Romain Euvrard, Marie Robert, Sabine Mainbourg, Stéphane Dalle, Jean-Christophe Lega
Background
Immune checkpoint inhibitors (ICI) represent a breakthrough in oncology in terms of prognosis and safety. They now constitute a cornerstone in the management of metastatic melanoma. However, a new kind of adverse event called immune-related adverse events (irAE) has emerged. These irAE could be conceptually considered as an indicator of the antitumoral immune response, but the association between irAE and prognosis is still a matter of debate.
Objective
The purpose of this study was to investigate the association between the overall survival (OS) and the prevalence of irAE in melanoma.
Methods
MEDLINE/PubMed, WebofScience, ClinicalTrials, and WHOTrials databases were searched to identify phase 3 randomized controlled trials (RCT) assessing ICI in melanoma and published up to April 2021. A weighted regression was performed to estimate this association according to standard method of surrogacy analysis.
Results
A total of 14 RCT including 7646 patients (median age: 59.3 years) with melanoma were included. All types of ICI were represented (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, as well as ipilimumab and nivolumab combination). irAE were frequent but rarely fatal. The combination of ICI caused more irAE than anti-PD1 (or PDL1) and anti-CTLA4 monotherapies. No relationship was found between the occurrence of irAE and OS (beta coefficient 0.078, R2 3%, p = 0.52), nor between cutaneous irAE and OS (beta coefficient 0.080, R2 6%, p = 0.33).
Conclusion
Although limited by the heterogeneity of ICI included in the regression and the low number of included RCT, the present study suggests an absence of association between irAE and prognosis in melanoma.
背景:免疫检查点抑制剂(ICI)在肿瘤预后和安全性方面取得了突破性进展。它们现在构成了转移性黑色素瘤治疗的基石。然而，一种新的不良事件被称为免疫相关不良事件(irAE)已经出现。这些irAE可以在概念上被认为是抗肿瘤免疫反应的一个指标，但irAE与预后之间的关系仍然是一个有争议的问题。目的:本研究的目的是探讨黑色素瘤患者总生存期(OS)与irAE患病率之间的关系。方法:检索MEDLINE/PubMed、WebofScience、ClinicalTrials和WHOTrials数据库，以确定评估黑素瘤ICI的3期随机对照试验(RCT)，并发表至2021年4月。根据代孕分析的标准方法进行加权回归来估计这种关联。结果:共纳入14项随机对照试验，包括7646例黑色素瘤患者(中位年龄:59.3岁)。代表了所有类型的ICI (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab，以及ipilimumab和nivolumab联合)。伊拉克战争频繁发生，但很少致命。ICI联合治疗比抗pd1(或PDL1)和抗ctla4单药治疗引起更多的irAE。irAE的发生与OS无相关性(β系数0.078,R2 3%， p = 0.52)，皮肤irAE与OS无相关性(β系数0.080,R2 6%， p = 0.33)。结论:尽管受回归中ICI异质性和纳入的RCT数量较少的限制，本研究提示irAE与黑色素瘤预后之间不存在关联。
{"title":"Association between immune-related adverse events and prognosis in patients treated with immune checkpoint inhibitors in melanoma: A surrogacy analysis","authors":"Romain Euvrard, Marie Robert, Sabine Mainbourg, Stéphane Dalle, Jean-Christophe Lega","doi":"10.1111/fcp.12966","DOIUrl":"10.1111/fcp.12966","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immune checkpoint inhibitors (ICI) represent a breakthrough in oncology in terms of prognosis and safety. They now constitute a cornerstone in the management of metastatic melanoma. However, a new kind of adverse event called immune-related adverse events (irAE) has emerged. These irAE could be conceptually considered as an indicator of the antitumoral immune response, but the association between irAE and prognosis is still a matter of debate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The purpose of this study was to investigate the association between the overall survival (OS) and the prevalence of irAE in melanoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>MEDLINE/PubMed, WebofScience, ClinicalTrials, and WHOTrials databases were searched to identify phase 3 randomized controlled trials (RCT) assessing ICI in melanoma and published up to April 2021. A weighted regression was performed to estimate this association according to standard method of surrogacy analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 14 RCT including 7646 patients (median age: 59.3 years) with melanoma were included. All types of ICI were represented (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, as well as ipilimumab and nivolumab combination). irAE were frequent but rarely fatal. The combination of ICI caused more irAE than anti-PD1 (or PDL1) and anti-CTLA4 monotherapies. No relationship was found between the occurrence of irAE and OS (beta coefficient 0.078, R<sup>2</sup> 3%, <i>p</i> = 0.52), nor between cutaneous irAE and OS (beta coefficient 0.080, R<sup>2</sup> 6%, <i>p</i> = 0.33).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Although limited by the heterogeneity of ICI included in the regression and the low number of included RCT, the present study suggests an absence of association between irAE and prognosis in melanoma.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 2","pages":"369-379"},"PeriodicalIF":2.9,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12966","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Çiğdem Çengelli Ünel, Ezgi Eroğlu, Orhan Özatik, Kevser Erol
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is still an unresolved problem in cisplatin (CIS) use.
