RESUMEN
BACKGROUND: Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. METHODS: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. RESULTS: We included 14 RCTs comprising 16â196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). CONCLUSION: Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.
Asunto(s)
Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Síndrome de QT Prolongado , Inhibidores de Proteínas Quinasas , Femenino , Humanos , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Aminopiridinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Síndrome de QT Prolongado/inducido químicamente , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Purinas/efectos adversos , Purinas/uso terapéutico , Purinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Roscovitina/efectos adversosRESUMEN
PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.
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Inhibidores de la Aromatasa , Neoplasias de la Mama , Purinas , Femenino , Humanos , Aminopiridinas/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana EdadRESUMEN
Antimicrobial resistance is a global health problem. In 2021, it was estimated almost half a million of multidrug-resistant tuberculosis (MDR-TB) cases. Besides, non-tuberculous mycobacteria (NTM) are highly resistant to several drugs and the emergence of fluoroquinolone (FQ) resistant M. tuberculosis (Mtb) is also a global concern making treatments difficult and with variable outcome. The aim of this study was to evaluate the activity of the FQ, DC-159a, against Mtb and NTM and to explore the cross-resistance with the currently used FQs.A total of 12 pre-extensively drug-resistant (XDR) Mtb, 2 XDR, 36 fully drug susceptible strains and 41 NTM isolates were included to estimate the in vitro activity of DC-159a, moxifloxacin (MOX) and levofloxacin (LX), using minimal inhibitory and bactericidal concentration (MIC and MBC). The activity inside the human macrophages and pulmonary epithelial cells were also determined.DC-159a was active in vitro and ex vivo against mycobacteria. Besides, it was more active than MOX/LX. Moreover, no cross-resistance was evidenced between DC-159a and LX/MOX as DC-159a could inhibit Mtb and MAC strains that were already resistant to LX/MOX.DC-159a could be a possible candidate in new therapeutic regimens for MDR/ XDR-TB and mycobacterioses cases.
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Aminopiridinas , Fluoroquinolonas , Pruebas de Sensibilidad Microbiana , Moxifloxacino , Mycobacterium tuberculosis , Fluoroquinolonas/farmacología , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Moxifloxacino/farmacología , Antituberculosos/farmacología , Micobacterias no Tuberculosas/efectos de los fármacos , Levofloxacino/farmacología , Macrófagos/efectos de los fármacos , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacosRESUMEN
Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects.
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Aminopiridinas , Ansiolíticos , Receptores de Hormona Liberadora de Corticotropina , Humanos , Ratas , Animales , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Hormona Liberadora de Corticotropina/metabolismo , Prueba de Laberinto Elevado , Corteza Insular , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiolíticos/farmacologíaRESUMEN
PURPOSE: To estimate the cost-effectiveness of adding a CDK4/6 inhibitor to standard endocrine therapy in the first-line setting for advanced HR+/HER2- breast cancer in postmenopausal and premenopausal women, from the perspective of the Mexican public healthcare system. METHODS: We used a partitioned survival model to simulate relevant health outcomes in a synthetic cohort of patients with breast cancer derived from the PALOMA-2, MONALEESA-2, MONARCH-3 trials for postmenopausal patients, and from the MONALEESA-7 study for premenopausal patients. Effectiveness was measured in life years gained. Cost-effectiveness is reported through incremental cost-effectiveness ratios (ICER). RESULTS: In postmenopausal patients, palbociclib led to an increase of 1.51 life years, ribociclib of 1.58 years, and abemaciclib of 1.75 years, compared to letrozole alone. The ICER was 36,648 USD, 32,422 USD, and 26,888 USD, respectively. In premenopausal patients, ribociclib led to an increase of 1.82 life years when added to goserelin and endocrine therapy, with an ICER of 44,579 USD. In the cost minimization analysis, for postmenopausal patients, ribociclib was the treatment with the highest costs due to follow-up requirements. CONCLUSION: Palbociclib, ribociclib, and abemaciclib demonstrated a significant increase in effectiveness in postmenopausal patients, and ribociclib in premenopausal patients, when added to standard endocrine therapy for patients with advanced HR+/HER2- breast cancer. At the national stablished willingness to pay, only the addition of abemaciclib to standard endocrine therapy in postmenopausal women would be considered cost-effective. However, differences on results between therapies for postmenopausal patients were not statistically significant.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Análisis Costo-Beneficio , México , Aminopiridinas/uso terapéutico , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Receptor ErbB-2 , Quinasa 4 Dependiente de la CiclinaRESUMEN
INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.
