Publications by authors named "Pingfei Fang"

12 Publications

  • Page 1 of 1

Isoliquiritigenin Alleviates Semen Strychni-Induced Neurotoxicity by Restoring the Metabolic Pathway of Neurotransmitters in Rats.

Front Pharmacol 2021 15;12:762290. Epub 2021 Nov 15.

Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China.

Acute neurotoxicity of Semen Strychni can result in sudden death in epilepsy. The detoxification method and mechanism of Semen Strychni acute poisoning have not been clarified. This experiment focused on the mechanism of Semen Strychni neurotoxicity and the alleviation effects of isoliquiritigenin. The rats were intraperitoneally injected with Semen Strychni extract (125 mg/kg), followed by oral administration of isoliquiritigenin (50 mg/kg) for 7 days. FJ-B staining was used to evaluate the degree of injury on hippocampus neurons. The concentration of monoamines, amino acids, and choline neurotransmitters, the Dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolic pathway in the hippocampus, cerebellum, striatum, prefrontal cortex, hypothalamus, serum, and plasma were detected by LC-MS/MS. The expression of neurotransmitter metabolic enzymes [catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO)] and neurotransmitter receptors [glutamate N-methyl-D-aspartic acid receptors (NMDARs) and gamma-aminobutyric acid type A receptor (GABRs)] were, respectively determined using ELISA and qRT-PCR. The results indicated that Semen Strychni induced neuronal degeneration in the hippocampal CA1 region. Meanwhile, Semen Strychni inhibited the mRNA expression of NMDAR1, NMDAR2A, NMDAR2B, GABRa1, GABRb2 and reduced the level of MAO, which disrupted the DA and 5-HT metabolic pathway. However, isoliquiritigenin reversed these effects. In summary, isoliquiritigenin showed alleviation effects on Semen Strychni-induced neurotoxicity, which could be attributed to restoring neurotransmitters metabolic pathway, most likely through the activation of NMDA receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.762290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634445PMC
November 2021

Single Dose of SHR-1222, a Sclerostin Monoclonal Antibody, in Healthy Men and Postmenopausal Women With Low Bone Mass: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation, Phase I Study.

Front Pharmacol 2021 20;12:770073. Epub 2021 Oct 20.

National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.

SHR-1222 is a humanized monoclonal antibody targeting sclerostin and has the potential to promote bone formation and reduce bone resorption. This study was aimed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1222 in healthy men and postmenopausal women with low bone mass (BMD). It was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Subjects received SHR-1222 at 50, 100, 200, 300, and 400 mg sequentially or matching placebo subcutaneously. Totally, 50 subjects with low BMD were enrolled and randomly assigned; 10 received placebo and 40 received SHR-1222 (50 mg, n = 4; 100, 200, 300, or 400 mg, n = 9). The most common adverse events that occurred at least 10% higher in subjects with SHR-1222 treatment than those with placebo were decreased blood calcium, blood urine present, increased blood cholesterol, electrocardiogram T wave abnormal, urinary tract infection, increased blood pressure diastolic, and positive bacterial test. All the above adverse events were mild in severity and well resolved except one of increased blood cholesterol in a subject lost to follow-up. The serum SHR-1222 concentration increased in a dose-dependent manner. Administration of SHR-1222 upregulated the bone-formation markers N-terminal propeptide of type 1 procollagen, osteocalcin, and bone-specific alkaline phosphatase, while downregulated the bone-resorption marker β-C-telopeptide. The BMD at the lumbar spine notably rose after a single dose of SHR-1222. The largest increase occurred in the 400 mg cohort (3.8, 6.7, and 6.1% on day 29, 57, and 85, respectively; compared with 1.4, 0.8, and 1.0% in the placebo group). Although 10.0% of subjects receiving SHR-1222 tested positive for anti-SHR-1222 antibodies, no obvious effects of antibody formation were found on pharmacokinetics. Overall, SHR-1222 was well tolerated at doses from 50 to 400 mg and is a promising new remedy for osteoporosis. http://www.clinicaltrials.gov, NCT03870100.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.770073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564351PMC
October 2021

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study.

