Résumé
SUMMARY: Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is highly expressed in various types of cancers including breast cancer. However, the role of AhR with its endogenous ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) on the progression of breast cancer remains poorly understood. We aimed to investigate cell proliferation and migration states in breast cancer after activating AhR with the endogenous ligand ITE. Breast cancer tissue was evaluated by cell lines, immunohistochemistry, reverse transcription-polymerase chain reaction, cell proliferation, flow cytometry, migration assays and western blot techniques. We found that AhR was widely expressed in breast cancer tissues and metastasis lymph node tissues, but not in normal tissues. The expression AhR was independent between the age, grades and TNM classifications for breast cancer tissues. ITE treatment significantly induced the activation of AhR in a time-dependent manner in both MCF-7 and T47D breast cancer cell lines. Meanwhile, ITE did not affect the cell migration but significantly suppressed the cell proliferation in estrogen receptor positive (ER+) MCF-7 andT47D cells, which probably attribute to the induction of cell cycle arrest in G1 phase and shortened S phase. Further mechanism study showed that ERK1/2 and AKT signaling were required for the activation of AhR in MCF-7 cells. These data suggest that AhR is a potential new target for treating patients with breast cancer. ITE may be more potentially used for therapeutic intervention for breast cancer with the kind of ER(+).
El receptor de hidrocarburo de arilo (AhR) es un factor de transcripción activado por ligando que se expresa en gran medida en varios tipos de cáncer, incluido el cáncer de mama. Sin embargo, el papel de AhR con su ligando endógeno 2- (1'H-indol-3'-carbonil)-tiazol-4-ácido carboxílico metil éster (ITE) en la progresión del cáncer de mama sigue siendo poco conocido. Nuestro objetivo fue investigar la proliferación celular y los estados de migración en el cáncer de mama después de activar AhR con el ligando endógeno ITE. El tejido de cáncer de mama se evaluó mediante líneas celulares, inmunohistoquímica, reacción en cadena de la polimerasa con transcriptasa inversa, proliferación celular, citometría de flujo, ensayos de migración y técnicas de transferencia Western. Descubrimos que AhR se expresó ampliamente en tejidos de cáncer de mama y en linfonodos con metástasis, pero no en tejidos normales. La expresión AhR fue independiente entre la edad, grados y clasificaciones TNM para tejidos de cáncer de mama. El tratamiento con ITE indujo significativamente la activación de AhR de manera dependiente del tiempo en las líneas celulares de cancer de mama MCF-7 y T47D. Mientras tanto, ITE no afectó la migración celular, pero suprimió significativamente la proliferación celular en células MCF-7 y T47D con receptor de estrógeno positivo (ER+), lo que probablemente se atribuye a la inducción de la detención del ciclo celular en la fase G1 y la fase S acortada. Un estudio adicional del mecanismo mostró que las señales de ERK1/2 y AKT eran necesarias para la activación de AhR en las células MCF-7. Estos datos sugieren que AhR es un nuevo objetivo potencial para el tratamiento de pacientes con cáncer de mama. ITE puede ser utilizado más potencialmente en la intervención terapéutica para el cáncer de mama con el tipo de ER (+).
Sujets)
Humains , Femelle , Thiazoles/administration et posologie , Tumeurs du sein/anatomopathologie , Récepteurs à hydrocarbure aromatique/effets des médicaments et des substances chimiques , Indoles/administration et posologie , Thiazoles/pharmacologie , Immunohistochimie , Récepteurs des oestrogènes , Technique de Western , Cytochrome P-450 CYP1A1/génétique , Lignée cellulaire tumorale/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tests de migration cellulaire , Cytochrome P-450 CYP1B1/génétique , Cytométrie en flux , Indoles/pharmacologieRésumé
Objective: To establish a high performance liquid chromatography method for the determination of 2-thioxothiazolidine-4-carboxylic acid (TTCA) in urine. Methods: After acidification with hydrochloric acid, TTCA in urine was first extracted by ethyl acetate with excessive sodium chloride, then gradient separated by a symmetry C18 column and then detected by a diode array detector. The quantification was based on a working curve of external standard method. Results: The linear relationship of TTCA in urine was good in the range of 0.03-10.00 mg/L, and the correlation coefficient was 0.9999. The detection limit and minimum quantitative concentration of TTCA in urine were 0.008 mg/L and 0.027 mg/L. The intra-assay precision of the method was 0.9%-1.4%, the inter-assay precision was 1.3%-3.5%, and the average recovery was 85.0%-92.7% while the concentrations of TTCA in urine was 0.8, 2.0 and 8.0 mg/L, respectively (n=6) . Conclusion: The gradient elution high performance liquid chromatography method has simple operation and high sensitivity, and it is suitable for the determination of TTCA on a low level in urine for occupational workers exposure to carbon disulfide.
