Rong Zhao, Jiaping Chen, Yangwei Wang, Han Xiao, Peiyuan Mei, Wei Lin, Mingxin Diao, Shiwen He, Yongde Liao, Wangyang Meng
Background
Many studies have demonstrated the relationship between METTL3 protein expression and clinical outcomes in various cancers and elucidated the mechanism by which METTL3 disrupts the behavior of cancer cells. Here, we attempted to define the prognostic value of METTL3 protein in patients with cancer via systematic analysis and explored the potential effect of inhibiting METTL3 using its specific inhibitor.
Methods
We searched PubMed, Embase, and the Web of Science databases for studies that elucidated the prognostic value of METTL3 protein expression in all cancer types and then calculated the pooled hazard ratios with 95% confidence intervals for the overall survival (OS) of all cancer types and subgroups. Data from The Cancer Genome Atlas dataset were used to study METTL3 mRNA expression in cancers. Further, the effects of a METTL3-specific inhibitor were studied in cancer cells via the colony formation assay, the cell proliferation assay, and apoptosis detection.
Results
Meta-analysis of the 33 cohorts in 32 studies (3666 patients in total) revealed that higher METTL3 protein expression indicated poor OS in the majority of cancers. Bioinformatics analysis of METTL3 mRNA expression and cancer prognosis did not show the extremely prominent prognostic value of METTL3 mRNA. Nevertheless, the METTL3-specific inhibitor attenuated cell proliferation and cell cloning formation and promoted apoptosis.
Conclusions
METTL3 protein expression is associated with poor prognosis in most cancer types and could be a biomarker for OS. Further, METTL3 inhibition might be a potential treatment strategy for cancers.
背景：许多研究已经证明了METTL3蛋白的表达与各种癌症的临床预后之间的关系，并阐明了METTL3扰乱癌细胞行为的机制。在此，我们试图通过系统分析来确定METTL3蛋白在癌症患者中的预后价值，并探索使用特异性抑制剂抑制METTL3的潜在效果：我们在PubMed、Embase和Web of Science数据库中检索了阐明METTL3蛋白表达在所有癌症类型中预后价值的研究，然后计算了所有癌症类型和亚组总生存期（OS）的汇总危险比及95%置信区间。癌症基因组图谱数据集的数据被用于研究癌症中METTL3 mRNA的表达。此外，还通过集落形成试验、细胞增殖试验和细胞凋亡检测，研究了METTL3特异性抑制剂对癌细胞的影响：对32项研究中的33个队列（共3666名患者）进行的元分析表明，METTL3蛋白表达较高表明大多数癌症的OS较差。对METTL3 mRNA表达和癌症预后的生物信息学分析并未显示出METTL3 mRNA极其突出的预后价值。然而，METTL3特异性抑制剂可减轻细胞增殖和细胞克隆形成，促进细胞凋亡：结论：METTL3蛋白表达与大多数癌症类型的不良预后有关，可作为OS的生物标志物。此外，抑制 METTL3 可能是一种潜在的癌症治疗策略。
{"title":"Prognostic roles of dysregulated METTL3 protein expression in cancers and potential anticancer value by inhibiting METTL3 function","authors":"Rong Zhao, Jiaping Chen, Yangwei Wang, Han Xiao, Peiyuan Mei, Wei Lin, Mingxin Diao, Shiwen He, Yongde Liao, Wangyang Meng","doi":"10.1111/fcp.13020","DOIUrl":"10.1111/fcp.13020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Many studies have demonstrated the relationship between METTL3 protein expression and clinical outcomes in various cancers and elucidated the mechanism by which METTL3 disrupts the behavior of cancer cells. Here, we attempted to define the prognostic value of METTL3 protein in patients with cancer via systematic analysis and explored the potential effect of inhibiting METTL3 using its specific inhibitor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched PubMed, Embase, and the Web of Science databases for studies that elucidated the prognostic value of METTL3 protein expression in all cancer types and then calculated the pooled hazard ratios with 95% confidence intervals for the overall survival (OS) of all cancer types and subgroups. Data from The Cancer Genome Atlas dataset were used to study METTL3 mRNA expression in cancers. Further, the effects of a METTL3-specific inhibitor were studied in cancer cells via the colony formation assay, the cell proliferation assay, and apoptosis detection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Meta-analysis of the 33 cohorts in 32 studies (3666 patients in total) revealed that higher METTL3 protein expression indicated poor OS in the majority of cancers. Bioinformatics analysis of METTL3 mRNA expression and cancer prognosis did not show the extremely prominent prognostic value of METTL3 mRNA. Nevertheless, the METTL3-specific inhibitor attenuated cell proliferation and cell cloning formation and promoted apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>METTL3 protein expression is associated with poor prognosis in most cancer types and could be a biomarker for OS. Further, METTL3 inhibition might be a potential treatment strategy for cancers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"924-939"},"PeriodicalIF":2.1,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288008","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}
