查找使用阿拉丁产品的科研文献

Herb-drug interaction of Xingnaojing injection and Edaravone via pharmacokinetics, mixed inhibition of UGTs, and molecular docking

Dongli Qi,Huihui Li,Chunxia Liang,Peijin Peng,Zhen Yang,Yanquan Gao,Ziwei Li,Qingqing Zhang,Zhidong Liu

Background Xingnaojing injection (XNJ) is a famous emergency Traditional Chinese medicine (TCM) derived from the classical Chinese prescription named An-Gong-Niu-Huang Pill. XNJ is often used along with Edaravone injection (EDA) to treat acute ischemic stroke, they have a synergistic effect in improving patients' blood coagulation and neurological function. However, this combination also causes herb-drug interactions (HDIs), raising the risk of adverse reactions. At present, little is known about the pharmacokinetics and potential mechanism of XNJ combined with EDA. Purpose This study investigates the pharmacokinetics and potential mechanism of the HDIs between XNJ and EDA. Study design and methods The pharmacokinetic interactions between XNJ and EDA were studied by GC–MS in rats, and the inhibition of XNJ and (-)-borneol on UDP-glucuronosyltransferase (UGTs) were assayed by LC-MS/MS in vitro. In vitro-in vivo extrapolation ( IVIVE ) and molecular docking were performed to reveal the potential for HDIs. Results The AUC 0-∞ of (-)-borneol was increased by 1.25-fold in group EDA+XNJ 10 min later, and the C max of edaravone was increased by 1.6-fold in group XNJ+EDA 10 min later ( p < 0.05). XNJ and (-)-borneol inhibited UGTs-mediated edaravone metabolism in HLM and RLM with a similar inhibitory intensity, in which both of them have stronger inhibition in RLM. These findings demonstrated that (-)-borneol in XNJ mainly exerted UGTs inhibition, which was consistent with the pharmacokinetic assays. (-)-Borneol moderately inhibited UGT2B7 and UGT1A6 by a mixed inhibition mechanism, with K i values of 101.393 and 136.217 μM, respectively. Due to the blood concentration of injection was dramatically increased, the HDIs caused by the inhibitory effect of XNJ on UGTs should be highly emphasized. The binding energies of (-)-borneol and edaravone toward UGT2B7 were −6.254 and −6.643 kcal/mol, and the scores towards UGT1A6 were −5.220 and −6.469 kcal/mol, respectively. Moreover, (-)-borneol has similar free energies to many drugs metabolized by UGT2B7 and UGT1A6. Conclusions (-)-Borneol modulates the pharmacokinetic behavior of edaravone via mixed inhibition of UGT2B7 and UGT1A6. It provides a theoretical basis for the synergistic effect of XNJ and EDA combinations in clinical practice. When XNJ is used along with UGT2B7 and UGT1A6 substrates, it should be used clinically with caution.

Self-nanomicellizing solid dispersion of edaravone: part I – oral bioavailability improvement

Ankit Parikh,Krishna Kathawala,Chun Chuan Tan,Sanjay Garg,Xin-Fu Zhou

Background Edaravone (EDR) is known for its free radical scavenging, antiapoptotic, antinecrotic, and anticytokine effects in neurological and non-neurological diseases. It is currently available clinically as Radicava® and Radicut®, intravenous medications, recently approved for the treatment of amyotrophic lateral sclerosis and cerebral infarction. However, the oral use of EDR is still restricted by its poor oral bioavailability (BA) due to poor aqueous solubility, stability, rapid metabolism, and low permeability. The present study reports the development of novel EDR formulation (NEF) using self-nanomicellizing solid dispersion (SNMSD) strategy with the aim to enable its oral use.Materials and methods The selection of a suitable carrier for the development of NEF was performed based on the miscibility study. The optimization of EDR-to-carrier ratio was conducted via kinetic solubility study after preparing SNMSDs using solvent evaporation technique. The drug–polymer carrier interaction and self-nanomicellizing properties of NEF were investigated with advanced characterization studies. In vitro permeation, metabolism, and dissolution study was carried out to examine the effect of the presence of a carrier on physico-chemical properties of EDR. Additionally, the dose-dependent pharmacokinetic study of NEF was conducted and compared with the EDR suspension.Results Soluplus® (SOL) as a carrier was selected based on the potential for improving aqueous solubility. The NEF containing EDR and SOL (1:5) resulted in the highest enhancement in aqueous solubility (17.53-fold) due to amorphization, hydrogen bonding interaction, and micellization. Moreover, the NEF demonstrated significant improvement in metabolism, permeability, and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2-, 16.1-, and 14.8-fold enhancement compared to EDR suspension at 46, 138, and 414 µmol/kg doses.Conclusion The results demonstrated that SNMSD strategy could serve as a promising way to enhance EDR oral BA and NEF could be a potential candidate for the treatment of diseases in which oxidative stress plays a key role in their pathogenesis.

