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1.
Immun Inflamm Dis ; 12(4): e1237, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38577984

RESUMO

BACKGROUND: Severe myocarditis is often accompanied by cardiac fibrosis, but the underlying mechanism has not been fully elucidated. CXCL4 is a chemokine that has been reported to have pro-inflammatory and profibrotic functions. The exact role of CXCL4 in cardiac fibrosis remains unclear. METHODS: Viral myocarditis (VMC) models were induced by intraperitoneal injection of Coxsackie B Type 3 (CVB3). In vivo, CVB3 (100 TCID50) and CVB3-AMG487 (CVB3: 100 TCID50; AMG487: 5 mg/kg) combination were administered in the VMC and VMC+AMG487 groups, respectively. Hematoxylin and eosin staining, severity score, Masson staining, and immunofluorescence staining were performed to measure myocardial morphology in VMC. Enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were performed to quantify inflammatory factors (IL-1ß, IL-6, TNF-α, and CXCL4). Aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase-myocardial band (CK-MB) levels were analyzed by commercial kits. CXCL4, CXCR3B, α-SMA, TGF-ß1, Collagen I, and Collagen III were determined by Western blot and immunofluorescence staining. RESULTS: In vivo, CVB3-AMG487 reduced cardiac injury, α-SMA, Collagen I and Collagen III levels, and collagen deposition in VMC+AMG487 group. Additionally, compared with VMC group, VMC+AMG group decreased the levels of inflammatory factors (IL-1ß, IL-6, and TNF-α). In vitro, CXCL4/CXCR3B axis activation TGF-ß1/Smad2/3 pathway promote mice cardiac fibroblasts differentiation. CONCLUSION: CXCL4 acts as a profibrotic factor in TGF-ß1/Smad2/3 pathway-induced cardiac fibroblast activation and ECM synthesis, and eventually progresses to cardiac fibrosis. Therefore, our findings revealed the role of CXCL4 in VMC and unveiled its underlying mechanism. CXCL4 appears to be a potential target for the treatment of VMC.


Assuntos
Acetamidas , Infecções por Coxsackievirus , Miocardite , Pirimidinonas , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa , Interleucina-6 , Colágeno , Fibrose
3.
Int Immunopharmacol ; 130: 111750, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38442577

RESUMO

BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.


Assuntos
Acetamidas , Artrite Experimental , Reposicionamento de Medicamentos , Iminas , Naftalenos , Óxido Nítrico Sintase Tipo II , Fator de Necrose Tumoral alfa , Animais , Camundongos , Acetamidas/uso terapêutico , Artrite Experimental/tratamento farmacológico , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Camundongos Endogâmicos DBA , Naftalenos/uso terapêutico , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores
4.
Bioorg Med Chem Lett ; 102: 129681, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38432288

RESUMO

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series. Overall, three compounds in the amide series have GI50 values as low as 0.2-0.3 µM and the results clearly indicate that the N-hydroxyl group is not necessary for high potency in vitro.


Assuntos
Antineoplásicos , Melanoma , Humanos , Animais , Camundongos , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Relação Estrutura-Atividade
5.
J Pharmacol Sci ; 154(4): 256-263, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38485343

RESUMO

Platelet-activating factor (PAF) is expected to increase esophageal motility. However, to the best of our knowledge, this has not been examined. Thus, we investigated the contractile effects of PAF on guinea pig (GP) esophageal muscularis mucosae (EMM) and the extracellular Ca2+ influx pathways responsible. PAF (10-9-10-6 M) contracted EMM in a concentration-dependent manner. PAF (10-6 M)-induced contractions were almost completely suppressed by apafant (a PAF receptor antagonist, 3 × 10-5 M). In EMM strips, PAF receptor and PAF-synthesizing/degrading enzyme mRNAs were detected. PAF (10-6 M)-induced contractions were abolished by extracellular Ca2+ removal but were not affected by diltiazem [a voltage-dependent Ca2+ channel (VDCC) inhibitor, 10-5 M]. PAF (10-6 M)-induced contractions in the presence of diltiazem were significantly suppressed by LOE-908 [a receptor-operated Ca2+ channel (ROCC) inhibitor, 3 × 10-5 M], SKF-96365 [an ROCC and store-operated Ca2+ channel (SOCC) inhibitor, 3 × 10-5 M], and LOE-908 plus SKF-96365. Among the tested ROCC/SOCC-related mRNAs, Trpc3, Trpc6, and Trpv4/Orai1, Orai3, and Stim2 were abundantly expressed in EMM strips. These results indicate that PAF potently induces GP EMM contractions that are dependent on extracellular Ca2+ influx through ROCCs/SOCCs, and VDCCs are unlikely to be involved.


