MOLECULES
·
2022
·Vol. 27
·期 8
·2550
·
IF 4.927
Lingzhi Liang,Xia Ren,Junyi Xu,Yurong Ma,Yunlin Xue,Tao Zhuang,Guisen Zhang
Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30(3 mg/kg) was significantly smaller (p< 0.05) than the theoretical ED30(5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.Keywords:olanzapine;SEP-363856;schizophrenia;synergistic;side effects
研究领域:
神经科学
·
药理学
·
精神病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2022
·
IF 3.841
Feifei Liang,Xiaofang Tan,Shuaishuai Hao,Wenwen Liu,Chenxin Duan,Guisen Zhang,Tao Zhuang,Yin Chen,Chao Hao
Olanzapine (OLZ) is a second-generation atypical anti-schizophrenia drug, and it had been developed into various formulations, including immediate release and long-acting formulations. Specific solubility properties of OLZ are very important to design formulations for specific administration. In present work, two novel cocrystals of OLZ were synthesized and characterized (OLZ-KAE·0.75EA·0.25H 2 O, OLZ-ORC, KAE = kaempferol , ORC = orcinol). Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), synchronous thermal analysis and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) were used to characterize the structure of the cocrystals. Hirshfeld surface analysis was used to understand intermolecular interactions in cocrystals. In OLZ-KAE·0.75EA·0.25H 2 O cocrystal, the ethyl acetate (EA) and H 2 O exist as channel crystalline solvate, and they can easily escape from the lattice channel. Powder dissolution study showed that OLZ-ORC improved the dissolution rate of OLZ in PH 6.8 phosphate buffer. However, OLZ-KAE·0.75EA·0.25H 2 O and its desolvation product decreased the dissolution rate of OLZ, and the release rate kept sustained and stable, which was very suitable for sustained release and long-acting muscle injection formulations.
研究领域:
药学
·
晶体学
✓ 已验证
产品关联
DOI
高影响因子
ANALYST
·
2023
·Vol. 148
·期 14
·3330-3340
·
IF 4.2
Kaikai Han,Jingjie Cui,Shaowei Chen,Tao Yu
Olanzapine (OLZ) and lithium carbonate (Li2CO3) are the main drugs for treating mental disorders related to dopamine (DA). A highly conductive carbon paper sensing electrode is used to investigate the effects of OLZ and Li2CO3 on DA oxidation due to its amplification of oxidation peak currents. Different chemical properties of drugs have different effects on DA oxidation. The presence of OLZ fouling on the electrode surface due to the irreversible adsorption weakens the sensing activity and thus reduces the DA oxidation peak current. However, the fixed DA oxidation peak potential at 0.22 V indicates no interaction between them. The hydrolysis effect of Li2CO3 increases the solution pH from 7.47 to 9.73, which promotes the deprotonation of DA, leading to a 156 mV negative shift of the DA oxidation peak potential. Additionally, a 94% decrease of the DA peak current may be related to the generation of polydopamine in alkaline media.
研究领域:
药理学
·
神经生物学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 3.756
Ning Li,Peng Quan,XiaoCao Wan,Chao Liu,Xiaochang Liu,Liang Fang
In this paper, based on the optimized formulation of olanzapine (OLN) transdermal patch, the role of sorbitan monooleate (SP) in OLN release and percutaneous absorption processes was probed in vitro and in vivo . Rheological test, DSC , FT-IR and molecular modeling were conducted to elucidate the effect of SP on the release process of OLN from transdermal patch . Additionally, the action of SP on the percutaneous absorption process was probed using tape stripping transdermal experiment, confocal laser scanning microscopy (CLSM), ATR-FTIR and molecular docking. The results showed that the hydrogen bonding interaction between OLN and pressure sensitive adhesive (PSA) was weakened by SP, which resulted in a decrease in the cohesive interaction between polymer chains and an increase in the formation of free volume of PSA, thus, the release of OLN from patch was promoted. Meanwhile, the O H groups of SP interacted with the polar head groups of the ceramides , which increased the fluidity of the skin lipids , thereby improved the ability of OLN percutaneous absorption. In summary, this study demonstrated that not only the release but also the percutaneous absorption processes were promoted by SP. This study provided comprehensive molecular level understanding on the effect of penetration enhancer on transdermal patch and strategies for rationally selection of chemical enhancer for transdermal drug delivery systems .
