Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Solid State Nucl Magn Reson ; 106: 101642, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-32035327

RESUMO

Characterization of lipid based (SPC/GDO/H2O) liquid crystal (LC) drug delivery system is non-trivial and highly complex, especially when multiple and intermediate phases are present. The phase behavior of such mixtures during hydration or delivery is still poorly understood and therefore, characterizing these systems is crucially important towards controlling their function and enhancing the understanding of their drug release behavior. Current work has established an easy way to identify liquid crystal phases and phase mixtures using deuterium (2H) solid-state nuclear magnetic (NMR) spectroscopy under static conditions without disrupting the three dimensional structure and phases, as magic-angle spinning (MAS) could lead to disruption of the phases. Small angle X-ray scattering (SAXS) technique and optical microscopy were also employed to corroborate the study.

2.
Nanomaterials (Basel) ; 9(10)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569757

RESUMO

Graphene powders obtained via the reduction of graphene oxide flakes have been widely used in various applications as they can be synthesized in large quantities with outstanding properties. The electrical conductivity of graphene powders is critical for their uses in fabricating high-performance devices or materials. Here, we investigated the bulk electrical conductivity of reduced graphene oxide (rGO) powders depending on the applied pressure and additional thermal annealing. The electrical conductivity of the rGO powders was correlated with the change in the carbon-to-oxygen ratio via additional thermal reduction. Furthermore, the effect of the morphology of the rGO powders was studied through electromechanical measurements. This study provides a reliable method for the electromechanical characterization of rGO powders and a better understanding of the electrical conductivity of graphene-based materials.

3.
Org Lett ; 21(22): 9198-9202, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31647672

RESUMO

This communication highlights the use of chiral sulfinamides as nitrogen nucleophiles in intermolecular aza-Michael reactions. When chiral sulfinamides are coupled to a chloroethyl group, the corresponding novel annulating reagents can be used to streamline the stereoselective synthesis of complex pyrrolidine-containing molecules. As a result, it has enabled a medicinal chemistry campaign for the synthesis of biologically active RORγt inverse agonists.

4.
Nat Commun ; 10(1): 3620, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399593

RESUMO

Composite metal-organic frameworks (MOFs) tend to possess complex interfaces that prevent facile and rational design. Here we present a joint computational/experimental workflow that screens thousands of MOFs and identifies the optimal MOF pairs that can seamlessly connect to one another by taking advantage of the fact that the metal nodes of one MOF can form coordination bonds with the linkers of the second MOF. Six MOF pairs (HKUST-1@MOF-5, HKUST-1@IRMOF-18, UiO-67@HKUST-1, PCN-68@MOF-5, UiO-66@MIL-88B(Fe) and UiO-67@MIL-88C(Fe)) yielded from our theoretical predictions were successfully synthesized, leading to clean single crystalline MOF@MOF, demonstrating the power of our joint workflow. Our work can serve as a starting point to accelerate the discovery of novel MOF composites that can potentially be used for many different applications.

5.
Injury ; 50(7): 1364-1370, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31182230

RESUMO

BACKGROUND: There has been heightened interest in the effect of osteoanabolic agents on acceleration of fracture healing. OBJECTIVES: The purpose of this study was to identify whether short-term daily teriparatide prescribed for osteoporosis treatment would improve postoperative outcomes including clinical scores, radiographic healing, and complication rates. METHODS: Between 2014 and 2017, we retrospectively assessed 112 patients who underwent closed reduction and internal fixation with proximal femoral nail (PFN) for unstable intertrochanteric fractures. In 60 of 112 patients, patients were treated with a PFN alone (group I). These patients were compared with 52 patients for whom the same device was used and a daily subcutaneous injection of teriparatide (1-34 PTH, Forsteo®) was prescribed postoperatively (group II). Teriparatide was administered by nurses during a hospital stay and then self-injection was monitored by follow-up visits to the outpatient clinic after discharge. Questionnaire surveys were conducted and patients completed a self-report Harris hip score (HHS) and visual analog scale (VAS) scores. RESULTS: Teriparatide therapy significantly increased HHS (p = 0.02) and decreased VAS pain scores (p = 0.008). The mean time to fracture healing post-operatively was 14.8 weeks (SD 7.1) and 12.1 weeks (SD 6.4) in group I and II, respectively (p = 0.002). The frequency of patients reporting postoperative complications was also markedly reduced in the teriparatide-treated groups (p = 0.028). CONCLUSIONS: Short-term daily teriparatide used for osteoporosis treatment improved radiographic fracture healing of a hip fracture and reduced complication rates. However, because of the limited power of the study, additional randomized placebo-controlled trials are needed to determine the potential benefit of PTH as an adjunct to enhance fracture healing and its efficacy in broader populations with varying comorbidities and fracture types.