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Fibrosis Quística , Humanos , Masculino , Niño , Adolescente , Femenino , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/uso terapéutico , Combinación de Medicamentos , Aminofenoles , Aminopiridinas , Benzodioxoles/efectos adversos , MutaciónRESUMEN
PURPOSE: Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed. MATERIALS AND METHODS: Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide. RESULTS: Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice. CONCLUSION: Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment.
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Leucemia Mieloide Aguda , Animales , Ratones , Leucemia Mieloide Aguda/tratamiento farmacológico , Fosforilación Oxidativa , Aminopiridinas/farmacología , Benzamidas , Apoptosis , Línea Celular TumoralRESUMEN
BACKGROUND: The Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that manifests as a rapidly progressive dementia syndrome. Currently, CJD has no cure, and many patients die within the first year, but some drugs are being studied as options for managing this condition. OBJECTIVE: To evaluate the effectiveness of pharmacological treatments offered to patients with CJD as a means to increase survival and reduce cognitive deterioration. METHODS: A systematic review of the literature was performed using 4 independent reviewers and 1 extra reviewer to resolve possible divergences in the search and analysis of papers indexed in MedLINE (PubMed), SciELO and Lilacs databases. The Medical Subject Heading (MeSH) terms used were: prion diseases, Creutzfeldt-Jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine, and pentosan polysulfate, with the Boolean operators AND and OR. This search included controlled clinical trials, uncontrolled clinical trials, and case series published from the year 2000 onwards, in the English language. RESULTS: A total of 85 papers were found using the descriptors used. At the end of the selection analyses, 9 articles remained, which were analyzed fully and individually. CONCLUSIONS: None of the drugs evaluated proved significantly effective in increasing survival in patients with CJD. Flupirtine appears to have a beneficial effect in reducing cognitive deterioration in patients with CJD. However, additional studies are needed to establish better evidence and therapeutic options for the management of patients with CJD.
ANTECEDENTES: A doença de Creutzfeldt-Jakob (DCJ) é uma encefalopatia espongiforme que se manifesta como síndrome demencial rapidamente progressiva. Atualmente, a DCJ não possui cura e muitos pacientes morrem no primeiro ano de doença, mas alguns medicamentos vêm sendo estudados como opções no manejo desta condição. OBJETIVO: Avaliar a eficácia dos tratamentos farmacológicos oferecidos aos pacientes com DCJ no aumento de sobrevida e na redução da deterioração cognitiva. MéTODOS: Foi realizada uma revisão sistemática da literatura utilizando 4 revisores independentes e 1 extra para resolver divergências eventuais na busca e na análise de trabalhos indexados nas bases de dados MedLINE (via PubMed), SciELO e Lilacs. Os termos Medical Subjects Heading (MeSH) utilizados foram: prion diseases, creutzfeldt jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine e pentosan polysulfate, com os operadores booleanos AND e OR. Essa pesquisa incluiu ensaios clínicos controlados, não controlados e séries de casos, publicados a partir do ano 2000 no idioma inglês. RESULTADOS: Ao todo, foram encontrados 85 trabalhos através dos descritores utilizados. Ao final das análises de seleção, restaram 9 artigos, que foram analisados na íntegra individualmente. CONCLUSõES: Nenhuma das drogas avaliadas se mostrou significativamente eficaz no aumento da sobrevida dos pacientes com DCJ. A flupirtina parece ter um efeito benéfico na redução da deterioração cognitiva dos pacientes com DCJ. Entretanto, estudos adicionais são necessários para o estabelecimento de melhores evidências e opções terapêuticas para o manejo dos pacientes com DCJ.
