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1.
PLoS One ; 16(10): e0258148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34618850

RESUMO

Proper protection of vascular access after haemodialysis is one of the key measures for the prevention of catheter-related infections. Various substances with bactericidal and anticoagulant properties are used to fill catheters, but due to the unsatisfactory clinical effects and occurrence of adverse reactions, the search for new substances is still ongoing. In the present paper, we compared the in vitro antimicrobial activity of solutions used for tunnelled catheter locking (taurolidine, trisodium citrate) and solutions of substances that could potentially be used for this purpose (sodium bicarbonate, polyhexanide-betaine). The studies have been conducted on bacteria that most commonly cause catheter-related infections. The values of both minimum inhibitory concentration and minimum biofilm eradication concentration of the substances were determined. The ability of the tested substances to eradicate biofilm from the dialysis catheter surface was also evaluated. The results showed that polyhexanide-betaine inhibited the growth of all microbes comparably to taurolidine, even after ≥ 32-fold dilution. The activity of trisodium citrate and sodium bicarbonate was significantly lower. Polyhexanide exhibited the highest activity in the eradication of bacterial biofilm on polystyrene plates. The biofilm formed on a polyurethane dialysis catheter was resistant to complete eradication by the test substances. Polyhexanide-betaine and taurolidine showed the highest activity. Inhibition of bacterial growth regardless of species was observed not only at the highest concentration of these compounds but also after dilution 32-128x (taurolidine) and 32-1024x (polyhexanide-betaine). Therefore, it can be assumed that taurolidine application as a locking solution prevents catheter colonization and systemic infection development. Taurolidine displays high antimicrobial efficacy against Gram-positive cocci as well as Gram-negative bacilli. On the contrary, the lowest antibacterial effect displayed product contained sodium bicarbonate. The inhibitions of bacterial growth were not satisfactory to consider it as a substance for colonization prevention. Polyhexanidine-betaine possessed potent inhibitory and biofilm eradication properties comparing to all tested products. PHMB is applied as a wound irrigation solution worldwide. However, based on our results, we assume that the PHMB is a promising substance for catheter locking solutions thanks to its safety and high antimicrobial properties.


Assuntos
Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Relacionadas a Cateter/prevenção & controle , Cateteres Venosos Centrais/microbiologia , Bactérias/patogenicidade , Biofilmes/efeitos dos fármacos , Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções Relacionadas a Cateter/microbiologia , Cateterismo , Soluções para Hemodiálise/química , Humanos , Diálise Renal/efeitos adversos , Taurina/análogos & derivados , Taurina/farmacologia , Tiadiazinas/farmacologia
2.
Molecules ; 26(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34641454

RESUMO

A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tiadiazinas/química , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361113

RESUMO

Efficient and safe nanopesticides play an important role in pest control due to enhancing target efficiency and reducing undesirable side effects, which has become a hot spot in pesticide formulation research. However, the preparation methods of nanopesticides are facing critical challenges including low productivity, uneven particle size and batch differences. Here, we successfully developed a novel, versatile and tunable strategy for preparing buprofezin nanoparticles with tunable size via anodic aluminum oxide (AAO) template-assisted method, which exhibited better reproducibility and homogeneity comparing with the traditional method. The storage stability of nanoparticles at different temperatures was evaluated, and the release properties were also determined to evaluate the performance of nanoparticles. Moreover, the present method is further demonstrated to be easily applicable for insoluble drugs and be extended for the study of the physicochemical properties of drug particles with different sizes.


Assuntos
Óxido de Alumínio/química , Materiais Revestidos Biocompatíveis/química , Inseticidas/química , Nanopartículas Metálicas/química , Tiadiazinas/química , Eletrodos , Teste de Materiais , Porosidade , Propriedades de Superfície
4.
Br J Nurs ; 30(14): S24-S32, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34288746