Development of a novel oral delivery system of edaravone for enhancing bioavailability

Ankit Parikh,Krishna Kathawala,Chun Chuan Tan,Sanjay Garg,Xin-Fu Zhou

Edaravone (EDR), a strong free radical scavenger, is known for its promising therapeutic potential in oxidative stress (OS) associated diseases, however poor oral bioavailability is the major obstacle in its potential use. Oral liquid dosage form is the most preferred delivery method in paediatric, geriatric and specialised therapies. The present research discusses the development of a Novel Oral Delivery System (NODS) of EDR to enhance oral bioavailability. From preformulation study, solubility, and stability were identified as key challenges and the requirement of an acidic environment and protection against oxidation were found to be critical. The NODS made up of a mixture of Labrasol (LBS) and an acidic aqueous system, was optimized on the basis of solubility and stability study. It can be stored ≤40   °C for at least one month. Drug release from NODS was slow, sustained and significantly better as compared to suspension. The significant reduction in metabolism and improvement in permeability across the small intestine were observed with NODS compared to free EDR. The oral pharmacokinetic study showed 571% relative bioavailability with NODS compared to EDR suspension. From the results obtained, NODS is a promising candidate for use in OS associated diseases.

Edaravone Alleviates Traumatic Brain Injury by Inhibition of Ferroptosis via FSP1 Pathway

Shi Haoyu,Song Libiao,Wu Yonghui,Shen Ruonan,Zhang Chenxu,Liao Xingzhi,Wang Qiuhong,Zhu Jie

Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.

Neuroprotective Effects of Edaravone Dexborneol in a Rat Model of Post-Stroke Depression

Jiao Yuxin,Mu Shengzhi,Kang Bei

Objective Post-stroke depression (PSD), a common stroke complication, negatively impacts physical function, cognition, and quality of life. Edaravone dexborneol (ED), a combination agent, helps alleviate ischemia-induced damage to neuro-motor and cognitive functions. This study aims to evaluate the neuroprotective effects of ED in a rat model of PSD. Methods The PSD model was established via filament inserting through the internal carotid artery and chronic unpredictable mild stress stimulation. After the model was established, ED treatment was given for 14 days ( i.p. at a dose of 3mg/kg). Subsequently, the therapeutic effects of ED on behavioral parameters and inflammatory biomarkers in the PSD rats were analyzed. Results ED has a tendency to increase the percentage of sucrose preference in PSD rats. ED could significantly shorten the forced swimming time of PSD rats ( P  < 0.05). ED significantly increased the level of 5-hydroxytryptamine in the brain tissue of PSD rats ( P  < 0.05) and reduced the expression of inflammatory markers interleukin-6 and tumor necrosis factor-α ( P  < 0.05). Conclusion ED demonstrates potential therapeutic efficacy in mitigating depressive-like behaviors in a PSD rat model, reducing neuroinflammation, minimizing brain tissue damage, and conferring neuroprotective benefits.

Edaravone Attenuates Aβ 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells

Guo Shenglong,Lei Qi,Guo Hena,Yang Qian,Xue Yanli,Chen Ruili

Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer’s disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aβ 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aβ 1-42 -induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1β and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aβ 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.

Effect of Edaravone (An Antioxidant) on the Performance of Organic Perovskite Solar Cells

Shuming Chen,Jintao Wang,Ning Jiang,Zhenyu Wang,Ziqiang Chen,Chenyang He,Kai Fang,Jian Zhang,Long Yuan,Ye Li,Chuannan Li,Ping Chen,Yu Duan

Perovskite solar cells (PSCs) have broad application prospects in the field of renewable energy. The photovoltaic performance and long-term stability of PSCs are important factors for the industrialization of PSCs. Passivation of perovskite films by antioxidants is an effective approach to not only reduce the density of defect states but also improve the environmental stability of the device. Herein, edaravone (EDA) is added to the perovskite precursor solution to passivate the defects and also scavenge ultraviolet(UV)-induced free radicals during photoaging. The EDA-optimized device achieves a champion power conversion efficiency (PCE) of 20.81%, and after 1000 h of exposure to the environment, the efficiency can maintain 72% of the original value.

