Pub Date : 2024-09-13DOI: 10.3389/fphar.2024.1426826
Alejandro Durán-Sotuela, Jorge Vázquez-García, Sara Relaño-Fernández, Vanesa Balboa-Barreiro, Juan Fernández-Tajes, Francisco J. Blanco, Ignacio Rego-Pérez
BackgroundIn the context of the cytokine storm the takes place in severe COVID-19 patients, the Interleukin 6 (IL6) pathway emerges as one of the key pathways involved in the pathogenesis of this hyperinflammatory state. The strategy of blocking the inflammatory storm by targeting the IL6 is a promising therapy to mitigate mortality. The use of Tocilizumab was recommended by the World Health Organization (WHO) to treat severe COVID-19 patients. However, the efficacy of Tocilizumab is variable. We hypothesize that the genetic background could be behind the efficacy of Tocilizumab in terms of mortality.MethodsWe performed a targeted-next generation sequencing of 287 genes, of which 264 belong to a community panel of ThermoFisher for the study of genetic causes of primary immunodeficiency disorders, and 23 additional genes mostly related to inflammation, not included in the original community panel. This panel was sequenced in an initial cohort of 425 COVID-19 patients, of which 232 were treated with Tocilizumab and standard therapy, and 193 with standard therapy only. Selected genetic variants were genotyped by single base extension in additional 245 patients (95 treated with Tocilizumab and 150 non-treated with Tocilizumab). Appropriate statistical analyses and internal validation, including logistic regression models, with the interaction between Tocilizumab and genetic variants, were applied to assess the impact of these genetic variants in the efficacy of Tocilizumab in terms of mortality.ResultsAge (p < 0.001) and cardiovascular disease (p < 0.001) are risk factors for mortality in COVID-19 patients. The presence of GG and TT genotypes at IL10Rβ (rs2834167) and IL1β (rs1143633) genes significantly associates with a reduced risk of mortality in patients treated with Tocilizumab (OR = 0.111; 95%CI = 0.015–0.829; p = 0.010 and OR = 0.378; 95%CI = 0.154–0.924; p = 0.028 respectively). The presence of CC genotype at IL1RN (rs2234679) significantly associates with an increased risk of mortality, but only in patients not treated with Tocilizumab (OR = 3.200; 95%CI = 1.512–6.771; p = 0.002). Exhaustive internal validation using a bootstrap method (B = 500 replicates) validated the accuracy of the predictive models.ConclusionWe developed a series of predictive models based on three genotypes in genes with a strong implication in the etiopathogenesis of COVID-19 disease capable of predicting the risk of mortality in patients treated with Tocilizumab.
{"title":"An exploratory analysis of associations of genetic variation with the efficacy of tocilizumab in severe COVID-19 patients. A pharmacogenetic study based on next-generation sequencing","authors":"Alejandro Durán-Sotuela, Jorge Vázquez-García, Sara Relaño-Fernández, Vanesa Balboa-Barreiro, Juan Fernández-Tajes, Francisco J. Blanco, Ignacio Rego-Pérez","doi":"10.3389/fphar.2024.1426826","DOIUrl":"https://doi.org/10.3389/fphar.2024.1426826","url":null,"abstract":"BackgroundIn the context of the cytokine storm the takes place in severe COVID-19 patients, the <jats:italic>Interleukin 6</jats:italic> (<jats:italic>IL6</jats:italic>) pathway emerges as one of the key pathways involved in the pathogenesis of this hyperinflammatory state. The strategy of blocking the inflammatory storm by targeting the <jats:italic>IL6</jats:italic> is a promising therapy to mitigate mortality. The use of Tocilizumab was recommended by the World Health Organization (WHO) to treat severe COVID-19 patients. However, the efficacy of Tocilizumab is variable. We hypothesize that the genetic background could be behind the efficacy of Tocilizumab in terms of mortality.MethodsWe performed a targeted-next generation sequencing of 287 genes, of which 264 belong to a community panel of ThermoFisher for the study of genetic causes of primary immunodeficiency disorders, and 23 additional genes mostly related to inflammation, not included in the original community panel. This panel was sequenced in an initial cohort of 425 COVID-19 patients, of which 232 were treated with Tocilizumab and standard therapy, and 193 with standard therapy only. Selected genetic variants were genotyped by single base extension in additional 245 patients (95 treated with Tocilizumab and 150 non-treated with Tocilizumab). Appropriate statistical analyses and internal validation, including logistic regression models, with the interaction between Tocilizumab and genetic variants, were applied to assess the impact of these genetic variants in the efficacy of Tocilizumab in terms of mortality.ResultsAge (<jats:italic>p</jats:italic> &lt; 0.001) and cardiovascular disease (<jats:italic>p</jats:italic> &lt; 0.001) are risk factors for mortality in COVID-19 patients. The presence of GG and TT genotypes at <jats:italic>IL10Rβ</jats:italic> (rs2834167) and <jats:italic>IL1β</jats:italic> (rs1143633) genes significantly associates with a reduced risk of mortality in patients treated with Tocilizumab (OR = 0.111; 95%CI = 0.015–0.829; <jats:italic>p</jats:italic> = 0.010 and OR = 0.378; 95%CI = 0.154–0.924; <jats:italic>p</jats:italic> = 0.028 respectively). The presence of CC genotype at <jats:italic>IL1RN</jats:italic> (rs2234679) significantly associates with an increased risk of mortality, but only in patients not treated with Tocilizumab (OR = 3.200; 95%CI = 1.512–6.771; <jats:italic>p</jats:italic> = 0.002). Exhaustive internal validation using a bootstrap method (B = 500 replicates) validated the accuracy of the predictive models.ConclusionWe developed a series of predictive models based on three genotypes in genes with a strong implication in the etiopathogenesis of COVID-19 disease capable of predicting the risk of mortality in patients treated with Tocilizumab.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.3389/fphar.2024.1426777