RESUMO

HIGHLIGHTS: 2% taurolidine catheter lock solution without additives is safe and efficient. CRBSI and dysfunction rates compare favorably against other studies in hemodialysis. BACKGROUND: In hemodialysis patients, catheter-related bloodstream infection (CRBSI) and catheter dysfunction are common and cause significant morbidity, mortality, and costs. Catheter lock solutions reduce CRBSI and catheter dysfunction rates, but solutions containing heparin, citrate, or antibiotics are associated with adverse effects. Due to its antimicrobial and antithrombotic properties and benign safety profile, taurolidine is suitable for use in catheter lock solutions. In this study the effectiveness and safety of a catheter lock solution containing 2% taurolidine without citrate or heparin (TauroSept®, Geistlich Pharma AG, Wolhusen, Switzerland) in hemodialysis patients were investigated for the first time. METHODS: Data from 21 patients receiving chronic hemodialysis via tunneled central venous catheters with 2% taurolidine solution as a catheter lock were analyzed in a single-center retrospective study and compared with the existing literature in a review. The primary endpoint was CRBSI rate. Secondary endpoints included catheter dysfunction, treatment, and costs; catheter technical problems, resolution, and costs; and adverse events. Data were compared to outcomes with standard lock solutions in the literature. RESULTS: No CRBSIs occurred during the observation period of 5,639 catheter days. The catheter dysfunction rate was 0.71 per 1,000 catheter days, and the catheter dysfunction treatment costs were CHF (Swiss Franc) 543 per patient. No technical problems or adverse events related to the use of 2% taurolidine-containing catheter lock solution were observed. These results compare favorably with other catheter lock solutions. CONCLUSIONS: A solution containing 2% taurolidine seems suitable as a hemodialysis catheter lock. In a Swiss cohort, it prevented CRBSI, limited catheter dysfunction, and was cost-efficient.


Assuntos
Bacteriemia , Infecções Relacionadas a Cateter , Cateteres Venosos Centrais , Taurina/análogos & derivados , Tiadiazinas , Bacteriemia/etiologia , Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/prevenção & controle , Cateteres Venosos Centrais/efeitos adversos , Falha de Equipamento , Humanos , Diálise Renal/instrumentação , Estudos Retrospectivos , Suíça , Taurina/uso terapêutico , Tiadiazinas/uso terapêutico
5.
Pest Manag Sci ; 77(10): 4627-4637, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34087044

RESUMO

BACKGROUND: Environmental stimuli-responsive release is one important way to reduce the dosage of pesticide, increase the usage efficiency and improve environmental compatibility. RESULTS: On this basis, we synthesized mesoporous silica nanoparticles (MSNs) and modified them to develop a thermosensitive pesticide controlled release formulation (CRF). In this study, MSNs prepared by the sol-gel method were used as the core, poly (N-IsoPropylAcrylaMide) [P (NIPAM-MAA)] was used as the shell, and buprofezin (Bup) was loaded by adsorption. The prepared Bup@MSNs@P(NIPAM-MAA) could effectively prevent the degradation of buprofezin under UV light and exhibited excellent adhesion to rice leaves. The bioassay results showed that the mortality of Nilaparvata lugens (Stål) treated by Bup@MSNs@P(NIPAM-MAA) was positively correlated with temperature, resulting mainly from the change of release amount of buprofezin caused by temperature variation. Bup@MSNs@P(NIPAM-MAA) had long duration (20 days) for controlling N. lugens, and did not hinder the growth of rice. Meanwhile, Bup@MSNs@P(NIPAM-MAA) had low toxicity to zebrafish and human pneumonocyte BEAS-2B cells. CONCLUSION: This novel thermosensitive pesticide CRF can be applied widely to other insecticides, thus greatly promoting the development of intelligent pesticide formulations. © 2021 Society of Chemical Industry.


Assuntos
Nanopartículas , Dióxido de Silício , Animais , Humanos , Controle de Pragas , Porosidade , Tiadiazinas , Peixe-Zebra
6.
Ecotoxicol Environ Saf ; 220: 112362, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34087650

RESUMO

Chloropicrin (Pic) and dazomet (DZ) are effective soil fumigants that are often used to reduce soil-borne pathogens that would otherwise reduce crop yield. As Pic is scheduled to be banned, we investigated whether its consumption could be halved by alternating it with DZ. We observed that Pic alternated with DZ increased the soil NH4+-N content by 28.74-47.07 times, increased available potassium content by 40.80%-46.81% and increased electrical conductivity by 39.23%-85.81%. It generally improved the soil's physicochemical properties. High-throughput DNA sequencing showed that Pic alternated with DZ changed the taxonomic diversity of bacteria and fungi by increasing the relative abundance of Bacillus and Firmicutes, and by decreasing Proteobacteria, Acidobacteria and Sphingomonas. Moreover, Pic alternated with DZ can inhibit key soil pathogens by more than 90% and significantly increased strawberry yield by 78.22%-116.12%. In terms of strawberry production, we recommend using DZ in the first year and Pic in the second year. Our results showed significant ecological benefit and yield benefit when Pic consumption was halved by alternating it with DZ.


