Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1445979
Saibin Wang, Qian Ye
Background: The impact of glucocorticoid use on mortality risk in pneumonia patients remains unclear. This study aimed to investigate the relationship between the accumulated dose of glucocorticoids (ADG) and secondary pneumonia mortality risk among patients receiving oral or intravenous glucocorticoids.
Methods: Data from the DRYAD database were analyzed, covering pneumonia patients from six academic hospitals over a 5-year period who had been administered oral or intravenous glucocorticoids. Piecewise linear regression and multivariate regression analysis were utilized to assess the association between ADG and mortality risk in pneumonia patients, while adjusting for potential confounders.
Results: Among the 628 pneumonia patients included, the 30-day mortality rate was 23.1% and the 90-day mortality rate was 26.4%. In the high-dose glucocorticoid group (≥24 mg/day of methylprednisolone or an equivalent glucocorticoid within 30 days before admission), the 30-day and 90-day mortality rates were 31.2% and 35.9%, respectively. Piecewise linear regression analysis demonstrated a non-linear relationship between ADG and mortality risk in pneumonia patients. Multivariate regression analysis revealed a significantly lower mortality risk in patients receiving an ADG of 20-39 g methylprednisolone compared to those receiving lower (<20 g) or higher doses (≥40 g), after adjusting for potential confounding factors. Additionally, in the high-dose glucocorticoid group, surpassing the inflection point of 20 g of methylprednisolone raised the 30-day and 90-day mortality risks (adjusted odds ratio, 95% confidence interval: 1.16, 1.03-1.30 and 1.23, 1.07-1.42, respectively). Notably, this threshold effect was observed exclusively in male patients.
Conclusion: This study provides evidence supporting a potential threshold effect between ADG and mortality risk in oral or intravenous glucocorticoid users with secondary pneumonia. Specifically, male patients receiving high-dose glucocorticoids should undergo close monitoring when the ADG of methylprednisolone exceeds 20 g, as it may be associated with an elevated risk of mortality.
{"title":"The glucocorticoid dose-mortality nexus in pneumonia patients: unveiling the threshold effect.","authors":"Saibin Wang, Qian Ye","doi":"10.3389/fphar.2024.1445979","DOIUrl":"10.3389/fphar.2024.1445979","url":null,"abstract":"<p><strong>Background: </strong>The impact of glucocorticoid use on mortality risk in pneumonia patients remains unclear. This study aimed to investigate the relationship between the accumulated dose of glucocorticoids (ADG) and secondary pneumonia mortality risk among patients receiving oral or intravenous glucocorticoids.</p><p><strong>Methods: </strong>Data from the DRYAD database were analyzed, covering pneumonia patients from six academic hospitals over a 5-year period who had been administered oral or intravenous glucocorticoids. Piecewise linear regression and multivariate regression analysis were utilized to assess the association between ADG and mortality risk in pneumonia patients, while adjusting for potential confounders.</p><p><strong>Results: </strong>Among the 628 pneumonia patients included, the 30-day mortality rate was 23.1% and the 90-day mortality rate was 26.4%. In the high-dose glucocorticoid group (≥24 mg/day of methylprednisolone or an equivalent glucocorticoid within 30 days before admission), the 30-day and 90-day mortality rates were 31.2% and 35.9%, respectively. Piecewise linear regression analysis demonstrated a non-linear relationship between ADG and mortality risk in pneumonia patients. Multivariate regression analysis revealed a significantly lower mortality risk in patients receiving an ADG of 20-39 g methylprednisolone compared to those receiving lower (<20 g) or higher doses (≥40 g), after adjusting for potential confounding factors. Additionally, in the high-dose glucocorticoid group, surpassing the inflection point of 20 g of methylprednisolone raised the 30-day and 90-day mortality risks (adjusted odds ratio, 95% confidence interval: 1.16, 1.03-1.30 and 1.23, 1.07-1.42, respectively). Notably, this threshold effect was observed exclusively in male patients.</p><p><strong>Conclusion: </strong>This study provides evidence supporting a potential threshold effect between ADG and mortality risk in oral or intravenous glucocorticoid users with secondary pneumonia. Specifically, male patients receiving high-dose glucocorticoids should undergo close monitoring when the ADG of methylprednisolone exceeds 20 g, as it may be associated with an elevated risk of mortality.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371449","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}
Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH's terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%-1%. The incidence of peripheral neuropathy is 2%-6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.
