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1.
Drug Saf ; 47(7): 617-641, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38607520

RESUMEN

Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.


Enzalutamide is a drug that is used to treat various stages of advanced prostate cancer, a type of cancer that begins in the prostate and may spread beyond the prostate. Enzalutamide stops testosterone from stimulating prostate cancer growth. Like other drugs, enzalutamide enters the bloodstream, and then is processed and removed from the body. Sometimes, when a person takes multiple drugs, one drug can make it difficult for the body to process and remove one or more of the other drugs. This is referred to as a drug interaction. Enzalutamide drug interactions can cause the level of other drugs in the body to increase or decrease in an abnormal way. It is also possible for certain other drugs to alter the levels of enzalutamide. Drug interactions that cause the level of a drug to get too low can prevent that drug from working effectively, whereas drug interactions that cause the level of a drug to get too high can lead to side effects of that drug. People with prostate cancer are mostly aged 65 years or older and often take medications to treat a variety of diseases. Examples include medications to treat heart conditions, diabetes, high cholesterol, high blood pressure, and many other conditions. Here, we describe enzalutamide drug interactions with these types of medications. Our goal is to provide a resource to help healthcare providers and patients better understand enzalutamide drug interactions and how to manage them to improve patient safety and drug effectiveness.


Asunto(s)
Benzamidas , Interacciones Farmacológicas , Nitrilos , Feniltiohidantoína , Humanos , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Nitrilos/efectos adversos , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Masculino , Seguridad del Paciente , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico
2.
Front Cell Infect Microbiol ; 14: 1351737, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38500508

RESUMEN

Monkeypox (now Mpox), a zoonotic disease caused by the monkeypox virus (MPXV) is an emerging threat to global health. In the time span of only six months, from May to October 2022, the number of MPXV cases breached 80,000 and many of the outbreaks occurred in locations that had never previously reported MPXV. Currently there are no FDA-approved MPXV-specific vaccines or treatments, therefore, finding drugs to combat MPXV is of utmost importance. The A42R profilin-like protein of the MPXV is involved in cell development and motility making it a critical drug target. A42R protein is highly conserved across orthopoxviruses, thus A42R inhibitors may work for other family members. This study sought to identify potential A42R inhibitors for MPXV treatment using computational approaches. The energy minimized 3D structure of the A42R profilin-like protein (PDB ID: 4QWO) underwent virtual screening using a library of 36,366 compounds from Traditional Chinese Medicine (TCM), AfroDb, and PubChem databases as well as known inhibitor tecovirimat via AutoDock Vina. A total of seven compounds comprising PubChem CID: 11371962, ZINC000000899909, ZINC000001632866, ZINC000015151344, ZINC000013378519, ZINC000000086470, and ZINC000095486204, predicted to have favorable binding were shortlisted. Molecular docking suggested that all seven proposed compounds have higher binding affinities to A42R (-7.2 to -8.3 kcal/mol) than tecovirimat (-6.7 kcal/mol). This was corroborated by MM/PBSA calculations, with tecovirimat demonstrating the highest binding free energy of -68.694 kJ/mol (lowest binding affinity) compared to the seven shortlisted compounds that ranged from -73.252 to -97.140 kJ/mol. Furthermore, the 7 compounds in complex with A42R demonstrated higher stability than the A42R-tecovirimat complex when subjected to 100 ns molecular dynamics simulations. The protein-ligand interaction maps generated using LigPlot+ suggested that residues Met1, Glu3, Trp4, Ile7, Arg127, Val128, Thr131, and Asn133 are important for binding. These seven compounds were adequately profiled to be potential antivirals via PASS predictions and structural similarity searches. All seven potential lead compounds were scored Pa > Pi for antiviral activity while ZINC000001632866 and ZINC000015151344 were predicted as poxvirus inhibitors with Pa values of 0.315 and 0.215, and Pi values of 0.052 and 0.136, respectively. Further experimental validations of the identified lead compounds are required to corroborate their predicted activity. These seven identified compounds represent solid footing for development of antivirals against MPXV and other orthopoxviruses.


Asunto(s)
Monkeypox virus , Profilinas , Simulación del Acoplamiento Molecular , Benzamidas , Antivirales/farmacología
3.
Phytother Res ; 38(6): 2619-2640, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38488455