Ran Jin, Caiyan Liu, Jinghao Chen, Mengjiao Cui, Bo Xu, Ping Yuan, Lu Chen
Purpose: Polypharmacy presents many challenges to patient medication self-management. This study aims to explore the self-management processes of medication in polypharmacy from the perspectives of both patients and healthcare providers, which can help identify barriers and facilitators to effective management.Methods: A systematic review of qualitative studies was performed by searching seven databases: PubMed, Web of Science, Cochrane Library, Embase, CINAHL, PsycINFO, and MEDLINE, from their establishment until August 2024. The Critical Appraisal Skills Programme (CASP) tool was employed to evaluate the quality of the studies included. The extracted data were then analysed thematically and integrated into The Taxonomy of Everyday Self-management Strategies (TEDSS) framework.Results: A total of 16 studies were included, involving 403 patients and 119 healthcare providers. Patient management measures were mapped into TEDSS framework, including categories such as medical management, support-oriented domains and emotional and role management.Conclusion: Enhancing patients’ proactive health awareness, improving medication literacy, balancing lifestyle adjustments with medication therapy, dynamically reviewing and optimizing medications, strengthening patients’ social support networks, and helping patients integrate medication management into their daily life are the key elements that can effectively assist patients in self-managing their medications. Future interventions to improve patient medication self-management ability should be designed for these issues.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024524742.
{"title":"Exploring medication self-management in polypharmacy: a qualitative systematic review of patients and healthcare providers perspectives","authors":"Ran Jin, Caiyan Liu, Jinghao Chen, Mengjiao Cui, Bo Xu, Ping Yuan, Lu Chen","doi":"10.3389/fphar.2024.1426777","DOIUrl":"https://doi.org/10.3389/fphar.2024.1426777","url":null,"abstract":"Purpose: Polypharmacy presents many challenges to patient medication self-management. This study aims to explore the self-management processes of medication in polypharmacy from the perspectives of both patients and healthcare providers, which can help identify barriers and facilitators to effective management.Methods: A systematic review of qualitative studies was performed by searching seven databases: PubMed, Web of Science, Cochrane Library, Embase, CINAHL, PsycINFO, and MEDLINE, from their establishment until August 2024. The Critical Appraisal Skills Programme (CASP) tool was employed to evaluate the quality of the studies included. The extracted data were then analysed thematically and integrated into The Taxonomy of Everyday Self-management Strategies (TEDSS) framework.Results: A total of 16 studies were included, involving 403 patients and 119 healthcare providers. Patient management measures were mapped into TEDSS framework, including categories such as medical management, support-oriented domains and emotional and role management.Conclusion: Enhancing patients’ proactive health awareness, improving medication literacy, balancing lifestyle adjustments with medication therapy, dynamically reviewing and optimizing medications, strengthening patients’ social support networks, and helping patients integrate medication management into their daily life are the key elements that can effectively assist patients in self-managing their medications. Future interventions to improve patient medication self-management ability should be designed for these issues.Systematic Review Registration:<jats:ext-link>https://www.crd.york.ac.uk/PROSPERO/</jats:ext-link>, identifier CRD42024524742.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.3389/fphar.2024.1450493
Frank Pietrantonio, Alex Serreqi, Horst Zerbe, Per Svenningsson, Ludwig Aigner
Multiple Sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system (CNS). It is characterized by a heightened activation of the immune system with ensuing inflammation, demyelination and neurodegeneration with consequences such as motor, sensory, cognitive, as well as autonomic dysfunctions. While a range of immune-modulatory drugs have shown certain efficacy in alleviating pathology and symptoms, none of the currently available therapeutics regenerates the damaged CNS to restore function. There is emerging evidence for leukotrienes and leukotriene receptors being involved in the various aspects of the MS pathology including neuroinflammation and de/remyelination. Moreover, leukotriene receptor antagonists such as the asthma drug montelukast diminish inflammation and promote regeneration/remyelination. Indeed, montelukast has successfully been tested in animal models of MS and a recent retrospective case-control study suggests that montelukast treatment reduces relapses in patients with MS. Therefore, we propose montelukast as a therapeutic adjuvant to the standard immune-modulatory drugs with the potential to reduce pathology and promote structural and functional restoration. Here, we review the current knowledge on MS, its pathology, and on the potential of leukotriene receptor antagonists as therapeutics for MS.