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Síndrome de Creutzfeldt-Jakob , Enfermedades por Prión , Aminopiridinas , Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Síndrome de Creutzfeldt-Jakob/psicología , Doxiciclina/uso terapéutico , Humanos , Poliéster Pentosan Sulfúrico/uso terapéutico , Quinacrina/uso terapéuticoRESUMEN
PURPOSE: Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. METHODS: We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts. RESULTS: We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C. CONCLUSIONS: Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.
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Neoplasias de la Mama , Aminopiridinas , Bencimidazoles , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Femenino , Hormonas/uso terapéutico , Humanos , Fosfatidilinositol 3-Quinasas , Complejo de la Endopetidasa Proteasomal/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Purinas , ARN Mensajero , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitinas/uso terapéuticoRESUMEN
PURPOSE: Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs' drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung cancer (NSCLC) patients was still unknown. METHODS: A lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order.Dear Editor: I have carefully confirmed that the author names have been identified correctly and are presented in right order.Thank you very much! Your sincerely BoXie RESULTS: The sensitivity of SNU-2535LR cells to lorlatinib was decreased significantly than that of SNU-2535 cells. EML4-ALK fusion was decreased both at protein level and DNA level in SNU-2535LR cells. More interesting, the crizotinib-resistant mutation ALK p.G1269A disappeared, while new TP53 mutation emerged in SNU-2535LR cells. APR-246 can reverse the lorlatinib resistance in SNU-2535LR cells, with a reversal index of 4.768. Compared with SNU-2535 cells, the sensitivity of SNU-2535LR cells to gemcitabine, docetaxel and paclitaxel was significantly increased (P < 0.05), but decreased to cisplatin (P < 0.05). CONCLUSION: This study demonstrated that the combination of p53 protein agonist and lorlatinib may provide a new therapeutic strategy for NSCLC patients with lorlatinib resistance and TP53 mutation. Furthermore, the results also provide guidance for selecting optimal chemo-regimens for NSCLC patients after ALK-TKIs failure.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aminopiridinas , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular , Cisplatino/uso terapéutico , Crizotinib/uso terapéutico , Docetaxel/uso terapéutico , Resistencia a Antineoplásicos/genética , Humanos , Lactamas , Lactamas Macrocíclicas/farmacología , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Microtúbulos/genética , Mutación , Paclitaxel/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via off-label routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mg·kg-1·day-1), oral roflumilast (5 mg·kg-1·day-1), or rectal roflumilast (5 mg·kg-1·day-1) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-α. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-α, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.
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Colitis , Aminopiridinas/uso terapéutico , Animales , Benzamidas/efectos adversos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Ciclopropanos , Modelos Animales de Enfermedad , Ratones , Peroxidasa , Ratas , Ácido Trinitrobencenosulfónico/efectos adversos , Factor de Necrosis Tumoral alfaRESUMEN
The combination of plant density, fungicide, and levels of genotype resistance to white mold (WM) has not been studied for its effect on performance of common bean with type III growth habit under WM pressure. We established four sprinkler-irrigated trials in the fall to winter season in Brazil, combining density (8, 14, 20, or 26 plants/m2), genotype (susceptible or partially resistant to WM), and fungicide to manage WM (two fluazinam applications or without fluazinam) at 0.5 m row spacing in fields infested with sclerotia. One trial was established in a warm region, aiming to obtain low WM pressure. For three trials, the linear mixed model was used. WM pressure in the trials ranged from low to high. Genotype × density × fungicide and genotype × density interactions were not significant for incidence, severity, and yield for all trials. In the three trials, severity was 29% lower at eight than at 26 plants/m2, and yield at 14 plants/m2 (3,294 kg/ha) was 14% higher than yield at eight plants/m2 (P = 0.035) where fluazinam was applied. However, without fluazinam, density did not affect yield. In conclusion, choices of plant density for type III bean cultivars do not need to take into account their resistance levels to WM in the fall to winter season. However, fungicide treatment to manage WM affects the choice of density, with 8 to 12 plants/m2 recommended if fungicide is not an option to manage WM (as in organic systems), and 10 to 14 plants/m2 recommended if fungicide applications are likely.
