Xenobiotica最新文献_第3页

Comprehensive in vitro assessment of drug-drug interactions of the major human metabolite of soticlestat. 索替列他主要人体代谢物的药物-药物相互作用的综合体外评估。

IF 1.2 4区医学

Xenobiotica Pub Date : 2025-06-01 Epub Date: 2025-07-27 DOI: 10.1080/00498254.2025.2532649

Miyuki Ugajin, Mitsuhiro Nishihara, T Eric Ballard, Lawrence Cohen, Bei-Ching Chuang, Junzo Takahashi, Hideki Hirabayashi

{"title":"Comprehensive in vitro assessment of drug-drug interactions of the major human metabolite of soticlestat.","authors":"Miyuki Ugajin, Mitsuhiro Nishihara, T Eric Ballard, Lawrence Cohen, Bei-Ching Chuang, Junzo Takahashi, Hideki Hirabayashi","doi":"10.1080/00498254.2025.2532649","DOIUrl":"10.1080/00498254.2025.2532649","url":null,"abstract":"Soticlestat (TAK-935) is a selective cholesterol 24S-hydroxylase inhibitor and represents a potential adjunctive treatment for Dravet and Lennox-Gastaut syndromes. The direct glucuronide metabolite of soticlestat TAK-935-G is the primary circulating drug-related material in humans. Thus, the potential of TAK-935-G as a perpetrator for drug-drug interactions (DDIs) was evaluated according to the current regulatory guideline. The DDI risk between soticlestat/TAK-935-G and representative anti-seizure medications (ASMs) was also investigated using various in vitro assays.TAK-935-G was not a perpetrator of cytochrome P450 enzymes (CYPs), uridine diphosphate glucuronosyl-transferase enzymes (UGTs) or transporters, except for CYP1A2 induction, where it demonstrated an induction with an Emax of 2.06- to 3.56-fold change and EC50 of 53.7-78.8 µM. Two ASMs are known to be substrates of CYP1A2; however, no serious DDI through CYP1A2 induction has been reported. The examined ASMs did not inhibit soticlestat glucuronidation. Moreover, soticlestat and TAK-935-G did not inhibit glucuronidation of the examined ASMs.Collectively, no notable concern exists regarding the clinical perpetrator risk of CYP, UGT and transporters with TAK-935-G, despite its high unbound plasma concentrations. The combined analysis of in vitro and clinical DDI results, alongside physiologically based pharmacokinetic modelling, exhibited a low DDI risk for soticlestat and TAK-935-G.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"499-506"},"PeriodicalIF":1.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643654","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

Dysregulation of kidney structural polysaccharides and miRNA-21/SIRT1/NF-κB axis of injury and fibrosis in thioacetamide-induced nephrotoxicity is protected by resveratrol. 在硫代乙酰胺引起的肾毒性中，肾脏结构多糖和miRNA-21/SIRT1/NF-κB轴损伤和纤维化的失调受到白藜芦醇的保护。

IF 1.2 4区医学

Xenobiotica Pub Date : 2025-06-01 Epub Date: 2025-07-30 DOI: 10.1080/00498254.2025.2535410

Mohammed Alshehri, Ibrahim Tawhari, Faris Almasabi, Hind Zafrah, Alia Albawardi, Nervana M Bayoumy, Mohamed Abd Ellatif, Bahjat Al-Ani, Norah M Alzamil, Samaa S Kamar

{"title":"Dysregulation of kidney structural polysaccharides and miRNA-21/SIRT1/NF-κB axis of injury and fibrosis in thioacetamide-induced nephrotoxicity is protected by resveratrol.","authors":"Mohammed Alshehri, Ibrahim Tawhari, Faris Almasabi, Hind Zafrah, Alia Albawardi, Nervana M Bayoumy, Mohamed Abd Ellatif, Bahjat Al-Ani, Norah M Alzamil, Samaa S Kamar","doi":"10.1080/00498254.2025.2535410","DOIUrl":"10.1080/00498254.2025.2535410","url":null,"abstract":"MicroRNA-21 (miRNA-21) expression is increased in patients with kidney disease, and polysaccharides provide the structural scaffolding of the glomerular and tubular basement membranes.We investigated whether the induction of renal injury by the industrial toxic chemical thioacetamide (TAA) can dysregulate the kidney miRNA-21/SIRT1/NF-κB axis as well as the structural polysaccharide content of the kidney tissue, and whether treatment with the polyphenolic compound resveratrol can inhibit these adverse effects.Kidney injury was induced in rats by TAA (200 mg/kg) injections. The protective group of rats was pre-treated with resveratrol (20 mg/kg) prior to kidney injury and subsequently kept on resveratrol until culled.TAA intoxication caused a significant (p < 0.0001) modulation in kidney and blood levels of miRNA-21, the tissue renoprotective molecule SIRT1, NF-κB p65, kidney structural polysaccharides, the macrophage biomarker cluster of differentiation 68 (CD68), tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA, hypernatremia, urea, and creatinine, as well as albuminuria that were significantly (p ≤ 0.0187) protected by resveratrol. Furthermore, a significant correlation between the miRNA-21/SIRT1/NF-κB axis, structural polysaccharides, renal fibrosis, and renal injury biomarkers was observed.These findings demonstrate an association between renal injury induced by TAA intoxication and the dysregulation of the kidney miRNA-21/SIRT1/NF-κB axis and polysaccharide levels while being protected by resveratrol.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"507-516"},"PeriodicalIF":1.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675931","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

