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1.
Rev Med Liege ; 76(10): 768-772, 2021 Oct.
Artigo em Francês | MEDLINE | ID: mdl-34632748

RESUMO

Here we present pharmacological and clinical properties of a new fixed triple inhaled combination including an inhaled corticoid, a long acting ?2 agonist and a long acting anticholinergic for the treatment of severe asthma. Enerzair® is the name of this triple combination which contains 160 µg mometasone, 150 µg indacaterol and 50 µg glycopyrronium administered by a Breezhaler®. As compared to an ICS/LABA combination Enerzair® improves expiratory flow rates and reduces exacerbation rate. The Breezhaler® device may be coupled to a sensor (Propeller Health) that, through a bluetooth system, allows to control patient adherence and provides recall to the patient to take his aerosol.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Asma/tratamento farmacológico , Glicopirrolato , Humanos , Indanos , Furoato de Mometasona/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas
2.
Tuberk Toraks ; 69(3): 399-402, 2021 Sep.
Artigo em Turco | MEDLINE | ID: mdl-34581162

RESUMO

Antibiotic hypersensitivity reactions can lead to marked morbidity, mortality and inadequate treatment options. Mycobacterium abscessus infection is a difficult management system for clinicians since it most commonly involves the lungs, progresses if untreated, and the organism is resistant to many antibiotics, as well as the agents used in treatment can cause undesirable side effects. Although macrolides are one of the most reliable antibiotic groups in terms of allergic reactions, early type hypersensitivity reactions against macrolides, one of the main antibiotics used in the treatment of Mycobacterium abscessus lung disease, may make the treatment management of the disease difficult. Due to the rapid increase in the use of quinolone in recent years, the frequency of developing allergic reactions with these agents also increases. In cases where antibiotic hypersensitivity is detected, the use of the responsible agent should be avoided, but desensitization may be necessary in cases without different treatment options. In this study, it was aimed to present a case of successful desensitization with clarithromycin and moxifloxacin in a patient who was diagnosed with Mycobacterium abscessus lung disease and developed anaphylaxis with clarithromycin and moxifloxacin after treatment was initiated.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Quinolonas , Antibacterianos/efeitos adversos , Humanos , Macrolídeos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/induzido quimicamente , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Quinolonas/efeitos adversos
3.
J Laryngol Otol ; 135(10): 911-917, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34399860

RESUMO

OBJECTIVE: This study aimed to identify pathogens isolated in acute external otitis cases and determine their distribution according to ages and seasons as well as investigate the susceptibility or resistance to the aminoglycoside and quinolone group antibiotics of which topical forms are available. METHOD: A total of 168 patients diagnosed with acute external otitis were evaluated retrospectively. Growing bacteria were identified according to the species by conventional methods. Antibiotic susceptibility status was determined for the growing bacteria. RESULTS: The most common bacteria detected were pseudomonas group bacteria (38.7 per cent). Resistance to the amikacin group of antibiotics was found to be the lowest and resistance to the ciprofloxacin group of antibiotics was the highest. CONCLUSION: External auditory canal cultures should be taken simultaneously with empirical treatment. Seasonal effect and age group should be taken into consideration in the choice of treatment and after questioning about chronic exposure to water. Empirical treatment should then be started.


Assuntos
Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Otite Externa/tratamento farmacológico , Otite Externa/microbiologia , Doença Aguda , Administração Tópica , Adulto , Fatores Etários , Amicacina/administração & dosagem , Amicacina/uso terapêutico , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Bactérias/crescimento & desenvolvimento , Ciprofloxacina/administração & dosagem , Ciprofloxacina/uso terapêutico , Resistência Microbiana a Medicamentos/fisiologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Pessoa de Meia-Idade , Otite Externa/diagnóstico , Pseudomonas/isolamento & purificação , Quinolonas/administração & dosagem , Quinolonas/uso terapêutico , Estudos Retrospectivos , Estações do Ano
4.
J Enzyme Inhib Med Chem ; 36(1): 1916-1921, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34461785

RESUMO

An earlier described three-component variant of the Castagnoli-Cushman reaction employing homophthalic anhydrides, carbonyl compound and ammonium acetate was applied towards the preparation of 1-oxo-3,4-dihydroisoquinoline-4-carboxamides with variable substituent in position 3. These compounds displayed inhibitory activity towards poly(ADP-ribose) polymerase (PARP), a clinically validated cancer target. The most potent compound (PARP1/2 IC50 = 22/4.0 nM) displayed the highest selectivity towards PARP2 in the series (selectivity index = 5.5), more advantageous ADME prameters compared to the clinically used PARP inhibitor Olaparib.