RESUMEN

Salidroside, a principal bioactive component of Rhodiola crenulata, is neuroprotective across a wide time window in stroke models. We investigated whether salidroside induced neurogenesis after cerebral ischemia and aimed to identify its primary molecular targets. Rats, subjected to transient 2 h of middle cerebral artery occlusion (MCAO), received intraperitoneal vehicle or salidroside ± intracerebroventricular HSC70 inhibitor VER155008 or TrkB inhibitor ANA-12 for up to 7 days. MRI, behavioural tests, immunofluorescent staining and western blotting measured effects of salidroside. Reverse virtual docking and enzymatic assays assessed interaction of salidroside with purified recombinant HSC70. Salidroside dose-dependently decreased cerebral infarct volumes and neurological deficits, with maximal effects by 50 mg/kg/day. This dose also improved performance in beam balance and Morris water maze tests. Salidroside significantly increased BrdU+/nestin+, BrdU+/DCX+, BrdU+/NeuN+, BrdU-/NeuN+ and BDNF+ cells in the peri-infarct cortex, with less effect in striatum and no significant effect in the subventricular zone. Salidroside was predicted to bind with HSC70. Salidroside dose-dependently increased HSC70 ATPase and HSC70-dependent luciferase activities, but it did not activate HSP70. HSC70 immunoreactivity concentrated in the peri-infarct cortex and was unchanged by salidroside. However, VER155008 prevented salidroside-dependent increases of neurogenesis, BrdU-/NeuN+ cells and BDNF+ cells in peri-infarct cortex. Salidroside also increased BDNF protein and p-TrkB/TrkB ratio in ischemic brain, changes prevented by VER155008 and ANA-12, respectively. Additionally, ANA-12 blocked salidroside-dependent neurogenesis and increased BrdU-/NeuN+ cells in the peri-infarct cortex. Salidroside directly activates HSC70, thereby stimulating neurogenesis and neuroprotection via BDNF/TrkB signalling after MCAO. Salidroside and similar activators of HSC70 might provide clinical therapies for ischemic stroke.


Asunto(s)
Isquemia Encefálica , Factor Neurotrófico Derivado del Encéfalo , Glucósidos , Proteínas del Choque Térmico HSC70 , Infarto de la Arteria Cerebral Media , Neurogénesis , Fármacos Neuroprotectores , Fenoles , Ratas Sprague-Dawley , Transducción de Señal , Animales , Fenoles/farmacología , Fenoles/química , Glucósidos/farmacología , Neurogénesis/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ratas , Masculino , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Isquemia Encefálica/tratamiento farmacológico , Proteínas del Choque Térmico HSC70/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína Doblecortina , Rhodiola/química , Receptor trkB/metabolismo , Modelos Animales de Enfermedad , Azepinas , Benzamidas
4.
Jpn J Clin Oncol ; 54(5): 584-591, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38305451

RESUMEN

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.


Asunto(s)
Antagonistas de Andrógenos , Benzamidas , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Nitrilos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/sangre , Anciano , Estudios Prospectivos , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/efectos adversos , Anciano de 80 o más Años , Persona de Mediana Edad , Compuestos de Tosilo/administración & dosificación , Compuestos de Tosilo/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Flutamida/administración & dosificación , Resultado del Tratamiento , Anilidas/administración & dosificación , Anilidas/efectos adversos , Antígeno Prostático Específico/sangre
5.
J Nat Med ; 78(3): 774-783, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38418720

RESUMEN

Epithelial-mesenchymal transition (EMT) has recently been associated with cancer invasion, metastasis, and resistance. In our previous study, we discovered nanaomycin K, a natural growth inhibitor for EMT-induced Madin Darby canine kidney (MDCK) cells, from the cultured broth of actinomycetes. However, the screening method was undeveloped, because the activity of nanaomycin K was discovered accidentally. In this study, we established a screening method by analyzing the characteristics of nanaomycin K in MDCK cells. Nanaomycin K showed the characteristic growth inhibitory activity on MDCK cells cultured under four conditions: medium containing dimethyl sulfoxide, SB431542, TGF-ß, and a mixture of SB431542 and TGF-ß. The activity was stronger in TGF-ß-treated cells than in DMSO-treated cells. In the mixture of SB431542 and TGF-ß-treated cells, the activity of nanaomycin K was suppressed. The anti-cancer agents, mitomycin C, cisplatin, and staurosporine, lacked the characteristics as that of nanaomycin K for these four treatment conditions. Since these four conditions distinguish between the effects of nanaomycin K and other anti-cancer agents in EMT-induced cells, the screening method was established. Among the 13,427 plant extracts tested, Piper betle leaf extract displayed growth inhibitory activity against EMT-induced cells. Through the purification of the extract via bio-guided fractionation, hydroxychavicol was isolated as an active compound. The cytotoxic activity of hydroxychavicol was stronger in EMT-induced MDCK cells than in control cells. However, its cytotoxic activity was suppressed in EMT-inhibited cells. Furthermore, hydroxychavicol exhibited same activity against SAS cells (human squamous cell carcinoma of the tongue). Thus, we have successfully established a screening method for growth inhibitors of EMT-induced cells and have discovered an inhibitor from plant-based sources.


