Publications by authors named "Guifang Dou"

45 Publications

Lycium barbarum mitigates radiation injury via regulation of the immune function, gut microbiota, and related metabolites.

Biomed Pharmacother 2021 Jul 3;139:111654. Epub 2021 May 3.

Tianjin University of Traditional Chinese Medicine, Tianjin, China; Beijing Institute of Radiation Medicine, Beijing, China. Electronic address:

Previous studies have suggested that Lycium barbarum (L. barbarum) has a radioprotective function, although more in-depth investigation is still required. We investigated the radioprotective efficacy of extract of the fruits of L. barbarum (LBE) and its radioprotective mechanisms. Mice were exposed to 8.5 Gy, 5.5 Gy, or 6.0 Gy total body irradiation (TBI), and the survival rate, lymphocyte percentage, amount of cytokines, and viability of the irradiated cells, as well as the gut microbiome and fecal metabolomics were studied. LBE enhanced the survival of the mice exposed to 8.5 Gy γ-ray TBI or 5.5 Gy X-ray TBI. After 6.0 Gy γ-ray TBI, LBE exhibited good immunomodulatory properties, mainly characterized by the accelerated recovery of lymphocyte percentages, and the enhanced expression of immune-related cytokines. LBE reconstituted the gut microbiota of irradiated mice, increased the relative abundance of potentially beneficial genera (e.g., Turicibacter, Akkermansia), and decreased the relative abundance of potentially harmful bacterial genera (e.g., Rikenellaceae_RC9_gut_group). Beneficial regulatory effects of LBE on the host metabolites were also noted, and the major upregulated metabolites induced by LBE, such as Tetrahydrofolic acid and N-ornithyl-L-taurine, were positively correlated with the immune factor interleukin (IL)-6. In vitro, LBE also increased the vitality of rat small intestinal epithelial cells (IEC-6) after 4.0 Gy γ-ray irradiation and promoted the growth of Akkermansia muciniphila. These results confirmed a radioprotective function of LBE and indicated that the radioprotective mechanism may be due to immunomodulation and the synergistically modulating effect on the gut microbiota and related metabolites.
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http://dx.doi.org/10.1016/j.biopha.2021.111654DOI Listing
July 2021

A phase I, single and continuous dose administration study on the safety, tolerability, and pharmacokinetics of neorudin, a novel recombinant anticoagulant protein, in healthy subjects.

Pharmacol Res Perspect 2021 May;9(3):e00785

Beijing Institute of Radiation Medicine, Beijing, China.

The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR-hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty-four subjects received EH as a single dose of between 0.2 and 2.0 mg/kg by intravenous bolus and drip infusion. In addition, 18 healthy subjects were randomly divided into three dose groups (0.15, 0.30, and 0.45 mg/kg/h) with 6 subjects in each group for the continuous administration trial. Single or continuous doses of neorudin were generally well tolerated by healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. Moreover, no subjects withdrew from the trial because of AEs. There were no clinically relevant changes in physical examination results, clinical chemistry, urinalysis, or vital signs. The incidence of adverse events was not significantly related to drug dose or systemic exposure. After single-dose and continuous administration, the serum EH concentration reached its peak at 5 min, and the exposure increased with the increase in the administered dose. The mean half-life (T ), clearance (Cl), and apparent volume of distribution (Vd) of EH ranged from 1.7 to 2.5 h, 123.9 to 179.7 ml/h/kg, and 402.7 to 615.2 ml/kg, respectively. The demonstrated safety, tolerability, and pharmacokinetic characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. Clinical trial registration: Chinadrugtrials.org identifier: CTR20160444.
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http://dx.doi.org/10.1002/prp2.785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101608PMC
May 2021

Rapid intestinal glucuronidation and hepatic glucuronide recycling contributes significantly to the enterohepatic circulation of icaritin and its glucuronides in vivo.

Arch Toxicol 2020 11 11;94(11):3737-3749. Epub 2020 Sep 11.

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA.