{"title":"The leukotriene receptor antagonist montelukast as a potential therapeutic adjuvant in multiple sclerosis – a review","authors":"Frank Pietrantonio, Alex Serreqi, Horst Zerbe, Per Svenningsson, Ludwig Aigner","doi":"10.3389/fphar.2024.1450493","DOIUrl":"https://doi.org/10.3389/fphar.2024.1450493","url":null,"abstract":"Multiple Sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system (CNS). It is characterized by a heightened activation of the immune system with ensuing inflammation, demyelination and neurodegeneration with consequences such as motor, sensory, cognitive, as well as autonomic dysfunctions. While a range of immune-modulatory drugs have shown certain efficacy in alleviating pathology and symptoms, none of the currently available therapeutics regenerates the damaged CNS to restore function. There is emerging evidence for leukotrienes and leukotriene receptors being involved in the various aspects of the MS pathology including neuroinflammation and de/remyelination. Moreover, leukotriene receptor antagonists such as the asthma drug montelukast diminish inflammation and promote regeneration/remyelination. Indeed, montelukast has successfully been tested in animal models of MS and a recent retrospective case-control study suggests that montelukast treatment reduces relapses in patients with MS. Therefore, we propose montelukast as a therapeutic adjuvant to the standard immune-modulatory drugs with the potential to reduce pathology and promote structural and functional restoration. Here, we review the current knowledge on MS, its pathology, and on the potential of leukotriene receptor antagonists as therapeutics for MS.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tetrandrine (TET) has been traditionally used in China as a medication to treat silicosis and has recently demonstrated anti-SARS-CoV-2 potential in vitro. By recognizing the disparity between in vitro findings and in vivo performance, we aimed to estimate the free lung concentration of TET using a physiologically based pharmacokinetic (PBPK) model to link in vitro activity with in vivo efficacy. Comparative pharmacokinetic studies of TET were performed in rats and dogs to elucidate the pharmacokinetic mechanisms as well as discern interspecies variations. These insights facilitated the creation of an animal-specific PBPK model, which was subsequently translated to a human model following thorough validation. Following validation of the pharmacokinetic profile from a literature report on single oral dosing of TET in humans, the plasma and lung concentrations were predicted after TET administration at approved dosage levels. Finally, the antiviral efficacy of TET in humans was assessed from the free drug concentration in the lungs. Both in vivo and in vitro experiments thus confirmed that the systemic clearance of TET was primarily through hepatic metabolism. Additionally, the lysosomal capture of basic TET was identified as a pivotal factor in its vast distribution volume and heterogeneous tissue distribution, which could modulate the absorption dynamics of TET in the gastrointestinal tract. Notably, the PBPK-model-based unbound lung concentration of TET (1.67–1.74 μg/mL) at the recommended clinical dosage surpassed the in vitro threshold for anti-SARS-CoV-2 activity (EC90 = 1.52 μg/mL). Thus, a PBPK model was successfully developed to bridge the in vitro activity and in vivo target exposure of TET to facilitate its repurposing.