Sujets)
Humains , Disulfure de carbone , Chromatographie en phase liquide à haute performance/méthodes , Thiazoles/urine , Thiazolidines , ThionesRésumé
In this present study, 63 different 5-[4-methyl-2-(pyridin-3/4-yl)thiazole-5-yl]-4-substituted-3-substituted benzylthio-4H-1,2,4-triazole derivatives were synthesized, and evaluated for their in vitro antimicrobial activity against various human pathogenic microorganisms and antioxidant activity. The derivatives were synthesized in a multi-step synthesis procedure including triazole and thiazole ring closure reactions, respectively. The synthesized derivatives (A1-24; B1-39) were screened for their antibacterial, antifungal, and antioxidant activities compared to standard agents. The derivatives possessing 3-pyridyl moiety particularly exhibited relatively high antibacterial activity (MIC= < 3.09-500 µg/mL) against Gram-positive bacteria, and compounds possessing 4-pyridyl moiety showed remarkable antioxidant activity
Sujets)
Pyridines/analyse , Thiazoles/analyse , Triazoles/analyse , Méthodes , Antioxydants , Techniques in vitro/méthodes , Bactéries à Gram positif/classificationRésumé
The first report about antimicrobial resistance was published in the 1940s. And today, the antimicrobial resistance has become a worldwide problem. Because of this problem, there is a need to develop new drugs. That's why we synthesized some novel thiazolidine-4-one derivatives and evaluated their antimicrobial activity. The final compounds were obtained by reacting 2-[(4,5-diphenylthiazol-2-yl)imino]thiazolidin-4-one with some aryl aldehydes. The synthesized compounds were investigated for their antimicrobial activity against four Candida species, five gram-negative and four gram-positive bacterial species. The lead compounds (4a- h) were obtained with a yield of at least 70%. All compounds showed antimicrobial activity. Compound 4f (MIC: 31.25 µg/ml) exhibited more efficacy than the other compounds against C. glabrata (ATCC 24433). Compound 4b (MIC: 62.5 µg/ml) was the most active compound against all bacterial species, particularly K. pneumoniae (NCTC 9633). Whereas, compound 4c (MIC: <31.25 µg/ml) was observed as the most active compound against E. coli (ATCC 25922). In general, all compounds (4a-4h) showed antimicrobial activity against all fungi and bacterial species. Compounds 4b (2,6-dichlorobenzylidene), 4c (2,6-dihydroxybenzylidene), 4f (1H-pyrrol-2- yl)methylene), 4g (4-triflouromethylbenzylidene) and 4h (2,3,4-trimethoxybenzylidene) were determined as the most active compounds
Sujets)
Azoles , Thiazoles/analyse , Candida/classification , Thiazolidines/analyse , Médicaments de Référence , Rapport de recherche , Plomb/agonistesRésumé
Objective: People with Alzheimer's disease (AD) dementia have impaired sleep. However, the characteristics of sleep in the early stages of AD are not well known, and studies with the aid of biomarkers are lacking. We assessed the subjective sleep characteristics of non-demented older adults and compared their amyloid profiles. Methods: We enrolled 30 participants aged ≥ 60 years, with no dementia or major clinical and psychiatric diseases. They underwent [11C]PiB-PET-CT, neuropsychological evaluations, and completed two standardized sleep assessments (Pittsburgh Sleep Quality Inventory and Epworth Sleep Scale). Results: Comparative analysis of subjective sleep parameters across the two groups showed longer times in bed (p = 0.024) and reduced sleep efficiency (p = 0.05) in individuals with positive amyloid. No differences in other subjective sleep parameters were observed. We also found that people with multiple-domain mild cognitive impairment (MCI) had shorter self-reported total sleep times (p = 0.034) and worse overall sleep quality (p = 0.027) compared to those with single-domain MCI. Conclusions: Older adults testing positive for amyloid had a longer time in bed and lower sleep efficiency, regardless of cognitive status. In parallel, individuals with multiple-domain MCI reported shorter sleep duration and lower overall sleep quality.