Assuntos
Fragaria/crescimento & desenvolvimento , Hidrocarbonetos Clorados/farmacologia , Microbiota/efeitos dos fármacos , Praguicidas/farmacologia , Tiadiazinas/farmacologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Fragaria/microbiologia , Fungos/classificação , Fungos/genética , Fungos/isolamento & purificação , Nutrientes/análise , Solo/química , Microbiologia do Solo
7.
PLoS One ; 16(5): e0251793, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34015014

RESUMO

BACKGROUND: The efficacy and cost-effectiveness of prophylactic thrombolytic locks in hemodialysis patients at high-risk of thrombotic dialysis catheter dysfunction is uncertain. We investigated this question in a double-blinded randomized controlled study. METHODS: Prevalent hemodialysis patients from 8 Belgian hemodialysis units, with ≥2 separate episodes of thrombotic dysfunction of their tunneled cuffed catheter during the 6 months before inclusion, were randomized to either: taurolidine heparin locks thrice weekly (control arm) or the same locks twice a week combined with taurolidine urokinase locks once a week before the longest interval without HD (TaurolockU arm). The primary efficacy outcome was the incidence rate of catheter thrombotic dysfunction requiring thrombolytic locks to restore function. RESULTS: 68 hemodialysis patients (32 controls, 36 urokinase) were followed during 9875 catheter days between May 2015 and June 2017. Incidence rate of thrombotic catheter dysfunction was 4.8 in TaurolockU vs 12.1/1000 catheter days in control group (rate ratio 0.39; 95%CI 0.23-0.64). 15/36 (42%) catheters in the treatment group required at least one therapeutic urokinase lock vs 23/32 (72%) in the control group (P = 0.012). The two groups did not differ significantly in catheter-related bloodstream infection and combined cost of prophylactic and therapeutic catheter locks. The TaurolockU group had a numerically higher number of episodes of refractory thrombosis. CONCLUSIONS: Prophylactic use of urokinase locks is highly effective in reducing the number of thrombotic catheter dysfunctions in catheters with a history of recurring dysfunction. Prophylactic use of urokinase locks did not reduce the overall costs associated with catheter locks and was associated with a numerically higher number of episodes of refractory thrombosis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02036255.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Diálise Renal/efeitos adversos , Taurina/análogos & derivados , Tiadiazinas/administração & dosagem , Trombose/prevenção & controle , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taurina/administração & dosagem , Trombose/etiologia
8.
Rev Chilena Infectol ; 38(1): 15-21, 2021 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-33844787

RESUMO

BACKGROUND: Taurolidine is a molecule with anti-endotoxic, anti-microbial and anti-inflammatory properties that inhibits bacterial adhesion, allowing for its use as lock therapy for the prevention of catheter-related bloodstream infections (CRBSI) in long-term central venous catheters (CVC). AIM: To report a preliminary experience, the first one in Chile, using lock therapy with taurolidine for the prevention of CRBSI and to report its efficacy. METHOD: A taurolidine-based solution was instilled in the CVC of three children with intestinal insufficiency dependent on parenteral nutrition, attended in a Chilean tertiary hospital, and the rate of CRBSI before and after its use was compared in retrospect. RESULTS: In the two patients who started lock therapy immediately after the installation of their CVC, the rate of CRBSI was brought to zero, whereas in the third patient, who had a 9 months-old CVC with a recurrent CRBSI history, an intercurrent CRBSI forced discontinuation of the prophylaxis. CONCLUSIONS: Lock therapy with a taurolidine-based solution prevented CRBSIs when it was begun immediately after installing the CVC, in contrast with an old CVC with a history of recurrent CRBSIs.


Assuntos
Bacteriemia , Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Tiadiazinas , Infecções Relacionadas a Cateter/prevenção & controle , Cateterismo Venoso Central/efeitos adversos , Criança , Chile , Humanos , Lactente , Taurina/análogos & derivados , Centros de Atenção Terciária , Tiadiazinas/uso terapêutico
9.
Eur J Med Chem ; 219: 113444, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33866238

RESUMO

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-ß and VchCA-γ) and Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.


