European Journal of Pharmaceutical Sciences最新文献

{"title":"Sex-dependent outcomes of bioequivalence studies in the absence of any sex-by-formulation effects on the drug absorption: Examining theoretical possibilities","authors":"Maitri Sanghavi ,&nbsp;Anyu Lin ,&nbsp;Elliot Warwick ,&nbsp;Amin Rostami-Hodjegan","doi":"10.1016/j.ejps.2025.107110","DOIUrl":"10.1016/j.ejps.2025.107110","url":null,"abstract":"<div><div>Arguments for including female volunteers in bioequivalence (BE) studies focus on achieving equity when drugs are intended for use in both sexes. Virtual bioequivalence (VBE) studies in female populations offer an alternative approach to address the gap, especially with ability to delineate likely differences in the outcome of BE using sex-related inputs in physiology and biology.</div><div>Whilst sex-by-formulation effects are suggested based on some animal studies, no research has comprehensively addressed sex-dependent BE outcomes, particularly in the absence of such effects on absorption. This study provides a theoretical background to potential sex-dependent outcomes in BE. It is demonstrated that, for a given difference between rate of absorption of a reference (R) and test (T) products, that is similar in both sexes, the impact on C_max as one of the BE assessment indices might be sex dependent. Various hypothetical scenarios within realistic boundaries of pharmacokinetic parameters [25–100% for absorption rate (k_a) of T vs. R, and up to 4-fold difference in elimination rate (k_e) between sexes] were tested. These simulations identified parameter spaces where BE outcomes diverged between males and females. The observed effects are linked to sex-dependent differences in elimination, influenced by variations in volume of distribution or enzyme abundance affecting clearance.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107110"},"PeriodicalIF":4.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced pulmonary delivery of spray-dried theophylline: investigation of the trehalose and amino acid combinations as innovative fine carriers","authors":"Lomass Soliman ,&nbsp;Petra Party ,&nbsp;Attila Nagy ,&nbsp;Árpád Farkas ,&nbsp;Dóra Paróczai ,&nbsp;Katalin Burián ,&nbsp;Rita Ambrus","doi":"10.1016/j.ejps.2025.107109","DOIUrl":"10.1016/j.ejps.2025.107109","url":null,"abstract":"<div><div>The emergence of novel carrier systems for dry powder inhalers is an attractive research subject. Additionally, the site-specific pulmonary delivery of theophylline (THN) remains challenging. Therefore, the present research aims to assess the potential enhancement of THN local delivery to the deep lung via powder inhalation for asthma treatment by developing appropriate fine carriers utilizing the well-established spray-drying technique.</div><div>The preliminary study aimed to develop novel trehalose-based carrier systems combined with amino acids leucine, glycine, and arginine. Aqueous feedstock solutions were spray-dried, and the obtained microparticulate carriers were assessed. Subsequently, therapeutic powders were produced by spray drying ethanol 10 % solutions of THN combined with candidate-developed carriers. Following each sample preparation, it was subjected to structural, thermal, morphological, rheological, aerodynamic, and particle size distribution characterization. Furthermore, THN solubility was determined. <em>In vitro</em> drug release and diffusion, <em>in vitro</em> and <em>in silico</em> simulated lung deposition, and aerodynamic particle count were analyzed by applying samples equivalent to 10 mg of THN.</div><div>To summarize the outcomes, carriers composed of trehalose with either leucine or a leucine-glycine combination demonstrated superior respirable properties and were considered candidates for further development. THN co-spray-dried samples showed less crystalline structure and particle size of 4–5 µm, leading to profound solubility enhancement (⁓20 fold) and rapid drug release compared to the pure THN (⁓100 % in 5 min). The <em>in vitro</em> and <em>in silico</em> aerodynamic measurements demonstrated that the THN-trehalose-leucine combination had a significantly enhanced fine particle fraction (43 %), leading to higher deep lung deposition (36 %), and the aerodynamic counter confirmed the development of fine particles (mean=3.61 µm). Moreover, the <em>in vitro</em> experiments on the A549 cells demonstrated that the optimized formulation has a low cytotoxicity profile.