Objectives
This study investigates possible anti-neuropathic effect of chlorogenic acid (CGA) against CIS-induced CIPN in rats while also investigating the contribution of nitric oxide (NO) to this phenomenon.
Methods
Initially, CGA (250–1000 μM) was tested by MTT assay on primary DRG neurons. Subsequently, CIPN was induced in Sprague–Dawley rats by 3 mg/kg intraperitoneal injections of CIS once/week for 5 weeks. CGA (100 mg/kg) was co-administered with CIS, both alone and in combination with l-arginine (LARG) or l-nitro-arginine-methyl-ester (LNAME), to elucidate the contribution of nitrergic system to anti-neuropathic effects. Mechanical allodynia, thermal hyperalgesia, and cold plate tests were performed to test CIPN. Rotarod, footprint analysis, and activitymeter were used to evaluate motor coordination and performance. Tumor necrosis factor alpha (TNF-α) was measured as a marker of inflammation. Histological evaluations of DRG and sciatic nerves (SNs) were performed utilizing toluidine blue staining. Two-way analysis of variance and Kruskal–Wallis following Tukey's test were used as statistical analysis.
Results
Higher concentration of CGA (1000 μM) exhibited protective effect against in vitro neurotoxicity. Neither LARG nor LNAME exerted significant change in this effect. Co-administration of CGA alleviated histological abnormalities and neuropathic effects induced by CIS. Ameliorative effect of CGA was not changed in mechanical allodynia but attenuated in cold allodynia, and motor activity/coordination tests by LARG and LNAME. Neuropathic effects of CIS remained unchanged with LARG and LNAME in behavioral experiments.
Conclusion
The study identified CGA as candidate agent in mitigating CIPN. NO seems to play a modulatory role in this effect.
{"title":"Chlorogenic acid co-administration alleviates cisplatin-induced peripheral neuropathy in rats","authors":"Çiğdem Çengelli Ünel, Ezgi Eroğlu, Orhan Özatik, Kevser Erol","doi":"10.1111/fcp.12970","DOIUrl":"10.1111/fcp.12970","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chemotherapy-induced peripheral neuropathy (CIPN) is still an unresolved problem in cisplatin (CIS) use.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study investigates possible anti-neuropathic effect of chlorogenic acid (CGA) against CIS-induced CIPN in rats while also investigating the contribution of nitric oxide (NO) to this phenomenon.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Initially, CGA (250–1000 μM) was tested by MTT assay on primary DRG neurons. Subsequently, CIPN was induced in Sprague–Dawley rats by 3 mg/kg intraperitoneal injections of CIS once/week for 5 weeks. CGA (100 mg/kg) was co-administered with CIS, both alone and in combination with <span>l</span>-arginine (LARG) or <span>l</span>-nitro-arginine-methyl-ester (LNAME), to elucidate the contribution of nitrergic system to anti-neuropathic effects. Mechanical allodynia, thermal hyperalgesia, and cold plate tests were performed to test CIPN. Rotarod, footprint analysis, and activitymeter were used to evaluate motor coordination and performance. Tumor necrosis factor alpha (TNF-α) was measured as a marker of inflammation. Histological evaluations of DRG and sciatic nerves (SNs) were performed utilizing toluidine blue staining. Two-way analysis of variance and Kruskal–Wallis following Tukey's test were used as statistical analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Higher concentration of CGA (1000 μM) exhibited protective effect against in vitro neurotoxicity. Neither LARG nor LNAME exerted significant change in this effect. Co-administration of CGA alleviated histological abnormalities and neuropathic effects induced by CIS. Ameliorative effect of CGA was not changed in mechanical allodynia but attenuated in cold allodynia, and motor activity/coordination tests by LARG and LNAME. Neuropathic effects of CIS remained unchanged with LARG and LNAME in behavioral experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The study identified CGA as candidate agent in mitigating CIPN. NO seems to play a modulatory role in this effect.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 3","pages":"523-537"},"PeriodicalIF":2.9,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138298877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Myocardial infarction poses major risks to human health because of their incredibly high rates of morbidity and mortality. Infarctions are more likely to develop as a result of dysregulation of cell death. Myrtenal can be considered for their bioactive beneficial activity in the context of cardiovascular pathologies and, particularly, in the protection toward oxidative stress followed by ischemic injury.
