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Biomedical subjects

D Henke

Publications and source records attributed to D Henke.

14 recordsLinked to original sources
PubMed1999

In vitro activities of designed antimicrobial peptides against multidrug-resistant cystic fibrosis pathogens.

The emergence of multidrug-resistant pathogens renders antibiotics ineffective in the treatment of lung infections in patients with cystic fibrosis (CF). Designed antimicrobial peptides (DAPs) are laboratory-synthesized peptide antibiotics that demonstrate a wide spectrum of antibacterial activity. Optimal conditions for susceptibility testing of these peptides have not yet been established. Medium composition is clearly a major factor influencing the results and reproducibilities of susceptibility tests. Using time-kill assays, we tested the effects of different media and buffers on the bactericidal activities of the peptides D2A21 and D4E1 on Staphylococcus aureus ATCC 29213 and Pseudomonas aeruginosa ATCC 27853. Each peptide at 1 and 5 microM was incubated with bacteria in the different media and buffers. Both peptides were most active in Tris-HCl buffer against S. aureus and P. aeruginosa. Among the more complex media tested, modified RPMI medium was the medium in which the peptides demonstrated the highest activity, while it supported the growth of the bacteria. The broth microdilution technique was used to test the activities of D2A21 and D4E1 in modified RPMI medium against multidrug-resistant pathogens from patients with CF. The MICs of DAPs for methicillin-resistant S. aureus ranged from 0.25 to 4 microg/ml, those for multidrug-resistant P. aeruginosa ranged from 0.125 to 4 microg/ml, those for Stenotrophomonas maltophilia ranged from 0.5 to 32 microg/ml, and those for Burkholderia cepacia ranged from 32 to >/=64 microg/ml. When the activity of peptide D2A21 was compared with that of the tracheal antimicrobial peptide (TAP), D2A21 had greater potency than TAP against P. aeruginosa. In addition, no difference in the MICs of D2A21 was seen when it was tested in nutrient broth supplemented with NaCl at different concentrations. Thus, DAPs are a class of salt-insensitive antibiotics potentially useful in the treatment of CF patients harboring multidrug-resistant P. aeruginosa.

Amino Acid Sequence↗
PubMed1994

Simultaneous determination of (R)- and (S)-brefanolol in human plasma: high-performance liquid chromatographic assay on a chiral stationary phase.

A new method for the quantitative enantiospecific determination of rac-brefanolol, a vasodilating beta-adrenoceptor blocking agent, in human plasma is described. After an alkaline liquid-liquid extraction from biological material and a preseparation on a silica gel column with fractional collection of the eluate, the separation of the underivatized enantiomers is performed by high-performance liquid chromatography on cellulose tris-4-methylbenzoic acid polymer coated on silica gel. The UV-absorbance of the eluate was monitored at 254 nm. Determination limits are 10 ng enantiomer per ml plasma and allow the performance of pharmacokinetic studies after the aimed therapeutic dosages.

Chromatography, High Pressure Liquid↗
PubMed1993

Saturable enantioselective first-pass effect for carvedilol after high oral racemate doses in rats.

Carvedilol shows a highly enantioselective first-pass extraction after therapeutic p.o. doses with preferential extraction of the S-enantiomer. To investigate, whether the enantioselective first-pass metabolism is saturable, male Sprague-Dawley rats were administered increasing single doses of R/S-carvedilol (p.o., 5-30 mg/kg; i.v., 5 and 10 mg/kg), and the individual stereopharmacokinetics were studied. Like in humans the plasma concentrations of R-carvedilol exceeded always those of S-carvedilol. As expected, a dose-dependent reduction in oral clearance was observed, while the total clearance after the i.v. doses was constant. Beyond 20 mg/kg an increased plasma half-life was found for both enantiomers, which is due to a reduced plasma clearance.

Administration, Oral↗
PubMed1993

Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: application to carvedilol stereopharmacokinetics.

As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective beta-adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac-carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)-carvedilol exceeded those of (S)-carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism.

Adrenergic beta-Antagonists↗
PubMed1993

Direct enantiospecific HPLC bioanalysis of (R,S)-atenolol on a chiral stationary phase.

The simultaneous determination of the enantiomers of the beta1-selective adrenergic antagonist atenolol in human plasma and urine is described. After an alkaline pre-extraction atenolol is extracted from biological material at pH 12.3 using dichloromethane/propan-2-ol. The separation of the underivatized enantiomers is achieved by high-performance liquid chromatography on a chiral stationary phase (Chiralcel OD, cellulose tris-3,5-dimethylphenylcarbamate, coated on silica gel) with fluorimetric detection. (--)-)S)-Pindolol is used as an internal standard. The detection limits of 5 ng/ml enantiomer in plasma and 50 ng/ml enantiomer in urine are sufficient for pharmacokinetic studies after therapeutic doses.

Atenolol↗
PubMed1993

Studies on placental transfer of celiprolol.

The maternofetal transfer of the beta 1-selective adrenergic antagonist celiprolol has been studied in four hypertensive pregnant women. Fetal plasma concentrations were about 25-50% of the levels found on the maternal side. There was no significant difference between the plasma concentrations of the two enantiomers in the child. Therefore, in further investigations only the racemate needs to be determined.

Celiprolol↗
PubMed1993

Pharmacokinetics of dilevalol and its conjugates in man. Assay method for plasma, blood, urine and bile samples and preliminary pharmacokinetic studies.

