Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.002
Filtrar
1.
Chemosphere ; 287(Pt 4): 132394, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34592213

RESUMO

This work investigates the reaction of 1-vinyl-2-pyrrolidinone (VP) and 2-piperazin-1-yletanamine (PPE) under UV radiation. Both substances are high-volume production chemicals (production >1000 tons/year) widely used in polymers, coatings and a wide array of applications, which have been classified as mobile chemicals and which can then lead to the formation of persistent and mobile transformation products (TPs). Thus, their reaction with UV light was studied by means of liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-QTOF-MS). Both compounds presented a high reactivity, the VP quantum yield was 0.28 mol/E; whereas, PPE had a quantum yield notably higher than 1 (16 mol/E). Five and 7 TPs were identified for VP and PPE, respectively. Some of them had been already reported in literature due to sunlight photodegradation or other oxidation processes, but most of them are reported here for the first time. Finally, the acute and chronical toxicity of precursors and TPs were estimated using two quantitative structure-activity relationship (QSAR) software tools which led to some discrepancies in the estimations, pointing to the need for experimental toxicity assays for these compounds.


Assuntos
Raios Ultravioleta , Poluentes Químicos da Água , Cromatografia Líquida , Fotólise , Pirrolidinonas , Poluentes Químicos da Água/análise
2.
J Agric Food Chem ; 69(46): 14037-14047, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34780189

RESUMO

Tea market is currently oversupplied, and unsold tea often needs to be properly stored for a period of time. However, the chemical changes occurring in black tea during storage are limitedly understood. In this study, a comprehensive nontargeted and targeted metabolomics approach was used to investigate the dynamic changes in compounds in time-series (0-19 months)-stored black teas. The contents of flavanols, theaflavins (TFs), theasinensins, procyanidins, most phenolic acids, amino acids, quercetin-O-glycosides, and myricetin-O-glycosides decreased during storage, while the contents of N-ethyl-2-pyrrolidinone-substituted flavanols, flavone-C-glycosides, and most kaempferol-O-glycosides increased. More importantly, four novel compounds strongly positively correlated with storage duration (r = 0.922-0.969) were structurally assigned as N-ethyl-2-pyrrolidinone-substituted TFs and validated with synthetic reactions of TFs and theanine standards. The content of N-ethyl-2-pyrrolidinone-substituted TFs was 51.54 µg/g in black tea stored for 19 months. To the best of our knowledge, N-ethyl-2-pyrrolidinone-substituted TFs were discovered in tea for the first time.


Assuntos
Camellia sinensis , Catequina , Biflavonoides , Catequina/análise , Metabolômica , Pirrolidinonas , Chá
3.
Nat Commun ; 12(1): 6055, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663813

RESUMO

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/administração & dosagem , Indóis/administração & dosagem , Leucina/administração & dosagem , Pirrolidinonas/administração & dosagem , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacocinética , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/farmacocinética , Animais , COVID-19/virologia , Chlorocebus aethiops , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano 229E/enzimologia , Inibidores de Protease de Coronavírus/efeitos adversos , Inibidores de Protease de Coronavírus/farmacocinética , Modelos Animais de Doenças , Desenho de Fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HeLa , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Infusões Intravenosas , Leucina/efeitos adversos , Leucina/farmacocinética , Camundongos , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/enzimologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Células Vero
4.
Int J Hyg Environ Health ; 238: 113856, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34619432