Assuntos
Diltiazem , Isoquinolinas , Fator de Ativação de Plaquetas , Cobaias , Animais , Diltiazem/farmacologia , Fator de Ativação de Plaquetas/farmacologia , Acetamidas , Canais de Cálcio/metabolismo , Mucosa/metabolismo , Cálcio/metabolismo
6.
Int J Biol Macromol ; 264(Pt 2): 130484, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38431002

RESUMO

The oxidative reaction of Fusarium mycotoxin deoxynivalenol (DON) using the dehydrogenase is a desirable strategy and environmentally friendly to mitigate its toxicity. However, a critical issue for these dehydrogenases shows widespread substrate promiscuity. In this study, we conducted pocket reshaping of Devosia strain A6-243 pyrroloquinoline quinone (PQQ)-dependent dehydrogenase (DADH) on the basis of protein structure and kinetic analysis of substrate libraries to improve preference for particular substrate DON (10a). The variant presented an increased preference for substrate 10a and enhanced catalytic efficiency. A 4.7-fold increase in preference for substrate 10a was observed. Kinetic profiling and molecular dynamics (MD) simulations provided insights into the enhanced substrate specificity and activity. Moreover, the variant exhibited stronger conversion of substrate 10a to 3-keto-DON compared to the wild DADH. Overall, this study provides a feasible protocol for the redesign of PQQ-dependent dehydrogenases with favourable substrate specificity and catalytic activity, which is desperately needed for DON antidote development.


Assuntos
Acetamidas , Quinonas , Tricotecenos , Especificidade por Substrato , Cinética
7.
Eur J Med Chem ; 269: 116332, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38508120

RESUMO

The inhibition of the α-glucosidase enzyme is crucial for targeting type 2 diabetes mellitus (DM). This study introduces a series of synthetic analogs based on thiomethylacetamide-quinoline derivatives linked to diphenyl-imidazole as highly potential α-glucosidase inhibitors. Twenty derivatives were synthesized and screened in vitro against α-glucosidase, revealing IC50 values ranging from 0.18 ± 0.00 to 2.10 ± 0.07 µM, in comparison to the positive control, acarbose. Among these derivatives, compound 10c (IC50 = 0.180 µM) demonstrated the highest potency and revealed a competitive inhibitory mechanism in kinetic studies (Ki = 0.15 µM). Docking and molecular dynamic evaluations elucidated the binding mode of 10c with the active site residues of the α-glucosidase enzyme. Moreover, in vivo assessments on a rat model of DM affirmed the anti-diabetic efficacy of 10c, evidenced by reduced fasting and overall blood glucose levels. The histopathological evaluation enhanced pancreatic islet architecture and hepatocytes in liver sections. In conclusion, novel 2-(quinoline-2-ylthio)acetamide derivatives as potent α-glucosidase inhibitors were developed. Compound 10c emerged as a promising candidate for diabetes management, warranting further investigation for potential clinical applications and mechanistic insights.


Assuntos
Compostos de Bifenilo , Diabetes Mellitus Tipo 2 , Quinolinas , Animais , Ratos , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , alfa-Glucosidases/metabolismo , Cinética , Simulação de Acoplamento Molecular , Imidazóis/farmacologia , Quinolinas/farmacologia , Quinolinas/química , Acetamidas/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular
8.
Front Immunol ; 15: 1342404, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469298

RESUMO

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%-30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development. Methods: The role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG-/- mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC. Results: In non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the pro-carcinogenic protocol, HRG-/- mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1ß, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients. Conclusion: Murine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.


