Fundamental & Clinical Pharmacology最新文献

{"title":"The relaxation effect of endocannabinoid anandamide on isolated rat bladder and vas deferens tissues and possible mechanisms","authors":"Yagmur Okcay,&nbsp;Cagil Onal Sis,&nbsp;Muhammed Cagri Ozpolat,&nbsp;Zeliha Rumanli,&nbsp;Kemal Gokhan Ulusoy,&nbsp;Oguzhan Yildiz,&nbsp;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 Ca²⁺-channel antagonistic effect of anandamide, concentration–response curves to CaCl₂ 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 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.</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}

{"title":"Effects of the nerve growth factor and its carrier protein on the inflammatory response from human monocytes","authors":"Yann Verres,&nbsp;Aude Bodin,&nbsp;Sarah Chevret,&nbsp;Tatiana Victoni,&nbsp;Thomas Gicquel,&nbsp;Emiliano Barreto,&nbsp;Véronique Freund-Michel,&nbsp;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}

{"title":"Cross-reactivity among and between macrolides, lincosamides, and streptogramins: Study on the French pharmacovigilance database","authors":"Quentin Le Baron,&nbsp;Delphine Bourneau-Martin,&nbsp;Marina Babin,&nbsp;Aurore Gouraud,&nbsp;Marie Tauber,&nbsp;Audrey Fresse,&nbsp;Bénédicte Lebrun-Vignes,&nbsp;Juliette Delaunay,&nbsp;Martine Morisset,&nbsp;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}

{"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,&nbsp;Daniel McCormack,&nbsp;Mina Tadrous,&nbsp;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}

{"title":"Dosing-time, feeding, and sex-dependent variations of everolimus pharmacokinetics in mice","authors":"Dilek Ozturk Civelek,&nbsp;Narin Ozturk Seyhan,&nbsp;Yasemin Kubra Akyel,&nbsp;Isil Gazioglu,&nbsp;Zeliha Pala Kara,&nbsp;Mehmet N. Orman,&nbsp;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_0–24h than males when fed (<i>P</i> = 0.043). Everolimus AUC_0–24h in the liver was substantially greater at ZT1 than at ZT13 in a fasted state (<i>P</i> = 0.001). Plasma C_max, AUC_0–24h, and AUC_total 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}

{"title":"Synergistic effects of epoxyazadiradione (EAD) and paclitaxel against triple-negative breast cancer cells","authors":"Kunnathully Sudhan Sijisha,&nbsp;Rajitha Anusha,&nbsp;Sulochana Priya","doi":"10.1111/fcp.13000","DOIUrl":"10.1111/fcp.13000","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Triple-negative breast cancer (TNBC) is the most aggressive and chemo-resistant form of breast cancer subtype, and chemotherapy is a vital treatment option for that. Paclitaxel is an effective chemo drug for TNBC. However, in clinical settings, paclitaxel has adverse side effects. The synergistic combination is the most promising method for overcoming undesirable toxicity and achieving a beneficial therapeutic outcome. Previous reports, including our study, showed certain anticancer potential of epoxyazadiradione (EAD), the neem limonoid, in different types of cancer cells, including TNBC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study was designed to investigate the possible synergistic effects of EAD and paclitaxel against TNBC cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined the effects of EAD and paclitaxel alone and in combination in MDA-MB 231 cells, and the percentage cytotoxicity was used to calculate synergism. Characteristic apoptotic changes were observed by visualizing cellular morphology, nuclear fragmentation and membrane integrity. We further estimated anti-migratory potential of experimental compounds by wound healing assay. The reduction in inflammation during combinatorial treatment was evaluated by observing NF-κB translocation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The combined treatment with EAD (5 μM) and paclitaxel (5 nM), which were used at doses lower than their individual IC₅₀ concentrations, showed a synergistic effect in MDA-MB-231 cells. This combination effectively induced apoptosis and antimigration and reduced the inflammatory reactions induced by the higher dose of paclitaxel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>To conclude, EAD could be the drug of choice for combined treatment with paclitaxel in a chemotherapy regimen.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 4","pages":"758-766"},"PeriodicalIF":2.1,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119245","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}

{"title":"Intradermal testing of iodinated contrast media: Should we test up to pure or with diluted compounds only?","authors":"Adrian A. Schmid,&nbsp;Martin N. Hungerbühler,&nbsp;Paolo Lombardo,&nbsp;Ingrid B. Boehm","doi":"10.1111/fcp.12998","DOIUrl":"10.1111/fcp.12998","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intradermal testing (IDT) with iodinated contrast media (ICMs) is an established diagnostic tool in patients with ICM hypersensitivity. Currently, it is unclear which test concentration is the more useful one, up to pure or up to 1:10 diluted ICMs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We searched the literature database PubMed for eligible papers dealing with ICM allergy and their IDT results. We analyzed the data presented by the papers and compared the pooled groups tested with diluted and undiluted ICMs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 29 eligible original papers, and extracted data of 1137 patients that formed the study population. Although in the cohort tested with diluted ICMs the number of tested ICMs was greater, the percentage of positive tests was significantly less (9.0% vs. 24.7%; <i>P</i> &lt; 0.0001; OR 0.30 [0.26–0.34]). The frequency of positive tested culprit ICMs was also lesser in the group tested with diluted ICMs (31.0% vs. 72.5%; <i>P</i> &lt; 0.0001; OR 0.17 [0.12–0.23]). The number of drug provocation tests (DPTs) was greater in patients with diluted IDTs (374 vs. 89; <i>P</i> &lt; 0.0001; OR 2.54 [1.93–3.36]). We detected an increased sensitivity in patients with undiluted tests (0.774 vs. 0.282) and a nearly identical specificity in both groups (1 vs. 0.983).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>For the first time, we show that IDT up to pure ICM concentrations is superior to using diluted ICMs only. Possibly, we can reduce the number of DPTs when performing IDTs with pure ICMs. In the undiluted group, there were no hints for skin irritations or unspecific test reactions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 4","pages":"789-798"},"PeriodicalIF":2.1,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.12998","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119244","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}