RESUMO

Toxicologically and/or epidemiologically derived guidance values referring to the internal exposure of humans are a prerequisite for an easy to use health-based interpretation of human biomonitoring (HBM) results. The European Joint Programme HBM4EU derives such values, named human biomonitoring guidance values (HBM-GVs), for priority substances which could be of regulatory relevance for policy makers and have been identified by experts of the participating countries, ministries, agencies and stakeholders at EU and national level. NMP and NEP are such substances for which unresolved policy relevant issues should be clarified by targeted research. Since widespread exposure of the general population in Germany to NMP and NEP was shown for the age groups 3-17 years and 20-29 years, further investigations on exposure to NMP and NEP in other European countries are warranted. The HBM-GVs derived for both solvents focus on developmental toxicity as decisive endpoint. They amount for the sum of the two specific urinary NMP metabolites 5-HNMP and 2-HMSI and likewise of the two specific urinary NEP metabolites 5-HNEP and 2-HESI to 10 mg/L for children and 15 mg/L for adolescents/adults. The values were determined following a consultation process on the value proposals within HBM4EU. A health-based risk assessment was performed using the newly derived HBM-GVGenPop and exposure data from two recent studies from Germany. The risk assessment revealed that even when considering the combined exposure to both substances by applying the Hazard Index approach, the measured concentrations are below the HBM-GVGenPop in all cases investigated (i.e., children, adolescents and young adults).


Assuntos
Monitoramento Biológico , Pirrolidinonas , Adolescente , Criança , Pré-Escolar , Monitoramento Ambiental , Humanos , Solventes/análise , Adulto Jovem
5.
Biochemistry ; 60(39): 2925-2931, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34506130

RESUMO

Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2. In this study, the crystal structures of rupintrivir were determined bound to enterovirus 68 (EV68) 3C protease and the 3C-like main protease (Mpro) from SARS-CoV-2. While the EV68 3C protease-rupintrivir structure was similar to previously determined complexes with other picornavirus 3C proteases, rupintrivir bound in a unique conformation to the active site of SARS-CoV-2 Mpro splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.


Assuntos
Antivirais/metabolismo , Proteases 3C de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Isoxazóis/metabolismo , Fenilalanina/análogos & derivados , Pirrolidinonas/metabolismo , SARS-CoV-2/enzimologia , Valina/análogos & derivados , Antivirais/química , Domínio Catalítico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/química , Enterovirus Humano D/enzimologia , Ligação de Hidrogênio , Isoxazóis/química , Fenilalanina/química , Fenilalanina/metabolismo , Ligação Proteica , Pirrolidinonas/química , Eletricidade Estática , Valina/química , Valina/metabolismo
6.
J Chromatogr A ; 1655: 462534, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34509123

RESUMO

In this work, three new mixed-mode stationary phases were prepared, based on different ratio of N-vinyl pyrrolidone (NVP) copolymerized together with undecylenic acid (UA) on silica microspheres surface without silanization, which named Sil@NVPUA series. The combination of NVP and UA rendered the Sil@NVPUA suitable for reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC), and shown excellent methyl, planar, isomers and ion selectivity. Five types of model analytes including eight polycyclic aromatic hydrocarbons, six alkylbenzenes, eight nucleosides and nucleobases, seven ginsenosides and five oxazolidinones can be well separated on this stationary phase. The preparation method of NVP and UA modified silica-based stationary phase is simple, and it also provides a new idea for the design of synthetic polymers to develop mixed-mode chromatography.


Assuntos
Cromatografia de Fase Reversa , Dióxido de Silício , Interações Hidrofóbicas e Hidrofílicas , Pirrolidinonas , Ácidos Undecilênicos
7.
ACS Appl Mater Interfaces ; 13(33): 38969-38978, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34399054

RESUMO

Controlling the microstructure of materials by means of phase separation is a versatile tool for optimizing material properties. Phase separation has been exploited to fabricate intricate microstructures in many fields including cell biology, tissue engineering, optics, and electronics. The aim of this study was to use phase separation to tailor the spatial location of drugs and thereby generate release profiles of drug payload over periods ranging from 1 week to months by exploiting different mechanisms: polymer degradation, polymer diluent dissolution, and control of microstructure. To achieve this, we used drop-on-demand inkjet three-dimensional (3D) printing. We predicted the microstructure resulting from phase separation using high-throughput screening combined with a model based on the Flory-Huggins interaction parameter and were able to show that drug release from 3D-printed objects can be predicted from observations based on single drops of mixtures. We demonstrated for the first time that inkjet 3D printing yields controllable phase separation using picoliter droplets of blended photoreactive oligomers/monomers. This new understanding gives us hierarchical compositional control, from droplet to device, allowing release to be "dialled up" without manipulation of device geometry. We exemplify this approach by fabricating a biodegradable, long-term, multiactive drug delivery subdermal implant ("polyimplant") for combination therapy and personalized treatment of coronary heart disease. This is an important advance for implants that need to be delivered by cannula, where the shape is highly constrained and thus the usual geometrical freedoms associated with 3D printing cannot be easily exploited, which brings a hitherto unseen level of understanding to emergent material properties of 3D printing.