{"title":"Quantitative pulmonary pharmacokinetics of tetrandrine for SARS-CoV-2 repurposing: a physiologically based pharmacokinetic modeling approach","authors":"Furun Wang, Liuhan Dong, Juanwen Hu, Shijie Yang, Lingchao Wang, Zhiwei Zhang, Wenpeng Zhang, Xiaomei Zhuang","doi":"10.3389/fphar.2024.1457983","DOIUrl":"https://doi.org/10.3389/fphar.2024.1457983","url":null,"abstract":"Tetrandrine (TET) has been traditionally used in China as a medication to treat silicosis and has recently demonstrated anti-SARS-CoV-2 potential <jats:italic>in vitro</jats:italic>. By recognizing the disparity between <jats:italic>in vitro</jats:italic> findings and <jats:italic>in vivo</jats:italic> performance, we aimed to estimate the free lung concentration of TET using a physiologically based pharmacokinetic (PBPK) model to link <jats:italic>in vitro</jats:italic> activity with <jats:italic>in vivo</jats:italic> efficacy. Comparative pharmacokinetic studies of TET were performed in rats and dogs to elucidate the pharmacokinetic mechanisms as well as discern interspecies variations. These insights facilitated the creation of an animal-specific PBPK model, which was subsequently translated to a human model following thorough validation. Following validation of the pharmacokinetic profile from a literature report on single oral dosing of TET in humans, the plasma and lung concentrations were predicted after TET administration at approved dosage levels. Finally, the antiviral efficacy of TET in humans was assessed from the free drug concentration in the lungs. Both <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic> experiments thus confirmed that the systemic clearance of TET was primarily through hepatic metabolism. Additionally, the lysosomal capture of basic TET was identified as a pivotal factor in its vast distribution volume and heterogeneous tissue distribution, which could modulate the absorption dynamics of TET in the gastrointestinal tract. Notably, the PBPK-model-based unbound lung concentration of TET (1.67–1.74 μg/mL) at the recommended clinical dosage surpassed the <jats:italic>in vitro</jats:italic> threshold for anti-SARS-CoV-2 activity (EC<jats:sub>90</jats:sub> = 1.52 μg/mL). Thus, a PBPK model was successfully developed to bridge the <jats:italic>in vitro</jats:italic> activity and <jats:italic>in vivo</jats:italic> target exposure of TET to facilitate its repurposing.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundIn response to the rising population of nursing home residents with frailty and multimorbidity, optimizing medication safety through drug utilization review and addressing medication-related problems (MRPs) is imperative. Clinical decision support systems help reduce medication errors and detect potential MRPs, as well as medication reviews performed by a multidisciplinary team, but these combined assessments are not commonly performed. The objective of this study was to evaluate the impact on medication plans of a multidisciplinary team intervention in nursing homes, by analyzing the medication plan before and after the intervention and assessing whether the recommendations given had been implemented.MethodsA multicenter before-after study, involving five nursing homes, assessed the impact of a multidisciplinary team intervention, to estimate effectiveness related to the review of the prescribed medications. The follow-up period for each patient was 12 months or until death if prior, from July 2020 to February 2022, and involved 483 patients. The clinical pharmacologist coordinated the intervention and reviewed all the prescribed medications to make recommendations, focused on the completion of absent data, withdrawal of a drug, verification of whether a drug was adequate, the substitution of a drug, and the addition of drugs. Since the intervention was performed during the COVID-19 pandemic, optimization of psychotropic drugs and absorbent pads were limited.ResultsThe intervention had an impact with recommendations given for 398 (82.4%) of the patients and which were followed by 58.5% of them. At least one drug was withdrawn in 293 (60.7%) of the patients, with a mean of 2.3 (SD 1.7). As for the total of 1,097 recommendations given, 355 (32.4%) were followed. From the intervention, antipsychotics, antidepressants, benzodiazepines, statins, and diuretics were the most frequently withdrawn.ConclusionThe findings underscore the impact of targeted interventions to reduce inappropriate medications and enhance medication safety in nursing homes. The proposed recommendations given and followed show the importance of a multidisciplinary team, coordinated by a clinical pharmacologist, for a patient-centered approach to make medication reviews regularly, with the help of clinical decision support systems, to help reduce potential MRPs and polypharmacy.
{"title":"The impact of a multidisciplinary team intervention on medication prescription in nursing homes in Catalonia","authors":"Emilie Anderssen-Nordahl, Eladio Fernández-Liz, Mònica Sabaté Gallego, Montserrat Bosch Ferrer, Margarita Sánchez-Arcilla Rosanas, Mercè Cervera León, Joaquim Miquel Magrinyà, Maria Estrella Barceló-Colomer","doi":"10.3389/fphar.2024.1445141","DOIUrl":"https://doi.org/10.3389/fphar.2024.1445141","url":null,"abstract":"BackgroundIn response to the rising population of nursing home residents with frailty and multimorbidity, optimizing medication safety through drug utilization review and addressing medication-related problems (MRPs) is imperative. Clinical decision support systems help reduce medication errors and detect potential MRPs, as well as medication reviews performed by a multidisciplinary team, but these combined assessments are not commonly performed. The objective of this study was to evaluate the impact on medication plans of a multidisciplinary team intervention in nursing homes, by analyzing the medication plan before and after the intervention and assessing whether the recommendations given had been implemented.MethodsA multicenter