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Ascomicetos , Fungicidas Industriales , Phaseolus , Aminopiridinas , Fungicidas Industriales/farmacología , Hábitos , Enfermedades de las Plantas/prevención & control , PlantasRESUMEN
PURPOSE: Cushing's disease is associated with significant morbidity; thus, additional tumor-directed drugs with the potential to exert antineoplastic effects on corticotroph adenoma cells are desired. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway, which plays regulatory role in cell survival and proliferation, is activated in pituitary adenomas. The present study evaluated the effects of BKM120 (Buparlisib), an oral PI3K inhibitor, on cell viability, apoptosis, cell cycle phase distribution, and ACTH production in mouse corticotroph tumor cells. METHODS: AtT-20/D16v-F2 mouse pituitary corticotroph tumor cells were treated with increasing concentrations of BKM120 or vehicle. Cell viability was measured using an MTS-based assay. Apoptosis was evaluated by Annexin V staining. Cell cycle analysis was performed by propidium iodide DNA staining and flow cytometry. Gene expression of cell cycle regulators (Cdkn1b, Ccnd1, Ccne1, Cdk2, Cdk4, Myc, and Rb1) was assessed by qPCR. Protein expression of p27, total and phosphorylated Akt was assessed by Western blot. ACTH levels were measured in the culture supernatants by chemiluminescent immunometric assay. RESULTS: Treatment with BKM120 decreased AtT-20/D16v-F2 cell viability, induced a G0/G1 cell cycle arrest, reduced the phosphorylation of Akt at Serine 473, and increased p27 expression. Furthermore, BKM120 treatment diminished ACTH levels in the cell culture supernatants. CONCLUSION: In vitro inhibition of PI3K/AKT pathway by BKM120 resulted in anti-proliferative effects on corticotroph tumor cells, decreasing cell viability and ACTH production. These encouraging findings shape the path for further experiments with the inhibition of PI3K/AKT pathway in Cushing's disease.
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Adenoma , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Neoplasias Hipofisarias , Adenoma/patología , Hormona Adrenocorticotrópica/metabolismo , Aminopiridinas , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Corticotrofos/metabolismo , Corticotrofos/patología , Humanos , Ratones , Morfolinas , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasa/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/metabolismo , Neoplasias Hipofisarias/patología , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Different data suggest that microglia may participate in the drug addiction process as these cells respond to neurochemical changes induced by the administration of these substances. In order to study the role of microglia in drug abuse, Swiss mice aged 8-9 weeks were treated with the CSF1R inhibitor PLX3397 (40 mg/kg, p.o.) and submitted to behavioral sensitization or conditioned place preference (CPP) induced by cocaine (15 mg/kg, i.p.). Thereafter, brains were used to evaluate the effects of CSF1R inhibition and cocaine administration on morphological, biochemical and molecular changes. CSF1R inhibition attenuated behavioral sensitization, reduced the number of Iba-1+ cells and increased ramification and lengths of the branches in the remaining microglia. Additionally, both cocaine and PLX3397 increased the cell body to total cell size ratio of Iba-1+ cells, as well as CD68+ and GFAP+ stained areas, suggesting an activated pattern of the glial cells. Besides, CSF1R inhibition increased CX3CL1 levels in the striatum, prefrontal cortex and hippocampus, as well as reduced CX3CR1 expression in the hippocampus. In this region, cocaine also reduced BDNF levels, an effect that was enhanced by CSF1R inhibition. In summary, our results suggest that microglia participate in the behavioral and molecular changes induced by cocaine. This study contributes to the understanding of the role of microglia in cocaine addiction.
