MONATSHEFTE FUR CHEMIE
·
2023
·Vol. 155
·期 1
·99-104
·
IF 1.8
Dong Wenwen,Gong Tengfei,Liu Chaoyang,Lin Jia,Jia Qiang,Chu Changhu
Apixaban is a highly potent, selective, and efficacious inhibitor of blood coagulation factor Xa. A practical and efficient process has been developed for the preparation of the key intermediate of apixaban. Starting from inexpensive 4-chloronitrobenzene and piperidine, an eight-step procedure for the intermediate has been developed. In this case, sodium chlorite is used twice to oxidize the piperidine cycle to the corresponding lactam under a CO 2 atmosphere, resulting in the construction of two lactams. Furthermore, most of these reactions are highly efficient and practical as they occur under mild conditions. Most of the intermediates can be obtained through simple slurry or recrystallization, and column chromatography purification is not necessary. Graphical abstract
研究领域:
药物化学
·
有机合成
✓ 已验证
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2016
·
IF 4.425
Yong Chen,Long Li,Jia Yao,Yu-Yu Ma,Jia-Mei Chen,Tong-Bu Lu
Apixaban (apx), with a trade name of Eliquis, is a highly selective and efficacious inhibitor of blood coagulation factor Xa. Apixaban has poor solubility in water (0.028 mg/mL at 24 °C) and a relatively low oral bioavailability (about 50% for a single 10 mg dose). The purpose of this study is to improve the solubility and consequently the oral bioavailability of apixaban via a cocrystal. A cocrystal of apixaban with oxalic acid (apx-oxa-H2O, 4:3:0.5) was successfully obtained and characterized. The structure of the cocrystal was determined by single-crystal X-ray diffraction. The solubility of the cocrystal in 0.1 M HCl (pH 1.0) and phosphate buffer of pH 6.8 was evaluated, and the results show the solubility values of the cocrystal are approximately 2.2 and 2.1 times as large as those of apixaban form N-1 (the marketed product), respectively. The pharmacokinetics in beagle dogs was also investigated, and the mean AUC0–24h of the cocrystal is approximately 2.7 times as large as that of apixaban form N-1, indicating that both solubility and bioavailability of apixaban can be improved via a cocrystal.
研究领域:
药学
·
药物化学
✓ 已验证
产品关联
DOI
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Yuxin Shen,Xiaohai Chen,Hualu Wu,Hailun Xia,Ren-ai Xu
Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC 50 ) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 μM and 117.40 μM, respectively. The IC 50 value of asciminib against apixaban in RLM and HLM was 4.28 μM and 18.42 μM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs , where AUC (0-t) , AUC (0-∞) , t 1/2 , T max , and C max were increased, while CL z /F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.
研究领域:
药理学
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临床医学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2021
·
IF 3.205
Yu-Fei Zhang,Xiao-Qin Liu,Yang Wang,Xin Xu,Ming-Kang Zhong,Pu Zhang,Chun-Lai Ma
Direct oral anticoagulants are widely used to treat and prevent thromboembolic disorders. With rising clinical application, monitoring concentrations of direct oral anticoagulants are necessary in certain clinical conditions. A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of dabigatran etexilate, dabigatran, rivaroxaban, edoxaban, and apixaban, in human plasma. Protein precipitation with methanol was performed for sample preparation. The direct oral anticoagulants and internal standards were separated under gradient conditions using a C18 column, at an analytical run time of 8 min. The mobile phase was composed of 0.1% (v/v) formic acid in water (solvent A) and 0.1% (v/v) formic acid in acetonitrile (solvent B) at a flow rate of 0.3 mL/min. Mass detection was performed in multiple reaction monitoring using positive ionization mode. The method was validated over a range of 1.0–500 ng/mL for dabigatran etexilate, 0.1–500 ng/mL for dabigatran, and 0.5–500 ng/mL for edoxaban, rivaroxaban, and apixaban. The method detection limits of five analytes were in the range of 0.05–0.5 ng/mL. The lower limits of quantification of five analytes ranged from 0.1 to 1 ng/mL. The linearity (r 2 values) was higher than 0.997. The accuracy of the low, medium, and high quality control samples were between 85.9 and 114%, and intra- and inter-day precision were below 9.47%. This validated method was successfully used to determine the plasma concentrations of rivaroxaban in 32 patients, and of dabigatran etexilate and dabigatran in 1 patient.
研究领域:
临床药理学
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分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2024
·
IF 3.6
Chengzhi Wang,Dayang Jiang,Huipeng Ge,Jianping Ning,Xia Li,Mingmei Liao,Xiangcheng Xiao
Anticoagulation treatment for patients with high bleeding risk during hemodialysis is challenging. Contact between the dialysis membrane and the blood leads to protein adsorption and activation of the coagulation cascade reaction. Activated coagulation Factor X (FXa) plays a central role in thrombogenesis, but anticoagulant modification of the dialysis membrane is rarely targeted at FXa. In this study, we constructed an anticoagulant membrane using the polydopamine coating method to graft FXa inhibitors (apixaban and rivaroxaban) on the membrane surface. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and atomic force microscopy (AFM) were used to characterize the membranes. The apixaban- and rivaroxaban-modified membranes showed lower water contact angles, decreased albumin protein adsorption, and suppressed platelet adhesion and activation compared to the unmodified PES membranes. Moreover, the modified membranes prolonged the blood clotting times in both the intrinsic and extrinsic coagulation pathways and inhibited FXa generation and complement activation, which suggested that the modified membrane enhanced biocompatibility and antithrombotic properties through the inhibition of FXa. Targeting FXa to design antithrombotic HD membranes or other blood contact materials might have great application potential.