Objective
This study aimed to put limelight on the antioxidant, anti-apoptotic, and antibacterial properties of Myrtenal.
Methods
An in vitro model of oxidative stress-induced injury was entrenched in H9c2 cells using hydrogen peroxide, and the effects of Myrtenal were investigated. The MTT, cellular enzyme level, staining, and flow cytometry analysis were used to examine protective, antioxidant, and anti-apoptotic effects. The gene expressions were detected by qPCR. Antibacterial effect and biofilm formation were also done.
Result
The findings revealed that Myrtenal alone had negligible cytotoxic effects and that Myrtenal protects H9c2 against H2O2-induced cell death at micromolar concentrations. Myrtenal pre-treatment inhibited the generation of reactive oxygen species (ROS) as well as remarkably decreased the fluorescence intensity of ROS. Additionally, Myrtenal considerably increased the synthesis of antioxidant enzymes while dramatically decreasing the production of MDA and LDH. qPCR demonstrated the downregulation of Cas-9, TNF-α, NF-κB, P53, BAX, iNOS, and IL-6 expression while an upregulation of Bcl-2 expression in Myrtenal pre-treated groups. Myrtenal also holds the magnificent property of inhibiting bacterial growth.
Conclusion
Myrtenal ameliorates H2O2-induced cardiomyocyte injury and protects cardiomyocyte by inhibiting oxidative stress, inflammation, and apoptosis and may be a promise drug for the treatment of heart diseases.
{"title":"Myrtenal exhibits cardioprotective effects by attenuating the pathological progression associated with myocardial infarction","authors":"N Abhirami, Mahesh Chandran, Athira Ramadasan, Dhanalekshmi Bhasura, Janeesh Plakkal Ayyappan","doi":"10.1111/fcp.12965","DOIUrl":"10.1111/fcp.12965","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myocardial infarction poses major risks to human health because of their incredibly high rates of morbidity and mortality. Infarctions are more likely to develop as a result of dysregulation of cell death. Myrtenal can be considered for their bioactive beneficial activity in the context of cardiovascular pathologies and, particularly, in the protection toward oxidative stress followed by ischemic injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to put limelight on the antioxidant, anti-apoptotic, and antibacterial properties of Myrtenal.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>An in vitro model of oxidative stress-induced injury was entrenched in H9c2 cells using hydrogen peroxide, and the effects of Myrtenal were investigated. The MTT, cellular enzyme level, staining, and flow cytometry analysis were used to examine protective, antioxidant, and anti-apoptotic effects. The gene expressions were detected by qPCR. Antibacterial effect and biofilm formation were also done.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>The findings revealed that Myrtenal alone had negligible cytotoxic effects and that Myrtenal protects H9c2 against H<sub>2</sub>O<sub>2</sub>-induced cell death at micromolar concentrations. Myrtenal pre-treatment inhibited the generation of reactive oxygen species (ROS) as well as remarkably decreased the fluorescence intensity of ROS. Additionally, Myrtenal considerably increased the synthesis of antioxidant enzymes while dramatically decreasing the production of MDA and LDH. qPCR demonstrated the downregulation of Cas-9, TNF-α, NF-κB, P53, BAX, iNOS, and IL-6 expression while an upregulation of Bcl-2 expression in Myrtenal pre-treated groups. Myrtenal also holds the magnificent property of inhibiting bacterial growth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Myrtenal ameliorates H<sub>2</sub>O<sub>2</sub>-induced cardiomyocyte injury and protects cardiomyocyte by inhibiting oxidative stress, inflammation, and apoptosis and may be a promise drug for the treatment of heart diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 2","pages":"276-289"},"PeriodicalIF":2.9,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138290719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthieu Brenkman, Tom Cartau, Elise Pape, Allan Kolodziej, Alexandre Charmillon, Emmanuel Novy, Jean-Yves Jouzeau, Nicolas Gambier, Julien Scala-Bertola
Background and Objectives
Beta-lactam antibiotics are reported for some of them to be subject to a rapid degradation in infusion solutions and in human blood samples. However, the current data of stability available in blood samples are limited to a few number of beta-lactam antibiotics, and the methodology of the corresponding studies may be discussed. The objective of the present study is to evaluate the stability of 10 beta-lactam antibiotics in human plasma samples.
