Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46.167
Filtrar
1.
Clin Pharmacol Drug Dev ; 11(2): 278-284, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34431240

RESUMO

Herein, we report a food-effect study of vonoprazan, an oral potassium-competitive acid blocker. In a phase 1, randomized, open-label, crossover study, healthy subjects received a single 20-mg dose of vonoprazan either following an overnight fast or 30 minutes after a high-fat breakfast. Plasma vonoprazan levels were determined at 0 hour and at 17 subsequent assessment points up to 48 hours after dosing. After a 5-day washout, subjects received a second 20-mg vonoprazan dose in the alternative fed/fasted state (identical process repeated). Twenty-four subjects completed the study. Vonoprazan exposure was not meaningfully affected by food. Geometric mean ratios for maximum concentration, area under the concentration-time curve from time 0 to 24 hours, and area under the plasma concentration-time curve extrapolated to infinity obtained under fed and fasting conditions were 1.05 (90% confidence interval, 0.98-1.12), 1.13 (1.09-1.18), and 1.15 (1.11-1.19), respectively. Four subjects experienced 6 adverse events that were all mild and considered unrelated to the study drug. Vonoprazan can be administered without regard to food intake.


Assuntos
Interações Alimento-Droga , Potássio , Administração Oral , Estudos Cross-Over , Humanos , Pirróis , Sulfonamidas
2.
Life Sci Alliance ; 5(9)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35534224

RESUMO

Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15 Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fatores de Processamento de RNA , Sulfonamidas/farmacologia
3.
Blood Cancer J ; 12(5): 77, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501304

RESUMO

In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a clinical trial. Triplet therapy was associated with significantly higher rates of complete remission (CR) (67% versus 32%, P = 0.002), CR/CRi (93% versus 70%, P = 0.02), FLT3-PCR negativity (96% versus 54%, P < 0.01), and flow-cytometry negativity (83% versus 38%, P < 0.01) than doublets. At the end of the first cycle, the median time to ANC > 0.5 (40 versus 21 days, P = 0.15) and platelet > 50 K (29 versus 25 days, P = 0.6) among responders was numerically longer with triplets, but 60-day mortality was similar (7% v 10%). With a median follow-up of 24 months (median 12 months for triplet arm, and 63 months for doublet arm), patients receiving a triplet regimen had a longer median overall survival (not reached versus 9.5 months, P < 0.01). LIC combined with FLT3 inhibitor and venetoclax (triplet) may be an effective frontline regimen for older/unfit FLT3 mutated AML that should be further validated prospectively.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Idoso , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Sulfonamidas , Tirosina Quinase 3 Semelhante a fms/genética
6.
Oxid Med Cell Longev ; 2022: 5759626, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35509835

RESUMO

Background: Arachidonic acid (ARA) metabolites are involved in the pathogenesis of epithelial-mesenchymal transformation (EMT). However, the role of ARA metabolism in the progression of EMT during pulmonary fibrosis (PF) has not been fully elucidated. The purpose of this study was to investigate the role of cytochrome P450 oxidase (CYP)/soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) metabolic disorders of ARA in EMT during PF. Methods: A signal intratracheal injection of bleomycin (BLM) was given to induce PF in C57BL/6 J mice. A COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation to EMT in PF mice. In vitro experiments, murine alveolar epithelial cells (MLE12) and human alveolar epithelial cells (A549) were used to explore the roles and mechanisms of PTUPB on transforming growth factor (TGF)-ß1-induced EMT. Results: PTUPB treatment reversed the increase of mesenchymal marker molecule α-smooth muscle actin (α-SMA) and the loss of epithelial marker molecule E-cadherin in lung tissue of PF mice. In vitro, COX-2 and sEH protein levels were increased in TGF-ß1-treated alveolar epithelial cells (AECs). PTUPB decreased the expression of α-SMA and restored the expression of E-cadherin in TGF-ß1-treated AECs, accompanied by reduced migration and collagen synthesis. Moreover, PTUPB attenuated TGF-ß1-Smad2/3 pathway activation in AECs via Nrf2 antioxidant cascade. Conclusion: PTUPB inhibits EMT in AECs via Nrf2-mediated inhibition of the TGF-ß1-Smad2/3 pathway, which holds great promise for the clinical treatment of PF.