The renal and biliary excretion of the beta-adrenoceptor blocking agent dilevalol (CAS 75659-07-3) and its conjugates was examined in a preliminary pharmacokinetic study. Plasma, urine and bile dilevalol concentrations were determined with a simplified procedure that is based on alkaline liquid-liquid extraction using diethyl ether and subsequent reversed-phase HPLC separation of the reconstituted samples (on a PRP-1 stationary phase using a mixture of methanol and pH 9.8 carbonate buffer as mobile phase). Triamterene was used as internal standard. The quantification of the conjugates was accomplished indirectly via enzymatic hydrolysis (glusulase) with and without addition of the beta-glucuronidase inhibitor 1,4-saccharolactone (at a final concentration of 5.5 mmol/l). In the pharmacokinetic study healthy volunteers and cholecystectomised patients with a T-drain received a single oral dose of 200 mg dilevalol. Furthermore, to healthy volunteers an i.v. dose of 60 mg dilevalol was given in order to estimate the absolute bioavailability. From the obtained data the systemic plasma clearance was calculated to be 1708 ml/min. The oral bioavailability was calculated to be 16%. The log concentration-time curves of the metabolites paralleled those of dilevalol in the terminal section with average terminal half-lives of approx. 5 h. In volunteers the fractions of the dose excreted renally were 0.5% for parent drug, 23% for the glucuronide(s) and 8% for the sulfate. The corresponding values found for the patients were not significantly different. In the patients' bile only 1.2% of the total dose were found (0.03% dilevalol, 1.1% dilevalol glucuronide(s), 0.1% dilevalol sulfate).(ABSTRACT TRUNCATED AT 250 WORDS)

Bile↗
PubMed1991

Determination of the quaternary compound ciclotropium in human biological material after hydrolysis and derivatization with the fluorophor flunoxaprofen chloride.

The quantitative determination of the quaternary spasmolytic compound ciclotropium and its metabolite N-isopropyltropinium is described for human plasma and urine. The analytical procedure consists of ion-pair extraction from biological material, alkaline hydrolysis, subsequent derivatization with the fluorophor flunoxaprofen chloride and separation by high-performance liquid chromatography on a reversed-phase column with fluorimetric monitoring. The detection limits of 0.5 ng/ml in plasma and 10 ng/ml in urine at signal-to-noise ratios higher than 3 permit the determination of pharmacokinetic parameters after therapeutic doses.

Benzoxazoles↗
PubMed1988

Metabolism of arachidonic acid by human nasal and bronchial epithelial cells.

Nasal and bronchial epithelium from normal human nasal turbinates was isolated from surgical specimens and used to study arachidonic acid metabolism. High-performance liquid chromatography analysis of cell incubations in the presence of calcium ionophore, A23187, showed the formation of 15-lipoxygenase products. The major arachidonic acid metabolite with bronchial and nasal tissue was 15-HETE identified by uv spectroscopy, coelution with the authentic standards by HPLC, and GC-mass spectrometry. The second major metabolite, formed from either arachidonic acid or 15-HPETE, was identified as 13-hydroxy-14,15-epoxy-5,8,11-eicosatetraenoic acid (15-alpha-HEPA) by uv spectroscopy, coelution with the authentic standard, and GC-mass spectrometry. In addition, two 8,15-diHETEs and two 8,15-LTs were identified by uv spectroscopy and coelution with the authentic standards by HPLC on both reverse-phase and normal-phase HPLC. Also isolated and identified were 14,15-diHETEs, and 12-HETE. Nasal epithelial cells appear to be more active than nasal bronchial cells in oxidizing arachidonic acid. However, the profile of metabolites from these normal tissue preparations was similar. The addition of 15-lipoxygenase products to nasal epithelium weakly stimulated Cl- ion secretion. These studies indicate that human pulmonary epithelial cells selectively oxidize arachidonic acid to 15-lipoxygenase metabolites.

Arachidonate 15-Lipoxygenase↗
PubMed1988

Arachidonic acid metabolism in respiratory epithelial cells.

1. Arachidonic acid metabolism by respiratory epithelial cells either freshly isolated or maintained in culture is discussed. 2. A comparison is made between rat, rabbit, canine and human cells and illustrates the considerable variation in the metabolism between various species. 3. The relationship between arachidonic acid metabolism and ion movement in these cells is reviewed.

Animals↗
PubMed1986

Arachidonic acid metabolism by isolated epidermal basal and differentiated keratinocytes from the hairless mouse.

The metabolism of arachidonic acid was studied using basal and differentiated keratinocytes as well as sebaceous cells isolated from hairless mice. These disassociated cells metabolized arachidonic acid predominantly to the prostaglandin H synthase products prostaglandins E2 and D2. 12-Hydroxyheptadecatrienoic acid (HHT), prostaglandin F2 alpha, thromboxane B2 and 6-ketoprostaglandin F1 alpha were also detected. Smaller amounts of the lipoxygenase products 5-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs) were also detected. The major lipoxygenase product observed was 12-HETE. No leukotrienes or dihydroxy fatty acids were observed. The identity of the metabolites was established using several high-pressure liquid chromatography solvent systems. The biosynthesis of prostaglandins E2 and D2 was very rapid and was inhibited by the addition of indomethacin to the cells. The mixed population of keratinocytes and sebaceous cells were separated into enriched fractions by metrizamide gradients and elutriation techniques. The small, undifferentiated cells had high prostaglandin H synthase and 12-lipoxygenase activity. The basal cell-enriched fractions had the highest activity. With increasing differentiation of the cells, decreased biosynthetic activity was observed. These results indicate that undifferentiated keratinocytes, that is, the basal cells, may be an important source of prostaglandins and 12-HETE but are not a source of leukotrienes for the hairless mouse. It also suggests a role for keratinocyte-derived eicosanoids in the normal physiology of epidermal differentiation.

Animals↗