Frontiers in Pharmacology
·
2022
·
IF 5.988
Chen Jiayun,Jiang Xiaojuan,Zhu Chunyan,Yang Lu,Liu Minting,Zhu Mingshe,Wu Caisheng
Rhubarb, as a traditional Chinese medicine, has several positive therapeutic effects, such as purging and attacking accumulation, clearing heat and purging fire, cooling blood, and detoxification. Recently, Rhubarb has been used in prescriptions for the prevention and treatment of COVID-19, with good efficacy. However, the exploration of effective quantitative approach to ensure the consistency of rhubarb’s therapeutic efficacy remains a challenge. In this case, this study aims to use non-targeted and targeted data mining technologies for its exploration and has comprehensively identified 72 rhubarb-related components in human plasma for the first time. In details, the area under the time-concentration curve (AUC)-pooled method was used to quickly screen the components with high exposure, and the main components were analyzed using Pearson correlation and other statistical analyses. Interestingly, the prototype component (rhein) with high exposure could be selected out as a Q-marker, which could also reflect the metabolic status changes of rhubarb anthraquinone in human. Furthermore, after comparing the metabolism of different species, mice were selected as model animals to verify the pharmacodynamics of rhein. The in vivo experimental results showed that rhein has a positive therapeutic effect on pneumonia, significantly reducing the concentration of pro-inflammatory factors [interleukin (IL)-6 and IL-1β] and improving lung disease. In short, based on the perspective of human exposure, this study comprehensively used intelligent data post-processing technologies and the AUC-pooled method to establish that rhein can be chosen as a Q-marker for rhubarb, whose content needs to be monitored individually.
研究领域:
中药学
·
药理学
·
数据挖掘
·
代谢
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2021
·
IF 5.194
Wei Li,Zhen Wang,Xiaoyu Wang,Xiaowei Cao,Caili Bi,Lili Jiang,Shuna Cui,Yong Liu
The drug-drug interaction (DDI) risk of phenytoin with several topical formulations of miconazole is still unclear. The present investigation conducted in vitro - in vivo extrapolation to predict the potential risks. Our data indicated that miconazole potently inhibited phenytoin hydroxylation in both pooled human liver microsomes (HLMs) and recombinant cytochrome P450 2C9 (CYP2C9) with the K i values of 125 ± 7 nM and 30 ± 2 nM, respectively. Quantitative prediction of DDI risk suggests that, beside intravenous administration or swallowed tablet, combination of phenytoin and miconazole high dose oral gel or buccal tablet may also result in a clinically significant increase of phenytoin AUC (>53%) by the inhibition of miconazole against phenytoin hydroxylation, consequently a higher frequency of adverse events, while the coadministration of miconazole vaginal formulation and phenytoin will be safe.
研究领域:
药理学
·
临床药学
·
药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-8
·
IF 3.9
Wang Yueyuan,Diao Zhipeng,Qu Yuchen,Fan Kai,Feng Chen,Lv Bo,Yu Yunli,Geng Zhou
Omadacycline, a third-generation tetracycline antibiotic, exhibits time-dependent pharmacokinetics. The ratio of the 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC 0−24 /MIC) serves as the primary pharmacokinetic/pharmacodynamic (PK/PD) index for omadacycline, demonstrating strong correlation with therapeutic efficacy, particularly in critically ill patient populations. To facilitate routine therapeutic drug monitoring (TDM) in clinical practice, a high-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS) method was developed for quantification of omadacycline in human plasma. An Agilent 1260 series liquid chromatograph and an API 4000 triple tandem quadrupole mass spectrometer were used for the determination of omadacycline and endocannabinoids. The separation was performed on a Phenomenex KINETEX XB-C18 column (2.6 μm, 3 × 50 mm) with 0.1% formic acid-water and pure acetonitrile as the mobile phases. The LC-MS/MS separation was carried out using a gradient elution procedure at a flow rate of 0.4 mL/ min, and the total run time was 5 min. An electrospray ionization (ESI) was selected, and the detection ions of omadacycline and the internal standard (fexofenadine-d6) were determined by mass spectrometry scanning with multiple reaction monitoring (MRM) in positive ion mode as follows: m/z 557.4→453.4 and m/z 508.4→472.8, respectively. The established linear range (20-2000 ng/mL) effectively covers the plasma concentration range encountered in > 98% of clinical samples, making it suitable for routine therapeutic drug monitoring. The method demonstrated acceptable selectivity, recovery, and matrix effect. The results of intra-day precision and inter-day precision show that the relative standard deviation (RSD) is less than 10%, while the relative error (RE) is within ± 10.00%. In this study, we developed and validated a simple, sensitive and accurate method to quantify the concentration of omadacycline in human plasma using LC-MS/MS. This offers essential technical support for the rational clinical application of omadacycline.
