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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}
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.
Objective
This study was designed to investigate the possible synergistic effects of EAD and paclitaxel against TNBC cells.
Methods
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.
Results
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.
Conclusion
To conclude, EAD could be the drug of choice for combined treatment with paclitaxel in a chemotherapy regimen.
{"title":"Synergistic effects of epoxyazadiradione (EAD) and paclitaxel against triple-negative breast cancer cells","authors":"Kunnathully Sudhan Sijisha, Rajitha Anusha, 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 IC<sub>50</sub> 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":null,"pages":null},"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}
Adrian A. Schmid, Martin N. Hungerbühler, Paolo Lombardo, Ingrid B. Boehm
Background
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.
Methods
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.
Results
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%; P < 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%; P < 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; P < 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).
Conclusions
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.
{"title":"Intradermal testing of iodinated contrast media: Should we test up to pure or with diluted compounds only?","authors":"Adrian A. Schmid, Martin N. Hungerbühler, Paolo Lombardo, 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> < 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> < 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> < 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":null,"pages":null},"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}
Yanan Wang, Jingjing Chen, Chen Wang, Tong Chen, Ling He
Background
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.
Objectives
The present study was conducted to investigate the efficacy of GW9508 administered peripherally on cognitive dysfunction in streptozotocin (STZ)-induced AD mice.
Methods
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.
Results
Intraperitoneal administration of GW9508 prevented STZ-induced cognitive impairment as well as decreased the level of p-tau and Aβ1–42 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.
Conclusion
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.
背景：G蛋白偶联受体40（GPR40）是阿尔茨海默病（AD）的潜在药物靶点，其激动剂GW9508通过静脉给药可改善认知障碍：本研究旨在探讨GW9508外周给药对链脲佐菌素（STZ）诱导的AD小鼠认知功能障碍的疗效：将70只雄性ICR小鼠随机分为7组：载体假组、模型组、多奈哌齐组、GW9508-L组、GW9508-M组、GW9508-H组和GW1100 + GW9508-H组，分别于第1天和第3天每天一次（上午9:00）双侧脑室内注射载体（人工脑脊液[aCSF]）或STZ（载体中含3 mg/kg）。恢复 2 周后，对所有小鼠进行药物治疗。行为实验用于检测小鼠的识别和空间记忆能力，分子生物学实验如 Western blot、ELISA 和 Nissl 染色则用于检测信号通路的相应变化：结果：腹腔注射GW9508可预防STZ诱导的认知障碍，并降低血浆和大脑中p-tau和Aβ1-42的水平。GW9508通过激活Akt/mTOR信号通路，上调PYY、CCK、IGF-1和GLP-1等肠脑多肽在血液循环和大脑中的表达，并下调自噬相关蛋白的表达水平。同时，GPR40拮抗剂GW1100能显著逆转GW9508的治疗效果：结论：外周给药 GW9508 具有神经保护作用，有望成为一种治疗 AD 的方法。GW9508的神经保护机制基于促进肠脑多肽分泌、激活Akt/mTOR信号通路和调节神经元自噬。
{"title":"GW9508 ameliorates cognitive dysfunction via autophagy pathway in streptozotocin-induced mouse model of Alzheimer's disease","authors":"Yanan Wang, Jingjing Chen, Chen Wang, Tong Chen, 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<sub>1–42</sub> 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":null,"pages":null},"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}
Anderson Gustavo Santos, Carlos Eduardo Kühl, Arisa Namie Higashijima, Luiz Kae Sales Kanazawa, Suzen Tortato Furtado de Souza, Roberto Andreatini
Background
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.
Objective
Thus, the aim of the present study was to screen adenosinergic drugs for antimanic-like effect in methylphenidate (MPH)-induced hyperlocomotion in mice.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Antimanic-like effect of dipyridamole in the methylphenidate-induced hyperlocomotion","authors":"Anderson Gustavo Santos, Carlos Eduardo Kühl, Arisa Namie Higashijima, Luiz Kae Sales Kanazawa, Suzen Tortato Furtado de Souza, 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":null,"pages":null},"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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号