Assuntos
Acetamidas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Doenças Metabólicas , Hepatopatia Gordurosa não Alcoólica , Proteínas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Carcinogênese , Cirrose Hepática/etiologia , Progressão da Doença
9.
Se Pu ; 42(3): 256-263, 2024 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-38503702

RESUMO

Herbicides play an important role in preventing and controlling weeds and harmful plants and are increasingly used in agriculture, forestry, landscaping, and other fields. However, the effective utilization rate of herbicides is only 20%-30%, and most herbicides enter the atmosphere, soil, sediment, and water environments through drift, leaching, and runoff after field application. Herbicide residues in the environment pose potential risks to ecological safety and human health. Therefore, establishing analytical methods to determine herbicide residues in environmental samples is of great importance. In this study, an analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive electrospray ionization mode (ESI+) was developed for the determination of isoxaflutole, metazachlor, and saflufenacil residues in soil, sediment, and water. The instrumental detection parameters, including electrospray ionization mode, mobile phase, and chromatographic column, were optimized. The mobile phases were methanol (A) and 0.1% formic acid aqueous solution (B). Gradient elution was performed as follows: 0-1.0 min, 60%A; 1.0-2.0 min, 60%A-90%A; 2.0-3.0 min, 90%A; 3.0-4.0 min, 90%A-60%A; 4.0-5.0 min, 60%A. The samples were salted after extraction with acetonitrile and cleaned using a C18 solid-phase extraction column. Different solid-phase extraction columns and leaching conditions were investigated during sample pretreatment. Working curves in the neat solvent and matrix were constructed by plotting the measured peak areas as a function of the concentrations of the analytes in the neat solvent and matrix. Good linearities were found for isoxaflutole, metazachlor, and saflufenacil in the solvent and matrix-matched standards in the range of 0.0005-0.02 mg/L, with r≥0.9961. The matrix effects of the three herbicides in soil, sediment, and water ranged from -10.1% to 16.5%. The limits of detection (LODs, S/N=3) for isoxaflutole, metazachlor, and saflufenacil were 0.05, 0.01, and 0.02 µg/kg, respectively. The limits of quantification (LOQs, S/N=10) for isoxaflutole, metazachlor, and saflufenacil were 0.2, 0.05, and 0.05 µg/kg, respectively. The herbicides were applied to soil, sediment, and water at spiked levels of 0.005, 0.1, and 2.0 mg/kg, respectively. The average recoveries for isoxaflutole, metazachlor, and saflufenacil in soil, sediment, and water were in the ranges of 77.2%-101.9%, 77.9%-105.1%, and 80.8%-107.1%, respectively. The RSDs for isoxaflutole, metazachlor, and saflufenacil were in the ranges of 1.4%-12.8%, 1.2%-7.7%, and 1.5%-11.5%, respectively. The established method was used to analyze actual samples collected from four different sites in Zhejiang Province (Xiaoshan, Taizhou, Dongyang, and Yuhang) and one site in Heilongjiang (Jiamusi). The proposed method is simple, rapid, accurate, stable, and highly practical. It can be used to detect isoxaflutole, metazachlor, and saflufenacil residues in soil, sediment, and water and provides a reference for monitoring the residual pollution and environmental behavior of herbicides.


Assuntos
Acetamidas , Herbicidas , Pirimidinonas , Sulfonamidas , Humanos , Cromatografia Líquida , Herbicidas/análise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem/métodos , Água/análise , Solo/química , Solventes/análise , Extração em Fase Sólida
10.
BMC Med ; 22(1): 142, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38532458

RESUMO

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance. METHODS: This multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety. RESULTS: Thirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%). CONCLUSIONS: Belumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04930562.


Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Humanos , Acetamidas , Corticosteroides/uso terapêutico , Doença Crônica
11.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542305

RESUMO

We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.


Assuntos
Acetamidas , Acetatos , Misoprostol , Hipertensão Ocular , Pirazinas , Sulfonamidas , Animais , Camundongos , Misoprostol/farmacologia , Misoprostol/uso terapêutico , Ativador de Plasminogênio Tecidual , Hipertensão Ocular/induzido quimicamente , Hipertensão Ocular/tratamento farmacológico , Receptores de Prostaglandina , Receptores de Prostaglandina E Subtipo EP4 , Esteroides
12.
J Environ Sci Health B ; 59(4): 192-201, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38433648

