Predominance of KPC-3 in a survey for carbapenemase-producing Enterobacteriaceae in Portugal.

Among the 2,105 Enterobacteriaceae tested in a survey done in Portugal, 165 were nonsusceptible to carbapenems, from which 35 (26 Klebsiella pneumoniae, 3 Escherichia coli, 2 Enterobacter aerogenes, and 3 Enterobacter cloacae isolates and 1 Klebsiella oxytoca isolate) were confirmed to be carbapenemase producers by the presence of 30 Tn4401d-blaKPC-3, 4 intI3-blaGES-5, and one intI1-blaVIM-2 gene, alone or in combination with other bla genes. The dissemination of blaKPC-3 gene carried by an IncF plasmid suggests lateral gene transfer as a major mechanism of dissemination.

Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215).

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.

Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor.

A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.

N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent.

N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.

Pyrrolopyridazine MEK inhibitors.

The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6.

A unified approach to the tedanolides: total synthesis of (+)-13-deoxytedanolide.

A unified approach for the construction of the potent marine antitumor agents (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) is described. Highlights of the synthetic strategy include the development of a versatile bifunctional dithiane-vinyl iodide linchpin, the unorthodox use of the Evans-Tishchenko reaction, and a late-stage high-risk stereocontrolled introduction of the C(18,19) epoxide to achieve a total synthesis of (+)-13-deoxytedanolide (2).

Total synthesis of (+)-13-deoxytedanolide.

In this communication we describe the first total synthesis of (+)-13-deoxytedanolide, an architecturally complex marine macrolide possessing significant antitumor activity. The cornerstone of the synthesis comprises a highly convergent dithiane coupling used to construct the carbon skeleton, followed by a novel use of the Evans-Tishchenko reduction to oxidize the C(1) aldehyde to an ester in the presence of the oxidatively labile dithiane.

Reflexões sobre a adesão terapêutica no adoecimento crônico e suas implicações para a atenção primária à saúde

A experiência foi obtida entre maio e dezembro de 2017. Adesão terapêutica por usuários com doenças crônicas e reflexões sobre a lógica prescritiva versus autonomia pessoal. Têm-se como objetivo relatar dilemas e reflexões obtidas a partir do cuidado a pacientes portadores de condições crônicas no nível primário de atenção à saúde. Trata-se de um relato de experiência de cunho reflexivo e dialético que foi obtido através do cuidado a pacientes portadores de Hipertensão Arterial Sistêmica (HAS) e Diabetes Mellitus (DM) em uma Unidade Básica de Saúde com Estratégia de Saúde da Família do município do Rio de Janeiro/RJ. As reflexões emergiram de atendimentos individuais e coletivos realizados entre de maio a dezembro de 2017. A partir da inserção em um serviço de atenção primária, os autores se depararam com um cenário de baixo índice de acompanhamento dos portadores de HAS e DM, relacionado, principalmente, ao abandono do tratamento. Surgiram, então, inquietações no tocante às relações de poder, a autonomia dos usuários e a frustração dos trabalhadores. A lógica prescritiva faz com que o processo do trabalho se dê numa perspectiva de obediência dos pacientes aos conhecimentos soberanos dos profissionais. Na atualidade, a alta carga de doenças crônicas lança alguns desafios para a saúde, dentre os quais se encontra a adesão ao tratamento. Por essas doenças serem predominantemente silenciosas, o autocuidado, a modificação dos estilos de vida e a adesão medicamentosa podem ser objetivos de difícil manejo. Os profissionais devem conhecer os fatores que influenciam a adesão e devem, conjuntamente, construir intervenções que respeitem a autonomia e o protagonismo dos sujeitos frente ao seu tratamento. Dessa forma, torna-se fundamental olhar para a singularidade dos sujeitos na medida em que cada um se relaciona de uma forma com o tratamento. Para que exista a adesão, a terapêutica deve fazer sentido para a pessoa e deve estar alinhada ao contexto sociocultural e aos hábitos individuais. O plano terapêutico deve ser firmado entre profissional e paciente, de maneira que este seja reconhecido como sujeito ativo de seu processo saúde-doença.