Assuntos
Acetatos/química , Antineoplásicos/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Quinolonas/química , Acetatos/farmacologia , Sequência de Aminoácidos , Antineoplásicos/farmacologia , Sítios de Ligação , Dano ao DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , NAD/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
5.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443308

RESUMO

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by 1H-NMR, 13C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC50 = 1.89 µM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cinamatos/síntese química , Cinamatos/farmacologia , Desenho de Fármacos , Quinolonas/síntese química , Quinolonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cinamatos/química , DNA Topoisomerases Tipo II/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Quinolonas/química , Inibidores da Topoisomerase/farmacologia
6.
Beijing Da Xue Xue Bao Yi Xue Ban ; 53(4): 716-720, 2021 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-34393234

RESUMO

OBJECTIVE: To investigate the role of rebamipide in the treatment of acute gout arthritis rats induced by monosodium urate (MSU) crystal. METHODS: Forty-two male rats were randomly divided into three groups (n=14). Group A was treated with oral rebamipide, group B with oral colchicine, and group C with oral placebo. The rats were monitored for the induction of arthritis with clinical manifestations and pathological changes, and the levels of interleukin (IL)-1ß、IL-6、IL-10, and tumor necrosis factor (TNF)-α in serum were measured. RESULTS: In group C, the clinical score and swelling index reached the maximum in 24 h, and then gradually decreased to 72 h. After 24 h of model induced, the clinical scores in group C were significantly higher than those in group A and group B [2 (1-3) vs. 0 (0-1) vs. 1 (0-2), P < 0.01], the swelling indexes in group C were significantly higher than those in group A and group B [0.36 (0.16-0.52) vs. 0.11 (0-0.20) vs. 0.12 (0-0.16), P < 0.01]. Histologically, after 24 h of model induced, there was a large number of neutrophil infiltration in the synovium of group C [scale score: 4 (2-4)], and there was no significant inflammatory cell infiltration in group A [1 (0-2)] and group B [1 (0-2)], the difference was statistically significant (P < 0.001). After 24 h of model induced, the levels of IL-1ß, IL-6, IL-10, and TNF-α in serum of group C were significantly higher than those in group A and B [IL-1ß: (41.86±5.72) vs. (27.35±7.47) vs. (27.76±5.28) ng/L, IL-6: (1 575.55±167.11) vs. (963.53±90.22) vs. (964.08±99.31) ng/L, IL-10: (37.96±3.76) vs. (21.68±4.83) vs. (16.20±2.49) ng/L, TNF-α: (21.32±1.34) vs. (15.82±2.54) vs. (17.35±7.47) µg/L, P < 0.001]. CONCLUSION: Rebamipide has a protective effect on acute gout arthritis rats induced by MUS crystals.


Assuntos
Artrite Gotosa , Quinolonas , Alanina/análogos & derivados , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Interleucina-1beta , Masculino , Ratos , Ácido Úrico
7.
Clin Lab ; 67(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383410

RESUMO

BACKGROUND: To investigate the epidemics of plasmid-mediated quinolone resistance (PMQR) gene in carbapenem-resistant Enterobacteriaceae (CRE) and the resistance mechanism. METHODS: We collected CRE bacteria isolated clinically between December 2017 and December 2018 for identification and drug sensitivity testing using a VITEK2 Compact Analyzer. Furthermore, genes, including qnrA, qnrB, qnrS, qepA, and acc (6') Ib-cr, were determined through the polymerase chain reaction and sequencing. The hori-zontal transfer of PMQR gene was validated through the plasmid conjugational test. RESULTS: Drug resistance rate of carbapenem-resistant Escherichia coli against quinolones was 100%, while the rate of carbapenem-resistant Klebsiella pneumoniae ranged from 15.56% to 33.33%. The detection rate of acc (6') Ib-cr was the highest (87.72%), followed by qnrB (77.19%) and qnrS (17.54%). Additionally, there were two bacteria carrying the qnrA gene (3.51%), but qepA gene was not isolated from the samples. In total, 84.21% of these bacteria carried 2 or 3 kinds of PMQR genes. Among 8 bacteria with successful plasmid conjugation, PMQR gene transfer was detected in all of them, but with no significant change in the minimum inhibitory concentration of quinolones. CONCLUSIONS: CRE remain sensitive to quinolones in spite of the high detection rate of PMQR gene in this hospital.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Infecções por Enterobacteriaceae , Quinolonas , Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Farmacorresistência Bacteriana/genética , Infecções por Enterobacteriaceae/diagnóstico , Infecções por Enterobacteriaceae/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Quinolonas/farmacologia
8.
Clin Drug Investig ; 41(9): 785-794, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34333742