Int J Clin Pharmacol Ther 2021 Aug;59(8):578-584

Objective: Clozapine is the most effective therapy for schizophrenia. This study compared the bioequivalence of a generic formulation of clozapine (ChangZhou Pharmaceutical Factory Co. Ltd. Jiangsu, China) to the brand name formulation (Clozaril, HLS Therapeutics, Inc., Philadelphia, PA, USA) after multiple doses in Chinese schizophrenic patients.

Materials And Methods: This was a randomized, open-label, multiple-dose, 2-way crossover study in which patients with schizophrenia received the generic clozapine or Clozaril 100 mg twice daily for 10 days before crossing over to the alternate formulation for the next 10 days. Blood samples were collected at regular intervals during each treatment period, and plasma concentration of clozapine was determined by high-performance liquid chromatography.

Results: 26 patients were enrolled, of whom 24 completed the study and were included in the steady-state analyses. The mean AUC was 6,003.29 h×ng/mL for generic clozapine and 6,347.53 h×ng/mL for Clozaril. The mean C was 698.52 ng/mL for generic clozapine and 739.75 ng/mL for Clozaril. The ratio of the adjusted geometric means and its 90% CI of the ratios for AUC was 96.24% (89.60 - 103.36%), and for C was 95.90% (88.91 - 103.44%). A total of 66 adverse events were reported by 22 (84.62%) subjects. Among them, 34 occurred in 17 (65.38%) patients during dosing of generic clozapine, and 32 occurred in 16 (61.54%) patients during dosing of brand-name clozapine.

Conclusion: The result demonstrated that the generic clozapine was bioequivalent to brand-name clozapine (Clozaril). This would provide physicians with reassurance that patients who receive the studied generic clozapine will achieve similar plasma drug concentrations to those of brand-name clozapine (Clozaril).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5414/CP203864DOI Listing
August 2021

Changes in clinical trials of endocrine disorder and metabolism and nutrition disorder drugs in mainland China over 2010-2019.

Pharmacol Res Perspect 2021 04;9(2):e00729

Clinical Trials Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.

With the improvements in relevant policies, laws, and regulations regarding drug clinical trials in China, the quantity and quality of drug clinical trials have gradually improved, and the development prospects of drug clinical trials for endocrine disorders and metabolism and nutrition disorders are promising. Based on information from the clinical trials from the online drug clinical trial registration platform of the National Medical Products Administration, we aimed to review and evaluate the development of clinical trials of drugs for endocrine disorders and metabolism and nutrition disorders in mainland China from 2010 to 2019, as well as the trends over time. A total of 861 trials were carried out on 254 types of drugs for endocrine disorders and metabolism and nutrition disorders, among which 531 (61.67%) involved endocrine disorders, and 330 (38.33%) addressed metabolism and nutrition disorders. The annual number of clinical trials has been increasing gradually, with a significant increase in 2017. Among them, the proportion of clinical trials with Chinese epidemiological characteristics was relatively large (Wu, Annual Report on Development Health Management and Health Industry in China, 2018). The largest number of trials were for diabetes drugs (55.63%), followed by trials of drugs for hyperlipidemia (19.4%) and those for hyperuricemia (7.9%). It was found that the geographical area of the leading units also showed obvious unevenness according to the analysis of the test unit data. Based on the statistics and evaluation of the data, comprehensive information is provided to support the cooperation of global pharmaceutical R&D companies and research units in China and the development of international multicenter clinical trials in China. This work additionally provides clinical trial units with a self-evaluation of scientific research competitiveness and hospital development strategies. At the same time, it provides a reference with basic data for sponsors and stakeholders in these trials to determine their development strategy goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prp2.729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931124PMC
April 2021

Absolute quantitative analysis of endogenous neurotransmitters and amino acids by liquid chromatography-tandem mass spectrometry combined with multidimensional adsorption and collision energy defect.

J Chromatogr A 2021 Feb 5;1638:461867. Epub 2021 Jan 5.

Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 210009, PR China. Electronic address:

Considering that neurotransmitters (NTs) and amino acids (AAs) exert pivotal roles in various neurological diseases, global detection of these endogenous metabolites is of great significance for the treatment of nervous system diseases. Herein, a workflow that could cope with various challenges was proposed to establish an extendable all-in-one injection liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for analyzing these small molecular metabolites with high coverage. To obtain a qualified blank biological matrix for the preparation of standard curves and quality control samples, different absorption solvents, including activated carbon (AC), calcite (Cal) and montmorillonite (Mnt) were systematically evaluated for efficient absorption of endogenous substances with minimum residue. We also firstly proposed a "Collision Energy Defect (CED)" strategy to solve the huge difference of mass signal strength caused by different properties and concentrations of 11 NTs and 17 AAs. The quantitative results were validated by LC-MS/MS. Sensitivity, accuracy, and recovery meeting generally accepted bioanalytic guidelines were observed in a concentration span of at least 100 to 500 times for each analyte. Then the temporal changes of intracerebral and peripheral NTs and AAs in ischemic stroke model and sham operated rats were successfully produced and compared using the described method. All these results suggested that the currently developed assay was powerful enough to simultaneously monitor a large panel of endogenous small molecule metabolites, which was expected to be widely used in the research of various diseases mediated by NTs and AAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chroma.2020.461867DOI Listing
February 2021

Quantitative monitoring of a panel of stress-induced biomarkers in human plasma by liquid chromatography-tandem mass spectrometry: an application in a comparative study between depressive patients and healthy subjects.

Anal Bioanal Chem 2019 Sep 14;411(22):5765-5777. Epub 2019 Jun 14.

Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.

Using a metabolomic approach, we have found that stress can induce oxidative damage by disturbing the creatine/phosphocreatine shuttle system and purinergic pathway, leading to an excessive membrane breakdown. To further validate our findings and to monitor the biological impact of stress in research of clinical psychiatry, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously determine a panel of biomarkers comprising choline, creatine, purinergic metabolites, neurosteroids, lysophosphatidylcholines, and phosphatidylethanolamines in human plasma. After optimization of the extraction protocol, all the 15 analytes plus 4 internal standards with distinct polarities were extracted into an organic phase using methyl tert-butyl ether/methanol (1:1, v/v). A reversed-phase C8 column under gradient elution consisting of aqueous phase A of 5 mM ammonium acetate buffer solution containing 0.1% formic acid and organic phase B of acetonitrile/2-propanol (3:7, v/v) was utilized for separation. Four sequential periods under positive or negative ion mode were combined for the determination of analytes with specific multiple reaction monitoring transitions. For all analytes, this method exhibited good linearity with coefficients of determination (R) higher than 0.99. The lower limit of quantification (LLOQ) values ranged from 0.05 to 80.0 ng/mL. Recovery between 70.5 and 97.3% was obtained by spiking standards to plasma samples stripped by powdered activated carbon. The intra- and inter-assay relative standard deviations (RSDs) of the analyses varied between 2.0 and 13.3%. The mean accuracy ranged from 90.6 to 109.0%. The matrix effect ranged from 91.2 to 107.3% with variations less than 9.0%. Stability under different conditions was tested, with mean recoveries varying between 90.4 and 109.7%. Finally, the established method was successfully applied to analyze the plasma samples from a small cohort of 30 patients with major depressive disorder and 30 matched healthy controls. Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00216-019-01956-2DOI Listing
September 2019

Dexamethasone changes the pharmacokinetics of amitriptyline and reduces its accumulation in rat brain: The roles of P-gp and cyp3a2.

J Pharmacol Sci 2019 May 4;140(1):54-61. Epub 2019 May 4.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, PR China; Institute of Clinical Pharmacy, Central South University, Changsha, 410011, PR China.