Asunto(s)
Transición Epitelial-Mesenquimal , Piper betle , Factor de Crecimiento Transformador beta , Animales , Perros , Humanos , Benzamidas/farmacología , Benzamidas/química , Proliferación Celular/efectos de los fármacos , Dioxoles/farmacología , Dioxoles/química , Transición Epitelial-Mesenquimal/efectos de los fármacos , Eugenol/farmacología , Eugenol/análogos & derivados , Inhibidores de Crecimiento/farmacología , Inhibidores de Crecimiento/química , Inhibidores de Crecimiento/aislamiento & purificación , Células de Riñón Canino Madin Darby , Extractos Vegetales/farmacología , Extractos Vegetales/química , Factor de Crecimiento Transformador beta/metabolismo , Piper betle/química
6.
Am J Physiol Gastrointest Liver Physiol ; 326(2): G120-G132, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38014444

RESUMEN

Seladelpar, a selective peroxisome proliferator-activated receptor δ (PPARδ) agonist, improves markers of hepatic injury in human liver diseases, but histological improvement of nonalcoholic steatohepatitis (NASH) and liver fibrosis has been challenging with any single agent. To discover how complementary agents could work with seladelpar to achieve optimal outcomes, this study evaluated a variety of therapeutics (alone and in combination) in a mouse model of NASH. Mice on a high-fat amylin liver NASH (AMLN) diet were treated for 12 wk with seladelpar, GLP-1-R (glucagon-like peptide-1 receptor) agonist liraglutide, apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib, farnesoid X receptor (FXR) agonist obeticholic acid, and with seladelpar in combination with liraglutide or selonsertib. Seladelpar treatment markedly improved plasma markers of liver function. Seladelpar alone or in combination resulted in stark reductions in liver fibrosis (hydroxyproline, new collagen synthesis rate, mRNA indices of fibrosis, and fibrosis staining) compared with vehicle and the other single agents. Robust reductions in liver steatosis were also observed. Seladelpar produced a reorganization of metabolic gene expression, particularly for those genes promoting peroxisomal and mitochondrial lipid oxidation. In summary, substantial improvements in NASH and NASH-induced fibrosis were observed with seladelpar alone and in combination with liraglutide in this model. Broad gene expression analysis suggests seladelpar should be effective in concert with diverse mechanisms of action.NEW & NOTEWORTHY NASH is a chronic, progressive, and increasingly problematic liver disease that has been resistant to treatment with individual therapeutics. In this study using a diet-induced mouse model of NASH, we found that the PPARδ agonist seladelpar reduced fibrosis and NASH pathology alone and in combinations with a GLP-1-R agonist (liraglutide) or an ASK1 inhibitor (selonsertib). Liver transcriptome analysis comparing each agent and coadministration suggests seladelpar should be effective in combination with a variety of therapeutics.


Asunto(s)
Acetatos , Benzamidas , Terapias Complementarias , Imidazoles , Enfermedad del Hígado Graso no Alcohólico , PPAR delta , Piridinas , Humanos , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Liraglutida/farmacología , Liraglutida/uso terapéutico , PPAR delta/metabolismo , PPAR delta/farmacología , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL
7.
Per Med ; 20(4): 321-338, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37746727

RESUMEN

Aim: To explore variations in the cost-effectiveness of entrectinib across different testing strategies and settings. Methods: Four testing strategies where adult cancer patients received entrectinib if they tested positive for NTRK gene fusions compared with 'no testing' and standard of care (SoC) for all patients were evaluated. Results: Immunohistochemistry for all patients followed by RNA-based next-generation sequencing after a positive result was the optimal strategy in all included countries. However, the incremental net monetary benefit compared with SoC was negative in all countries, ranging between international euros (int€) -206 and -404. In a subgroup analysis with only NTRK-positive patients, the incremental net monetary benefit was int€ 8405 in England, int€ -53,088 in Hungary and int€ 54,372 in The Netherlands. Conclusion: Using the cost-effectiveness thresholds recommended by national guidelines, none of the testing strategies were cost-effective compared with no testing. The implementation of entrectinib is unlikely to become cost-effective in Hungary, due to the large cost difference between the entrectinib and SoC arms, while there might be more potential in England and The Netherlands.


Histology-independent pharmaceuticals are a new phenomenon in cancer care. Most chemotherapies are prescribed based on the tumor's (primary) location, while histology-independent therapies are prescribed based on genetic markers in the tumor DNA. In this study, the added value of the histology-independent treatment entrectinib, which is aimed at cancer patients with so-called NTRK gene fusions, was investigated. Because these patients must be identified before they can be given entrectinib, various strategies for diagnostic testing were considered. An economic model was programmed to gain insight into the costs and health outcomes associated with the different testing strategies. The same analysis was done for three different countries (England, Hungary and The Netherlands) using local data. In all three countries, the health gains from receiving entrectinib may be large for patients with NTRK gene fusions. However, treatment with entrectinib was also much more expensive than standard-care treatment, especially in Hungary. In each of the three countries, all evaluated testing strategies were found to offer a negative net benefit to society (i.e., a net loss). This may be partially explained by the fact that NTRK gene fusions are rare, meaning that a large group of cancer patients has to receive (costly) testing while, subsequently, only a few patients enjoy the benefit of switching to a treatment that is more effective for them (i.e., entrectinib). Nonetheless, in England and Hungary, even if the most accurate test was provided for free, the net benefit to society of implementing entrectinib remained negative. Further changes, such as a reduction in the price of entrectinib, may therefore be needed.