Sujets)
Humains , Sujet âgé , Maladie d'Alzheimer/imagerie diagnostique , Dysfonctionnement cognitif/imagerie diagnostique , Sommeil , Thiazoles , Études cas-témoins , Tomographie par émission de positons , Tomographie par émission de positons couplée à la tomodensitométrie , Dérivés de l'anilineRésumé
Abstract The present work aims to investigate the antiparasitic and the immunomodulating effects of nitazoxanide (NTZ) and ivermectin (IVC) alone or combined together or combined with selenium (Se), on Cryptosporidium infection in diabetic mice. The results revealed that the combined NTZ and IVC therapy achieved the highest reduction of fecal oocysts (92%), whereas single NTZ showed the lowest reduction (63%). Also, adding Se to either NTZ or IVC resulted in elevation of oocyst reduction from 63% to 71% and from 82% to 84% respectively. All treatment regimens, with the exception of NTZ monotherapy, showed a significant improvement in the intestinal histopathology, the highest score was in combined NTZ and IVC therapy. The unique results of immunohistochemistry in this study showed reversal of the normal CD4/CD8 T cell ratio in the infected untreated mice, however, following therapy it reverts back to a normal balanced ratio. The combined (NTZ+ IVC) treatment demonstrated the highest level of CD4 T cell expression. Taken together, NTZ and IVC combined therapy showed remarkable anti-parasitic and immunostimulatory effects, specifically towards the CD4 population that seem to be promising in controlling cryptosporidiosis in diabetic individuals. Further research is required to explore other effective treatment strategies for those comorbid patients.
Resumo O presente trabalho tem como objetivo investigar os efeitos anti-parasitários e imunomodulantes da nitazoxanida (NTZ) e ivermectina (IVC), isoladas ou em associação, e do selênio (SE), associado à NTZ ou à IVC, sobre a infecção por Cryptosporidium em camundongos diabéticos. Os resultados revelaram que a terapia combinada com NTZ e IVC resultou em maior redução de oocistos fecais, enquanto a NTZ isolada mostrou a menor redução de oocistos fecais (63%). Além disso, a associação do SE com a NTZ ou IVC resultou em redução do número de oocistos fecais de 63% para 71% e de 82% para 84%, respectivamente. Todos os tratamentos, com exceção da monoterapia com NTZ, mostraram uma melhora significativa nos índices relacionados à histopatologia intestinal. Os resultados da imuno-histoquímica mostraram reversão da razão celular CD4/CD8 T normal nos camundongos infectados não tratados, no entanto, após a terapia, houve retorno à razão celular CD4/CD8 T normal. O tratamento combinado (NTZ+ IVC) demonstrou o mais alto nível de expressão celular CD4 T. Em conclusão, a terapia combinada com NTZ e IVC mostrou efeitos anti-parasitários e imunoestimuladores notáveis, especificamente para a população CD4, que parecem ser promissores para o controle da criptosporidiose em indivíduos diabéticos.