Assuntos
Anti-Hipertensivos/química , Doença das Coronárias/tratamento farmacológico , Portadores de Fármacos/química , Excipientes/química , Indóis/química , Polímeros/química , Anti-Hipertensivos/farmacologia , Dioxanos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Indóis/farmacologia , Metacrilatos/química , Transição de Fase , Poliésteres/química , Impressão Tridimensional , Pirrolidinonas/química , Relação Estrutura-Atividade
8.
J Org Chem ; 86(17): 11845-11861, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34378926

RESUMO

We report synthesis of two diastereomeric structures previously proposed for the complex secondary metabolite pseurotin A2. Both structures were accessed from the same building blocks taking advantage of a stereodivergent nickel(II)-diamine-catalyzed 1,4-addition of a chiral 2-alkoxycarbonyl-3(2H)-furanone. Late-stage Csp-Csp3 cross-coupling of a highly functionalized bromoalkyne featured in the pseurotin A2 side-chain assembly. The work supports the 2016 stereochemical revision of pseurotin A2 and represents the first chemical synthesis of this natural product.


Assuntos
Produtos Biológicos , Pirrolidinonas , Estereoisomerismo
9.
Phytochemistry ; 190: 112851, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34217043

RESUMO

Fungal endophytes are remarkable sources of biologically active metabolites of ecological and pharmacological significance. In this study, fungal isolates producing yellow pigments and originating from grass roots, were identified as the recently described grass root colonizing dark septate endophyte (DSE), Flavomyces fulophazii (Periconiaceae, Pleosporales). While analyzing the metabolite composition of 17 isolates of this fungus, 11 previously undescribed compounds, including four tetramic acids (dihydroxyvermelhotin, hydroxyvermelhotin, methoxyvermelhotin, oxovermelhotin), and seven chlorinated azaphilones (flavochlorines A-G), together with the known tetramic acid vermelhotin, were tentatively identified by high performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS). Among them, flavochlorine A, flavochlorine G, hydroxyvermelhotin and vermelhotin could be isolated by preparative HPLC, thus their structures were also confirmed by nuclear magnetic resonance (NMR) spectroscopy. Vermelhotin was found to be the main compound, reaching its maximum level of 5.5 mg/g in the in vitro cultures of a selected F. fulophazii isolate. A significant amount of vermelhotin was isolated by preparative HPLC from these cultures (4.8 mg from 1.0 g lyophilized culture), confirming the practical utility of F. fulophazii in high-yield vermelhotin production. The main compounds of this endophyte expressed no activity in standardized plant bioassays (i.e., in the Lactuca sativa seed germination and Lemna minor growth tests). An antiproliferative study of the isolated compounds confirmed moderate activity of vermelhotin against a panel of twelve cancer cell lines, with IC50 ranges of 10.1-37.0 µM, without inhibiting the non-cancer Vero cells, suggesting its selectivity towards cancers.


Assuntos
Ascomicetos , Espectrometria de Massas em Tandem , Animais , Benzopiranos , Chlorocebus aethiops , Endófitos , Pigmentos Biológicos , Pirrolidinonas , Células Vero
10.
J Med Econ ; 24(1): 939-948, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34311671