before-after study, involving five nursing homes, assessed the impact of a multidisciplinary team intervention, to estimate effectiveness related to the review of the prescribed medications. The follow-up period for each patient was 12 months or until death if prior, from July 2020 to February 2022, and involved 483 patients. The clinical pharmacologist coordinated the intervention and reviewed all the prescribed medications to make recommendations, focused on the completion of absent data, withdrawal of a drug, verification of whether a drug was adequate, the substitution of a drug, and the addition of drugs. Since the intervention was performed during the COVID-19 pandemic, optimization of psychotropic drugs and absorbent pads were limited.ResultsThe intervention had an impact with recommendations given for 398 (82.4%) of the patients and which were followed by 58.5% of them. At least one drug was withdrawn in 293 (60.7%) of the patients, with a mean of 2.3 (SD 1.7). As for the total of 1,097 recommendations given, 355 (32.4%) were followed. From the intervention, antipsychotics, antidepressants, benzodiazepines, statins, and diuretics were the most frequently withdrawn.ConclusionThe findings underscore the impact of targeted interventions to reduce inappropriate medications and enhance medication safety in nursing homes. The proposed recommendations given and followed show the importance of a multidisciplinary team, coordinated by a clinical pharmacologist, for a patient-centered approach to make medication reviews regularly, with the help of clinical decision support systems, to help reduce potential MRPs and polypharmacy.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1459909
Zih-Ning Huang, Sin-Yi Lee, Jie-Mao Chen, Zih-Ting Huang, Lu-Shiun Her
Introduction: Huntington's disease (HD) is a hereditary neurodegenerative disorder that primarily affects the striatum, a brain region responsible for movement control. The disease is characterized by the mutant huntingtin (mHtt) proteins with an extended polyQ stretch, which are prone to aggregation. These mHtt aggregates accumulate in neurons and are the primary cause of the neuropathology associated with HD. To date, no effective cure for HD has been developed.
Methods: The immortalized STHdhQ111/Q111 striatal cell line, the mHtt-transfected wild-type STHdhQ7/Q7 striatal cell line, and N2a cells were used as Huntington's disease cell models. Flow cytometry was used to assess cellular reactive oxygen species and transfection efficiency. The CCK-8 assay was used to measure cell viability, while fluorescence microscopy was used to quantify aggregates. Immunoblotting analyses were used to evaluate the effects on protein expression.
Results: Polyphenols are natural antioxidants that offer neuroprotection in neurological disorders. In this study, we provide evidence that oleuropein, the primary polyphenol in olive leaves and olive oil, enhances cell viability in HD cell models, including. STHdhQ7/Q7 STHdhQ7/Q7 striatal cells, N2a cells ectopically expressing the truncated mHtt, and STHdhQ111/Q111 striatal cells expressing the full-length mHtt. Oleuropein effectively reduced both soluble and aggregated forms of mHtt protein in these HD model cells. Notably, the reduction of mHtt aggregates associated with oleuropein was linked to increased proteasome activity rather than changes in autophagic flux. Oleuropein seems to modulate proteasome activity through an unidentified pathway, as it did not affect the 20S proteasome catalytic β subunits, the proteasome regulator PA28γ, or multiple MAPK pathways.
Discussion: We demonstrated that oleuropein enhances the degradation of mHtt by increasing proteasomal protease activities and alleviates mHtt-induced cytotoxicity. Hence, we propose that oleuropein and potentially other polyphenols hold promise as a candidate for alleviating Huntington's disease.
{"title":"Oleuropein enhances proteasomal activity and reduces mutant huntingtin-induced cytotoxicity.","authors":"Zih-Ning Huang, Sin-Yi Lee, Jie-Mao Chen, Zih-Ting Huang, Lu-Shiun Her","doi":"10.3389/fphar.2024.1459909","DOIUrl":"10.3389/fphar.2024.1459909","url":null,"abstract":"<p><strong>Introduction: </strong>Huntington's disease (HD) is a hereditary neurodegenerative disorder that primarily affects the striatum, a brain region responsible for movement control. The disease is characterized by the mutant huntingtin (mHtt) proteins with an extended polyQ stretch, which are prone to aggregation. These mHtt aggregates accumulate in neurons and are the primary cause of the neuropathology associated with HD. To date, no effective cure for HD has been developed.</p><p><strong>Methods: </strong>The immortalized ST<i>Hdh</i> <sup><i>Q111/Q111</i></sup> striatal cell line, the mHtt-transfected wild-type ST<i>Hdh</i> <sup><i>Q7/Q7</i></sup> striatal cell line, and N2a cells were used as Huntington's disease cell models. Flow cytometry was used to assess cellular reactive oxygen species and transfection efficiency. The CCK-8 assay was used to measure cell viability, while fluorescence microscopy was used to quantify aggregates. Immunoblotting analyses were used to evaluate the effects on protein expression.</p><p><strong>Results: </strong>Polyphenols are natural antioxidants that offer neuroprotection in neurological disorders. In this study, we provide evidence that oleuropein, the primary polyphenol in olive leaves and olive oil, enhances cell viability in HD cell models, including. ST<i>Hdh</i> <sup><i>Q7/Q7</i></sup> ST<i>Hdh</i> <sup><i>Q7/Q7</i></sup> striatal cells, N2a cells ectopically expressing the truncated mHtt, and ST<i>Hdh</i> <sup><i>Q111/Q111</i></sup> striatal cells expressing the full-length mHtt. Oleuropein effectively reduced both soluble and aggregated forms of mHtt protein in these HD model cells. Notably, the reduction of mHtt aggregates associated with oleuropein was linked to increased proteasome activity rather than changes in autophagic flux. Oleuropein seems to modulate proteasome activity through an unidentified pathway, as it did not affect the 20S proteasome catalytic β subunits, the proteasome regulator PA28γ, or multiple MAPK pathways.