Sujets)
Animaux , Lapins , Maladies des rongeurs , Sélénium/usage thérapeutique , Cryptosporidiose/traitement médicamenteux , Cryptosporidium , Diabète expérimental/traitement médicamenteux , Thiazoles , Ivermectine/usage thérapeutique , Composés nitrés , Antiparasitaires/usage thérapeutiqueRésumé
Mastitis causes significant economic losses to the dairy cattle industry. The present study aimed to evaluate the antibacterial properties of 39 heterocyclic derivatives (1,3-thiazoles and 4-thiazolidinones) against clinical mastitis isolates from dairy cows. Milk samples were collected from cows with clinical mastitis and the bacterial species were identified by PCR. Antibacterial activity was assessed using the broth microdilution method. First, 39 heterocyclic compounds were tested against four bacterial isolates (Staphylococcus aureus, Streptococcus agalactiae, Corynebacterium bovis and Escherichia coli) randomly chosen from those recovered from the milk samples (Study 1). Subsequently, the compounds with the strongest antibacterial activity were tested against all the bacterial isolates recovered from the milk samples (Study 2). 1,3-thiazoles showed the strongest antibacterial activity, specially compounds 30 and 38, which also showed bactericidal properties according to their minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values. Corynebacterium spp. and Enterobacteriaceae isolates were the most susceptible to compounds 30 and 38. Compounds 30 and 38 are promising targets for new antimicrobial agents.(AU)
A mastite causa significativas perdas econômicas à indústria leiteira bovina. O presente estudo teve como objetivo avaliar as propriedades antibacterianas de 39 derivados heterocíclicos (1,3-tiazóis e 4-tiazolidinonas) contra isolados clínicos de mastite em vacas leiteiras. Amostras de leite foram coletadas de vacas com mastite clínica e as espécies bacterianas isoladas foram identificadas por PCR. A atividade antibacteriana foi avaliada pelo método de microdiluição em caldo. Primeiramente, os 39 compostos heterocíclicos foram testados contra quatro isolados bacterianos (Staphylococcus aureus, Streptococcus agalactiae, Corynebacterium bovis e Escherichia coli) escolhidos aleatoriamente dentre os recuperados das amostras de leite (Estudo 1). Posteriormente, compostos com atividade antibacteriana mais forte foram testados contra todos os isolados bacterianos recuperados das amostras de leite (Estudo 2). Os compostos 1,3-tiazóis apresentaram a maior atividade antibacteriana, principalmente os compostos 30 e 38, que também apresentaram propriedades bactericidas de acordo com seus valores de concentração inibitória mínima (CIM) e concentração bactericida mínima (CBM). Os isolados Corynebacterium spp. e Enterobacteriaceae foram os mais suscetíveis aos compostos 30 e 38. Os compostos 30 e 38 mostraram-se promissores como novos agentes antimicrobianos.(AU)
Sujets)
Animaux , Bovins , Thiazoles/administration et posologie , Mastite/immunologie , Antibactériens , Staphylococcus aureus , Streptococcus agalactiae , Bovins/microbiologieRésumé
ABSTRACT Zika virus (ZIKV) infection during pregnancy is associated with a congenital syndrome. Although the virus can be detected in human placental tissue and sexual transmission has been verified, it is not clear how the virus reaches the fetus. Despite the emerging severity caused by ZIKV infection, no specific prophylactic and/or therapeutic treatment is available. The aim of the present study was to evaluate the effectiveness antiviral of nitazoxanide (NTZ) in two important congenital transmission targets: (i) a primary culture of human placental chorionic cells, and (ii) human cervical epithelial cells (C33-A) infected with Brazilian ZIKV strain. Initially, NTZ activity was screened in ZIKV infected Vero cells under different treatment regimens with non-toxic drug concentrations for 48 h. Antiviral effect was found only when the treatment was carried out after the viral inoculum. A strong effect against the dengue virus serotype 2 (DENV-2) was also observed suggesting the possibility of treating other Flaviviruses. Additionally, it was shown that the treatment did not reduce the production of infectious viruses in insect cells (C6/36) infected with ZIKV, indicating that the activity of this drug is also related to host factors. Importantly, we demonstrated that NTZ treatment in chorionic and cervical cells caused a reduction of infected cells in a dose-dependent manner and decreased viral loads in up to 2 logs. Pre-clinical in vitro testing evidenced excellent therapeutic response of infected chorionic and cervical cells and point to future NTZ activity investigation in ZIKV congenital transmission models with the perspective of possible repurposing of NTZ to treat Zika fever, especially in pregnant women.