Shahin Gavanji, Azizollah Bakhtari, Rania Abdel-latif, Elena Bencurova, Eman M. Othman
Background
Diabetes mellitus poses a global health challenge, driving the need for innovative therapeutic solutions. Experimental methods play a crucial role in evaluating the efficacy of potential antidiabetic drugs, both in vitro and in vivo. Yet concerns about reproducibility persist, necessitating comprehensive reviews.
Objectives
This review aims to outline experimental approaches for inducing diabetes and evaluating antidiabetic activity, synthesizing data from authoritative sources and academic literature.
Methods
We conducted a systematic search of prominent databases, including PubMed, ScienceDirect, and Scopus, to identify relevant articles spanning from 1943 to the present. A total of 132 articles were selected for inclusion in this review, focusing on in vitro and in vivo experimental validations of antidiabetic treatments.
Results
Our review highlights the diverse array of experimental methods employed for inducing diabetes mellitus and evaluating antidiabetic interventions. From cell culture assays to animal models, researchers have employed various techniques to study the effectiveness of novel therapeutic agents.
Conclusion
This review provides a comprehensive guide to experimental approaches for assessing antidiabetic activity. By synthesizing data from a range of sources, we offer valuable insights into the current methodologies used in diabetes research. Standardizing protocols and enhancing reproducibility are critical for advancing effective antidiabetic treatments.
{"title":"Experimental approaches for induction of diabetes mellitus and assessment of antidiabetic activity: An in vitro and in vivo methodological review","authors":"Shahin Gavanji, Azizollah Bakhtari, Rania Abdel-latif, Elena Bencurova, Eman M. Othman","doi":"10.1111/fcp.13009","DOIUrl":"10.1111/fcp.13009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diabetes mellitus poses a global health challenge, driving the need for innovative therapeutic solutions. Experimental methods play a crucial role in evaluating the efficacy of potential antidiabetic drugs, both in vitro and in vivo. Yet concerns about reproducibility persist, necessitating comprehensive reviews.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This review aims to outline experimental approaches for inducing diabetes and evaluating antidiabetic activity, synthesizing data from authoritative sources and academic literature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a systematic search of prominent databases, including PubMed, ScienceDirect, and Scopus, to identify relevant articles spanning from 1943 to the present. A total of 132 articles were selected for inclusion in this review, focusing on in vitro and in vivo experimental validations of antidiabetic treatments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our review highlights the diverse array of experimental methods employed for inducing diabetes mellitus and evaluating antidiabetic interventions. From cell culture assays to animal models, researchers have employed various techniques to study the effectiveness of novel therapeutic agents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review provides a comprehensive guide to experimental approaches for assessing antidiabetic activity. By synthesizing data from a range of sources, we offer valuable insights into the current methodologies used in diabetes research. Standardizing protocols and enhancing reproducibility are critical for advancing effective antidiabetic treatments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"842-861"},"PeriodicalIF":2.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921864","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}
Maria Lucilene Queiroz da Silva, Natália Ferreira de Sousa, Antonia Thassya Lucas dos Santos, Gabriela Ribeiro de Sousa, Victor Juno Alencar Fonseca, Henrique Douglas Melo Coutinho, José Maria Barbosa Filho, Jailton de Souza Ferrari, Marcus Tullius Scotti, Jaime Ribeiro-Filho, João Paulo Martins de Lima, João Batista Teixeira da Rocha, Maria Flaviana Bezerra Morais-Braga
Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.