Arachidonic acid ameliorates the liver and kidney injuries induced by thioacetamide in rats. 花生四烯酸对硫乙酰胺所致大鼠肝肾损伤的改善作用。

IF 1.2 4区医学

Xenobiotica Pub Date : 2025-06-01 Epub Date: 2025-08-03 DOI: 10.1080/00498254.2025.2535407

Siyu Xiang, Dong Kwon Yang, Jin-Shang Kim, Shang-Jin Kim

{"title":"Arachidonic acid ameliorates the liver and kidney injuries induced by thioacetamide in rats.","authors":"Siyu Xiang, Dong Kwon Yang, Jin-Shang Kim, Shang-Jin Kim","doi":"10.1080/00498254.2025.2535407","DOIUrl":"10.1080/00498254.2025.2535407","url":null,"abstract":"Arachidonic acid (ArA) is an essential omega-6 polyunsaturated fatty acid is crucial in various physiological processes and disease conditions. Nevertheless, the effects of arachidonic acid on liver and kidney damage are not well understood. Therefore, this study aimed to explore the beneficial role of ArA on liver and kidney injuries caused by thioacetamide (TAA) in rats, focusing on the associated hematological changes.The six groups, each consisting of 10 rats, are as follows; Control, 30 mg/kg ArA-treated, 20 mg/kg TAA-induced liver injury, ArA (10, 20, and 30 mg/kg)-pre-treated liver injury groups.The pre-treatment of ArA ameliorated histopathological injuries of hepatic and kidney tissues and hepatic dysfunction in TAA-treated rats. TAA increased hepatic and kidney injury serum biomarkers, otherwise, ArA significantly suppressed increased levels of these parameters and inhibited metabolic acidosis and dehydration due to TAA treatment. Besides, ArA effectively preserved protein and cholesterol metabolism against TAA-induced hepatic injury. ArA suppressed TAA caused ionic imbalance. Notably, the highest AA dosage (30 mg/kg) provided the most protective effects against TAA-induced liver and kidney damage.This study demonstrated that ArA effectively reduces liver and kidney injuries caused by TAA, indicating its potential as a promising preventive or therapeutic approach.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"517-525"},"PeriodicalIF":1.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754581","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

Machine learning-driven bioavailability prediction in early-stage drug development: a KNIME-based computational workflow for digital health applications. 早期药物开发中机器学习驱动的生物利用度预测：用于数字健康应用的基于knime的计算工作流。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-05-28 DOI: 10.1080/00498254.2025.2508804

Majdi Hammami, Walid Yeddes, Hamza Gadhoumi, Raghda Yazidi, Moufida Saidani Tounsi, Kamel Msaada

{"title":"Machine learning-driven bioavailability prediction in early-stage drug development: a KNIME-based computational workflow for digital health applications.","authors":"Majdi Hammami, Walid Yeddes, Hamza Gadhoumi, Raghda Yazidi, Moufida Saidani Tounsi, Kamel Msaada","doi":"10.1080/00498254.2025.2508804","DOIUrl":"10.1080/00498254.2025.2508804","url":null,"abstract":"Bioavailability prediction remains a significant challenge in early-stage drug development, where conventional experimental approaches are time-consuming and resource-intensive. This study explores the application of machine learning techniques to enhance the efficiency of bioavailability prediction. By leveraging computational workflows within the KNIME Analytics Platform, we aim to automate bioavailability assessment and reduce dependence on costly in vitro and in vivo studies.A dataset comprising 475 drug-like compounds characterised by key molecular descriptors was analysed using multiple machine learning models, including Random Forest, Gradient Boosting, Decision Trees, k-Nearest Neighbours, and neural networks. Model performance was assessed through 5-fold cross-validation, with ensemble models outperforming linear and neural network-based approaches. Random Forest demonstrated the highest predictive performance (R2 = 0.87, RMSE = 0.08). Feature importance analysis identified topological polar surface area and solubility as the most influential factors in bioavailability prediction.The findings underscore the potential of integrating open-source tools and machine learning methodologies in pharmaceutical research, improving workflow efficiency while adhering to FAIR (Findable, Accessible, Interoperable, and Reusable) data principles. This approach facilitates rapid and cost-effective bioavailability assessment, supporting AI-driven predictive modelling and digital health applications in drug development.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"339-348"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112216","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