研究领域:
药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGY
·
2016
·
IF 1.533
Zhou Hong-Yu,Gu Er-Min,Chen Qiu-lei,Zhan Yun-Yun,Wang Shuang-Hu,Liang Bing-Qing,Dai Da-Peng,Cai Jian-Ping,Hu Guo-Xin
The objective of this study was to assess the catalytic activity of 22 novel CYP2D6 allelic variants (2D6*87-*98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C and R497C) to olanzapine in vitro. Their protein products expressed in Spodoptera frugiperda 21 (Sf21) insect cells were incubated with olanzapine 100-2,000 μmol/l for 30 min. The kinetic parameters of Km, Vmax and intrinsic clearance were determined by 2-hydroxymethylolanzapine, the metabolite of olanzapine mediated by CYP2D6, using ultra-performance liquid chromatography tandem mass spectrometry. Results showed that the kinetic parameters of 2 alleles, CYP2D6*92 and 2D6*96, could not be detected; 17 allelic variants, CYP2D6*87-*88, 2D6*90-*91, 2D6*93-*95, 2D6*97, R25Q, F164L, E215K, F219S, V327M, V342M, R344Q, R440C and R497C, significantly reduced the intrinsic clearance of olanzapine; 2 variants, CYP2D6*89 and 2D6*98, increased the intrinsic clearance of olanzapine; no difference was found in intrinsic clearance of D336N. Furthermore, 6 alleles, CYP2D6*87, 2D6*88, 2D6*91, 2D6*93, 2D6*97 and R497C, exhibited higher Km values in a range of 120.80-217.56% relative to wild-type CYP2D6*1. The research demonstrated the metabolic phenotype of the 22 novel CYP2D6 variants for olanzapine that were different from probe drugs we used previously and might provide beneficial information to the personalized medicine of olanzapine
研究领域:
药理学
·
临床医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2019
·
IF 3.499
Ting Jiang,Yingqiong Zhang,Mengru Bai,Ping Li,Wei Wang,Mingyang Chen,Zhiyuan Ma,Su Zeng,Hui Zhou,Huidi Jiang
Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic β-hydroxybutyrate level (indicator of fatty acid β-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 μM of IC 50 ), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.
研究领域:
药理学
·
肝病学
·
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
Cuilian Guo,Jinxin Liu,Huqun Li
Aims The present study aimed to investigate the possible effects of metformin on the olanzapine-induced insulin resistance in rats. Methods Rats were randomly divided into three groups: the control (Control) group, the olanzapine (Ola) group and the olanzapine + metformin (Ola + Met) group. Rats in the Ola group received olanzapine (8 mg/kg/day) intraperitoneally while rats in the Ola + Met group received olanzapine (8 mg/kg/day) intraperitoneally and metformin (300 mg/kg/day) orally for 8 weeks. Rats in the Control group received vehicle accordingly. Body weight and fasting blood glucose were recorded routinely. Inflammatory cytokines TNF-α, IL-6 and IL-1β and IL-10 were measured by ELISA. The gene expression of macrophages markers was examined by qPCR. The epididymal white adipose tissue, liver and skeletal muscle were also isolated for immunohistochemical analysis. Results Olanzapine significantly induced body weight gain and insulin resistance compared to the control, which was markedly alleviated by metformin. Pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were upregulated while the anti-inflammatory cytokine IL-10 was downregulated by olanzapine in plasma and epididymal white adipose tissue compared to the control, but not the liver and skeletal muscle. However, metformin co-administration significantly decreased the levels of TNF-α, IL-6 and IL-1β while increased the level of IL-10 in epididymal white adipose tissue compared to olanzapine-treated rats. Moreover, olanzapine treatment markedly increased the expression of the CD68 and the M1 macrophage markers while decreased the expression of the M2 macrophage markers in epididymal white adipose tissue in rats compared to the control. However, metformin co-treatment ameliorated the effects of olanzapine. Conclusions Our results suggest that metformin alleviated olanzapine-induced insulin resistance possibly by suppressing the inflammatory responses mediated by macrophage infiltration and polarization in epididymal white adipose tissue.
研究领域:
药理学
·
内分泌学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2023
·
IF 9.7
Lin Liu,Min Liu,Jingya Xiu,Bowen Zhang,Haiyang Hu,Mingxi Qiao,Dawei Chen,Jiulong Zhang,Xiuli Zhao
Depression is one of the most common mental diseases, which seriously affects patients’ physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H 2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. Statement of Significance ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.
研究领域:
药学
·
神经科学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
·
2025
·
IF 3.4
Mukhammet N. Gabdulkhaev,Nailya F. Idiyatullina,Khasan R. Khayarov,Artem O. Surov,Marat A. Ziganshin,Valery V. Gorbatchuk
Olanzapine is among the drugs with notoriously elusive polymorphs that are challenging to prepare in their phase-pure form. A first solution to this problem is offered in the present work using the ability of water to compete with organic solvent for inclusion in the drug crystal lattice and the ability of solvate-hydrates with an optimal composition to give a solvent-free amorphous olanzapine and its phase-pure polymorph II upon desolvation. In the screening performed, saturation of the drug solid forms with solvent vapors was used to select an organic solvent that could be partially or completely replaced by vapors of water in the solvate. Besides, water vapors were found to be passive enough in comparison with vapors of other studied solvents in their ability to change the polymorphic state of olanzapine or be included by its stable form. The conditions used for preparation of the amorphous olanzapine form are mild enough to prevent its partial thermal decomposition. These conditions also create phase restrictions that stop the desolvation of solvate-hydrate on the intermediate Ostwald stage of polymorph II that is phase-pure above the sensitivity level of powder X-ray diffractometry and thermal analysis.
