AAPS open最新文献

{"title":"Oral delivery of the non-β-blocking R-carvedilol enantiomer for skin cancer chemoprevention in SKH-1 mice.","authors":"Pabitra K Sardar, Steven Yeung, Ruby Tow, Jacqueline Luga, Matthew Huang, Ayaz Shahid, Bradley T Andresen, Ying Huang","doi":"10.1186/s41120-024-00103-1","DOIUrl":"10.1186/s41120-024-00103-1","url":null,"abstract":"<p><strong>Purpose: </strong>Skin cancer remains the most prevalent cancer worldwide with its incidence continuously rising. Previous studies have demonstrated the efficacy of the β-blocker carvedilol and its non-β-blocking enantiomer R-carvedilol in mitigating UV-induced skin carcinogenesis through topical application. The current study investigated whether orally administered R-carvedilol could prevent the development of skin cancer in SKH-1 mice.</p><p><strong>Methods: </strong>Efficacy of orally delivered R-carvedilol was examined in SKH-1 mice exposed to repeated UV radiations for 25 weeks. Pharmacokinetic studies were conduced in mice to evaluate the drug levels in plasma and skin tissues. Pharmacodynamic studies were used to evaluate the effects of oral R-carvedilol and racemic carvedilol on mouse blood pressure.</p><p><strong>Results: </strong>The findings revealed a statistical difference in tumor incidence between the group receiving R-carvedilol (20 mg/kg) and the UV-only control group (<i>p</i> = 0.00860), while lower doses of R-carvedilol (1.5 mg/kg and 5 mg/kg) did not exhibit a significant impact on tumor incidence. While tumor multiplicity varied significantly between groups (<i>p</i> = 0.005325), tumor volume analysis showed no statistical difference. Pharmacokinetic studies indicated that R-carvedilol accumulated in a dose-dependent manner within plasma and skin tissues. Notably, at a dosage of 32 mg/kg, oral R-carvedilol did not influence blood pressure, in contrast to carvedilol, highlighting its potential for chemoprevention with minimal cardiovascular side effects.</p><p><strong>Conclusions: </strong>These data support oral administration of R-carvedilol as a viable strategy for the chemoprevention of skin cancer, given its efficacy and minimal impact on the cardiovascular system. Further studies determining the optimal doses and timing of drug treatment are warranted.</p>","PeriodicalId":520495,"journal":{"name":"AAPS open","volume":"11 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin.","authors":"Lauren E Thompson, Stacey M Tuey, Paola Garcia Gonzalez, Carly S Chesterman, Courtney D McGinnis, M Scott Lucia, Lauren M Aleksunes, Charles L Edelstein, Melanie S Joy","doi":"10.1186/s41120-025-00107-5","DOIUrl":"https://doi.org/10.1186/s41120-025-00107-5","url":null,"abstract":"<p><strong>Objective: </strong>Acute kidney injury (AKI) occurs in approximately one-third of patients treated with cisplatin and there is an outstanding need for mitigation strategies to decrease the frequency and severity of cisplatin-induced AKI. This study evaluated bardoxolone methyl (BARD) as a nephroprotectant in a multidose, tumor-bearing mouse model of cisplatin-induced AKI. BARD is an attractive therapeutic intervention due to its ability to protect against cisplatin-induced nephrotoxicity by activating Nrf2 and previous reports suggesting anti-tumorigenic effects.</p><p><strong>Methods: </strong>In this study, CMT167 tumor-bearing mice were treated with four weekly doses of cisplatin with or without BARD and evaluated for survival, tumor growth, and clinical and histological measures of AKI. Kidney injury and/or function were evaluated by quantification of urinary kidney injury molecule-1 (KIM-1) and serum creatinine (SCr) levels as well as histopathology.</p><p><strong>Results: </strong>Compared to mice receiving cisplatin alone, co-treatment with BARD significantly enhanced survival (<i>p</i> = 0.01). Moreover, BARD prevented elevation of urinary KIM-1 concentrations as early as one week after cisplatin treatment (<i>p</i> < 0.01) - a response that was observed throughout the 4-week study period. Cisplatin increased SCr concentrations by four weeks, which was prevented by BARD co-administration (<i>p</i> < 0.01). Cisplatin treatment significantly decreased tumor burden compared to vehicle-treated mice (<i>p</i> < 0.05 after two cisplatin doses) - a response that was not altered by BARD co-treatment.</p><p><strong>Conclusions: </strong>Overall, the results of this study demonstrate that BARD has the potential to improve survival and reduce clinical measures of kidney injury in tumor-bearing mice treated with cisplatin, suggesting it could be used as a nephroprotectant to mitigate cisplatin-induced AKI.</p>","PeriodicalId":520495,"journal":{"name":"AAPS open","volume":"11 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12387945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144985811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}