</div><div>In conclusion, the acquired characteristics suggest that inhalable co-spray-dried THN with the trehalose-leucine fine carrier may be a practical approach for local asthma therapy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107109"},"PeriodicalIF":4.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of 3′-modified xylofuranosyl nucleosides bearing 5′-silyl or -butyryl groups and their antiviral effect against RNA viruses","authors":"Miklós Bege ,&nbsp;Krisztina Leiner ,&nbsp;Miklós Lovas ,&nbsp;Réka Pető ,&nbsp;Ilona Bereczki ,&nbsp;Jan Hodek ,&nbsp;Jan Weber ,&nbsp;Anett Kuczmog ,&nbsp;Anikó Borbás","doi":"10.1016/j.ejps.2025.107107","DOIUrl":"10.1016/j.ejps.2025.107107","url":null,"abstract":"<div><div>D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3′-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2′,5′-di-O-silyl-3′-exomethylene uridine. Sequential desilylation and 5′-O-butyrylation of the 3′-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC₅₀ values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2′,5′-di-O-silylated 3′-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC₅₀ values, with the 5′-butyryl-2′-silyl-3′-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2′-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3′-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC₅₀ value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107107"},"PeriodicalIF":4.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of a model characterizing the release characteristics of a new letrozole long-acting injectable formulation","authors":"Adriana Castiñeiras Pardines ,&nbsp;Gema López Ginés ,&nbsp;Gastón García Orueta ,&nbsp;Iñaki F․ Trocóniz","doi":"10.1016/j.ejps.2025.107103","DOIUrl":"10.1016/j.ejps.2025.107103","url":null,"abstract":"<div><div>Treating a chronic condition such as breast cancer usually requires daily oral drug administration for extended periods of time, which is associated with non-adherence to the prescribed therapy that may cause disease progression. New delivery strategies such as long-acting injectable (LAI) implants have entered the picture in order to solve oral administration drawbacks while improving bioavailability, plasma levels variability or treatment compliance. This has motivated the development of a new polymeric and biodegradable <em>in situ</em> forming long-acting implant of letrozole. This new formulation is provided as a kit of two syringes (one of them containing letrozole and Poly-Lactic Acid, and the other one containing dimethyl sulfoxide as solvent for reconstitution). Once the formulation is reconstituted and injected into the muscle, the solvent diffuses into tissue fluids and the insoluble polymer precipitates, forming a semi-solid implant that traps the API and allows a sustained drug release. In order to optimize both the formulation and the development process, traditional <em>in vitro</em> dissolution assessment and predictive dissolution modelling were conducted to identify which formulation characteristics show an impact on the kinetics of the release, which may provide a first basis to potentially establish an <em>in vitro-in vivo</em> correlation (IVIVC) with both pre-clinical and clinical data in the future. Two dissolution methods (real-time and accelerated) were used to describe the <em>in vitro</em> dissolution profiles of 15 letrozole LAI formulations differing on their Critical Material Attributes (CMAs). The release profiles were best described using the Weibull distribution and estimating the fraction of the dose loss during injection. The first order rate constant of release (K_D) was increased by 1.87 times in the case of the accelerated conditions, and was 30 % reduced and increased by 1.34 times in the case of higher and lower viscosity of the formulations, respectively. This work allowed for quantitative characterization of the formulation related characteristics responsible for controlling drug release. It provides a new understanding of the formulation that will serve to guide in the development of a robust formulation and to establish product quality control specifications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107103"},"PeriodicalIF":4.