Asunto(s)
Benzamidas , Neoplasias , Adulto , Humanos , Análisis Costo-Beneficio , Europa (Continente) , Benzamidas/uso terapéutico , Indazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética
9.
Org Biomol Chem ; 20(40): 7861-7885, 2022 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-36185038

RESUMEN

In recent years, isoquinoline-1,3(2H,4H)-dione compounds have attracted extensive attention from synthetic chemists, with the aim of finding simple, mild, green and efficient synthetic methods. In this review, we summarize the diverse range of synthetic methods employing acryloyl benzamides as key substrates to furnish isoquinoline-1,3-diones using different radical precursors, such as those containing carbon, sulphur, phosphorus, nitrogen, silicon and bromine. This will stimulate the interest of readers to engage in research in this field.


Asunto(s)
Bromo , Silicio , Isoquinolinas/química , Benzamidas/química , Nitrógeno , Fósforo , Azufre , Carbono
10.
Drug Des Devel Ther ; 16: 3385-3394, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36199632

RESUMEN

Objective: A sensitive and rapid UPLC-MS/MS method for determination of tazemetostat in rat plasma was developed, and the pharmacokinetics of herb-drug interactions (HDIs) of plumbagin (PLB) and tazemetostat was investigated. Methods: After the rat plasma samples were precipitated by acetonitrile, tazemetostat and verubecestat (ISTD) were detected. Gradient elution was performed with 0.1% formic acid and acetonitrile as mobile phases. The multi-reaction monitoring was used with ESI+ source, and the ion pairs for tazemetostat and ISTD were m/z 573.12→135.99 and m/z 410.10→124.00, respectively. 12 SD rats were randomly divided into the control group and the experimental group, 6 rats in each group. The rats in the experimental group were given PLB 100 mg/kg by gavage once a day for 7 consecutive days. The rats in the control group were given the same amount of 0.1% sodium carboxymethyl cellulose solution by gavage once a day for 7 consecutive days. At the seventh day, tazemetostat (80 mg/kg) was given and the blood was collected at different time points. The main parameters of pharmacokinetics were calculated and the herb-drug interactions (HDIs) were evaluated. Results: In the calibrated range of 1-1000 ng/mL, tazemetostat had a good linearity. The extraction recovery was more than 84%, and the RSD of intra-batch and inter-batch precision were both less than 15%. The Cmax of tazemetostat in the experimental group was 32.48% higher than that in the control group, and the AUC(0-t) and AUC(0-∞) of tazemetostat in the experimental group were 46.24% and 46.67% higher than that in the control group, respectively, and the t1/2 was prolonged from 10.56 h to 11.73 h. Conclusion: A simple, rapid and sensitive UPLC-MS/MS method for the determination of tazemetostat in rat plasma was established. PLB can inhibit the metabolism of tazemetostat and increase the plasma exposure of tazemetostat in rats.


Asunto(s)
Interacciones de Hierba-Droga , Espectrometría de Masas en Tándem , Acetonitrilos , Animales , Benzamidas , Compuestos de Bifenilo , Carboximetilcelulosa de Sodio , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Morfolinas , Naftoquinonas , Piridonas , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sodio , Espectrometría de Masas en Tándem/métodos
11.
J Inorg Biochem ; 236: 111972, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36087434

RESUMEN

Excessive organophosphate flame retardant (OPFR) use in consumer products has been reported to increase human disease susceptibility. However, the adverse effects of tris(2-chloroethyl) phosphate (TCEP) (a chlorinated alkyl OPFR) on the heart remain unknown. In this study, we tested whether cardiac fibrosis occurred in animal models of TCEP (10 mg/kg b.w./day) administered continuously by gavage for 30 days and evaluated the specific role of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). First, we confirmed that TCEP could trigger cardiac fibrosis by histopathological observation and cardiac fibrosis markers. We further verified that cardiac fibrosis occurred in animal models of TCEP exposure accompanied by SERCA2a, SERCA2b and SERCA2c downregulation. Notably, inductively coupled plasma-mass spectrometry (ICP-MS) analysis revealed that the cardiac concentrations of Ca2+ increased by 45.3% after TCEP exposure. Using 4-Isopropoxy-N-(2-methylquinolin-8-yl)benzamide (CDN1163, a small molecule SERCA activator), we observed that Ca2+ overload and subsequent cardiac fibrosis caused by TCEP were both alleviated. Simultaneously, the protein levels of endoplasmic reticulum (ER) markers (protein kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring protein 1α (IRE1α), eukaryotic initiation factor 2 α (eIF2α)) were upregulated by TCEP, which could be abrogated by CDN1163 pretreatment. Furthermore, we observed that CDN1163 supplementation prevented overactive autophagy induced by TCEP in the heart. Mechanistically, TCEP could lead to Ca2+ overload by inhibiting the expression of SERCA, thereby triggering ER stress and overactive autophagy, eventually resulting in cardiac fibrosis. Together, our results suggest that the Ca2+ overload/ER stress/autophagy axis can act as a driver of cardiotoxicity induced by TCEP.


