ABSTRACT
We describe a novel approach to investigate and evaluate combined effect of a large number of clinical and pharmacogenetic factors on treatment outcome. We have used this approach to investigate predictors of methotrexate (MTX)-induced adverse events (AEs) leading to treatment discontinuation in rheumatoid arthritis (RA) patients. In total, 333 RA patients were genotyped for 34 polymorphisms in MTX transporters, folate and adenosine pathways. The effect of clinical and pharmacogenetic factors was assessed with penalized regression in the cause-specific Cox proportional hazards model. The predictive capacity was evaluated with the area under time-dependent receiver operating characteristic curve where cross-validation was applied. SLC19A1, ABCG2, ADORA3 and TYMS were associated with discontinuation because of AEs in clinical-pharmacogenetic model. Cross-validation showed that both clinical-pharmacogenetic model and nongenetic model had worthless predictive ability for MTX discontinuation because of AEs. These models could be further improved, either with additional polymorphisms or with epigenetic predictors.
Subject(s)
Antirheumatic Agents/adverse effects , Antirheumatic Agents/pharmacokinetics , Arthritis, Rheumatoid/drug therapy , Methotrexate/adverse effects , Methotrexate/pharmacokinetics , Polymorphism, Genetic , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Aged , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/genetics , Female , Genotype , Humans , Male , Methotrexate/therapeutic use , Middle Aged , Neoplasm Proteins/genetics , Nucleoside Transport Proteins/genetics , Pharmacogenomic Testing , Predictive Value of Tests , Proportional Hazards Models , Reduced Folate Carrier Protein/genetics , Thymidylate Synthase/genetics , Treatment OutcomeABSTRACT
UDP-N-acetylmuramic acid (UDP-MurNAc) is a substrate of MurC, an important enzyme in the intracellular pathway of bacterial peptidoglycan biosynthesis. Various approaches towards preparation of UDP-MurNAc have been published but these synthetic preparations were shown to include many problematic steps. An optimization study with the focus on muramyl phosphate and UMP-morpholidate coupling was performed, resulting in a synthetic procedure enabling robust and easily reproducible production on a multi-gram scale.
Subject(s)
Uridine Diphosphate N-Acetylmuramic Acid/chemical synthesis , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Indicators and Reagents , Magnetic Resonance Spectroscopy , PhosphorylationABSTRACT
The new and convenient method for the separation, isolation and characterization of the N-ciano-N'-methyl-N"-(2-/(5-methylimidazol-4-yl)methylthio/ethyl) guanidine and its biotransformation and degradation products was developed. Mass spectra obtained with the FAB (Fast Atom Bombardment) method are described. This method proved to be very successful for the analysis and characterization of studied compounds.