{"title":"Inhibition of the morphological transition of Candida spp. by riparins I–IV","authors":"Maria Lucilene Queiroz da Silva, Natália Ferreira de Sousa, Antonia Thassya Lucas dos Santos, Gabriela Ribeiro de Sousa, Victor Juno Alencar Fonseca, Henrique Douglas Melo Coutinho, José Maria Barbosa Filho, Jailton de Souza Ferrari, Marcus Tullius Scotti, Jaime Ribeiro-Filho, João Paulo Martins de Lima, João Batista Teixeira da Rocha, Maria Flaviana Bezerra Morais-Braga","doi":"10.1111/fcp.13007","DOIUrl":"10.1111/fcp.13007","url":null,"abstract":"<p><i>Candida</i> spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of <i>Aniba riparia</i>, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of <i>Candida albicans</i>, <i>Candida tropicalis</i>, and <i>Candida krusei</i>. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as <i>N</i>-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all <i>Candida</i> strains. In conclusion, this study demonstrated that riparins inhibit <i>Candida</i> morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"946-957"},"PeriodicalIF":2.1,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911958","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}
Yagmur Okcay, Cagil Onal Sis, Muhammed Cagri Ozpolat, Zeliha Rumanli, Kemal Gokhan Ulusoy, Oguzhan Yildiz, Ismail Mert Vural
Background
The endocannabinoid system plays important roles in various systems, including the genitourinary system; however, its mechanism of action is not fully understood.
Objectives
This study aimed to investigate the direct relaxant effects of anandamide and its possible mechanisms in isolated rat bladder and vas deferens tissues.
Methods
Twenty-one adult male Wistar albino rats were used. Bladder and vas deferens (prostatic and epididymal portions) tissues were mounted in 10 mL of organ baths. Relaxation responses to anandamide were recorded at 3 and 10 μM concentrations. After the rest period, the procedures were repeated in the presence of cannabinoid (CB) and vanilloid receptor antagonists, various potassium channel blockers, cyclo-oxygenase, and nitric oxide synthase inhibitors. In different tissues to investigate the Ca2+-channel antagonistic effect of anandamide, concentration–response curves to CaCl2 were obtained in the absence and presence of anandamide.
Results
Anandamide caused a significant relaxation response in the bladder and epididymal vas deferens tissues, but not in the prostatic portion. The effect of anandamide was antagonized in the presence of the CB1 antagonist AM251 or the non-selective potassium channel blocker tetraethylammonium in bladder tissue. In the epididymal vas deferens, anandamide significantly inhibited the calcium contraction responses, especially at high concentrations. The CB2 antagonist AM630 reversed this inhibition.
Conclusions
The results show that anandamide has a direct relaxant effect on the isolated rat bladder and epididymal vas deferens. Anandamide triggers different mechanisms in different types of tissues, and further studies are needed to elucidate the mechanism of action of anandamide.