Icaritin (ICT), a prenylflavonoid derivative extracted from the Epimedium genus, has exhibited antitumor effects in hepatocellular carcinoma (HCC) cells and safety and tolerance in clinical settings. However, ICT exhibits low blood concentration and the in vivo dominant plasma species of ICT is glucuronides [icaritin-3-glucuronide (G1), icaritin-7-glucuronide (G2) and icaritin-3, 7-diglucuronide (DIG)]. Therefore, how ICT reaches the liver and exerts its effect with low toxicity remains unknown. Therefore, pharmacokinetic experiments (p.o. 5 mg/kg with/out 50 mg/kg inhibitor combo), intestinal perfusion (2 μM ICT), portal vein infusion (1.6 μM ICT, 7.1 μM G1, 6.8 μM G2 and 4.4 μM DIG), and in vitro studies (the concentration range of substrates: 0.3-10 μM) were conducted in the present study. Ultimately, ICT was shown to undergo glucuronidation by the intestine and subsequent uptake by hepatocytes via organic anion transporting peptides (OATPs) as conjugates, followed by biliary excretion mainly as diglucuronide. In conclusion, we found for the first time that the intestine is considered as the major metabolic organ, liver as the main recycling organ for the enterohepatic recycling (EHR) of ICT. Moreover, DIG is the main species in the systemic circulation following oral administration of ICT which explains the low toxicity of ICT in clinical settings.
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http://dx.doi.org/10.1007/s00204-020-02867-3DOI Listing
November 2020

Predicting the metabolic characteristics of neorudin, a novel anticoagulant fusion protein, in patients with deep vein thrombosis.

Thromb Res 2020 10 1;194:121-134. Epub 2020 Jun 1.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China. Electronic address:

Introduction: Recombinant neorudin (EPR-hirudin, EH) is an inactive prodrug that is converted to its active metabolite, hirudin variant 2-Lys47 (HV2), at the thrombus site. We aimed to investigate the mechanism underlying site-selective bioconversion of EH to HV2 at the thrombus target site and metabolic transformation of EH in patients with deep vein thrombosis (DVT).

Materials And Methods: Metabolites in healthy volunteer plasma and urine after intravenous administration of EH were determined to elucidate how EH was metabolised after releasing HV2 at the target site in patients with DVT. After intravenous administration of EH in rats with venous thrombosis, the concentrations of EH in the blood and thrombus and the antithrombotic activity of EH were measured to predict whether EH could release HV2 at the thrombus site to exert anticoagulant effect in patients with DVT.

Results: In healthy volunteers, EH and HV2 were predominantly excreted in the urine. Nine EH metabolites and ten HV2 metabolites truncated at the C-terminal were identified as N-terminal fragments, and these had the same cleavage sites. In rats with venous thrombosis, the area under the curve ratio of HV2 between the thrombus and blood was 29.5. The weight of wet thrombus was decreased with the production of HV2 by the cleavage of EH. The prothrombin time (PT) and prothrombin time (TT) changed proportionally to the concentration of EH and HV2 in the blood.

Conclusion: EH selectively accumulates and releases HV2 in the thrombus to exert antithrombotic effects, thus lowering the bleeding risk. Moreover, after conversion, EH may follow the same metabolic profile as that of HV2 in patients with DVT.
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http://dx.doi.org/10.1016/j.thromres.2020.05.048DOI Listing
October 2020

Clinical Multi-Omics Study on the Gut Microbiota in Critically Ill Patients After Cardiovascular Surgery Combined With Cardiopulmonary Bypass With or Without Sepsis (MUL-GM-CSCPB Study): A Prospective Study Protocol.

Front Med (Lausanne) 2020 8;7:269. Epub 2020 Jul 8.

Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Fever of unknown origin (FUO) and hemodynamic instability are complications that develop after cardiac surgery combined with cardiopulmonary bypass (CPB) for heart disease. Patients who develop fever with hemodynamic instability after cardiac surgery may have systemic inflammatory response syndrome or sepsis. Cardiopulmonary bypass (CPB) is a technique that temporarily takes over the function of the heart and lungs during cardiac surgery. Recent reports suggest that early bloodstream infections of patients undergoing CPB are due to gram-negative bacteria that are present in the intestinal flora. The theory of intestinal flora translocation has growing evidence. Intestinal ischemia-reperfusion that occurs during cardiac surgery with CPB will induce a systemic inflammatory reaction and may cause intestinal flora translocation. Does this systemic reaction cause sepsis? We therefore propose this protocol to determine whether the changes in the intestinal flora in patients after cardiac surgery with CPB are related to sepsis. This study is a prospective observational case-control study to analyze the variation in the intestinal microflora and metabolites in patients undergoing cardiac surgery with CPB and to observe the outcomes of patients with routine clinical interventions. The control group will include healthy people without intestinal illness. Feces and blood samples will be acquired 1 day before cardiac surgery and within 24-72 h after cardiac surgery, and will be used for genomics and metabolomics analyses. Demographic data describing age, sex, main diagnosis, and past medical history and data related to the CPB time and application of antibiotics are available. Sequential (sepsis-related) organ failure assessment, infection-related laboratory items, infection site, and pathogenic microorganisms, and nutrition, and gastrointestinal function assessment are additionally recorded. Group analysis of data will be conducted according to the outcomes (sepsis vs. non-sepsis and survivors vs. non-survivors). This protocol has been ethically approved by the Ethics Committee of Peking Union Medical College (ID: ZS-1612). Informed consent will be obtained before subject enrolment, and data will be stored in a secured database. The results will be submitted to international peer-reviewed journals and presented at international conferences. NCT04032938.
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http://dx.doi.org/10.3389/fmed.2020.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360671PMC
July 2020

Author Correction: Connexin 32-mediated cell-cell communication is essential for hepatic differentiation from human embryonic stem cells.

Sci Rep 2020 Apr 6;10(1):6165. Epub 2020 Apr 6.

Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing, 100850, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-62384-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136247PMC
April 2020

Preclinical pharmacokinetics of M10 after intragastrical administration of M10-H and M10-Na in Wistar rats.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Mar 30;1140:121905. Epub 2019 Nov 30.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Haidian District, Beijing 100850, China. Electronic address:

As a myricetin derivative, M10 is a potent agent of anti-chronic colonic inflammation. It has better activity than myricetin in preventing azoxymethane/dextran sulfate sodium - induced ulcerative colitis. Here, we introduce a sensitive quantification method based on ultra performance liquid chromatography-tandem mass spectrometry for the determination of M10-H and M10-Na in Wistar rat plasma. Samples were treated with L - ascorbic acid and phosphate buffer solution to maintain stability and with acetonitrile to remove the proteins in the plasma. The supernatant was separated with BEH C18 column and eluted with ultrapure water and acetonitrile both containing 0.1% formic acid. The detection was performed by a triple quadrupole mass spectrometer with positive electrospray ionization mode in multiple reactive monitoring. This method was validated for the carryover effect, selectivity, accuracy, precision, matrix effect, stability, and recovery. A linear correlation was established between concentration and response by the calibration curves over 10-2000 ng·mL (r > 0.99). This method was applied to a pharmacokinetic study of intragastrical administration of M10-H and M10-Na in Wistar rats. In addition, the relative bioavailability of M10-H to M10-Na in Wistar rats was 60 ± 19%, calculated by the ratio of area under concentration (AUC) of M10-H to M10-Na after intragastrical administration of a single dose (100 mg·kg for M10-H and M10-Na, respectively) in Wistar rats.
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http://dx.doi.org/10.1016/j.jchromb.2019.121905DOI Listing
March 2020

Characterization and Hemostatic Potential of Two Kaolins from Southern China.

Molecules 2019 Aug 30;24(17). Epub 2019 Aug 30.

Academy of Military Medical Sciences, Beijing 100850, China.

The physicochemical properties and potential hemostatic application of Wenchang kaolin and Maoming kaolin were inspected and evaluated. Chemical composition analysis, Fourier transform infrared (FTIR) spectroscopy, surface area determination, X-ray diffraction, particle size, scanning electron microscopy (SEM) observations, and zeta potential analysis were performed to quantify the physical and chemical properties of the two kaolins. The results showed that both kaolins have typical FTIR bands of kaolinite with a weight fraction for kaolinite over 90 wt%. Larger conglobate aggregates of Maoming kaolin demonstrated wider particle size distributions with two peaks at 3.17 and 35.57 μm, while the book-like Wenchang kaolin had narrow particle size distribution, with a frequent size of 5.64 μm. Furthermore, thrombelastography, the whole blood clotting tests (WBCT), plasma recalcification time (PRT) measurement, and MTT assay were performed to measure the clotting activities and biocompatibility of the two kaolins. The results showed that both kaolins could promote blood coagulation with good cytocompatibility, while Wenchang kaolin had a better procoagulant activity than Maoming kaolin. These findings demonstrated Wenchang kaolin to be a more suitable local source material for application as a hemostatic agent.
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http://dx.doi.org/10.3390/molecules24173160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749497PMC
August 2019

Simultaneous quantitation of E0703, a novel radioprotective agent and its oxidative metabolite M1 in human plasma by UPLC-MS/MS, and application to clinical pharmacokinetics.

