BRITISH JOURNAL OF PHARMACOLOGY
·
2023
·
IF 7.3
Luyao Ma,Fangjun Yu,Di He,Lianxia Guo,Yu Yang,Wangchun Li,Tianpeng Zhang
Background and purpose The role of CLOCK in regulation of drug chronoefficacy and chronotoxicity remains elusive. Here, we aimed to uncover the impact of CLOCK and dosing time on clopidogrel efficacy and toxicity. Experimental Approach The antiplatelet effect, toxicity and pharmacokinetics experiments were conducted with Clock −/− and wild-type mice after gavage administration of clopidogrel at different circadian time points. The expression levels of drug metabolizing enzymes were determined by qPCR and Western blotting. Transcriptional gene regulation was investigated using luciferase reporter and chromatin immunoprecipitation assays. Key Results The antiplatelet effect and toxicity of clopidogrel in wild-type mice showed a dosing-time dependent variation. Clock ablation reduced the antiplatelet effect of clopidogrel, increased clopidogrel-induced hepatotoxicity, and blunted their rhythms. This was associated with attenuated rhythms of clopidogrel active metabolite (Clop-AM) and clopidogrel, respectively. We further found that Clock regulated the diurnal variation of Clop-AM formation by modulating the rhythmic expression of CYP1A2 and CYP3A11, and altered clopidogrel chronopharmacokinetics by circadian regulation of CES1D expression. Mechanistic studies revealed that CLOCK activated Cyp1a2 and Ces1d transcription by directly binding to the E-box elements in their promoters, and promoted Cyp3a11 transcription through enhancing the transactivation activity of DBP and TEF. Conclusion and implication CLOCK regulates the diurnal rhythmicity in clopidogrel efficacy and toxicity through regulation of CYP1A2, CYP3A11 and CES1D expression. The findings may contribute to the optimization of dosing schedule for clopidogrel, and deepen understanding of the connection between the circadian clock and chronopharmacology.
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2019
·
IF 2.983
Shuai Ji,Xian Shao,Zhen-yu Su,Lei Ji,Yu-jie Wang,Yun-su Ma,Lu Zhao,Yan Du,Meng-zhe Guo,Dao-quan Tang
Fufang Danshen Dripping Pill (FDDP) and Clopidogrel Bisulfate Tablet (CBT) are usually combined for treatment of coronary artery diseases in clinical. To investigate the pharmacokinetic interaction between FDDP and CBT after oral administration of FDDP, CBT and their combination in rats, a novel LC–MS method with segmented scan modes (multiple reaction monitoring and selected ion monitoring) and polarity (positive and negative ionization) was developed. Clopidogrel and the main active ingredients of FDDP, with different chemical and ionization properties, were simultaneously quantified in plasma in a single run. The method was validated in terms of specificity, linearity, precision, accuracy, recovery, matrix effect and stability. As a result, co-administration of FDDP and CBT significantly altered the pharmacokinetic parameters of danshensu, ginsenoside Rb1, dihydrotanshinone I, tanshinone I and tanshinone IIA of FDDP, as well as clopidogrel. Mechanism studies suggested that induction of liver cytochrome P450 isozymes CYP2C11 and CYP3A1 by co-administration, as well as inhibition of carboxyl esterase 1, was partly responsible for FDDP-CBT pharmacokinetic interactions. The developed LC–MS method could be used to simultaneously quantify different types of in vivo analytes in a single run, and the results could be used for clinical medication guidance of FDDP and CBT.
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Chemical Biology & Drug Design
·
2018
·Vol. 93
·期 6
·1073-1082
·
IF 2.328
Bo Fan,Yunfei Li,Yong Bi,Ling Tong,Dongxiang Li,Yi Wang
In recent years, multi-component therapies are increasingly utilized to treat complex diseases such as cancer, diabetes, and other chronic complex diseases. Here, we proposed the protocol for rational design of drug combination with poly-pharmacological effects by integration of design of experiments (DOE), computational modeling, and multiple-objective optimization algorithm. Here, we introduce a common workflow for modeling quantitative relationship of chemical composition and multiple activities of drug combinations. As an example, anti-oxidation, neuroprotective, and anti-platelet activities of three different salvia polyphenols were measured, which were mathematically represented by multivariant regression models to evaluate the effect of combination. In validation, the optimized combination which obtained by weighed-sum method showed good activities in all three models. Our results demonstrate that the multiple-objective optimization strategy is suitable to optimize the ratio of the compounds so to induce the best therapeutic action.
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Nature Nanotechnology
·
2025
·
IF 34.9
Zhong Yixin,Ni Qiankun,Huang Liandi,Qing Guangchao,Zhang Fuxue,Gong Ningqiang,Wu Hongyun,Liao Yukun,Jiang Huiting,Tu Zaiqian,Wang Zhifei,Jiramonai Luksika,Zhu Haidong,Teng Gao-Jun,Liang Xing-Jie
Antiplatelet drugs have represented a milestone in treating patients at high risk of thrombosis. However, their clinical use remains limited by bleeding-associated risk and limited efficacy. Excessive reactive oxygen species (ROS) produced by damaged vascular endothelial cells have been shown to stimulate thrombosis. Here we propose that a ROS-chemotactic nanoscavenger (MDCP), formed by crosslinking melanin and catalase, prevents acute thrombosis by protecting vascular endothelial cells from oxidative stress. We demonstrate that treatment with MDCP inhibits ROS-induced apoptosis of endothelial cells, thereby maintaining endothelial integrity and preventing collagen exposure, which consequently prevents platelet activation and thrombosis. By avoiding direct interference with platelet function, this modulation of vascular redox homeostasis via MDCP provides a promising alternative antithrombotic strategy that addresses the bleeding risk of current clinical antithrombotic drugs.
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