Assuntos
Proteínas de Bactérias/metabolismo , Burkholderia pseudomallei/enzimologia , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Sulfonamidas/química , Tiadiazinas/química , Vibrio cholerae/enzimologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/química , Desenho de Fármacos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Cinética , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 219: 113441, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33862517

RESUMO

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ligantes , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fármacos Neuroprotetores/síntese química , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Azóis/química , Azóis/metabolismo , Azóis/farmacologia , Azóis/uso terapêutico , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/metabolismo , Óxidos S-Cíclicos/farmacologia , Óxidos S-Cíclicos/uso terapêutico , Desenho de Fármacos , Humanos , Interleucina-6/metabolismo , Isoindóis , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Compostos Organosselênicos/química , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Selênio/química , Transdução de Sinais/efeitos dos fármacos , Tiadiazinas/química , Tiadiazinas/metabolismo , Tiadiazinas/farmacologia , Tiadiazinas/uso terapêutico
11.
Sci Rep ; 11(1): 2121, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483532

RESUMO

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.


Assuntos
Antimaláricos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Fígado/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Células Hep G2 , Humanos , Fígado/parasitologia , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/fisiologia , Plasmodium falciparum/genética , Plasmodium falciparum/fisiologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Reprodutibilidade dos Testes , Relação Estrutura-Atividade , Tiadiazinas/química , Tiadiazinas/farmacologia
12.
Sci Rep ; 11(1): 2101, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483556

RESUMO

The toxicity of seven biorational insecticides [five insect growth regulators (Buprofezin, Fenoxycarb, Pyriproxyfen, Methoxyfenozide, and Tebufenozide) and two oil-extracts of neem and bitter gourd seeds] against Bemisia tabaci and their selectivity for its parasitoid, Encarsia formosa were evaluated in laboratory and field conditions for 2 years (2018-2019) in Pakistan. Toxicity results demonstrate that Pyriproxyfen, Buprofezin, and Fenoxycarb proved to be effective (80-91% mortality and 66.3-84.2% population-reduction) against B. tabaci followed by Methoxyfenozide, Tebufenozide (50-75% mortality and 47.8-52.4% population-reduction), and then oil-extracts of neem and bitter gourd (25-50% mortality and 36.5-39.8% population-reduction) in the laboratory [72 h post-application exposure interval (PAEI)] and field trails (168 h PAEI), respectively. All tested biorationals, except Methoxyfenozide [(slightly-harmful/Class-II), i.e., causing mortality of parasitoids between a range of 25-50%] and Tebufenozide [(moderately-harmful/Class-III), i.e., causing mortality of parasitoids between the ranges of 51-75%], proved harmless/Class-I biorationals at PAEI of 7-days in the field (parasitism-reduction < 25%) and 3-days in the lab (effect < 30%). In laboratory bioassays, exposure of parasitized-pseudopupae and adult-parasitoids to neem and bitter gourd oils demonstrated that these compounds proved harmless/Class-I biorationals (< 30% mortality). Alternatively, Pyriproxyfen, Buprofezin, Fenoxycarb, Methoxyfenozide, and Tebufenozide were slightly-harmful biorationals (30-79% mortality) against the respective stages of E. formosa. We conclude that most of the tested biorationals proved harmless or slightly harmful to E. formosa, except tebufenozide after PAEI of 7-days (168 h) in the field and, therefore, may be used strategically in Integrated Pest Management (IPM) of B. tabaci.


Assuntos
Gossypium/parasitologia , Hemípteros/fisiologia , Inseticidas/toxicidade , Controle Biológico de Vetores/métodos , Vespas/fisiologia , Animais , Azadirachta/química , Gossypium/genética , Interações Hospedeiro-Parasita/efeitos dos fármacos , Hidrazinas/toxicidade , Hormônios Juvenis/toxicidade , Larva/efeitos dos fármacos , Larva/fisiologia , Momordica charantia/química , Fenilcarbamatos/toxicidade , Extratos Vegetais/toxicidade , Plantas Geneticamente Modificadas , Piridinas/toxicidade , Tiadiazinas/toxicidade , Resultado do Tratamento
13.
Artigo em Inglês | MEDLINE | ID: mdl-33430085

