RESUMO
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.
Assuntos
Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Polimorfismo Genético , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Feminino , Genótipo , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Transporte de Nucleosídeos/genética , Testes Farmacogenômicos , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Proteína Carregadora de Folato Reduzido/genética , Timidilato Sintase/genética , Resultado do TratamentoRESUMO
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.
Assuntos
Uridina Difosfato Ácido N-Acetilmurâmico/síntese química , Fenômenos Químicos , Química , Cromatografia Líquida de Alta Pressão , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , FosforilaçãoRESUMO
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.
