis-retinoic acid (9-cis-RA) the pharmacokinetics and metabolism of this retinoic acid isomer can also be examined.

Chromatography, High Pressure Liquid↗
PubMed1996

Determination of paclitaxel in biological fluids by micellar electrokinetic chromatography.

A method has been developed for the determination of paclitaxel (Taxol) in plasma and urine using capillary electrophoresis with sodium dodecyl sulfate as additive in the run buffer. The samples are extracted and preconcentrated with tert.-butyl methyl ether. Taxotere has been used as the internal standard. The limit of detection of paclitaxel is 20 ng/ml. In comparison to high-performance liquid chromatography, the capillary electrophoresis method is simple and needs less organic solvents.

Acetonitriles↗
PubMed1996

Analysis of charged cyclomalto-oligosaccharides (cyclodextrin) derivatives by ion-spray, matrix-assisted laser-desorption/ionization time-of-flight and fast-atom bombardment mass spectrometry, and by capillary electrophoresis.

The use of electrospray-ionization mass spectrometry (ESIMS), matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDITOFMS), and fast-atom bombardment mass spectrometry (FABMS) for the rapid determination of molecular weight, degree of substitution (ds), and purity is demonstrated for charged derivatives of cyclomalto-heptaose (beta CD) and -octaose (gamma CD). The access to anionic sulfoalkyl ethers (alkyl: ethyl, n-propyl, and n-butyl) and to beta CD-2-hydroxy-3-trimethylammoniumpropyl ether chlorides (HTAP-beta CD) leads only to mixtures of products, the compositions of which can be determined directly from ESI and MALDITOF mass spectra. All charged derivatives consist of a mixture of unreacted and higher substituted compounds. The substitution patterns obtained by MS are in good agreement with the results of experiments on the separation of beta CD-sulfoalkyl ethers by capillary electrophoresis (CE).

Capillary Action↗
PubMed1996

Direct determination of zolpidem and its main metabolites in urine using capillary electrophoresis with laser-induced fluorescence detection.

Zolpidem is a new sleep inducer belonging to the imidazopyridine class. We wish to report a method for the determination of zolpidem and its main metabolites in urine without extraction using capillary electrophoresis with UV laser-induced fluorescence detection with a He-Cd laser. A 10-nl sample of urine can be directly applied to the capillary. The separation is carried out within 10 min, and the limit of detection is 2 ng/ml. This procedure is very simple and fast. No organic solvents are necessary.

Electrophoresis, Capillary↗
PubMed1996

Enantioselective determination of zopiclone and its metabolites in urine by capillary electrophoresis.

A method has been developed for the stereoselective determination of zopiclone and its main metabolites in urine. After the addition of the internal standard zolpidem the urine samples were extracted at pH 8 with chloroform-isopropanol (9:1). Analyses were carried out using capillary electrophoresis (CE) with beta-cyclodextrin as the chiral selector. The analytes were detected using UV laser-induced fluorescence detection with a He-Cd laser operated at 325 nm. Urine samples of two volunteers after oral administration of 7.5 mg zopiclone were investigated. The S-(+)-enantiomers of zopiclone and its metabolites were always excreted in higher amounts than the R-(-)-enantiomers. With the same method the zopiclone enantiomers were quantified in saliva. Compared to high-performance liquid chromatography, the CE method is very fast and simple.

Azabicyclo Compounds↗
PubMed1996

Analysis of "Ecstasy" by capillary electrophoresis.

Capillary electrophoresis (CE) and it's applications in forensic toxicology are demonstrated by the investigation of amphetamine derivatives in "Ecstasy" tablets. The method is based on capillary zone electrophoresis (CZE) with a phosphate running buffer (pH 2.2). The drugs were dissolved in 0.01 N hydrochloric acid, diluted with distilled water and phenylephrine was added to the samples as an internal standard. A separation of the charged substances is obtained by the different velocities in the electric field. The qualitative determination can be made by the migration times or more accurately by the relative migration times. Other possibilities for identification are the UV-spectra using a diode array detector or the on-column standard addition procedure. By this procedure the sample solution is initially injected followed by the standard solution. Both are concentrated in the column before separation begins. CE shows clear advantages in comparison to high-performance liquid (HPLC) or gas chromatography (GC). The quantitative analysis was carried out using the internal standard phenylephrine. The values obtained for 56 "Ecstasy" tablets and powder containing amphetamine or its derivatives were compared in this study after analysis with CE and HPLC. The results were in very good agreement. Because of it's speed, the high resolving power and the possibility of identification with the on-column standard addition, CE is a powerful alternative to HPLC or GC for the investigation of "Ecstasy" tablets.

Amphetamines↗
PubMed1996

Simultaneous determination of the phase II metabolites of the non steroidal anti-inflammatory drug etodolac in human urine.

Etodolac, an antirheumatic and analgetic drug, is metabolized in humans by hydroxylation and acyl glucuronidation to yield the corresponding 1-O-glucuronides. The acylglucuronides of etodolac and one of its hydroxylated metabolites were determined by HPLC using a RP18 column. In order to increase the lipophilicity of these metabolites the hydroxy groups were acetylated and the carboxylic functions were methylated. In a study with five human volunteers a stereoselective excretion of the acylglucuronides could be observed. The S-etodolac-glucuronide is mainly excreted during the first 6 hours after administration of 400 mg of etodolac whereas the elimination of the R-glucuronide predominates at longer periods of time. The S-glucuronide of 7-hydroxy-etodolac was preferenetively excreted during the period of time observed. An unknown metabolite of etodolac could be characterized by chemical and enzymatically hydrolysis and by MS and NMR.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Investigation of the in vitro biotransformation and simultaneous enantioselective separation of thalidomide and its neutral metabolites by capillary electrophoresis.