研究领域:
药理学
·
分析化学
·
临床药理学
·
质谱分析
·
治疗药物监测
✓ 已验证
DOI
PubMed
高影响因子
PARASITOLOGY RESEARCH
·
2021
·Vol. 120
·期 8
·2827-2837
·
IF 2.289
Guo Wenju,Li Ning,Ren Guolian,Wang RongRong,Chai Liqing,Li Yujie,Wang Xi,Yang Qingshan,Wang Ruili,Zhang Guoshun,Yang Liuqing,Yi Bofang,Zhang Shuqiu
Currently, conjugation of artemisinin-derived dimers, trimers, and tetramers is a viable strategy for developing new effective antimalarial candidates. Furthermore, nanotechnology is an effective means to achieve intravenous administration of hydrophobic drugs. In this paper, an ester-linked dihydroartemisinin trimer (DHA 3 ) was synthesized and further prepared as self-assembled nanoparticles (DHA 3 NPs) by a one-step nanoprecipitation method. The pharmacokinetics and antimalarial pharmacodynamics of DHA 3 NPs were studied in rats and mice infected with Plasmodium yoelii BY265 (PyBY265) . DHA 3 NPs had a regular spherical shape with a uniform size distribution of 140.27 ± 3.59 nm, entrapment efficiency (EE) of 99.63 ± 0.17%, and drug loading efficiency (DL) of 79.62 ± 0.11%. The in vitro release characterization revealed that DHA 3 NPs were easily hydrolysed into DHA in an esterase environment. The pharmacokinetics study demonstrated that the area under the concentration–time curve ( AUC 0-t ) of DHA in DHA 3 NPs group was 2070.52 ± 578.76 h×ng×mL −1 , which was higher than that of DHA and artesunate (AS) control groups ( AUC 0-t values of 724.18 ± 94.32 and 448.40 ± 94.45 h×ng×mL −1 , respectively) ( P < 0.05). The antimalarial pharmacodynamics in vivo suggested that DHA 3 NP S (ED 90 7.82 ± 1.16 μmol×(kg×day) −1 ) had a superior antimalarial effect compared with that of control groups (ED 90 values of 14.68 ± 0.98 (DHA) and 14.34 ± 1.96 (AS) μmol×(kg×day) −1 ) ( P < 0.05). In addition, DHA 3 NP S reduced the recurrence ratio and improved the cure ratio and survival time. In summary, DHA 3 NPs exhibited promising pharmacokinetic characteristics and antimalarial pharmacodynamics in vivo.
研究领域:
药理学
·
纳米技术
·
疟疾研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2019
·
IF 4.213
Ruoning Wang,Jiawei Han,Ai Jiang,Rong Huang,Tingming Fu,Lingchong Wang,Qin Zheng,Wen Li,Junsong Li
Curcumin (CUR) has gained increasing interest worldwide due to multiple biological activities . However, the therapeutic application remains limited because of its low aqueous solubility, intestinal metabolism and poor membrane permeability. In present study, an excipient-free CUR solid dispersion co-formed with piperine (PIP), the absorption enhancer involving metabolism-permeability, was successfully prepared by melting and quench cooling (co-amorphous CUR-PIP). The co-amorphous CUR-PIP exhibited superior performance in non-sink dissolution compared with crystalline and amorphous CUR, and showed physically stable at least 3 months, attributing to the strong molecular interactions between CUR and PIP as evaluated by FTIR spectra. Furthermore, the combination of PIP with CUR in the co-amorphous formulation could inhibit the glucuronidation of CUR, as exhibited in the in vitro assay of rat intestinal microsomes. The co-amorphous CUR-PIP would also exhibit higher gastrointestinal membrane permeability of CUR, as confirmed by P app of CUR in Caco-2 model. After administration of co-amorphous CUR-PIP, the AUC of CUR significantly increased by 2.16- and 1.92-fold those in crystalline and amorphous CUR, respectively. This study demonstrates that the developed co-amorphous CUR-PIP can enhance the bioavailability of CUR by increasing its dissolution, inhibiting metabolic processes, and facilitating membrane permeability.
