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1.
Clin Infect Dis ; 69(1): 130-136, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-30281074

RESUMO

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) often result from intraluminal microbial colonization and are associated with morbidity, mortality, and substantial costs. The use of antimicrobial catheter lock solutions may reduce the incidence of CLABSI. METHODS: Patients undergoing hemodialysis (HD) through a prevalent central venous catheter (CVC) were randomly assigned to have their CVC locked between dialysis sessions with an antimicrobial catheter lock solution that contained trimethoprim 5 mg/mL, ethanol 25%, and Ca-EDTA 3% (investigational medical device [IMD]) or heparin 5000 U/mL active control heparin (ACH). Exit site care was standardized by protocol-driven use of skin antiseptics and occlusive dressings. The composite primary endpoint consisted of the incidence of CLABSI and intracatheter thrombolytic treatment (TT). Given the viscosity and odor of the IMD, blinding was impossible. Therefore, a blinded endpoint committee adjudicated the incidence of CLABSI. RESULTS: A total of 270 patients on HD were enrolled and followed for 43738 CVC-days. Despite the low CLABSI incidence of 0.41/1000 CVC-days in patients randomized to ACH, the IMD further reduced the incidence 4.56-fold to 0.09/1000 CVC-days (P < .03). The product was well tolerated, and the frequency and severity of adverse events were comparable between groups. Intracatheter instillation of thrombolytics was more frequent in patients who received the IMD (12% ACH, 40% IMD; P < .001), but rates of catheter removal did not differ (13% ACH, 11% IMD). Overall, dialysis adequacy was comparable between groups. CONCLUSIONS: In patients on chronic HD, a trimethoprim, ethanol, and Ca-EDTA lock solution significantly reduced the incidence of CLABSI. CLINICAL TRIALS REGISTRATION: NCT01989091.


Assuntos
Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/prevenção & controle , Catéteres , Ácido Edético/química , Etanol/química , Diálise Renal/instrumentação , Trimetoprima/química , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/química , Anti-Infecciosos Locais/química , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
2.
J Med Chem ; 48(5): 1596-609, 2005 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-15743201

RESUMO

Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Técnicas de Química Combinatória , Cristalização , Desenho de Fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Relação Estrutura-Atividade
3.
J Med Chem ; 46(26): 5663-73, 2003 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-14667220

RESUMO

The structure-based design, synthesis, and biological activity of a novel indazole-containing inhibitor series for S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Use of 5-aminoindazole as the core scaffold provided a structure-guided series of low nanomolar inhibitors with broad-spectrum antimicrobial activity. The implementation of structure-based methodologies provided a 6000-fold increase in potency over a short timeline (several months) and an economy of synthesized compounds.


Assuntos
Antibacterianos/síntese química , Indazóis/síntese química , N-Glicosil Hidrolases/antagonistas & inibidores , Sulfonamidas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Indazóis/química , Indazóis/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , N-Glicosil Hidrolases/química , Neisseria meningitidis/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
4.
Curr Eye Res ; 24(2): 86-91, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12187478

RESUMO

PURPOSE: We studied the effects of intravitreally administered prinomastat on the take rate and growth of uveal melanoma after xenograft implantation in rabbit uveal melanoma model. METHODS: Uveal melanoma xenograft was implanted to suprachoroidal space in each eye of 24 pigmented rabbits which were immunosuppressed with cyclosporine. One week after surgery, the eyes were randomized to receive prinomastat or the vehicle of the prinomastat intravitreally every week for 4 weeks. The take rate of the xenograft, tumor height, apoptosis, and necrosis in the eyes which developed tumors from the treatment and control groups were compared. RESULTS: A tumor mass was identified in 8 of 24 (33%) prinomastat-treated eyes and 20 of 24 (83%) of the vehicle-treated eyes. Echographic measurements revealed a mean tumor height of 2.2 mm in the prinomastat-treated group and 3.8 mm in the control group in those eyes with take of tumor (p < 0.001). Stereomicroscopic measurements showed a mean tumor height of 1.9 mm in the treatment group and 3.9 mm in the control group (p < 0.001). The mean number of apoptotic nuclei detected per mm(2) of the histologic section in the non-necrotic tumor was 8.12 in the prinomastat-treated group and 0.57 in the control group (p < 0.001). Evaluation of the digital images in microscopic sections of the tumors on histologic slides revealed 29.6% necrosis in prinomastat-treated eyes as compared to 10.9% in vehicle-treated eyes (p = 0.003). CONCLUSIONS: These results suggest that prinomastat treatment significantly reduces the take rate and the growth rate of xenograft in uveal melanoma rabbit model.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Metaloproteinases de Matriz , Melanoma Experimental/patologia , Compostos Orgânicos , Neoplasias Uveais/patologia , Animais , Apoptose/efeitos dos fármacos , Fundo de Olho , Humanos , Melanoma Experimental/fisiopatologia , Camundongos , Camundongos SCID , Transplante de Neoplasias , Coelhos , Transplante Heterólogo , Neoplasias Uveais/fisiopatologia
5.
Curr Eye Res ; 24(1): 33-8, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12187492