{"title":"Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement.","authors":"Jishnu Sankar, Anjali Chauhan, Ramandeep Singh, Dinesh Mahajan","doi":"10.3389/fphar.2024.1441147","DOIUrl":"10.3389/fphar.2024.1441147","url":null,"abstract":"<p><p>Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is <i>in vivo</i> metabolism involving biotransformation on its terminal -NH<sub>2</sub> group owing to its high nucleophilic nature. The human <i>N-acetyltransferase-2</i> enzyme (NAT-2) exploits the reactivity of INH's terminal -NH<sub>2</sub> functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH<sub>2</sub> group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%-1%. The incidence of peripheral neuropathy is 2%-6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH<sub>2</sub> group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371545","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1456565
Beatriz Fernández-Alarcón, Oscar Nolberger, Anna Vidal-Alabró, Raul Rigo-Bonnin, Josep M Grinyó, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alex Favà, Sergi Codina, Josep M Cruzado, Helena Colom, Nuria Lloberas
Aims: The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period.
Methods: A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24 h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5.
Results: A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60 years and younger.
Conclusion: The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60 years or younger would be highest, while CYP3A5*/1 non-carriers older than 60 years would require the lowest doses.
{"title":"Guiding the starting dose of the once-daily formulation of tacrolimus in \"<i>de novo\"</i> adult renal transplant patients: a population approach.","authors":"Beatriz Fernández-Alarcón, Oscar Nolberger, Anna Vidal-Alabró, Raul Rigo-Bonnin, Josep M Grinyó, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alex Favà, Sergi Codina, Josep M Cruzado, Helena Colom, Nuria Lloberas","doi":"10.3389/fphar.2024.1456565","DOIUrl":"10.3389/fphar.2024.1456565","url":null,"abstract":"<p><strong>Aims: </strong>The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in <i>de novo</i> kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in <i>de novo</i> adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period.</p><p><strong>Methods: </strong>A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24 h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5.</p><p><strong>Results: </strong>A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (<i>p</i> < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (<i>p</i> < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5<i>*1</i> carriers was 51% higher than that of CYP3A5<i>*1</i> non-carriers. Age also influenced CL/F variability (<i>p</i> < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60 years and younger.</p><p><strong>Conclusion: </strong>The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5<i>*/1</i> carriers in patients aged 60 years or younger would be highest, while CYP3A5<i>*/1</i> non-carriers older than 60 years would require the lowest doses.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371543","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1422363
Ahmed Attia Ahmed Abdelmoaty, Jing Chen, Kun Zhang, Changhui Wu, Ye Li, Peng Li, Jianhua Xu
Background: Ganoderma lucidum (G. lucidum) is a famous medicinal mushroom that has been reported to prevent and treat a variety of diseases. Different extractions from G. lucidum have been used to manage age-related diseases, including cancer. Nevertheless, the senolytic activity of G. lucidum against senescent cancer cells has not been investigated. Although cellular senescence causes tumor growth inhibition, senescent cells promote the growth of the neighboring tumor cells through paracrine effects. Therefore, the elimination of senescent cells is a new strategy for cancer treatment.
Methods: In this study, senescence was triggered in HCC cells by the chemotherapeutic agent Adriamycin (ADR), and subsequently, cells were treated with TC to assess its senolytic activity.
Results: We found for the first time that the triterpenoid complex (TC) from G. lucidum had senolytic effect, which could selectively eliminate adriamycin (ADR)-induced senescent cells (SCs) of hepatocellular carcinoma (HCC) cells via caspase-dependent and mitochondrial pathways-mediated apoptosis and reduce the levels of senescence markers, thereby inhibiting the progression of cancers caused by SCs. TC could block autophagy at the late stage in SCs, resulting in a significant activation of TC-induced apoptosis. Furthermore, TC inhibited the senescence-associated secretory phenotype (SASP) in SCs through the inhibition of NF-κB, TFEB, P38, ERK, and mTOR signaling pathways and reducing the number of SCs. Sequential administration of ADR and TC in vivo significantly reduced tumor growth and reversed the toxicity of ADR.