Sujets)
Animaux , Femelle , Humains , Grossesse , Virus Zika , Infection par le virus Zika , Thiazoles , Réplication virale , Cellules Vero , Brésil , Chlorocebus aethiops , Infection par le virus Zika/traitement médicamenteux , Composés nitrésSujets)
Humains , Femelle , Enfant , Jeu et accessoires de jeu , Eczéma de contact allergique/étiologie , Substances viscoélastiques/effets indésirables , Thiazoles/effets indésirables , Tests épicutanés , Chlorpromazine/analogues et dérivés , Chlorpromazine/effets indésirables , Eczéma de contact allergique/anatomopathologieRésumé
Abstract Background: Kathon CG, a combination of methylchloroisothiazolinone and methylisothiazolinone, is widely used as preservative in cosmetics, as well in household cleaning products, industrial products such as paints and glues. It has emerged as an important sensitizing agent in allergic contact dermatitis. Objectives: This study evaluated the reactivity to this substance in patients subjected to patch tests at the Dermatology Institute in Bauru, São Paulo from 2015 to 2017 and its correlation with other preservatives, the professional activity and location of the lesions. Methods: The patients were submitted to standard series of epicutaneous tests, standardized by the Brazilian Group Studies on Contact Dermatitis. Results: Out the 267 patients tested, 192 presented positivity to at least one substance and 29 of the patients (15.10%) presented reaction to Kathon CG, with predominance of the female gender (n = 27); main professional activity associated with Kathon CG sensibilization was cleaning (17.24%), followed by aesthetic areas (13.79%) and health care (10.34%). The most prevalent sensitizations among the substances tested were nickel sulphate (56.3%), followed by cobalt chloride (23.4%), neomycin (18.2%), potassium dichromate (17.7%), thimerosal (14.5%), formaldehyde (13.2%), paraphenylenediamine (9.3%), and fragrance mix (8.3%). Study limitations: We do not have data from patients that were submitted to patch test a decade ago in order to confront to current data and establish whether or no sensitization to Kathon CG has increased. Conclusion: High positivity to Kathon CG corroborates the recent findings in the literature, suggesting more attention to concentration of this substance, used in cosmetics and products for domestic use.
Sujets)
Thiazoles/analyse , Tests épicutanés/méthodes , Eczéma de contact allergique/diagnostic , Conservateurs pharmaceutiques/effets indésirables , Conservateurs pharmaceutiques/composition chimique , Thiazoles/effets indésirables , Brésil , Tests épicutanés/statistiques et données numériques , Modèles logistiques , Études rétrospectives , Eczéma de contact allergique/étiologie , Statistique non paramétrique , Cosmétiques/effets indésirables , Cosmétiques/composition chimique , Adulte d'âge moyenRésumé
BACKGROUND It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20 showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.
Sujets)
Humains , Animaux , Souris , Thiazoles/pharmacologie , Albendazole/pharmacologie , Giardia lamblia/effets des médicaments et des substances chimiques , Protéines du cytosquelette/effets des médicaments et des substances chimiques , Antiprotozoaires/pharmacologie , Thiazoles/composition chimique , Facteurs temps , Albendazole/composition chimique , Technique d'immunofluorescence indirecte , Tests de sensibilité parasitaire , Antiprotozoaires/composition chimiqueRésumé
BACKGROUND It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide. OBJETIVES To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity. METHODS CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis. FINDINGS CMC-20 showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole. MAIN CONCLUSIONS The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.