Assuntos
Fibrose Pulmonar , Fator de Crescimento Transformador beta1 , Células Epiteliais Alveolares/metabolismo , Animais , Caderinas/metabolismo , Ciclo-Oxigenase 2/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/patologia , Pirazóis , Sulfonamidas , Fator de Crescimento Transformador beta1/metabolismo
7.
Virulence ; 13(1): 833-843, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35521696

RESUMO

We exploited bacterial infection assays using the fruit fly Drosophila melanogaster to identify anti-infective compounds that abrogate the pathological consequences in the infected hosts. Here, we demonstrated that a pyridine-3-N-sulfonylpiperidine derivative (4a) protects Drosophila from the acute infections caused by bacterial pathogens including Pseudomonas aeruginosa. 4a did not inhibit the growth of P. aeruginosa in vitro, but inhibited the production of secreted toxins such as pyocyanin and hydrogen cyanide, while enhancing the production of pyoverdine and pyochelin, indicative of iron deprivation. Based on its catechol moiety, 4a displayed iron-chelating activity in vitro toward both iron (II) and iron (III), more efficiently than the approved iron-chelating drugs such as deferoxamine and deferiprone, concomitant with more potent antibacterial efficacy in Drosophila infections and unique transcriptome profile. Taken together, these results delineate a Drosophila-based strategy to screen for antipathogenic compounds, which interfere with iron uptake crucial for bacterial virulence and survival in host tissues.


Assuntos
Drosophila , Infecções por Pseudomonas , Animais , Drosophila melanogaster , Ferro , Quelantes de Ferro/farmacologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Sulfonamidas
8.
Pediatr Int ; 64(1): e15153, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35522644

RESUMO

BACKGROUND: We investigated the efficacy of sivelestat sodium hydrate (SSH) as a treatment for Kawasaki disease, and its pharmacological action sites, in mice with Candida albicans water-soluble fraction-induced vasculitis. METHODS: Sivelestat sodium hydrate was administered intraperitoneally to Candida albicans water-soluble fraction-induced vasculitis model mice to assess its efficacy in preventing the development of coronary artery lesions based on the degree of inflammatory cell infiltration in the aortic root and coronary arteries (vasculitis score). The pharmacological sites of action were investigated based on changes in neutrophil elastase (NE) and intercellular adhesion molecule 1 (ICAM-1) positive areas, ICAM-1 and tumor necrosis factor-α mRNA expression levels in the upper heart, and the proportion of monocytes in the peripheral blood. RESULTS: The vasculitis score decreased below the lower limit of the 95% confidence interval of untreated mice in 69% of the SSH-treated mice. The NE- and ICAM-1-positive regions, and the mRNA expression of ICAM-1 and tumor necrosis factor-α were lower in the SSH-treated mice than in the untreated mice. The proportion of monocytes in the peripheral blood was higher in the SSH-treated mice than in the untreated mice, whereas monocyte migration to inflammation areas was suppressed in the SSH-treated mice. CONCLUSIONS: Our results showed that SSH might prevent the development of coronary artery lesions and ameliorate disease activity. In addition to its NE-inhibitory effect, SSH sites of action may also include monocytes.


Assuntos
Glicina , Síndrome de Linfonodos Mucocutâneos , Sulfonamidas , Vasculite , Animais , Candida albicans , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Camundongos , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , RNA Mensageiro , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa , Vasculite/induzido quimicamente , Vasculite/tratamento farmacológico
9.
FASEB J ; 36(6): e22342, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35524750

RESUMO

Renal fibrosis is the final common outcome of chronic kidney disease (CKD), which remains a huge challenge due to a lack of targeted treatment. Growing evidence suggests that during the process of CKD, the integrity and function of mitochondria in renal tubular epithelial cells (TECs) are generally impaired and strongly connected with the progression of renal fibrosis. Mitophagy, a selective form of autophagy, could remove aberrant mitochondria to maintain mitochondrial homeostasis. Deficiency of mitophagy has been reported to aggravate renal fibrosis. However, whether induction of mitophagy could alleviate renal fibrosis has not been stated. In this study, we explored the effect of mitophagy activation by UMI-77, a compound recently verified to induce mitophagy, on murine CKD model of unilateral ureteral obstruction (UUO) in vivo and TECs in vitro. In UUO mice, we found the changes of mitochondrial damage, ROS production, transforming growth factor (TGF)-ß1/Smad pathway activation, as well as epithelial-mesenchymal transition phenotype and renal fibrosis, and these changes were ameliorated by mitophagy enhancement using UMI-77. Moreover, TEC apoptosis, nuclear factor (NF)-κB signaling activation, and interstitial inflammation after UUO were significantly mitigated by augmented mitophagy. Then, we found UMI-77 could effectively and safely induce mitophagy in TECs in vitro, and reduced TGF-ß1/Smad signaling and downstream profibrotic responses in TGF-ß1-treated TECs. These changes were restored by a mitophagy inhibitor. In conclusion, we demonstrated that mitophagy activation protected against renal fibrosis through improving mitochondrial fitness, downregulating TGF-ß1/Smad signaling and alleviating TEC injuries and inflammatory infiltration in kidneys.