Conclusion: A triterpenoid complex isolated from G. lucidum may serve as a novel senolytic agent against SCs, and its combination with chemotherapeutic agents may enhance their antitumor efficacy.
{"title":"Senolytic effect of triterpenoid complex from <i>Ganoderma lucidum</i> on adriamycin-induced senescent human hepatocellular carcinoma cells model <i>in vitro</i> and <i>in vivo</i>.","authors":"Ahmed Attia Ahmed Abdelmoaty, Jing Chen, Kun Zhang, Changhui Wu, Ye Li, Peng Li, Jianhua Xu","doi":"10.3389/fphar.2024.1422363","DOIUrl":"10.3389/fphar.2024.1422363","url":null,"abstract":"<p><strong>Background: </strong><i>Ganoderma lucidum</i> (<i>G. lucidum</i>) is a famous medicinal mushroom that has been reported to prevent and treat a variety of diseases. Different extractions from <i>G. lucidum</i> have been used to manage age-related diseases, including cancer. Nevertheless, the senolytic activity of <i>G. lucidum</i> against senescent cancer cells has not been investigated. Although cellular senescence causes tumor growth inhibition, senescent cells promote the growth of the neighboring tumor cells through paracrine effects. Therefore, the elimination of senescent cells is a new strategy for cancer treatment.</p><p><strong>Methods: </strong>In this study, senescence was triggered in HCC cells by the chemotherapeutic agent Adriamycin (ADR), and subsequently, cells were treated with TC to assess its senolytic activity.</p><p><strong>Results: </strong>We found for the first time that the triterpenoid complex (TC) from <i>G. lucidum</i> had senolytic effect, which could selectively eliminate adriamycin (ADR)-induced senescent cells (SCs) of hepatocellular carcinoma (HCC) cells via caspase-dependent and mitochondrial pathways-mediated apoptosis and reduce the levels of senescence markers, thereby inhibiting the progression of cancers caused by SCs. TC could block autophagy at the late stage in SCs, resulting in a significant activation of TC-induced apoptosis. Furthermore, TC inhibited the senescence-associated secretory phenotype (SASP) in SCs through the inhibition of NF-κB, TFEB, P38, ERK, and mTOR signaling pathways and reducing the number of SCs. Sequential administration of ADR and TC <i>in vivo</i> significantly reduced tumor growth and reversed the toxicity of ADR.</p><p><strong>Conclusion: </strong>A triterpenoid complex isolated from <i>G. lucidum</i> may serve as a novel senolytic agent against SCs, and its combination with chemotherapeutic agents may enhance their antitumor efficacy.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371548","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}
Background: Gastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from Nelumbo nucifera Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism.
Methods: ISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, in vitro tests were used to establish the impact of ISO on GC cells.
Results: Through bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-β-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-β-triggered migration, invasion, and activation of the TGF-β-Smad pathway.
Conclusion: Our research suggests that ISO specifically targets TGFBR1 and regulates the TGF-β-Smad signaling pathway to suppress the proliferation and migration of GC cells.