Genetic polymorphisms of ABCC2 and CBR3 can influence the efficacy and toxicity of doxorubicin therapy in Egyptian patients with non-Hodgkin lymphoma. ABCC2和CBR3基因多态性可影响阿霉素治疗埃及非霍奇金淋巴瘤患者的疗效和毒性。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-05-29 DOI: 10.1080/00498254.2025.2508814

Hagar A Elmekawy, Khaled Abdelkawy, Galal Magdy, Emad Sadaka, Gamal El-Azab, Ahmed Ali, Noha El-Khodary, Fawzy Elbarbry

{"title":"Genetic polymorphisms of ABCC2 and CBR3 can influence the efficacy and toxicity of doxorubicin therapy in Egyptian patients with non-Hodgkin lymphoma.","authors":"Hagar A Elmekawy, Khaled Abdelkawy, Galal Magdy, Emad Sadaka, Gamal El-Azab, Ahmed Ali, Noha El-Khodary, Fawzy Elbarbry","doi":"10.1080/00498254.2025.2508814","DOIUrl":"10.1080/00498254.2025.2508814","url":null,"abstract":"This study investigated the impact of single nucleotide polymorphisms (SNPs) in genes involved in doxorubicin (DOX) transport and metabolism on clinical outcomes and toxicity in Egyptian patients with non-Hodgkin lymphoma.Ninety-two patients received at least six DOX treatment cycles. SNP genotyping was performed using real-time PCR with high-resolution melting analysis. Laboratory tests were conducted at baseline, during, and after treatment.The AA genotype of ABCC2 (rs8187710) showed the strongest association with elevated DOX plasma levels and a significantly increased risk of acute cardiotoxicity (OR 26.9; 95% CI: 1.47-492; p = 0.026). The GA genotype was linked to a lower complete response rate and increased risks of leukopoenia (OR 2.66; 95% CI: 1.07-6.61; p = 0.034) and lymphocytopenia (OR 10; 95% CI: 3.57-27.9; p < 0.0001), with intermediate peak DOX levels. For CBR3 (rs8133052), the GA genotype was significantly associated with a higher risk of anaemia (OR 3.5; 95% CI: 1.05-11.7; p = 0.042), acute cardiotoxicity (OR 4.4; 95% CI: 1.86-11.5; p = 0.002), cardiac-related symptoms, and higher peak plasma DOX levels, along with reduced complete response.Polymorphisms in ABCC2 and CBR3 genes may contribute to individual variability in DOX-related toxicity and treatment response.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"349-359"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120981","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

Evaluation of antihypertensive effects of Ophioglossum vulgatum: in silico and in vivo evidence in spontaneously hypertensive. 蛇舌草抗高血压作用的评价：自发性高血压的体内和计算机证据。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-06-30 DOI: 10.1080/00498254.2025.2519820

Zi-Han Shen, Baozhen Chen, Congchao Wan, Jia-Xin Ye, Zixing Li, Shuang Lin, Xin Zhang, Yuehua Huang, Max K Leong, Tongjie Ye, Rong Wang, Yaw-Syan Fu

{"title":"Evaluation of antihypertensive effects of Ophioglossum vulgatum: in silico and in vivo evidence in spontaneously hypertensive.","authors":"Zi-Han Shen, Baozhen Chen, Congchao Wan, Jia-Xin Ye, Zixing Li, Shuang Lin, Xin Zhang, Yuehua Huang, Max K Leong, Tongjie Ye, Rong Wang, Yaw-Syan Fu","doi":"10.1080/00498254.2025.2519820","DOIUrl":"10.1080/00498254.2025.2519820","url":null,"abstract":"This study investigated and evaluated the antihypertensive effects and mechanisms of Ophioglossum vulgatum(OV) through a combination of computational simulations and in vivo experiments.Initially, an in silico analysis using network pharmacology was employed to identify target proteins, followed by molecular docking and molecular dynamics simulations. Network pharmacology data indicated that OV may influence several pathways involved in blood pressure regulation. Molecular docking revealed the effective targets of OV, showing that some of its major active compounds could potentially bind directly to the active sites of angiotensin receptors and calcium channel proteins. In vivo experiments demonstrated that administration of 20 mg/kg crude OV extract to spontaneously hypertensive rats (SHR) significantly reduced mean blood pressure by 31.53% within 60 min, alleviating hypertensive symptoms. Based on our in silico and in vivo evidence, the rapid antihypertensive effects of OV may be related to its action on the RAS and calcium channels, leading to vasodilation.These acute antihypertensive effects suggest that OV has the potential to be a candidate for blood pressure medication, particularly for urgent blood pressure reduction, and an effective antihypertensive agent in plant-based medicine.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"386-396"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318122","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