RESUMO

The adsorption mechanism of S-Metolachlor in an aqueous solution by sawdust biochar derived from Acacia auriculiformis (SAB) was studied. SAB was manufactured at 500 °C for 4 h under oxygen-limited conditions and characterized for SEM, EDS, pHpzc, BET, and FTIR. The adsorption kinetics, isotherm, and diffusion studies of S-Metolachlor and SAB were further explored. Moreover, the effects of the solution pH were examined on the adsorption of S-Metolachlor by SAB. The BET analysis of SAB was achieved at 106.74 m2.g-1 and the solution pH did not significantly influence the S-Metolachlor adsorption. The adsorption data were fitted into a Langmuir isotherm and the PSO model. The film diffusion coefficient Df (4.93 × 10-11 to 8.17 × 10-11 m2.s-1) and the particle diffusion coefficient Dp (1.68 × 10-11 to 2.65 × 10-11 m2.s-1) were determined and the rate-limiting step of S-Metolachlor adsorption and SAB was governed by liquid film diffusion. The S-Metolachlor adsorption process onto SAB was controlled by multiple mechanisms, including pore filling, H-bonding, hydrophobic interaction, and π-π EDA interactions. H-bonding is the main interaction for the adsorption of S-Metolachlor and SAB. Conclusively, the study illustrates that biochar produced from Acacia auriculiformis sawdust possessed effective adsorption properties for S-Metolachlor herbicide.


Assuntos
Acacia , Acetamidas , Poluentes Químicos da Água , Adsorção , Poluentes Químicos da Água/química , Carvão Vegetal/química , Cinética
13.
Vascul Pharmacol ; 154: 107280, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38309551

RESUMO

BACKGROUND: Oral prostanoids are recommended in patients with pulmonary arterial hypertension (PAH) and an unsatisfactory response to first-line therapy. OBJECTIVE: To compare the effectiveness of oral therapies targeting the prostacyclin pathway in PAH patients. METHODS: An online search of Medline, Cochrane Registry, Scopus and EMBASE libraries (from inception to May, 12,020) was conducted. Eight randomized controlled studies were included in the meta-analysis involving 3023 patients, with 828 receiving oral treprostinil, 607 patients receiving selexipag, 125 patients receiving beraprost, and 1463 patients receiving placebo. RESULTS: Compared to placebo, oral treprostinil (WMD 9.05, 95% CI 3.0280-15.0839, p = 0.0032) and beraprost (WMD 21.98, 95% CI 5.0536-38.9063, p = 0.0109) were associated with a significant increase in 6-min walking distance (6MWD) at follow-up from baseline, whereas selexipag use was associated with a non-significant increase in 6MWD (WMD 15.41, 95% CI -0.6074; 31.4232, p = 0.0593). Compared to placebo, the risk of clinical worsening was significantly lowered by selexipag (RR 0.47, 95% CI 0.35-0.65, p < 0.001) and oral treprostinil (RR 0.65, 95% CI 0.46-0.90, p 0.012), whereas a non-significant reduction of the outcome was related to beraprost use (RR 0.70, 95% CI 0.36-1.38, p 0.31). No significant difference in 6MWD change and clinical worsening reduction were found among oral treprostinil and selexipag. Beraprost use less frequently caused adverse events as compared to selexipag and oral treprostinil. CONCLUSIONS: No differences in 6MWD change, clinical worsening reduction and adverse events rates were found among oral treprostinil and selexipag, resulting in similar efficacy and safety profiles.


Assuntos
Anti-Hipertensivos , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Acetamidas , Anti-Hipertensivos/uso terapêutico , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Metanálise em Rede , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pirazinas
14.
Ann Clin Transl Neurol ; 11(3): 768-779, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38375995

RESUMO

OBJECTIVE: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures. METHODS: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union). RESULTS: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%). INTERPRETATION: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.