背景:胃癌(GC)是全球发病率排名第五的癌症,其明显的侵袭性和扩散倾向给治疗带来了巨大挑战。目前,还没有治疗胃癌患者的有效药物。Isoliensinine (ISO) 是一种双苄基异喹啉生物碱,从 Nelumbo nucifera Gaertn 中分离出来。它具有抗肿瘤、抗氧化和其他生理作用。然而,目前还没有关于 ISO 对 GC 影响的研究,需要进一步研究以了解其分子机制:方法:确定了 ISO 靶点和 GC 相关基因,并获得了 ISO 和 GC 的交叉靶点。然后,我们研究了交叉靶点,并发现了在 GC 中差异表达的基因。我们利用Kaplan-Meier生存曲线筛选靶基因,并利用STRING数据库和Cytoscape 3.9.1构建了蛋白质-蛋白质相互作用和药物-靶点网络。此外,分子对接研究证实了 ISO 筛选靶标之间的相互作用。最后,通过体外试验确定了 ISO 对 GC 细胞的影响:通过生物信息学研究,我们发现 TGFBR1 是 ISO 在 GC 中的靶点。结果:通过生物信息学研究,我们确定了 TGFBR1 是 ISO 在 GC 中的靶点。此外,我们还发现 ISO 处理后,GC 细胞的增殖、迁移和侵袭活动受到了极大的抑制。此外,我们还发现 ISO 治疗能有效抑制 TGF-β 诱导的上皮-间质转化(EMT)和 TGF-β-Smad 通路的激活。此外,我们还发现 siTGFBR1 使 ISO 对 TGF-β 诱导的迁移、侵袭和 TGF-β-Smad 通路激活的影响无效:我们的研究表明,ISO能特异性靶向TGFBR1并调节TGF-β-Smad信号通路,从而抑制GC细胞的增殖和迁移。
{"title":"Isoliensinine suppressed gastric cancer cell proliferation and migration by targeting TGFBR1 to regulate TGF-β-smad signaling pathways.","authors":"Jinda Hu, Shangming Dai, Mengqin Yuan, Fengjiao Li, Shuoguo Xu, Lichen Gao","doi":"10.3389/fphar.2024.1438161","DOIUrl":"10.3389/fphar.2024.1438161","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) ranks as the fifth most prevalent cancer globally, and its pronounced invasiveness and propensity to spread provide significant challenges for therapy. At present, there are no efficacious medications available for the treatment of patients with GC. Isoliensinine (ISO), a bisbenzylisoquinoline alkaloid, was isolated from <i>Nelumbo nucifera</i> Gaertn. It possesses anti-tumor, antioxidant, and other physiological effects. Nevertheless, there is currently no available study on the impact of ISO on GC, and further investigation is needed to understand its molecular mechanism.</p><p><strong>Methods: </strong>ISO target points and GC-related genes were identified, and the cross-target points of ISO and GC were obtained. We then examined cross-targeting and found genes that were differentially expressed in GCs. Kaplan-Meier survival curves were used to screen target genes, and the STRING database and Cytoscape 3.9.1 were used to construct protein-protein interactions and drug-target networks. In addition, molecular docking studies confirmed the interactions between ISO screen targets. Finally, <i>in vitro</i> tests were used to establish the impact of ISO on GC cells.</p><p><strong>Results: </strong>Through bioinformatics research, we have identified TGFBR1 as the target of ISO in GC. In addition, we noticed a substantial inhibition in GC cell proliferation, migration, and invasion activities following ISO treatment. Moreover, we noticed that ISO treatment effectively suppressed TGF-β-induced epithelial-mesenchymal transition (EMT) and activation of the TGF-β-Smad pathway. Furthermore, we discovered that siTGFBR1 nullified the impact of ISO on TGF-β-triggered migration, invasion, and activation of the TGF-β-Smad pathway.</p><p><strong>Conclusion: </strong>Our research suggests that ISO specifically targets TGFBR1 and regulates the TGF-β-Smad signaling pathway to suppress the proliferation and migration of GC cells.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371544","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1447324
F J Esplugues, I Andújar, J V Esplugues
Introduction: Pharmaceutical spending accounts for a significant portion of public healthcare budgets. To manage these costs, EU countries implement various cost-containment policies, including competitive tendering for pharmaceuticals. This study examines the impact of EU public procurement regulations on medication procurement practices.
Methods: A search for all published tenders of adalimumab in Spain from 2018 to 2024 in the Spanish Public Sector Procurement Database, a period that coincides with the implementation of European legislation and the emergence of adalimumab biosimilars. All available documentation for each tender was reviewed, including the tender offer, technical specifications, specific administrative clauses, appointments of evaluation commissions, supporting memorandum, and evaluation reports.
Results and discussion: Our findings reveal substantial price reductions following the introduction of adalimumab biosimilars, yet highlight significant variability in tender criteria and practices across different regions. Despite adherence to EU directives, the inconsistent application of economic and non-economic factors and an erratic criteria concerning price undermine the intended balance of quality and cost, complicating procurement processes and potentially affecting the availability of a given treatment for patients.