J Pharm Biomed Anal 2019 Sep 10;174:63-69. Epub 2019 May 10.

Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China. Electronic address:

A rapid, sensitive and reliable bioanalytical method was firstly developed and validated based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), for simultaneous quantitation of the novel radioprotective compound E0703 and its oxidative metabolite M1 in human plasma. Plasma samples were deproteinated with acetonitrile containing the internal standard IS1229 as precipitant and separated on a short CAPCELL PAK C18 IF2 column (2.0 mm × 20 mm, 2 μm) by gradient elution using acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) with a run time of 2.5 min per sample. MS detection was carried out on a triple quadrupole mass spectrometer (Xevo TQ-S) coupled with electrospray ionization in positive multiple reaction monitoring (MRM) mode. The method was linear over the concentration ranges of 0.100-50.0 ng/mL for E0703 and 0.200-100 ng/mL for M1, with correlation coefficient (r) values ≥0.993. A full validation of this method was performed, and all results were within acceptable limits. The novel assay was sensitive enough to monitor E0703 and M1 levels in human plasma, and was successfully applied to a clinical pharmacokinetic study of healthy Chinese subjects after a single oral administration of 30 mg E0703 tablets. In conclusion, the validated method is accurate, sensitive and high-throughput, and can be successfully implemented for subsequent clinical pharmacokinetic studies of E0703 and M1.
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http://dx.doi.org/10.1016/j.jpba.2019.05.020DOI Listing
September 2019

Calcium ion-exchange cross-linked porous starch microparticles with improved hemostatic properties.

Int J Biol Macromol 2019 Aug 14;134:435-444. Epub 2019 May 14.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Haidian 100850, PR China. Electronic address:

Starch hemostatic agents have been clinically used in surgical hemostasis in recent years. Calcium ion (Ca)-exchange cross-linked porous starch microparticles (CaCPSMs) were prepared as a new hemostatic agent to enhance the hemostatic efficacy. A series of CaCPSMs with varying Ca contents were prepared and characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), scanning electron microscope (SEM), and ion content analysis. The XPS and FT-IR results indicated that the surface of CaCPSMs was modified by Ca, which might form coordination bonds with oxygen atoms of starch molecules. CaCPSMs revealed a porous surface structure and a lower crystallinity degree according to SEM and XRD, which facilitated the phosphate buffer saline (PBS) uptake rate and enzymatic degradation in vitro. The fast release of Ca from CaCPSMs accelerated the whole blood clotting rate, shortened the activated partial thromboplastin time, and promoted platelet adhesion. The physical hemostatic mechanism benefited from the rapid PBS uptake capacity and porous surface structure of CaCPSMs, in addition to the chemical activation of coagulation process by Ca, thus achieving a significant hemorrhage control in the mouse tail amputation model.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.05.086DOI Listing
August 2019

Silver sulfadiazine nanosuspension-loaded thermosensitive hydrogel as a topical antibacterial agent.

Int J Nanomedicine 2019 28;14:289-300. Epub 2018 Dec 28.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China,

Background: Silver sulfadiazine (AgSD) is widely employed as an antibacterial agent for surface burn management. However, the antibacterial activity of AgSD was restrained because of the lower drug solubility and possible cytotoxicity.

Objective: This study aimed to formulate stable silver sulfadiazine/nanosuspensions (AgSD/NSs) with improved AgSD solubility and prepare a suitable carrier for AgSD/NS delivery. Nanotechnology was used to overcome the low drug dissolution rate of AgSD, while the new carrier loaded with AgSD/NS was assumed to decrease the possible cytotoxicity, enhance antibacterial activity, and promote wound healing.

Methods: AgSD/NSs were prepared by high pressure homogenization method. Poloxamer 407-based thermoresponsive hydrogels were prepared by cold method as carriers of AgSD/NS to obtain AgSD/NS-loaded thermoresponsive hydrogel. Scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) were used to measure the physicalchemical properties of AgSD/NSs and AgSD/NS-loaded gel. The cytotoxicity of the AgSD/NS-loaded gel was evaluated using methyl thiazolyltetrazolium assay with L929 mouse fibroblast cell lines. In vitro antibacterial activities of AgSD/NSs and AgSD/NS loaded gel were also measured.

