Frontiers in pharmacology
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Frontiers in pharmacology · Jan 2019
The Differences in the Safety and Tolerability of Immune Checkpoint Inhibitors as Treatment for Non-Small Cell Lung Cancer and Melanoma: Network Meta-Analysis and Systematic Review.
Background: Immune checkpoint inhibitors (ICIs) have evolved for the treatment of solid tumors. In addition to the efficacy of ICIs for cancer, the adverse events (AEs) of ICIs are also noteworthy for gradually more extensive clinical use. Objective: To conduct a systematic review and network meta-analysis to evaluate the treatment-related AEs that occurred in clinical trials using different kinds of ICIs, to explore the differences in AEs among ICIs for treating non-small cell lung cancer (NSCLC) and melanoma, and to compare select immune-related AEs. ⋯ A combination of nivolumab and ipilimumab had the highest risk for colitis, while pembrolizumab and atezolizumab had a lower possibility than the other ICIs. Conclusion: Atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks were ordinarily safer than other ICIs. When treating NSCLC, nivolumab had the lowest risk; when treating melanoma, pembrolizumab had the lowest toxicity.
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Frontiers in pharmacology · Jan 2019
ReviewAdapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease.
Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy. ⋯ There is emerging experimental and clinical evidence that supports the notion that impaired cellular proteostasis and autophagy plays a central role in regulating pathogenesis of chronic CF lung disease. Thus, correcting the underlying proteostasis and autophagy defect in controlling CF pulmonary disease, primarily via correcting the protein processing defect of F508del-CFTR protein has emerged as a novel intervention strategy. Hence, we discuss here both the rationale and significant therapeutic utility of emerging proteostasis and autophagy modulating drugs/compounds in controlling chronic CF lung disease, where targeted delivery is a critical factor-influencing efficacy.
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Frontiers in pharmacology · Jan 2019
Influence of CYP2C19 Metabolizer Status on Escitalopram/Citalopram Tolerability and Response in Youth With Anxiety and Depressive Disorders.
In pediatric patients, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and citalopram (es/citalopram) are commonly prescribed for anxiety and depressive disorders. However, pharmacogenetic studies examining CYP2C19 metabolizer status and es/citalopram treatment outcomes have largely focused on adults. We report a retrospective study of electronic medical record data from 263 youth < 19 years of age with anxiety and/or depressive disorders prescribed escitalopram or citalopram who underwent routine clinical CYP2C19 genotyping. ⋯ Meanwhile, faster metabolizers responded more quickly to es/citalopram (p = 0.005) and trended toward less time spent in subsequent hospitalizations (p = 0.06). These results highlight a disparity in treatment outcomes with es/citalopram treatment in youth with anxiety and/or depressive disorders when standardized dosing strategies were used without consideration of CYP2C19 metabolizer status. Larger, prospective trials are warranted to assess whether tailored dosing of es/citalopram based on CYP2C19 metabolizer status improves treatment outcomes in this patient population.
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Frontiers in pharmacology · Jan 2019
Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.
Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. ⋯ In addition, changes in pro-inflammatory cytokine (TNF-α, IL-1β) expression and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development.
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Frontiers in pharmacology · Jan 2019
Edgeworthia gardneri (Wall.) Meisn. Water Extract Ameliorates Palmitate Induced Insulin Resistance by Regulating IRS1/GSK3β/FoxO1 Signaling Pathway in Human HepG2 Hepatocytes.
The flower of Edgeworthia gardneri (Wall.) Meisn is commonly used in beverage products in Tibet and has potential health benefits for diabetes. However, the mechanisms underlying anti-insulin resistance (IR) action of the flower of E. gardneri are not fully understood. This study aims to investigate the effects of the water extract of the flower of E. gardneri (WEE) on IR in palmitate (PA)-exposed HepG2 hepatocytes. ⋯ The GLUT2 and GLUT4 translocation were also promoted by WEE treatment in PA-treated HepG2 cells. Taken together, WEE has potential anti-IR effect in PA-exposed HepG2 cells; the underlying mechanism of this action may be associated with the regulation of IRS1/GSK3β/FoxO1 signaling pathway. This study provides a pharmacological basis for the application of WEE in the treatment of metabolic diseases such as type 2 diabetes mellitus.