6.
J Ethnopharmacol ; 239: 111912, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029758

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acer tegmentosum Maxim (AT), the East Asian stripe maple, is an herb used to treat liver disease and is approved as a functional food in Korea. AT protects against hepatic disorders, atopic dermatitis, and diabetes mellitus. AIM OF THE STUDY: We explored the mechanism of the hepatoprotective effects of AT extract in in vitro and in vivo levels. MATERIALS AND METHODS: AT extract from Acer tegmentosum Maxim was extracted by hot water. Hepatoprotective effects of AT extract were confirmed using carbon tetrachloride (CCl4)- or alcohol-induced mouse model, and H2O2- or alcohol-induced HepG2 (liver hepatocellular carcinoma cell line) cells by measuring GOT, GPT, TG, and MDA levels. Hematoxylin and eosin (H&E) staining was used to observe the pathological analysis. Cytotoxicity or protective effect of AT extract was confirmed using MTT assay in HepG2 cells. Antioxidant effect of AT extract was measured using DPPH or H2DCFDA assay. Mechanism study of antioxidant and autophagy was carried out using western blotting and immunofluorescence analysis. RESULTS: AT extract increased the viability of HepG2 cells treated with H2O2 and ethanol, and protected the liver against damage induced by CCl4 and alcohol. The AT extract increased the levels of nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1 (HO-1). The level of microtubule-associated protein light chain 3 (LC3)-Ⅱ, beclin-1, autophagy-related genes (Atg) such as Atg3 and Atg12-5 as markers of autophagy activation was also increased. Moreover, the AT extract increased activation of mitogen-activated protein kinase (MAPK), which regulated autophagy and HO-1. CONCLUSION: Therefore, these results indicate that the AT extract has a hepatoprotective effect by increasing antioxidant activity and inducing autophagy.


Assuntos
Acer , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Tetracloreto de Carbono , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Extratos Vegetais/farmacologia , Caules de Planta , Espécies Reativas de Oxigênio/metabolismo
7.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891145

RESUMO

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

8.
BMC Complement Altern Med ; 19(1): 55, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841887

RESUMO

BACKGROUND: Mulberry is a Korean medicinal herb that shows effective prevention and treatment of obesity and diabetes. Bioconversion is the process of producing active ingredients from natural products using microorganisms or enzymes. METHODS: In this study, we prepared bioconverted mulberry leaf extract (BMLE) with Viscozyme L, which we tested in insulin-sensitive cells (i.e., skeletal muscle cells and adipocytes) and insulin-secreting pancreatic ß-cells, as well as obese diabetic mice induced by co-administration of streptozotocin (100 mg/kg, IP) and nicotinamide (240 mg/kg, IP) and feeding high-fat diet, as compared to unaltered mulberry leaf extract (MLE). RESULTS: BMLE increased the glucose uptake in C2C12 myotubes and 3 T3-L1 adipocytes and increased glucose-stimulated insulin secretion in HIT-T15 pancreatic ß-cells. The fasting blood glucose levels in diabetic mice treated with BMLE or MLE (300 and 600 mg/kg, PO, 7 weeks) were significantly lower than those of the vehicle-treated group. At the same concentration, BMLE-treated mice showed better glucose tolerance than MLE-treated mice. Moreover, the blood concentration of glycated hemoglobin (HbA1C) in mice treated with BMLE was lower than that in the MLE group at the same concentration. Plasma insulin levels in mice treated with BMLE or MLE tended to increase compared to the vehicle-treated group. Treatment with BMLE yielded significant improvements in insulin resistance and insulin sensitivity. CONCLUSION: These results indicate that in the management of diabetic condition, BMLE is superior to unaltered MLE due to at least, in part, high concentrations of maker compounds (trans-caffeic acid and syringaldehyde) in BMLE.


Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Morus/química , Extratos Vegetais/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Hipoglicemiantes/metabolismo , Resistência à Insulina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/metabolismo , Folhas de Planta/química
9.
AAPS PharmSciTech ; 19(8): 3462-3480, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30411240

RESUMO

The impact of pharmaceutical materials properties on drug product quality and manufacturability is well recognised by the industry. An ongoing effort across industry and academia, the Manufacturing Classification System consortium, aims to gather the existing body of knowledge in a common framework to provide guidance on selection of appropriate manufacturing technologies for a given drug and/or guide optimization of the physical properties of the drug to facilitate manufacturing requirements for a given processing route. Simultaneously, material scientists endeavour to develop characterisation methods such as size, shape, surface area, density, flow and compactibility that enable a stronger understanding of materials powder properties. These properties are routinely tested drug product development and advances in instrumentation and computing power have enabled novel characterisation methods which generate larger, more complex data sets leading to a better understanding of the materials. These methods have specific requirements in terms of data management and analysis. An appropriate data management strategy eliminates time-consuming data collation steps and enables access to data collected for multiple methods and materials simultaneously. Methods ideally suited to extract information from large, complex data sets such as multivariate projection methods allow simpler representation of the variability contained within the data and easier interpretation of the key information it contains. In this review, an overview of the current knowledge and challenges introduced by modern pharmaceutical material characterisation methods is provided. Two case studies illustrate how the incorporation of multivariate analysis into the material sciences workflow facilitates a better understanding of materials.


Assuntos
Indústria Farmacêutica , Tecnologia Farmacêutica , Desenvolvimento de Medicamentos , Pós
10.
J Orthop Surg (Hong Kong) ; 26(3): 2309499018802485, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30296889

RESUMO

Slow recovery after hip fracture has been associated with negative consequences. Thus, there is medical need to improve healing and functional recovery after intertrochanteric fracture. The aim of this study was to measure whether short-term teriparatide would improve healing in intertrochanteric fractures after internal fixation as measured by (1) clinical scores, (2) radiographic fracture healing, and (3) complication rates. We retrospectively reviewed 96 patients (average age, 82 years) who underwent closed reduction and internal fixation with proximal femoral nail (PFN) for unstable intertrochanteric fractures between 2014 and 2016. Of the 96 patients, 56 patients were treated with a PFN alone (group 1). These patients were compared with 46 patients for whom the same device was used and a weekly subcutaneous injection of PTH 1-34 (teriparatide) was prescribed postoperatively (group 2). Questionnaire surveys or telephone interviews were conducted, and patients completed a self-report Harris hip score and visual analog scale scores. The radiological time to fracture healing was assessed as the primary end point. Postoperative complication rates were compared. Functional outcomes at 6 months after surgery were similar in both groups. There were no differences between groups in the proportion of patients achieving radiographic fracture healing. The frequency of patients reporting adverse events was 20% (10 of 50) in group 1 versus 17% (8 of 46) in group 2 ( p = 0.744). Short-term teriparatide did not improve radiographic signs of fracture healing of an intertrochanteric fracture and reduce the incidence of complications. The effect of teriparatide on fracture healing remains uncertain. Further multicenter prospective studies are needed to demonstrate objective long-term results of parathyroid hormone therapy in patient with hip fracture. LEVEL OF EVIDENCE: Level IV, therapeutic study.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Fixação Interna de Fraturas , Consolidação da Fratura/efeitos dos fármacos , Fraturas do Quadril/cirurgia , Teriparatida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
11.
Maxillofac Plast Reconstr Surg ; 40(1): 22, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30206538