Methods
Stability of amoxicillin, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, imipenem, meropenem, and piperacillin was evaluated at low and high concentrations at 20°C, 4°C, −20°C, and −80°C for 1, 7, 60, and 90 days, respectively.
Results
Amoxicillin, cefepime, meropenem, and piperacillin were the least stable antibiotics. The maximum durations allowing the stability for all the evaluated beta-lactams at both tested concentrations were estimated at 3 h, 23 h, 10 days, and 35 days at 20°C, 4°C, −20°C, and −80°C, respectively.
Conclusion
We recommend to transport antibiotic plasma samples in ice at 4°C and even at −20°C if these samples come from external hospitals. Ideally, plasma samples should be stored at −80°C if possible; if not, the analysis of the samples should be performed as soon as possible in the limit of 10 days after a storage at −20°C.
{"title":"In vitro stability study of 10 beta-lactam antibiotics in human plasma samples","authors":"Matthieu Brenkman, Tom Cartau, Elise Pape, Allan Kolodziej, Alexandre Charmillon, Emmanuel Novy, Jean-Yves Jouzeau, Nicolas Gambier, Julien Scala-Bertola","doi":"10.1111/fcp.12969","DOIUrl":"10.1111/fcp.12969","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Objectives</h3>\u0000 \u0000 <p>Beta-lactam antibiotics are reported for some of them to be subject to a rapid degradation in infusion solutions and in human blood samples. However, the current data of stability available in blood samples are limited to a few number of beta-lactam antibiotics, and the methodology of the corresponding studies may be discussed. The objective of the present study is to evaluate the stability of 10 beta-lactam antibiotics in human plasma samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Stability of amoxicillin, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, imipenem, meropenem, and piperacillin was evaluated at low and high concentrations at 20°C, 4°C, −20°C, and −80°C for 1, 7, 60, and 90 days, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Amoxicillin, cefepime, meropenem, and piperacillin were the least stable antibiotics. The maximum durations allowing the stability for all the evaluated beta-lactams at both tested concentrations were estimated at 3 h, 23 h, 10 days, and 35 days at 20°C, 4°C, −20°C, and −80°C, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We recommend to transport antibiotic plasma samples in ice at 4°C and even at −20°C if these samples come from external hospitals. Ideally, plasma samples should be stored at −80°C if possible; if not, the analysis of the samples should be performed as soon as possible in the limit of 10 days after a storage at −20°C.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 3","pages":"502-510"},"PeriodicalIF":2.9,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div> <section> <h3> Background</h3> <p>It was evidenced that cetylpyridinium-chloride (CPC) mouthwash could inhibit SARS-COV-2 activity and reduce salivary viral load, thus reducing SARS-CoV-2 transmission. However, due to insufficient residence time in the oral cavity, CPC-containing mouthwashes have no prolonged antiviral effect. The duration of action of the CPC buccal tablet is expected to be longer than that of the mouthwash. However, there are currently no reports on the salivary drug concentration of CPC buccal tablets.</p> </section> <section> <h3> Objective</h3> <p>The study aimed to investigate the salivary drug concentration of CPC buccal tablets and the antiviral effect of CPC on SARS-CoV-2 in vitro.</p> </section> <section> <h3> Trial design</h3> <p>This is a single-dose, single-arm clinical trial, involving 10 Chinese healthy subjects who received 2-mg CPC buccal tablet to collect saliva samples and to detect saliva concentration at different timepoints within 2 h (Clinical Trial Registration Number: NCT05802628, Registration Date: April 6, 2023).</p> </section> <section> <h3> Materials and methods</h3> <p>CPC concentration in saliva was detected by liquid chromatography tandem mass spectrometry (LC–MS/MS), and pharmacokinetic parameters were calculated based on the non-compartmental model. With an in vitro antiviral experiment, the activity of CPC buccal tablets against SARS-CoV-2 and its cellular toxicity was tested.</p> </section> <section> <h3> Results</h3> <p>Drug concentrations in saliva at 15 min, 30 min, 1 h, 1.5 h, and 2 h after administration were 8008.33 (1042.25, 41081.11), 2093.34 (373.15, 5759.83), 1016.58 (378.66, 3480.68), 891.77 (375.66, 6322.07), and 717.43 (197.87, 2152.71) ng/mL. PK parameters of saliva concentration: C<sub>max</sub> = 8008.33 (1042.25, 41081.11) ng/mL, AUC<sub>0-t</sub> = 4172.37 (904.42, 13912.61) ng/mL * h, AUC<sub>0-∞</sub> = 6712.85 (1856.77, 19971.12) ng/mL * h, T<sub>1/2</sub> = 1.22 (0.59, 2.83) h, T<sub>max</sub> = 0.25 (0.25, 0.25) h. As determined in in vitro experiment, CPC was active on SARS-CoV-2 with cytotoxic and inhibitory activity of CC50 = 35.75 μM (≈12155 ng/mL) and EC50 = 7.39 μM (≈2512.6 ng/mL).</p> </section> <section> <h3> Conclusions</h3> <p>The comparison between the salivary CPC concentration and EC50/CC50 values from in vitro antiviral experiments suggests that CPC buccal tablets may inhibit SARS-CoV-2 activity, and the inhibition may last for approximately 30 min without cytotoxicity.</p>