RESUMO

BACKGROUND AND OBJECTIVE: In asthma, symptom control is a primary goal that is not consistently met with available treatment options. The first commercially available fixed-dose combination in a single inhaler of a long-acting beta-agonist (indacaterol, IND), an inhaled corticosteroid (mometasone furoate, MF) and a long-acting muscarinic antagonist (glycopyrronium, GLY) has shown promising clinical results in phase III trials. The aim of the present study is to evaluate the cost-utility of IND/GLY/MF fixed-dose combination relative to a combination of salmeterol/fluticasone and tiotropium or salmeterol/fluticasone or IND/MF in adult patients with asthma, from the Italian Health Service (NHS) perspective. METHODS: A two-state and 4-week cycle Markov model was used to estimate lifetime clinical outcomes and costs. Patients entered the model in stable disease and could experience a non-fatal exacerbation event. The exacerbation rate is dependent upon the therapy a patient is receiving, as per the IND/GLY/MF clinical trials. The impact of each type of exacerbation is accounted by applying a utility decrement, obtained from the literature, and a treatment cost. Utility values were obtained from the EQ-5D questionnaires in the IND/GLY/MF clinical trials. Lifetime costs considered in the analysis were drugs and exacerbation management. Probabilistic sensitivity analyses were carried out, with the aim of evaluating the impact of uncertainty on input parameters. RESULTS: IND/GLY/MF is associated with a higher quality of life [+ 0.25 quality-adjusted life-year (QALY)] than salmeterol/fluticasone plus tiotropium, with an incremental cost of -€3213.90. The incremental cost-utility ratio indicates dominance. At a threshold of €5000 per QALY, IND/GLY/MF has nearly a 100% probability of being cost effective. IND/GLY/MF is associated with a higher quality of life (+ 0.21 QALY) than salmeterol/fluticasone, with an incremental cost of €2547.76. Incremental cost-utility ratio results in €11,897 per QALY. At a threshold of €20,000 per QALY, IND/GLY/MF has nearly a 100% probability of being cost effective. IND/GLY/MF is associated with a higher quality of life (+ 0.34 QALY) than IND/MF, with an incremental cost of €4745.91. Incremental cost-utility ratio results in €14,088 per QALY. At a threshold of €20,000 per QALY, IND/GLY/MF has nearly a 100% probability of being cost effective. CONCLUSION: The results indicate that IND/GLY/MF is cost effective against the considered comparators in a cohort representative of adult patients with asthma in Italy.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Acetatos/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Análise Custo-Benefício , Combinação de Medicamentos , Glicopirrolato , Humanos , Indanos , Furoato de Mometasona/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Quinolonas , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-34444027

RESUMO

We conducted environmental surveillance of antimicrobial resistance (AMR) bacteria in the Msimbazi river basin in Tanzania to determine the occurrence of extended-spectrum ß-lactamase (ESBL)-producing, carbapenem resistant Enterobacteriaceae (CRE) and quinolone resistant Escherichia coli and Klebsiella spp. A total of 213 Enterobacteriaceae isolates were recovered from 219 samples. Out of the recovered isolates, 45.5% (n = 97) were Klebsiella pneumoniae and 29.6% (n = 63) were Escherichia coli. K. pneumoniae isolates were more resistant in effluent (27.9%) compared to the E. coli (26.6%). The E. coli had a higher resistance in river water, sediment and crop soil than the K. pneumoniae (35 versus 25%), respectively. Higher resistance in K. pneumoniae was found in nalidixic acid (54.6%) and ciprofloxacin (33.3%) while the E. coli isolates were highly resistant to ciprofloxacin (39.7%) and trimethoprim/sulfamethoxazole (38%). Resistance increased from 28.3% in Kisarawe, where the river originates, to 59.9% in Jangwani (the middle section) and 66.7% in Upanga West, where the river enters the Indian Ocean. Out of 160 E. coli and K. pneumoniae isolates, 53.2% (n = 85) were resistant to more than three classes of the antibiotic tested, occurrence being higher among ESBL producers, quinolone resistant and carbapenem resistant strains. There is an urgent need to curb environmental contamination with antimicrobial agents in the Msimbazi Basin.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Quinolonas , Antibacterianos/farmacologia , Ecossistema , Escherichia coli , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Rios , Tanzânia , beta-Lactamases
10.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199768

RESUMO

Single mutations can confer resistance to antibiotics. Identifying such mutations can help to develop and improve drugs. Here, we systematically screen for candidate quinolone resistance-conferring mutations. We sequenced highly diverse wastewater E. coli and performed a genome-wide association study (GWAS) to determine associations between over 200,000 mutations and quinolone resistance phenotypes. We uncovered 13 statistically significant mutations including 1 located at the active site of the biofilm dispersal gene bdcA and 6 silent mutations in the aminoacyl-tRNA synthetase valS. The study also recovered the known mutations in the topoisomerases gyrase (gyrA) and topoisomerase IV (parC). In summary, we demonstrate that GWAS effectively and comprehensively identifies resistance mutations without a priori knowledge of targets and mode of action. The results suggest that mutations in the bdcA and valS genes, which are involved in biofilm dispersal and translation, may lead to novel resistance mechanisms.


Assuntos
Farmacorresistência Bacteriana/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Mutação/genética , Quinolonas/farmacologia , Valina-tRNA Ligase/genética , Águas Residuárias/microbiologia , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Loci Gênicos , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação/genética , Modelos Moleculares , Fenótipo , Filogenia
11.
Medicine (Baltimore) ; 100(28): e26538, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260531

RESUMO

ABSTRACT: Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.


Assuntos
Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Síndrome do QT Longo/mortalidade , SARS-CoV-2 , Idoso , COVID-19/virologia , Cloroquina/efeitos adversos , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/efeitos adversos , Eletrocardiografia , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Hidroxicloroquina/efeitos adversos , Indóis/efeitos adversos , Interferons/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Lopinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Quinolonas/efeitos adversos , Estudos Retrospectivos , Ritonavir/efeitos adversos , Índice de Gravidade de Doença
12.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299226

RESUMO

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/tratamento farmacológico , Pneumonia/tratamento farmacológico , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzodioxóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Transporte de Íons , Pulmão/metabolismo , Pulmão/fisiologia , Macrófagos/metabolismo , Quinolonas/uso terapêutico , Transdução de Sinais
13.
J Antimicrob Chemother ; 76(12 Suppl 2): ii37-ii44, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312652

RESUMO

OBJECTIVES: Data on quinolone consumption in the community were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of main subgroups of quinolones. METHODS: For the period 1997-2017, data on consumption of quinolones, i.e. ATC group J01M, in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Quinolone consumption was analysed by subgroups based on pharmacokinetic profile, and presented as trends, seasonal variation, presence of change-points and compositional changes. RESULTS: In 2017, quinolone consumption in the community expressed in DDD per 1000 inhabitants per day varied by a factor of 8.2 between countries with the highest (Bulgaria) and the lowest (Norway) consumption. The second-generation quinolones accounted for >50% of quinolone consumption in most countries. Quinolone consumption significantly increased up to 2001, and did not change significantly afterwards. Seasonal variation increased significantly over time. Proportional consumption of third-generation quinolones significantly increased over time relative to that of second-generation quinolones, while proportional consumption of both third- and second-generation quinolones significantly increased relative to that of first-generation quinolones. Levofloxacin and moxifloxacin represented >40% of quinolone consumption in the community in southern EU/EEA countries. CONCLUSIONS: Quinolone consumption in the community is no longer increasing in the EU/EEA, but its seasonal variation continues to increase significantly as is the proportion of quinolones to treat respiratory infections.