{"title":"The impact of EU public procurement regulations on tenders in Spain: a study with adalimumab.","authors":"F J Esplugues, I Andújar, J V Esplugues","doi":"10.3389/fphar.2024.1447324","DOIUrl":"10.3389/fphar.2024.1447324","url":null,"abstract":"<p><strong>Introduction: </strong>Pharmaceutical spending accounts for a significant portion of public healthcare budgets. To manage these costs, EU countries implement various cost-containment policies, including competitive tendering for pharmaceuticals. This study examines the impact of EU public procurement regulations on medication procurement practices.</p><p><strong>Methods: </strong>A search for all published tenders of adalimumab in Spain from 2018 to 2024 in the Spanish Public Sector Procurement Database, a period that coincides with the implementation of European legislation and the emergence of adalimumab biosimilars. All available documentation for each tender was reviewed, including the tender offer, technical specifications, specific administrative clauses, appointments of evaluation commissions, supporting memorandum, and evaluation reports.</p><p><strong>Results and discussion: </strong>Our findings reveal substantial price reductions following the introduction of adalimumab biosimilars, yet highlight significant variability in tender criteria and practices across different regions. Despite adherence to EU directives, the inconsistent application of economic and non-economic factors and an erratic criteria concerning price undermine the intended balance of quality and cost, complicating procurement processes and potentially affecting the availability of a given treatment for patients.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371450","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1459683
Zhipeng Jiang, Wen Luo, Zongmin Long, Jie Chen
Chronic prostatitis is a prevalent male urinary system disorder characterized by pelvic discomfort or pain, bladder dysfunction, sexual dysfunction, and infertility. Pain and lower urinary tract symptoms (LUTS) are the most common symptoms, significantly impacting patients' quality of life and driving them to seek medical attention. Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective calcium ion-dependent cation channel in the TRPV channel family that is widely distributed in neural tissue and plays a role in signal transmission. In this review, we provide a comprehensive overview of the current understanding of the role of TRPV1 in chronic prostatitis. The discussion focuses on the connection between TRPV1 and prostatitis pain and LUTS, and highlights the potential for targeting this channel in the development of novel treatment strategies.
{"title":"The role of TRPV1 in chronic prostatitis: a review.","authors":"Zhipeng Jiang, Wen Luo, Zongmin Long, Jie Chen","doi":"10.3389/fphar.2024.1459683","DOIUrl":"10.3389/fphar.2024.1459683","url":null,"abstract":"<p><p>Chronic prostatitis is a prevalent male urinary system disorder characterized by pelvic discomfort or pain, bladder dysfunction, sexual dysfunction, and infertility. Pain and lower urinary tract symptoms (LUTS) are the most common symptoms, significantly impacting patients' quality of life and driving them to seek medical attention. Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective calcium ion-dependent cation channel in the TRPV channel family that is widely distributed in neural tissue and plays a role in signal transmission. In this review, we provide a comprehensive overview of the current understanding of the role of TRPV1 in chronic prostatitis. The discussion focuses on the connection between TRPV1 and prostatitis pain and LUTS, and highlights the potential for targeting this channel in the development of novel treatment strategies.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371451","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1418609
Chang Ge, Liuyin Jin, Jing-Jing Tian, Na Yang, Jian Xu
Background: Epilepsy is a chronic neurological condition requiring effective management with minimal adverse effects. Lacosamide (LCM) and Perampanel (PER), two promising treatments, have distinct profiles that merit comparative analysis to guide clinical decision-making.
Methods: This study utilizes a pharmacovigilance analysis of adverse events reported in the FDA Adverse Event Reporting System database from Q1 2009 to Q3 2023. Employing disproportionality and Bayesian analyses, we assessed and compared the AE signals associated with LCM and PER to elucidate their safety profiles in epilepsy treatment.
Results: The analysis included 12,576 AE reports for LCM and 2,703 for PER, highlighting a higher incidence of psychiatric disorders, including aggression with LCM, and a notable association of PER with psychiatric disorders such as psychotic disorders and dizziness. LCM showed a relatively safe profile during pregnancy, whereas PER's data suggested caution due to reported cases of suicidal ideation and attempts.
Conclusion: This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of LCM and PER in clinical practice, providing valuable insights for personalized epilepsy management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events.