研究领域:
材料科学
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生物医学工程
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血液透析
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Hongxia Pu,Tao Yu,Yao Xiong,Canyu Wang,Zhizhuo Zhou,Gaocan Li,Yunbing Wang
Valvular heart disease (VHD) is a leading global health concern, contributing to significant mortality rates and imposing substantial economic burdens annually. To date, numerous bioprosthetic heart valves (BHVs) based on decellularized extracellular matrix (dECM) have been engineered as prosthetic solutions for the treatment of VHD. However, the irreversible deterioration of BHVs, driven by thrombosis, inflammatory responses, and calcification, represents a persistent and unresolved clinical concern. Moreover, the simultaneous optimization of multiple properties through a single technological approach presents a formidable challenge for BHVs. Herin, a dual regulation strategy based on functional hydrogel encapsulated with self-regulating bioreactors has been proposed to develop functional BHV materials, which involve nanoparticle-coated architectures with the intrinsic feedback mechanism. Specifically, a self-feedback thrombin-responsive peptide nanoparticle delivery system encapsulated with anticoagulant apixaban (Thr NPs) has been employed. Meanwhile, with the nanoparticles as bridging agents, the functional hydrogel coatings can be formed to provide passive defense against biofouling, while the three-dimensional network structures serve as the high-capacity reservoir for drug delivery. The excellent biocompatibility, superior anticoagulation, reduced calcification, and minimal inflammation are demonstrated for the developed BHV materials by a series of investigations in vitro and in vivo . Notably, the carotid artery implantation and endo-covered stent model are established to further confirm the blood compatibility and the enhancement of endothelialization of the developed BHV materials after implantation. It is expected that this dual regulation strategy might provide a good reference for the self-feedback biomedical material design and the application of blood-contact materials.
研究领域:
生物医学工程
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心血管材料
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再生医学
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药物递送系统
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生物材料
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Yanan Wang,Qiongjun Zhu,Zhezhe Chen,Xiaoyu Wang,Boxuan Ma,Yao Wang,Yun Xiao,Rifang Luo,Wenbin Zhang,Yunbing Wang,Guosheng Fu
Therapeutic-coated vascular stents are one of the key directions in the clinical treatment of atherosclerosis. However, vascular injury and implant stimulation trigger a feedback loop between coagulation and inflammation, impairing endothelial cell (EC) function, which is critical for long-term success in atherosclerotic vessels. Here, we designed a self-adaptive covalent coating stent that integrates thrombin-responsive release of apixaban as a coagulation modulator and an antioxidant polyphenol as an anti-inflammatory. This pathologic microenvironment-responsive coating regulates coagulation-inflammation loop post-implantation. The nanogels within the coating dynamically response to thrombin, the upstream initiator of coagulation-inflammation, to release apixaban in high thrombotic risk conditions while retaining it in low-risk states. Epigallocatechin gallate (EGCG), functioning as a cross-linker and the ROS scavagener, detaches in response to oxidative stress. As such, the coating enables blockade of coagulation-inflammation loop, synergistically protects ECs from inflammatory damage, promotes endothelial regeneration, and inhibits endothelial-to-mesenchymal transition (EndMT), efficiently modulating the inflammatory microenvironment via localized and coordinated regulation of coagulation-inflammation loop. Furthermore, the implantation in an atherosclerotic rabbit model demonstrated that the coating inhibits plaque deterioration linked to inflammation and endothelial damage. This dual-responsive strategy offers a promising avenue for therapeutic stents by mitigating the coagulation-inflammation loop and supporting endothelial repair in atherosclerotic vessels.
研究领域:
生物医学工程
·
纳米技术
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心脏病学
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生物材料
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炎症研究
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血栓学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Results in Chemistry
·
2025
·
IF 4.2
Oushan Tang,Shitong Wang,Guanguan Qiu,Majun Zhang,Liping Ling,Yan Zhang,Meiqun Guo,Chunxia Shen,Bin Quan,Hongjie Lang,Qing Shen,Keyun Cheng
This study proposes a method combining the Captiva enhanced matrix removal (EMR)-Lipid solid-phase extraction column with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the qualitative and quantitative analysis of five common oral anticoagulants (OACs) (rivaroxaban, apixaban, edoxaban, dabigatran, and warfarin) in plasma samples. The method, through a simplified sample pretreatment, significantly enhances the recovery rate of OACs (ranging from 88% to 96%), demonstrating superior purification effects compared to traditional solid-phase extraction methods, and effectively removes matrix interference. The method exhibits good linearity over a concentration range of 0.010 to 5.0 × 10 2 ng·mL −1 (r 2 = 0.9514 to 0.9998), with high sensitivity, detection limits of 0.010 to 0.10 ng·mL −1 , and quantification limits of 0.10 to 1.0 ng·mL −1 . The recovery and precision analysis indicate that the method is highly accurate and stable, suitable for the analysis of large batches of plasma samples containing OACs. This method provides an efficient and reliable testing tool for clinical drug monitoring, contributing to the optimization and enhancement of safety in personalized anticoagulation therapy.
研究领域:
临床药理学
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药物代谢
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分析化学
·
个体化医学
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毒理学
·
生物分析
·
抗凝治疗
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）