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro biophysical and biological profiling of commercial lipid-based dry eye products","authors":"Janika Jäntti ,&nbsp;Tuomo Viitaja ,&nbsp;Julia Sevón ,&nbsp;Jukka Moilanen ,&nbsp;Tatu Lajunen ,&nbsp;Katja Pajula ,&nbsp;Filip. S. Ekholm ,&nbsp;Marika Ruponen","doi":"10.1016/j.ejps.2025.107104","DOIUrl":"10.1016/j.ejps.2025.107104","url":null,"abstract":"<div><div>There is an increasing number of products available for treatment of dry eye disease (DED), thereby creating a challenge in selecting a suitable product. Commercial products have rarely been studied in the same experimental setup, and in the case of lipid-based products, their baseline capabilities to target central defects of DED requires a more thorough investigation. This study aims to discern potential differences in their abilities to stabilize the tear film, reduce the evaporation of water, and impact on corneal epithelial cell viability and recovery utilizing various biophysical and biological <em>in vitro</em> techniques.</div><div>Seven commercial lipid-based eye drops (Cationorm®, Desodrop®, Evotears®, Oxyal® Triple Action, Puro™ Suoja, Systane® Complete, Thealipid®) were selected for the <em>in vitro</em> biophysical and biological profiling studies. Biophysical properties critical for tear film stability and evaporation reduction were evaluated using Langmuir trough techniques, while cell viability and recovery were assessed by an MTT assay after exposing either healthy or damaged human corneal epithelial cells to the products.</div><div>The majority of the products spread reasonably well at the aqueous-air interface, suggesting that they bear intrinsic properties which may be beneficial to improving the coverage of the tear film lipid layer. However, only subtle evaporation reduction capabilities were observed, indicating that the products are not optimal at targeting this defect. Clear differences in cell viability and recovery were observed, with three of the products being able to promote the recovery of damaged cells. The significance of our findings with regards to DED treatment outcomes will require additional studies in the future.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107104"},"PeriodicalIF":4.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent binding of 5-tetradecyloxy-2-furoic acid (TOFA) and c(RGDfK) and its co-delivery with Lipusu, a novel synergistic strategy to inhibit the proliferation of nasopharyngeal cancer","authors":"Min Feng ,&nbsp;Wei Gong ,&nbsp;Xin Zhu ,&nbsp;Juan Zhu ,&nbsp;Junjie Hu ,&nbsp;Weihua Xu ,&nbsp;Zhichao Ma ,&nbsp;Shengmiao Fu ,&nbsp;Xinping Chen","doi":"10.1016/j.ejps.2025.107092","DOIUrl":"10.1016/j.ejps.2025.107092","url":null,"abstract":"<div><div>As the world's only commercially available paclitaxel liposome, Lipusu (Lip) has been clinically used in chemotherapy for &gt;20 years, but the design concept of Lip remains largely unchanged since its initial development. Based on the study of Acetyl-CoA-carboxylase 1 (ACC1) in nasopharyngeal carcinoma (NPC), we proposed the concept of next-generation liposomes (NGL) utilizing lipid demand balance. In this study, we evaluated the feasibility of ACC1 and integrin α_Vβ₃ as NPC targets, and designed 10 conjugates of 5-tetradecyloxy-2-furoic acid (TOFA) and c(RGDfK) that can bind to Lip. Considering the results of chemical parameter prediction, molecular docking, molecular dynamics simulation (MD) and other aspects, we finally selected and synthesized the compound F, and successfully constructed F-Lip by simple incubation method. Compared with Lip, F-Lip showed stronger toxicity in both HONE-1 cells and corresponding tumor-bearing mice. In conclusion, by regulating the balance of lipid demand, the toxicity of Lip can be improved so as to achieve the goal of inhibiting the proliferation of NPC. This study provides a new model for the future design and development of Lip.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107092"},"PeriodicalIF":4.