{"title":"The relaxation effect of endocannabinoid anandamide on isolated rat bladder and vas deferens tissues and possible mechanisms","authors":"Yagmur Okcay, Cagil Onal Sis, Muhammed Cagri Ozpolat, Zeliha Rumanli, Kemal Gokhan Ulusoy, Oguzhan Yildiz, Ismail Mert Vural","doi":"10.1111/fcp.13008","DOIUrl":"10.1111/fcp.13008","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The endocannabinoid system plays important roles in various systems, including the genitourinary system; however, its mechanism of action is not fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to investigate the direct relaxant effects of anandamide and its possible mechanisms in isolated rat bladder and vas deferens tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-one adult male Wistar albino rats were used. Bladder and vas deferens (prostatic and epididymal portions) tissues were mounted in 10 mL of organ baths. Relaxation responses to anandamide were recorded at 3 and 10 μM concentrations. After the rest period, the procedures were repeated in the presence of cannabinoid (CB) and vanilloid receptor antagonists, various potassium channel blockers, cyclo-oxygenase, and nitric oxide synthase inhibitors. In different tissues to investigate the Ca<sup>2+</sup>-channel antagonistic effect of anandamide, concentration–response curves to CaCl<sub>2</sub> were obtained in the absence and presence of anandamide.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Anandamide caused a significant relaxation response in the bladder and epididymal vas deferens tissues, but not in the prostatic portion. The effect of anandamide was antagonized in the presence of the CB<sub>1</sub> antagonist AM251 or the non-selective potassium channel blocker tetraethylammonium in bladder tissue. In the epididymal vas deferens, anandamide significantly inhibited the calcium contraction responses, especially at high concentrations. The CB<sub>2</sub> antagonist AM630 reversed this inhibition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results show that anandamide has a direct relaxant effect on the isolated rat bladder and epididymal vas deferens. Anandamide triggers different mechanisms in different types of tissues, and further studies are needed to elucidate the mechanism of action of anandamide.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"967-977"},"PeriodicalIF":2.1,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876253","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}
Yann Verres, Aude Bodin, Sarah Chevret, Tatiana Victoni, Thomas Gicquel, Emiliano Barreto, Véronique Freund-Michel, Vincent Lagente
Background
The nerve growth factor (NGF) has been previously shown to be involved in cellular proliferation, differentiation, survival, or wound healing. This factor displays a variety of biological effects that yet remain to be explored. Previous data on cell lines show a pro-inflammatory role of NGF on monocytes.
Objectives
The objective of the study was to investigate the pro-inflammatory effect of NGF, using a model of fresh human monocytes.
Methods
Monocytes obtained from PBMC were exposed to NGF at various concentrations. Alternatively, monocytes were exposed to BSA, the NGF carrier protein without the NGF. Gene expression and cytokine release in the supernatant were monitored.
Results
We found that NGF increased the expression of pro-inflammatory, chemotactic, and remodeling genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-X-C motif ligand (CXCL)8. The protein levels of CXCL8 and matrix metalloproteinase (MMP)-9 were also increased in the cell supernatants following NGF exposure. BSA alone was found to drive part of this response, bringing nuance to the inflammatory potential of the NGF.
Conclusion
These data suggest that NGF is able to enhance monocyte inflammatory responses once cells are stimulated with another signal but is possibly not able to directly activate it. This could have implications for example in patients with bacterial infections, where NGF could worsen the local inflammation by over-activating immune cells.