RESUMO

Background: Cross-facial nerve graft is considered the treatment of choice for facial reanimation in patients with unilateral facial palsy caused by central facial nerve damage. In most cases, a traditional parotidectomy skin incision is used to locate the buccal and zygomatic branches of the facial nerve. Methods: In this study, cross-facial nerve graft with the sural nerve was planned for three patients with facial palsy through an intraoral approach. Results: An incision was made on the buccal cheek mucosa, and the dissection was performed to locate the buccal branch of the facial nerve. The parotid papillae and parotid duct were used as anatomic landmarks to locate the buccal branch. Conclusions: The intraoral approach is more advantageous than the conventional extraoral approach because of clear anatomic marker (parotid papilla), invisible postoperative scar, reduced tissue damage from dissection, and reduced operating time.

12.
J Korean Med Sci ; 33(35): e220, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30140190

RESUMO

Background: We aimed to estimate whether elevated levels of complement C3a and C5a in amniotic fluid (AF) are independently associated with increased risks of intra-amniotic infection and/or inflammation (IAI) and spontaneous preterm delivery (SPTD) in women with cervical insufficiency or a short cervix (≤ 25 mm). Methods: We conducted a retrospective cohort study of 96 consecutive women with cervical insufficiency (n = 62) or a short cervix (n = 34) at 17 to 27 weeks, and who underwent an amniocentesis. AF was cultured and analyzed for C3a and C5a by enzyme-linked immunosorbent assay kits. The primary outcome measures were IAI (defined as a positive AF culture and/or an elevated AF interleukin-6 level [≥ 7.6 ng/mL]) and SPTD at < 32 weeks. Results: In multivariable analysis, AF level of C3a was the only variable significantly associated with IAI, whereas C5a level in AF and serum C-reactive protein level were not associated with IAI. Using SPTD at < 32 weeks as the outcome variable in logistic regression, elevated AF levels of C3a were associated with increased risk of SPTD at < 32 weeks after adjusting for other baseline confounders, whereas elevated AF levels of C5a were not. Conclusion: In women with cervical insufficiency or a short cervix, elevated AF level of C3a, but not C5a, is independently associated with increased risks of IAI and SPTD at < 32 weeks. These findings suggest that subclinical IAI or SPTD in the context of cervical insufficiency is related to activation of complement system in AF.


Assuntos
Complemento C3a/análise , Adulto , Amniocentese , Líquido Amniótico , Colo do Útero , Corioamnionite , Complemento C5a , Feminino , Idade Gestacional , Humanos , Inflamação , Gravidez , República da Coreia , Estudos Retrospectivos , Seul
13.
PLoS One ; 13(7): e0200311, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29979758

RESUMO

OBJECTIVE: We aimed to assess the correlations among multiple cytokine concentrations in the maternal plasma, cervicovaginal fluid (CVF), and amniotic fluid (AF) compartments in women with preterm premature rupture of membranes (pPROM), and to develop a prediction model based on non-invasive measures, having better sensitivity and specificity for the identification of microbial invasion of amniotic cavity (MIAC). METHOD: This retrospective study included 75 consecutive women with pPROM (20+0-34+0 weeks), who underwent amniocentesis. Both maternal plasma and CVF samples were collected at the time of amniocentesis. Stored AF, plasma and CVF samples were assayed for cytokine levels [interleukin (IL)-6, IL-8, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1ß] using a multiplex immunoassay kit. RESULTS: Levels of inflammatory proteins measured in the CVF were significantly correlated with AF proteins levels, whereas none of the proteins in plasma correlated significantly with any in the AF or CVF. Proteins levels measured in the AF and CVF were significantly higher in women with MIAC compared to those without, whereas only high levels of IL-6 in plasma were significantly associated with MIAC. By using stepwise regression analysis, a non-invasive model (using clinical factors and CVF cytokine levels) for the prediction of MIAC was developed; the area under curve of this non-invasive model was similar to that of the invasive model (using clinical factors and AF cytokines). CONCLUSIONS: The levels of inflammatory proteins in the CVF correlated with those in the AF, whereas those in the plasma showed no correlation. A non-invasive model using clinical factors and CVF cytokine levels predicted the risk of MIAC in women with pPROM.


