Publications by authors named "Christoph Siethoff"

11 Publications

  • Page 1 of 1

Blood schizontocidal and gametocytocidal activity of 3-hydroxy-N'-arylidenepropanehydrazonamides: a new class of antiplasmodial compounds.

J Med Chem 2014 Oct 25;57(19):7971-6. Epub 2014 Sep 25.

Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstrasse 1, 40225 Düsseldorf, Germany.

3-Hydroxy-N'-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro.
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http://dx.doi.org/10.1021/jm500811pDOI Listing
October 2014

In-depth study of homogeneity in DBS using two different techniques: results from the EBF DBS-microsampling consortium.

Bioanalysis 2013 Sep 5;5(17):2161-9. Epub 2013 Jul 5.

Quotient Bio Analytical Sciences (part of the LGC group), Newmarket Road, Fordham, Cambridgeshire, CB7 5WW, UK.

Background: At the start of their work, the European Bioanalysis Forum dried blood spots microsampling consortium did not form a dedicated team to investigate the spot homogeneity. However, two teams performed experiments that produced results relating to sample homogeneity.

Results: The data, which were produced via two different approaches (a radiolabeled and a nonradiolabeled approach), are highly complementary and demonstrate clear effects on sample inhomogeneity due to the substrate type, compound and hematocrit levels.

Conclusion: The results demonstrate that sample inhomogeneity is a significant hurdle to the use of dried blood spots for regulated bioanalysis that should be investigated further in the method establishment phase if the whole spot is not sampled.
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http://dx.doi.org/10.4155/bio.13.171DOI Listing
September 2013

The effect of hematocrit on bioanalysis of DBS: results from the EBF DBS-microsampling consortium.

Bioanalysis 2013 Sep 5;5(17):2147-60. Epub 2013 Jul 5.

Janssen R&D NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.

Background: The European Bioanalysis Forum dried blood spots (DBS)/microsampling consortium is reporting back from the experiments they performed on further documenting the potential hurdles of the DBS technology. This paper is focused on the impact of hematocrit changes on DBS analyses.

Results: The hematocrit can have an effect on the size of the blood spot, on spot homogeneity and on extraction recovery in a compound-dependent manner. The extraction recovery can change upon aging in an hematocrit-dependent way. Different card materials can give different outcomes.

Conclusions: The results from the conducted experiments show that the issues of DBS in regulated bioanalysis are real and that the technology will need improvements to be ready for use as a general tool for regulated bioanalysis.
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http://dx.doi.org/10.4155/bio.13.170DOI Listing
September 2013

Recommendations on bioanalytical method stability implications of co-administered and co-formulated drugs by Global CRO Council for Bioanalysis (GCC).

Bioanalysis 2012 Sep;4(17):2117-26

Advion Bioanalytical Laboratories, Quintiles, NY, USA.

An open letter written by the Global CRO Council for Bioanalysis (GCC) describing the GCC survey results on stability data from co-administered and co-formulated drugs was sent to multiple regulatory authorities on 14 December 2011. This letter and further discussions at different GCC meetings led to subsequent recommendations on this topic of widespread interest within the bioanalytical community over the past 2 years.
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http://dx.doi.org/10.4155/bio.12.192DOI Listing
September 2012

Determination of 6-keto prostaglandin F1α and its metabolites in human plasma by LC-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2012 Jul 16;901:67-71. Epub 2012 Jun 16.

Swiss BioQuant AG, Kägenstrasse 18, 4153 Reinach, Switzerland.

An HPLC-MS/MS method was developed and validated for the quantification of 6-keto prostaglandin F1α, the stable hydrolysis product of prostacyclin, and its metabolites 2,3-dinor-6-keto prostaglandin F1α and 6,15-diketo-13,14-dihydro prostaglandin F1α in human plasma. For sample preparation, a solid phase extraction step was combined with a column switching approach for analytes enrichment and further sample clean-up of the processed sample. The assay was validated in the concentration range 50.0-5000 pg/mL for 6-keto prostaglandin F1α and 6,15-diketo-13,14-dihydro prostaglandin F1α, and 100-10,000 pg/mL for 2,3-dinor-6-keto prostaglandin F1α. The inter-batch precision was better than 12.7%, 9.2%, and 9.4% for 6-keto prostaglandin F1α, 2,3-dinor-6-keto prostaglandin F1α, and 6,15-diketo-13,14-dihydro prostaglandin F1α, respectively. The inter-batch accuracy was between 97.3% and 100.8% for 6-keto prostaglandin F1α, between 97.5% and 103.0% for 2,3-dinor-6-keto prostaglandin F1α, and between 92.0% and 100.0% for 6,15-diketo-13,14-dihydro prostaglandin F1α. Further it has been demonstrated that the analytes were stable in plasma for 20 h at room temperature, during three freeze-and-thaw cycles, for 96 days at -25 °C storage temperature, and 50h in the autosampler tray at room temperature.
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http://dx.doi.org/10.1016/j.jchromb.2012.05.044DOI Listing
July 2012

First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials.

Br J Clin Pharmacol 2013 Feb;75(2):524-37

Medicines for Malaria Venture, Geneva, Switzerland.

Aims: To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers.

Methods: OZ439 was administered as single oral daily doses of a capsule formulation (50-1200 mg) or an oral dispersion (400-1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800 mg day(-1)). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS.

