Journal of Pharmacy and Pharmacology最新文献_第10页

Rhein induces apoptosis of AGS and MGC803 cells by regulating the Ras/PI3K/AKT and p38/MAPK signaling pathway. Rhein 通过调节 Ras/PI3K/AKT 和 p38/MAPK 信号通路诱导 AGS 和 MGC803 细胞凋亡。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-06-09 DOI: 10.1093/jpp/rgae115

Meiqi Wan, Anna Gan, Jun Dai, Fei Lin, Ruixuan Wang, Bo Wu, Tingxu Yan, Ying Jia

{"title":"Rhein induces apoptosis of AGS and MGC803 cells by regulating the Ras/PI3K/AKT and p38/MAPK signaling pathway.","authors":"Meiqi Wan, Anna Gan, Jun Dai, Fei Lin, Ruixuan Wang, Bo Wu, Tingxu Yan, Ying Jia","doi":"10.1093/jpp/rgae115","DOIUrl":"10.1093/jpp/rgae115","url":null,"abstract":"Objectives: Rhein is one of the main bioactive compounds in the Polygonaceae plant, and has been proven to have anti-cancer activity in some reports. But the mechanism of Rhein in the treatment of gastric cancer (GC) is limited reported. In this research, network pharmacology combined with in vitro experiments was used for systematically studying the mechanism of Rhein.Methods: Network pharmacology confirmed the major effect signaling pathway and key targets of Rhein in the treatment of GC. Cell viability assay, colony formation assay, fluorescence probe assay, apoptosis assay, western blot and qRT-PCR verified the mechanism of Rhein in the treatment of GC cells (AGS and MGC803 cells).Key findings: The results showed that Rhein significantly induced the apoptosis process of AGS and MGC803 cells by regulating the Ras/phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) and the p38/mitogen-activated protein kinase signaling pathways. The AKT activator (SC79) and p38 inhibitor (SB202190) inhibited Rhein-induced apoptosis.Conclusions: All results proved that Rhein could be recognized as a potential natural drug for the treatment of GC.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"783-793"},"PeriodicalIF":2.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406534","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}

引用次数: 0

Repurposing the familiar: Future treatment options against chronic kidney disease. 重新利用熟悉的：慢性肾脏疾病的未来治疗方案。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-06-09 DOI: 10.1093/jpp/rgaf002

Rohan Bhadange, Anil Bhanudas Gaikwad

{"title":"Repurposing the familiar: Future treatment options against chronic kidney disease.","authors":"Rohan Bhadange, Anil Bhanudas Gaikwad","doi":"10.1093/jpp/rgaf002","DOIUrl":"10.1093/jpp/rgaf002","url":null,"abstract":"Objectives: Chronic kidney disease (CKD) is a serious health issue with rising morbidity and mortality rates. Despite advances in understanding its pathophysiology, effective therapeutic options are limited, necessitating innovative treatment approaches. Also, current frontline treatments that are available against CKD are not uniformly effective and often come with significant side effects. Therefore, identifying new therapeutic targets or improving existing treatments for CKD is crucial. Drug repurposing is a promising strategy in the drug discovery process that involves screening existing approved drugs for new therapeutic applications.Key findings: This review discusses the pharmacological mechanisms and clinical evidence that support the efficacy of these repurposed drugs. Various drugs classes such as inodilators, endothelin-1 type A (ET-1A) receptor antagonists, bisphosphonates, mineralocorticoid receptor (MR) antagonists, DNA demethylating agents, nuclear factor erythroid 2-related factor 2 (NRF2) activators, P2X7 inhibitors, autophagy modulators, hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) are discussed that could remarkably contribute against CKD.Summary: The review critically examines the potential for repurposing well-established drugs to slow the progression of CKD and enhance patient outcomes. This review emphasizes the importance of a multidisciplinary approach in advancing the field of drug repurposing, ultimately paving the way for innovative and effective therapies for patients suffering from CKD.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"715-728"},"PeriodicalIF":2.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007254","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}

