RESUMO
BACKGROUND: The decision to extubate brain-injured patients with residual impaired consciousness holds a high degree of uncertainty of success. The authors developed a pragmatic clinical score predictive of extubation failure in brain-injured patients. METHODS: One hundred and forty brain-injured patients were prospectively included after the first spontaneous breathing trial success. Assessment of multiparametric hemodynamic, respiratory, and neurologic functions was performed just before extubation. Extubation failure was defined as the need for ventilatory support during intensive care unit stay. Extubation failure within 48 h was also analyzed. Neurologic outcomes were recorded at 6 months. RESULTS: Extubation failure occurred in 43 (31%) patients with 31 (24%) within 48 h. Predictors of extubation failure consisted of upper-airway functions (cough, gag reflex, and deglutition) and neurologic status (Coma Recovery Scale-Revised visual subscale). From the odds ratios, a four-item predictive score was developed (area under the curve, 0.85; 95% CI, 0.77 to 0.92) and internally validated by bootstrap. Cutoff was determined with sensitivity of 92%, specificity of 50%, positive predictive value of 82%, and negative predictive value of 70% for extubation failure. Failure before and beyond 48 h shared similar risk factors. Low consciousness level patients were extubated with 85% probability of success providing the presence of at least two operating airway functions. CONCLUSIONS: A simplified clinical pragmatic score assessing cough, deglutition, gag reflex, and neurologic status was developed in a preliminary prospective cohort of brain-injured patients and was internally validated (bootstrapping). Extubation appears possible, providing functioning upper airways and irrespective of neurologic status. Clinical practice generalizability urgently needs external validation.
Assuntos
Extubação/estatística & dados numéricos , Lesões Encefálicas/complicações , Desmame do Respirador/estatística & dados numéricos , Extubação/métodos , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/fisiopatologia , Estudos de Coortes , Tosse/diagnóstico , Tosse/fisiopatologia , Deglutição/fisiologia , Feminino , Engasgo/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Respiração Artificial/estatística & dados numéricos , Fatores de Risco , Sensibilidade e Especificidade , Falha de Tratamento , Desmame do Respirador/métodosRESUMO
A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/farmacologia , Técnicas de Química Combinatória , Metaloendopeptidases/antagonistas & inibidores , Metaloendopeptidases/farmacologia , Naftalenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Inibidores da Enzima Conversora de Angiotensina/síntese química , Enzimas Conversoras de Endotelina , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/químicaRESUMO
Iron- and cobalt-catalyzed cross-couplings between iodo-azetidines, -pyrrolidines, -piperidines, and Grignard reagents are disclosed. The reaction is efficient, cheap, chemoselective and tolerates a large variety of (hetero)aryl Grignard reagents.
Assuntos
Azetidinas/química , Cobalto/química , Ferro/química , Piperidinas/química , Pirrolidinas/química , Catálise , Técnicas de Química Combinatória , Indicadores e Reagentes , Estrutura MolecularRESUMO
The immunodominant epitope of bovine type II collagen (CII256-270) in Aq mice carries a hydroxylysine-264 linked galactose (Gal-Hyl264), the recognition of which is central to the development of collagen-induced arthritis. This study explores the molecular interactions involved in the engagement of T-cell receptors (TCRs) with such epitopes. Responses of three anti-CII T-cell hybridomas and clone A9.2 (all sharing close TCR sequences) to a panel of CII256-270 analogues incorporating Gal-Hyl264 with a modified side chain were determined. Recognition of naturally occurring CII256-270 peptides by either group of T cells depended strictly upon the presence of the carbohydrate and, more precisely, its intact HO-4 group. Modifications of primary amino group on the hydroxylysine side chain eliminated T-cell reactivity, notwithstanding the presence of the galactosyl moiety. Moderate stereochemical changes, such as altered sugar orientation and methylation at the galactose anchor position, were still permissive. Conversely, robust transformations affecting the relative positions of the key elements were detrimental to TCR recognition. To conclude, these data provide strong new experimental evidence that integrity of both galactose HO-4 and hydroxylysine side chain primary amino groups are mandatory for activation of anti-Gal-Hyl264 TCRs. They also indicate that there is a certain degree of TCR plasticity in peptide-TCR interactions.