Screening the active contituents from duhaldea nervosa via integrated UHPLC-Q-exactive Orbitrap-MS and network pharmacology. 结合UHPLC-Q-Exactive Orbitrap-MS和网络药理学技术筛选海参有效成分。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-07-02 DOI: 10.1080/00498254.2025.2523961

Lianghong Liu, Kailin Li, Mingjuan Liu, Lian Zhu, Zichao Shang, Wei Cai

{"title":"Screening the active contituents from duhaldea nervosa via integrated UHPLC-Q-exactive Orbitrap-MS and network pharmacology.","authors":"Lianghong Liu, Kailin Li, Mingjuan Liu, Lian Zhu, Zichao Shang, Wei Cai","doi":"10.1080/00498254.2025.2523961","DOIUrl":"10.1080/00498254.2025.2523961","url":null,"abstract":"Duhaldea nervosa (Wallich ex Candolle) A. Anderberg (Asteraceae) (D. nervosa), has been used as a folk medicine for the treatment of diseases including bone fractures and bone wounds. However, the metabolic profiling of D. nervosa and mechanism of action for treating fracture are unknown.In this study, an integrated analysis method based on UHPLC-Q-Exactive Orbitrap MS and network pharmacology was established to research the metabolic characteristic of D. nervosa. Serum in the blank group and drug group were collected after intragastric administration of D. nervosa. The serum samples were analysed using UHPLC-MS. In addition, network pharmacology and cell proliferation assays were used to analysis the mechanism of fracture healing of D. nervosa.A total of 62 constituents, including 24 prototype compounds and 38 metabolites were identified in rat serum. The result of network pharmacology revealed that the fracture healing effect of 23 metabolites was probably acting through 65 genes targets. Serum samples promoted osteoblast proliferation in a concentration-dependent manner in mouse osteoblast cell line (MC3T3-E1 cells).To our best knowledge, it is the first time to report the constituents in vivo of D. nervosa. This work provided a general method for understanding the bioactive compounds of D. nervosa.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"373-385"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144498186","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

Association of valproic acid-related pharmacodynamics, pharmacokinetic pathways and transporter gene polymorphisms and antiepileptic efficacy in Chinese patients. 中国患者丙戊酸相关药效学、药动学途径和转运体基因多态性与抗癫痫疗效的关系。

IF 1.2 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-06-23 DOI: 10.1080/00498254.2025.2519825

Linlin Wang, Guangting Zeng, Jianqiang Li, Huilan Li, Jia Luo, Zanling Zhang

{"title":"Association of valproic acid-related pharmacodynamics, pharmacokinetic pathways and transporter gene polymorphisms and antiepileptic efficacy in Chinese patients.","authors":"Linlin Wang, Guangting Zeng, Jianqiang Li, Huilan Li, Jia Luo, Zanling Zhang","doi":"10.1080/00498254.2025.2519825","DOIUrl":"10.1080/00498254.2025.2519825","url":null,"abstract":"1. Valproic acid (VPA) has great individual differences in clinical efficacy, the study aimed to investigate the effects of VPA-related pharmacogenomics on its antiepileptic efficacy, providing evidence for clinical rational drug use.2. The patients were followed up for one year, and the number of seizures within one year was used as the evaluation index of efficacy. The target SNPS were genotyped by SNP scan method.3. A total of 253 patients with epilepsy treated with valproate monotherapy were enrolled in this study, including 125 patients in the valproate-sensitive group and 128 patients in the valproate-resistant group. χ2 Test showed that the frequency of C allele of CACNA1H rs3751664 in valproate-sensitive group was significantly higher than that in valproate-resistant group (93.6% vs. 87.5%, p = 0.023), and the difference was still statistically significant after adjusting for confounding factors by logistic regression analysis (p = 0.037). Haplotype analysis showed no association between gene polymorphisms and efficacy of valproic acid.4. CACNA1C rs1051375 GG and GA genotype patients have a lower risk of drug resistance than AA genotype patients, CACNA1H rs3751664 T allele is a risk factor for VPA monoresistance, while APEH rs3816877 CT genotype patients have a trend of drug resistance during VPA treatment.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"424-435"},"PeriodicalIF":1.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318120","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