背景:癫痫是一种慢性神经系统疾病,需要有效的治疗和最小的不良反应。拉科萨胺(Lacosamide,LCM)和培南帕尼(Perampanel,PER)是两种很有前景的治疗方法,它们的不良反应各不相同,值得进行比较分析,以指导临床决策:本研究采用药物警戒分析法,分析了 2009 年第一季度至 2023 年第三季度 FDA 不良事件报告系统数据库中报告的不良事件。采用不对称和贝叶斯分析法,我们评估并比较了与 LCM 和 PER 相关的 AE 信号,以阐明它们在癫痫治疗中的安全性:分析包括 12,576 份关于 LCM 和 2,703 份关于 PER 的 AE 报告,其中 LCM 的攻击行为等精神疾病发生率较高,而 PER 与精神疾病(如精神障碍和头晕)有明显关联。LCM 在孕期显示出相对安全的特征,而 PER 的数据则表明,由于有自杀意念和企图自杀的病例报告,因此应谨慎使用:这项综合评估强调了在临床实践中了解 LCM 和 PER 不同的 AE 特征的重要性,为个性化癫痫管理提供了宝贵的见解。建议今后采用严格的前瞻性设计开展研究,以验证这些发现并探索所报告不良事件的发生机制。
{"title":"Comparative safety analysis of lacosamide and perampanel in epilepsy management: insights from FAERS database.","authors":"Chang Ge, Liuyin Jin, Jing-Jing Tian, Na Yang, Jian Xu","doi":"10.3389/fphar.2024.1418609","DOIUrl":"10.3389/fphar.2024.1418609","url":null,"abstract":"<p><strong>Background: </strong>Epilepsy is a chronic neurological condition requiring effective management with minimal adverse effects. Lacosamide (LCM) and Perampanel (PER), two promising treatments, have distinct profiles that merit comparative analysis to guide clinical decision-making.</p><p><strong>Methods: </strong>This study utilizes a pharmacovigilance analysis of adverse events reported in the FDA Adverse Event Reporting System database from Q1 2009 to Q3 2023. Employing disproportionality and Bayesian analyses, we assessed and compared the AE signals associated with LCM and PER to elucidate their safety profiles in epilepsy treatment.</p><p><strong>Results: </strong>The analysis included 12,576 AE reports for LCM and 2,703 for PER, highlighting a higher incidence of psychiatric disorders, including aggression with LCM, and a notable association of PER with psychiatric disorders such as psychotic disorders and dizziness. LCM showed a relatively safe profile during pregnancy, whereas PER's data suggested caution due to reported cases of suicidal ideation and attempts.</p><p><strong>Conclusion: </strong>This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of LCM and PER in clinical practice, providing valuable insights for personalized epilepsy management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371541","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1443988
Athanasios Chamzas, Eglis Tellez, Andrew SyBing, Jogarao V S Gobburu, Mathangi Gopalakrishnan
Aim: Tacrolimus, an immunosuppressant used to prevent organ rejection in renal transplant patients, exhibits high inter-patient variability, necessitating therapeutic drug monitoring. Early post-transplant tacrolimus exposure in Hispanics is understudied. Although genotypic information is linked to pharmacokinetic differences, its clinical application remains limited. This study aimed to use a real-world data-driven, pharmacokinetic model-based approach for tacrolimus in Hispanics to determine a suitable initial dose and design an optimal dose titration strategy by simulations to achieve plasma trough concentration target levels of 10-12 ng/mL at the earliest.
Methods: Sparse concentration-time data of tacrolimus were obtained from electronic medical records for self-identified Hispanic subjects following renal transplant. Rich pharmacokinetic literature data was leveraged to estimate structural pharmacokinetic model parameters, which were then fixed in the current analysis. Only apparent clearance was estimated with the sparse tacrolimus data and potential covariates were identified. Simulations of various starting doses and different dose titration strategies were then evaluated.