RESUMO

AIMS: To study the association between initiation of first adjunctive therapy with eslicarbazepine acetate (ESL) vs. brivaracetam (BRV) on healthcare resource utilization (HCRU) and charges among patients with treated focal seizures (FS). MATERIALS AND METHODS: Symphony Health's Integrated Dataverse (IDV) claims data (1 April 2015 to 30 June 2018) were used to identify two cohorts as first adjunctive therapy with ESL or BRV following a generic anti-seizure drug (ASD). The index date was the earliest claim for a new ESL or BRV prescription. Key inclusion criteria were only 1 generic ASD in the 12 months before the index date; ≥1 medical claim with an FS diagnosis. Unit of analysis was the 90-day person-time-block. Changes in HCRU and charges were assessed using a difference-in-differences framework. Both unadjusted and adjusted analyses were performed. The adjusted model utilized person-specific fixed effects and propensity score-based weighting to control for differences in baseline covariates. Bias-corrected bootstrap confidence intervals (CIs) were calculated for charge outcomes. RESULTS: 208 and 137 patients initiated first adjunctive therapy with ESL (43.7 years, 51.9% female) or BRV (39.3 years, 51.8% female). Patients in the ESL cohort had numerically larger reductions in all-cause and FS-related inpatient hospitalizations and outpatient visits and FS-related emergency department visits. Compared to patients initiating BRV, patients treated with ESL had significantly larger reductions in total charges (-$3,446, CI: -$13,716, -$425), all-cause (-$3,166, CI: -$13,991, -$323) and FS-related (-$2,969, CI: -$21,547, -$842) medical charges, all-cause (-$3,397, CI: -$15,676, -$818) and FS-related (-$2,863, CI: -$19,707, -$787) outpatient charges, and non-ASD-related prescription charges (-$420, CI: -$1,058, -$78). LIMITATIONS: Claims may be missing, or miscoded; outcomes may be influenced by variables not accounted for in the analysis; only information on submitted charges was included. CONCLUSIONS: Among patients with FS, initiation of first adjunctive therapy with ESL was associated with significantly larger reductions in medical and non-ASD-related prescriptions charges compared to BRV.


Assuntos
Anticonvulsivantes , Dibenzazepinas , Custos de Cuidados de Saúde , Pirrolidinonas , Convulsões , Anticonvulsivantes/economia , Anticonvulsivantes/uso terapêutico , Dibenzazepinas/economia , Dibenzazepinas/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pirrolidinonas/economia , Pirrolidinonas/uso terapêutico , Convulsões/tratamento farmacológico , Resultado do Tratamento
11.
ACS Chem Biol ; 16(7): 1288-1297, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34232635

RESUMO

Inducing the formation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs) represents a potential approach to repairing the loss of myelin observed in multiple sclerosis and other diseases. Recently, we demonstrated that accumulation of specific cholesterol precursors, 8,9-unsaturated sterols, is a dominant mechanism by which dozens of small molecules enhance oligodendrocyte formation. Here, we evaluated a library of 56 sterols and steroids to evaluate whether other classes of bioactive sterol derivatives may also influence mouse oligodendrocyte precursor cell (OPC) differentiation or survival. From this library, we identified U-73343 as a potent enhancer of oligodendrocyte formation that induces 8,9-unsaturated sterol accumulation by inhibition of the cholesterol biosynthesis enzyme sterol 14-reductase. In contrast, we found that mouse OPCs are remarkably vulnerable to treatment with the glycosterol OSW-1, an oxysterol-binding protein (OSBP) modulator that induces Golgi stress and OPC death in the low picomolar range. A subsequent small-molecule suppressor screen identified mTOR signaling as a key effector pathway mediating OSW-1's cytotoxic effects in mouse OPCs. Finally, evaluation of a panel of ER and Golgi stress-inducing small molecules revealed that mouse OPCs are highly sensitive to these perturbations, more so than closely related neural progenitor cells. Together, these studies highlight the wide-ranging influence of sterols and steroids on OPC cell fate, with 8,9-unsaturated sterols positively enhancing differentiation to oligodendrocytes and OSW-1 able to induce lethal Golgi stress with remarkable potency.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Esteróis/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Colestenonas/farmacologia , Colestenonas/toxicidade , Avaliação Pré-Clínica de Medicamentos , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estrenos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Pirrolidinonas/farmacologia , Saponinas/farmacologia , Saponinas/toxicidade , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/toxicidade , Esteróis/toxicidade
13.
Org Lett ; 23(16): 6194-6199, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34324347

RESUMO

The 5S, 8'R, and 10'R configurations of militarinone B (3), which is a natural product from Paecilomyces militaris, should equal those in its biosynthetic precursor, militarinone C. The configuration at C-1' emerged from syntheses of the militarinone B candidates 1''S- and 1''R-(5S,8'R,10'R)-3 from the building blocks 9, 11, 14, and 15a while introducing TMB as a more acid-labile N-protecting group for ß-ketoamides than DMB. Comparisons of 1''S- and 1''R-(5S,8'R,10'R)-3 with natural militarinone B (3; reisolated from Nature) revealed identity versus distinctness.