Assuntos
Líquido Amniótico/metabolismo , Corioamnionite/diagnóstico , Citocinas/metabolismo , Ruptura Prematura de Membranas Fetais/diagnóstico , Infecções por Mycoplasma/diagnóstico , Infecções por Ureaplasma/diagnóstico , Adulto , Líquido Amniótico/microbiologia , Corioamnionite/metabolismo , Corioamnionite/microbiologia , Citocinas/sangue , Feminino , Ruptura Prematura de Membranas Fetais/metabolismo , Ruptura Prematura de Membranas Fetais/microbiologia , Humanos , Mycoplasma/isolamento & purificação , Infecções por Mycoplasma/metabolismo , Infecções por Mycoplasma/microbiologia , Gravidez , Prognóstico , Estudos Retrospectivos , Ureaplasma/isolamento & purificação , Infecções por Ureaplasma/metabolismo , Infecções por Ureaplasma/microbiologia , Adulto Jovem
14.
Org Lett ; 20(14): 4218-4222, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29956545

RESUMO

Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent stereogenic centers using the combination of N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.

15.
PLoS One ; 13(6): e0198842, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29879190

RESUMO

OBJECTIVE: To determine whether vitamin D-binding protein (VDBP) in cervicovaginal fluid (CVF) is independently predictive of intra-amniotic infection and imminent spontaneous preterm delivery (SPTD, delivery within 48 hours) in women with preterm labor with intact membranes (PTL) or preterm premature rupture of membranes (PPROM). METHOD: This was a single-center retrospective cohort study. CVF samples for VDBP assays were obtained along with serum C-reactive protein (CRP) levels immediately after amniocentesis in consecutive women with PTL (n = 148) or PPROM (n = 103) between 23.0 and 34.0 weeks of gestation. VDBP levels in CVF were determined by enzyme-linked immunosorbent assay kits. The primary outcome measures were intra-amniotic infection [defined as positive amniotic fluid (AF) culture] and SPTD within 48 hours after sampling. RESULTS: In the multivariable analysis, elevated VDBP levels in CVF samples of PTL women were significantly associated with intra-amniotic infection and imminent preterm delivery, even after adjusting for potential confounders (e.g., gestational age at sampling, parity, and serum CRP). However, these relationships were not found in women with PPROM. In women with PTL, the areas under receiver operating characteristic curves of CVF VDBP level for predicting intra-amniotic infection and imminent preterm delivery were 0.66 and 0.71, with cut-off values of 1.76 µg/mL (sensitivity of 64.3% and specificity of 78.4%) and 1.37 µg/mL (sensitivity of 65.4% and specificity of 72.6%), respectively. The CVF VDBP levels were significantly higher in women with PPROM than in those with PTL. CONCLUSIONS: VDBP in the CVF independently predicts intra-amniotic infection and imminent preterm delivery in women with PTL, whereas in women with PPROM, an elevated VDBP level in CVF is not associated with increased risks of these two outcome variables.