Results: Stable AgSD/NSs with an average particle size of 369 nm were formulated while 1.5% P407 was selected as a stabilizer. The optimized AgSD/NS thermoresponsive hydrogel exhibited the gelation temperature of approximately 30°C. A significant improvement in solubility was observed for AgSD nanoparticles (96.7%) compared with AgSD coarse powders (12.5%). The results of FTIR and XRD revealed that the physicochemical properties of AgSD/NS were reserved after incorporating into the hydrogel. The cell viability after incubation with AgSD/NS-loaded thermoresponsive hydrogel improved from 60.7% to 90.6% compared with incubation with AgSD/NS directly. Drug release profiles from the thermoresponsive hydrogel increased compared with the commercial AgSD cream, implying less application frequency of AgSD cream clinically. In vitro antibacterial studies manifested that AgSD nanocrystallization significantly enhanced the antibacterial activity compared with the AgSD coarse powder.

Conclusion: The combination of AgSD nanosuspensions and thermoresponsive hydrogel effectively improved the AgSD antibacterial activity and decreased the cytotoxicity. This study also suggested that a poloxamer thermoresponsive hydrogel could be used as a delivery system for other nanocrystals to decrease possible nanotoxicity.
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http://dx.doi.org/10.2147/IJN.S187918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314312PMC
February 2019

Pharmacokinetic Properties of Arsenic Species after Intravenous and Intragastrical Administration of Arsenic Trioxide Solution in Cynomolgus Macaques Using HPLC-ICP-MS.

Molecules 2019 Jan 10;24(2). Epub 2019 Jan 10.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, 27 Taiping Road, Haidian District, Beijing 100850, China.

A rapid and sensitive method was established for arsenic (As) speciation based on high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). This method was validated for the quantification of four arsenic species, including arsenite (As), arsenate (As), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in cynomolgus macaque plasma. Separation was achieved in just 3.7 min with an alkyl reverse phase column and highly aqueous mobile phase containing 20 mM citric acid and 5 mM sodium hexanesulfonate (pH = 4.3). The calibration curves were linear over the range of 5⁻500 ng·mL (measured as As), with > 0.99. The above method was validated for selectivity, precision, accuracy, matrix effect, recovery, carryover effect and stability, and applied in a comparative pharmacokinetic study of arsenic species in cynomolgus macaque samples following intravenous and intragastrical administration of arsenic trioxide solution (0.80 mg·kg; 0.61 mg·kg of arsenic); in addition, the absolute oral bioavailability of the active ingredient As of arsenic trioxide in cynomolgus macaque samples was derived as 60.9 ± 16.1%.
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http://dx.doi.org/10.3390/molecules24020241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359110PMC
January 2019

Development of a mass spectrometry method for the characterization of a series of chitosan.

Int J Biol Macromol 2019 Jan 30;121:89-96. Epub 2018 Sep 30.

Department of Pharmaceutical Science, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address:

Chitosan has multiple biological activities, but a sensitive and rapid characterization method is yet to be developed for its further application. This study presented an optional mass spectrometry method for the characterization of chitosan. Nine kinds of chitosan (degree of deacetylation (DD), 63.08%-89.06% & MW, 106.1-485.0 kDa) were adopted for the method development. Most species of chitosan, detected by an ESI-MS technique, were observed below 1000 m/z, which seemed that only chito-oligosaccharide (COS) impurities were detected. Then, a sensitive UPLC-ESI-MS/MS method was established to assess the COS impurities in chitosan, and no COS impurities were detected. However, dissociation of chitosan and COSs in the ESI source were observed, and then the mass spectra patterns were deeply evaluated via an accurate Q-TOF mass spectrometer. Our research demonstrated that the mass spectra of COSs and chitosan resulted from the dissociation of glycosidic linkage and dehydration. Although the distribution of GlcN and GlcNAc units in these chitosan samples might be different, similar dissociation efficiencies were observed. Furthermore, good linearities were obtained between the intensities of product ions, detected by an UPLC-pseuedo-MS2 method, and DDs determined by conventional method. This method could be suitable for the DD determination and quantitative analysis of chitosan.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.09.194DOI Listing
January 2019

In vitro and in vivo pharmacokinetic and pharmacodynamic study of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent.