{"title":"Effects of the nerve growth factor and its carrier protein on the inflammatory response from human monocytes","authors":"Yann Verres, Aude Bodin, Sarah Chevret, Tatiana Victoni, Thomas Gicquel, Emiliano Barreto, Véronique Freund-Michel, Vincent Lagente","doi":"10.1111/fcp.13006","DOIUrl":"10.1111/fcp.13006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The nerve growth factor (NGF) has been previously shown to be involved in cellular proliferation, differentiation, survival, or wound healing. This factor displays a variety of biological effects that yet remain to be explored. Previous data on cell lines show a pro-inflammatory role of NGF on monocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The objective of the study was to investigate the pro-inflammatory effect of NGF, using a model of fresh human monocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Monocytes obtained from PBMC were exposed to NGF at various concentrations. Alternatively, monocytes were exposed to BSA, the NGF carrier protein without the NGF. Gene expression and cytokine release in the supernatant were monitored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that NGF increased the expression of pro-inflammatory, chemotactic, and remodeling genes such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-X-C motif ligand (CXCL)8. The protein levels of CXCL8 and matrix metalloproteinase (MMP)-9 were also increased in the cell supernatants following NGF exposure. BSA alone was found to drive part of this response, bringing nuance to the inflammatory potential of the NGF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data suggest that NGF is able to enhance monocyte inflammatory responses once cells are stimulated with another signal but is possibly not able to directly activate it. This could have implications for example in patients with bacterial infections, where NGF could worsen the local inflammation by over-activating immune cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"940-945"},"PeriodicalIF":2.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.13006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831427","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}
Quentin Le Baron, Delphine Bourneau-Martin, Marina Babin, Aurore Gouraud, Marie Tauber, Audrey Fresse, Bénédicte Lebrun-Vignes, Juliette Delaunay, Martine Morisset, Marie Briet
Background
Hypersensitivity reactions (HSR) are reported for the macrolides, lincosamides, and streptogramins (MLS) antibiotic family. Data about cross-reactivity among and between MLS remain scarce or controversial.
Objectives
The aim of this study was to provide an overview of hypersensitivity cross-reactions among MLSs based on data extracted from the French National Pharmacovigilance Database (FPVD).
Methods
Cases of HSR to MLSs reported between January 1985 and December 2019 were extracted from the FPVD using standardized MedDRA queries (SMQ). Cases including an allergological test involving multiple MLSs and giving at least one positive result were included.
Results
Of the 8394 cases reviewed, 149 were included. HSR mainly involved pristinamycin (n = 83; 53.2%) and spiramycin (n = 31; 19.9%). HSR to MLS was immediate in 54 cases and delayed in 94 cases. Skin tests represented the majority of the allergological tests performed (n = 728; 84.7%), followed by reintroduction tests (n = 79; 9.2%). Eighty-six cross-reactivities among MLS were identified in 62 cases (41.6%). All the 25 explorations performed for streptogramins showed cross-reactivities, but only 30/253 among macrolides (11.9%). Cross-reactivities between the three MLS were observed in 31/322 (9.6%) of the allergological explorations.
Conclusion
This study highlights the possibility of cross-reactivity among and between MLSs. Dermatologists and allergologists managing patients with HSR to MLSs should be aware of a risk of cross-reactivity among the macrolides and between the different classes of MLS and to perform MLSs allergological testing before recommending an alternative antibiotic, especially in severe drug hypersensitivity from the MLS family.
{"title":"Cross-reactivity among and between macrolides, lincosamides, and streptogramins: Study on the French pharmacovigilance database","authors":"Quentin Le Baron, Delphine Bourneau-Martin, Marina Babin, Aurore Gouraud, Marie Tauber, Audrey Fresse, Bénédicte Lebrun-Vignes, Juliette Delaunay, Martine Morisset, Marie Briet","doi":"10.1111/fcp.13005","DOIUrl":"10.1111/fcp.13005","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hypersensitivity reactions (HSR) are reported for the macrolides, lincosamides, and streptogramins (MLS) antibiotic family. Data about cross-reactivity among and between MLS remain scarce or controversial.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The aim of this study was to provide an overview of hypersensitivity cross-reactions among MLSs based on data extracted from the French National Pharmacovigilance Database (FPVD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cases of HSR to MLSs reported between January 1985 and December 2019 were extracted from the FPVD using standardized MedDRA queries (SMQ). Cases including an allergological test involving multiple MLSs and giving at least one positive result were included.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the 8394 cases reviewed, 149 were included. HSR mainly involved pristinamycin (<i>n</i> = 83; 53.2%) and spiramycin (<i>n</i> = 31; 19.9%). HSR to MLS was immediate in 54 cases and delayed in 94 cases. Skin tests represented the majority of the allergological tests performed (<i>n</i> = 728; 84.7%), followed by reintroduction tests (<i>n</i> = 79; 9.2%). Eighty-six cross-reactivities among MLS were identified in 62 cases (41.6%). All the 25 explorations performed for streptogramins showed cross-reactivities, but only 30/253 among macrolides (11.9%). Cross-reactivities between the three MLS were observed in 31/322 (9.6%) of the allergological explorations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study highlights the possibility of cross-reactivity among and between MLSs. Dermatologists and allergologists managing patients with HSR to MLSs should be aware of a risk of cross-reactivity among the macrolides and between the different classes of MLS and to perform MLSs allergological testing before recommending an alternative antibiotic, especially in severe drug hypersensitivity from the MLS family.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"988-997"},"PeriodicalIF":2.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.13005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140582200","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}
Tony Antoniou, Daniel McCormack, Mina Tadrous, Tara Gomes
Background
Alpha-1 receptor antagonists may interfere with IL-6 signaling and could therefore be a potential treatment for COVID-19. However, the effectiveness of these drugs in mitigating the risk of clinical deterioration among non-hospitalized patients with COVID-19 is unknown.