{"title":"GW9508 ameliorates cognitive dysfunction via autophagy pathway in streptozotocin-induced mouse model of Alzheimer's disease","authors":"Yanan Wang,&nbsp;Jingjing Chen,&nbsp;Chen Wang,&nbsp;Tong Chen,&nbsp;Ling He","doi":"10.1111/fcp.13002","DOIUrl":"10.1111/fcp.13002","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>G protein-coupled receptor 40 (GPR40) is a potential drug target for Alzheimer's disease (AD), and its agonist GW9508 ameliorates cognitive impairment by intravenous administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The present study was conducted to investigate the efficacy of GW9508 administered peripherally on cognitive dysfunction in streptozotocin (STZ)-induced AD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Seventy male ICR mice were randomly divided into seven groups: vehicle sham group, model, Donepezil, GW9508-L, GW9508-M, GW9508-H, and GW1100 + GW9508-H groups, and administered either vehicle (artificial cerebrospinal fluid [aCSF]) or STZ (3 mg/kg in the vehicle) once a day (9:00 a.m.) by intracerebroventricular injection bilaterally on day 1 and day 3, respectively. After 2 weeks of recovery, all mice were given drug treatment. Behavioral experiments were applied to test the recognition and spatial memory of mice, while molecular biology experiments such as Western blot, ELISA, and Nissl staining were used to detect the corresponding changes of signaling pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Intraperitoneal administration of GW9508 prevented STZ-induced cognitive impairment as well as decreased the level of p-tau and Aβ_1–42 in plasma and brain. GW9508 upregulated the expression of gut-brain peptides like PYY, CCK, IGF-1, and GLP-1 both in blood circulation and brain and downregulated the expression level of autophagy-related proteins through activating Akt/mTOR signaling pathway. Meanwhile, the treatment effect of GW9508 was reversed by GPR40 antagonist GW1100 significantly.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Peripheral administration of GW9508 exhibits neuroprotective effects, and it could be a promising therapy for AD. The neuroprotective mechanism of GW9508 was based on promoting gut-brain peptide secretion, activating Akt/mTOR signal pathway, and regulating neuronal autophagy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"906-923"},"PeriodicalIF":2.1,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131214","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}

{"title":"Antimanic-like effect of dipyridamole in the methylphenidate-induced hyperlocomotion","authors":"Anderson Gustavo Santos,&nbsp;Carlos Eduardo Kühl,&nbsp;Arisa Namie Higashijima,&nbsp;Luiz Kae Sales Kanazawa,&nbsp;Suzen Tortato Furtado de Souza,&nbsp;Roberto Andreatini","doi":"10.1111/fcp.13001","DOIUrl":"10.1111/fcp.13001","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add-on therapy in manic patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Thus, the aim of the present study was to screen adenosinergic drugs for antimanic-like effect in methylphenidate (MPH)-induced hyperlocomotion in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male and female Swiss mice received a single allopurinol (50 and 200 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) administration before an acute MPH challenge (5 mg/kg, sc). In experiments with repeated treatment, male mice received a daily administration of allopurinol (25 and 50 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) for 14 days. Finally, pretreatment with aminophylline (2 mg/kg, sc), an unspecific adenosine receptor antagonist, was used to evaluate a putative adenosinergic mediation. Locomotor activity was measured in the automated activity chamber for 20 min.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Acute and repeated dipyridamole reduced the increase in locomotor activity induced by MPH, while allopurinol and inosine had no effect. Aminophylline blocked the effect of dipyridamole in MPH-induced hyperlocomotion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The present results suggest that dipyridamole may have an antimanic-like effect through adenosine receptors and reinforce the proposal that the adenosine system may be an interesting target for new antimanic drugs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"897-905"},"PeriodicalIF":2.1,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112589","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}

{"title":"Challenges and opportunities of medicines for treating tendon inflammation and fibrosis: A comprehensive and mechanistic review","authors":"Zohreh Najafi,&nbsp;Pouria Rahmanian-Devin PharmD, PhD,&nbsp;Vafa Baradaran Rahimi PharmD, PhD,&nbsp;Ali Nokhodchi PharmD, PhD,&nbsp;Vahid Reza Askari PharmD, PhD","doi":"10.1111/fcp.12999","DOIUrl":"10.1111/fcp.12999","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Tendinopathy refers to conditions characterized by collagen degeneration within tendon tissue, accompanied by the proliferation of capillaries and arteries, resulting in reduced mechanical function, pain, and swelling. While inflammation in tendinopathy can play a role in preventing infection, uncontrolled inflammation can hinder tissue regeneration and lead to fibrosis and impaired movement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The inability to regulate inflammation poses a significant limitation in tendinopathy treatment. Therefore, an ideal treatment strategy should involve modulation of the inflammatory process while promoting tissue regeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The current review article was prepared by searching PubMed, Scopus, Web of Science, and Google Scholar databases. Several treatment approaches based on biomaterials have been developed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This review examines various treatment methods utilizing small molecules, biological compounds, herbal medicine-inspired approaches, immunotherapy, gene therapy, cell-based therapy, tissue engineering, nanotechnology, and phototherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These treatments work through mechanisms of action involving signaling pathways such as transforming growth factor-beta (TGF-β), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), all of which contribute to the repair of injured tendons.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"802-841"},"PeriodicalIF":2.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101427","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}