Assuntos
Insuficiência Renal Crônica , Animais , Células Epiteliais/metabolismo , Fibrose , Rim/metabolismo , Camundongos , Mitocôndrias/metabolismo , Mitofagia , NF-kappa B/metabolismo , Insuficiência Renal Crônica/metabolismo , Sulfonamidas , Tioglicolatos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismo
10.
Curr Microbiol ; 79(6): 186, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35524830

RESUMO

Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P.


Assuntos
Antivirais , Hepatite C , Compostos Macrocíclicos , MicroRNAs , 2-Naftilamina , Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Ciclopropanos , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Compostos Macrocíclicos/uso terapêutico , MicroRNAs/genética , Prolina/análogos & derivados , Prolina/uso terapêutico , RNA Mensageiro , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas , Receptor 2 Toll-Like , Resultado do Tratamento , Uracila/análogos & derivados , Valina
11.
J Enzyme Inhib Med Chem ; 37(1): 1278-1298, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35506234

RESUMO

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with a release of the proton. CA, especially CAIX and CAXII isoforms gained the attention of many researchers interested in anticancer drug design due to pivotal functions of enzymes in the cancer cell metastasis and response to hypoxia, and their expression restricted to malignant cells. This offers an opportunity to develop new targeted therapies with fewer side effects. Continuous efforts led to the discovery of a series of diverse compounds with the most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule and antibody-based targeting of CAIX/CAXII in cancer.


Assuntos
Anidrases Carbônicas , Neoplasias , Anticorpos Monoclonais/farmacologia , Anidrase Carbônica IX/metabolismo , Anidrases Carbônicas/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Isoformas de Proteínas , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
12.
Medicina (Kaunas) ; 58(4)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35454352

RESUMO

Background and Objectives: Tocilizumab and baricitinib have been observed to improve the outcomes of patients with coronavirus disease 2019 (COVID-19). However, a comparative evaluation of these drugs has not been performed. Materials and Methods: A retrospective, single-center study was conducted using the data of COVID-19 patients admitted to Hokkaido University hospital between April 2020 and September 2021, who were treated with tocilizumab or baricitinib. The clinical characteristics of the patients who received tocilizumab were compared to those of patients who received baricitinib. Univariate and multivariate logistic regression analyses of the outcomes of all-cause mortality and improvement in respiratory status were performed. The development of secondary infection events was analyzed using the Kaplan-Meier method and the log-rank test. Results: Of the 459 patients hospitalized with COVID-19 during the study, 64 received tocilizumab treatment and 34 baricitinib treatment, and those 98 patients were included in the study. Most patients were treated with concomitant steroids and exhibited the same severity level at the initiation of drug treatment. When compared to each other, neither tocilizumab nor baricitinib use were associated with all-cause mortality or improvement in respiratory status within 28 days from drug administration. Conclusions: Age, chronic renal disease and early administration of TCZ or BRT from the onset of COVID-19 were independent prognostic factors for all-cause mortality, whereas anti-viral drug use and the severity of COVID-19 at baseline were associated with an improvement in respiratory status. Secondary infection-free survival rates of patients treated with tocilizumab and those treated with baricitinib did not significantly differ. The results suggest that both tocilizumab and baricitinib could be clinically equivalent agents of choice in treatment of COVID-19.


