JOURNAL OF MOLECULAR LIQUIDS
·
2024
·
IF 5.3
Huixiang Zhang,Yang Zhang,Fumin Xue,Hui Chen,Zhenguo Gao,Shichao Du,Yan Wang
Valsartan is an angiotensin II receptor antagonist used to treat hypertension. Crystals of valsartan were prepared and the stability of the valsartan (form E) at different solvents and temperatures was investigated. The solid-liquid equilibrium solubility of valsartan (form E) in twelve pure solvents was determined by a dynamic method at the temperature from 278.15 K to 323.15 K. Among the solvents used in the experiment, the solubility of valsartan (form E) was found to be highest in methanol and lowest in acetonitrile. In straight-chain alcohols, the solubility decreases with the increase of carbon chain length. The modified Apelblat model, λh model and NRTL model were used to correlate the solubility data. The thermodynamic properties of the mixing process such as Gibbs free energy, enthalpy and entropy were estimated by applying the NRTL model. The KAT-LSER model was adopted to explore solvent effects. Hirshfeld surface analysis and molecular electrostatic potential (ESP) were employed to visualize close contacts and charge distribution of valsartan and solvents. In addition, molecular dynamics (MD) simulation was performed to calculate intermolecular interactions between solute and solvent. Radial distribution function (RDF) and the mean square displacement (MSD) analyses were also carried out to explore molecular association and molecular diffusion.
研究领域:
药学
·
物理化学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2018
·
IF 2.297
Wenhao Xu,Ying Sun,Liping Du,Yulia S. Chistyachenko,Alexandr V. Dushkin,Weike Su
Valsartan has been used for the treatment of hypertension disease. However, the oral bioavailability of valsartan has been reported to be only ∼23%, accompanied with high permeability and poor aqueous solubility. The object of this research was to prepare solid dispersions of valsartan with an inorganic (CaCO 3 ) and organic base ( N -methyl- d -glucamine) in an effort to increase the aqueous solubility and dissolution rate of the drug. The as-prepared solid dispersions of valsartan were prepared in an environmentally friendly manner using CaCO 3 and MG and a roll mill. The physicochemical properties were studied in the solid state using DSC , PXRD and IR. Furthermore, the solubility of valsartan increased 46-fold in solid dispersion with CaCO 3 and 9-fold in solid dispersion with MG. More than 95% of valsartan in solid dispersions was found to be released in simulated intestinal fluid, whereas only 35% was found to be released using pure valsartan within the same time interval. Storage tests showed that the as-prepared solid dispersions were equally stable compared to pure valsartan at 40 °C. Potentially, the synthesized solid dispersions of valsartan with enhanced solubility and dissolution rates may represent promising formulations for improving the overall oral bioavailability of the drug in clinical applications.
研究领域:
药剂学
·
药物化学
✓ 已验证
DOI
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2023
·
IF 3.4
Quancheng Yang,Peng Cao,Yi Lv,Hua Peng,Xuejia Zhai
Pediatric heart failure (HF) is an important clinical disease with high hospitalization rates, morbidity, mortality and medical costs. Sacubitril/valsartan (also known as Entresto), was approved for the treatment of adult HF and is recently used in pediatrics. However, clinical therapy on children is more challenging than adults, and the pharmacokinetics of Entresto in children are still largely unknown and urgently needed. Herein, we aim to develop a simple and sensitive analytic method to monitor Entresto in pediatric patients, which is of great importance for individualized safe medication in children. Specifically, a liquid chromatography tandem mass spectrometry method for simultaneously quantification of valsartan, sacubitril and its bio-active metabolite sacubitrilat in human plasma has been developed and validated in pediatric patients. Plasma samples were pretreated with acetonitrile for protein precipitation. Elution was performed on X Select HSS T3 column (2.1 × 100 mm, 5 µm; Waters) column using an isocratic mobile phase process consisting of 0.1% formic acid aqueous solution and 0.1% formic acid acetonit rile with a total run time of 3.0 min. Valsartan-d3, sacubitrilin-d4 and sacubitrilat-d4 were used as the corresponding deuterium internal standards. According to the Bioanalytical Method Validation Guidance for Industry, the method was validated in the range of 0.5–5000 ng/mL. Intra- and inter-day accuracy of sacubitril,valsartan and sacubitrilat ranged from 93%− 108%, 98%− 109%, 91%− 102%, respectively, with relative standard deviation of precision ranging from 2.0% to 5.1%, 2.4%− 7.5%, 1,3%− 7.4%. The proposed method demonstrated good accuracy, precision and linearity. The matrix factors normalized by internal standard meet the acceptance criteria. The method was fully validated and applied in 39 children. Trough concentration of the three substances to be measured were: valsartan (11.3–938.0 ng/mL), sacubitril (0.5–395.5 ng/mL) and sacubitrilat (522.1–4890.0 ng/mL). Overall, this is the first study to simultaneously determined the plasma valsartan, sacubitril and sacubitrilat concentrations in children, which is believed to facilitate the clinical management of pediatric HF.