研究领域:
药剂学
·
药理学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CLINICA CHIMICA ACTA
·
2022
·
IF 6.314
Jiyun Zhang,Zhizhen Lai,Rui Ding,Jinyu zhou,Zhonghao Yuan,Dan Li,Xuzhen Qin,Jiang Zhou,Zhili li
Background Altered glycosylation modulates the structure and function of disease-related proteins. The associations between serotransferrin (STF) N -glycosylation and liver diseases (LDs) have been revealed. However, how intact N -glycopeptides vary among different types of liver diseases remains unclear. Methods Intact STF N -glycopeptides from patients with chronic liver disease (CLD, n = 92), primary liver cancer (PLC, n = 123), metastatic liver cancer (MLC, n = 57), and healthy controls (HCs, n = 59) were determined using high-resolution mass spectrometry. Results Significant changes were displayed in STF glycosylation among 4 groups. The LD screening model, including Asn432 G1S/G2S, Asn432 G2S/G2S2, and Asn630 G2NS2/G2FNS2, was constructed to differentiate LDs from HCs, with a AUC of 0.92. The liver cancer (LC) diagnostic model, a combination of Asn432 G1-N/G1S-N, Asn432 G1/G2, Asn432 G2FS/G2FS2, and Asn630 G1S-N /G1S, showed good performance in discriminating LC from CLD (AUC = 0.93). Moreover, AFP-negative LC patients (93 %) were successfully predicted by the LC diagnostic model. Furthermore, the MLC triage model, composed of Asn432 G1/G2, Asn432 G3F/G3FS, Asn630 G2/G2S, Asn630 G2S2/G2NS2, and Asn630 G3FS/G3FS2, yielded an AUC of 0.98 between PLC and MLC. Conclusions STF N -glycosylation is a potential biomarker for the accurate classification of different LDs.
研究领域:
医学研究
·
分子生物学
·
临床诊断
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Physical Science
·
2025
·
IF 7.3
Haiyu Zhao,Wenxiao Li,Xuan Li,Zhiyu Kuang,Shengyao Xu,Zhenzhen Zhao,Jin Sun,Zhonggui He,Chunwang Fu,Yixin Sun,Bingjun Sun
Covalent albumin conjugation revolutionizes drug circulation prolongation, where binding affinity and binding sites critically govern therapeutic efficacy, but mechanisms remain unclear. Here, we report four gemcitabine (GEM) prodrugs whose pharmacodynamics and safety profiles strictly depend on the above parameters. Specifically, two prodrugs, MG and BG, employ albumin-binding modification modules derived from N-ethylmaleimide and acryloyl chloride, while others containing succinimide and propionyl chloride serve as non-albumin-binding controls. Regarding affinity, MG exhibits the highest albumin affinity, with 45-fold higher area under the curve (AUC) and 9-fold longer half-life compared to GEM, and the strongest antitumor activity. However, its reduced safety contrasts with the moderate-affinity BG, which achieves optimal efficacy-to-safety balance. Binding sites further modulate outcomes: pre-conjugation of BG to albumin remarkably increases bioavailability (23-fold higher AUC than GEM), while pre-binding of MG diminishes efficacy. These results highlight the need to optimize both binding affinity and binding sites in albumin-conjugated prodrugs.
