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An exploratory study of drug concentration and inhibitory effect of cetylpyridinium chloride buccal tablets on SARS-CoV-2 infection among 10 Chinese subjects 氯代十六烷基吡啶含片药物浓度及对10例中国人SARS-CoV-2感染抑制作用的探索性研究
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-11-20 DOI: 10.1111/fcp.12972
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

Background

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.

Objective

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.

Trial design

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).

Materials and methods

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.

Results

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: Cmax = 8008.33 (1042.25, 41081.11) ng/mL, AUC0-t = 4172.37 (904.42, 13912.61) ng/mL * h, AUC0-∞ = 6712.85 (1856.77, 19971.12) ng/mL * h, T1/2 = 1.22 (0.59, 2.83) h, Tmax = 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).

Conclusions

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.

背景:十六烷基氯吡啶(CPC)漱口水可以抑制SARS-COV-2活性，降低唾液病毒载量，从而减少SARS-COV-2的传播。然而，由于在口腔内停留时间不足，含cpc漱口水没有持久的抗病毒效果。CPC含片的作用时间预计比漱口水的作用时间长。然而，目前还没有关于CPC含片唾液药物浓度的报道。目的:研究复方中药材含片的唾液药浓度及复方中药材对SARS-CoV-2的体外抗病毒作用。试验设计:本试验为单剂量、单臂临床试验，10名中国健康受试者接受2 mg CPC口腔片，采集唾液样本，检测2 h内不同时间点唾液浓度(临床试验注册号:NCT05802628，注册日期:2023年4月6日)。材料与方法:采用液相色谱-串联质谱法(LC-MS/MS)检测唾液中CPC浓度，并基于非室室模型计算药动学参数。通过体外抗病毒实验，检测了CPC口腔片对SARS-CoV-2的抗病毒活性及其细胞毒性。结果:给药后15 min、30 min、1 h、1.5 h、2 h唾液中药物浓度分别为8008.33(1042.25、41081.11)、2093.34(373.15、5759.83)、1016.58(378.66、3480.68)、891.77(375.66、6322.07)、717.43(197.87、2152.71)ng/mL。唾液浓度PK参数:Cmax = 8008.33 (1042.25, 41081.11) ng/mL, AUC0-t = 4172.37 (904.42, 13912.61) ng/mL * h, AUC0-∞= 6712.85 (1856.77,19971.12)ng/mL * h, T1/2 = 1.22 (0.59, 2.83) h, Tmax = 0.25 (0.25, 0.25) h。体外实验表明，CPC对SARS-CoV-2具有细胞毒活性，CC50 = 35.75 μM(≈12155 ng/mL)， EC50 = 7.39 μM(≈2512.6 ng/mL)。结论:体外抗病毒实验中唾液CPC浓度和EC50/CC50值的比较表明，CPC口腔片可抑制SARS-CoV-2活性，且抑制时间约为30 min，无细胞毒性。
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引用次数: 0
Physiologically Based Pharmacokinetic modelling of drugs in pregnancy: A mini-review on availability and limitations 基于生理的药物在妊娠期的药代动力学模型:一个关于可用性和局限性的小回顾。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-11-15 DOI: 10.1111/fcp.12967
Monika Berezowska, Pradeep Sharma, Venkatesh Pilla Reddy, Paola Coppola

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.

妊娠期基于生理的药代动力学(PBPK)建模是一种相对较新的方法，越来越多地被用于评估孕妇全身药物暴露，以潜在地为剂量调整提供信息。整个怀孕期间的生理变化被纳入数学模型，以模拟药物在母体和胎儿室的处置以及药物在胎盘中的转移。这篇小型综述收集了目前可用的妊娠期常用药物的PBPK模型。此外，还收集了所使用的主要PBPK建模平台、代谢途径、药物转运体、数据可用性和药物标签等信息。这篇小型综述的目的是提供一个简明的概述，展示该领域的趋势，突出研究不足的领域，并确定目前孕期PBPK建模的差距。从临床、监管和工业的角度讨论了这种PBPK方法未来可能的应用。
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引用次数: 0
Alterations in the gene expression of SARS-COV-2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice 受控和非受控糖尿病小鼠肺和心脏中严重急性呼吸系统综合征冠状病毒2型进入受体和酶的基因表达变化。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-11-10 DOI: 10.1111/fcp.12964
Ohood Alkhawaldeh, Yazun Jarrar, Munir Gharaibeh, Sara Abudahab, Dina Abulebdah, Bashir Jarrar

Background

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.