研究领域:
药理学
·
儿科学
·
临床医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 4
·483
·
IF 5.5
Ramsha Khalid,Syed Mahmood,Zarif Mohamed Sofian,Zamri Chik,Yi Ge
Background: Hypertension (HTN) is recognized as a major risk factor for cardiovascular disease, chronic kidney disease, and peripheral artery disease. Valsartan (VAL), an angiotensin receptor blocker drug for hypertension, has been limited due to its poor solubility and poor absorption from the GIT, which leads to low oral bioavailability. Objectives/Method: In the present research, firstly, VAL-loaded nanoliposomes were formulated and optimized using the Box–Behnken design (BBD). Optimized VAL-nanoliposomes were physically characterized and their fate was examined by scanning and transmission microscopy, DSC, FTIR, XRD, and ex vivo studies using rat skin. In vitro studies using human keratinocyte (HaCaT) cells showed a decrease in cell viability as the liposome concentration increased. Secondly, the formulation of VAL-loaded nanoliposomes was integrated into dissolvable microneedles (DMNs) to deliver the VAL transdermally, crossing the skin barrier for better systemic delivery. Results: The optimized nanoliposomes showed a vesicle size of 150.23 (0.47) nm, a ZP of −23.37 (0.50) mV, and an EE% of 94.72 (0.44)%. The DMNs were fabricated using a ratio of biodegradable polymers, sodium alginate (SA), and hydroxypropyl methylcellulose (HPMC). The resulting VAL-LP-DMNs exhibited sharp pyramidal microneedles, adequate mechanical properties, effective skin insertion capability, and rapid dissolution of the microneedles in rat skin. In the ex vivo analysis, the transdermal flux of VAL was significantly (5.36 (0.39) μg/cm 2 /h) improved by VAL-LP-DMNs. The enhancement ratio of the VAL-LP-DMNs was 1.85. In conclusion, liposomes combined with DMNs have shown high potential and bright prospects as carriers for the transdermal delivery of VAL. Conclusions: These DMNs can be explored in studies focused on in vivo evaluations to confirm their safety, pharmacokinetics profile, and pharmacodynamic efficacy.
研究领域:
药剂学
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2022
·
IF 6.633
Lin Chen,Li Ge,Qinghui Liang,Zhenbo Zhao,Kedi Yang
The enantioseparation of valsartan enantiomers using chiral eutectic solvents (ESs) as extractants was initially studied. The hydrophobic ESs (LM-DTTA) formed by L-menthol and (+)-Di-p-toluoyl-D-tartaric acid is a suitable chiral medium for the enantioselective extraction of R- and S-valsartan. Four principal parameters affecting chiral extraction, such as phase volume ratio, initial rac -valsartan concentration, extraction temperature, and system pH, were evaluated. The results showed that LM-DTTA has better and higher enantioselectivity levels, and one-step chiral extraction achieved an ee value of S-valsartan up to 91% under the optimized conditions. In addition, this chiral medium can be recycled through simple back-extraction with sodium bicarbonate solution and reused at least five times, giving similar results. This work provides a clear example of enantioseparation of the rac -valsartan via liquid–liquid enantioselective extraction using the LM-DTTA as a novel chiral recognition and separation medium. As a result, the established enantioselective extraction method can efficiently separate the R- and S-enantiomer and promote sustainable development for the production of S-valsartan.