The wide spread use of central nervous system (CNS) drugs has caused thousands of deaths in clinical practice while there are few antidotes or effective treatments to decrease their accumulation in CNS. In this study, we used amitriptyline (AMI) and dexamethasone (DEX) as the corresponding poisoning and pre-protecting drugs, respectively, to study whether DEX has the potential to reduce AMI accumulation in brain. By measuring the pharmacokinetic data of AMI and its main metabolite nortriptyline (NOR), we found that DEX possibly accelerated the metabolism and elimination of AMI with minimal effects on the concentrations of NOR in blood. Nevertheless, the results indicated that DEX reduced the brain/plasma concentration ratio of AMI and NOR, even if the plasma concentration of NOR had an upward trend. Western blot results showed the overexpression of cyp3a2 and P-gp in rat liver and brain capillaries tissues. We propose that cyp3a2 and P-gp could be upregulated in the liver and blood-brain barrier (BBB) when using DEX. Further experiments suggest that DEX may serve as the ligand of PXR to induce P-gp expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphs.2019.04.007DOI Listing
May 2019

Dihydromyricetin affect the pharmacokinetics of triptolide in rats.

Xenobiotica 2020 Mar 27;50(3):332-338. Epub 2019 May 27.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, PR China.

1. Dihydromyricetin (DMY) has anti-tumor and hepatoprotective activities and inhibits the activity of CYP enzymes and P-gp. In this research, we explored the effect of DMY on the pharmacokinetics of triptolide (TP), an anti-tumor Chinese medicine that is mainly metabolized by CYP enzymes and is the substrate of P-gp.2. Rats were administrated TP (1.2 mg/kg) with and without DMY in different dosage regimens, then a sensitive and reliable LC-MS/MS method was developed and applied to assess the pharmacokinetics of TP. The blood samples for TP were collected from each rat up to 120 min after administration of TP.3. When co-administrated with single dose of DMY (100 mg/kg), the AUC, Cmax and T1/2 of TP were significantly enhanced by 98, 83 and 66%, respectively. The T1/2 of TP was significantly prolonged from 23.6 ± 6.4 to 70.5 ± 12.5 min with 14-doses pretreatment of DMY (500 mg/kg), conversely, the Cmax was decreased by 30% and the AUC was enhanced by 24%.4. These results hinted that administration of DMY with TP did alter the pharmacokinetics of TP, and provided the theoretical pharmacokinetic basis to study on the protective effects of DMY against acute liver injury caused by TP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00498254.2019.1616851DOI Listing
March 2020

Nrf2-dependent antioxidant response mediated the protective effect of tanshinone IIA on doxorubicin-induced cardiotoxicity.

Exp Ther Med 2018 Oct 17;16(4):3333-3344. Epub 2018 Aug 17.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.

Doxorubicin (DOX), a potent and widely used anticancer agent, can give rise to severe cardiotoxicity that limits its clinical use by inducing oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the central regulator of cellular responses to electrophilic/oxidative stress, which serves a critical role in maintenance of normal cardiac function. Tanshinone IIA (Tan IIA) has previously been reported to protect against DOX-induced cardiotoxicity. The aim of the present study was to elucidate whether Nrf2 signaling serves a role in the underlying mechanism. In the animal model, DOX induced acute cardiotoxicity, whereas Tan IIA pretreatment reduced the activity of myocardial enzymes, and increased activity of the antioxidant enzymes superoxide dismutase, catalase and glutathione (GSH). Furthermore, Tan IIA pretreatment (3-10 µM) significantly increased the cell viability and markedly restored morphological changes in DOX-injured H9c2 cells, decreased the generation of reactive oxygen species, and increased the level of intracellular GSH. Additionally, Tan IIA pretreatment also induced the nuclear accumulation of Nrf2 and its downstream genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone) 1, and glutamate-cysteine ligase catalytic subunit in both the mice cardiac tissues and H9c2 cells. Nrf2 knockdown by small interfering RNA downregulated Tan IIA-induced Nrf2 activation and reversed the effect of Tan IIA on the DOX-induced inhibition of cell viability. These results suggest that the Nrf2-dependent antioxidant response mediates the protective effect of Tan IIA on DOX-induced cardiotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/etm.2018.6614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143869PMC
October 2018

Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters.

Front Pharmacol 2018 16;9:226. Epub 2018 Mar 16.

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.