Asunto(s)
Aminopiridinas/farmacología , Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/prevención & control , Cocaína/toxicidad , Microglía/efectos de los fármacos , Pirroles/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Quimiocina CX3CL1/genética , Quimiocina CX3CL1/metabolismo , Trastornos Relacionados con Cocaína/etiología , Trastornos Relacionados con Cocaína/patología , Condicionamiento Clásico , Inhibidores de Captación de Dopamina/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Inhibición Psicológica , Masculino , Ratones , Microglía/metabolismo , Microglía/patologíaRESUMEN
Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation.
Asunto(s)
Aminopiridinas/farmacología , Arginasa/metabolismo , Benzamidas/farmacología , Isquemia Encefálica , Proteínas de Unión al Calcio/metabolismo , Disfunción Cognitiva , Proteínas de Microfilamentos/metabolismo , Enfermedades Neuroinflamatorias , Animales , Conducta Animal/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/inmunología , Isquemia Encefálica/psicología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Ciclopropanos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Fármacos Neuroprotectores/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Recuperación de la Función/efectos de los fármacos , Resultado del Tratamiento , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/metabolismoRESUMEN
Antidepressant drugs are first-line treatment for panic disorder. Facilitation of 5-HT1A receptor-mediated neurotransmission in the dorsal periaqueductal gray (dPAG), a key panic-associated area, has been implicated in the panicolytic effect of the selective serotonin reuptake inhibitor fluoxetine. However, it is still unknown whether this mechanism accounts for the antipanic effect of other classes of antidepressants drugs (ADs) and whether the 5-HT interaction with 5-HT2C receptors in this midbrain area (which increases anxiety) is implicated in the anxiogenic effect caused by short-term treatment with ADs. The results showed that previous injection of the 5-HT1A receptor antagonist WAY-100635 in the dPAG blocked the panicolytic-like effect caused by chronic systemic administration of the tricyclic AD imipramine in male Wistar rats tested in the elevated T-maze. Neither chronic treatment with imipramine nor fluoxetine changed the expression of 5-HT1A receptors in the dPAG. Treatment with these ADs also failed to significantly change ERK1/2 (extracellular-signal regulated kinase) phosphorylation level in this midbrain area. Blockade of 5-HT2C receptors in the dPAG with the 5-HT2C receptor antagonist SB-242084 did not change the anxiogenic effect caused by a single acute injection of fluoxetine or imipramine in the Vogel conflict test. These results reinforce the view that the facilitation of 5-HT1A receptor-mediated neurotransmission in the dPAG is a common mechanism involved in the panicolytic effect caused by chronic administration of ADs. On the other hand, the anxiogenic effect observed after short-term treatment with these drugs does not depend on 5-HT2C receptors located in the dPAG.
Asunto(s)
Antidepresivos/farmacología , Ansiedad/tratamiento farmacológico , Pánico/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Receptor de Serotonina 5-HT1A/fisiología , Receptor de Serotonina 5-HT2C/fisiología , Aminopiridinas/farmacología , Animales , Western Blotting , Prueba de Laberinto Elevado , Fluoxetina/farmacología , Imipramina/farmacología , Indoles/farmacología , Masculino , Prueba de Campo Abierto/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiología , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Receptor de Serotonina 5-HT2C/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
Numerous methodologies to obtain pyridines from ylidenemalononitriles are described in the literature. Nevertheless, they are limited to the use of microwave or conventional heat and few lead to 2,3,4 or 2,3,4,5-substituted pyridines as multi-proposal molecular scaffolds or even universal pyridines. Herein, we present a mild and facile solvent-free methodology to obtain a scope of multi-substituted pyridines at room temperature. We also report an example where one of the resulting amino-nicotinonitriles exhibits a preliminary evidence of aggregation-induced emission (AIE).