研究领域:
药物化学
·
分离科学
✓ 已验证
产品关联
DOI
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 2
·268
·
IF 5.5
Yunhua Teng,Jiaojiao Ma,Junxia Zhang,Bohan Liang,Aijie Zhang,Yanjie Li,Shiqi Dong,Huirong Fan
Background:It has been documented that radiation can influence the pharmacokinetics of chemotherapy drugs, yet the underlying mechanisms remain poorly understood. In clinical practice, a considerable number of cancer patients undergo radiotherapy, and those with comorbid hypertension required antihypertensive drugs, including valsartan, an angiotensin II receptor blocker. However, there is no research investigating whether radiotherapy poses a risk of altering the pharmacokinetics.Objective:The objective of this study is to investigate the impact of X-ray abdominal irradiation on the pharmacokinetics of valsartan and to preliminarily elucidate the underlying mechanism.Methods:The pharmacokinetics of valsartan after X-ray irradiation was investigated in rats and in vitro by detecting the concentration of valsartan in biological samples by LC-MS/MS. The oxidative stress in the intestine and the mRNA expression of partial transporters and Nrf2 in the liver and small intestine were detected by biochemical reagent kit or RT-qPCR.Results: In vivo studies showed that X-ray irradiation resulted in a significant decrease in the AUC and Cmaxof valsartan, and the cumulative fractional excretion of valsartan in bile and urine, although there was no significant change in fecal excretion. In vitro studies showed that the uptake of valsartan by both intestine and Caco-2 cells decreased after irradiation, and the cellular uptake could be restored by Mrp2 inhibitor MK571. The levels of GSH, SOD, and CAT in the intestine decreased after irradiation. The mRNA expressions of Mrp2 and P-gp in the intestine or Caco-2 cells were significantly upregulated after irradiation while there was a downregulation of Mrp2 and oatp1b2 in liver. Nrf2 and HO-1 in the intestine were also significantly upregulated, which clarified the involvement of Mrp2 and the possible molecular mechanism.Conclusions:Abdominal X-ray irradiation can cause oxidative stress and upregulate intestinal Mrp2, which may be related to oxidative stress and upregulation of Nrf2, reducing intestinal absorption of valsartan and leading to a significant decrease in the blood concentration of valsartan.
研究领域:
药理学
·
分子生物学
·
放射医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
POLYMERS FOR ADVANCED TECHNOLOGIES
·
2020
·Vol. 32
·期 3
·1262-1271
·
IF 2.578
Qingzhen Zhu,Baogang Zhang,Yuandou Wang,Xinghua Liu,Weiwei Li,Feng Su,Suming Li
Poly( D , L -lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) diblock copolymers with different compositions were synthesized by ring-opening polymerization of D , L -lactide and glycolide, using monomethoxy PEG as macro-initiator. The resulting copolymers were characterized by nuclear magnetic resonance, gel permeation chromatography, and critical micelle concentration analyses. Self-assembly of the copolymers yielded aggregates of different architectures, including spherical micelles and a mixture of spherical and worm-like micelles with Y-junctions. The self-assembled architecture depends on both the hydrophilic/hydrophobic balance and the molar mass of copolymers. Valsartan, a widely used drug in the treatment of hypertension, was loaded in micelles using a co-solvent evaporation method. High drug-loading content was obtained for worm-like micelles. in vitro drug release was performed at 37°C in pH 7.4 phosphate-buffered saline. An initial burst release is detected in all cases, followed by slower release up to 9 days. The overall release rate is strongly dependent on the degradation of micelles. Copolymers with short PLGA blocks exhibit faster drug release due to faster degradation of micelles, and worm-like micelles present slower drug release as compared to spherical ones. Therefore, PLGA-PEG copolymer micelles with high drug-loading capacity, different architectures, and variable drug release rates could be most attractive for sustained delivery of valsartan.