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selected new approaches and future perspectives in liquid chromatography for the analysis of emerging modalities","authors":"Szabolcs Fekete ,&nbsp;Mateusz Imiołek ,&nbsp;Fabrice Gritti ,&nbsp;Matthew Lauber ,&nbsp;Balasubrahmanyam Addepalli ,&nbsp;MingCheng Xu","doi":"10.1016/j.ejps.2025.107101","DOIUrl":"10.1016/j.ejps.2025.107101","url":null,"abstract":"<div><div>Emerging biopharmaceutical modalities, such as genetic medicines and RNA therapies, offer transformative potential for treating previously intractable diseases. However, these complex drugs present unique analytical challenges due to their intricate structures, sophisticated manufacturing processes, and modality-specific product quality attributes. Liquid chromatography (LC) has emerged as a versatile tool for addressing these challenges, enabling precise characterization and quality control strategies. This review highlights recent advancements in LC technologies, including low-adsorption hardware, ultra-wide pore size exclusion chromatography (SEC) columns, and innovative separation modes such as slalom chromatography and pressure-enhanced liquid chromatography (PELC). These developments tackle issues such as non-specific adsorption, carryover, and inadequate selectivity while improving resolution and robustness for large biomolecules like mRNA, adeno-associated viruses (AAVs), and lipid nanoparticles (LNPs). Novel approaches, such as tandem SEC systems, gradient SEC columns, and dual stationary phase gradients, further expand the scope of LC techniques by enhancing separations for diverse analyte sizes and complexities. Additionally, practical innovations like bracketed injection methods and new enzymatic tools for oligo-mapping improve reproducibility, efficiency, and confidence in RNA sequence analysis. These advancements not only address current analytical limitations but also pave the way for regulatory-compliant approaches, which will support the broader adoption of LC in both discovery and quality control settings. As the field continues to evolve, these innovations are poised to play a pivotal role in ensuring the safety, efficacy, and consistency of next-generation therapeutics.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107101"},"PeriodicalIF":4.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review on quinolines: New green synthetic methods and bioactive potential","authors":"Laura M. Ferreira,&nbsp;Pilar García-García,&nbsp;Pablo A. García,&nbsp;María Ángeles Castro","doi":"10.1016/j.ejps.2025.107097","DOIUrl":"10.1016/j.ejps.2025.107097","url":null,"abstract":"<div><div>Quinolines have been an interest of study for a few decades due to the importance of this system in natural and pharmaceutical products. Since their discovery in the nineteenth century, many medicinal properties have been found for quinoline compounds. Firstly, as an anti-parasitic agent against malaria and then against many other diseases, such as, other parasitic infections, HIV, bacterial infections and cancer. Consequently, many synthetic methods have been developed to afford the quinoline ring.</div><div>In this review we look back at traditional methods and look forward to the most recent and promising “green” methods for the synthesis of quinolines. Also, we review the newest advances in therapeutic compounds based on the quinoline skeleton for the treatment of parasitic and cancer diseases and the most recent applications of quinoline derivatives in drug delivery systems.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107097"},"PeriodicalIF":4.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of FOXO3a Nuclear Localization by Linagliptin (BI-1356) Reveals a New Therapeutic Target in Chronic Ulcerative Colitis","authors":"Abdulaziz Saad Alshahrani ,&nbsp;Sameh Saber ,&nbsp;Ohoud Shafi Alruwaili ,&nbsp;Zubida M. Al-Majdoub ,&nbsp;Rabab S. Hamad ,&nbsp;Mustafa Ahmed Abdel-Reheim ,&nbsp;Bahaa Eldin Ali Khaled ,&nbsp;Alaa Alibrahim ,&nbsp;Asmaa Ramadan ,&nbsp;Attalla F. El-kott ,&nbsp;Ali S. AlSheri ,&nbsp;Sally Negm ,&nbsp;Elsayed A. Elmorsy ,&nbsp;Amira Karam Khalifa ,&nbsp;Rasha Abdelhady","doi":"10.1016/j.ejps.2025.107100","DOIUrl":"10.1016/j.ejps.2025.107100","url":null,"abstract":"<div><div>Globally, the incidence and prevalence rates of ulcerative colitis (UC) show a rising pattern. The limited efficacy and significant adverse effects associated with current treatment options underscore the need for novel therapeutic approaches. It has been found that linagliptin, a dipeptidyl peptidase-4 inhibitor, activates AMPK in different disease conditions. The main objective