Asunto(s)
Endorribonucleasas , Retardadores de Llama , Aminoquinolinas , Animales , Autofagia , Benzamidas/metabolismo , Calcio/metabolismo , Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Endorribonucleasas/farmacología , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2 Eucariótico de Iniciación/farmacología , Fibrosis , Retardadores de Llama/metabolismo , Retardadores de Llama/farmacología , Humanos , Inositol/metabolismo , Inositol/farmacología , Organofosfatos , Fosfatos/metabolismo , Fosfinas , Proteínas Serina-Treonina Quinasas , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/farmacología
12.
Zhongguo Zhong Yao Za Zhi ; 47(18): 5106-5112, 2022 Sep.
Artículo en Chino | MEDLINE | ID: mdl-36164921

RESUMEN

This study aims to investigate the efficacy, safety, and cost-effecctiveness of Qizhi Weitong Granules in the treatment of functional dyspepsia. Specifically, two commonly used clinical protocols for the treatment of functional dyspepsia were selected: Qizhi Weitong Granules+Mosapride vs Mosapride alone(control). Meta-analysis of previous clinical studies was performed to examine the efficacy and safety, and pharmacoeconomic evaluation was carried out according to the results of the Meta-analysis. The cost-effectiveness analysis was carried out to elucidated the incremental cost-effectiveness ratio(ICER), and the sensitivity was analyzed with tornado dia-gram and Monte Carlo simulation. The willingness-to-pay threshold of patients for functional dyspepsia was investigated and compared with the ICER to evaluate whether Qizhi Weitong Granules was cost-effective. The result showed that the effective rate of Qizhi Weitong Granules combined with Mosapride in the treatment of functional dyspepsia was 95.49%, which was higher than that of Mosapride alone(73.30%)(OR=8.52, 95%CI[4.36, 16.64])(P<0.000 1). The two groups showed no significant difference in safety. The price of Qizhi Weitong Granules+Mosapride was higher than that of Mosapride alone. The ICER was 640.29 CNY, 1 506.67 CNY lower than the willingness-to-pay threshold. The sensitivity analysis showed that the analysis results were relatively stable. Thus, Qizhi Weitong Granules+Mosapride is safe, effective, and economical in the treatment of functional dyspepsia, which should be further promoted in clinical settings.


Asunto(s)
Dispepsia , Benzamidas , Análisis Costo-Beneficio , Dispepsia/tratamiento farmacológico , Economía Farmacéutica , Fármacos Gastrointestinales/uso terapéutico , Humanos , Morfolinas , Resultado del Tratamiento
13.
Cells ; 11(14)2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35883638

RESUMEN

Neuronal hypothalamic insulin resistance is implicated in energy balance dysregulation and contributes to the pathogenesis of several neurodegenerative diseases. Its development has been intimately associated with a neuroinflammatory process mainly orchestrated by activated microglial cells. In this regard, our study aimed to investigate a target that is highly expressed in the hypothalamus and involved in the regulation of the inflammatory process, but still poorly investigated within the context of neuronal insulin resistance: the α7 nicotinic acetylcholine receptor (α7nAchR). Herein, we show that mHypoA-2/29 neurons exposed to pro-inflammatory microglial conditioned medium (MCM) showed higher expression of the pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α, in addition to developing insulin resistance. Activation of α7nAchR with the selective agonist PNU-282987 prevented microglial-induced inflammation by inhibiting NF-κB nuclear translocation and increasing IL-10 and tristetraprolin (TTP) gene expression. The anti-inflammatory role of α7nAchR was also accompanied by an improvement in insulin sensitivity and lower activation of neurodegeneration-related markers, such as GSK3 and tau. In conclusion, we show that activation of α7nAchR anti-inflammatory signaling in hypothalamic neurons exerts neuroprotective effects and prevents the development of insulin resistance induced by pro-inflammatory mediators secreted by microglial cells.