{"title":"An exploratory study of drug concentration and inhibitory effect of cetylpyridinium chloride buccal tablets on SARS-CoV-2 infection among 10 Chinese subjects","authors":"Yanting Li, Zhenwei Xie, Liming Chen, Xiangxing Liu, Shuang Li, Shichun Ye, Hongyan Tang, Chongyou Lee, Qun Gu, Fang Men, Jiaojiao Zhang, Dingyuan Hu, Yuanli Jiang, Xiaochun Wang, Qian Wang, Yufei Feng, Suping Niu, Yan Liu, Yi Fang","doi":"10.1111/fcp.12972","DOIUrl":"10.1111/fcp.12972","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>It was evidenced that cetylpyridinium-chloride (CPC) mouthwash could inhibit SARS-COV-2 activity and reduce salivary viral load, thus reducing SARS-CoV-2 transmission. However, due to insufficient residence time in the oral cavity, CPC-containing mouthwashes have no prolonged antiviral effect. The duration of action of the CPC buccal tablet is expected to be longer than that of the mouthwash. However, there are currently no reports on the salivary drug concentration of CPC buccal tablets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The study aimed to investigate the salivary drug concentration of CPC buccal tablets and the antiviral effect of CPC on SARS-CoV-2 in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial design</h3>\u0000 \u0000 <p>This is a single-dose, single-arm clinical trial, involving 10 Chinese healthy subjects who received 2-mg CPC buccal tablet to collect saliva samples and to detect saliva concentration at different timepoints within 2 h (Clinical Trial Registration Number: NCT05802628, Registration Date: April 6, 2023).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and methods</h3>\u0000 \u0000 <p>CPC concentration in saliva was detected by liquid chromatography tandem mass spectrometry (LC–MS/MS), and pharmacokinetic parameters were calculated based on the non-compartmental model. With an in vitro antiviral experiment, the activity of CPC buccal tablets against SARS-CoV-2 and its cellular toxicity was tested.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Drug concentrations in saliva at 15 min, 30 min, 1 h, 1.5 h, and 2 h after administration were 8008.33 (1042.25, 41081.11), 2093.34 (373.15, 5759.83), 1016.58 (378.66, 3480.68), 891.77 (375.66, 6322.07), and 717.43 (197.87, 2152.71) ng/mL. PK parameters of saliva concentration: C<sub>max</sub> = 8008.33 (1042.25, 41081.11) ng/mL, AUC<sub>0-t</sub> = 4172.37 (904.42, 13912.61) ng/mL * h, AUC<sub>0-∞</sub> = 6712.85 (1856.77, 19971.12) ng/mL * h, T<sub>1/2</sub> = 1.22 (0.59, 2.83) h, T<sub>max</sub> = 0.25 (0.25, 0.25) h. As determined in in vitro experiment, CPC was active on SARS-CoV-2 with cytotoxic and inhibitory activity of CC50 = 35.75 μM (≈12155 ng/mL) and EC50 = 7.39 μM (≈2512.6 ng/mL).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The comparison between the salivary CPC concentration and EC50/CC50 values from in vitro antiviral experiments suggests that CPC buccal tablets may inhibit SARS-CoV-2 activity, and the inhibition may last for approximately 30 min without cytotoxicity.</p>\u0000 ","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 3","pages":"579-587"},"PeriodicalIF":2.9,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Physiologically based pharmacokinetic (PBPK) modelling in pregnancy is a relatively new approach that is increasingly being used to assess drug systemic exposure in pregnant women to potentially inform dosing adjustments. Physiological changes throughout pregnancy are incorporated into mathematical models to simulate drug disposition in the maternal and fetal compartments as well as the transfer of drugs across the placenta. This mini-review gathers currently available pregnancy PBPK models for drugs commonly used during pregnancy. In addition, information about the main PBPK modelling platforms used, metabolism pathways, drug transporters, data availability and drug labels were collected. The aim of this mini-review is to provide a concise overview, demonstrate trends in the field, highlight understudied areas and identify current gaps of PBPK modelling in pregnancy. Possible future applications of this PBPK approach are discussed from a clinical, regulatory and industry perspective.