研究领域:
药学
·
生物化学
·
肿瘤学
·
药物递送
·
药物化学
✓ 已验证
产品关联
DOI
高影响因子
Chinese Herbal Medicines
·
2018
·
IF 0
Xiao-jun Zhang,Jia-hui Chen,Liang Luo,Wei He,Guang-hui Liu,Jing Gong,Yi-feng Zeng,Zhi-yong Xie,Qiong-feng Liao
Objective To compare the brain pharmacokinetics of five protoberberine-type alkaloids ( i.e. berberine , palmatine , coptisine , epiberberine, and jatrorrhizine), which were the main bioactive constituents of Jiaotai Pills (JTP), in normal and insomnic rats orally administrated with JTP. Methods The detection was conducted by a fully validated liquid chromatography-tandem mass spectrometry combinated with brain microdialysis method. Brain microdialysis probes were inserted into the hippocampus of rats. JTP extracts were administrated intragastrically and then brain microdialysates were collected at 30 min time intervals for 10 h. The separation of the five protoberberine-type alkaloids was carried out on a BDS Hypersil C 18 column using a mobile phase consisting of acetonitrile and water (containing 5 mmol ammonium acetate adjusted to pH 5.0) within 4 min. The quantification was performed by multiple reaction monitoring with the transitions of m / z 336.0-320.1 for berberine, m / z 352.0-336.1 for palmatine, m / z 338.0-322.1 for jatrorrhizine , m / z 336.0-320.1 for epiberberine, m / z 320.0-292.1 for coptisine and m / z 356.4-192.1 for IS. Results The lower limit of quantification for five protoberberine-type alkaloids was 0.05 ng/mL. Linearity, accuracy, precision, stability and matrix effect of five analytes were all satisfactory. Five protoberberine-type alkaloids were quickly distributed in the brain. Moreover, significant differences in the principal pharmacokinetic parameters such as AUC and T 1/2 of the analytes were observed between two groups. Conclusion The LC-MS/MS method combinated with microdialysis is useful in the brain pharmacokinetic study of five protoberberine-type alkaloids. The results indicated that the rates of analytes absorption in insomnic rats were significantly higher than those in normal rats. Besides, the protoberberine-type alkaloids could bring a direct effect on the neuron in the hippocampus.
研究领域:
药理学
·
神经科学
·
分析化学
✓ 已验证
产品关联
DOI
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2022
·
IF 5.062
Wan Liu,Meng Cheng,Fangying Yuan,Jiaying He,Yulin Feng,Yi Jin,Jianfang Feng,Shilin Yang,Liangxing Tu
Nanocrystal technology is a common strategy to enhance the oral bioavailability of poorly-soluble drugs, and how to enlarge the enhancing ability on oral absorption via nanocrystals has become a pharmaceutical research field. In this study, we selected andrographolide (ADR), a typical poorly-soluble drug, as the model drug, and employed sodium dodecyl sulfate and D-ɑ-Tocopherol polyethylene glycol 1000 succinate copolymer (SDS-TPGS) to construct novel SDS-TPGS modified andrographolide nanocrystals (S-TANs). We found that the particle sizes of SDS/TPGS physical mixture modified nanocrystals (STANs) were about 553.4 ± 4.1 nm , while that of SDS-TPGS modified nanocrystals (S-TANs) were 604.6 ± 5.7 nm. During the production process of nanocrystals, the crystallinity of ADR was slightly decreased. Nanocrystals enhanced the saturation solubility of ADR, and improved oral absorption, C max and AUC 0-∞ of S-TANs was about 2.10 and 1.24 fold increased, STAN about 2.63, 2.97 fold. In a Real-time distribution study, we found the distribution time of andrographolide, SDS and TPGS in SDS/TPGS physical mixture modified nanocrystals system varies widely, while the distribution times of these materials were similar in SDS-TPGS copolymer modified nanocrystals system. These results indicated that modified with functional stabilizer was an efficient strategy to enlarge the enhancing ability on oral absorption of nanocrystals, and synthesized copolymer containing different functional stabilizers showed higher ability on enhancing oral bioavailability than physical mixtures.
研究领域:
药学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Xiaoshun Jia,Jinfeng Chen,Hongqing Cheng,Xinxin Pan,Yixin Ke,Tingming Fu,Hongzhi Qiao,Xiaobing Cui,Wen Li,Lisi Zou,Jianming Cheng,Junsong Li
This paper aimed to improve in vitro dissolution/solubility as well as inhibit intestinal metabolism and thus enhance oral bioavailability for a BDDCS class II drug by constructing surfactant-based amorphous solid dispersions using resveratrol (RES) as a model drug. After preliminary screening of polymers and surfactants, and subsequent prescription optimization, two optimized spray-drying RES-polymer-surfactant ASDs were obtained and exhibited a significant increase in solubility of RES by 2.69–3.45-fold compared to crystalline RES, and by 1.13–1.56-fold compared to corresponding RES-polymer ASDs, maintaining a higher concentration in the dissolution process. A metabolism study using everted sacs showed that two optimized ASDs reduced the concentration ratio of RES-G to RES to 51.66%–52.05% of crystalline RES on the serosal side of the rat everted intestinal sac at 2 h. Consequently, these two RES-polymer-surfactant ASDs achieved significantly higher exposure of RES in the plasma with significant enhancements in C max (2.33–2.35-fold higher than crystalline RES, and 1.72–2.04-fold higher than corresponding RES-polymer ASDs), and in AUC 0–∞ (3.51–3.56-fold higher than crystalline RES, and 1.38–1.41-fold higher than corresponding RES-polymer ASDs). These advantages of the RES-polymer-surfactant ASDs in oral absorption of RES were attributed to solubilization by ASDs and metabolic inhibition by UGT inhibitors. The introduction of surfactants including EL and Lab to ASDs plays an important role in inhibiting glucuronidation and further improving solubility. This study demonstrated that such surfactant-based amorphous solid dispersions may serve as a new approach to increase the oral absorption of BDDCS class II drugs.