Aims

The present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse Ace2, Tmprss2, and Ctsl and correlate it with the pathological alterations in the lungs and the heart of DM mice.

Methods

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 Ace2, Tmprss2, Ctsl, Cyp4a11, and Adrb1 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.

Results

After inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (P < 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 Ace2 gene expression (P < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of Ctsl gene expression in their hearts (P < 0.05). Notably, Cyp4a12 gene expression was significantly downregulated (P < 0.05) in UDM mice but returned to normal levels in CDM mice.

Conclusions

We conclude from this study that T1DM downregulates Ace2 receptor and Cyp4a12 gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the

背景：严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）进入宿主细胞是通过特定的受体和酶进行的，包括人血管紧张素转换酶2受体（ACE2）、跨膜丝氨酸蛋白酶2（TMPRSS2）和组织蛋白酶-L（CTSL）。患有糖尿病（DM）等合并症的新冠肺炎患者更容易出现严重症状，死亡风险更高。目的：本研究旨在研究控制型和非控制型1型糖尿病（T1DM）对小鼠Ace2、Tmprss2和Ctsl基因表达的影响，并将其与DM小鼠肺和心脏的病理变化联系起来。方法：Balb/c小鼠单次给药240 mg/kg链脲佐菌素诱导T1DM。测量血糖水平以确认糖尿病的诱导。使用0.1 mL/kg Mixtard®胰岛素治疗实现了T1DM小鼠血糖水平的正常化。采集小鼠的肺和心脏，提取mRNA并转化为cDNA。使用定量实时聚合酶链式反应（RT-PCR）测量在肺和心脏稳态中起作用的Ace2、Tmprss2、Ctsl、Cyp4a11和Adrb1基因的基因表达。除了病理学检查外，还使用相对心肺重量评估T1DM诱导的心肺病理变化。结果：诱导T1DM 14天后 天，我们观察到未受控制的糖尿病（UDM）小鼠的总重量显著减轻（P结论：我们从这项研究中得出结论，T1DM下调了Ace2受体和Cyp4a12基因的表达，这与肺泡壁增厚和肺泡囊表面变窄有关。控制T1DM的胰岛素给药改善了这些病理改变。这些结果有助于加深我们对控制和肺部未控制的T1DM，至少部分解释了新冠肺炎DM患者症状恶化的原因。
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引用次数: 0
Cardiac and hepatic side effects of fluoxetine in male and female adolescent rats 氟西汀对雄性和雌性青春期大鼠的心脏和肝脏副作用。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-11-08 DOI: 10.1111/fcp.12963
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.

背景：氟西汀（FLX）在青少年人群中被广泛用作抗抑郁药物。目的：尽管FLX在成人中有一些不良反应的报道，但本研究旨在调查青少年时期FLX治疗对心脏和肝脏系统的副作用。方法：雄性和雌性大鼠于出生后21至60天灌胃FLX（5mg/kg/天）。治疗后，采集血样并评估肝酶。对动物的肝脏和心脏标本进行组织病理学评估。结果：氟西汀显著提高雄性动物的血清丙氨酸氨基转移酶（ALT）和碱性磷酸酶（ALP），而雄性和雌性动物的天冬氨酸氨基转移酶水平均升高。在组织病理学研究中，青春期雄性大鼠的肝板受影响更严重，血窦不规则。观察到变性变化，尤其是在FLX处理的雄性大鼠的第一和第二肝区。在肝小叶的门脉三联体中经常观察到炎症和淋巴群聚集的迹象。这些变化在男性肝脏中更为严重。在女性肝载玻片中观察到最小或几乎正常的变化。此外，组织学评估表明，在青春期接受FLX治疗也会增加雄性动物，尤其是雌性动物的心脏重量和左右心室壁厚（肥大）。结论：我们的研究结果可能为FLX的心脏和肝脏不良反应提供新的见解。
{"title":"Cardiac and hepatic side effects of fluoxetine in male and female adolescent rats","authors":"Hajar Babaaeyan,&nbsp;Nona Sakhaie,&nbsp;Farshid Sadegzadeh,&nbsp;Hakimeh Saadati,&nbsp;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":null,"pages":null},"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}
引用次数: 0
Analgesic switching in chronic users of dextropropoxyphene in France 法国右丙氧芬慢性使用者的镇痛转换。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-10-21 DOI: 10.1111/fcp.12962
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.