Results: The pharmacokinetic (PK) profile of OZ439 was characterized by a t(max) of around 3 h, followed by a multiphasic profile with a terminal half-life of 25-30 h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t(1/2) of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites.

Conclusion: The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.
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http://dx.doi.org/10.1111/j.1365-2125.2012.04368.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3558805PMC
February 2013

Workshop/conference report on EMA draft guideline on validation of bioanalytical methods.

Eur J Pharm Sci 2011 Feb 24;42(3):300-5. Epub 2010 Dec 24.

SocraTec CSC GmbH, Oberursel, Germany.

This is a summary report of the workshop on the EMA Draft Guideline on Validation of Bioanalytical Methods held April 15-16th 2010 in Brussels (Belgium) and jointly organised by the European Bioanalysis Forum (EBF) and the European Federation for Pharmaceutical Sciences (EUFEPS). Aim of the workshop was to discuss the current scientific knowledge in the area of bioanalysis, the regulatory requirements with special focus on the new Draft Guideline and their subsequent implementation to the work in bioanalytical laboratories. Comments on the Draft Guideline were presented and discussed with representatives from regulatory authorities in Europe. The workshop started with discussions on the scope of the Guideline and the need for implementation of GLP. A special focus was set on method validation of chromatographic procedures and subsequent study sample analysis. In addition, requirements for ligand-binding assays were briefly addressed. Intention of this Conference Report is to summarise important aspects of the discussions in order to draw certain conclusions, and to identify points which remain open and may require clarification at a later stage.
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http://dx.doi.org/10.1016/j.ejps.2010.12.008DOI Listing
February 2011

Simultaneous determination of capecitabine and its metabolite 5-fluorouracil by column switching and liquid chromatographic/tandem mass spectrometry.

J Mass Spectrom 2004 Aug;39(8):884-9

Swiss BioAnalytics AG, Sternenfeldstrasse 16, 4127 Birsfelden.

A liquid chromatographic/tandem mass spectrometric method was developed and validated for the quantitation of capecitabine and its metabolite 5-fluorouracil in human plasma. The simultaneous determination of both analytes was achieved by a column switching method using a trapping column and two analytical columns with different stationary phases. Isocratic elution was used for the separation of capecitabine on a C18 column whereas 5-fluorouracil was separated using gradient elution on an non-polar carbon phase. The calibration curves were linear for both compounds with a correlation factor (R2) > 0.9993 for 5-fluorouracil and >0.9942 for capecitabine. The assay was validated in the concentration range 5.00-1000 ng ml(-1) for both compounds. The intra-day precision was better than 10% for 5-fluorouracil and better than 11% for capecitabine whereas the inter-day precision was better than 8% for 5-fluorouracil and better than 14% for capecitabine.
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http://dx.doi.org/10.1002/jms.655DOI Listing
August 2004

Proteomics application exercise of the Swiss Proteomics Society: report of the SPS'02 session.

Proteomics 2003 Aug;3(8):1562-6

Swiss Institute of Bioinformatics (SIB), Centre Médical Universitaire, 1 Michel-Servet, CH-1211 Geneva 4, Switzerland.

After the success of the mass spectrometry (MS) round table that was held at the first Swiss Proteomics Society congress (SPS'01) in Geneva, the SPS has organized a proteomics application exercise and allocated a full session at the SPS'02 congress. The main objective was to encourage the exchange of expertise in protein identification, with a focus on the use of mass spectrometry, and to create a bridge between the users' questions and the instrument providers' solutions. Two samples were sent to fifteen interested labs, including academic groups and MS hardware providers. Participants were asked to identify and partially characterize the samples. They consisted of a complex mixture of peptide/proteins (sample A) and an almost pure recombinant peptide carrying post-translational modifications (sample B). Sample A was an extract of snake venom from the species Bothrops jararaca. Sample B was a recombinant and modified peptide derived from the shrimp Penaeus vannamei penaeidin 3a. The eight labs that returned results reported the use of a wide range of MS instrumentation and techniques. They mentioned a variety of time and manpower allocations. The origin of sample A was generally identified together with a number of database protein entries. The difficulty of the sample identification lay in the incomplete knowledge of the Bothrops species genome sequence and is discussed. Sample B was generally and correctly identified as penaeidin. However, only one group reported the full primary structure. Interestingly, the approaches were again varied and are discussed in the text.
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http://dx.doi.org/10.1002/pmic.200300458DOI Listing
August 2003

Coupling of a Nucleoside with DNA by a Methyltransferase.

Angew Chem Int Ed Engl 1998 Nov;37(20):2888-2891

Max-Planck-Institut für molekulare Physiologie, Abteilung Physikalische Biochemie, Rheinlanddamm 201, D-44139 Dortmund (Germany), Fax: (+49) 231-1206-229.

How to outwit a methyltransferase: Methyltransferases (Mtases) catalyze the transfer of the activated methyl group from the cofactor S-adenosyl-L-methionine (1) to acceptors R within a large variety of biomolecules. Through the use of the cofactor analogue 2 a whole nucleoside was coupled to DNA in a Mtase-catalyzed reaction.
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http://dx.doi.org/10.1002/(SICI)1521-3773(19981102)37:20<2888::AID-ANIE2888>3.0.CO;2-4DOI Listing
November 1998