{"title":"Physiologically Based Pharmacokinetic modelling of drugs in pregnancy: A mini-review on availability and limitations","authors":"Monika Berezowska, Pradeep Sharma, Venkatesh Pilla Reddy, Paola Coppola","doi":"10.1111/fcp.12967","DOIUrl":"10.1111/fcp.12967","url":null,"abstract":"<p>Physiologically based pharmacokinetic (PBPK) modelling in pregnancy is a relatively new approach that is increasingly being used to assess drug systemic exposure in pregnant women to potentially inform dosing adjustments. Physiological changes throughout pregnancy are incorporated into mathematical models to simulate drug disposition in the maternal and fetal compartments as well as the transfer of drugs across the placenta. This mini-review gathers currently available pregnancy PBPK models for drugs commonly used during pregnancy. In addition, information about the main PBPK modelling platforms used, metabolism pathways, drug transporters, data availability and drug labels were collected. The aim of this mini-review is to provide a concise overview, demonstrate trends in the field, highlight understudied areas and identify current gaps of PBPK modelling in pregnancy. Possible future applications of this PBPK approach are discussed from a clinical, regulatory and industry perspective.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 3","pages":"402-409"},"PeriodicalIF":2.9,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134648837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ohood Alkhawaldeh, Yazun Jarrar, Munir Gharaibeh, Sara Abudahab, Dina Abulebdah, Bashir Jarrar
<div> <section> <h3> Background</h3> <p>The entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin-converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin-L (CTSL). COVID-19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality.</p> </section> <section> <h3> Aims</h3> <p>The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse <i>Ace2</i>, <i>Tmprss2</i>, and <i>Ctsl</i> and correlate it with the pathological alterations in the lungs and the heart of DM mice.</p> </section> <section> <h3> Methods</h3> <p>Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of <i>Ace2</i>, <i>Tmprss2</i>, <i>Ctsl</i>, <i>Cyp4a11</i>, and <i>Adrb1</i> genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real-time polymerase chain reaction (RT-PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination.</p> </section> <section> <h3> Results</h3> <p>After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (<i>P</i> < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of <i>Ace2</i> gene expression (<i>P</i> < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of <i>Ctsl</i> gene expression in their hearts (<i>P</i> < 0.05). Notably, <i>Cyp4a12</i> gene expression was significantly downregulated (<i>P</i> < 0.05) in UDM mice but returned to normal levels in CDM mice.</p> </section> <section> <h3> Conclusions</h3> <p>We conclude from this study that T1DM downregulates <i>Ace2</i> receptor and <i>Cyp4a12</i> gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the
{"title":"Alterations in the gene expression of SARS-COV-2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice","authors":"Ohood Alkhawaldeh, Yazun Jarrar, Munir Gharaibeh, Sara Abudahab, Dina Abulebdah, Bashir Jarrar","doi":"10.1111/fcp.12964","DOIUrl":"10.1111/fcp.12964","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin-converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin-L (CTSL). COVID-19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse <i>Ace2</i>, <i>Tmprss2</i>, and <i>Ctsl</i> and correlate it with the pathological alterations in the lungs and the heart of DM mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Balb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of <i>Ace2</i>, <i>Tmprss2</i>, <i>Ctsl</i>, <i>Cyp4a11</i>, and <i>Adrb1</i> genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real-time polymerase chain reaction (RT-PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (<i>P</i> < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of <i>Ace2</i> gene expression (<i>P</i> < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of <i>Ctsl</i> gene expression in their hearts (<i>P</i> < 0.05). Notably, <i>Cyp4a12</i> gene expression was significantly downregulated (<i>P</i> < 0.05) in UDM mice but returned to normal levels in CDM mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We conclude from this study that T1DM downregulates <i>Ace2</i> receptor and <i>Cyp4a12</i> gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the ","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 2","pages":"328-340"},"PeriodicalIF":2.9,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72209122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hajar Babaaeyan, Nona Sakhaie, Farshid Sadegzadeh, Hakimeh Saadati, Ali Niapour