Objectives
The aim of this study is to examine the association between alpha-1 antagonist exposure and the 30-day risk of a hospital encounter or death in nonhospitalized patients with COVID-19.
Methods
We conducted a population-based cohort study of Ontario residents aged 35 years and older who were eligible for public drug coverage and who had a positive test for SARS-CoV-2 between January 1, 2020, and March 1, 2021. We matched each individual receiving an alpha-1 antagonist at the time of their positive test with two non-exposed individuals using propensity scores. Our outcome was a composite of a hospital admission, emergency department visit, or death, 1 to 30 days following the positive test.
Results
We matched 3289 alpha-1 antagonist exposed patients to 6189 unexposed patients. Overall, there was no difference in the 30-day risk of the primary outcome among patients exposed to alpha-1 antagonists at the time of their diagnosis relative to unexposed individuals (28.8% vs. 28.0%; OR 1.00, 95% CI 0.91 to 1.11). In a secondary analysis, individuals exposed to alpha-1 antagonists had a lower risk of death in the 30 days following a COVID diagnosis (OR 0.79; 95% CI 0.66 to 0.93).
Conclusion
Alpha-1 antagonists did not mitigate the 30-day risk of clinical deterioration in non-hospitalized patients with COVID-19. Our findings do not support the general repurposing of alpha-1 antagonists as a treatment for such patients, although there may be subgroups of patients in whom further research is warranted.
{"title":"Alpha-1 adrenergic antagonists and the risk of hospitalization or death in non-hospitalized patients with COVID-19: A population-based study","authors":"Tony Antoniou, Daniel McCormack, Mina Tadrous, Tara Gomes","doi":"10.1111/fcp.13004","DOIUrl":"10.1111/fcp.13004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alpha-1 receptor antagonists may interfere with IL-6 signaling and could therefore be a potential treatment for COVID-19. However, the effectiveness of these drugs in mitigating the risk of clinical deterioration among non-hospitalized patients with COVID-19 is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The aim of this study is to examine the association between alpha-1 antagonist exposure and the 30-day risk of a hospital encounter or death in nonhospitalized patients with COVID-19.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a population-based cohort study of Ontario residents aged 35 years and older who were eligible for public drug coverage and who had a positive test for SARS-CoV-2 between January 1, 2020, and March 1, 2021. We matched each individual receiving an alpha-1 antagonist at the time of their positive test with two non-exposed individuals using propensity scores. Our outcome was a composite of a hospital admission, emergency department visit, or death, 1 to 30 days following the positive test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We matched 3289 alpha-1 antagonist exposed patients to 6189 unexposed patients. Overall, there was no difference in the 30-day risk of the primary outcome among patients exposed to alpha-1 antagonists at the time of their diagnosis relative to unexposed individuals (28.8% vs. 28.0%; OR 1.00, 95% CI 0.91 to 1.11). In a secondary analysis, individuals exposed to alpha-1 antagonists had a lower risk of death in the 30 days following a COVID diagnosis (OR 0.79; 95% CI 0.66 to 0.93).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Alpha-1 antagonists did not mitigate the 30-day risk of clinical deterioration in non-hospitalized patients with COVID-19. Our findings do not support the general repurposing of alpha-1 antagonists as a treatment for such patients, although there may be subgroups of patients in whom further research is warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"998-1007"},"PeriodicalIF":2.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.13004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140582425","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}
Dilek Ozturk Civelek, Narin Ozturk Seyhan, Yasemin Kubra Akyel, Isil Gazioglu, Zeliha Pala Kara, Mehmet N. Orman, Alper Okyar
Background
Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window and shows chronotoxicity with the best time at ZT13 and worst time at ZT1 (ZT; Zeitgeber time, time after light onset) in the preclinical setting.