Assuntos
Amidas/química , Piridonas/síntese química , Pirrolidinonas/química , Estrutura Molecular
14.
BMC Pulm Med ; 21(1): 208, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210314

RESUMO

BACKGROUND: Molecular targeted therapy for non-small cell lung carcinoma (NSCLC) is restricted due to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). This study evaluated the effects of dual targeting of MEK and PI3K in human EGFR-TKI resistant NSCLC cell lines. METHODS: EGFR-TKI resistant NSCLC cell lines H1975, H460, and A549, with different mutation and amplification status in EGFR, K-RAS, PIK3CA, and MET genes, were treated with a MEK162 (MEK inhibitor) and BKM120 (PI3K inhibitor) combination or a BIBW2992 (EGFR inhibitor) and ARQ197 (MET inhibitor) combination and assayed for cell proliferation, apoptosis, and cell cycle distribution. RESULTS: Dual targeting of MEK and PI3K efficiently inhibited the cell proliferation, induced apoptosis and the G0/G1 cell cycle, and decreased the phosphorylation of ERK1/2, AKT, S6, and 4E-BP1. H460 cells with K-RAS and PIK3CA mutation were most sensitive to MEK162 and BKM120 combinations. H1975 cells with EGFR and PIK3CA mutation and MET amplification were sensitive to BIBW2992 and ARQ197 combinations. CONCLUSION: Dual targeting regulated the proliferation of EGFR-TKI-resistant NSCLC cells, especially mutants in K-RAS and PIK3CA that are promising for EGFR-TKI-resistant NSCLC therapeutics.


Assuntos
Afatinib/farmacologia , Aminopiridinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Morfolinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinonas/farmacologia , Quinolinas/farmacologia
15.
Adv Ther ; 38(7): 4082-4099, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34155568

RESUMO

INTRODUCTION: The aim was to evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with severely drug-resistant focal seizures versus adults with less drug-resistant disease. METHODS: Data were pooled from patients with focal seizures on 1-2 concomitant antiseizure medications (ASMs) randomized to BRV 50, 100, 200 mg/day, or placebo in 3 phase 3 trials (N01252 [NCT00490035], N01253 [NCT00464269], and N01358 [NCT01261325]) with a 12-week treatment period. Outcomes were assessed in patients with ≥ 5 and 0-4 previous ASMs (stopped before trial drug initiation). RESULTS: In ≥ 5 previous ASMs subgroup (BRV 50, 100, 200 mg/day: n = 26, n = 137, n = 120; placebo: n = 151), percentage reduction over placebo in 28-day adjusted focal seizure frequency was 13.0% for 50 mg/day (p = 0.38), 18.1% for 100 mg/day (p = 0.006), 19.8% for 200 mg/day (p = 0.004), and 17.0% for all BRV-treated patients (p = 0.001). The 50% responder rate was 26.9%, 29.9%, 30.0%, and 29.7% for BRV 50, 100, 200, and 50-200 mg/day, respectively (placebo: 13.2%); odds ratios versus placebo were statistically significant (p < 0.05) for BRV 100, 200, and 50-200 mg/day. In 0-4 previous ASMs subgroup (BRV 50, 100, 200 mg/day: n = 135, n = 195, n = 129; placebo: n = 267), all BRV dosages showed statistically significant (1) percentage reduction over placebo in 28-day adjusted focal seizure frequency (21.4-28.7%); (2) differences from placebo in median percentage reduction in 28-day adjusted focal seizure frequency from baseline (35.5-45.9%; placebo: 21.3%); and (3) odds ratios versus placebo (favoring BRV) for 50% responder rates. In BRV-treated patients, treatment-emergent adverse event (TEAE) incidence (73.8% [217/294] vs. 64.6% [329/509]) and discontinuation due to TEAEs (10.5% vs. 4.5%) were higher in the ≥ 5 versus 0-4 previous ASMs subgroup; serious TEAEs were rare in both subgroups (≥ 5 previous ASMs: 3.1%; 0-4 previous ASMs: 2.9%). CONCLUSION: Adjunctive BRV showed efficacy and was generally well tolerated in adults with focal seizures independent of the number of previous ASMs.