Sujets)
Humains , Animaux , Souris , Thiazoles/pharmacologie , Albendazole/pharmacologie , Giardia lamblia/effets des médicaments et des substances chimiques , Protéines du cytosquelette/effets des médicaments et des substances chimiques , Antiprotozoaires/pharmacologie , Thiazoles/composition chimique , Facteurs temps , Albendazole/composition chimique , Technique d'immunofluorescence indirecte , Tests de sensibilité parasitaire , Antiprotozoaires/composition chimiqueRésumé
ABSTRACT Purpose To evaluate the efficacy and tolerability of mirabegron in females with overactive bladder (OAB) symptoms after surgical treatment for stress urinary incontinence (SUI). Materials and Methods The study was conducted with a prospective, randomized and double-blinded design. 62 patients over the age of 40 who met the inclusion-exclusion criterias of the study were enrolled and randomly divided into two groups as Group A (mirabegron 50mg) and B (solifenacin 5mg). Patients were compared based on efficacy of treatment [Patient Perception of Bladder Condition (PPBC) scale and micturition diaries], safety of treatment (heart rate, systolic and diastolic blood pressure, adverse events), number of micturitions per day, patient's satisfaction status after treatment [Visual Analog Scale(VAS)] and quality of life. Results The mean age of the population was 48.2±3.8 years and the duration of OAB symptoms was 5.9±2.9 months. Baseline values for the mean number of micturitions, volume voided in each micturition, nocturia episodes, urgency and urgency incontinence episodes were 15.3±0.34, 128±3.88mL, 3.96±1.67, 5.72±1.35 and 4.22±0.69, respectively. After treatment, values for these parameters were 11.7±0.29, 164.7±2.9mL, 2.25±0.6, 3.38±0.71, 2.31±0.49 respectively. Quality of life score, symptom bother score, VAS for treatment satisfaction score, PPBC score after treatment were 66.1±0.85, 43.7±0.77, 4.78±0.14, 4.78±0.14, respectively. There were no significant differences between two groups on any parameter. However, mirabegron showed better tolerability than solifenacin, particularly after 6 months. Conclusion Mirabegron is safe, effective and tolerable in the long-term treatment of females with OAB symptoms after surgery for stress urinary incontinence.
Sujets)
Humains , Femelle , Adulte , Thiazoles/usage thérapeutique , Incontinence urinaire d'effort/chirurgie , Vessie hyperactive/traitement médicamenteux , Agonistes des récepteurs bêta-3 adrénergiques/usage thérapeutique , Acétanilides/usage thérapeutique , Qualité de vie , Valeurs de référence , Incontinence urinaire d'effort/physiopathologie , Méthode en double aveugle , Études prospectives , Reproductibilité des résultats , Résultat thérapeutique , Antagonistes muscariniques/usage thérapeutique , Vessie hyperactive/physiopathologie , Échelle visuelle analogique , Succinate de solifénacine/usage thérapeutique , Adulte d'âge moyenRésumé
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.
Sujets)
Humains , Thiazoles/administration et posologie , Antagonistes muscariniques/administration et posologie , Vessie hyperactive/traitement médicamenteux , Agonistes des récepteurs bêta-3 adrénergiques/administration et posologie , Acétanilides/administration et posologie , Pyrrolidines/administration et posologie , Benzilates/administration et posologie , Benzofuranes/administration et posologie , Brésil , Association de médicaments , Tartrate de toltérodine/administration et posologie , Succinate de solifénacine/administration et posologie , Prise de décision clinique , Acides mandéliques/administration et posologie , Antidépresseurs/administration et posologie , Nortropanes/administration et posologieRésumé
SUMMARY Mirabegron is a kind of β3 adrenergic receptor agonist which is an effective drug for the treatment of overactive bladder. In this research, a UPLC-MS/MS method is developed and validated for the study of mirabegron pharmacokinetic in rats. A protein precipitation method is applied for sample preparation with acetonitrile. m/z 397.3→379.6, m/z 326.4→121.0 for mirabegron, tolterodine (IS), respectively in the positive ion mode was performed for quantitation. The method is reliable and reproducible in our study (intra-day precision≤11.06%, inter-day precision≤11.43%) with concentration curves linear from 5 to 2500 ng/mL(R2>0.999). Stability studies demonstrated that mirabegron was stable under a variety of storage conditions. This method was successfully applied for determining mirabegron in rats after oral and intravenous administration.