背景：右丙氧基苯/对乙酰氨基酚（DXP/P）是处方最多的阿片类止痛药，直到2011年停用 退出后数月。方法：从2006年到2015年，使用法国报销数据库每年重复进行一次横断面研究。慢性DXP/P使用者被定义为在停药前一年至少接受40盒DXP/P的患者。在DXP/P停药（T0）时分析镇痛药分配数据，然后每6次分析一次 18个月 月。结果：共63 671名受试者在停药前一年获得了DXP/P报销，其中7.1%被确定为慢性使用者（平均年龄：71.5岁，女性：68.7%），其余主要为停药（14.1%）或死亡。在接下来的12 几个月后，大多数只服用外周镇痛药的受试者继续接受这种治疗，而一半同时服用阿片类药物/外周镇痛剂或只服用镇痛药的被试者仍在接受这种治疗。结论：DXP/P停药18个月后，超过10%的患者停止服用镇痛药。需要对止痛药的任何变化保持警惕，定期重新评估患者的疼痛，在阿片类药物治疗的情况下，监测使用障碍的风险。
{"title":"Analgesic switching in chronic users of dextropropoxyphene in France","authors":"Amélie Daveluy,&nbsp;Michael Charles Bryan,&nbsp;Ghada Miremont-Salamé,&nbsp;Régis Lassalle,&nbsp;Clémentine Lacueille,&nbsp;Angela Grelaud,&nbsp;Marie Floccia,&nbsp;Françoise Haramburu,&nbsp;Maryse Lapeyre-Mestre,&nbsp;Joëlle Micallef,&nbsp;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":null,"pages":null},"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}
引用次数: 0
Epothilone B loaded in acellular nerve allograft enhanced sciatic nerve regeneration in rats 载Epothilone B的脱细胞同种异体神经增强大鼠坐骨神经再生。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-10-19 DOI: 10.1111/fcp.12961
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.

背景：Epothilone B（EpoB）是一种具有神经保护作用的微管稳定剂。目的：本研究检测了添加EpoB的ANA对雄性Wistar大鼠坐骨神经缺损的再生特性。方法：为此，用含有0.1、1和10nM浓度的EpoB的无细胞同种异体神经移植物（ANAs）填充10mm的神经间隙。对感觉运动恢复进行了评估，直到16 手术后数周。实时聚合酶链式反应、组织形态计量学分析和电生理学评估也用于评估神经再生过程。结果：与ANA、ANA/EpoB（1nM）和ANA/EpoB.（10nM）组相比，ANA/EpoB-（0.1nM）显著改善了大鼠的感觉运动恢复。这导致肌肉萎缩减少，坐骨神经功能指数改善，热爪退缩反射潜伏期增加，表明神经再生和靶器官神经再支配。电生理学和组织形态计量学结果也证实了ANA/EpoB的再生特性（0.1 nM）。EpoB仅在0.1 nM时增强ANA的再生特性，在更高浓度时没有治疗作用。结论：总的来说，我们得出结论，负载0.1nM EpoB的ANA可以有效地重建大鼠坐骨神经切断，可能是通过增强轴突的发芽和伸展。
{"title":"Epothilone B loaded in acellular nerve allograft enhanced sciatic nerve regeneration in rats","authors":"Zhikal Omar Khudhur,&nbsp;Shang Ziyad Abdulqadir,&nbsp;Abdullah Faqiyazdin Ahmed Mzury,&nbsp;Abdulrahman Aziz Rasoul,&nbsp;Shukur Wasman Smail,&nbsp;Mohammad B. Ghayour,&nbsp;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":null,"pages":null},"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}
引用次数: 0
Synthesis, molecular docking, ADMET, and evaluation of the anxiolytic effect in adult zebrafish of synthetic chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one: An in vivo and in silico approach 合成查尔酮（E）-3-（4-（二甲基氨基）苯基）-1-（2-羟基苯基）丙-2-烯-1-酮的合成、分子对接、ADMET和对成年斑马鱼抗焦虑作用的评估：体内和计算机方法。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-10-16 DOI: 10.1111/fcp.12960
Larissa Santos Oliveira, Maria Kueirislene Amâncio Ferreira, Francisco Wagner de Queiroz Almeida-Neto, Antonio Wlisses da Silva, José Ivo Lima Pinto Filho, Matheus Nunes da Rocha, Emanuelle Machado Marinho, Walber Henrique Ferreira Ribeiro, Márcia Machado Marinho, Emmanuel Silva Marinho, Jane Eire Silva Alencar de Menezes, Hélcio Silva dos Santos

