RESUMO
BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with human immunodeficiency virus (HIV)-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400 mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among men who have sex with men (MSM) who have been diagnosed with HIV. METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV (400 mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50â copies/mL) at 48 weeks per US Food and Drug Administration Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression, and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (P < .001), respectively, discontinued treatment because of adverse effects, death, or lost to follow-up. The median increase of CD4 count was 181 and 223â cells/µL (P = .020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < .001). CONCLUSIONS: BIC/FTC/TAF was more efficacious and safer than EFV (400 mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.
Assuntos
Alcinos , Fármacos Anti-HIV , Benzoxazinas , Ciclopropanos , Emtricitabina , Infecções por HIV , Homossexualidade Masculina , Lamivudina , Tenofovir , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Adulto , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , China , Emtricitabina/uso terapêutico , Emtricitabina/administração & dosagem , Ciclopropanos/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Alcinos/uso terapêutico , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Benzoxazinas/uso terapêutico , Alanina/uso terapêutico , Pessoa de Meia-Idade , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Contagem de Linfócito CD4 , Dioxolanos/uso terapêutico , Dioxolanos/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Carga Viral , Adulto Jovem , Combinação de Medicamentos , HIV-1/efeitos dos fármacos , Amidas , PiridonasRESUMO
Difenoconazole (DFZ), classified as a "low-toxicity pesticide," has seen widespread application in recent years. Nevertheless, the non-target toxicity of the substance, particularly towards aquatic creatures, has generated considerable apprehension. The anti-inflammatory and antioxidant effects of Ferulic Acid (FA) have attracted considerable study in this particular setting. This study established a chronic exposure model to DFZ and investigated the protective effects of FA on chronic respiratory inhibition leading to gill damage in freshwater carp. Histological analyses via HE staining indicated that FA effectively alleviated gill tissue damage induced by chronic DFZ exposure. The qRT-PCR results showed that the addition of FA reduced the expression of IL-1ß, IL-6 and TNF-α while boosting the expression of IL-10 and TGF-ß1. Biochemical analyses and DHE staining revealed that FA reduced MDA levels and increased CAT and GSH activities, along with T-AOC, decreased ROS accumulation in response to chronic DFZ exposure. The results obtained from Western blotting analysis demonstrated that the addition of FA effectively suppressed the activation of the NF-κB signalling pathway and the NLRP3 inflammasome pathway in the gills subjected to prolonged exposure to DFZ. In summary, FA ameliorated gill tissue inflammation and blocked ROS accumulation in carp exposed to chronic DFZ, mitigating tissue inflammation and restoring redox homeostasis through the NF-κB-NLRP3 signaling pathway. Hence, the application of FA has been found to be efficacious for improving respiratory inhibition and mitigating gill tissue inflammation and oxidative stress resulting from DFZ pollution in aquatic habitats.
Assuntos
Ração Animal , Carpas , Ácidos Cumáricos , Dioxolanos , Proteínas de Peixes , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio , Animais , Carpas/imunologia , Ácidos Cumáricos/administração & dosagem , Ácidos Cumáricos/farmacologia , NF-kappa B/metabolismo , NF-kappa B/genética , Espécies Reativas de Oxigênio/metabolismo , Dioxolanos/administração & dosagem , Dioxolanos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ração Animal/análise , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Triazóis/farmacologia , Triazóis/administração & dosagem , Brânquias/efeitos dos fármacos , Suplementos Nutricionais/análise , Dieta/veterinária , Poluentes Químicos da Água/efeitos adversos , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Antiretrovirals have the potential to cause drug interactions leading to inefficacy or toxicity via induction of efflux transporters through nuclear receptors, altering drug concentrations at their target sites. RESEARCH DESIGN AND METHODS: This study used molecular dynamic simulations and qRT-PCR to investigate bictegravir's interactions with nuclear receptors PXR and CAR, and its effects on efflux transporters (P-gp, BCRP, MRP1) in rat PBMCs. PBMC/plasma drug concentrations were measured using LC-MS/MS to assess the functional impact of transporter expression. RESULTS: Bictegravir significantly increased the expression of ABC transporters, with Car identified as a key mediator. This suggests that bictegravir's influence on nuclear receptors could affect drug transport and efficacy at the cellular level. CONCLUSIONS: Bictegravir activates nuclear receptors enhancing efflux transporter expression. Understanding these interactions is crucial for preventing drug-drug interactions and reducing toxicity in clinical use. Combining CAR antagonists with bictegravir may prevent drug resistance and toxicity. However, these findings are based on preclinical data and necessitate further clinical trials to confirm their applicability in clinical settings.
Assuntos
Interações Medicamentosas , Compostos Heterocíclicos de 4 ou mais Anéis , Leucócitos Mononucleares , Espectrometria de Massas em Tandem , Animais , Ratos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Piperazinas/farmacologia , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Simulação de Dinâmica Molecular , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Receptor Constitutivo de Androstano , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Cromatografia Líquida/métodos , Ratos Sprague-Dawley , Dioxolanos/farmacologia , Dioxolanos/farmacocinética , Dioxolanos/administração & dosagem , Amidas , PiridonasRESUMO
Cisplatin alone or in combination with 5FU and docetaxel is the preferred chemotherapy regimen for advanced-stage OSCC patients. However, its use has been linked to recurrence and metastasis due to the development of drug resistance. Therefore, sensitization of cancer cells to conventional chemotherapeutics can be an effective strategy to overcome drug resistance. Piperlongumine (PL), an alkaloid, have shown anticancer properties and sensitizes numerous neoplasms, but its effect on OSCC has not been explored. However, low aqueous solubility and poor pharmacokinetics limit its clinical application. Therefore, to improve its therapeutic efficacy, we developed piperlongumine-loaded PLGA-based smart nanoparticles (smart PL-NPs) that can rapidly release PL in an acidic environment of cancer cells and provide optimum drug concentrations to overcome chemoresistance. Our results revealed that smart PL-NPs has high cellular uptake in acidic environment, facilitating the intracellular delivery of PL and sensitizing cancer cells to cisplatin, resulting in synergistic anticancer activity in vitro by increasing DNA damage, apoptosis, and inhibiting drug efflux. Further, we have mechanistically explored the Hippo-YAP signaling pathway, which is the critical mediator of chemoresistance, and investigated the chemosensitizing effect of PL in OSCC. We observed that PL alone and in combination with cisplatin significantly inhibits the activation of YAP and its downstream target genes and proteins. In addition, the combination of cisplatin with smart PL-NPs significantly inhibited tumor growth in two preclinical models (patient-derived cell based nude mice and zebrafish xenograft). Taken together, our findings suggest that smart PL-NPs with cisplatin will be a novel formulation to reverse cisplatin resistance in patients with advanced OSCC.