RESUMO

This study determined residual buprofezin levels in fresh ginseng and evaluated their changes during processing. Supervised field trials were conducted at Yeongju, Geumsan, and Goesan, Korea. Buprofezin 12.5% EC was applied to 5-y ginseng in accordance with the Korean good agriculture practice (GAP). Samples were collected at 0, 7, 14, 21, and 30 d after the final application. On day 14 (GAP-equivalent preharvest date), the ginseng was processed to obtain dried and red ginseng. The average buprofezin concentrations on day 0 were 0.076 (Yeongju), 0.055 (Geumsan), and 0.078 mg kg-1 (Goesan). Residual concentrations increased as ginseng was processed into dried and red ginseng. Residue levels in dried ginseng manufactured by hot air drying were higher than in red ginseng obtained by steaming, hot air, and sunlight drying. However, the absolute amount of pesticides decreased by approximately 20-30% as a result of calculating the reduction factor considering the dry yield and moisture content. Therefore, the residual concentration in processed products may vary depending on the processing method, and it is deemed necessary to consider the processing yield and moisture content when evaluating the safety of residual pesticides in dried processed products.


Assuntos
Panax , Tiadiazinas , Dessecação , República da Coreia
14.
J Antibiot (Tokyo) ; 74(4): 244-254, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33479520

RESUMO

Therapeutic strategies that target bacterial virulence have received considerable attention. The type III secretion system (T3SS) is important for bacterial virulence and represents an attractive therapeutic target. Recently, we developed a new small-molecule inhibitor belonging to a class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones, Fluorothiazinon (FT-previously called CL-55). FT effectively suppressed T3SS of Chlamydia spp., Pseudomonas aeruginosa, and Salmonella without affecting bacterial growth in vitro. FT was previously characterized by low toxicity, stability, and therapeutic efficacy in animal models. Salmonella T3SS inhibition by FT was studied using in vitro assays for effector proteins detection and estimation of salmonella replication in peritoneal macrophages. The antibacterial effect of FT in vivo was investigated in murine models of salmonella chronic systemic and acute infection. Oral administration of the virulent strain of Salmonella enterica serovar Typhimurium to mice-induced chronic systemic infection with the pathogen persistence in different lymphoid organs such as spleens, Peyer's plaques, and mesenteric lymph nodes. We found that FT suppressed orally induced salmonella infection both with therapeutic and prophylactic administration. Treatment by FT at a dose of 50 mg/kg for 4 days starting from day 7 post-infection (therapy) as well as for 4 days before infection (prevention) led to practically complete eradication of salmonella in mice. FT shows a strong potential for antibacterial therapy and could be used as a substance in the design of antibacterial drugs for pharmaceutical intervention including therapy of antibiotic-resistant infections.


Assuntos
Anilidas/farmacologia , Antibacterianos/farmacologia , Infecções por Salmonella/tratamento farmacológico , Tiadiazinas/farmacologia , Ampicilina/farmacologia , Anilidas/administração & dosagem , Anilidas/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos Endogâmicos , Coelhos , Intoxicação Alimentar por Salmonella/tratamento farmacológico , Intoxicação Alimentar por Salmonella/prevenção & controle , Infecções por Salmonella/prevenção & controle , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/metabolismo , Salmonella typhimurium/patogenicidade , Tiadiazinas/administração & dosagem , Tiadiazinas/farmacocinética , Distribuição Tecidual , Sistemas de Secreção Tipo III/antagonistas & inibidores
15.
J Vasc Access ; 22(3): 370-379, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32691665