引用次数: 0

Correction to: Isoliquiritigenin attenuates inflammation and modulates Nrf2/caspase-3 signalling in STZ-induced aortic injury. 更正：异尿酸原可减轻stz诱导的主动脉损伤中的炎症并调节Nrf2/caspase-3信号。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-06-06 DOI: 10.1093/jpp/rgaf046

引用次数: 0

DST regulates cisplatin resistance in colorectal cancer via PI3K/Akt pathway. DST 通过 PI3K/Akt 通路调节结直肠癌的顺铂耐药性

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae104

Jianwei Yu, Xueqiong Deng, Xueqin Lin, Li Xie, Sisi Guo, Xiaoliang Lin, Dong Lin

{"title":"DST regulates cisplatin resistance in colorectal cancer via PI3K/Akt pathway.","authors":"Jianwei Yu, Xueqiong Deng, Xueqin Lin, Li Xie, Sisi Guo, Xiaoliang Lin, Dong Lin","doi":"10.1093/jpp/rgae104","DOIUrl":"10.1093/jpp/rgae104","url":null,"abstract":"Objectives: Dystonin (DST), a potential tumor suppressor gene, plays a crucial role in regulating cancer cell proliferation and resistance to chemotherapy. However, DST's specific role in colorectal cancer (CRC) has not been thoroughly investigated, and this study aims to elucidate its molecular role in modulating cisplatin (DDP) resistance in CRC.Methods: DST expression was analyzed in CRC tumors, DDP-resistant CRC tissues, paracancer tissues, and normal tissues. Lentiviral overexpression and shRNA knockdown were conducted in advanced CRC and DDP-resistant cell lines to assess cell viability, apoptosis, invasion, migration, proliferation, and angiogenesis. Xenograft mouse models studied DST's impact on CRC tumor growth and DDP resistance in vivo.Results: DST expression was significantly reduced in CRC tumor and DDP-resistant CRC tissues compared to paracancer and normal tissues (P < .001). Upregulating DST inhibited CRC and DDP-resistant cell viability, proliferation, invasion, and migration while promoting apoptosis. DST overexpression also reduced angiogenesis and attenuated DDP-induced cytotoxicity in CRC cells. Mechanistically, DST upregulation suppressed DDP resistance in CRC cells via the PI3K/Akt signaling pathway. DST upregulation reduced CRC tumor growth and mitigated DDP resistance, in vivo.Conclusion: DST plays a crucial role in limiting CRC progression and overcoming DDP resistance, suggesting potential for targeted CRC therapies.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"698-713"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142468354","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}

引用次数: 0

Osteogenic effect of alogliptin in chemical-induced bone loss: a tri-modal in silico, in vitro, and in vivo analysis. 阿格列汀在化学物质诱导的骨质流失中的成骨作用：硅学、体外和体内三模式分析。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae112

Faraha Ahmed, Syed Sufian Ahmad, Mohammad Mumtaz Alam, Mohammad Shaquiquzzaman, Mohammad Altamish, Anuja Krishnan, Divya Vohora, Abul Kalam Najmi, Mohammad Ahmed Khan