Assuntos
Infecções Bacterianas , Quinolonas , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Uso de Medicamentos , Europa (Continente) , União Europeia , Humanos , Pacientes Ambulatoriais
14.
J Antimicrob Chemother ; 76(12 Suppl 2): ii60-ii67, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312656

RESUMO

OBJECTIVES: The quality of antibiotic consumption in the community can be assessed using 12 drug-specific quality indicators (DSQIs) developed by the European Surveillance of Antimicrobial Consumption (ESAC) project. We compared quality in 2009 and 2017 in the EU/European Economic Area (EEA) and evaluated the impact of using different DDD values (ATC/DDD indices 2011 and 2019) for the 2009 quality assessment using these DSQIs and a joint scientific opinion (JSO) indicator. METHODS: We calculated the 12 DSQIs and the JSO indicator for 2017 and for 2009 for EU/EEA countries able to deliver values. For each of the indicators we grouped the 2017 and 2009 indicator values into four quartiles. To evaluate changes in quality between 2009 and 2017, we used the quartile distribution of the 2009 indicator values in 30 EU/EEA countries as benchmarks. In addition, we compared the quality assessment for 2009 using the ATC/DDD indices 2011 and 2019. RESULTS: In 2017, a difference in the quality of antibiotic consumption in the community between northern and southern EU/EEA countries remained, but also several eastern EU/EEA countries shifted towards lower quality. Quality of antibiotic consumption decreased between 2009 and 2017 in particular indicator values for penicillin, quinolone, relative ß-lactam and broad- versus narrow-spectrum antibiotic consumption, and seasonal variation. Using different ATC/DDD indices did not substantially change countries' ranking based on their DSQI values. CONCLUSIONS: The quality of antibiotic consumption in the community as measured by the DSQIs further decreased between 2009 and 2017, especially in Southern and Eastern European countries. A continuous effort to improve antibiotic consumption is essential to reduce antibiotic consumption in general and the use of broad-spectrum antibiotics in particular.


Assuntos
Antibacterianos , Quinolonas , Antibacterianos/uso terapêutico , Uso de Medicamentos , Europa (Continente) , União Europeia , Humanos , Penicilinas
15.
J Chem Phys ; 154(20): 204201, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34241187

RESUMO

Pseudomonas aeruginosa is an opportunistic human pathogen implicated in both acute and chronic diseases, which resists antibiotic treatment, in part by forming physical and chemical barriers such as biofilms. Here, we explore the use of confocal Raman imaging to characterize the three-dimensional (3D) spatial distribution of alkyl quinolones (AQs) in P. aeruginosa biofilms by reconstructing depth profiles from hyperspectral Raman data. AQs are important to quorum sensing (QS), virulence, and other actions of P. aeruginosa. Three-dimensional distributions of three different AQs (PQS, HQNO, and HHQ) were observed to have a significant depth, suggesting 3D anisotropic shapes-sheet-like rectangular solids for HQNO and extended cylinders for PQS. Similar to observations from 2D imaging studies, spectral features characteristic of AQs (HQNO or PQS) and the amide I vibration from peptide-containing species were found to correlate with the PQS cylinders typically located at the tips of the HQNO rectangular solids. In the QS-deficient mutant lasIrhlI, a small globular component was observed, whose highly localized nature and similarity in size to a P. aeruginosa cell suggest that the feature arises from HHQ localized in the vicinity of the cell from which it was secreted. The difference in the shapes and sizes of the aggregates of the three AQs in wild-type and mutant P. aeruginosa is likely related to the difference in the cellular response to growth conditions, environmental stress, metabolic levels, or other structural and biochemical variations inside biofilms. This study provides a new route to characterizing the 3D structure of biofilms and shows the potential of confocal Raman imaging to elucidate the nature of heterogeneous biofilms in all three spatial dimensions. These capabilities should be applicable as a tool in studies of infectious diseases.


Assuntos
Biofilmes/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Quinolonas/farmacologia , Biofilmes/crescimento & desenvolvimento , Microscopia Confocal , Quinolonas/química , Análise Espectral Raman
16.
J Enzyme Inhib Med Chem ; 36(1): 1454-1471, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34210212

RESUMO

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC50 values (0.002 - 0.004 µM) comparing to Staurosporine of IC50; 0.005 µM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC50 range 0.0149 - 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-ß, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-ß of IC50 values 0.17 × 10-3, 0.07 × 10-3 µM in comparison with the reference drug sorafenib of IC50; 0.28 × 10-3, 0.13 × 10-3 µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.