Reversed-phase liquid chromatography is a long established method for the analysis of drug metabolism. The current investigation demonstrates that micellar electrokinetic capillary chromatography can be an attractive alternative. Two methods were developed using sodium dodecyl sulfate and hexadecyltrimethylammonium bromide for the determination of possible hydroxylated metabolites of the former sedative drug thalidomide (Contergan) in order to study the in vitro metabolism of the drug by incubation with rat liver microsomes. The biotransformation was found to be stereoselective: S-(-)-thalidomide mainly formed 5-hydroxythalidomide, whereas R-(+)-thalidomide was preferentially transformed to two metabolites tentatively assigned to be diastereomers of 5'-hydroxythalidomide. Furthermore, the simultaneous enantioseparation of thalidomide and two of its possible hydroxylated metabolites was achieved using capillary electrophoresis with negatively charged carboxymethyl-beta-cyclodextrin. The dependencies of the selectivity of the enantioseparation on the concentration of the chiral additive and the pH of the run buffer were investigated.

Animals↗
PubMed1995

Investigation of the stereoselective metabolism of the chiral H1-antihistaminic drug terfenadine by high-performance liquid chromatography.

The enantiomers of the racemic H1-antihistaminic drug terfenadine (1) have been resolved by fractional crystallization of the diastereomeric salts with optically active 2-chlorotartranilic acid. The enantiomeric excess of both terfenadine enantiomers was determined using an achiral and a chiral HPLC system after formation of diastereomers with S-(+)-naphthylethylisocyanate. To investigate the metabolism of terfenadine after oral administration, an achiral HPLC system, equipped with a conventional reversed-phase column, was used to quantify the main metabolite MDL 16.455 (2) in human serum and urine. The determination of the enantiomeric composition of 2 was achieved using an Ultron ES-OVM column as chiral stationary phase. Metabolite 2, extracted from human blood plasma, was found to be enriched in the R-enantiomer, but was excreted in urine as racemate. The results of a study including six volunteers are presented.

Chromatography, High Pressure Liquid↗
PubMed1995

Determination of the stereoselective aspects in in-vitro and in-vivo metabolism of the analgesic meptazinol by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method to separate meptazinol and its phase I metabolites has been developed using a LiChrosper 100 CN column and a mobile phase of trimethylammoniumacetate buffer (pH 5.5)-acetonitrile-methanol. Quantification of meptazinol and N-desmethylmeptazinol in biological samples was achieved by extraction with organic solvents and chromatographic analysis (detection limit 0.4 and 0.25 micrograms/ml, respectively). Afterwards the enantiomeric ratio of the two compounds was determined on a Chiral AGP column with a mobile phase of phosphate buffer (pH 7.0)-acetonitrile (alpha = 1.29 and 1.49, respectively). In-vitro metabolism data after incubation of the racemic compound and the enantiomers with liver supernatant and microsomes of different species are presented. Finally urinary data of two volunteers after oral application of the racemic drug were determined.

Animals↗
PubMed1995

Transdermal absorption of dimethindene in man.

Dimethindene and its metabolite N-demethyldimethindene were determined in human urine after dermal administration of dimethindene. The HPLC-method used was previously described. Data of 8 volunteers are presented. After 32 h an average of 0.023% of the administered dose of dimethindene and 0.022% of N-demethyldimethindene were excreted into urine. Since also after oral administration of dimethindene only about 1% of unmetabolised dimethindene is found in urine it can be concluded that a certain amount of dimethindene is absorbed through the skin after dermal administration.

Administration, Cutaneous↗
PubMed1995

A specific immunoassay for the detection of flunitrazepam.

The development of an immunochemical procedure for the determination of flunitrazepam in whole blood is described. Flunitrazepam was derivatized in position 3 of the benzodiazepine ring to a hapten which was coupled to a carrier protein. To obtain antibodies, rabbits were immunized with these immunogens and the collected antisera were tested in a heterogeneous, competitive RIA. The antibodies showed a very specific reaction with flunitrazepam and hardly any cross-reactivity with related 1,4-benzodiazepines. Because of its high specificity the antiserum has the advantage of a definite determination of low levels of flunitrazepam without the risk of false-negative results obtained by using the commercially available group-specific test systems. The drug was extracted from whole blood in a simple batch process with a polystyrene suspension and the extracts were measured by RIA. The advantages of an immunochemical system, such as short analysis time and simple sample preparation, and the exactness of a drug-specific method are combined in this procedure, which allowed the specific and very sensitive determination of flunitrazepam in the low therapeutic range.

Animals↗
PubMed1995

Metabolism of dimetindene in rats.

The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tartrate salts. HPLC on alpha-AGP (alpha 1-acid glycoprotein) was used for confirmation of the enantiomeric purity. After administration of the enantiomers to rats the AUC and Cmax of S(+) dimetindene and (-)N-demethyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimethindene was excreted into urine after administration of the individual enantiomers. S(+) dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induction conversion of the enantioselectivity with respect to unmetabolised dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetindene is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identical. The formation of 6-hydroxy-N-demethyldimetindene was proved for the first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.

Animals↗