{"title":"Osteogenic effect of alogliptin in chemical-induced bone loss: a tri-modal in silico, in vitro, and in vivo analysis.","authors":"Faraha Ahmed, Syed Sufian Ahmad, Mohammad Mumtaz Alam, Mohammad Shaquiquzzaman, Mohammad Altamish, Anuja Krishnan, Divya Vohora, Abul Kalam Najmi, Mohammad Ahmed Khan","doi":"10.1093/jpp/rgae112","DOIUrl":"10.1093/jpp/rgae112","url":null,"abstract":"Objective: To investigate the effects of Alogliptin in chemical-induced post-menopausal osteoporosis.Methodology: The binding affinity of alogliptin with osteogenic proteins was analysed in silico. The effect of alogliptin on osteogenic proteins and mineralization of osteoblastic cells was evaluated in UMR-106 cells. Further, in vivo anti-osteoporotic activity of alogliptin was evaluated in postmenopausal osteoporosis. Various bone turnover markers were assayed in serum. This followed the analysis of microarchitecture of bone, histology, and immunohistochemistry (IHC) of bone tissue.Results: Docking scores showed that alogliptin has binding affinity for bone alkaline phosphatase (BALP), osteocalcin, and bone morphogenic protein (BMP-2). Alogliptin also enhanced mineralization of osteoblast cells, evidenced with increased ALP, osteocalcin, and BMP-2. Animal studies revealed significant elevation of bone formation markers, bone ALP, osteocalcin and BMP-2, and decreased bone resorption markers, receptor activator of NF-κβ (RANKL), cathepsin K (CTSK), tartrate resistant acid phosphatase (TRAcP5b) in VCD-induced post-menopausal osteoporosis. Micro computed tomography (μCT) analysis and histology of femur bone and lumbar vertebrae demonstrated decrease in trabecular separation and improved bone density. IHC of femur showed reduced DPP4 enzyme.Conclusions: Alogliptin increased mineralization in osteoblast cells. It had beneficial effects also altered bone turnover markers, repaired the trabecular microstructure, improved bone mineral density, and exhibited bone forming capacity targeting DPP-4 enzyme in postmenopausal osteoporosis.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"668-684"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365642","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}

引用次数: 0

Decoding the power of saponins in ferroptosis regulation and disease intervention: a review. 解码皂苷在铁变态反应调节和疾病干预中的作用：综述。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae144

Min Ouyang, Jianhua Wu, Xizhuo Hu, Changfu Liu, Dan Zhou

{"title":"Decoding the power of saponins in ferroptosis regulation and disease intervention: a review.","authors":"Min Ouyang, Jianhua Wu, Xizhuo Hu, Changfu Liu, Dan Zhou","doi":"10.1093/jpp/rgae144","DOIUrl":"10.1093/jpp/rgae144","url":null,"abstract":"Objectives: This review endeavors to elucidate the complex interplay underlying diseases associated with ferroptosis and to delineate the multifaceted mechanisms by which triterpenoid and steroidal saponins modulate this form of cell death.Methods: A meticulous examination of the literature was undertaken, drawing from an array of databases including Web of Science, PubMed, and Wiley Library, with a focus on the keywords \"ferroptosis,\" \"saponin,\" \"cancer,\" \"inflammation,\" \"natural products,\" and \"signaling pathways.\"Key findings: Ferroptosis represents a distinctive mode of cell death that holds considerable promise for the development of innovative therapeutic strategies targeting a wide range of diseases, especially cancer and inflammatory disorders. This review reveals the nuanced interactions between saponins and critical signaling pathways, including system Xc--GSH-GPX4, Nrf2, p53, and mTOR. These interactions highlight the dual capacity of saponins to modulate ferroptosis, thereby offering fresh perspectives for therapeutic intervention.Conclusions: The insights garnered from this review significantly advance our comprehension of the dynamic relationship between saponins and ferroptosis. By shedding light on these mechanisms, this work sets the stage for leveraging these insights in the creation of pioneering approaches to disease treatment, marking a significant stride in the evolution of therapeutic modalities.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"593-608"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823545","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}

引用次数: 0

Integrated metabolomics and network pharmacology analysis to reveal the mechanisms of naringin against atherosclerosis. 综合代谢组学和网络药理学分析揭示柚皮苷抗动脉粥样硬化的机制。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae156

Gaoning Zhang, Xiaoyi Yin, Xiao Tang, Kexin Wang, Yifan Liu, Lili Gong, Zhenhua Tian