Triptolide (TP), the main bioactive component of Hook F, can cause severe hepatotoxicity. Isoliquiritigenin (ISL) has been reported to be able to protect against TP-induced liver injury, but the mechanisms are not fully elucidated. This study aims to explore the role of nuclear transcription factor E2-related factor 2 (Nrf2) and hepatic transporters in TP-induced hepatotoxicity and the reversal protective effect of ISL. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to the disorder of bile acid (BA) profiles in mice livers. Combined treatment of TP with ISL effectively alleviated TP-induced hepatotoxicity. Furthermore, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NAD(P)H: quinine oxidoreductase 1 (NQO1) expression. Expressions of hepatic P-gp, MRP2, MRP4, bile salt export pump, and OATP2 were also induced. In addition, transport assays identified that neither was TP exported by MRP2, OATP1B1, or OATP1B3, nor did TP influence the transport activities of P-gp or MRP2. All these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous BAs and exogenous TP as well as its metabolites by enhancing the expressions of Nrf2, NQO1, and hepatic influx and efflux transporters. Effects of TP on hepatic transporters are mainly at the transcriptional levels, and changes of hepatic BA profiles are very important in the mechanisms of TP-induced hepatotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.00226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865274PMC
March 2018

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P-gp In Vitro.

Phytother Res 2017 Jul 16;31(7):1090-1096. Epub 2017 May 16.

Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.

Triptolide (TP) is an active ingredient isolated from Tripterygium wilfordii Hook. f. (TWHF), which is a traditional herbal medicine widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, its adverse reactions of hepatotoxicity and nephrotoxicity have been frequently reported which limited its clinical application. The aim of this study was to investigate the mechanism of glycyrrhetinic acid (GA) effecting on the elimination of TP in HK-2 cells and the role of the efflux transporters of P-gp and multidrug resistance-associated proteins (MRPs) in this process. An ultra performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) analytical method was established to determine the intracellular concentration of TP. In order to study the role of efflux transporters of P-gp and MRPs in GA impacting on the accumulation of TP, the inhibitors of efflux transporters (P-gp: verapamil; MRPs: MK571) were used in this study. The results showed that GA could enhance the elimination of TP and reduce the TP accumulation in HK-2 cells. Verapamil and MK571 could increase the intracellular concentration of TP; in addition, GA co-incubation with verapamil significantly increased the TP cellular concentration compared with the control group. In conclusion, GA could reduce the accumulation of TP in HK-2 cells, which was related to P-gp. This is probably one of the mechanisms that TP combined with GA to detoxify its toxicity. Copyright © 2017 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.5831DOI Listing
July 2017

[Effect of 18alpha-glycyrrhizic acid and 18beta-glycyrrhizic acid on P-gp function and expression in Caco-2 cells].

Zhongguo Zhong Yao Za Zhi 2012 Jan;37(1):99-103

Clinical Pharmacy & Pharmacology Institute, Second Xiangya Hospital, Central South University, Changsha 410011, China.

Objective: The aim of the present study was to evaluate the modulating effect of glycyrrhizic acid C-18 epimers, 18alpha-glycyrrhizic acid (alpha-GL) and 18beta-glycyrrhizic acid (beta-GL) on both P-glycoprotein (P-gp) activity and expression in Caco-2 cell.

Method: The effects of P-gp activity were analyzed by rhodamine (Rhd 123) accumulation test, and those of P-gp expression were analyzed by flow cytometry and real-time PCR.

Result: At middle and high concentrations (10, 60 micromol x L(-1)), alpha-GL inhibited the function of P-gp and with on dose dependent while beta-GL induced the function of P-gp at three test concentrations with no dose dependent too. At middle and high concentrations (10, 60 micromol x L(-1)), alpha-GL down-regulated the expression of MDR1 mRNA. At high concentrations (60 micromol x L(-1)), beta-GL up-regulated the expression of MDR1 mRNA; At high concentrations (60 micromol x L(-1)), beta-GL induced the expression of P-gp protein while alpha-GL has no effect on the expression of P-gp protein at three test concentrations.

Conclusion: The effects of alpha-GL and beta-GL on the expression of MDR1 mRNA and CYP3A mRNA showed the same trend. The character that epimers of GL act on CYP3A and P-gp show similar stereo selectivity whether relate to PXR need further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2012
-->