Background

Anxiety disorders represent the complex interaction between biological, psychological, temperamental, and environmental factors; drugs available to treat anxiety such as benzodiazepines (BZDs) are associated with several unwanted side effects. Although there are useful treatments, there is still a need for more effective anxiolytics with better safety profiles than BZDs. Chalcones or 1,3-diphenyl-2-proper-1-ones can be an alternative since this class of compounds has shown therapeutic potential mainly due to interactions with GABAA receptors and serotonergic system.

Objectives

This study evaluated the anxiolytic potential of chalcone (E)-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (C2OHPDA) in adult zebrafish (Danio rerio) (ZFa).

Methods

Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 μL) with the chalcone (4, 20, and 40 mg/kg) and with the vehicle (DMSO 3%; 20 μL), being submitted to the tests of locomotor activity and 96-h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1, 5-HTR2A/2C, and 5-HTR3A/3B receptors. It was investigated the prediction of the chalcone's position and preferential orientation concerning its receptor, as well as the pharmacokinetic parameters (ADMET) involved in the process after administration.

Results

As a result, C2OHPDA was not toxic and reduced the locomotor activity of ZFa. Furthermore, chalcone demonstrated an anxiolytic effect on the central nervous system (CNS), mediated by the serotonergic system, with action on 5-HT2A and 5-HTR3A/3B receptors. The interaction of C2OHPDA with 5-HT2AR and 5-HT3A receptors was confirmed by molecular docking study, the affinity energy observed was −8.7 and −9.1 kcal/mol, respectively.

Conclusion

Thus, this study adds new evidence and highlights that chalcone can potentially be used to develop compounds with anxiolytic properties.

背景：焦虑症表现为生物、心理、气质和环境因素之间的复杂相互作用；可用于治疗焦虑症的药物，如苯二氮卓类药物（BZDs），会产生一些不必要的副作用。尽管有有用的治疗方法，但仍需要比BZD更有效、安全性更好的抗焦虑药物。查尔酮或1,3-二苯基-2-丙烯-1-酮可以是一种替代品，因为这类化合物主要由于与GABAA受体和5-羟色胺能系统的相互作用而显示出治疗潜力。目的：本研究评价查尔酮（E）-3-（4-（二甲基氨基）苯基）-1-（2-羟基苯基）丙-2-烯-1-酮（C2OHPDA）对成年斑马鱼（Danio rerio）（ZFa）的抗焦虑作用 = 6/组）腹膜内治疗（i.p.；20 μL）与查尔酮（4、20和40 mg/kg）和载体（DMSO 3%；20 μL），进行运动活性和96小时急性毒性试验。还进行了光/暗测试，并通过5-HTR1、5-HTR2A/2C和5-HTR3A/3B受体的拮抗剂评估5-羟色胺能机制（5-HT）。研究了查尔酮的位置及其受体的优先取向的预测，以及给药后该过程中涉及的药代动力学参数（ADMET）。结果：C2OHPDA无毒性，能降低ZFa的运动活性。此外，查尔酮对中枢神经系统（CNS）表现出抗焦虑作用，由5-羟色胺能系统介导，对5-HT2A和5-HTR3A/3B受体起作用。分子对接研究证实了C2OHPDA与5-HT2A受体和5-HT3A受体的相互作用，观察到的亲和能分别为-8.7和-9.1 kcal/mol。结论：因此，这项研究增加了新的证据，并强调查尔酮有可能用于开发具有抗焦虑特性的化合物。
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引用次数: 0
Exploring signals of myopathy associated with statin and contraindicated comedications in the realworld 探讨现实世界中与他汀类药物和禁忌症相关的肌病信号。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-10-11 DOI: 10.1111/fcp.12959
Sewon Park, Ju Won Lee, Dal Ri Nam, Sun-Young Jung