Bioorg Med Chem 2018 09 4;26(16):4687-4692. Epub 2018 Aug 4.

School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China. Electronic address:

MBRI-001 was demonstrated preliminary better pharmacokinetics and antitumor effects than that of plinabulin in vivo. In this approach, we further carried out systematic pharmacokinetic and pharmacodynamic study of MBRI-001 in vitro and in vivo. MBRI-001 was tested stable in rat plasma and more stable in liver microsomes than plinabulin in vitro. In vivo, MBRI-001 could be distributed rapidly and widely in various tissues, especially the concentration of MBRI-001 in lung was remarkably higher than other tissues. Excretion study indicated that MBRI-001 might been decomposed and excreted as metabolites. Additionally, the combination treatment of MBRI-001 and gefitinib revealed better antitumor inhibition rate than monotherapy in vivo. Therefore, we suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
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http://dx.doi.org/10.1016/j.bmc.2018.08.009DOI Listing
September 2018

An optimized LC-MS/MS method for determination of HYNIC-3PRGD, a new promising imaging agent for tumor targeting, in rat plasma and its application.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Sep 21;1095:142-148. Epub 2018 Jul 21.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.

HYNIC-3PRGD is used to prepare a new Tc-radiolabeled tracer. HYNIC-3PRGD, which has a high binding affinity for the integrin αβ due to its special structure, has become a promising tumor imaging agent for diagnosis and monitor of the clinical response to therapeutic effects of anti-tumor agents. Here, we developed and validated a method for determination of HYNIC-3PRGD concentration in rat plasma using ultra-high performance liquid chromatography-tandem mass spectrometry system. Following sample extraction by methanol precipitation, satisfactory separation through chromatography was achieved on an hydrophilic reverse-phase C column AQ (2.1 mm × 100 mm, 2.7 μm) at a flow rate of 0.2 mL·min with an gradient elution using mobile phase consisting of ultrapure water and acetonitrile fortified with 0.1% formic acid respectively. The calibration curve was developed over a linear range of 3.125-100 ng·mL with the lower limit of quantification of 3.125 ng·mL. The HYNIC-3PRGD and its internal standard c(RGDfK)(RK5) were detected and quantified with the multiple reaction monitoring (MRM) mode on a triple-quadrupole tandem mass spectrometer. This method was successfully validated and applied for pharmacokinetic evaluation of HYNIC-3PRGD during pre-clinical experiments.
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http://dx.doi.org/10.1016/j.jchromb.2018.07.026DOI Listing
September 2018

A LC-MS/MS method to monitor the concentration of HYD-PEP06, a RGD-modified Endostar mimetic peptide in rat blood.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Aug 29;1092:296-305. Epub 2018 May 29.

State Key Laboratory of Drug Metabolism and Pharmacokinetics, Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China. Electronic address:

HYD-PEP06 is a novel RGD-modified Endostar mimetic peptide with 30 amino acids that is intended to suppress the formation of neoplasm vessels. This assay was developed and validated to monitor the level of the peptide HYD-PEP06 in rat blood, using liquid chromatography tandem mass spectrometry (LC-MS/MS). HYD-PEP10, another peptide similar to the analyte, was used as an internal standard (IS). A triple quadrupole mass spectrometry in Multiple Reaction Monitoring (MRM) mode and an electrospray interface (ESI) in the positive mode were used for MS analysis. The analysis was optimized with addition of 0.3% formic acid (FA) into the mobile phase as well as with a needle washing solution to overcome the carryover effect. In addition, the carryover was reduced by optimizing the mobile phase gradient. Methanol was used as a diluent of working solutions to avoid any adsorption. Methanol:acetonitrile (1:1, v:v) containing 0.3% FA was employed to precipitate the blood samples. Unknown blood samples must be placed in ice bath immediately, and precipitating agents should be added within 30 min to ensure the stability of blood samples. The assay was established and validated. This method showed a good linear relationship for the HYD-PEP06 in the range of 10 ng·mL to 2000 ng·mL, with R > 0.99. HYD-PEP06 was determined with accuracy values (RE%) of -5.06%-8.54%, intra- and inter-day precisions (RSD%) of 3.13%-4.87% and 4.81%-9.42%. The method was successfully in monitoring the concentration of HYD-PEP06 in rat blood.
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http://dx.doi.org/10.1016/j.jchromb.2018.05.042DOI Listing
August 2018

Evaluating prodrug characteristics of a novel anticoagulant fusion protein neorudin, a prodrug targeting release of hirudin variant 2-Lys47 at the thrombosis site, by means of in vitro pharmacokinetics.