RESUMO Mirabegron é um tipo de agonista do receptor adrenérgico beta 3 que demonstra eficácia no tratamento de bexiga hiperativa. Nesta pesquisa, o método UPLC-MS/MS é desenvolvido e validado para o estudo da farmacocinética mirabegron em ratos. Um método de precipitação de proteínas é aplicado para a preparação de amostras com acetonitrilo. 397.3 → 379.6 M / Z, M / Z 326.4 → 121.0 para mirabegron, tolterodina (IS), respectivamente, para o íon positivo foi realizado para quantificação. O método é fiável e reprodutível em nosso estudo (precisão intradia ≤ 11,06%; precisão entredia ≤ 11.43%), com curvas de concentração linear de 5 a 2 ng/ml (R2 > 0,999). Estudos de estabilidade demonstraram que mirabegron permanece estável sob uma variedade de condições de armazenamento. Este método foi aplicado com sucesso para a determinação de mirabegron em ratos após administração oral e intravenosa.
Sujets)
Animaux , Mâle , Rats , Thiazoles/pharmacocinétique , Agonistes des récepteurs bêta-3 adrénergiques/pharmacocinétique , Acétanilides/pharmacocinétique , Thiazoles/administration et posologie , Thiazoles/sang , Administration par voie orale , Reproductibilité des résultats , Chromatographie en phase liquide à haute performance , Rat Sprague-Dawley , Spectrométrie de masse en tandem , Agonistes des récepteurs bêta-3 adrénergiques/administration et posologie , Agonistes des récepteurs bêta-3 adrénergiques/sang , Administration par voie intraveineuse , Acétanilides/administration et posologie , Acétanilides/sangRésumé
Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban have at least comparable efficacy as vitamin K antagonists along with a better safety profile, reflected by a lower incidence of intracranial hemorrhage. Specific reversal agents have been developed in recent years. Namely, idarucizumab, a specific antidote for dabigatran, is currently approved in most countries. Andexanet, which reverses factor Xa inhibitors, has been recently approved by the FDA, and ciraparantag, a universal antidote targeted to reverse all DOACs, is still under investigation. In this review we provide an update on the pharmacology of DOACs, the risk of hemorrhagic complications associated with their use, the measurement of their anticoagulant effect and the reversal strategies in case of DOAC-associated bleeding.
Sujets)
Humains , Facteurs de la coagulation sanguine/usage thérapeutique , Antithrombiniques/administration et posologie , Antithrombiniques/effets indésirables , Anticorps monoclonaux humanisés/usage thérapeutique , Hémorragie/induit chimiquement , Hémorragie/thérapie , Pyrazoles/administration et posologie , Pyrazoles/effets indésirables , Pyridines/administration et posologie , Pyridines/effets indésirables , Pyridones/administration et posologie , Pyridones/effets indésirables , Thiazoles/administration et posologie , Thiazoles/effets indésirables , Administration par voie orale , Facteurs de risque , Rivaroxaban/administration et posologie , Rivaroxaban/effets indésirables , Dabigatran/administration et posologie , Dabigatran/effets indésirables , Antidotes/usage thérapeutiqueRésumé
OBJECTIVE@#Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI). In current clinical situation, availability of different oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) has enabled physicians to switch among therapies owing to specific clinical scenarios. Although optimum time, loading dose and interval of transition between P2Y12 inhibitors is still controversial and needs further evidence, switching between oral inhibitors frequently occurs in clinical practice for several reasons.@*DATA SOURCES@#This review was based on data in articles published in PubMed up to June 2018, with the following keywords "antiplatelet therapy", "ACS", "PCI", "ticagrelor", and "clopidogrel".@*STUDY SELECTION@#Original articles and critical reviews on de-escalation strategy in ACS patients after PCI were selected. References of the retrieved articles were also screened to search for potentially relevant papers.@*RESULTS@#Safety concerns associated with switching between antiplatelet agents, has prompted the use of clopidogrel for patients with ACS especially after PCI as a de-escalation strategy. Practical considerations for de-escalating therapies in patients with ACS such as reducing dose of P2Y12 inhibitors or shortening duration of DAPT (followed by aspirin or P2Y12 receptor inhibitor monotherapy) as potential options are yet to be standardized and validated.@*CONCLUSIONS@#Current review will provide an overview of the pharmacology of common P2Y12 inhibitors, definitions of de-escalation and different de-escalating strategies and its outcomes, along with possible direction to be explored in de-escalation.