Assuntos
Anticonvulsivantes , Epilepsias Parciais , Adulto , Criança , Humanos , Pré-Escolar , Lacosamida/efeitos adversos , Anticonvulsivantes/efeitos adversos , Reprodutibilidade dos Testes , Epilepsias Parciais/tratamento farmacológico , Acetamidas/efeitos adversos , Quimioterapia Combinada , Relação Dose-Resposta a Droga , Resultado do Tratamento , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente
15.
Ecotoxicology ; 33(2): 190-204, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38386230

RESUMO

Extensive pesticide use for agriculture can diffusely pollute aquatic ecosystems through leaching and runoff events and has the potential to negatively affect non-target organisms. Atrazine and S-metolachlor are two widely used herbicides often detected in high concentrations in rivers that drain nearby agricultural lands. Previous studies focused on concentration-response exposure of algal monospecific cultures, over a short exposure period, with classical descriptors such as cell density, mortality or photosynthetic efficiency as response variables. In this study, we exposed algal biofilms (periphyton) to a concentration gradient of atrazine and S-metolachlor for 14 days. We focused on fatty acid composition as the main concentration-response descriptor, and we also measured chlorophyll a fluorescence. Results showed that atrazine increased cyanobacteria and diatom chlorophyll a fluorescence. Both herbicides caused dissimilarities in fatty acid profiles between control and high exposure concentrations, but S-metolachlor had a stronger effect than atrazine on the observed increase or reduction in saturated fatty acids (SFAs) and very long-chain fatty acids (VLCFAs), respectively. Our study demonstrates that two commonly used herbicides, atrazine and S-metolachlor, can negatively affect the taxonomic composition and fatty acid profiles of stream periphyton, thereby altering the nutritional quality of this resource for primary consumers.


Assuntos
Acetamidas , Atrazina , Herbicidas , Perifíton , Poluentes Químicos da Água , Atrazina/toxicidade , Clorofila A , Rios , Ecossistema , Ácidos Graxos , Herbicidas/toxicidade , Poluentes Químicos da Água/toxicidade
17.
Medicina (Kaunas) ; 60(2)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38399512

RESUMO

Background and Objectives: Tirbanibulin 1% ointment is a novel synthetic anti-proliferative agent that inhibits tubulin polymerization. It is approved for treating actinic keratosis (AK) on the face and scalp in adults. It has demonstrated good efficacy, an adequate safety profile and excellent patient adherence in the phase 3 clinical trials, however data about its real-life efficacy and safety are lacking. Here we report the experience of the dermatology unit of the University Hospital of Messina. Materials and Methods: We performed a spontaneous open-label, prospective non-randomized study to assess the effectiveness and safety of tirbanibulin 1% ointment for the treatment of 228 AKs in 38 consecutive patients-28 males (73%) and 10 females (26%)-aged between 52 and 92 years (mean age: 72 ± 8.92 years). Results: Total clearance was recorded in 51% of lesions, while partial clearance was recorded in 73% of lesions. An excellent tolerability profile and high compliance rate were observed, with no treatment discontinuation due to the onset of adverse events. Conclusion: Our real-life experience confirms the effectiveness and safety of tirbanibulin ointment for the treatment of AKs.


Assuntos
Acetamidas , Ceratose Actínica , Morfolinas , Piridinas , Adulto , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Ceratose Actínica/tratamento farmacológico , Estudos Prospectivos , Pomadas/uso terapêutico , Cooperação do Paciente , Resultado do Tratamento
18.
Environ Geochem Health ; 46(2): 68, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38342781

RESUMO

These days, the presence of pesticide residues in drinking water sources is a serious concern. In drinking water treatment plants (DWTPs), various methods have been proposed to remove pesticide residues. This study was designed with the objectives of monitoring the occurrence and seasonal variations of pesticides in the output of drinking water treatment plants in two Northern provinces of Iran, Gilan and Golestan, and identifying their human health risks. Seventeen pesticide residues from different chemical structures were determined by using a gas chromatograph-mass spectrometer (GC-MS). The results showed that only Alachlor, Diazinon, Fenitrothion, Malathion, and Chlorpyrifos were detected. The pesticide concentrations ranged from ND to 405.3 ng/L and were higher in the first half-year period. The total non-carcinogenic human health risks was in safe range for infants, children, and adults (HI < 1). The carcinogenic human health risks of Alachlor for infants, children, and adults were in the range of 4.3 × 10-7 to 1.3 × 10-6, 2.0 × 10-7 to 9.6 × 10-7, and 1.1 × 10-7 to 5.5 × 10-7, respectively. These values do not pose health risks for adults and children, but may present a possible cancer risk for infants in two DWTPs of Golestan. In conclusion, considering the possibility of exposure to these pesticides through other routes, simultaneously, it is suggested to carry out a study that examines the level of risk by considering all exposure routes. We also propose stricter regulations for the sale and use of pesticides in Iran.