Asunto(s)
Resistencia a la Insulina , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Benzamidas , Compuestos Bicíclicos con Puentes , Glucógeno Sintasa Quinasa 3/metabolismo , Hipotálamo/metabolismo , Inflamación/patología , Ratones , Microglía/metabolismo , Neuronas/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo
14.
Environ Sci Pollut Res Int ; 29(53): 80612-80623, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35723826

RESUMEN

The dissipation and risk assessment studies on fluopyram, trifloxystrobin and their metabolites were carried out on onion under field conditions after two treatments of fluopyram 250 g/L + trifloxystrobin 250 g/L SC @ 150 and 300 g a.i. ha-1. The onion bulb samples were collected at 0, 3, 7, 14, and 21 days after second spray to study the pattern of dissipation using QuEChERS methodology for processing and analysis on GC-MS/MS. The total initial residues of fluopyram (fluopyram + fluopyram benzamide) in immature onion bulb were 2.14 and 4.93 mg kg-1, at single and double dose, respectively. The residues of 0.02 and 0.06 mg kg-1 persisted in the mature onion bulb collected at the harvest (30 days after treatment). The total initial residues of trifloxystrobin (trifloxystrobin + CGA 321113) in immature onion bulb were 0.65 and 1.97 mg kg-1, at single and double dose, respectively, which reached < LOQ and 0.06 mg kg-1 at the respective doses at the harvest time. Dissipation of fluopyram followed second-order kinetics with DT50 values of 1.83 and 1.74 days, whereas trifloxystrobin followed first-order kinetics with DT50 values of 4.73 and 4.78 days, at single and double dose respectively. Risk assessment in terms of hazard quotient was done to estimate the risk that can occur due to application of this combination pesticide. It was observed that even the spray at the double recommended dose could not have dietary risks on the consumers.


Asunto(s)
Fungicidas Industriales , Residuos de Plaguicidas , Contaminantes del Suelo , Cebollas/química , Fungicidas Industriales/análisis , Residuos de Plaguicidas/análisis , Cromatografía de Gases y Espectrometría de Masas , Espectrometría de Masas en Tándem , Contaminantes del Suelo/análisis , Triazoles/análisis , Benzamidas/análisis , Medición de Riesgo , Semivida
15.
Ecotoxicol Environ Saf ; 238: 113587, 2022 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-35512468

RESUMEN

Fomesafen herbicide application has become major pollution in the growth and production of crops. Spraying fomesafen on the target crops may drift out to non-target crops. In northeast China, sugar beets are always planted adjacent to soybeans. Salicylic acid (SA) plays an important role in crop growth and alleviating abiotic stress, however, the role of SA in relieving fomesafen stress in sugar beet growth has rarely been investigated. Therefore, a pot study was conducted to elucidate the effects of different concentrations (0.025, 0.25, 0.5, 1, 5, and 10 mM) of SA on morphological parameters, photosynthetic performance, and antioxidant defense system in sugar beet seedlings under fomesafen (22.5 g a.i. ha-1) stress. The results showed that fomesafen stress inhibited the growth of sugar beet seedlings, and photosynthetic performance, while increased membrane lipid peroxidation and oxidative stress. However, exogenous SA alleviated the fomesafen stress and increased plant height, biomass, photosynthetic pigment contents, net photosynthetic rate (Pn), and photochemical efficiency of PSⅡ (Fv/Fm) in sugar beet leaves. Meanwhile, exogenous SA maintained the cell membrane integrity by reducing the content of malondialdehyde (MDA) and electrolyte permeability and regulating the activities of antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and polyphenol (PPO). Therefore, it is concluded that exogenous SA ameliorated the adverse effects of fomesafen on the growth of sugar beet seedlings, with a pronounced effect at 1 mM SA. The present study results may have useful implications in managing other plants that are poisoned by herbicides.


Asunto(s)
Antioxidantes , Beta vulgaris , Antioxidantes/metabolismo , Benzamidas , Beta vulgaris/metabolismo , Clorofila/metabolismo , Fotosíntesis , Hojas de la Planta/metabolismo , Ácido Salicílico/metabolismo , Ácido Salicílico/farmacología , Plantones , Azúcares/metabolismo
16.
Ecotoxicol Environ Saf ; 239: 113628, 2022 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-35576801