of the present work was to elucidate the potential implications of the AMPK/FOXO3a mediated by linagliptin in rats with chronic colitis. The findings of the current report revealed the first robust in-vivo evidence advocating the coloprotective effect of linagliptin against dextran sodium sulfate-induced chronic UC in rats. It has demonstrated potential beyond its antidiabetic effects by modulating FOXO3a localization. By shifting FOXO3a from the cytosol to the nucleus, linagliptin enhanced the transcription of genes involved in attenuation of pro-inflammatory events and restoration of redox homeostasis. Nuclear FOXO3a also impacted NFκB activity, reducing inflammation. This conclusion was fundamentally supported by the documented improvements in histopathological changes evidenced by reduced inflammation, edema, crypt atrophy, and submucosal fibrosis. Moreover, decreased colon weight/length ratio, as well as reduced scores of disease activity and macroscopic damage indices, were observed. Furthermore, it corrected body weight loss during the time frame of the experiment. These findings underscore the anti-inflammatory potential of therapies that promote the nuclear localization of FOXO3a in inflammatory conditions. Linagliptin's ability to modulate FOXO3a localization might be particularly useful for diabetic patients suffering from inflammatory bowel diseases. However, further molecular investigations are required to validate the findings and to assess the clinical application of this approach as a valid tool for alleviating UC.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107100"},"PeriodicalIF":4.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E1231/SR647 protects against unilateral renal ischemia-reperfusion injury by modulating SIRT1/FOXO3 interactions with Nrf2 and NFκB pathways","authors":"Sameh Saber ,&nbsp;Rabab S. Hamad ,&nbsp;Elsayed A. Elmorsy ,&nbsp;Mustafa Ahmed Abdel-Reheim ,&nbsp;Alshaimaa A. Farrag ,&nbsp;Amany M. Ismaiel ,&nbsp;Zubida M. Al-Majdoub ,&nbsp;Sara T. Elazab ,&nbsp;Noura El Adle Khalaf ,&nbsp;Hala Magdy Anwer ,&nbsp;Ahmed Abdel-monem Elmetwally ,&nbsp;Dalia M.Abdel Ghaffar ,&nbsp;Shereen Hamed ,&nbsp;Amira A. Haleem ,&nbsp;Walid Mostafa Sayed Ahmed ,&nbsp;Sherin Zohdy Mohamed ,&nbsp;Karem Mohamed Salem ,&nbsp;Rasha Abdelhady ,&nbsp;Ahmed Shata ,&nbsp;Asmaa Ramadan","doi":"10.1016/j.ejps.2025.107099","DOIUrl":"10.1016/j.ejps.2025.107099","url":null,"abstract":"<div><div>Ischemia is a major contributor to acute kidney injury (AKI), for which current treatment options remain limited. One NAD⁺-dependent deacetylase that can preserve renal cells is SIRT1. To date, no research has directly explored the effects of E1231, a SIRT1 activator, in the context of renal ischemia-reperfusion (IR) injury. Enhancing NAD⁺ levels is essential for sustaining SIRT1 activity. Hence, the combined use of E1231 and SR647, a NAD⁺ precursor, could potentially amplify protective effects by supporting prolonged SIRT1 activation. This study is the first to investigate the therapeutic potential of combining E1231 and SR647 in mitigating unilateral renal IR injury. Rats treated with E1231/SR647 effectively demonstrated reduced tubular damage, inflammation, and necrosis. These improvements correlated with a reduced kidney-to-body weight ratio and increased urine output and flow rate. Additionally, rats with IR injury demonstrated reductions in serum creatinine, BUN, UAER, and cystatin C, as well as urinary NGAL and both serum and urinary KIM-1 levels. On the other hand, elevations in urine creatinine and creatinine CL were recorded. E1231 alone provided moderate functional recovery, which was negated when co-administered with a SIRT1 inhibitor. E1231/SR647 treatment upregulated SIRT1 levels and activity, subsequently enhancing FOXO3 activation. It also boosted Nrf2 levels and activity, upregulating the antioxidant protein expression of HO-1 and NQO1. Furthermore, E1231/SR647 reduced the inflammatory response by inhibiting NFκB activity. In conclusion, E1231/SR647 is a promising therapy that may protect renal function during ischemic events through the modulation of SIRT1/FOXO3 control over Nrf2 and NFκB pathways.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"209 ","pages":"Article 107099"},"PeriodicalIF":4.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}