Sujets)
Humains , Syndrome coronarien aigu , Traitement médicamenteux , Thérapeutique , Acide acétylsalicylique , Utilisations thérapeutiques , Diamines , Utilisations thérapeutiques , Intervention coronarienne percutanée , Antiagrégants plaquettaires , Utilisations thérapeutiques , Antagonistes des récepteurs purinergiques P2Y , Utilisations thérapeutiques , Thiazoles , Utilisations thérapeutiquesRésumé
BACKGROUND: To analyze the relative expression of PELI3 and its mechanistic involvement in the non-small cell lung cancer (NSCLC). Methods: PELI3 expression in NSCLC tissue samples was determined by the immunohistochemistry. The transcripts abundance of PELI3 was measured with real-time PCR. The protein intensity was analyzed by western blot. The overall survival in respect to PELI3 or miR-365a-5p expression was plotted by the Kaplan-Meier's analysis. Cell growth was determined by colony formation assay. Cell viability was measured by MTT assay. The migration and invasion were evaluated by wound healing and transwell assay respectively. The regulatory effect of miR-365a-5p on PELI3 was interrogated with luciferase reporter assay. The direct binding between miR-365a-5p and PELI3 was analyzed by pulldown assay. RESULTS: PELI3 was aberrantly up-regulated in NSCLC both in vivo and in vitro. High level of PELI3 associated with poor prognosis. PELI3-deficiency significantly inhibited cell viability, colony formation, migration and invasion. We further identified that miR-365a-5p negatively regulated PELI3 in this disease. Ectopic expression of miR-365a-5p in both A549 and H1299 phenocopied PELI3-deficiency. Meanwhile, PELI3-silencing significantly abolished the pro-tumoral effect elicited by miR-365a-5p inhibition. CONCLUSIONS: Our results highlighted the importance of dysregulated miR-365a-5p-PELI3 signaling axis in NSCLC.
Sujets)
Humains , Animaux , Régulation négative/physiologie , Carcinome pulmonaire non à petites cellules/métabolisme , microARN/métabolisme , Ubiquitin-protein ligases/métabolisme , Tumeurs du poumon/métabolisme , Sels de tétrazolium , Thiazoles , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , microARN/usage thérapeutique , Lignée cellulaire tumorale , Ubiquitin-protein ligases/pharmacologie , Modèles animaux de maladie humaine , Agents colorants , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacologieRésumé
Diabetes mellitus is a chronic disease resulting in oxidative stress that promotes tissue damage. The appearance of this disease is highly related to lifestyle and food of the population, being of great interest to search for a dietary supplement that can also act by reducing oxidative alterations. Based on the broad range of biological activity of thiazole derivatives, this work aimed to evaluate the in vitro antioxidant activity of a novel hydrazine-thiazole derivative and studies in vivo. In in vivo experiments, the liver extracts of healthy and diabetic Wistar rats were used, with analysis to determine the enzymatic activity of SOD, CAT, GPx, and GR, and determination of lipid peroxidation. Finally, in the blood of these animals, biochemical parameters were evaluated. Statistical evidence of changes caused in liver enzymes and liquid peroxidation was not detected; however, these parameters were also not changed between control groups with and without diabetes. On the other hand, concerning biochemical parameters, significant differences were detected in uric acid, alkaline phosphatase, ALT, and urea, indicating a possible antioxidant protective role of such substances in the liver and kidney of diabetic animals that could be acting by means other than that commonly reported in the literature.