Edaravone dexborneol alleviates cerebral ischemia-reperfusion injury through NF-κB/NLRP3 signal pathway

Guanghong Shen,Chengjian Lou,Qunfeng Li,Bingxin Zhao,Yuhuan Luo,Fei Wu,Dian Jiao,Marong Fang,Yu Geng

Inflammatory injury following ischemia-reperfusion (I/R) severely limits the efficacy of stroke treatment. Edaravone dexborneol (C.EDA) has been shown to reduce inflammation following a cerebral hemorrhage. However, the precise anti-inflammatory mechanism of C.EDA is unknown. In this study, we investigated whether C.EDA provides neuroprotection after I/R in rats, as well as the potential mechanisms involved. A middle cerebral artery occlusion/reperfusion (I/R) model was created using Sprague-Dawley rats. The blood flow of the central cerebral artery was monitored by a laser speckle imaging system. The neurological score was used to assess behavioral improvement. Cerebral infarction volume was measured by TTC staining. And the integrity of the blood–brain barrier was detected by Evan's blue staining. The expression of the nuclear factor kappa-B (NF-κB)/ the NOD-like receptor protein (NLRP3) inflammasome signal pathway and microglia polarization were detected by immunofluorescence and Western blotting. The cerebral blood flow ratio indicates that the cerebral I/R model was successfully established. After reperfusion for 72 h, the improvement of neurological scores, infarct volume reduction, and integrity of the blood–brain barrier was observed in I/R rats with C.EDA treatment. Meanwhile, the immunofluorescence result showed that the expression of iNOS, NLRP3, and NF-κB protein was decreased and the level of Arg1 was increased. Western blot analysis showed that the expression of NF-κB/NLRP3 signal pathway-related protein was decreased. In conclusion, this study indicates that C.EDA alleviates I/R injury by blocking the activation of the NLRP3 inflammasome and regulating the polarization of M1/M2 microglia via the NF-κB signal pathway.

Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation

Ankit Parikh,Krishna Kathawala,Chun Chuan Tan,Sanjay Garg,Xin-Fu Zhou

A new method of consistency evaluation of brain drugs: a case study of edaravone

Liqiang Gu,Yanping Hu,Yinfang Lai,Sheng Zhang,Haoran Wang,Xiaozhen Xu,Lingfang Chen,Yuhua Shi,Jiechao Chen,Xiaochun Sun,Yuan Zhang,Lingzhi Hu

Bioequivalence test is typically conducted by determining the drug concentration in plasma. However, this is not suitable for brain drugs (like Edaravone) that have targets in CNS. The amount of a drug in target site in the CNS is responsible for its activity in the brain, while the concentration of a drug in the blood has a weak impact on the CNS. In this paper, a new consistency evaluation method for brain drugs was established. 16 rats were divided into two groups. One group was administered the test preparation, and the other group was administered the control preparation. Then, cerebrospinal fluid (CSF) samples were collected. All of the CSF samples were examined by LC-MS. The 90 % confidence interval of the geometric mean ratio of AUC 0-t was 90.30–150.59 %, and 91.79–211.06 % for C max . In addition, the result indicated that the two preparations were not bioequivalent in the CNS, although the concentration-time profile and pharmacokinetic parameters were quite similar. The results revealed the particularity and complexity of the bioequivalence test for brain drugs that have targets in the CNS. The feasibility of the test was confirmed, and our results provide useful information for the consistency evaluation of brain drugs.

Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability

Qu Jin,Yu Cai,Sihan Li,Haoran Liu,Xingyu Zhou,Chunqiang Lu,Xihui Gao,Jun Qian,Jun Zhang,Shenghong Ju,Cong Li

Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro . HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.

Edaravone protects against liver fibrosis progression via decreasing the IL-1β secretion of macrophages

Rongrong Zhao,Huajun Zhao,Quanjuan Guo,Yongliang Mu,Jian Zhang,Yuhang Su,Qiuju Han

Edaravone (EDA), a strong novel free radical scavenger, have been demonstrated to exert neurovascular protective effects clinically. Furthermore, EDA can suppress the lung injury, pulmonary fibrosis and skin fibrosis , while the precise effects and mechanisms of EDA on liver injury and fibrosis remain unclear. The effects of EDA on the Thioacetamide (TAA)-induced liver fibrosis were evaluated by sirius red staining, α-SMA immunohistochemistry. The percentages of immune cell subsets were analyzed by flow cytometry. Immunofluorescence assay was performed to identify the fibrotic properties of hepatic stellate cells (HSCs). Western blot and qPCR were used to detect the levels of liver fibrosis-related molecules and IL-1β. EDA displayed a hepatic protective role in TAA-induced chronic liver fibrosis via inhibiting monocyte/macrophages recruitment and IL-1β production of macrophages. Mechanically, EDA inhibited of NF-κB signal pathway and reactive oxygen species (ROS) production in macrophages. Moreover, EDA treatment indirectly suppressed the activation of HSCs by decreasing the IL-1β secretion of macrophages. Together, EDA protects against TAA-induced liver fibrosis via decreasing the IL-1β production of macrophages, thereby providing a feasible solution for clinical treatment of liver fibrosis.