Assuntos
Anticonvulsivantes , Convulsões , Adulto , Anticonvulsivantes/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Pirrolidinonas , Convulsões/tratamento farmacológico , Resultado do Tratamento
16.
J Biomed Nanotechnol ; 17(5): 846-858, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34082871

RESUMO

The blood-retina barrier (BRB), analogous to the blood-brain barrier, is a major hurdle for the passage of drugs from the blood to the central nervous system. Here, we designed polymeric nanoparticles from amphiphilic poly-/V-vinylpyrrolidone (Amph-PVP NPs) as a new carrier-system and investigated their ability to pass the BRB using a live In-Vivo neuroimaging system for the retina in rats and ex-vivo wholemounted retinae preparation. Amph-PVP NPs were loaded with hydrophobic fluorescent markers as a surrogate for hydrophobic drugs. Linking these NPs with the hydrophobic fluorescence marker Carboxyfluorescein-succinimidyl-ester (CFSE) to the surface, induced the passage of the cargo into the retina tissue. In particular, we observed a substantial internalization of the CFSE-linked NPs into blood cells. We propose surface- modified Amph-PVP NPs as a potential new nano-carrier platform to target posterior eye and potentially brain diseases while camouflaged by blood cells.


Assuntos
Nanopartículas , Animais , Barreira Hematoencefálica , Neuroimagem , Pirrolidinonas , Ratos , Retina
17.
Spectrochim Acta A Mol Biomol Spectrosc ; 262: 120097, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34182296

RESUMO

Formation of catechins-human serum albumin (HSA) complex contributes to stably transporting catechins and regulating their bioavailability. Recently, a new class of catechins namely flavoalkaloids have been reported from tea. The unique structural modification with an N-ethyl-2-pyrrolidinone ring at catechins from these flavoalkaloids has raised our interest in their HSA binding affinity. Thus, we investigated the interaction between HSA and flavoalkaloids by molecular docking, UV-Vis spectroscopy (UV), fluorescence quenching approaches, and surface plasmon resonance (SPR). Thermodynamic parameters suggest that electrostatic forces contribute greatly to the interaction. The binding ability is affected by different ester group (galloyl or cinnamoyl) at 3-OH, N-ethyl-2-pyrrolidinone substituted position (C-6 or C-8), C-2, C-3 and C-5''' configurations, and hydroxyl group numbers at B ring, among which the 3-O-cinnamoyl substitution and 5'''-R configuration present the strongest contributions. UV showed slight changes in the conformation and microenvironment of HSA during the binding process. The quenching and binding constants suggest that the quenching is a static type. The small KD values (1-20 µM) detected by SPR confirmed the strong binding affinities between HSA and flavoalkaloids. Present study will help us to understand the interaction mechanism between flavoalkaloids and HSA, shedding light on structural modification of common catechins to enhance the stability, bioavailability and bioactivities.


Assuntos
Catequina/química , Pirrolidinonas , Albumina Sérica Humana , Chá/química , Alcaloides/química , Sítios de Ligação , Dicroísmo Circular , Flavanonas/química , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Espectrometria de Fluorescência , Termodinâmica
18.
Biomolecules ; 11(6)2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067463

RESUMO

Submerged mycelial cultures of the ascomycete Colpoma quercinum CCTU A372 were found to produce five previously undescribed tetramic acids, for which we propose the trivial names colposetins A-C (1-3) and colpomenoic acids A and B (4 and 5), along with the known compounds penicillide (6) and monodictyphenone (7). The planar structures of 1-5 were determined by high-resolution electrospray ionization mass spectrometry (HR-ESIMS) and extensive 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Their absolute configurations were determined by the combination of electronic circular dischroism (ECD) analysis, J-based configurational analysis, and a rotating-frame Overhauser effect spectroscopy (ROESY) experiment. Colposetin B displayed weak antimicrobial activity against Bacillus subtilis and Mucor hiemalis (MIC 67 µg/mL).