Assuntos
Infecções Bacterianas/metabolismo , Líquidos Corporais/metabolismo , Ruptura Prematura de Membranas Fetais/metabolismo , Trabalho de Parto Prematuro/metabolismo , Complicações Infecciosas na Gravidez/metabolismo , Proteína de Ligação a Vitamina D/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , Valor Preditivo dos Testes , Gravidez , Estudos Retrospectivos
16.
Korean J Physiol Pharmacol ; 22(3): 349-360, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29719457

RESUMO

Autophagy has been studied as a therapeutic strategy for cardiovascular diseases. However, insufficient studies have been reported concerning the influence of vascular smooth muscle cells (VSMCs) through autophagy regulation. The aim of the present study was to determine the effects of VSMCs on the regulation of autophagy under in vitro conditions similar to vascular status of the equipped microtubule target agent-eluting stent and increased release of platelet-derived growth factor-BB (PDGF-BB). Cell viability and proliferation were measured using MTT and cell counting assays. Immunofluorescence using an anti-α-tubulin antibody was performed to determine microtubule dynamic formation. Cell apoptosis was measured by cleavage of caspase-3 using western blot analysis, and by nuclear fragmentation using a fluorescence assay. Autophagy activity was assessed by microtubule-associated protein light chain 3-II (LC-II) using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured using H2DCFDA. The proliferation and viability of VSMCs were inhibited by microtubule regulation. Additionally, microtubule-regulated and PDGF-BB-stimulated VSMCs increased the cleavage of caspase-3 more than only the microtubule-regulated condition, similar to that of LC3-II, implying autophagy. Inhibitory autophagy of microtubule-regulated and PDGF-BB-stimulated VSMCs resulted in low viability. However, enhancement of autophagy maintained survival through the reduction of ROS. These results suggest that the apoptosis of conditioned VSMCs is decreased by the blocking generation of ROS via the promotion of autophagy, and proliferation is also inhibited. Thus, promoting autophagy as a therapeutic target for vascular restenosis and atherosclerosis may be a good strategy.

17.
ACS Med Chem Lett ; 9(5): 472-477, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795762

RESUMO

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

18.
BMC Pregnancy Childbirth ; 18(1): 146, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743041

RESUMO

BACKGROUND: We investigated whether various inflammatory and immune proteins in plasma predict intra-amniotic infection and imminent preterm delivery in women with preterm labor and compared their predictive ability with that of amniotic fluid (AF) interleukin (IL)-6 and serum C-reactive protein (CRP). METHODS: This retrospective cohort study included 173 consecutive women with preterm labor who underwent amniocentesis for diagnosis of infection and/or inflammation in the AF. The AF was cultured, and assayed for IL-6. CRP levels and cervical length by transvaginal ultrasound were measured at the time of amniocentesis. The stored maternal plasma was assayed for IL-6, matrix metalloproteinase (MMP)-9, and complements C3a and C5a using ELISA kits. The primary and secondary outcome criteria were positive AF cultures and spontaneous preterm delivery (SPTD) within 48 h, respectively. Univariate, multivariate, and receiver operating characteristic analysis were used for the statistical analysis. RESULTS: In bivariate analyses, elevated plasma IL-6 level was significantly associated with intra-amniotic infection and imminent preterm delivery, whereas elevated plasma levels of MMP-9, C3a, and C5a were not associated with these two outcomes. On multivariate analyses, an elevated plasma IL-6 level was significantly associated with intra-amniotic infection and imminent preterm delivery after adjusting for confounders, including high serum CRP levels and short cervical length. In predicting intra-amniotic infection, the area under the curve (AUC) was significantly lower for plasma IL-6 than for AF IL-6 but was similar to that for serum CRP. Differences in the AUCs between plasma IL-6, AF IL-6, and serum CRP were not statistically significant in predicting imminent preterm delivery. CONCLUSIONS: Maternal plasma IL-6 independently predicts intra-amniotic infection in women with preterm labor; however, it has worse diagnostic performance than that of AF IL-6 and similar performance to that of serum CRP. To predict imminent preterm delivery, plasma IL-6 had an overall diagnostic performance similar to that of AF IL-6 and serum CRP. Plasma MMP-9, C3a, and C5a levels could not predict intra-amniotic infection or imminent preterm delivery.