{"title":"Integrated metabolomics and network pharmacology analysis to reveal the mechanisms of naringin against atherosclerosis.","authors":"Gaoning Zhang, Xiaoyi Yin, Xiao Tang, Kexin Wang, Yifan Liu, Lili Gong, Zhenhua Tian","doi":"10.1093/jpp/rgae156","DOIUrl":"10.1093/jpp/rgae156","url":null,"abstract":"Objectives: The purpose of this study was to explore the mechanism of naringin in atherosclerotic mice from the perspective of network pharmacology and non-targeted metabolomics.Methods: ApoE-/- mice were induced to establish an atherosclerotic model to explore the pharmacodynamics and potential mechanism of naringin in atherosclerosis (AS). Pathological section and blood lipid levels were used to evaluate the intervention effects. The core targets, metabolites, and related pathways of naringin alleviating atherosclerotic were predicted through network pharmacology and metabolomics analysis. Furthermore, the inflammatory factors and pathway-related protein expression were detected using ELISA and Western blot methods.Key findings: It turned out that compared with the model group, the naringin could reduce the development degree in atherosclerotic mice. The network pharmacology suggested that PI3K-AKT pathway was an important mechanism for naringin to interfere with AS. Serum metabolic data were collected and analyzed, and a total of 27 potential biomarkers were identified, involving vitamin B6 metabolism, arginine metabolism, and retinol metabolism. The experiment verified that naringin inhibited inflammation in AS through the PI3K-AKT/TLR4/NF-κB pathway.Conclusions: This study provides a strategy combining metabolomics and network pharmacology to explore the alleviation of AS by naringin and offers a new idea for its application.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"621-634"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414470","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}

引用次数: 0

Molecular mechanisms of endoplasmic reticulum stress-mediated acute kidney injury in juvenile rats and the protective role of mesencephalic astrocyte-derived neurotrophic factor. 内质网应激介导的幼年大鼠急性肾损伤的分子机制及间脑星形胶质细胞源性神经营养因子的保护作用

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae134

Li-Ran Zhu, Wei Cui, Hai-Peng Liu

{"title":"Molecular mechanisms of endoplasmic reticulum stress-mediated acute kidney injury in juvenile rats and the protective role of mesencephalic astrocyte-derived neurotrophic factor.","authors":"Li-Ran Zhu, Wei Cui, Hai-Peng Liu","doi":"10.1093/jpp/rgae134","DOIUrl":"10.1093/jpp/rgae134","url":null,"abstract":"Objectives: This study examined the role of endoplasmic reticulum stress in pediatric acute kidney injury and the therapeutic effect of midbrain astrocyte-derived neurotrophic factor.Methods: Two-week-old Sprague-Dawley rats were divided into: Sham, ischemia-reperfusion injury-induced acute kidney injury (AKI), mesencephalic astrocyte-derived neurotrophic factor (MANF)-treated, tauroursodeoxycholic acid (TUDCA)-treated. Analyses were conducted 24 h post-treatment. Serum creatinine, cystatin C, Albumin, MANF levels were measured, cytokine concentrations in serum and renal tissues were determined using a Luminex assay. Histopathology was assessed via light and electron microscopy. Western blotting and RT-qPCR analyzed markers for oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, and autophagy. HK-2 cells underwent hypoxia/reoxygenation (H/R) to simulate AKI and were treated with MANF or TUDCA.Results: AKI rats had increased serum creatinine, cystatin C, and inflammatory cytokines, along with significant renal damage, and showed loose and swollen ER structures, reduced cell proliferation, and elevated levels of IRE1, PERK, ATF6, CHOP, LC3-II/I, KIM-1, TLR4, JNK, and NF-κB. MANF treatment reduced these biomarkers and protein levels, improved ER structure and cell proliferation, alleviated oxidative stress, apoptosis, ER stress, and inhibited JNK/TLR4/NF-κB signaling. In HK-2 cells, MANF reduced ER stress and inflammation post-H/R exposure.Conclusions: MANF treatment alleviates ER stress, oxidative stress, apoptosis, and inflammation in pediatric AKI, improving renal function and morphology.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"609-620"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502628","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}

引用次数: 0

Silencing c-myc gene by siRNA delivered by cationic niosomes in MCF-7 cells. 在 MCF-7 细胞中用阳离子纳米囊递送 siRNA 沉默 c-myc 基因。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae146