</p><p><strong>Discussion: </strong>We demonstrated that oleuropein enhances the degradation of mHtt by increasing proteasomal protease activities and alleviates mHtt-induced cytotoxicity. Hence, we propose that oleuropein and potentially other polyphenols hold promise as a candidate for alleviating Huntington's disease.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11440197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundCINV is a frequent adverse response to cancer treatment. There is still much to learn about the pathophysiology and initiating event of CINV, which necessitates continued research despite decades of effort. Identifying the current foci of the complex disease and assessing the scientific impact of pertinent study are made more difficult by the abundance of publications on CINV. Therefore, our goals in this article are to evaluate developments in this field, examine patterns in research domains, and gauge the expansion of CINV research production globally.MethodsArticles about CINV published between 2012 and 2022 were found by searching the Web of Science Core Collection of Clarivate Analytics. The number of publications over time was visualized using Microsoft Office Excel 2019. CiteSpace and VOSviewer were utilized to create knowledge maps that analyzed collaborations between nations, organizations, and writers. They also presented the history of CINV research and highlighted its current areas of focus.ResultsIn this study, 846 papers in all were assessed. Most publications (237, 28.01%) came from the United States. University of Toronto was the most productive institution (34, 4.01%). With 25 articles published, or 2.96% of the total, Aapro Matti published the most. The most frequently published journal was found to be Supportive Care (158, 18.68%). “Palonosetron,” “Moderately emetogenic chemotherapy,” “5-HT3 receptor antagonist,” and “Neurokinin 1 receptor antagonists” were considered the hot topics. It can be seen that the research focus is on the drug treatment of chemotherapy-induced nausea and vomiting.ConclusionThrough bibliometric analysis, we were able to gain profound insights into CINV research for the first time. Researchers looking to uncover research frontiers and comprehend important information in this discipline may find the study’s findings useful.
{"title":"Research trends on chemotherapy induced nausea and vomiting: a bibliometric analysis","authors":"Chunhui Ning, Yunzi Yan, Yansong Wang, Rui Li, Wenjie Liu, Linjie Qiu, Lingyun Sun, Yufei Yang","doi":"10.3389/fphar.2024.1369442","DOIUrl":"https://doi.org/10.3389/fphar.2024.1369442","url":null,"abstract":"BackgroundCINV is a frequent adverse response to cancer treatment. There is still much to learn about the pathophysiology and initiating event of CINV, which necessitates continued research despite decades of effort. Identifying the current foci of the complex disease and assessing the scientific impact of pertinent study are made more difficult by the abundance of publications on CINV. Therefore, our goals in this article are to evaluate developments in this field, examine patterns in research domains, and gauge the expansion of CINV research production globally.MethodsArticles about CINV published between 2012 and 2022 were found by searching the Web of Science Core Collection of Clarivate Analytics. The number of publications over time was visualized using Microsoft Office Excel 2019. CiteSpace and VOSviewer were utilized to create knowledge maps that analyzed collaborations between nations, organizations, and writers. They also presented the history of CINV research and highlighted its current areas of focus.ResultsIn this study, 846 papers in all were assessed. Most publications (237, 28.01%) came from the United States. University of Toronto was the most productive institution (34, 4.01%). With 25 articles published, or 2.96% of the total, Aapro Matti published the most. The most frequently published journal was found to be Supportive Care (158, 18.68%). “Palonosetron,” “Moderately emetogenic chemotherapy,” “5-HT3 receptor antagonist,” and “Neurokinin 1 receptor antagonists” were considered the hot topics. It can be seen that the research focus is on the drug treatment of chemotherapy-induced nausea and vomiting.ConclusionThrough bibliometric analysis, we were able to gain profound insights into CINV research for the first time. Researchers looking to uncover research frontiers and comprehend important information in this discipline may find the study’s findings useful.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fphar.2024.1474868
Kun Zhang, Shanshan Zhao, Jialin Du, Lan Zhang
BackgroundParkinson’s disease psychosis (PDP) is a common and distressing complication of Parkinson’s disease (PD), characterized by hallucinations and delusions. This research aimed to assess the pharmacokinetics and safety of NH130, a selective serotonin 5-HT2A inverse agonist, as a potential PDP treatment in healthy individuals.MethodsWe conducted clinical pharmacokinetic studies and safety evaluations for NH130, employing a physiologically based pharmacokinetic (PBPK) model to predict its behavior in human body.ResultsIn a single-dose escalation study, healthy volunteers received NH130 at varying doses (2 mg, 6 mg, 12 mg, 24 mg, 40 mg, 60 mg, and 90 mg) or a placebo. The drug demonstrated favorable pharmacokinetics, with no serious adverse events (AEs) reported. Clinical plasma concentrations correlated well with PBPK model predictions, validating the model’s utility for guiding future clinical development.ConclusionNH130 showed promising pharmacokinetic characteristics and safety profile, supporting its progression to multi-dose trials and suggesting its potential as a therapeutic agent for PDP.Clinical Trial Registrationhttp://www.chinadrugtrials.org.cn/index.html, Identifier CTR20230409.
