RESUMO
Acquired haemophilia was diagnosed following detailed investigation of a post-partum haemorrhage unresponsive to standard management. Circulating factor VIII inhibitors and low factor VIII levels were detected and intravenous DDAVP treatment lead to a resolution of symptoms. This case highlights the importance of haematological investigations in persisting post-partum haemorrhage.
Assuntos
Fator VIII/imunologia , Hemorragia Pós-Parto/imunologia , Adulto , Autoanticorpos , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/uso terapêutico , Fator VIII/análise , Feminino , Hemofilia A/imunologia , Hemostáticos/uso terapêutico , Humanos , Tempo de Tromboplastina Parcial , Hemorragia Pós-Parto/tratamento farmacológico , Ácido Tranexâmico/uso terapêuticoRESUMO
The design, synthesis, biochemical, and biological evaluation of a novel series of 5-thia-2,6-diamino-4(3H)-oxopyrimidine inhibitors of glycinamide ribonucleotide transformylase (GART) are described. The compounds were designed using the X-ray crystal structure of human GART. The monocyclic 5-thiapyrimidinones were synthesized by coupling an alkyl thiol with 5-bromo-2, 6-diamino-4(3H)-pyrimidinone, 20. The bicyclic compounds were prepared in both racemic and diastereomerically pure forms using two distinct synthetic routes. The compounds were found to have human GART KiS ranging from 30 microM to 2 nM. The compounds inhibited the growth of both L1210 and CCRF-CEM cells in culture with potencies down to the low nanomolar range and were found to be selective for the de novo purine biosynthesis pathway. The most potent inhibitors had 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene ring to give compounds 10, 18, and 19 resulted in inhibitors with significantly decreased mFBP affinity.