RESUMO

INTRODUCTION: The surface of tunnelled cuffed catheters provides an optimal environment for the development of biofilms, which have recently been described as conditioning films because of the presence of adherent biological materials. These biofilms are associated with infection and thrombosis and potentially increase patients' inflammatory response. These complications could be reduced by the use of locking solutions. OBJECTIVE: To analyse biofilm formation, using confocal and electron microscopy, in tunnelled cuffed catheters locked with three different solutions and to determine the relationship between these solutions and inflammatory response. STUDY DESIGN: This prospective study included 35 haemodialysis patients with tunnelled cuffed catheter removal for non-infection-related reasons. The participants were divided into three groups according to the lock solution used: (1) heparin 1: 5000 IU; (2) citrate 4%; and (3) taurolidine 1.35%, citrate 4% and heparin 500 IU (taurolock); in the latter group, 25,000 IU taurolidine-urokinase was used in the last weekly session. All tunnelled cuffed catheters were cultured, and the inner surface was evaluated with confocal and electron microscopy. The inflammatory profile of included patients was determined at tunnelled cuffed catheter removal. RESULTS: There were no differences in clinical or demographic variables between the three subgroups. Biofilm thickness was lower in the taurolidine group than in the citrate 4% and heparin groups (28.85 ± 6.86 vs 49.99 ± 16.56 vs 56.2 ± 15.67 µm, respectively; p < 0.001), as was biofilm volume (1.01 ±1.18 vs 3.7 ± 2.15 vs 5.55 ±2.44, µm3, respectively; p < 0.001). The mean interleukin-6 value was 39%, which was 50% lower than in the citrate and heparin groups, but without significance differences. CONCLUSION: Our results show that biofilms were found in all tunnelled cuffed catheters, but the thickness and volume were significantly lower in tunnelled cuffed catheters locked with taurolidine solution. Therefore, the type of locking solution used in tunnelled cuffed catheters should maintain tunnelled cuffed catheter sterility and prevent catheter-related bloodstream infections. No significant difference was observed in the inflammatory profile according to the type of locking solution.


Assuntos
Anti-Infecciosos/administração & dosagem , Anticoagulantes/administração & dosagem , Biofilmes/efeitos dos fármacos , Infecções Relacionadas a Cateter/prevenção & controle , Cateteres de Demora , Ácido Cítrico/administração & dosagem , Heparina/administração & dosagem , Inflamação/prevenção & controle , Diálise Renal/instrumentação , Taurina/análogos & derivados , Tiadiazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/efeitos adversos , Anticoagulantes/efeitos adversos , Biofilmes/crescimento & desenvolvimento , Infecções Relacionadas a Cateter/diagnóstico , Infecções Relacionadas a Cateter/microbiologia , Ácido Cítrico/efeitos adversos , Desenho de Equipamento , Feminino , Heparina/efeitos adversos , Humanos , Inflamação/sangue , Inflamação/etiologia , Mediadores da Inflamação/sangue , Interleucina-6/sangue , Masculino , Microscopia Confocal , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Diálise Renal/efeitos adversos , Propriedades de Superfície , Taurina/administração & dosagem , Taurina/efeitos adversos , Tiadiazinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
J Alzheimers Dis ; 79(1): 275-287, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33252075

RESUMO

BACKGROUND: We performed exploratory analyses of retinal thickness data from a clinical trial of the AßPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD). OBJECTIVE: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. METHODS: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. RESULTS: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant. CONCLUSION: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline. TRIAL REGISTRATION: Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Óxidos S-Cíclicos/uso terapêutico , Retina/diagnóstico por imagem , Tiadiazinas/uso terapêutico , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Atrofia , Encéfalo/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Retina/patologia , Tomografia de Coerência Óptica
17.
J Vasc Access ; 22(2): 261-265, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32605474

RESUMO

BACKGROUND: Relapsing peritonitis due to the development of a biofilm in the catheter's lumen remains an important complication of peritoneal dialysis therapy that endangers technique continuity. Taurolidine catheter lock has proven efficient reducing infection rates in permanent hemodialysis catheters based on its biocidal activity and biofilm detachment effect. Efficacy evidence on its use in peritoneal dialysis catheters is lacking. METHODS: We retrospectively analyzed all relapsing peritonitis episodes from June 2018 until October 2019 in our center. Patients were identified and data were collected from our electronic renal registry and patient's records. RESULTS: Six patients were identified during the study period. Most patients (66.6%) were on automated peritoneal dialysis and the median duration of peritoneal dialysis before the episode of taurolidine was started was 43.66 ± 29.64 months. Mean taurolidine doses were 10 (range: 9-11) and 83.3% (five patients, with peritonitis caused by Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Corynebacterium propinquum) had a favorable response and microbial eradication without relapses after taurolidine treatment. Only one patient relapsed by the same organism (Corynebacterium amycolatum) due to non-adherence to the antibiotic treatment prescribed. None of the patients experienced any relevant adverse events, with only two out of six presenting mild transient abdominal discomfort. CONCLUSION: We believe that peritoneal catheter taurolidine lock could be considered in cases of relapsing or refractory peritonitis, as it could prevent catheter removal and permanent switch to hemodialysis in selected cases, although literature is scarce and further studies are needed.