RESUMO

PURPOSE: To study the activity of the novel anti-angiogenic compound AG3340 (Prinomastat), a selective inhibitor of matrix metalloproteases, in an animal model of retinal neovascularization. METHODS: C57BL/6J mice were used to produce oxygen-induced retinal neovascularization. Mice were exposed to room air from birth (P0) to postnatal 7 days (P7) and to hyperoxia (75% oxygen) for the next 5 days. On postnatal day 12 (P12) the animals were returned to the room air and were treated until postnatal day 16 (P16) with intraperitoneal injections of AG 3340. Four groups were assigned: no drug, 1.6 mg/kg/day, 16 mg/kg/day and 48 mg/kg/day. On day 17 (P17) the animals were sacrificed and the eyes prepared for histological sectioning. Preretinal neovascularization was assessed by counting neovascular nuclei of endothelial cells in the preretinal side of the internal limiting membrane (ILM). The use of animals for this study complies with the ARVO guidelines for animal research. RESULTS: AG3340 administered systemically by intraperitoneal injections inhibited hypoxia-induced retinal neovascularization. The inhibition was dose dependent with highly significant decrease of neovascular nuclei counts among eyes treated with 0, 1.6 mg/kg, 16 mg/kg and 48 mg/kg doses. There appears to be a saturation effect of inhibition at the level of 70% at the two highest doses of 16 mg/kg and 48 mg/kg. CONCLUSIONS: AG3340 administered systemically significantly inhibits oxygen-induced retinal neovascularization in an animal model and appears to be a promising candidate for the treatment of neovascular retinal diseases.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Metaloendopeptidases/antagonistas & inibidores , Compostos Orgânicos , Neovascularização Retiniana/tratamento farmacológico , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipóxia/complicações , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/patologia
6.
FEBS Lett ; 583(17): 2939-46, 2009 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-19665020

RESUMO

FabH (beta-ketoacyl-acyl carrier protein synthase III) is unique in that it initiates fatty acid biosynthesis, is inhibited by long-chain fatty acids providing means for feedback control of the process, and dictates the fatty acid profile of the organism by virtue of its substrate specificity. We report the crystal structures of bacterial FabH enzymes from four different pathogenic species: Enterococcus faecalis, Haemophilus influenzae, Staphylococcus aureus and Escherichia coli. Structural data on the enzyme from different species show important differences in the architecture of the substrate-binding sites that parallel the inter-species diversity in the substrate specificities of these enzymes.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , Proteínas de Bactérias/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Enterococcus faecalis/enzimologia , Escherichia coli/enzimologia , Haemophilus influenzae/enzimologia , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Alinhamento de Sequência , Staphylococcus aureus/enzimologia , Especificidade por Substrato
7.
Bioorg Med Chem Lett ; 14(12): 3165-8, 2004 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15149667

RESUMO

The structure-based design, synthesis, and biological activity of novel inhibitors of S-adenosyl homocysteine/methylthioadenosine (SAH/MTA) nucleosidase are described. Using 6-substituted purine and deaza purines as the core scaffolds, a systematic and structure guided series of modifications provided low nM inhibitors with broad-spectrum antimicrobial activity.


Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , N-Glicosil Hidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Homocisteína/antagonistas & inibidores , Homocisteína/metabolismo , N-Glicosil Hidrolases/metabolismo , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/metabolismo , Purinas/síntese química , Purinas/farmacologia , Relação Estrutura-Atividade
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