Results: The analysis included 121 renal transplant patients with 2,215 trough tacrolimus concentrations. A two-compartment transit absorption model with allometrically scaled body weight and time-varying hematocrit on apparent clearance adequately described the data. The estimated apparent clearance was 13.7 L/h for a typical patient weighing 70 kg and at 30% hematocrit, demonstrating a 40% decrease in clearance compared to other patient populations. Model based simulations indicated the best initial dose for the Hispanic population is 0.1 mg/kg/day. The proposed titration strategy, with three dose adjustments based on trough levels of tacrolimus, increased the proportion of patients within the target range (10-12 ng/mL) more than 2.5-fold and decreased the proportion of patients outside the therapeutic window by 50% after the first week of treatment.
Conclusion: Hispanic renal transplant population showed an estimated 40% decrease of apparent clearance in the typical patient compared to other populations with similar characteristics. The proposed dose adjustment attained the target range rapidly and safely. This study advocates for tailored tacrolimus dosing regimens based on population pharmacokinetics to optimize therapy in Hispanic renal transplant recipients.
{"title":"Optimizing tacrolimus dosing in Hispanic renal transplant patients: insights from real-world data.","authors":"Athanasios Chamzas, Eglis Tellez, Andrew SyBing, Jogarao V S Gobburu, Mathangi Gopalakrishnan","doi":"10.3389/fphar.2024.1443988","DOIUrl":"10.3389/fphar.2024.1443988","url":null,"abstract":"<p><strong>Aim: </strong>Tacrolimus, an immunosuppressant used to prevent organ rejection in renal transplant patients, exhibits high inter-patient variability, necessitating therapeutic drug monitoring. Early post-transplant tacrolimus exposure in Hispanics is understudied. Although genotypic information is linked to pharmacokinetic differences, its clinical application remains limited. This study aimed to use a real-world data-driven, pharmacokinetic model-based approach for tacrolimus in Hispanics to determine a suitable initial dose and design an optimal dose titration strategy by simulations to achieve plasma trough concentration target levels of 10-12 ng/mL at the earliest.</p><p><strong>Methods: </strong>Sparse concentration-time data of tacrolimus were obtained from electronic medical records for self-identified Hispanic subjects following renal transplant. Rich pharmacokinetic literature data was leveraged to estimate structural pharmacokinetic model parameters, which were then fixed in the current analysis. Only apparent clearance was estimated with the sparse tacrolimus data and potential covariates were identified. Simulations of various starting doses and different dose titration strategies were then evaluated.</p><p><strong>Results: </strong>The analysis included 121 renal transplant patients with 2,215 trough tacrolimus concentrations. A two-compartment transit absorption model with allometrically scaled body weight and time-varying hematocrit on apparent clearance adequately described the data. The estimated apparent clearance was 13.7 L/h for a typical patient weighing 70 kg and at 30% hematocrit, demonstrating a 40% decrease in clearance compared to other patient populations. Model based simulations indicated the best initial dose for the Hispanic population is 0.1 mg/kg/day. The proposed titration strategy, with three dose adjustments based on trough levels of tacrolimus, increased the proportion of patients within the target range (10-12 ng/mL) more than 2.5-fold and decreased the proportion of patients outside the therapeutic window by 50% after the first week of treatment.</p><p><strong>Conclusion: </strong>Hispanic renal transplant population showed an estimated 40% decrease of apparent clearance in the typical patient compared to other populations with similar characteristics. The proposed dose adjustment attained the target range rapidly and safely. This study advocates for tailored tacrolimus dosing regimens based on population pharmacokinetics to optimize therapy in Hispanic renal transplant recipients.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371547","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}
Pub Date : 2024-09-19eCollection Date: 2024-01-01DOI: 10.3389/fphar.2024.1415951
Nan Wang, Qianqian Ma, Junxian Zhang, Jie Wang, Xiaojun Li, Yan Liang, Xueqiong Wu
Background: Integrated traditional Chinese medicine and biomedicine is an effective method to treat tuberculosis (TB). In our previous research, traditional Chinese medicine preparation NiuBeiXiaoHe (NBXH) achieved obvious anti-TB effects in animal experiments and clinical practice. However, the action mechanism of NBXH has not been elucidated.
Method: Peripheral blood mononuclear cells (PBMCs) were collected to extract mRNA and differentially expressed (DE) genes were obtained using gene microarray technology. Finally, GEO databases and RT-qPCR were used to verify the results of expression profile.