Assuntos
Amniocentese/estatística & dados numéricos , Corioamnionite/imunologia , Trabalho de Parto Prematuro/imunologia , Complicações Infecciosas na Gravidez/imunologia , Nascimento Prematuro/imunologia , Adulto , Líquido Amniótico/imunologia , Líquido Amniótico/microbiologia , Proteína C-Reativa/análise , Medida do Comprimento Cervical , Corioamnionite/sangue , Corioamnionite/microbiologia , Complemento C3a/análise , Complemento C5a/análise , Feminino , Idade Gestacional , Humanos , Interleucina-6/análise , Interleucina-6/sangue , Testes para Triagem do Soro Materno , Metaloproteinase 9 da Matriz/sangue , Análise Multivariada , Trabalho de Parto Prematuro/microbiologia , Valor Preditivo dos Testes , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/microbiologia , Nascimento Prematuro/microbiologia , Curva ROC , Estudos Retrospectivos
19.
J Org Chem ; 83(7): 3928-3940, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29557160

RESUMO

An efficient, concise enantioselective total synthesis of the potent antitumor antibiotic (+)-duocarmycin SA is described. The invented route is based on a disconnection strategy that was devised to facilitate rapid and efficient synthesis of key core compounds to enable preclinical structure-activity relationship investigations. The key tricycle core was constructed with a highly enantioselective indole hydrogenation to set the stereocenter and a subsequent hitherto unexplored vicarious, nucleophilic-substitution/cyclization sequence to effectively forge a final indole ring. Additionally, the development of a stable sulfonamide protecting group capable of mild chemoselective cleavage greatly enhanced sequence yield and throughput. An understanding of key reaction parameters ensured a robust, reproducible sequence easily executable on decagram scales to this highly promising class of compounds.


Assuntos
Indóis/química , Indóis/síntese química , Ciclização , Hidrogenação , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Estereoisomerismo
20.
Pediatr Neonatol ; 59(6): 586-594, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29428705

RESUMO

BACKGROUND: We aimed to identify prenatal and postnatal risk factors associated with abnormal newborn hearing screen (NHS) results and subsequently confirmed sensorineural hearing loss (SNHL) in preterm twin neonates. METHODS: Electronic medical records of 159 twin neonates who were born alive after ≤32 weeks were retrospectively reviewed for hearing loss in both ears. Histopathologic examination of the placenta was performed and clinical data, including method of conception and factors specific to twins, were retrieved from a computerized perinatal database. The main outcome measure was failure to pass the NHS test. The generalized estimation equations model was used for twins. RESULTS: Thirty-two neonates (20.1%) had a "refer" result, and, on the confirmation test, permanent SNHL was identified in 4.4% (7/159) of all neonates. Neonates who had a "refer" result on the NHS test were more likely to be of lower birth weight, more likely to have been conceived with the use of in vitro fertilization (IVF), and more likely to have higher rates of intraventricular hemorrhage (IVH) and bronchopulmonary dysplasia. However, monochorionic placentation, death of the co-twin, or being born first was not associated with a "refer" result on the NHS test. Multivariable logistic regression revealed that conception after IVF and the presence of IVH were the only variables to be statistically significantly associated with "refer" on the NHS test. No parameters studied were found to be significantly different between the SNHL and no SNHL groups, probably because of the relatively small number of cases of SNHL. CONCLUSION: In preterm twin newborns, IVF and the presence of IVH were independently associated with an increased risk of abnormal NHS results, whereas the factors specific to twins were not associated with abnormal NHS results.


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Testes Auditivos , Triagem Neonatal , Displasia Broncopulmonar/epidemiologia , Hemorragia Cerebral Intraventricular/epidemiologia , Feminino , Fertilização In Vitro , Perda Auditiva Neurossensorial/epidemiologia , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Gravidez , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Gêmeos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA