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1.
Sci Total Environ ; 803: 150064, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34525700

RESUMO

Chloroacetamides are commonly used in herbicide formulations, and their occurrence has been reported in soils and groundwater. However, how their chemical structures affect transformation kinetics and pathways in the presence of environmental reagents such as hydrogen sulfide species and black carbon has not been investigated. In this work, we assessed the impact of increasing Cl substituents on reaction kinetics and pathways of six chloroacetamides. The contribution of individual pathways (reductive dechlorination vs. nucleophilic substitution) to the overall decay of selected chloroacetamides was differentiated using various experimental setups; both the transformation rates and product distributions were characterized. Our results suggest that the number of Cl substituents affected reaction pathways and kinetics: trichloroacetamides predominantly underwent reductive dechlorination whereas mono- and dichloroacetamides transformed via nucleophilic substitution. Furthermore, we synthesized eight dichloroacetamide analogs (Cl2CHC(=O)NRR') with differing R groups and characterized their transformation kinetics. Dynamic NMR spectroscopy was employed to quantify the rotational energy barriers of dichloroacetamides. Our results suggest that adsorption of dichloroacetamides on black carbon constrained R groups from approaching the dichloromethyl carbon and subsequently favored nucleophilic attack. This study provides new insights to better predict the fate of chloroacetamides in subsurface environments by linking their structural characteristics to transformation kinetics and pathways.


Assuntos
Carbono , Sulfetos , Acetamidas , Cinética , Espectroscopia de Ressonância Magnética , Oxirredução
2.
Sci Total Environ ; 802: 149826, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34455281

RESUMO

The aim of the present study was to evaluate the enantioselective bioaccumulation, metabolism, and toxic effects of metolachlor and S-metolachlor in zebrafish. Five-month-old zebrafish were exposed to metolachlor and S-metolachlor for 28 days, then transferred to clean water and purified for 7 days. In the uptake phase, S-metolachlor was preferentially accumulated at low concentrations, while metolachlor was preferentially accumulated at high concentrations. The two chemicals were metabolized by >70% in zebrafish on the first day and showed same metabolic process. At the accumulation endpoint, S-metolachlor had no significant inhibitory effect on the enzymes activities of superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) and developmental indicators of zebrafish. However, 300 µg/L metolachlor significantly inhibited the enzymes activities of SOD, CAT and GST and affected the liver development. The preferential enrichment of metolachlor at the high concentration may be the reason for its higher toxicity to zebrafish. Further research demonstrated that metolachlor significantly altered the expression of hypothalamic-pituitary-gonadal (HPG) axis-related genes, including gnrh2, gnrh3, lhß, 17ßhsd and cyp19a, thereby reducing the levels of testosterone (T) in females and sex hormones (estradiol and testosterone) in males. S-metolachlor increased the levels of estradiol (E2) in females by altering the expression of HPG axis-related genes such as fshß, cyp17, 17ßhsd and cyp19a. The mechanism of metolachlor and S-metolachlor on the endocrine disrupting effects of zebrafish is different, which may be sex-specific. 7 days after transferring the exposed zebrafish to clean water, most of the enzymes activities, sex hormone levels and related gene expression levels returned to normal, which may be related to the rapid metabolism of the two chemicals.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Acetamidas , Animais , Bioacumulação , Feminino , Masculino , Estereoisomerismo , Poluentes Químicos da Água/toxicidade
4.
Kardiologiia ; 61(10): 104-107, 2021 Oct 30.
Artigo em Russo | MEDLINE | ID: mdl-34763645

RESUMO

The article presents a clinical case of successful triple combination therapy in a female patient with functional class III idiopathic pulmonary arterial hypertension. Supplementing the previous macitentan and riociguat treatment with selexipag reduced the severity of clinical manifestations of pulmonary hypertension. Also, the treatment efficacy was demonstrated by improvement of laboratory and instrumental indexes. Time-related changes were evaluated at 3 months after initiation of the selexipag treatment.


Assuntos
Anti-Hipertensivos , Acetamidas , Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Humanos , Pirazinas , Pirazóis , Pirimidinas , Sulfonamidas
5.
AAPS PharmSciTech ; 22(8): 261, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34705130

RESUMO

The first melatonergic antidepressant drug, agomelatine (AGM), is commonly used for controlling major depressive disorders. AGM suffers low (< 5%) oral bioavailability owing to the hepatic metabolism. The current work investigated the potential of low-frequency sonophoresis on enhancing transdermal delivery of AGM-loaded novasomes and, hence, bioavailability of AGM. Drug-loaded novasomes were developed using free fatty acid (stearic acid or oleic acid), surfactant (span 60 or span 80), and cholesterol via thin-film hydration technique. The systems (N1-N16) were assessed for zeta potential (ZP), particle size (PS), encapsulation efficiency (EE%), and drug percent released after 0.5 h (Q0.5 h) and 8 h (Q8h), drug-crystallinity, morphology, and ex vivo drug permeation. Skin pre-treatment with low-frequency ultrasound (LFU) waves, via N13-novasomal gel systems, was optimized to enhance ex vivo drug permeation. Influences of LFU mode (continuous or pulsed), duty cycle (50% or 100%), and application period (10 or 15 min) were optimized. The pharmacokinetics of the optimized system (N13-LFU-C4) was assessed in rabbits. N13 was the best achieved novasomal system with respect to PS (471.6 nm), ZP (- 63.6 mv), EE% (60.5%), Q0.5 h (27.8%), Q8h (83.9%), flux (15.5 µg/cm2/h), and enhancement ratio (6.9). N13-LFU-C4 was the optimized novasomal gel system (desirability; 0.997) which involves skin pre-treatment with LFU in a continuous mode, at 100% duty cycle, for 15 min. Compared to AGM dispersion, the significantly (P < 0.05) higher flux (26.7 µg/cm2/h), enhancement ratio (11.9), Cmax (118.23 ng/mL), and relative bioavailability (≈ 8.6 folds) could elucidate the potential of N13-LFU-C4 system in improving transdermal drug permeability and bioavailability.


Assuntos
Transtorno Depressivo Maior , Absorção Cutânea , Acetamidas , Administração Cutânea , Animais , Disponibilidade Biológica , Transtorno Depressivo Maior/metabolismo , Sistemas de Liberação de Medicamentos , Tamanho da Partícula , Coelhos , Pele/metabolismo
6.
Environ Sci Process Impacts ; 23(11): 1791-1802, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34709265

RESUMO

Knowledge of direct and indirect photodegradation of pesticides and associated isotope fractionation can help to assess pesticide degradation in surface waters. Here, we investigated carbon (C) and nitrogen (N) isotope fractionation during direct and indirect photodegradation of the herbicides atrazine and S-metolachlor in synthetic agriculturally impacted surface waters containing nitrates (20 mg L-1) and dissolved organic matter (DOM, 5.4 mgC L-1). Atrazine and S-metolachlor were quickly photodegraded by both direct and indirect processes (half-lives <5 and <7 days, respectively). DOM slowed down photodegradation while nitrates increased degradation rates. The analysis of transformation products showed that oxidation mediated by hydroxyl radicals (HO˙) predominated during indirect photodegradation. UV light (254 nm) led to significant C and N isotope fractionation, yielding isotopic fractionation values εC = 2.7 ± 0.3 and 0.8 ± 0.1‰, and εN = 2.4 ± 0.3 and -2.6 ± 0.7‰ for atrazine and S-metolachlor, respectively. In contrast, photodegradation under simulated sunlight led to negligible C and slight N isotope fractionation, emphasizing the effect of the radiation wavelengths on the isotope fractionation induced by direct photodegradation. Altogether, these results highlight the importance of using simulated sunlight to obtain environmentally-relevant isotopic fractionation values and to distinguish photodegradation and other dissipation pathways in surface waters.


Assuntos
Atrazina , Poluentes Químicos da Água , Acetamidas , Isótopos , Fotólise , Água , Poluentes Químicos da Água/análise
7.
Anal Chem ; 93(41): 13886-13892, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34623153

RESUMO

Given the great harm of pesticide residues to the environment and public health, exploring ultrasensitive and low-cost methods for their quantitative analysis becomes intensely necessary. Herein, we proposed a double-functionalized gold nanoparticle (AuNP) probe as a signal amplification immunoassay for the detection of acetochlor (ATC), metolachlor, and propisochlor. The AuNP was modified with IgG and fluorophore-labeled duplex DNA by a polyadenine-based freezing method. The quenched fluorescence can be effectively recovered via duplex-specific nuclease (DSN) with excellent cleaving activity. This approach provided limits of detection (LODs) down to 0.03 ng/mL for ATC, 0.10 ng/mL for metolachlor, 0.14 ng/mL for propisochlor, and 0.08 ng/mL for their mixture. The average recoveries of ATC, metolachlor, and propisochlor were 93.0-106.6% from a corn sample, which are in good agreement with the commercial kit (R2 = 0.9995). This "turn-off" fluorescence immunoassay presents considerable potential in the analysis of chloroacetamide herbicide due to its simple process of probe preparing and ultrahigh sensitivity.


Assuntos
Ouro , Nanopartículas Metálicas , Acetamidas , Imunoensaio , Toluidinas
8.
Sensors (Basel) ; 21(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34640950

RESUMO

A sample of nitrogen and boron co-doped graphene (NB-Gr) was obtained by the hydrothermal method using urea and boric acid as doping sources. According to XRD analysis, the NB-Gr sample was formed by five-layer graphene. In addition, the XPS analysis confirmed the nitrogen and boron co-doping of the graphene sample. After synthesis, the investigation of the electro-catalytic properties of the bare (GC) and graphene-modified electrode (NB-Gr/GC) towards cymoxanil detection (CYM) was performed. Significant differences between the two electrodes were noticed. In the first case (GC) the peak current modulus was small (1.12 × 10-5 A) and appeared in the region of negative potentials (-0.9 V). In contrast, when NB-Gr was present on top of the GC electrode it promoted the transfer of electrons, leading to a large peak current increase (1.65 × 10-5 A) and a positive shift of the peak potential (-0.75 V). The NB-Gr/GC electrode was also tested for its ability to detect cymoxanil from a commercial fungicide (CURZATE MANOX) by the standard addition method, giving a recovery of 99%.


Assuntos
Grafite , Acetamidas , Boro , Nitrogênio
9.
Clin Hemorheol Microcirc ; 79(1): 73-80, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34487035

RESUMO

BACKGROUND AND OBJECTIVE: Liver function is one of the most important parameters for the outcome of transarterial chemoembolization (TACE). The liver maximum capacity (LiMAx) test is a bedside test that provides a real-time option for liver function testing. The objective of this pilot study was to investigate the suitability of the LiMAX test for predicting the TACE outcome. METHODS: 20 patients with intermediate-stage hepatocellular carcinoma (HCC) received a LiMAx test 24 h pre and post TACE. In addition, laboratory values were collected to determine liver function and model for endstage liver disease (MELD) scores. The success of TACE was assessed 6 weeks post intervention by morphological imaging tests using modified response evaluation criteria in solid tumors (mRECIST). RESULTS: Patients with an objective response (OR = CR + PR) according to mRECIST post TACE had significantly higher values in the pre-interventional LiMAx test than patients with a non-OR (PD or SD) post TACE (r(14) = 0.62, p = 0.01). Higher pre-interventional LiMAx values therefore indicate OR. Patients with a disease control (DC = CR + PR + SD) according to mRECIST post TACE had significantly higher values in the pre-interventional LiMAx test than patients with a non-DC (PD) post TACE (r(14) = 0.65, p = 0.01). Higher pre-interventional LiMAx values therefore indicate DC. The point biserial correlations of LiMAx values pre and post TACE with the outcome OR or DC were descriptively stronger than those of MELD with OR or DC. This suggests that the LiMAx test correlates better with the treatment response than the MELD score. CONCLUSIONS: For the first time, we were able to show in our study that patients who are scheduled for TACE could benefit from a LiMAx test to be able to estimate the benefit of TACE. The higher the pre-interventional LiMAx values, the higher the benefit of TACE. On the other hand, laboratory parameters summarized in the form of the MELD score had significantly less descriptive correlation with the TACE outcome.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Acetamidas , Testes Respiratórios , Isótopos de Carbono , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapia , Projetos Piloto , Estudos Retrospectivos , Resultado do Tratamento
10.
Molecules ; 26(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34577120

RESUMO

Referring to the structural information of the "hit" compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl- and thioether/sulfoxide/sulfone-containing acetamide derivatives have been designed and synthesized. The structures of new compounds were confirmed by 1H NMR, 13C NMR and HRMS. The single-crystal structure of A was firstly reported. All the new synthesized compounds were evaluated for insecticidal activities on Mythimna separata Walker and Plutella xylostella L. Through a step-by-step structural optimization, the high insecticidal agents, especially towards Plutella xylostella L., have been found, and thienylpyridyl- and sulfone/thioether-containing acetamides Iq, Io, Ib and A, which are comparable with the control insecticides cartap, triflumuron and chlorantraniliprole in the present study, can be used as novel lead structures for new insecticides innovation research. In addition, some of the compounds, e.g., A, Ih, Id, Io and Iq, also exhibited favourable fungicidal activities against Physalospora piricola, Rhizoctonia cerealis and Sclerotinia sclerotiorum and would provide useful guidance for the design and development of new fungicides.


Assuntos
Acetamidas , Praguicidas , Animais , Ascomicetos , Basidiomycota , Inseticidas/química , Mariposas/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfetos
11.
Clin Drug Investig ; 41(10): 885-894, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34480725

RESUMO

BACKGROUND AND OBJECTIVE: Methicillin-resistant Staphylococcus aureus bloodstream infections (MRSAB) cause significant mortality, and often require extended antibiotic therapy. Vancomycin, the most common initial MRSAB treatment, carries significant monitoring burden and nephrotoxicity risks. Our objective was to compare the cost-effectiveness of vancomycin and other antibiotic regimens against MRSAB. METHODS: We estimated the cost-effectiveness of intravenous antibiotics (vancomycin, daptomycin, linezolid, ceftaroline/daptomycin) for Veterans Health Administration patients with MRSAB using an exploratory decision-tree model. Primary effectiveness outcome was composite of microbiological failure at 7 days and adverse drug event (ADE)-related discontinuation after at least 7 days. RESULTS: In base-case analyses, intravenous linezolid was the least expensive regimen at 4 and 6 weeks. Daptomycin was more expensive and more effective than linezolid, with an incremental cost-effectiveness ratio (ICER) of ~$13,000 (4 weeks) per composite failure avoided. With 6 weeks of treatment, daptomycin was more expensive and more effective than vancomycin (ICER ~$21,000 per composite failure avoided). Vancomycin and ceftaroline/daptomycin were dominated strategies at both 4 and 6 weeks. In one-way sensitivity analyses, vancomycin was favored when its microbiological failure risk was less than 20.1% (base-case: 27.2%), assuming a willingness to pay (WTP) threshold of $40,000/composite treatment failure avoided. In two-way sensitivity analyses, intravenous linezolid was favored if linezolid microbiological failure and ADE-related discontinuation rates were < 22.5% and < 17.3%, respectively. Daptomycin, vancomycin, and linezolid were favored in 50%, 31%, and 17% of 4-week probabilistic iterations, respectively, at $40,000 WTP. CONCLUSION: Daptomycin is likely less expensive and more effective than vancomycin or other initial regimens for MRSAB. More data are needed on the safety of linezolid against MRSAB.


Assuntos
Daptomicina , Staphylococcus aureus Resistente à Meticilina , Oxazolidinonas , Sepse , Infecções Estafilocócicas , Acetamidas/efeitos adversos , Antibacterianos/efeitos adversos , Análise Custo-Benefício , Humanos , Linezolida , Sepse/tratamento farmacológico , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/efeitos adversos
12.
Asian J Psychiatr ; 65: 102866, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34592623

RESUMO

Agomelatine is a novel antidepressant that was developed to counter the adverse effects associated with the standard SSRIs and SNRIs that limited their usage. Publication bias was identified in antidepressant trials which can potentially overestimate the treatment efficacy. This meta-analysis was designed to assess the overall antidepressant effect of Agomelatine by pooling all the published and unpublished studies available till date. Studies conducted on adult patients who met with the criteria for MDD that evaluated efficacy of Agomelatine at acute phase (6-12weeks) and at long term phase (24weeks) were included. The primary efficacy measured with SMD of final mean scores of HAM-D and MADRS. Secondary efficacy measures of Response, remission and safety parameters were evaluated with relative risks. RevMan version 5.4 was used for analysis of both continuous (Standardized mean difference) and dichotomous outcomes (response, remission and all cause of discontinuation). Efficacy parameters were presented with 99% confidence intervals while safety parameters were presented with 95% CI. A total of 9233 patients were included from 27 studies. In acute phase placebo controlled studies, Agomelatine had a statistically significant SMD of - 0.24 (-0.39 to -0.09) and response rate of (1.25, 1.07-1.47). In comparison (RR 0.99, 0.92-1.07) Agomelatine is an effective antidepressant having similar efficacy with the currently used antidepressants.


Assuntos
Acetamidas , Inibidores da Recaptação de Serotonina e Norepinefrina , Acetamidas/efeitos adversos , Adulto , Antidepressivos/efeitos adversos , Humanos , Inibidores de Captação de Serotonina
13.
Angew Chem Int Ed Engl ; 60(43): 23232-23240, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34339587

RESUMO

The microbiome has a fundamental impact on the human host's physiology through the production of highly reactive compounds that can lead to disease development. One class of such compounds are carbonyl-containing metabolites, which are involved in diverse biochemical processes. Mass spectrometry is the method of choice for analysis of metabolites but carbonyls are analytically challenging. Herein, we have developed a new chemical biology tool using chemoselective modification to overcome analytical limitations. Two isotopic probes allow for the simultaneous and semi-quantitative analysis at the femtomole level as well as qualitative analysis at attomole quantities that allows for detection of more than 200 metabolites in human fecal, urine and plasma samples. This comprehensive mass spectrometric analysis enhances the scope of metabolomics-driven biomarker discovery. We anticipate that our chemical biology tool will be of general use in metabolomics analysis to obtain a better understanding of microbial interactions with the human host and disease development.


Assuntos
Acetaldeído/análise , Acetona/análise , Aldeídos/análise , Butanonas/análise , Di-Hidroxiacetona/análise , Metabolômica/métodos , Acetaldeído/sangue , Acetaldeído/química , Acetaldeído/urina , Acetamidas/química , Acetona/sangue , Acetona/química , Acetona/urina , Aldeídos/sangue , Aldeídos/química , Aldeídos/urina , Butanonas/sangue , Butanonas/química , Butanonas/urina , Carbono/química , Isótopos de Carbono/química , Di-Hidroxiacetona/sangue , Di-Hidroxiacetona/química , Di-Hidroxiacetona/urina , Fezes/química , Microbioma Gastrointestinal , Humanos , Indicadores e Reagentes/química , Limite de Detecção , Urina/química
14.
Adv Ther ; 38(Suppl 2): 52-60, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34417992

RESUMO

Recent network meta-analyses support the use of pharmacotherapy in patients with generalised anxiety disorder (GAD). Compared with placebo, drug treatment can improve symptoms and quality of life, and is more effective in preventing relapse. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are generally considered the first-line agents of choice in GAD, but in some patients, an alternative evidence-based treatment with a different mechanism of action may also be considered (e.g. those with severe GAD, inadequate response, adverse effects and/or contraindications). One example is agomelatine, a melatonin receptor agonist and serotonin 2C (5-HT2C) receptor antagonist, which has been shown to have efficacy that is greater than placebo in patients with GAD, and to have a tolerability profile that compares favourably with that of escitalopram. Both agomelatine and escitalopram are efficacious in treating patients with GAD, including those with severe symptoms. Video Abstract.


Assuntos
Acetamidas , Qualidade de Vida , Acetamidas/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Humanos , Inibidores de Captação de Serotonina/uso terapêutico
15.
Int J Pharm ; 607: 121006, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34391848

RESUMO

The current work attempted to achieve bypassed hepatic metabolism, controlled release, and boosted brain distribution of agomelatine by loading in NLC and administering via transdermal route. Agomelatine-loaded NLC (AG-NLC) was fabricated employing melt-emulsification technique and optimized using central composite design. The optimized AG-NLC had 183.16 ± 6.82 nm particle size, 0.241 ± 0.0236 polydispersity index, and 83.29 ± 2.76% entrapment efficiency. TEM and FESEM visually confirmed the size and surface morphology of AG-NLC, respectively. DSC thermogram confirmed the conversion of AG from crystalline to amorphous form, which indicates improved solubility of AG when loaded in NLC. For further stability and improved applicability, AG-NLC was converted into a hydrogel. The texture analysis of AG-NLC-Gel showed appropriate gelling property in terms of hardness (142.292 g), cohesiveness (0.955), and adhesiveness (216.55 g.sec). In comparison to AG-suspension-Gel (38.036 ± 6.058%), AG-NLC-Gel (89.440 ± 2.586%) exhibited significantly higher (P < 0.005) skin permeation profile during the 24 h study. In the CLSM study, Rhodamine-B loaded AG-NLC-Gel established skin penetration up to the depth of 45 µm, whereas AG-Suspension-Gel was restricted only to a depth of 25 µm. γ-scintigraphy in wistar rats revealed ~ 55.38% brain distribution potential of 99mTc-AG-NLC-Gel at 12 h, which was 6.31-fold higher than 99mTc-AG-Suspension-Gel. Overall, the gamma scintigraphy assisted brain distribution study suggests that NLC-Gel system may improve the brain delivery of agomelatine, when applied transdermally.


Assuntos
Portadores de Fármacos , Nanoestruturas , Acetamidas , Animais , Encéfalo , Lipídeos , Tamanho da Partícula , Ratos
16.
Clin Immunol ; 230: 108823, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400321

RESUMO

Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil-containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-ß signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.


Assuntos
Doença Enxerto-Hospedeiro/enzimologia , Quinases Associadas a rho/imunologia , Acetamidas/farmacologia , Animais , Doença Crônica , Modelos Animais de Doenças , Fibrose , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Imunomodulação , Modelos Imunológicos , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T Reguladores/imunologia , Quinases Associadas a rho/antagonistas & inibidores
17.
Life Sci ; 284: 119904, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453945

RESUMO

AIM: Alcohol abuse is a significant causative factor of death worldwide. The Notch1 signaling pathway is involved in alcohol tolerance, withdrawal and dependence. Agomelatine is a known antidepressant acting as a melatonin receptor (MT1/2) agonist and a 5-hydroxytryptamine receptor-2C antagonist. However, its effects on alcohol cravings and alcohol withdrawal symptoms have not been investigated. In this study, we assessed the possibility of using agomelatine for the treatment of these symptoms in a rat model of alcoholism and the possible role of Notch1 signaling. MAIN METHODS: We induced alcoholism in rats using a free-choice drinking model for 60 days. From day 61, free-choice was continued until day 82 for the craving model, whereas only water was offered in the withdrawal model. Meanwhile, the treated groups for both models received agomelatine (50 mg/kg/day) orally from day 61 to 82, followed by behavioral, histopathological and biochemical assessment. KEY FINDINGS: Agomelatine treatment caused significant decrease in alcohol consumption with a positive effect on anxiety-like behavior in the open field, memory in the Morris water maze and immobility in the forced swim test. Moreover, agomelatine induced the expression of Notch1 pathway markers, including Notch1, NICD, CREB, CCNE-2, Hes-1, both total and phosphorylated ERK1/2, MMP9, Per2and RGS-2 in the hippocampal formation. By contrast, NMDAR expression was reduced. Furthermore, agomelatine normalized the serum levels of BDNF, cortisol, dopamine and glutamate which were disrupted by alcohol consumption. SIGNIFICANCE: Based on these findings, agomelatine reversed alcohol cravings and withdrawal symptoms associated with alcohol dependence by modulating the Notch1 signaling pathway.


Assuntos
Acetamidas/uso terapêutico , Bebidas Alcoólicas/efeitos adversos , Fissura , Receptor Notch1/metabolismo , Transdução de Sinais , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/metabolismo , Acetamidas/farmacologia , Animais , Ansiedade/patologia , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Hipocampo/metabolismo , Hidrocortisona/sangue , Masculino , Teste do Labirinto Aquático de Morris , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/sangue , Teste de Campo Aberto , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
18.
Eur J Pharm Sci ; 166: 105979, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34425232

RESUMO

Nanocrystal formulations of the BCS class II agomelatine, were developed by wet media milling. The most suitable stabilizer was identified and effects of process and formulation variables on the nanocrystal size and ζ-potential were evaluated employing a Box-Behnken experimental design. The optimized nanosuspensions were dried and subsequently evaluated for redispersibility and physicochemical properties. Computational simulation of solid state properties was applied to rationalize crystal fracture. It was found that low viscosity hydroxypropylcellulose with sodium dodecyl sulfate is the most suitable stabilizer. Stabilizer concentration exerts a statistically significant effect on particle size, which depends on the mill's rotation speed. The milling process induces a polymorphic transition to form II, which could affect size reduction kinetics. The solidified nanosuspensions' redispersibility is deteriorating progressively with storage time, with only minor differences between drying methods, retaining enhanced dissolution rate. Crystal lattice simulations suggest high mechanical anisotropy of form I crystals, which could be an additional reason for fast particle size reduction prior to the polymorphic transformation. Wet media milling, combined with a suitable drying method, can be an efficient technique for the production of stable nanocrystals of agomelatine. Particle informatics methods can enhance our understanding of the mechanisms responsible for agomelatine's nanocomminution.