研究领域:
药剂学
·
生物材料
·
高分子化学
✓ 已验证
DOI
高影响因子
Crystals
·
2020
·Vol. 10
·期 10
·922
·
IF 2.404
Xiao Juan Liu,Yang Zhang,Xue Zhong Wang
In situ ATR-FTIR spectroscopy and imaging and image analysis were applied to the study of the multicomponent co-crystallization process involvingS-valsartan and sacubitril in which LCZ696 crystals were formed. LCZ696 is a combination drug for use in heart failure that was approved by the FDA in 2015 following development by Novartis Pharmaceuticals. Though much work was reported on LCZ696 about its pharmacokinetic and pharmacodynamic effects in the evaluation and clinical testing, less attention was paid to study on the co-crystallization process. LCZ696 crystals have shown difficulties in filtration mainly due to the small particle size. In this work, LCZ696 crystals were prepared successfully byS-valsartan and sacubitril, and characterized by SEM, XRPD, TG-DSC and ATR-FTIR. ATR-FTIR and imaging and image analysis were used to monitoring solution concentration and investigating the co-crystallization mechanism. It revealed that the nucleation process was very slow compared with the transformation process, which is indication that the co-crystallization was controlled by nucleation. LCZ696 crystals are composed of very thin hexagonal plates, which seems indicating that LCZ696 crystals grow mainly in two size dimensions. Stirrer speed and crystal seeds were found to have noticeable effect on the induction time, transformation time and crystal size distribution. The Johnson-Mehl-Avrami equation was found to be able to describe the co-crystallization process.Keywords:S-valsartan and sacubitril co-crystallization;LCZ696;ATR-FTIR;On-line process imaging
研究领域:
药学
·
材料科学
·
分析化学
✓ 已验证
产品关联
DOI
高影响因子
POLYMERS FOR ADVANCED TECHNOLOGIES
·
2023
·
IF 3.4
Chihao Gao,Lixia Pan,Jie Song,Min Wei,Haozhi Sun,Feng Su,Xin Shen,Suming Li
Valsartan is almost insoluble, resulting in very low bioavailability. Preparing prolonged sustained-release systems to achieve valsartan drug delivery is essential. Herein, two types of poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles loading valsartan and carboxymethyl chitosan/aldehyde sodium hyaluronate hydrogels were prepared. The nanoparticles and hydrogel composites(NPs@Gel) were obtained by physical mixing. The NPs@Gel composites have swelling ratios within the scope from 157.87% to 206.51% and mass loss within the scope from 12.85% to 17.32%, influenced by incorporating PEG-PLGA nanoparticles. Moreover, the NPs@Gel composites had properties of self-healing and injection proven by rheological measurements. Importantly, adding nanoparticles could significantly reduce the swelling ratios of the hydrogels by shrinking the void fraction and enhancing the mechanical properties. Meanwhile, NPs@Gel composites also present excellent biocompatibility as evidenced by hemolysis test and MTT assay. Therefore, a potential prolonged sustained-release system of NPs@Gel for the delivery of valsartan was achieved.
研究领域:
药剂学
·
生物材料
·
药物递送
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Xiaowei Zhang,Liang Zhao,Shixie Xiang,Yiran Sun,Pan Wang,Jenny Jie Chen,Brian Sheng-Xian Teo,Zhishen Xie,Zhenqiang Zhang,Jiangyan Xu
Ethnopharmacological relevance Yishen Tongluo formula (YSTLF) is formulated based on traditional Chinese medicine theory for the treatment of Diabetic kidney disease (DKD) and has been shown to be effective in improving the symptoms of DKD according to the clinical observation. Aim of the study To explore the effect of YSTLF on DKD and figure out whether its effects were due to the regulation Sirt6/TGF-β1/Smad2/3 pathway and promoting degradation of TGF-β1. Materials and methods The extract of YSTLF at 1, 2.5 and 5 g/kg was orally administered to C57BLKS/J ( db/db ) mice for 8 weeks and db/db mice were given valsartan as a positive control. The littermate db/m and db/db mice were given vehicle as the control and model group, respectively. Blood urea nitrogen and serum creatinine were detected and the urinary albumin excretion, urea albumin creatinine ratio was calculated. The histopathological change of renal tissues in each group was determined. Simultaneously, the levels of fibrosis-related proteins and messenger RNA (mRNA) in kidney and high glucose (HG)-induced SV40-MES-13 cells were detected. The roles of YSTLF in regulating of Sirt6/TGF-β1/Smad2/3 signaling pathway were investigated in HG-stimulated SV40-MES-13 cells and validated in db/db mice. Furthermore, the effect of YSTLF on TGF-β1 degradation was investigated in HG-stimulated SV40-MES-13 cells. Results YSTLF significantly improved the renal function in DKD mice. YSTLF dose-dependently attenuated pathological changes and suppressed the expression of type I collagen , alpha smooth muscle actin , type IV collagen , and fibronectin in vitro and in vivo , resulting in ameliorating of renal fibrosis . YSTLF positively regulated Sirt6 expression, while inhibited the activating of TGF-β1/Smad2/3 signaling pathway. TGF-β1 was steady expressed in HG-stimulated SV40-MES-13 cells, whereas was continuously degraded under YSTLF treatment. Conclusions YSTLF significantly ameliorates renal damages and fibrosis may via regulating Sirt6/TGF-β1/Smad2/3 signaling pathway as well as promoting the degradation of TGF-β1.