Assuntos
COVID-19 , Anticorpos Monoclonais Humanizados , Azetidinas , COVID-19/tratamento farmacológico , Humanos , Purinas , Pirazóis , Estudos Retrospectivos , Sulfonamidas , Resultado do Tratamento
13.
Int J Mol Sci ; 23(8)2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35456961

RESUMO

Due to its high efficiency, good safety profile, and potential cardio-protective properties, metformin, a dimethyl biguanide, is the first-line medication in antihyperglycemic treatment for type 2 diabetic patients. The aim of our present study was to assess the effects of eight new sulfonamide-based derivatives of metformin on selected plasma parameters and vascular hemostasis, as well as on endothelial and smooth muscle cell function. The compounds with an alkyl chain (1-3), trifluoromethyl substituent (4), or acetyl group (5) significantly elevated glucose utilization in human umbilical endothelial cells (HUVECs), similarly to metformin. Our novel findings showed that metformin analogues 1-3 presented the most beneficial properties because of their greatest safety profile in the WST-1 cell viability assay, which was also proved in the further HUVEC integrity studies using RTCA DP. Compounds 1-3 did not affect either HUVEC or aortal smooth muscle cell (AoSMC) viability up to 3.0 mM. Importantly, these compounds beneficially affected some of the coagulation parameters, including factor X and antithrombin III activity. In contrast to the above-mentioned metformin analogues, derivatives 4 and 5 exerted more profound anticoagulation effects; however, they were also more cytotoxic towards HUVECs, as IC50 values were 1.0-1.5 mM. In conclusion, the chemical modification of a metformin scaffold into sulfonamides possessing alkyl substituents results in the formation of novel derivatives with potential bi-directional activity including anti-hyperglycemic properties and highly desirable anti-coagulant activity.


Assuntos
Metformina , Coagulação Sanguínea , Células Endoteliais , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Metformina/química , Sulfonamidas/química , Sulfonamidas/farmacologia
14.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35457059

RESUMO

Toxoplasma gondii (T. gondii) is a highly prevalent parasite that has no gold standard treatment due to the poor action or the numerous side effects. Focused sulfonamide-1,2,3-triazole hybrids 3a-c were wisely designed and synthesized via copper catalyzed 1,3-dipolar cycloaddition approach between prop-2-yn-1-alcohol 1 and sulfa drug azides 2a-c. The newly synthesized click products were fully characterized using different spectroscopic experiments and were loaded onto chitosan nanoparticles to form novel nanoformulations for further anti-Toxoplasma investigation. The current study proved the anti-Toxoplasma effectiveness of all examined compounds in experimentally infected mice. Relative to sulfadiazine, the synthesized sulfonamide-1,2,3-triazole (3c) nanoformulae demonstrated the most promising result for toxoplasmosis treatment as it resulted in 100% survival, 100% parasite reduction along with the remarkable histopathological improvement in all the studied organs.


Assuntos
Toxoplasma , Toxoplasmose , Animais , Antiparasitários/farmacologia , Camundongos , Sulfonamidas/farmacologia , Triazóis/química
15.
Bioengineered ; 13(4): 10944-10955, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35477364

RESUMO

Breast cancer is characterized by high morbidity and mortality. GDC-0941 is a PI3K inhibitor with oncogenic effects in breast cancer. However, certain breast cancer cells are insensitive to GDC-0941. Hence, the mechanism of GDC-0941 in breast cancer resistance was investigated in this study. Breast cancer cell lines BT-474, MCF7, Hs-578-T, MDA-MB-231, MDA-MB-453, and MDA-MB-468 were cultured in different medium and then treated with 100 or 500 nM GDC-0941, 100 nM OSU-T315, or TNF-α antibody. Moreover, ILK and shILK were transfected into cells. The half maximal inhibitory concentrations (IC50) for GDC-0941 were detected using CCK-8 assay. The levels of ILK, AKT, PDK1, S6, and p70S6K expression were detected using western blotting and qPCR. In addition, the mouse model of breast cancer was constructed to measure the tumor size, volume, and weight. The results showed that GDC-0941 decreased cell survival rate, downregulated the phosphorylation of AKT, S6, and p70S6K, and promoted the expression of ILK, while it had little effect on PDK1 expression. GDC-0941 inhibited the increases in p-AKT, p-S6, and p-p70S6K caused by ILK overexpression and promoted ILK knockdown-induced reduction of p-AKT, p-S6, and p-p70S6K. In addition, the combination of OSU-T315 and GDC-0941 decreased p-AKT, p-S6, and p-p70S6K level, tumor volume, and tumor weight. GDC-0941 promoted ILK expression by upregulating TNF-α level. Taken together, GDC-0941 increased ILK level by upregulating TNF-α, thus affecting AKT expression and the sensitivity of breast cancer cells to GDC-0941.


