RESUMO
The Health Insurance Marketplace was designed to increase the affordability of health insurance. The success of the marketplace depends on people's awareness and use of it. In a statewide mail survey of West Virginians, we found that respondents' awareness of the West Virginia Health Insurance Marketplace increased from 2013 to 2014. However, large percentages of respondents continued to be unaware of the availability of federal subsidies and were unsure of their personal eligibility for these subsidies. It is essential that awareness and enrollment efforts continue and that they be expanded in novel ways to continue growth in access to health insurance through the marketplace.
Assuntos
Conscientização , Trocas de Seguro de Saúde/organização & administração , Adulto , Definição da Elegibilidade , Feminino , Trocas de Seguro de Saúde/economia , Política de Saúde , Humanos , Masculino , Assistência Médica , Pessoa de Meia-Idade , Fatores Socioeconômicos , West VirginiaRESUMO
ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Assuntos
Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Cilastatina/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Imipenem/química , Inibidores de beta-Lactamases , Cilastatina/farmacologia , Combinação Imipenem e Cilastatina , Cristalografia por Raios X , Combinação de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Imipenem/farmacologia , Concentração Inibidora 50 , Klebsiella/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Pseudomonas/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
Assuntos
Antibacterianos/química , Inibidores Enzimáticos/química , Monobactamas/síntese química , Inibidores de beta-Lactamases , Antibacterianos/síntese química , Antibacterianos/farmacologia , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Monobactamas/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , beta-Lactamases/metabolismoRESUMO
Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.
Assuntos
Carbapenêmicos/química , Descoberta de Drogas/métodos , Imipenem/química , Inibidores de beta-Lactamases , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carbapenêmicos/farmacologia , Combinação de Medicamentos , Imipenem/farmacologia , Camundongos , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/enzimologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Relação Estrutura-Atividade , Resistência beta-Lactâmica/efeitos dos fármacos , Resistência beta-Lactâmica/fisiologia , beta-Lactamases/metabolismoRESUMO
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Assuntos
Receptor alfa de Estrogênio/antagonistas & inibidores , Indóis/química , Indóis/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Ligantes , Útero/efeitos dos fármacosRESUMO
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Assuntos
Androstenodiol/análogos & derivados , Androstenodiol/farmacologia , Receptor beta de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Androstenodiol/síntese química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Moduladores Seletivos de Receptor Estrogênico/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
Assuntos
Cromanos/química , Cromanos/farmacologia , Receptor alfa de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Sítios de Ligação , Linhagem Celular , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Modelos Químicos , Estrutura Molecular , Tamanho do Órgão , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Útero/efeitos dos fármacosRESUMO
The CphA metallo-beta-lactamase from Aeromonas hydrophilia has been expressed, purified and crystallized by the hanging-drop vapor-diffusion method using ammonium sulfate as the precipitant. The crystals exhibit orthorhombic symmetry (P2(1)2(1)2), with unit-cell parameters a = 40.75, b = 42.05, c = 128.88 A. There is one monomer in the asymmetric unit and the solvent content is estimated to be 44% by volume. A data set extending to 1.8 A has been measured.
Assuntos
Aeromonas hydrophila/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , beta-Lactamases/química , beta-Lactamases/genética , Proteínas de Bactérias/isolamento & purificação , Cristalografia por Raios X , Escherichia coli/enzimologia , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Transfecção , Difração de Raios X , beta-Lactamases/isolamento & purificaçãoRESUMO
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Assuntos
Oxati-Inas/farmacologia , Pirrolidinas/química , Receptores de Estrogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Ligantes , Modelos Moleculares , Oxati-Inas/química , Receptores de Estrogênio/metabolismoRESUMO
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.