研究领域:
药理学
·
内分泌学
·
分子生物学
·
中医
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY
·
2018
·Vol. 29
·期 10
·1436-1443
·
IF 2.873
Yi-Lin Sun,Peng-Hui Li,Ling Shi,Wan-Zhen Su,De-Sheng Li,Gen-Long Xue,Yue Zhao,Chang-Zhu Li,Ying Li,Yang Zhou,Shang-Xuan Li,Yang Zhang,Yan-Jie Lu,Zhen-Wei Pan
Introduction: Deficiency of testosterone was associated with the susceptibility of atrial fibrillation (AF). Angiotensin-II (AngII) receptor antagonists were shown to reduce AF by improving atrial electrical remodeling. This study investigated the effects and mechanism of valsartan, an AngII receptor antagonist, on the susceptibility to AF with testosterone deficiency. Methods and Results: Five-week-old male ICR mice were castrated and valsartan was administered orally (50 mg/kg/d). High-frequency electrical stimulation method was used to induce atrial arrhythmia. Patch-clamp technique was used for recording action potential duration (APD), transient outward potassium current ( I to ), sustained outward potassium current ( I ksus ), and late sodium current ( I Na-L ). Optical mapping technique was used to examine atrial conduction velocity (CV). The expression of connexin40 (Cx40) and Cx43 were detected by Western blot analysis. The occurrence rate of AF was significantly increased in castrated mice and APDs measured at 50% and 90% repolarization were markedly prolonged in castrated mice than controls, which were alleviated by the administration of valsartan. Valsartan suppressed the increase of I Na-L and rescued the reduction of I to and I ksus in castrated mice. The left atrial CV in castrated mice was decreased and the expression of Cx43 reduced than controls, which were restored after valsartan treatment. Conclusions: Valsartan reduced the susceptibility of AF in castrated mice, which may be related to the inhibition of action potential prolongation and improvement of atrial conduction impairment. This study indicates that valsartan may represent a useful agent for the prevention of AF pathogenesis in elderly male patients.
研究领域:
心脏病学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Gaojun Wu,Zhengxian Wang,Peiren Shan,Shanjun Huang,Shuang Lin,Weijian Huang,Zhouqing Huang
Background Myocardial remodeling caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. Netrin-1, which is an axonal guidance cue, has been shown to be involved in the inflammatory response, tumorigenesis, and angiogenesis in non-neuronal tissues. However, the role of Netrin-1 in cardiac remodeling has not been fully elucidated. Methods The rat cardiomyocyte cell line H9c2 and primary neonatal rat cardiomyocytes were treated with Ang II. Cells were transfected with siRNA to silence Netrin-1 expression. Real-time polymerase chain reaction and Western blot analysis were used to detect the markers for fibrosis, apoptosis, and hypertrophy in cardiomyocytes. An Annexin V-EGFP/PI cell apoptosis detection kit was used to measure the level of apoptosis caused by angiotensin II. Results We found that Netrin-1 expression was upregulated in the H9c2 cells and the neonatal rat cardiomyocytes stimulated by Ang II. The increased Netrin-1 expression was decreased by valsartan to block AT1R. Importantly, the application of Netrin-1 siRNA significantly alleviated the degrees of myocardial hypertrophy, fibrosis (reflected by Myhc, collagen I, and TGF-β) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II. In addition, the silencing of Netrin-1 substantially decreased the phosphorylation of PKCα, JNK, and P38. We treated H9c2 cells with LY317615, SP600125, and SB203580, inhibitors of PKCα, JNK, and P38, respectively, thereby resulting in a substantial decrease in hypertrophy, fibrosis, and apoptosis. Conclusions Ang II produces cardiac hypertrophy, fibrosis, and apoptosis through the upregulation of Netrin-1 and the activation of the AT1R/PKCα/MAPK (JNK, P38) pathway. Suppression of Netrin-1 can relieve Ang II-induced cardiac remodeling via inhibition of the PKCα/MAPK (JNK and P38) signaling pathway. Thus, Netrin-1 may be a novel therapeutic target for Ang II-mediated cardiac remodeling.
研究领域:
心脏病学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）