Background
Fluoxetine (FLX) is widely prescribed as an antidepressant medicine in the juvenile population.
Objectives
Although some adverse effects of FLX have been reported in adults, the present study aimed to investigate the side effects of FLX treatment during adolescence on the cardiac and hepatic systems.
Methods
Male and female rats were gavaged with FLX (5 mg/kg/day) on postnatal days (PND) 21 to PND 60. Following treatment, blood samples were collected and hepatic enzymes were evaluated. The specimens of the liver and heart of animals were subjected to histopathological assessment.
Results
Fluoxetine significantly raised serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in males, whereas the aspartate aminotransferase (AST) level increased in both male and female animals. In the histopathological study, hepatic plates were more seriously affected, and the sinusoids were irregular in adolescent male rats. Degenerative changes were observed especially in the first and second hepatic zones of FLX-treated male rats. Signs of inflammation and accumulation of lymphoid groups were frequently observed in the portal triad of the hepatic lobules. These alterations were more severe in male livers. Minimum or nearly normal changes were observed in female liver slides. In addition, the histological assessment indicated that treatment with FLX during adolescence also increased the heart's weight and the wall thickness of the right and left ventricles (hypertrophy) in male and especially female animals.
Conclusion
Our findings may provide new insights into the cardiac and hepatic adverse effects of FLX.
{"title":"Cardiac and hepatic side effects of fluoxetine in male and female adolescent rats","authors":"Hajar Babaaeyan, Nona Sakhaie, Farshid Sadegzadeh, Hakimeh Saadati, Ali Niapour","doi":"10.1111/fcp.12963","DOIUrl":"10.1111/fcp.12963","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Fluoxetine (FLX) is widely prescribed as an antidepressant medicine in the juvenile population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Although some adverse effects of FLX have been reported in adults, the present study aimed to investigate the side effects of FLX treatment during adolescence on the cardiac and hepatic systems.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male and female rats were gavaged with FLX (5 mg/kg/day) on postnatal days (PND) 21 to PND 60. Following treatment, blood samples were collected and hepatic enzymes were evaluated. The specimens of the liver and heart of animals were subjected to histopathological assessment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Fluoxetine significantly raised serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in males, whereas the aspartate aminotransferase (AST) level increased in both male and female animals. In the histopathological study, hepatic plates were more seriously affected, and the sinusoids were irregular in adolescent male rats. Degenerative changes were observed especially in the first and second hepatic zones of FLX-treated male rats. Signs of inflammation and accumulation of lymphoid groups were frequently observed in the portal triad of the hepatic lobules. These alterations were more severe in male livers. Minimum or nearly normal changes were observed in female liver slides. In addition, the histological assessment indicated that treatment with FLX during adolescence also increased the heart's weight and the wall thickness of the right and left ventricles (hypertrophy) in male and especially female animals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings may provide new insights into the cardiac and hepatic adverse effects of FLX.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 2","pages":"320-327"},"PeriodicalIF":2.9,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71480701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amélie Daveluy, Michael Charles Bryan, Ghada Miremont-Salamé, Régis Lassalle, Clémentine Lacueille, Angela Grelaud, Marie Floccia, Françoise Haramburu, Maryse Lapeyre-Mestre, Joëlle Micallef, Francesco Salvo
Background
The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011.