Background

Using statins in combination with other drugs was reported to increase the risk of myopathy. However, there was a sparse number of studies on the incidence of adverse events (AEs) associated with the concomitant use of statin and contraindicated drugs in the real world.

Objectives

This study aimed to identify the risk of concomitant use of statins with contraindicated drugs by exploring signals related to statin–drug interactions.

Methods

We performed a disproportionality analysis for drugs and AEs by applying the case/non-case study using the KIDS-KAERS database (KIDS-KD), 2016–2020. A case was defined as an individual case safety reports (ICSRs) including “rhabdomyolysis/myopathy.” A non-case was defined as an ICSR, including all other AEs. We applied Ω shrinkage measure model, chi-square statics model, additive model, multiplicative model, and combination risk ratio model to detect signals of myopathy due to statin with concomitant drugs including antiviral agents, immunosuppressants, and antifungals.

Results

Among 1 011 234 ICSRs, 2708 were cases, with 861 cases of statin monotherapy and 1248 of concomitant uses of statin. The adjusted reporting odds ratios were 3.27 (95% confidence interval [CI]: 3.11–3.43), 8.70 (95% CI: 8.04–9.40), and 1.83 (95% CI: 1.73–1.94), respectively. Several combinations of signals were detected through an additive model or multiplicative model.

Conclusion

Signals of an increased risk of myopathy associated with the use of statins with concomitant drugs, including contraindicated drugs, were confirmed in a real-world setting.

背景：据报道，他汀类药物与其他药物联合使用会增加肌病的风险。然而，在现实世界中，关于与他汀类药物和禁忌症药物同时使用相关的不良事件（AE）发生率的研究数量很少。目的：本研究旨在通过探索他汀类药物相互作用的相关信号，确定他汀类药物与禁忌症药物同时使用的风险。方法：我们使用KIDS-KAERS数据库（KIDS-KD），2016-2020，通过应用病例/非病例研究，对药物和AE进行了不均衡性分析。一个病例被定义为包括“横纹肌溶解症/肌病”在内的个别病例安全性报告（ICSRs）。非病例则被定义为ICSR，包括所有其他AE。我们应用Ω收缩测量模型、卡方静态模型、加法模型、乘法模型和组合风险比模型来检测他汀类药物与抗病毒药物、免疫抑制剂和抗真菌药物联合引起的肌病信号。结果：在1 011 234例ICSRs，2708例为病例，861例为他汀类药物单药治疗，1248例为同时使用他汀类药物。调整后的报告比值比分别为3.27（95%置信区间[CI]:3.11-3.43）、8.70（95%置信指数：8.04-9.40）和1.83（95%置信度：1.73-1.94）。通过加法模型或乘法模型来检测信号的几种组合。结论：在现实世界中，他汀类药物与包括禁忌症药物在内的联合用药导致肌病风险增加的信号得到了证实。
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引用次数: 0
Breast cancer resistance protein polymorphism ABCG2 c.421C>A (rs2231142) moderates the effect of valproate on lamotrigine trough concentrations in adults with epilepsy 乳腺癌症耐药性蛋白多态性ABCG2 c.421C>A（rs2231142）调节丙戊酸钠对成年癫痫患者拉莫三嗪谷浓度的影响。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-10-04 DOI: 10.1111/fcp.12958
Ivana Šušak Sporiš, Nada Božina, Iva Klarica Domjanović, Davor Sporiš, Silvio Bašić, Ivana Bašić, Mila Lovrić, Lana Ganoci, Vladimir Trkulja

Background

Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein.

Methods

In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose-adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild-type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7–161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]).