Assuntos
Anti-Infecciosos/uso terapêutico , Infecções Relacionadas a Cateter/prevenção & controle , Cateterismo/instrumentação , Cateteres de Demora , Diálise Peritoneal/instrumentação , Peritonite/prevenção & controle , Taurina/análogos & derivados , Tiadiazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/efeitos adversos , Infecções Relacionadas a Cateter/microbiologia , Cateterismo/efeitos adversos , Cateteres de Demora/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/efeitos adversos , Peritonite/microbiologia , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taurina/efeitos adversos , Taurina/uso terapêutico , Tiadiazinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
18.
Ying Yong Sheng Tai Xue Bao ; 31(9): 3085-3092, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-33345510

RESUMO

In this study, we examined the effects of dazomet fumigation with different concentrations (0, 0.1, 0.2, 0.4 g·kg-1) on the microbial characteristics of continuous cropping soil and growth of Malus hupehensis seedling in greenhouse and open-field pot. The results showed that all the treatment of dazomet fumigation could promote the growth of M. hupehensis seedlings in continuous cropping soil, with 0.2 g·kg-1 treatment showing the strongest effect. Compared to the control, plant height, stem diameter, dry weight of M. hupehensis seedlings in 0.2 g·kg-1 dazomet fumigation were increased by 192.9% and 91.8%, 72.8% and 60.1%, 196.8% and 195.0%, 138.5% and 130.7%, respectively in greenhouse and open-field. The root related indices (root length, root area, root volume, root respiration rate) were significantly promoted. The activities of SOD, POD, CAT in roots were increased by 114.6% and 118.5%, 123.5% and 107.6%, 164.6% and 175.6% respectively compared with the control, whereas the content of malondialdehyde was significantly lowered. Soil bacterial content, fungal content, copy number of Fusarium oxysporum gene and soil enzyme activity were significantly decreased with the increasing dazomet concentrations. In conclusion, 0.2 g·kg-1 dazomet fumigation could increase the biomass of M. hupehensis seedlings in continuous cropping, improve soil environment, and effectively alleviate the continuous cropping obstacle. Therefore, 0.2 g ·kg-1 dazomet fumigation could be given priority during the reconstruction of old apple orchards.


Assuntos
Produtos Biológicos , Malus , Fumigação , Fusarium , Plântula , Solo , Tiadiazinas
19.
Sci Rep ; 10(1): 21668, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303943

RESUMO

Fusarium wilt disease causes severe decline of watermelon yield and quality. Researches have been reported that soil fumigation with dazomet can help control crop disease. Firstly, we discovered that the dazomet application suppressed watermelon wilt in field experiment compared to the control group. While the importance of microbial community in regulating plant health has been rising up, we therefore focused on examining the soil microbial diversity at six different sampling times after dazomet application by using Illumina MiSeq platform. Remarkably, our research results showed that some beneficial microbial genera have been altered, and these beneficial microbial genera have dominated the entire community, such as Nitrolancea, Pseudomonas and Penicillium after dazomet application. Instead, the relative abundance of Fusarium genus and the pathogen FON (Fusarium oxysporum f. sp. niveum, FON) had the decreased. As there was a significant accumulation of AP (available soil phosphorus) after dazomet application, we noticed that the beneficial microbes as Bacillus, Nitrolancea, Paenibacillus and Penicillium have significant positive correlation with AP but negatively related to morbidity. Together, these results demonstrate that the altered soil microbial community structure by dazomet application is critical to suppress watermelon Fusarium wilt. Thus, our results will drive investigations aimed to deploy interaction of microbiota contribute and plant immunity.


Assuntos
Citrullus , Fumigação , Fusarium/patogenicidade , Microbiota , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Microbiologia do Solo , Tiadiazinas/administração & dosagem , Citrullus/imunologia , Interações entre Hospedeiro e Microrganismos , Microbiota/efeitos dos fármacos , Doenças das Plantas/imunologia , Tiadiazinas/farmacologia
20.
Brain ; 143(12): 3816-3826, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33253354

RESUMO

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/diagnóstico por imagem , Óxidos S-Cíclicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Tiadiazinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Imagem de Tensor de Difusão , Método Duplo-Cego , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo
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