Objectives
This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal.
Methods
A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months.
Results
A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment.
Conclusion
Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders.
{"title":"Analgesic switching in chronic users of dextropropoxyphene in France","authors":"Amélie Daveluy, Michael Charles Bryan, Ghada Miremont-Salamé, Régis Lassalle, Clémentine Lacueille, Angela Grelaud, Marie Floccia, Françoise Haramburu, Maryse Lapeyre-Mestre, Joëlle Micallef, Francesco Salvo","doi":"10.1111/fcp.12962","DOIUrl":"10.1111/fcp.12962","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 2","pages":"389-397"},"PeriodicalIF":2.9,"publicationDate":"2023-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12962","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49676710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhikal Omar Khudhur, Shang Ziyad Abdulqadir, Abdullah Faqiyazdin Ahmed Mzury, Abdulrahman Aziz Rasoul, Shukur Wasman Smail, Mohammad B. Ghayour, Arash Abdolmaleki
Background
Epothilone B (EpoB) is a microtubule-stabilizing agent with neuroprotective properties.
Objectives
This study examines the regenerative properties of ANA supplemented with EpoB on a sciatic nerve deficit in male Wistar rats.
Methods
For this purpose, the 10 mm nerve gap was filled with acellular nerve allografts (ANAs) containing EpoB at 0.1, 1, and 10 nM concentrations. The sensorimotor recovery was evaluated up to 16 weeks after the operation. Real-time PCR, histomorphometry analysis, and electrophysiological evaluation were also used to evaluate the process of nerve regeneration.
Results
ANA/EpoB (0.1 nM) significantly improved sensorimotor recovery in rats compared to ANA, ANA/EpoB (1 nM), and ANA/EpoB (10 nM) groups. This led to reduced muscle atrophy, improved sciatic functional index, and thermal paw withdrawal reflex latency, indicating nerve regeneration and target organ reinnervation. The electrophysiological and histomorphometry findings also confirmed the ANA/EpoB regenerative properties (0.1 nM). EpoB only enhanced ANA regenerative properties at 0.1 nM, with no therapeutic effects at higher concentrations.
Conclusion
Totally, we concluded that ANA loaded with 0.1 nM EpoB can effectively reconstruct the transected sciatic nerve in rats, likely by enhancing axonal sprouting and extension.
{"title":"Epothilone B loaded in acellular nerve allograft enhanced sciatic nerve regeneration in rats","authors":"Zhikal Omar Khudhur, Shang Ziyad Abdulqadir, Abdullah Faqiyazdin Ahmed Mzury, Abdulrahman Aziz Rasoul, Shukur Wasman Smail, Mohammad B. Ghayour, Arash Abdolmaleki","doi":"10.1111/fcp.12961","DOIUrl":"10.1111/fcp.12961","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Epothilone B (EpoB) is a microtubule-stabilizing agent with neuroprotective properties.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study examines the regenerative properties of ANA supplemented with EpoB on a sciatic nerve deficit in male Wistar rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>For this purpose, the 10 mm nerve gap was filled with acellular nerve allografts (ANAs) containing EpoB at 0.1, 1, and 10 nM concentrations. The sensorimotor recovery was evaluated up to 16 weeks after the operation. Real-time PCR, histomorphometry analysis, and electrophysiological evaluation were also used to evaluate the process of nerve regeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ANA/EpoB (0.1 nM) significantly improved sensorimotor recovery in rats compared to ANA, ANA/EpoB (1 nM), and ANA/EpoB (10 nM) groups. This led to reduced muscle atrophy, improved sciatic functional index, and thermal paw withdrawal reflex latency, indicating nerve regeneration and target organ reinnervation. The electrophysiological and histomorphometry findings also confirmed the ANA/EpoB regenerative properties (0.1 nM). EpoB only enhanced ANA regenerative properties at 0.1 nM, with no therapeutic effects at higher concentrations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Totally, we concluded that ANA loaded with 0.1 nM EpoB can effectively reconstruct the transected sciatic nerve in rats, likely by enhancing axonal sprouting and extension.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 2","pages":"307-319"},"PeriodicalIF":2.9,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49676711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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