Asunto(s)
Alquenos/química , Aminopiridinas/síntesis química , Nitrilos/química , Estructura MolecularRESUMEN
BACKGROUND: Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-ßRI inhibitor) seeking to overcome GB treatment resistance. METHODS: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. RESULTS: Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-ß-dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. CONCLUSION: This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Metilasas de Modificación del ADN/antagonistas & inhibidores , Enzimas Reparadoras del ADN/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Temozolomida/farmacología , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Aminopiridinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Astrocitos/efectos de los fármacos , Bencimidazoles/farmacología , Neoplasias Encefálicas/enzimología , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ciclina D/antagonistas & inhibidores , Resistencia a Antineoplásicos/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular , Glioblastoma/enzimología , Guanina/análogos & derivados , Guanina/farmacología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/efectos de los fármacos , Neuronas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Pirazoles/farmacología , Quinolinas/farmacología , Proteínas Smad/efectos de los fármacosRESUMEN
Chronic exposure to adverse events has been proposed as a prominent factor involved in etiology and progression of cardiovascular dysfunctions in humans and animals. However, the neurobiological mechanisms involved are still poorly understood. In this sense, chronic stress has been reported to evoke neuroplasticity in corticotropin-releasing factor (CRF) neurotransmission in several limbic structures, including the bed nucleus of the stria terminalis. However, a possible involvement of BNST CRF neurotransmission in cardiovascular dysfunctions evoked by chronic stress has never been reported. Thus, this study investigated the involvement of CRF1 and CRF2 receptors within the BNST in cardiovascular changes evoked by chronic stress in rats. We identified that exposure to a 10-day chronic variable stress (CVS) protocol decreased expression of both CRF1 and CRF2 receptors within the BNST. These effects were followed by increased arterial pressure and impairment of baroreflex function, but without changes on heart rate. Bilateral microinjection of either the selective CRF1 receptor antagonist CP376395 or the selective CRF2 receptor antagonist antisauvagine-30 into the BNST did not affect CVS-evoked arterial pressure increase. Nevertheless, BNST treatment with CP376395 decreased both tachycardic and bradycardic responses of the baroreflex in non-stressed rats; but these effects were not identified in chronically stressed animals. BNST pharmacological treatment with antisauvagine-30 decreased the reflex tachycardia in control animals, whereas reflex bradycardic response was increased in CVS animals. Altogether, the results reported in the present study indicate that down regulation of both CRF1 and CRF2 receptors within the BNST is involved in baroreflex impairment evoked by chronic stress.
Asunto(s)
Barorreflejo/fisiología , Receptores de Hormona Liberadora de Corticotropina/genética , Núcleos Septales/metabolismo , Aminopiridinas/farmacología , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Masculino , Fragmentos de Péptidos/farmacología , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Núcleos Septales/efectos de los fármacos , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
BACKGROUND: The hippocampus is a limbic structure involved in anxiety-like behaviors. We aimed to evaluate the role of the dorsal (DH) and ventral (VH) hippocampus in anxiety-like behaviors in the elevated plus maze (EPM). METHODS: We inhibited these brain regions using cobalt chloride (CoCl2: 1.0 nmol) microinjections. We also investigated the involvement of corticotropin-releasing factor (CRF) action and protein kinase A (PKA) pathway using intra-DH and intra-VH microinjections of the CRF1 receptor antagonist CP376395 (0, 3.0, or 6.0 nmol) and the PKA inhibitor H-89 (0, 2.5, or 5.0 nmol). RESULTS: The results indicated that intra-VH CoCl2 microinjection increased the percentage of time spent and entries in the open arms. The mice also exhibited fewer stretch attend postures in the protected area and increased percentage of open arm entries. Further, intra-VH injection of 3.0 nmol CP376395 increased time spent in the open arms. Intra-DH injection of 6.0 nmol CP376395 increased the frequency of unprotected head dipping, whereas intra-VH injection of 6 nmol CP376395 increased the frequency of protected head dipping. Intra-VH, but not intra-DH, microinjection of 2.5 nmol H-89 increased the percentages of open arm entries and time spent in the open arms. Microinjection of 2.5 and 5.0 nmol H-89 reduced the frequency of protected head dipping behavior. CONCLUSIONS: This study demonstrated that VH modulates anxiety-like behaviors in EPM. Moreover, CRF and the cAMP/PKA pathway seem to modulate these effects.