Assuntos
Neoplasias da Mama , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Indazóis , Integrinas , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sulfonamidas , Fator de Necrose Tumoral alfa/genética
16.
In Vivo ; 36(3): 1438-1443, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35478152

RESUMO

BACKGROUND/AIM: Patients with hepatitis C virus (HCV)-associated cirrhosis are more prone to developing type 2 diabetes mellitus than patients with any other etiology of cirrhosis. The main objective of this study was to evaluate the impact of all oral antiviral treatment with ritonavir-boosted paritaprevir/ombitasvir and dasabuvir (OBV/PTV/r + DSV) in patients with chronic genotype 1b HCV infection. PATIENTS AND METHODS: We retrospectively evaluated 806 patients who underwent antiviral therapy between December 2015 and July 2019. The laboratory data analyzed were liver function tests, kidney function tests, HCV viremia, fasting glucose levels, and glycosylated hemoglobin. RESULTS: Patients with impaired glucose metabolism were predominantly male and of older age compared to patients with normal glucose tolerance, and also had higher levels of transaminases. Proteinuria and higher creatinine levels were found in patients with impaired glucose metabolism. Overall, we found a 98.01% rate of sustained virologic response (SVR), with a non-significant difference between patients with normal and abnormal glucose metabolism. A statistically significant difference in SVR rates in patients with low degrees of fibrosis (F0-F2) versus those with advanced degrees of fibrosis (F3-F4) was found in both groups. Antiviral treatment resulted in significant decreases in fasting glucose levels and glycosylated hemoglobin levels in all patients with impaired glucose metabolism at SVR. CONCLUSION: Patients with pre-diabetes, as well as diabetic patients, achieved a better glycemic control after SVR obtained by ritonavir-boosted paritaprevir/ombitasvir and dasabuvir.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatite C Crônica , Compostos Macrocíclicos , 2-Naftilamina , Anilidas/efeitos adversos , Anilidas/uso terapêutico , Antivirais , Carbamatos/efeitos adversos , Ciclopropanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Feminino , Glucose , Hemoglobina A Glicada/uso terapêutico , Controle Glicêmico , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Cirrose Hepática/complicações , Cirrose Hepática/etiologia , Compostos Macrocíclicos/efeitos adversos , Compostos Macrocíclicos/uso terapêutico , Masculino , Prolina/análogos & derivados , Estudos Retrospectivos , Ritonavir/uso terapêutico , Sulfonamidas , Uracila/análogos & derivados , Valina
17.
In Vivo ; 36(3): 1491-1496, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35478158

RESUMO

BACKGROUND/AIM: Recent advances in antiviral treatment have achieved a sustained viral response (SVR) in over 95% of hepatitis C virus (HCV) infections. HCV elimination is suggested to improve several lifestyle-related factors; however, few studies have focused on dietary habit-/appetite-related factors. PATIENTS AND METHODS: HCV-infected patients who received Daclatasvir/Asnaprevir (DCV/ASV) therapy were enrolled, and the changes in appetite-related molecules after antiviral therapy were assessed with a multiple cytokine-measuring system. RESULTS: Among 119 HCV-infected patients who received DCV/ASV treatment, 104 (87.3%) achieved an SVR. In the SVR group, DCV/ASV treatment improved several liver-related variables at 24 weeks after the completion of therapy. In patients with an SVR, the values of glucagon-like peptide 1 (GLP-1) and leptin were significantly increased at 24 weeks after completing direct-acting antiviral therapy. However, no significant change was observed in non-SVR patients, regardless of the receipt of direct-acting antiviral treatment. CONCLUSION: Gastrointestinal hormones related to the dietary habit and/or appetite may be influenced by HCV elimination.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Apetite , Quimioterapia Combinada , Genótipo , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Isoquinolinas/uso terapêutico , Sulfonamidas
18.
BMC Vet Res ; 18(1): 151, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477466