Assuntos
Artrite Experimental/metabolismo , Epitopos de Linfócito T/metabolismo , Galactose/química , Galactose/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Sítios de Ligação/fisiologia , Bovinos , Epitopos de Linfócito T/química , Camundongos , Camundongos Endogâmicos DBA , Conformação MolecularRESUMO
A series of azacyclic phosphonic acids were synthesized from L-pyroglutamic acid, 6-oxo-L-pipecolic acid, and their enantiomers. The objective was to study the effect of constraining acyclic inhibitors of endothelin converting enzyme on inhibitory activity. Potential pharmacophoric tethers were introduced by stereocontrolled reactions to give highly substituted pyrrolidine- and piperidine-alpha-phosphonic acids. Weak inhibitory activity was observed for one diastereomer in each series having the same relative orientation of substituents.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Aza/síntese química , Compostos Aza/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Compostos Aza/química , Desenho de Fármacos , Enzimas Conversoras de Endotelina , Inibidores Enzimáticos/química , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Conformação Molecular , Sensibilidade e Especificidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Five analogues of the bovine type II collagen (bCII) immunodominant glycopeptide [beta-D-Gal-(5R)-5-Hyl264]CII(256-270) (1) carrying diverse modifications at the critical hydroxylysine (Hyl) 264 side chain were designed and synthesised, to explore the fine specificity of bCII-reactive T cells involved in the initiation and/or regulation of collagen-induced arthritis (CIA), a mouse model for rheumatoid arthritis (RA). Beta-D-galactosyl-(5R)-5-hydroxy-L-lysine (19) and corresponding mimetics (22-25), conveniently protected for solid-phase synthesis, were all obtained by a divergent route involving enantiopure 5-hydroxylated 6-oxo-1,2-piperidinedicarboxylates as the key intermediates. All three bCII-specific T hybridomas used, as well as a recurrent pathogenic CD4+ T-cell clone isolated from bCII-immunised DBA/1 mice, recognised the galactosylated form 1 of the immunodominant bCII (256-270) epitope. These cells were extremely sensitive to changes at the epsilon-amino group of Hyl264, but differed in their pattern of recognition of analogues with a Hyl264 side chain modified at C-5 (i.e. inversion of stereochemistry, methylation). These data further document the importance of collagen post-translational modifications in autoimmunity and in the CIA model in particular, and provide a new insight into the molecular interaction between glycopeptide 1 and the TCR of pathogenic T cells.
Assuntos
Artrite Experimental/imunologia , Linfócitos T CD4-Positivos/imunologia , Colágeno Tipo II/química , Glicopeptídeos/síntese química , Hidroxilisina/análogos & derivados , Animais , Autoimunidade/imunologia , Materiais Biomiméticos/química , Colágeno Tipo II/imunologia , Glicopeptídeos/imunologia , Hidroxilisina/imunologia , Epitopos Imunodominantes/imunologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos DBARESUMO
X-ray studies reveal that tert-butyl (6S)-6-isobutyl-2,4-dioxopiperidine-1-carboxylate occurs in the 4-enol form, viz. tert-butyl (6S)-4-hydroxy-6-isobutyl-2-oxo-1,2,5,6-tetrahydropyridine-1-carboxylate, C14H23NO4, when crystals are grown from a mixture of dichloromethane and pentane, and has an axial orientation of the isobutyl side chain at the 6-position of the piperidine ring. Reduction of the keto functionality leads predominantly to the corresponding beta-hydroxylated delta-lactam, tert-butyl (4R,6S)-4-hydroxy-6-isobutyl-2-oxopiperidine-1-carboxylate, C14H25NO4, with a cis configuration of the 4-hydroxy and 6-isobutyl groups. The two compounds show similar molecular packing driven by strong O-H...O=C hydrogen bonds, leading to infinite chains in the crystal structure.
RESUMO
The crystal structure of (6S)-6-isobutylpiperidine-2,4-dione, C9H15NO2, shows that the keto tautomer is favoured in the solid state. The reduction of the keto functionality leads to the corresponding 4-hydroxy-6-isobutylpiperidin-2-one, C9H17NO2, with an 84:16 cis/trans ratio, containing the 4R,6S and 4S,6S isomers; the ratio of the two isomers was determined by NMR analysis of the reaction mixture. Crystals obtained from the mixture of both isomers have been studied and shown to contain the isomers in a 86:14 ratio. Hence, both X-ray and NMR analyses show that crystallization does not select the major diastereomer formed by the reduction. In both crystal structures, the two independent molecules dimerize through an R2(2)(8) hydrogen-bond motif between adjacent amide groups.
RESUMO
A novel resin called DEUSS (perdeuterated poly(oxyethylene)-based solid support) has been prepared by anionic polymerization of deuterated [D4]ethylene oxide, followed by cross-linking with deuterated epichlorohydrin. DEUSS can be suspended in a wide range of solvents including organic and aqueous solutions, in which it displays a high swelling capacity. As measured by proton HRMAS of the swollen polymer, the signal intensity of the oxyethylene protons is reduced by a factor of 110 relative to the corresponding nondeuterated poly(oxyethylene)poly(oxypropylene) (POEPOP) resin, thus facilitating detailed HRMAS NMR studies of covalently linked molecules. This 1H NMR invisible matrix was used for the solid-phase synthesis of peptides, oligoureas, and a series of amides as well as their characterization by HRMAS NMR spectroscopy. On-bead NMR spectra of high quality and with resolution comparable to that of liquid samples were obtained and readily interpreted. The complete absence of the parasite resin signals will be of great advantage, for example, for the optimization of multistep solid-phase stereoselective reactions, and for the conformational study of resin-bound molecules in a large variety of solvents.