RESUMEN

Fomesafen is the most widely used herbicide in the soybean field. However, there are urgent practical challenges with the long-term persistence of fomesafen in soil and its effects on the subsequent crops in agricultural production. Therefore, pot experiments were conducted to study the effects of fomesafen residues (0-0.05 mg kg-1) on growth, photosynthetic characteristics, and the antioxidant defense system of sugar beet seedlings. The results showed that with the increase of fomesafen residues, the phytotoxicity index increased, while the plant height, leaf area, root length, root volume, and dry weight of sugar beet decreased. Photosynthetic pigment content, net photosynthetic rate (Pn), maximum photosynthetic efficiency (Fv/Fm), and actual photosynthetic efficiency (Y(II)) declined with a dose-dependent manner of fomesafen, but the intercellular CO2 concentration (Ci) and non-photochemical quenching coefficient (NPQ) increased under fomesafen. On the other hand, the residues of fomesafen increased the content of malondialdehyde (MDA) and membrane permeability by aggravating oxidative stress and triggering the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO). In addition, sugar beet seedlings were significantly sensitive to fomesafen as the concentration of fomesafen in the soil was up to 0.025 mg kg-1. In conclusion, the present study showed that fomesafen residues in the soil could affect the morphophysiology and photosynthetic performance of sugar beet. This study is beneficial for understanding the effects of the herbicide fomesafen residues on non-target crops.


Asunto(s)
Beta vulgaris , Herbicidas , Benzamidas , Clorofila/farmacología , Herbicidas/toxicidad , Fotosíntesis , Hojas de la Planta , Plantones , Suelo/química , Azúcares
17.
Oxid Med Cell Longev ; 2022: 4139330, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35602108

RESUMEN

Ischemic stroke, a cerebrovascular disease worldwide, triggers a cascade of pathophysiological events, including blood-brain barrier (BBB) breakdown. Brain microvascular endothelial cells (BMECs) play a vital role in maintaining BBB function. The injury of BMECs may worsen neurovascular dysfunction and patients' prognosis. Therefore, uncover the principal molecular mechanisms involved in BBB disruption in stroke becomes pressing. The endocannabinoid system (ECS) has been implicated in increasingly physiological functions, both in neurometabolism and cerebrovascular regulation. Modulating its activities by the fatty acid amide hydrolase (FAAH) shows anti-inflammatory characteristics. Andrographolide (AG), one Chinese herbal ingredient, has also attracted attention for its role in immunomodulatory and as a therapeutic target in BBB disorders. Recently, the FAAH inhibitor URB597 and AG have important regulatory effects on neuronal and vascular cells in ischemia. However, the effects of URB597 and AG on BMEC permeability and apoptosis in oxygen-glucose deprivation (OGD) and the underlying mechanisms remain unclear. To address these issues, cultured BMECs (bEnd.3 cells) were exposed to OGD. The cell viability, permeability, tube formation, and apoptosis were assessed following treatment with URB597, AG, and cotreatment. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), proinflammatory factors, tight junction (TJ) proteins, and oxidative stress-mediated Nrf2 signaling were also investigated. Results revealed that OGD broke the endothelial barrier, cell viability, MMP, and tube formation, which was reversed by URB597 and AG. OGD-induced enhancement of ROS, MDA, and apoptosis was reduced after drug interventions. URB597 and AG exhibited antioxidant/anti-inflammatory and mitochondrial protective effects by activating Nrf2 signaling. These findings indicated that URB597 and AG protect BMECs against OGD-induced endothelial permeability impairment and apoptosis by reducing mitochondrial oxidative stress and inflammation associated with activation of Nrf2 signaling. URB597 and AG showing the vascular protection may have therapeutic potential for the BBB damage in ischemic cerebrovascular diseases.


Asunto(s)
Células Endoteliales , Glucosa , Humanos , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Apoptosis , Benzamidas , Encéfalo/metabolismo , Carbamatos , Diterpenos , Células Endoteliales/metabolismo , Glucosa/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Oxígeno/metabolismo , Permeabilidad , Especies Reactivas de Oxígeno/metabolismo
18.
Inorg Chem ; 61(23): 8729-8745, 2022 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-35638247