Results

The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)—ratio of GMRs 1.61 (95%CI 1.23–2.11) (frequentist) and 1.63 (95%CrI 1.26–2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 μmol/L vs. no valproate; or valproate ≥364 μmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low.

Conclusion

Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.

背景：丙戊酸钠抑制拉莫三嗪的清除，并大大增加其浓度。我们评估了这种影响是否受到乳腺癌症耐药性蛋白多态性（ABCG2 c.421C>a）的调节。方法：在对成人癫痫患者进行的两项连续的独立研究中，拉莫三嗪单药治疗或与丙戊酸钠联合治疗：（i）暴露于丙戊酸钠被认为是治疗，（ii）稳定状态下的剂量调整拉莫三嗪谷是结果，（iii）ABCG2 c.421C>A基因型（野生型[wt]纯合性或变异携带）是测试的调节因子。我们使用熵平衡（主要分析）和精确/最优完全匹配（次要分析）来控制混杂，包括被认为影响拉莫三嗪暴露的多态性（和连锁多态性）（UGT1A4*3c.142T>G，rs2011425；UGT2B7-161C>T，rs7668258；ABCB1 1236C>T，rss1128503），以产生丙戊酸钠效应的频率学家和贝叶斯估计（几何平均数比值[GMR]）。结果：两项研究产生了一致的结果（重复）；因此，我们分析了组合数据（总N= 471140例接受治疗，331例对照，378例ABCG2 c.421C>A wt受试者，93例变异携带者）。初步分析：在变异携带者中，丙戊酸钠对拉莫三嗪的作用（治疗，n= 21与对照组，n= 72）比wt受试者（治疗后= 119与对照组，n= 259）-GMRs的比值为1.61（95%CI 1.23-2.11）（频率学家）和1.63（95%CI 1.26-2.10）（贝叶斯）。在二次分析中发现，变异携带者和wt受试者之间的丙戊酸钠作用存在类似差异（丙戊酸钠波谷高达364μmol/L与无丙戊酸钠相比；或丙戊酸钠≥364μmol/L vs.无丙戊酸盐）。估计值对未测量的混杂因素的敏感性较低。结论：rs2231142多态性调节丙戊酸钠对拉莫三嗪暴露的影响。
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引用次数: 0
Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review 利鲁唑对阿尔茨海默病的神经保护作用：综述。
IF 2.9 4区 医学 Q2 Medicine
Fundamental & Clinical Pharmacology
Pub Date : 2023-09-27 DOI: 10.1111/fcp.12955
Maryam Golmohammadi, Mohammadreza Mahmoudian, Ekhlas Khammas Hasan, Shadia Hamoud Alshahrani, Rosario Mireya Romero-Parra, Jitendra Malviya, Ahmed Hjazi, Mazin A. A. Najm, Abbas F. Almulla, Mohammad Yasin Zamanian, Mona Kadkhodaei, Nazanin Mousavi

Background

Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases.

Objective

The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms.

Methods

The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles.

Results

Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2.

Conclusion

In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease.

背景：尽管数百项药物的临床试验最初显示出了希望，但阿尔茨海默病（AD）的临床改善有限。这可能归因于该疾病背后至少存在25种异常细胞途径。单一药物不太可能解决所有或大部分这些途径，因此即使是单独用药也不太可能产生显著效果。根据先前的研究，已经发现八种药物，即丹特罗林、红细胞生成素、锂、美金刚、米诺环素、吡拉西坦、利鲁唑和水飞蓟素，靶向参与AD发展的多种途径。在这些药物中，利鲁唑目前适用于治疗成人和儿童的疾病，由于其在神经退行性疾病兴奋性毒性假说中的潜力，它越来越受到科学家的关注。目的：从细胞和分子机制探讨药物对AD的影响。方法：本研究的文献检索利用Scopus、ScienceDirect、PubMed和Google Scholar数据库来识别相关文章。结果：利鲁唑通过多种途径在AD中发挥作用，包括抑制电压依赖性钠和钙通道，阻断AMPA和NMDA受体，抑制谷氨酸释放和刺激EAAT1-EAAT2，这可以使该疾病的患者受益。
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