Biomedical subjects

Robert Jansen

Publications and source records attributed to Robert Jansen.

5 recordsLinked to original sources

PubMed2006

Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel.

PURPOSE: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. EXPERIMENTAL DESIGN: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. RESULTS: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A three-compartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (-25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1 and the pharmacokinetics could be identified. CONCLUSIONS: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2005

LC-MS/MS systematic toxicological analysis: comparison of MS/MS spectra obtained with different instruments and settings.

OBJECTIVES: To compare the mass spectra obtained using a linear-ion-trap (LIT) tandem mass spectrometer (QTRAP) operated in the "enhanced product ion scan" (EPI) mode with those obtained in the classical triple-quadrupole product ion scan (PIS) mode run on the same as well as on two other instruments (TSQ-Quantum and Quattro-Micro). DESIGN AND METHODS: After tentative standardization of ion fragmentation and transmission in both polarities using a reference compound (glafenine) on the three instruments, eight test compounds detected in the positive mode and five in the negative mode were systematically infused in different ionization sources and spectral acquisition performed over approximately 5 s. The relative intensity of the ions present in the resulting spectra was quantitatively and statistically compared. Also, the intra-day and inter-day variabilities of these relative intensities, as well as the effect of increasing compound concentration, were studied using QTRAP operated in EPI mode. RESULTS: The EPI and PIS modes operated on a single LIT MS/MS instrument resulted in significant differences in relative ion intensities in both polarities, and so did the other two instruments despite prior standardization with glafenine. Some fragments could be absent in certain spectra, but no unexpected or unique fragments showed up. Intra-day variability was smaller in the LIT EPI than in the regular PIS mode and in the positive than in the negative polarity. In EPI mode, both intra- and inter-day variabilities increased when the relative intensity decreased. The effect of increasing concentration on the relative intensity of major and minor ions was small but significant in both polarities. Finally, contamination and cleansing of the ionization source also had noticeable effects on MS/MS spectra, though the cause is unclear. CONCLUSIONS: MS/MS spectra do not offer the expected inter-instrument reproducibility despite an attempt at standardizing the fragmentation conditions using a reference compound. However, although the inter-instrument differences in ion relative intensity were significant, the spectra obtained looked almost similar. This suggests that in library searching algorithms, higher weight should be assigned for the m/z ratios than for their relative intensity in the spectra.

Chromatography, Liquid↗

PubMed2003

Phosphoramidate protides of 2',3'-dideoxy-3'-fluoroadenosine and related nucleosides with potent activity against HIV and HBV.

Syntheses of phosphoramidate protides of several 2',3'-dideoxy-3'-fluoroadenosine derivatives by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleoside against HIV and HBV. Especially marked was the improvement in potency of phosphoramidate protides of 2',3'-dideoxy-3'-fluoroadenosine against both HIV and HBV.

Amides↗

PubMed2003

Single embryo transfer in IVF to prevent multiple pregnancies.

As the success rates of IVF clinics improve, one of the adverse consequences is the increased incidence of twins, due largely to the number of embryos transferred. Even if the number of embryos transferred is restricted to two, the twinning rate can exceed 40% of the pregnancies. An obvious way to reduce this high twin rate would be to transfer only one embryo. This would require that cryopreservation of the supernumerary embryos be efficacious enough so that the chance of achieving an ongoing pregnancy is not diminished by transferring a single embryo in the stimulated cycle. Previous studies utilising embryos on day 2 and 3 of development have shown that the pregnancy rates can be acceptable (about 40%) and that the cumulative rate can be up to 60%. Most of these studies, however, do not include a comparison with the cumulative pregnancy rate with two embryos transferred in the stimulated cycle. Therefore, the efficacy has not been proven. We present clinical data from the past few years to illustrate the increase in success rates and the concomitant increase in twinning rates. The increased success in the cryopreservation program has enabled us to trial a single embryo transfer program and compare the results to the transfer of two embryos. The results strongly suggest that the transfer of a single embryo is the better clinical option.

Embryo Transfer↗

PubMedDate not supplied

Pattern identification in biogeography.

Identifying common patterns among area cladograms that arise in historical biogeography is an important tool for biogeographical inference. We develop the first rigorous formalization of these pattern-identification problems. We develop metrics to compare area cladograms. We define the maximum agreement area cladogram (MAAC) and we develop efficient algorithms for finding the MAAC of two area cladograms, while showing that it is NP-hard to find the MAAC of several binary area cladograms. We also describe a linear-time algorithm to identify if two area cladograms are identical.

Algorithms↗