Assuntos
Acetamidas , Água Potável , Resíduos de Praguicidas , Praguicidas , Adulto , Criança , Humanos , Resíduos de Praguicidas/toxicidade , Resíduos de Praguicidas/análise , Irã (Geográfico) , Praguicidas/toxicidade , Praguicidas/análise , Medição de Risco
19.
ACS Nano ; 18(7): 5632-5646, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38344992

RESUMO

Physical stimulation with mild heat possesses the notable ability to induce immunomodulation within the tumor microenvironment (TME). It transforms the immunosuppressive TME into an immune-active state, making tumors more receptive to immune checkpoint inhibitor (ICI) therapy. Transient receptor potential vanilloid 1 (TRPV1), which can be activated by mild heat, holds the potential to induce these alterations in the TME. However, achieving precise temperature control within tumors while protecting neighboring tissues remains a significant challenge when using external heat sources. Taking inspiration from the heat sensation elicited by capsaicin-containing products activating TRPV1, this study employs capsaicin to chemically stimulate TRPV1, imitating immunomodulatory benefits akin to those induced by mild heat. This involves developing a glutathione (GSH)-responsive immunomodulatory prodrug micelle system to deliver capsaicin and an ICI (BMS202) concurrently. Following intravenous administration, the prodrug micelles accumulate at the tumor site through the enhanced permeability and retention effect. Within the GSH-rich TME, the micelles disintegrate and release capsaicin and BMS202. The released capsaicin activates TRPV1 expressed in the TME, enhancing programmed death ligand 1 expression on tumor cell surfaces and promoting T cell recruitment into the TME, rendering it more immunologically active. Meanwhile, the liberated BMS202 blocks immune checkpoints on tumor cells and T cells, activating the recruited T cells and ultimately eradicating the tumors. This innovative strategy represents a comprehensive approach to fine-tune the TME, significantly amplifying the effectiveness of cancer immunotherapy by exploiting the TRPV1 pathway and enabling in situ control of immunomodulation within the TME.


Assuntos
Acetamidas , Neoplasias , Pró-Fármacos , Piridinas , Humanos , Micelas , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Temperatura Alta , Microambiente Tumoral , Imunoterapia , Imunomodulação , Neoplasias/tratamento farmacológico
20.
Clin Cardiol ; 47(2): e24245, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38402556

RESUMO

BACKGROUND: While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with pulmonary arterial hypertension (PAH), multicenters studies concerning diverse triple oral combination therapies based on selexipag are limited. HYPOTHESIS: This study was conducted to evaluate the effects of various sequential triple oral combination therapies on PAH outcomes. METHODS: A retrospective study was carried out involving 192 patients from 10 centers, who were receiving sequential triple oral combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase 5 inhibitor (PDE5i)/riociguat and selexipag. Clinical parameters, event-free survival, and all-cause survival were assessed and analyzed at baseline and posttreatment. RESULTS: Among the 192 patients, 37 were treated with ERA + riociguat + selexipag, and 155 patients received ERA + PDE5i + selexipag. Both sequential triple oral combination therapies improved the World Health Organization functional class and raised the count of low-risk parameters. As a result of the larger patients' population in the ERA + PDE5i + selexipag group, these individuals exhibited significant increases in 6-minute walking distance (6MWD), pulmonary arterial systolic pressure, pulmonary arterial pressure, right ventricle, and eccentricity index, and significant decreases in N-terminal probrain natriuretic peptide after 6 months of treatment. Nevertheless, both sequential triple oral combination therapy groups demonstrated similar shifts in these clinical parameters between baseline and 6 months. Baseline 6MWD and mean pulmonary arterial pressure were independent predictors of survival in patients undergoing ERA + PDE5i + selexipag therapy. Importantly, no significant differences were found in 6-month event-free survival and all-cause survival between two groups. CONCLUSIONS: Different oral sequential triple combination therapies based on selexipag could comparably improve outcomes in patients with PAH.


Assuntos
Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Acetamidas , Pirazinas/efeitos adversos
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