Biomedical subjects

Peter Zbinden

Publications and source records attributed to Peter Zbinden.

4 recordsLinked to original sources

PubMed2005

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of (14)C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t(max) 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 +/- 0.095 mug/ml (mean +/- S.D., n = 4) for imatinib and 0.115 +/- 0.026 mug/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 +/- 0.9 h for imatinib, 20.6 +/- 1.7 h for CGP74588, and 57.3 +/- 12.5 h for (14)C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC(0-24 h) (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

Adult↗

PubMed2004

The evolution of microarrayed compound screening.

This review describes recent developments in the evolutionary process of microarrayed compound screening (microARCS to become a robust and efficient ultra-high-throughput screening technology. Improvements in compound spotting (including new quality-control methods), gel casting and imaging, together with software capable of automatic analysis and deconvolution of images, have helped to streamline the screening process. A variety of screening projects using cell-based and non-cell-based approaches have been successfully concluded using microARCS. Comparison of hits derived from standard microtitre-plate-based screening and from microARCS reveals excellent overlap. Furthermore, there seems to be no bias towards finding compounds within a particular range of logP values, even though compounds are solubilized from a dry state during the course of the assay.

Biological Assay↗

PubMed2004

High throughput screening of beta-amyloid secretion inhibitors using homogenous time-resolved fluorescence.

A cell-based assay using homogeneous time-resolved fluorescence has been developed for high throughput screening of putative beta-amyloid (Abeta)production inhibitors. In this assay, total Abeta is detected by simply adding two commercially available antibody complexes. The first was a biotinylated monoclonal antibody (4G8), specifically recognizing an epitope comprising the residues 17-24 of the Abetapeptide, complexed with europium cryptate-streptavidin conjugate. The second was a polyclonal antibody (BioS-N), raised against the N-terminus of the Abeta peptide, complexed with an allophycocyanin-anti rabbit antibody conjugate. Binding of the two complexes to the Abeta peptide brought europium cryptate (fluorescence donor) and allophycocyanin (fluorescence acceptor) into close proximity, consequently a fluorescent resonance energy transfer signal was produced upon excitation at 337 nm. The resulting fluorescence signal (665 nm) was then detected using a Discovery or a ViewLux reader. Detection of Abeta by the proposed method is possible at concentrations of approximately 1 nM. The method was employed for the detection of Abeta secreted from a stable transfected human neuroglioma cell line (H4) overexpressing a mutated form of the human amyloid precursor protein (APP695NL) and developed for robotic automation. At optimized conditions, signal-to-background ratios exceeding 5 and Z' factors around 0.7 were achieved in a 384-well format. High throughput screening of 56,913 potential Abeta production inhibitors led to identification of new non-cytotoxic and cell permeable compounds with potencies in the submicromolar range.

Amyloid beta-Peptides↗

PubMed1997

[Target proteins and mechanisms of ochratoxin toxicity. A contribution to the identification of potential ochratoxin antagonists]

Ochratoxins are mycotoxins released by moulds on grain, peanuts and vegetables. Toxicological investigations have shown that ochratoxin A displays nephrotoxic, genotoxic, teratogenic, cancerogenic and immunosuppressive effects. Increased blood levels observed in humans would seem to suggest a link to a kidney desease (Balcan Endemic Nephropaty) frequently observed in the Balkan countries. The adverse effects of ochratoxin A are mainly associated with its impact on phenylalanine-metabolizing enzymes. Based on the three-dimensional structure of phenylalanine-t-RNA-synthetase, its interactions with ochratoxins are analyzed as well as with Aspartam. In animal models, Aspartam has been shown to almost fully prevent toxic effects of ochratoxin A. The topology of the binding site of phenylalanine-t-RNA-synthetase would seem to be favorable towards a few affinity-enhancing modifications of the Aspartame molecule. A known molecular mechanism is a prerequisite for a systematic search of antagonizing substances for toxins. Based on a receptor structure, binding properties of such drugs can be identified and optimized using computer-aided drug design. Susequently, only the most potent candidate structures must be subjected to a determination of their biological activity, which can lead to a significant reduction of substances to be tested in vivo. Such experiments are particularly stressful as the animals must be intoxicated beforehand. The extent of an antagonistic impact on humans suffering from a chronical ochratoxin A intoxication must be subject of clinical studies.

Journal Article↗