RESUMO

BACKGROUND: Canine allergic dermatitis is a common diagnosis in veterinary practices which can lead to secondary infections requiring treatment with antimicrobials. A previous study suggested that dogs treated with oclacitinib in an Australian referral hospital required fewer courses of antimicrobial therapy compared to dogs receiving other anti-pruritic treatments. This study aimed to quantify the effect of oclacitinib treatment on the use of antimicrobials and other therapies in general practice veterinary clinics across Australia. A retrospective case-controlled review of patient records was designed to investigate the number of courses of antimicrobials and other therapies in dogs that received oclacitinib (Apoquel®), compared with those who received an anti-pruritic treatment that was not oclacitinib. RESULTS: The target population included canine patients with a presumptive diagnosis of allergic dermatitis presenting between 2008 and 2018 to general practices contributing to the VetCompass Australia database. Patient records of interest were identified using search terms relating to allergic dermatitis, resulting in over 700,000 observations. Multivariable logistic regression models were developed to determine whether cases were prescribed fewer antimicrobial courses than controls, after adjusting for the presence of concurrent skin infections or infectious agents in ears. Our results indicate that fewer antimicrobial courses were prescribed in the cases compared to the controls. After adjusting for the concurrent skin infections, there was a significant reduction in the use of cefovecin [OR:0.62(0.39-0.98), P = 0.043], chlorhexidine [OR:0.57(0.42-0.77), P < 0.001], neomycin [OR:0.4(0.28-0.56), P < 0.001] and amoxycillin clavulanic acid (AMC) [OR: 0.55(0.39-0.78), P = 0.001] in cases compared to controls. CONCLUSION: This study demonstrates a potential sparing effect of oclacitinib on the prescription of antimicrobials for the treatment of allergic skin diseases in dogs. This information may assist in the planning of treatment for canine allergic dermatitis, with consideration for antimicrobial stewardship.


Assuntos
Anti-Infecciosos , Dermatite Atópica , Fármacos Dermatológicos , Doenças do Cão , Hipersensibilidade , Animais , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Austrália , Estudos de Casos e Controles , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/veterinária , Fármacos Dermatológicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/veterinária , Pirimidinas , Estudos Retrospectivos , Sulfonamidas
19.
ACS Chem Neurosci ; 13(8): 1315-1332, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35410469

RESUMO

Focused modification of a sulfonamide-based kappa opioid receptor (KOR) antagonist series previously reported by this laboratory was investigated. A total of 32 analogues were prepared to explore linker replacement, constraint manipulation, and aryl group or amine substitution. All analogues were assayed for KOR antagonist activity, and the initial lead compound was assessed for in vivo CNS penetration. The most improved analogue possessed a 4-fold increase of potency (IC50 = 18.9 ± 4.4 nM) compared with the lead compound (IC50 = 83.5 ± 20 nM) from an earlier work. The initial lead compound was found to attain suitable brain levels and to possess a shorter clearance time than canonical KOR antagonists such as JDTic.


Assuntos
Receptores Opioides kappa , Tetra-Hidroisoquinolinas , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacologia , Sulfonamidas/farmacologia , Tetra-Hidroisoquinolinas/química
20.
Molecules ; 27(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35408768

RESUMO

Chlrosulfuron, a classical sulfonylurea herbicide that exhibits good safety for wheat but causes a certain degree of damage to subsequent corn in a wheat-corn rotation mode, has been suspended field application in China since 2014. Our previous study found that diethylamino-substituted chlorsulfuron derivatives accelerated the degradation rate in soil. In order to obtain sulfonylurea herbicides with good crop safety for both wheat and corn, while maintaining high herbicidal activities, a series of pyrimidine- and triazine-based diethylamino-substituted chlorsulfuron derivatives (W102-W111) were systematically evaluated. The structures of the synthesized compounds were confirmed with 1H NMR, 13C NMR, and HRMS. The preliminary biological assay results indicate that the 4,6-disubstituted pyrimidine and triazine derivatives could maintain high herbicidal activity. It was found that the synthesized compounds could accelerate degradation rates, both in acidic and alkaline soil. Especially, in alkaline soil, the degradation rate of the target compounds accelerated more than 22-fold compared to chlorsulfuron. Moreover, most chlorsulfuron analogs exhibited good crop safety for both wheat and corn at high dosages. This study provided a reference for the further design of new sulfonylurea herbicides with high herbicidal activity, fast degradation rates, and high crop safety.


Assuntos
Herbicidas , Herbicidas/química , Pirimidinas , Solo , Relação Estrutura-Atividade , Sulfonamidas , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Triazinas/farmacologia , Zea mays
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...