Assuntos
Ascomicetos/química , Bacillus subtilis/crescimento & desenvolvimento , Mucor/crescimento & desenvolvimento , Micélio/química , Pirrolidinonas , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Irã (Geográfico) , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia
19.
Neuroimage ; 238: 118236, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34091034

RESUMO

The mismatch in the spatial resolution of Arterial Spin Labeling (ASL) MRI perfusion images and the anatomy of functionally distinct tissues in the brain leads to a partial volume effect (PVE), which in turn confounds the estimation of perfusion into a specific tissue of interest such as gray or white matter. This confound occurs because the image voxels contain a mixture of tissues with disparate perfusion properties, leading to estimated perfusion values that reflect primarily the volume proportions of tissues in the voxel rather than the perfusion of any particular tissue of interest within that volume. It is already recognized that PVE influences studies of brain perfusion, and that its effect might be even more evident in studies where changes in perfusion are co-incident with alterations in brain structure, such as studies involving a comparison between an atrophic patient population vs control subjects, or studies comparing subjects over a wide range of ages. However, the application of PVE correction (PVEc) is currently limited and the employed methodologies remain inconsistent. In this article, we outline the influence of PVE in ASL measurements of perfusion, explain the main principles of PVEc, and provide a critique of the current state of the art for the use of such methods. Furthermore, we examine the current use of PVEc in perfusion studies and whether there is evidence to support its wider adoption. We conclude that there is sound theoretical motivation for the use of PVEc alongside conventional, 'uncorrected', images, and encourage such combined reporting. Methods for PVEc are now available within standard neuroimaging toolboxes, which makes our recommendation straightforward to implement. However, there is still more work to be done to establish the value of PVEc as well as the efficacy and robustness of existing PVEc methods.


Assuntos
Algoritmos , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/análise , Compostos de Anilina , Encéfalo/patologia , Encéfalo/fisiopatologia , Radioisótopos de Carbono , Artérias Cerebrais , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Córtex Entorrinal/diagnóstico por imagem , Córtex Entorrinal/patologia , Córtex Entorrinal/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Hipocampo/fisiopatologia , Processamento de Imagem Assistida por Computador/métodos , Glicoproteínas de Membrana/análise , Proteínas do Tecido Nervoso/análise , Tamanho do Órgão , Perfusão , Tomografia por Emissão de Pósitrons , Piridinas , Pirrolidinonas , Compostos Radiofarmacêuticos , Marcadores de Spin , Vesículas Sinápticas/química , Tiazóis
20.
Neuroimage ; 239: 118302, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34174391

RESUMO

The positron emission tomography (PET) radioligand [11C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [11C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [11C]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was studied using [11C]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [11C]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between transgenic and age-matched wild type (WT) mice. The L61 mice displayed 11-13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [11C]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18-20 months) showed lower [11C]UCB-J brain exposure than younger WT mice (8-9 months). Together, these data imply that [11C]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modelling.


Assuntos
Peptídeos beta-Amiloides/análise , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono/farmacocinética , Modelos Animais de Doenças , Glicoproteínas de Membrana/análise , Proteínas do Tecido Nervoso/análise , Fragmentos de Peptídeos/análise , Tomografia por Emissão de Pósitrons/métodos , Piridinas/farmacocinética , Pirrolidinonas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Vesículas Sinápticas/ultraestrutura , Sinucleinopatias/diagnóstico por imagem , Envelhecimento , Doença de Alzheimer , Peptídeos beta-Amiloides/genética , Animais , Área Sob a Curva , Encéfalo/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Doença de Parkinson , Fragmentos de Peptídeos/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...