Result: After MTB infection, most upregulated DE genes in mice were immune-related genes, including cxcl9, camp, cfb, c4b, serpina3g, and ngp. Downregulated DE genes included lrrc74b, sult1d1, cxxc4, and grip2. After treatment with NBXH, especially high-dose NBXH, the abnormal gene expression was significantly corrected. Some DE genes have been confirmed in multiple GEO datasets or in pulmonary TB patients through RT-qPCR.
Conclusion: MTB infection led to extensive changes in host gene expression and mainly caused the host's anti-TB immune responses. The treatment using high-dose NBXH partially repaired the abnormal gene expression, further enhanced the anti-TB immunity included autophagy and NK cell-mediated cytotoxicity, and had a certain inhibitory effect on overactivated immune responses.
背景:中药与生物医药相结合是治疗结核病的有效方法。在我们之前的研究中,中药制剂牛膝细辛(NBXH)在动物实验和临床实践中取得了明显的抗结核效果。然而,NBXH 的作用机制尚未阐明:方法:采集外周血单核细胞(PBMC)提取 mRNA,利用基因芯片技术获得差异表达基因(DE)。最后,利用 GEO 数据库和 RT-qPCR 验证表达谱结果:结果:小鼠感染MTB后,大多数上调的DE基因为免疫相关基因,包括cxcl9、camp、cfb、c4b、serpina3g和ngp。下调的 DE 基因包括 lrrc74b、sult1d1、cxxc4 和 grip2。经 NBXH(尤其是大剂量 NBXH)治疗后,异常基因表达得到明显纠正。一些 DE 基因已在多个 GEO 数据集或肺结核患者中通过 RT-qPCR 得到证实:结论:MTB 感染导致宿主基因表达的广泛变化,主要引起宿主的抗结核免疫反应。结论:MTB 感染导致宿主基因表达发生广泛变化,主要引起宿主的抗结核免疫反应,大剂量 NBXH 治疗可部分修复异常基因表达,进一步增强自噬和 NK 细胞介导的细胞毒性等抗结核免疫能力,并对过度激活的免疫反应有一定的抑制作用。
{"title":"Transcriptomics-based anti-tuberculous mechanism of traditional Chinese polyherbal preparation NiuBeiXiaoHe intermediates.","authors":"Nan Wang, Qianqian Ma, Junxian Zhang, Jie Wang, Xiaojun Li, Yan Liang, Xueqiong Wu","doi":"10.3389/fphar.2024.1415951","DOIUrl":"10.3389/fphar.2024.1415951","url":null,"abstract":"<p><strong>Background: </strong>Integrated traditional Chinese medicine and biomedicine is an effective method to treat tuberculosis (TB). In our previous research, traditional Chinese medicine preparation NiuBeiXiaoHe (NBXH) achieved obvious anti-TB effects in animal experiments and clinical practice. However, the action mechanism of NBXH has not been elucidated.</p><p><strong>Method: </strong>Peripheral blood mononuclear cells (PBMCs) were collected to extract mRNA and differentially expressed (DE) genes were obtained using gene microarray technology. Finally, GEO databases and RT-qPCR were used to verify the results of expression profile.</p><p><strong>Result: </strong>After MTB infection, most upregulated DE genes in mice were immune-related genes, including <i>cxcl9</i>, <i>camp</i>, <i>cfb</i>, <i>c4b</i>, <i>serpina3g</i>, and <i>ngp</i>. Downregulated DE genes included <i>lrrc74b</i>, <i>sult1d1</i>, <i>cxxc4</i>, and <i>grip2</i>. After treatment with NBXH, especially high-dose NBXH, the abnormal gene expression was significantly corrected. Some DE genes have been confirmed in multiple GEO datasets or in pulmonary TB patients through RT-qPCR.</p><p><strong>Conclusion: </strong>MTB infection led to extensive changes in host gene expression and mainly caused the host's anti-TB immune responses. The treatment using high-dose NBXH partially repaired the abnormal gene expression, further enhanced the anti-TB immunity included autophagy and NK cell-mediated cytotoxicity, and had a certain inhibitory effect on overactivated immune responses.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371452","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}