Assuntos
Nanocompostos , Nanopartículas , Acetamidas , Composição de Medicamentos , Tamanho da Partícula , Solubilidade , Suspensões
19.
Brain Behav ; 11(8): e2311, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34333871

RESUMO

OBJECTIVE: To compare the effectiveness and tolerability of agomelatine with mirtazapine in patients with depressive disorder. To illustrate the prescribing pattern of agomelatine and identify factors that affect the pattern of treatment result and therapeutic outcome of it. METHODS: The clinical data of patients using agomelatine or mirtazapine, 93 patients in each group, were included and reviewed in this retrospective study. Background characteristics, adverse events, therapeutic outcomes (discontinued or continued), reason of discontinuation, and the presence of positive pattern of treatment result were assessed. Positive pattern of treatment result was defined as either recovery or improvement of depressive disorder after therapy. RESULTS: Patients using agomelatine were associated with higher starting dose and higher dose titrated than mirtazapine. More patients started agomelatine due to intolerability, and less due to ineffectiveness of the previous antidepressant. More patients started agomelatine before the use of at least two selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI). Patients using agomelatine were associated with less discontinuation due to intolerability, and less experience of adverse events within 90 days of initiation or dose increase, but more discontinuation due to ineffectiveness versus mirtazapine. The use of 50 mg resulted in less discontinuation. The use of at least two SSRI(s)/SNRI(s) before and more concomitant medications are independently associated with more discontinuation due to intolerability. The use of at least two SSRI(s)/SNRI(s) before was also associated with more adverse events. Using agomelatine as an augmentation to other antidepressant(s) and at a higher dose were independently associated with the experience of positive pattern of treatment result. CONCLUSION: Agomelatine was more tolerable than mirtazapine, but could result in more discontinuation due to ineffectiveness. The use of higher dose and as an augmentation to other antidepressant(s) could improve the desired treatment result of agomelatine.


Assuntos
Transtorno Depressivo Maior , Preparações Farmacêuticas , Acetamidas , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Mirtazapina , Estudos Retrospectivos , Inibidores de Captação de Serotonina
20.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361749

RESUMO

Cefquinome and ceftiofur are ß-lactam antibiotics used for the treatment of bacterial infections in swine. Although these antimicrobials are administered intramuscularly, the exposure of the gut microbiota to these cephalosporins is not well described. This exposure can contribute to the emergence and spread of antimicrobials in the environment and to the possible spread of antimicrobial resistance genes. To assess the impact of drug administration on the intestinal excretion of these antimicrobials it is essential to measure the amounts of native compound and metabolites in feces. Two (ultra)-high-performance liquid chromatography-tandem mass spectrometry ((U)HPLC-MS/MS) methods were developed and validated, one for the determination of cefquinome and ceftiofur and the other for the determination of ceftiofur residues, measured as desfuroylceftiofuracetamide, in porcine feces. The matrix-based calibration curve was linear from 5 ng g-1 to 1000 ng g-1 for cefquinome (correlation coefficient (r) = 0.9990 ± 0.0007; goodness of fit (gof) = 3.70 ± 1.43) and ceftiofur (r = 0.9979 ± 0.0009; gof = 5.51 ± 1.14) and quadratic from 30 ng g-1 to 2000 ng g-1 for desfuroylceftiofuracetamide (r = 0.9960 ± 0.0020; gof = 7.31 ± 1.76). The within-day and between-day precision and accuracy fell within the specified ranges. Since ß-lactam antibiotics are known to be unstable in feces, additional experiments were conducted to adjust the sampling protocol in order to minimize the impact of the matrix constituents on the stability of the analytes. Immediately after sampling, 500 µL of an 8 µg mL-1 tazobactam solution in water was added to 0.5 g feces, to reduce the degradation in matrix.


Assuntos
Acetamidas/isolamento & purificação , Antibacterianos/isolamento & purificação , Cefalosporinas/isolamento & purificação , Cromatografia Líquida de Alta Pressão/normas , Furanos/isolamento & purificação , Espectrometria de Massas em Tandem/normas , Acetamidas/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Calibragem , Cefalosporinas/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodos , Fezes/química , Feminino , Furanos/administração & dosagem , Injeções Intramusculares , Masculino , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Suínos , Espectrometria de Massas em Tandem/métodos , Tazobactam/química
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