研究领域:
药物晶体学
·
固态化学
·
多晶现象
·
药物研发
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF FOOD COMPOSITION AND ANALYSIS
·
2026
·
IF 4.6
Wenjia Yang,Lu Zeng,Xinyu Zhang,Xiangrui Li,Qiujin Zhu
The illegal addition of fluoxetine (FLX) to weight-loss products poses significant health risks to consumers. In this study, computer-aided simulation technology was utilized to design and screen FLX hapten. By optimizing the alkyl linker strategy, while preserving the structural similarity with the parent molecule, the hydrophobic interaction was enhanced, thereby significantly improving antibody performance. Based on this strategy, we successfully developed a highly sensitive monoclonal antibody (mAb). Leveraging this, we established an immunochromatographic assay (ICA) utilizing time-resolved fluorescent microspheres (TRFMs) for detecting FLX in capsule, tablet, and beverage samples, with limits of detection (LODs) of 3.010 and 1.549 µg/kg, and 0.886 ng/mL, respectively. Notably, the proposed ICA demonstrated acceptable selectivity, stability, and reproducibility. The recovery rates for FLX in the aforementioned matrices were 97.9 %-101.8 %, 96.9 %-103.4 %, and 99.1 %-101.7 %, respectively. These results were consistent with those obtained via LC-MS/MS. The TRFMs-based ICA provides a reliable, rapid, high-sensitivity, and real-time method for monitoring FLX levels. Moreover, this assay provides a promising strategy for the rapid detection of unauthorized non-food additives in food products.
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Yuying Chen,Qingwei He,Huangjie Lu,Jie Yang,Jiongming Han,Ying Zhu,Ping Hu
This study addresses the challenging task of quantitatively investigating drug release from PLGA microspheres after in vivo administration. The objective is to employ Förster resonance energy transfer (FRET) to visualize drug-encapsulated microspheres in both in vitro and in vivo settings. The primary goal is to establish a quantitative correlation between FRET fluorescence changes and microsphere drug release. The study selects drugs with diverse structures and lipid solubility to explore release mechanisms, using PLGA as the matrix material. Clozapine and risperidone serve as model drugs. FRET molecules, Cy5 and Cy5.5, along with Cy7 derivatives, create FRET donor–acceptor pairs. In vitro results show that FRET fluorescence changes align closely with microsphere drug release, particularly for the Cy5.5-Cy7 pair. In vivo experiments involve subcutaneous administration of microspheres to rats, tracking FRET fluorescence changes while collecting blood samples. Pharmacokinetic studies on clozapine and risperidone reveal in vivo absorption fractions using the Loo-Riegelman method. Correlating FRET and in vivo absorption data establishes an in vitro – in vivo relationship (IVIVR). The study demonstrates that FRET-based fluorescence changes quantitatively link to microsphere drug release, offering an innovative method for visualizing and monitoring release in both in vitro and in vivo settings, potentially advancing clinical applications of such formulations.
研究领域:
药剂学
·
生物医学工程
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
eLife
·
2024
·
IF 6.4
Lu Yang,Zijin Lin,Ruijing Mu,Wenhan Wu,Hao Zhi,Xiaodong Liu,Hanyu Yang,Li Liu
Blood–brain barrier (BBB) prevents neurotoxins from entering central nervous system. We aimed to establish and characterize an in vitro triple co-culture BBB model consisting of brain endothelial cells hCMEC/D3, astrocytoma U251 cells, and neuroblastoma SH-SY5Y cells. Co-culture of SH-SY5Y and U251 cells markedly enhanced claudin-5 and VE-cadherin expression in hCMEC/D3 cells, accompanied by increased transendothelial electrical resistance and decreased permeability. Conditioned medium (CM) from SH-SY5Y cells (S-CM), U251 cells (U-CM), and co-culture of SH-SY5Y and U251 cells (US-CM) also promoted claudin-5 and VE-cadherin expression. Glial cell line-derived neurotrophic factor (GDNF) levels in S-CM and US-CM were significantly higher than CMs from hCMEC/D3 and U-CM. Both GDNF and US-CM upregulated claudin-5 and VE-cadherin expression, which were attenuated by anti-GDNF antibody and GDNF signaling inhibitors. GDNF increased claudin-5 expression via the PI3K/AKT/FOXO1 and MAPK/ERK pathways. Meanwhile, GDNF promoted VE-cadherin expression by activating PI3K/AKT/ETS1 and MAPK/ERK/ETS1 signaling. The roles of GDNF in BBB integrity were validated using brain-specific Gdnf silencing mice. The developed triple co-culture BBB model was successfully applied to predict BBB permeability. In conclusion, neurons enhance BBB integrity by upregulating claudin-5 and VE-cadherin expression through GDNF secretion and established triple co-culture BBB model may be used to predict drugs’ BBB permeability.
研究领域:
神经科学
·
细胞生物学
·
药理学
✓ 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）