{"title":"Phase I clinical trial of NH130 and the prediction of its pharmacokinetics using physiologically based pharmacokinetic modeling","authors":"Kun Zhang, Shanshan Zhao, Jialin Du, Lan Zhang","doi":"10.3389/fphar.2024.1474868","DOIUrl":"https://doi.org/10.3389/fphar.2024.1474868","url":null,"abstract":"BackgroundParkinson’s disease psychosis (PDP) is a common and distressing complication of Parkinson’s disease (PD), characterized by hallucinations and delusions. This research aimed to assess the pharmacokinetics and safety of NH130, a selective serotonin 5-HT<jats:sub>2A</jats:sub> inverse agonist, as a potential PDP treatment in healthy individuals.MethodsWe conducted clinical pharmacokinetic studies and safety evaluations for NH130, employing a physiologically based pharmacokinetic (PBPK) model to predict its behavior in human body.ResultsIn a single-dose escalation study, healthy volunteers received NH130 at varying doses (2 mg, 6 mg, 12 mg, 24 mg, 40 mg, 60 mg, and 90 mg) or a placebo. The drug demonstrated favorable pharmacokinetics, with no serious adverse events (AEs) reported. Clinical plasma concentrations correlated well with PBPK model predictions, validating the model’s utility for guiding future clinical development.ConclusionNH130 showed promising pharmacokinetic characteristics and safety profile, supporting its progression to multi-dose trials and suggesting its potential as a therapeutic agent for PDP.Clinical Trial Registration<jats:ext-link>http://www.chinadrugtrials.org.cn/index.html</jats:ext-link>, Identifier CTR20230409.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundTeduglutide, the first glucagon-like peptide 2 analogue, has been demonstrated to facilitate the absorption of gut nutrient and lessen the need for parenteral assistance in patients with Short Bowel Syndrome (SBS). However, its adverse drug events (AEs) are primarily documented in clinical trials, with a deficit in real-world data. This study evaluates the AEs profile of teduglutide based on Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data.MethodA disproportionality analysis of FAERS data from Quarter 1 (Q1) 2013 to Quarter 3 (Q3) 2023 was conducted to examine the association between teduglutide and adverse events, employing Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) methods.ResultsOut of 13,809,302 reports in the FAERS database, 10,114 reports identified teduglutide as the “primary suspect” in AEs identification. During the dosing observation period, the median occurrence of adverse events was 393 days (interquartile range [IQR] 97–996 days). Teduglutide-associated AEs occurred in 27 System Organ Classes (SOC), of which renal and urinary disorders is not mentioned in the specification. Based on the four algorithms, a total of 260 major disproportionality preferred terms (PTs) were filtered out, including previously unreported AEs including weight decreased (n = 805), vascular device infection (n = 683), dehydration (n = 596) and nephrolithiasis (n = 146).ConclusionOur findings corroborate the AEs listed in the teduglutide prescribing information and additionally unveil new adverse reaction signals such as nephrolithiasis. These discoveries could aid in clinical monitoring and risk identification for teduglutide.