研究领域:
药剂学
·
药物递送系统
·
药代动力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2021
·
IF 3.981
Rongrong Wang,Guolian Ren,Liqing Chai,Wenju Guo,Yujie Li,Ruili Wang,Yongdan Zhao,Shuqiu Zhang
Artemisinin and its derivates (ARTs) exert antimalarial effect by virtue of unique endoperoxide bridge, which is generally considered to generate oxygen free radicals and then form carbon-centered free radicals to damage parasites. The known high level of glutathione (GSH) in parasites plays a key role in maintaining redox balance to protect parasites from oxidative stress damage, which may be a risk factor for the failure of ARTs-based combination therapy and drug resistance. Nevertheless, the highly reducing environment in cytoplasm of malaria parasites provides an available trigger for intracellular nanoparticle disassembly to responsively release drug. In this study, a reduction-responsive releasing dihydroartemisinin (DHA) prodrug (C 14 -SS-DHA) was synthesized by conjugating DHA and tetradecylamine (C 14 –NH 2 ) with disulfide bond (–SS–) as a linker. As a control, a DHA carbon-carbon bond (–CC–) prodrug (C 14 -CC-DHA) was synthesized using succinic anhydride as a –CC– linker. To note, DHA prodrugs were prepared as self-assembled nanoparticles (C 14 -SS-DHA NPs and C 14 -CC-DHA NPs). The size and zeta potential of C 14 -SS-DHA NPs were 121 ± 1.582 nm and −29 ± 0.635 mV, and those of C 14 -CC-DHA NPs were 137.5 ± 0.5132 nm and −41 ± 0.377 mV, respectively. The C 14 -SS-DHA NPs can release DHA in a reductive media in vitro . The pharmacokinetics study showed that the area under the curve ( AUC (0-t) ) of plasma concentration versus time of DHA from C 14 -SS-DHA NPs was 20737.2 ± 6028.3 h μg L −1 , which was much higher than that of C 14 -CC-DHA NPs (6254.5 ± 2578.8) or DHA solution (857.6 ± 103.7 h μg L −1 ). The pharmacodynamics study presented that the ED 90 of C 14 -SS-DHA NPs was 3.81 ± 0.35 μmol/kg, which was lower than that of C 14 -CC-DHA NPs (12.70 ± 1.63 μmol/kg)) or DHA solution (17.67 ± 3.38 μmol/kg). C 14 -SS-DHA NPs showed significantly higher systemic exposure and better antimalarial activity in comparison with C 14 -CC-DHA NPs or DHA solution ( P < 0.05).
研究领域:
药理学
·
纳米技术
·
疟疾研究
✓ 已验证
产品关联
DOI
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2017
·
IF 5.72
Zhichun Shen,Bowen Li,Yajun Liu,Guirong Zheng,Yan Guo,Ruirui Zhao,Kai Jiang,Lulu Fan,Jingwei Shao
Ursolic acid (UA), a natural triterpene acid, is a promising anti-cancer drug due to its inhibitory effect on tumor growth and metastasis. However, clinical translation of UA is limited by its poor water solubility and low bioavailability. To overcome these problems, herein an amphiphilic self-assembly nanodrug composed of UA, lactobionic acid (LA) and low-polyamidoamine (low-PAMAM) dendrimers is developed. This near-spherical nanodrug with a uniform size (~180 nm) demonstrated to have an enhanced cytotoxicity against liver cancer SMMC7721 cells, and could attenuate the migration and adhesion of SMMC7721 cells at non-toxic concentrations by suppressing metastasis-related protein MMP-9 expression. Furthermore, in vivo study indicates that the nanodrug exhibited prolonged circulation time in blood as well as increased AUC, MRT and C max , and could effectively inhibit the tumor growth in H22 mice model. Overall, the UA-based nanodrug delivery system reported in the present work represents a novel strategy for targeted tumor therapy.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）