Exposure to crack cocaine induces genotoxicity and degenerative changes in multiple organs of Wistar rats. 暴露于快克可卡因可引起Wistar大鼠多器官的遗传毒性和退行性改变。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-06-29 DOI: 10.1080/00498254.2025.2522737

Daniel Vitor de Souza, Barbara Dos Anjos Rosario, Lorrany Da Silva Avanci, Gabriel Carvalhal de Aguiar, Viviane Carlin, Milena De Barros Viana, Daniel Araki Ribeiro

{"title":"Exposure to crack cocaine induces genotoxicity and degenerative changes in multiple organs of Wistar rats.","authors":"Daniel Vitor de Souza, Barbara Dos Anjos Rosario, Lorrany Da Silva Avanci, Gabriel Carvalhal de Aguiar, Viviane Carlin, Milena De Barros Viana, Daniel Araki Ribeiro","doi":"10.1080/00498254.2025.2522737","DOIUrl":"10.1080/00498254.2025.2522737","url":null,"abstract":"Crack cocaine is a widely consumed illicit substance worldwide, with Brazil identified as its largest consumer. This study evaluated its harmful effects on various organs in rats.Twenty-four male Wistar rats were distributed into four groups: G1-exposed to 25 mg of crack cocaine; G2-50 mg; G3-100 mg; and a control group with no intervention. The experimental groups inhaled crack cocaine smoke once daily for five days.Histopathological changes were observed in the liver of G3 and in the kidneys of all exposed groups. Increased 8-OHdG immunoexpression occurred in the kidneys of G1 and G2. Ki-67 immunoexpression in the liver and kidneys was elevated in G1 and G2. GST-P-positive foci increased in G1 and G2. Micronucleated cells in bone marrow were significantly higher in all exposed groups. In the liver, hepatocytes with micronuclei increased in G1 and G2, while binucleated cells were more frequent in G3. Karyolysis increased in G2 and G3, and karyorrhectic hepatocytes were more frequent in G1 and G2.These findings demonstrate that crack cocaine inhalation induces degenerative and genotoxic effects in the liver, kidneys, and bone marrow of Wistar rats, supporting its potential carcinogenicity and underscoring the need for targeted public health interventions.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"360-372"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340469","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

From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets. 从实验室到临床与模型知情处方开发：羟嗪SR片的案例研究。

IF 1.3 4区医学

Xenobiotica Pub Date : 2025-05-01 Epub Date: 2025-05-21 DOI: 10.1080/00498254.2025.2497045

Aditya Murthy, Shubham Jamdade, Manoj Gundeti, Maddukuri Harika, Rahul Chiliveri, Sangmesh Chaudhari, Veena Kambam, Sohel Khan, Anup Choudhury, Tausif Ahmed

{"title":"From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets.","authors":"Aditya Murthy, Shubham Jamdade, Manoj Gundeti, Maddukuri Harika, Rahul Chiliveri, Sangmesh Chaudhari, Veena Kambam, Sohel Khan, Anup Choudhury, Tausif Ahmed","doi":"10.1080/00498254.2025.2497045","DOIUrl":"10.1080/00498254.2025.2497045","url":null,"abstract":"Model Informed Formulation Development (MIFD) uses physiologically based pharmacokinetic (PBPK) modelling and other in silico tools to facilitate new product development. These tools help set target profiles, predict in vivo formulation performance, guide iterative development, define dissolution parameters, and convince the regulatory agencies about a drug's safety and efficacy.This study involves development of a sustained release formulation for Hydroxyzine, an anti-histamine with sedation as a significant side effect. The aim was to design a formulation that releases the drug slowly, reducing the peak plasma concentration without losing on the effectiveness. A preliminary absorption model was developed using immediate release formulation data, and various hypothetical dissolution profiles were evaluated in this model. The new drug product, manufactured using MatrixealTM technology, underwent preliminary bioequivalence (BE) studies in healthy volunteers. These results were used to refine the model and further modify the formulation, whose performance was predicted via virtual BE studies. Confirmatory BE studies with 70 volunteers under fasting state validated the new formulation. The model also established clinically relevant dissolution specifications and assessed the food effect on the drug product.This work showcases the application of PBPK modelling in developing new modified release drug product of Hydroxyzine.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"329-338"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044770","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