{"title":"The real-world analysis of adverse events with teduglutide: a pharmacovigilance study based on the FAERS database","authors":"Xiaogan Wang, Hao Chen, Shuangshuang Han, Lingbo Li, Hongjin Chen, Bolin Yang","doi":"10.3389/fphar.2024.1404658","DOIUrl":"https://doi.org/10.3389/fphar.2024.1404658","url":null,"abstract":"BackgroundTeduglutide, the first glucagon-like peptide 2 analogue, has been demonstrated to facilitate the absorption of gut nutrient and lessen the need for parenteral assistance in patients with Short Bowel Syndrome (SBS). However, its adverse drug events (AEs) are primarily documented in clinical trials, with a deficit in real-world data. This study evaluates the AEs profile of teduglutide based on Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data.MethodA disproportionality analysis of FAERS data from Quarter 1 (Q1) 2013 to Quarter 3 (Q3) 2023 was conducted to examine the association between teduglutide and adverse events, employing Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) methods.ResultsOut of 13,809,302 reports in the FAERS database, 10,114 reports identified teduglutide as the “primary suspect” in AEs identification. During the dosing observation period, the median occurrence of adverse events was 393 days (interquartile range [IQR] 97–996 days). Teduglutide-associated AEs occurred in 27 System Organ Classes (SOC), of which renal and urinary disorders is not mentioned in the specification. Based on the four algorithms, a total of 260 major disproportionality preferred terms (PTs) were filtered out, including previously unreported AEs including weight decreased (n = 805), vascular device infection (n = 683), dehydration (n = 596) and nephrolithiasis (n = 146).ConclusionOur findings corroborate the AEs listed in the teduglutide prescribing information and additionally unveil new adverse reaction signals such as nephrolithiasis. These discoveries could aid in clinical monitoring and risk identification for teduglutide.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.3389/fphar.2024.1472771
Venkata Kiran Kumar Mandlem, Ana Rivera, Zaina Khan, Sohel H. Quazi, Farah Deba
Ion channels play an important role in mediating pain through signal transduction, regulation, and control of responses, particularly in neuropathic pain. Transient receptor potential channel superfamily plays an important role in cation permeability and cellular signaling. Transient receptor potential channel Melastatin 2 (TRPM2) subfamily regulates Ca2+ concentration in response to various chemicals and signals from the surrounding environment. TRPM2 has a role in several physiological functions such as cellular osmosis, temperature sensing, cellular proliferation, as well as the manifestation of many disease processes such as pain process, cancer, apoptosis, endothelial dysfunction, angiogenesis, renal and lung fibrosis, and cerebral ischemic stroke. Toll-like Receptor 4 (TLR4) is a critical initiator of the immune response to inflammatory stimuli, particularly those triggered by Lipopolysaccharide (LPS). It activates downstream pathways leading to the production of oxidative molecules and inflammatory cytokines, which are modulated by basal and store-operated calcium ion signaling. The cytokine production and release cause an imbalance of antioxidant enzymes and redox potential in the Endoplasmic Reticulum and mitochondria due to oxidative stress, which results from TLR-4 activation and consequently induces the production of inflammatory cytokines in neuronal cells, exacerbating the pain process. Very few studies have reported the role of TRPM2 and its association with Toll-like receptors in the context of neuropathic pain. However, the molecular mechanism underlying the interaction between TRPM2 and TLR-4 and the quantum of impact in acute and chronic neuropathic pain remains unclear. Understanding the link between TLR-4 and TRPM2 will provide more insights into pain regulation mechanisms for the development of new therapeutic molecules to address neuropathic pain.
{"title":"TLR4 induced TRPM2 mediated neuropathic pain","authors":"Venkata Kiran Kumar Mandlem, Ana Rivera, Zaina Khan, Sohel H. Quazi, Farah Deba","doi":"10.3389/fphar.2024.1472771","DOIUrl":"https://doi.org/10.3389/fphar.2024.1472771","url":null,"abstract":"Ion channels play an important role in mediating pain through signal transduction, regulation, and control of responses, particularly in neuropathic pain. Transient receptor potential channel superfamily plays an important role in cation permeability and cellular signaling. Transient receptor potential channel Melastatin 2 (TRPM2) subfamily regulates Ca<jats:sup>2+</jats:sup> concentration in response to various chemicals and signals from the surrounding environment. TRPM2 has a role in several physiological functions such as cellular osmosis, temperature sensing, cellular proliferation, as well as the manifestation of many disease processes such as pain process, cancer, apoptosis, endothelial dysfunction, angiogenesis, renal and lung fibrosis, and cerebral ischemic stroke. Toll-like Receptor 4 (TLR4) is a critical initiator of the immune response to inflammatory stimuli, particularly those triggered by Lipopolysaccharide (LPS). It activates downstream pathways leading to the production of oxidative molecules and inflammatory cytokines, which are modulated by basal and store-operated calcium ion signaling. The cytokine production and release cause an imbalance of antioxidant enzymes and redox potential in the Endoplasmic Reticulum and mitochondria due to oxidative stress, which results from TLR-4 activation and consequently induces the production of inflammatory cytokines in neuronal cells, exacerbating the pain process. Very few studies have reported the role of TRPM2 and its association with Toll-like receptors in the context of neuropathic pain. However, the molecular mechanism underlying the interaction between TRPM2 and TLR-4 and the quantum of impact in acute and chronic neuropathic pain remains unclear. Understanding the link between TLR-4 and TRPM2 will provide more insights into pain regulation mechanisms for the development of new therapeutic molecules to address neuropathic pain.","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：