Shatha N Abdeljaber, Alaa A Aljabali, Bahaa Altrad, Mohammad A Obeid

{"title":"Silencing c-myc gene by siRNA delivered by cationic niosomes in MCF-7 cells.","authors":"Shatha N Abdeljaber, Alaa A Aljabali, Bahaa Altrad, Mohammad A Obeid","doi":"10.1093/jpp/rgae146","DOIUrl":"10.1093/jpp/rgae146","url":null,"abstract":"Objectives: Gene therapy has a strong potential to treat different cancer types cancers with high therapeutic outcomes. c-myc is believed to be responsible for more than 15% of all gene regulation and functions as a transcription factor for proteins essential for cell proliferation. This study aimed to develop niosome nanocarriers to knockdown c-myc expression using anti-c-myc short-interfering RNA (siRNA) in MCF-7 cells. Altering the activity of the c-myc proto-oncogene has been identified as an important element in minimizing cancer cell growth because anti-c-myc siRNA degrades c-myc mRNA.Methods: Noisomes were prepared from Tween 85, cholesterol, and didodecyldimethylammonium bromide at 50:40:10 and 40:40:20 molar ratios. Anti-c-myc siRNA was loaded in the prepared niosomes and then applied on MCF-7 cells.Key findings: Niosomes had a total positive charge formed electrostatic interactions with siRNA. Niosomes were spherical with a size range of 70-100 nm. The prepared niosomes were nontoxic to MCF-7 cells, with IC50 values of >250 µg/ml for both formulations. After encapsulation of anti-c-myc siRNA, nioplexes reduced c-myc mRNA expression by more than 50% compared with the untreated cells. Empty niosomes did not affect c-myc mRNA expression levels, indicating that the effect was due to siRNA rather than the particles themselves.Conclusions: This study provides evidence that niosomes can function as suitable carriers for siRNA delivery to knockdown the c-myc oncogene in MCF-7 cells, thus reducing cancer cell growth.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"658-667"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687173","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}

引用次数: 0

Case study: cremophor EL-based liquid formulations as simple substitutes for amorphous solid dispersions in early preclinical in vivo studies. 案例研究：基于 cremophor EL 的液体制剂在早期临床前体内研究中作为无定形固体分散体的简单替代品。

IF 2.8 4区医学

Journal of Pharmacy and Pharmacology Pub Date : 2025-05-02 DOI: 10.1093/jpp/rgae099

Kalle Sigfridsson, Xiang Zhang, Antonio Llinas

{"title":"Case study: cremophor EL-based liquid formulations as simple substitutes for amorphous solid dispersions in early preclinical in vivo studies.","authors":"Kalle Sigfridsson, Xiang Zhang, Antonio Llinas","doi":"10.1093/jpp/rgae099","DOIUrl":"10.1093/jpp/rgae099","url":null,"abstract":"Objectives: The objective of the present case study was to increase the exposure of the poorly soluble crystalline compound A.Methods: Mice received 10 mg/kg of crystalline compound A formulated in eight different cosolvent, oil, and cyclodextrin mixtures.Key findings: In all cases, AUC0-24h and maximum blood/plasma concentration (Cmax) were in the range of 6-16 µM × h and <1.4 µm, respectively, with a bioavailability below 18%. When 6% cremophor (CrEL) was added to three selected vehicles, AUC0-24h and Cmax increased ~5-10 times. The obtained pharmacokinetic profile of the most improved formulation using CrEL was possible to superimpose on the one obtained after administration of a CrEL-free amorphous solid dispersion (ASD, HPMC-AS:drug, 80:20) suspension of compound A.Conclusions: It is crucial to find an optimal screen vehicle as early as possible for a poorly water-soluble lead series and then avoid time and resource-consuming vehicle testing of multiple compounds in vivo. An ASD approach is more suited for clinical development when more time and resources are allocated to the project. In this case study, some preclinical formulations were used to maximize exposure but also as preindicators for ASDs later in the development chain.","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":" ","pages":"645-657"},"PeriodicalIF":2.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751972","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}

引用次数: 0