RESUMEN

Chalcogen-bonding interactions have recently gained considerable attention in the field of synthetic chemistry, structure, and bonding. Here, three organo-spiroselenuranes, having a Se(IV) center with a strong intramolecular Se···N chalcogen-bonded interaction, have been isolated by the oxidation of the respective bis(2-benzamide) selenides derived from an 8-aminoquinoline ligand. Further, the synthesized spiroselenuranes, when assayed for their antioxidant activity, show disproportionation of hydrogen peroxide into H2O and O2 with first-order kinetics with respect to H2O2 for the first time by any organoselenium molecules as monitored by 1H NMR spectroscopy. Electron-donating 5-methylthio-benzamide ring-substituted spiroselenurane disproportionates hydrogen peroxide at a high rate of 15.6 ± 0.4 × 103 µM min-1 with a rate constant of 8.57 ± 0.50 × 10-3 s-1, whereas 5-methoxy and unsubstituted-benzamide spiroselenuranes catalyzed the disproportionation of H2O2 at rates of 7.9 ± 0.3 × 103 and 2.9 ± 0.3 × 103 µM min-1 with rate constants of 1.16 ± 0.02 × 10-3 and 0.325 ± 0.025 × 10-3 s-1, respectively. The evolved oxygen gas from the spiroselenurane-catalyzed disproportion of H2O2 has also been confirmed by a gas chromatograph-thermal conductivity detector (GCTCD) and a portable digital polarographic dissolved O2 probe. Additionally, the synthesized spiroselenuranes exhibit thiol peroxidase antioxidant activities for the reduction of H2O2 by a benzenethiol co-reductant monitored by UV-visible spectroscopy. Next, the Se···N bonded spiroselenuranes have been explored as catalysts in synthetic oxidation iodolactonization and bromination of arenes. The synthesized spiroselenurane has activated I2 toward the iodolactonization of alkenoic acids under base-free conditions. Similarly, efficient chemo- and regioselective monobromination of various arenes with NBS catalyzed by chalcogen-bonded synthesized spiroselenuranes has been achieved. Mechanistic insight into the spiroselenuranes in oxidation reactions has been gained by 77Se NMR, mass spectrometry, UV-visible spectroscopy, single-crystal X-ray structure, and theoretical (DFT, NBO, and AIM) studies. It seems that the highly electrophilic nature of the selenium center is attributed to the presence of an intramolecular Se···N interaction and a vacant coordination site in spiroselenuranes is crucial for the activation of H2O2, I2, and NBS. The reaction of H2O2, I2, and NBS with tetravalent spiroselenurane would lead to an octahedral-Se(VI) intermediate, which is reduced back to Se(IV) due to thermodynamic instability of selenium in its highest oxidation state and the presence of a strong intramolecular N-donor atom.


Asunto(s)
Peróxido de Hidrógeno , Selenio , Antioxidantes/química , Benzamidas , Catálisis , Peróxido de Hidrógeno/química , Oxidación-Reducción , Selenio/química
19.
Drug Deliv ; 29(1): 1312-1325, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35475384

RESUMEN

Photothermal therapy (PTT) has become one of the most promising therapies in cancer treatment as its noninvasiveness, high selectivity, and favorable compliance in clinic. However, tumor thermotolerance and distal metastasis reduce its efficacy, becoming the bottleneck of applying PTT in clinic. In this study, a chidamide-loaded magnetic polypyrrole nanocomposite (CMPP) has been fabricated as a visualized cancer photothermal agent (PTA) to counter tumor thermotolerance and metastasis. The efficacy of CMPP was characterized by in vitro and in vivo assays. As a result, this kind of magnetic polypyrrole nanocomposites were black spherical nanoparticles, possessing a favorable photothermal effect and the suitable particle size of 176.97 ± 1.45 nm with a chidamide loading rate of 12.92 ± 0.45%. Besides, comparing with PTT, CMPP exhibited significantly higher cytotoxicity and cellular apoptosis rate in two tumor cell lines (B16-F10 and HepG2). In vivo study, the mice showed obvious near-infrared (NIR) and magnetic resonance imaging (MRI) dual-modal imaging at tumor sites and sentinel lymph nodes (SLNs); on the other hand, magnetic targeting guided CMPP achieved a cure level on melanoma-bearing mice through preventing metastasis and thermotolerance. Overall, with high loading efficiency of chidamide and strong magnetic targeting to tumor sites and SLNs, CMPP could significantly raise efficiency of PTT by targeting tumor thermotolerance and metastasis, and this strategy may be exploited therapeutically to upgrade PTT with MPP as one of appropriate carriers for histone deacetylase inhibitors (HDACis).


Asunto(s)
Neoplasias , Termotolerancia , Aminopiridinas , Animales , Benzamidas , Imagen por Resonancia Magnética/métodos , Ratones , Neoplasias/tratamiento farmacológico , Fototerapia , Terapia Fototérmica , Polímeros/química , Pirroles
20.
Actas Urol Esp (Engl Ed) ; 46(5): 301-309, 2022 06.
Artículo en Inglés, Español | MEDLINE | ID: mdl-35256324

RESUMEN

PURPOSE: We designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide. METHODS: 101 mCRPC patients were included. PNI was calculated using formula 10 x serum albumin value (gr/dL) + 0.005 × total lymphocyte count (per mm3). ROC analysis was used for determining prognostic PNI value. RESULTS: The statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30 %-50%-90% PSA response at any time) were much better in PNI > 46.62 group than the PNI ≤ 46.62 group (p < 0.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: 0.42, p < 0.01), radiologic PFS (HR: 0.53, p < 0.01), and OS (HR: 0.42, p < 0.01). In the PNI ≤ 46.62 group, median OS was 7.4 months (95% CI: 4.1-10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1-25.1) for enzalutamide subgroups (p < 0.01). CONCLUSION: PNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.


Asunto(s)
Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Acetato de Abiraterona/uso terapéutico , Benzamidas , Humanos , Masculino , Nitrilos , Evaluación Nutricional , Feniltiohidantoína , Pronóstico , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/patología
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