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1.
ERJ Open Res ; 8(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35136823

RESUMO

BACKGROUND: Prone positioning has a beneficial role in coronavirus disease 2019 (COVID-19) patients receiving ventilation but lacks evidence in awake non-ventilated patients, with most studies being retrospective, lacking control populations and information on subjective tolerability. METHODS: We conducted a prospective, single-centre study of prone positioning in awake non-ventilated patients with COVID-19 and non-COVID-19 pneumonia. The primary outcome was change in peripheral oxygenation in prone versus supine position. Secondary outcomes assessed effects on end-tidal CO2, respiratory rate, heart rate and subjective symptoms. We also recruited healthy volunteers to undergo proning during hypoxic challenge. RESULTS: 238 hospitalised patients with pneumonia were screened; 55 were eligible with 25 COVID-19 patients and three non-COVID-19 patients agreeing to undergo proning - the latter insufficient for further analysis. 10 healthy control volunteers underwent hypoxic challenge. Patients with COVID-19 had a median age of 64 years (interquartile range 53-75). Proning led to an increase in oxygen saturation measured by pulse oximetry (SpO2) compared to supine position (difference +1.62%; p=0.003) and occurred within 10 min of proning. There were no effects on end-tidal CO2, respiratory rate or heart rate. There was an increase in subjective discomfort (p=0.003), with no difference in breathlessness. Among healthy controls undergoing hypoxic challenge, proning did not lead to a change in SpO2 or subjective symptom scores. CONCLUSION: Identification of suitable patients with COVID-19 requiring oxygen supplementation from general ward environments for awake proning is challenging. Prone positioning leads to a small increase in SpO2 within 10 min of proning though is associated with increased discomfort.

3.
J Card Surg ; 35(3): 713-715, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31999375

RESUMO

The use of transcatheter aortic valve implantation (TAVI) in the emergency setting has not been widely reported, and TAVI is generally contraindicated in the context of endocarditis. Here we describe a patient developing acute cardiogenic shock due to prosthetic aortic valve degeneration with free-flow aortic regurgitation 8 months after receiving treatment for confirmed infective endocarditis. Due to his clinical status, he was deemed unfit for redo surgery, and he underwent salvage valve-in-valve (ViV)-TAVI. The patient made an excellent recovery. Postprocedure he was treated with a 6-week course of antibiotics, and at 18-months follow-up remains very well with no evidence of reinfection. This case may demonstrate that for selected patients with degenerative prosthetic aortic valve disease, despite a history of infective endocarditis, ViV-TAVI may be considered an alternative to redo surgery in the emergency setting.


Assuntos
Valva Aórtica , Endocardite/terapia , Próteses Valvulares Cardíacas/efeitos adversos , Falha de Prótese , Substituição da Valva Aórtica Transcateter/métodos , Doença Aguda , Idoso , Insuficiência da Valva Aórtica/cirurgia , Contraindicações de Procedimentos , Emergências , Seguimentos , Humanos , Masculino , Choque Cardiogênico/etiologia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do Tratamento
5.
ACS Med Chem Lett ; 7(1): 100-4, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819674

RESUMO

The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone 1, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein.

6.
J Med Chem ; 58(22): 8877-95, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26455919

RESUMO

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Genes erbB-1/efeitos dos fármacos , Animais , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cães , Desenho de Fármacos , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Mutação , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Org Biomol Chem ; 10(1): 162-70, 2012 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-22076284

RESUMO

Four-component reactions between amino alcohols, aldehydes, isocyanides and thiols proceed rapidly under microwave or conventional heating at 60 °C in methanol. The reaction is successful with a wide range of components and gives access to potentially drug-like products containing amine, amide and thioether functionality in moderate to excellent yield. The reaction conditions are also applicable to the synthesis of a range of 8-10 membered medium ring lactones via three-component reactions of amino alcohols, isocyanides and acid-aldehydes. Incorporation of L-prolinol as the amino alcohol component in each case gives access to multicomponent products with moderate to high diastereoselectivity.


Assuntos
Amidas/síntese química , Amino Álcoois/química , Cianetos/química , Espectrometria de Massas
8.
J Phys Chem A ; 115(44): 12201-11, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21939265

RESUMO

High-resolution solid-state (2)H MAS NMR studies of the α and γ polymorphs of fully deuterated glycine (glycine-d(5)) are reported. Analysis of spinning sideband patterns is used to determine the (2)H quadrupole interaction parameters, and is shown to yield good agreement with the corresponding parameters determined from single-crystal (2)H NMR measurements (the maximum deviation in quadrupole coupling constants determined from these two approaches is only 1%). From analysis of simulated (2)H MAS NMR sideband patterns as a function of reorientational jump frequency (κ) for the -N(+)D(3) group in glycine-d(5), the experimentally observed differences in the (2)H MAS NMR spectrum for the -N(+)D(3) deutrons in the α and γ polymorphs is attributed to differences in the rate of reorientation of the -N(+)D(3) group. These simulations show severe broadening of the (2)H MAS NMR signal in the intermediate motion regime, suggesting that deuterons undergoing reorientational motions at rates in the range κ ≈ 10(4)-10(6) s(-1) are likely to be undetectable in (2)H MAS NMR measurements for materials with natural isotopic abundances. The (1)H NMR chemical shifts for the α and γ polymorphs of glycine have been determined from the (2)H MAS NMR results, taking into account the known second-order shift. Further quantum mechanical calculations of (2)H quadrupole interaction parameters and (1)H chemical shifts reveal the structural dependence of these parameters in the two polymorphs and suggest that the existence of two short intermolecular C-H···O contacts for one of the H atoms of the >CH(2) group in the α polymorph have a significant influence on the (2)H quadrupole coupling and (1)H chemical shift for this site.


Assuntos
Glicina/química , Espectroscopia de Ressonância Magnética/métodos , Deutério , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Estrutura Molecular
9.
J Phys Chem A ; 115(22): 5568-78, 2011 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-21563791

RESUMO

High-resolution solid-state (2)H NMR spectroscopy provides a method for measuring (1)H NMR chemical shifts in solids and is advantageous over the direct measurement of high-resolution solid-state (1)H NMR spectra, as it requires only the application of routine magic angle sample spinning (MAS) and routine (1)H decoupling methods, in contrast to the requirement for complex pulse sequences for homonuclear (1)H decoupling and ultrafast MAS in the case of high-resolution solid-state (1)H NMR. However, a significant obstacle to the routine application of high-resolution solid-state (2)H NMR is the very low natural abundance of (2)H, with the consequent problem of inherently low sensitivity. Here, we explore the feasibility of measuring (2)H MAS NMR spectra of various solids with natural isotopic abundances at high magnetic field (850 MHz), focusing on samples of amino acids, peptides, collagen, and various organic solids. The results show that high-resolution solid-state (2)H NMR can be used successfully to measure isotropic (1)H chemical shifts in favorable cases, particularly for mobile functional groups, such as methyl and -N(+)H(3) groups, and in some cases phenyl groups. Furthermore, we demonstrate that routine (2)H MAS NMR measurements can be exploited for assessing the relative dynamics of different functional groups in a molecule and for assessing whole-molecule motions in the solid state. The magnitude and field-dependence of second-order shifts due to the (2)H quadrupole interaction are also investigated, on the basis of analysis of simulated and experimental (1)H and (2)H MAS NMR spectra of fully deuterated and selectively deuterated samples of the α polymorph of glycine at two different magnetic field strengths.


Assuntos
Deutério/química , Glicina/química , Magnetismo , Glicina/análogos & derivados , Espectroscopia de Ressonância Magnética
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