Objectives
In the present study, we aimed to investigate whether the pharmacokinetics of everolimus vary according to dosing time and whether sex and feeding status interfere with the chronopharmacokinetics.
Method
A single dosage of 5 mg/kg everolimus was administered orally to C57BL/6J male and female mice, in fed or fasted states at ZT1-rest and ZT13-activity times and blood and tissue samples were collected at 0.5, 1, 2, 4, 12, and 24 h following drug administration. Ileum, liver, plasma, and thymus concentrations of everolimus were determined.
Results
Females had a greater ileum AUC0–24h than males when fed (P = 0.043). Everolimus AUC0–24h in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (P = 0.001). Plasma Cmax, AUC0–24h, and AUCtotal were not statistically significant between the groups (P = 0.098). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (P = 0.029).
Conclusion
Our findings imply that the pharmacokinetics of everolimus in mice may differ according to dosing time, sex, and feeding. Greater tissue distribution of everolimus at ZT1 may be associated with the worst tolerated time of everolimus. Our research suggests that oral chronomodulated everolimus therapy may be more effective and safer for cancer patients.
{"title":"Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in mice","authors":"Dilek Ozturk Civelek, Narin Ozturk Seyhan, Yasemin Kubra Akyel, Isil Gazioglu, Zeliha Pala Kara, Mehmet N. Orman, Alper Okyar","doi":"10.1111/fcp.13003","DOIUrl":"10.1111/fcp.13003","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor used as an immunosuppressant and anticancer. Its pharmacokinetics is highly variable, it has a narrow therapeutic window and shows chronotoxicity with the best time at ZT13 and worst time at ZT1 (ZT; Zeitgeber time, time after light onset) in the preclinical setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In the present study, we aimed to investigate whether the pharmacokinetics of everolimus vary according to dosing time and whether sex and feeding status interfere with the chronopharmacokinetics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>A single dosage of 5 mg/kg everolimus was administered orally to C57BL/6J male and female mice, in fed or fasted states at ZT1-rest and ZT13-activity times and blood and tissue samples were collected at 0.5, 1, 2, 4, 12, and 24 h following drug administration. Ileum, liver, plasma, and thymus concentrations of everolimus were determined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Females had a greater ileum AUC<sub>0–24h</sub> than males when fed (<i>P</i> = 0.043). Everolimus AUC<sub>0–24h</sub> in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (<i>P</i> = 0.001). Plasma C<sub>max</sub>, AUC<sub>0–24h</sub>, and AUC<sub>total</sub> were not statistically significant between the groups (<i>P</i> = 0.098). In one of the target organs of everolimus, the thymus, males had considerably higher amounts at ZT1 than females (<i>P</i> = 0.029).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings imply that the pharmacokinetics of everolimus in mice may differ according to dosing time, sex, and feeding. Greater tissue distribution of everolimus at ZT1 may be associated with the worst tolerated time of everolimus. Our research suggests that oral chronomodulated everolimus therapy may be more effective and safer for cancer patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"883-896"},"PeriodicalIF":2.1,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157951","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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