Assuntos
Neoplasias da Mama/prevenção & controle , Química Verde , Quinolonas/química , Quinolonas/farmacologia , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/síntese química , Análise Espectral/métodos
17.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298987

RESUMO

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients' muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3ß (GSK-3ß), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Sítio Alostérico/efeitos dos fármacos , Antígeno CD56/análise , Calpaína/deficiência , Calpaína/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/química , Humanos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/enzimologia , Proteínas do Tecido Nervoso/química , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/fisiologia , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos
18.
J Enzyme Inhib Med Chem ; 36(1): 1541-1552, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238111

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour in the central nervous system (CNS). As the ideal targets for GBM treatment, Src family kinases (SFKs) have attracted much attention. Herein, a new series of imidazo[4,5-c]pyridin-2-one derivatives were designed and synthesised as SFK inhibitors. Compounds 1d, 1e, 1q, 1s exhibited potential Src and Fyn kinase inhibition in the submicromolar range, of which were next tested for their antiproliferative potency on four GBM cell lines. Compound 1s showed effective activity against U87, U251, T98G, and U87-EGFRvIII GBM cell lines, comparable to that of lead compound PP2. Molecular dynamics (MDs) simulation revealed the possible binding patterns of the most active compound 1s in ATP binding site of SFKs. ADME prediction suggested that 1s accord with the criteria of CNS drugs. These results led us to identify a novel SFK inhibitor as candidate for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Quinases da Família src/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Quinases da Família src/metabolismo
19.
Eur J Pediatr ; 180(9): 2731-2739, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34213646

RESUMO

Cystic fibrosis is the most prevalent inherited disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impaired electrolyte homeostasis caused by the mutated or absent protein leads to symptoms in multiple organ systems. However, the pulmonary manifestation with chronic infections and eventually respiratory failure remains the most important threat. Until one decade ago, only symptomatic treatment was available. However, since 2012, different combinations of CFTR modulators are available for people with cystic fibrosis (pwCF) that carry different mutations. The advent of these drugs has impressively changed life expectancy and quality of life in people with cystic fibrosis and raised new challenges regarding long-term complications and tapering of conventional therapies.Conclusion: In this review, we provide an update on the latest developments around diagnostics, treatment, and prognosis of pwCF. What is Known: • Cystic fibrosis is an incurable and life-shortening disease asking for life-long symptomatic treatment. • Three combination CFTR modulating drugs has gained marked approval over the last 10 years. What is New: • The emerge of new (modulating) therapies contribute to the increasing life expectancy. • A high unmet need to develop new therapies for people with CF who cannot access or benefit from these drugs remains. This review gives an update on the current status.


Assuntos
Fibrose Cística , Quinolonas , Aminofenóis/uso terapêutico , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Qualidade de Vida , Quinolonas/uso terapêutico
20.
Environ Sci Pollut Res Int ; 28(39): 54950-54959, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34120285

RESUMO

In this work, the effect of a carrier modified with a carbon-carbon double bond (C=C) on preparing multi-templates surface molecularly imprinted polymer MIP (C=C@MIP) for simultaneous detection of sulfonamides and quinolones was investigated. The results showed that the adsorption capacities of the C=C@MIP were obviously higher than those of MIP, which is the carrier without modified C=C, suggesting that C=C played a key role in preparing MIP with higher adsorption capacities. Then, C=C@MIP was used as adsorbents for solid-phase extraction (SPE) and coupled with high-performance liquid chromatography (HPLC) for the simultaneous determination of sulfonamides and quinolones in water. The method showed excellent applicability, with the adsorption capacities of 19.92, 16.38, 12.92, 18.37, 14.49, 12.01, 16.98, 23.33, and 14.29 mg/g for SDZ, STZ, SMZ, SMX, SDM, ENRO, OFL, LOME, and GATI, respectively. The spiked recoveries and relative standard deviations (RSDs) of sulfonamides and quinolones using C=C@MIP were 81.59-100.7 % and 3.75-7.37 %, respectively. The limits of detection (LODs) for SDZ, STZ, SMZ, SMX, SDM, ENRO, OFL, LOME, and GATI were 0.013, 0.012, 0.012, 0.013, 0.014, 0.012, 0.013, 0.015, and 0.015 µg/L, respectively.


Assuntos
Quinolonas , Carbono , Polímeros Molecularmente Impressos , Sulfonamidas , Água
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