Eur J Pharm Sci 2018 08 23;121:166-177. Epub 2018 May 23.

State Key Laboratory of Drug Metabolism and Pharmacokinetics, Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, China. Electronic address:

Recombinant neorudin (EPR-hirudin, EH), a low-bleeding anticoagulant fusion protein, is an inactive prodrug designed to be converted to the active metabolite, hirudin variant 2-Lys47 (HV2), locally at the thrombus site by FXa and/or FXIa, following activation of the coagulation system. Our aim was to evaluate the prodrug characteristics of EH by comparing the biotransformation of EH and HV2 in biological matrices, including rat blood, liver, and kidney homogenates, demonstrating the cleavage of EH to HV2 by FXa and FXIa, and comparing the conversion of EH to HV2 between fresh whole blood and whole-blood clot homogenate, using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Both EH and HV2 were stable in blood and unstable in the liver and kidney homogenates. Eight EH metabolites and eight HV2 metabolites identified as N-terminal fragments were found in the liver and kidney. C-terminal proteolysis is therefore the major metabolic pathway, with serine/cysteine carboxypeptidases and metallocarboxypeptidases being responsible for the degradation of EH and HV2 in the liver and kidney, respectively. EH was cleaved to release HV2 by FXIa. Higher levels of HV2 were produced from EH in the whole-blood clot homogenate, in which the coagulation system was activated compared with those in fresh whole blood. In conclusion, the metabolism of EH and HV2 shares the same cleavage pattern, and EH is transformed into HV2 when the coagulation system is activated, where FXIa is a specific enzyme. Our in vitro study revealed the anticipated prodrug characteristics of EH newly designed as an inactive prodrug of hirudin.
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http://dx.doi.org/10.1016/j.ejps.2018.05.025DOI Listing
August 2018

Preparation and characterization of a new type of porous starch microspheres (PSM) and effect of physicochemical properties on water uptake rate.

Int J Biol Macromol 2018 Sep 12;116:707-714. Epub 2018 May 12.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Haidian 100850, PR China. Electronic address:

Porous starch (PS) is a multifunctional biomaterial and has been widely applied in both pharmaceutical and food industry. This study was carried out to develop a new type of porous starch microspheres (PSM) through the dual-modification of the alcohol-alkaline treatment and inverse crosslinking-emulsion method, which could rapidly uptake water. The chemical and physical characteristics of the PSMs were determined by FTIR, SEM, XRD, DSC, ESD (equilibrium swelling ratio) and WS (water solubility). The results showed that PSMs could reach its saturated water uptake volume (about 1 mL/100 mg) in 60 s. The PSMs also revealed rough surface with observable pores and lower crystallinity degree after the dual-modification according to SEM and XRD. The use of epichlorohydrin (ECH) as a crosslinking agent could introduce crosslinks between starch molecular chains, which was determined by ESD, WS and the thermal properties. These results indicated that the dual-modification could be successfully used for preparation of rapid water uptake PSMs with enhanced structure stability.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.05.059DOI Listing
September 2018

Time-Course Investigation of Small Molecule Metabolites in MAP-Stored Red Blood Cells Using UPLC-QTOF-MS.

Molecules 2018 Apr 16;23(4). Epub 2018 Apr 16.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.

Red blood cells (RBCs) are routinely stored for 35 to 42 days in most countries. During storage, RBCs undergo biochemical and biophysical changes known as RBC storage lesion, which is influenced by alternative storage additive solutions (ASs). Metabolomic studies have been completed on RBCs stored in a number of ASs, including SAGM, AS-1, AS-3, AS-5, AS-7, PAGGGM, and MAP. However, the reported metabolome analysis of laboratory-made MAP-stored RBCs was mainly focused on the time-dependent alterations in glycolytic intermediates during storage. In this study, we investigated the time-course of alterations in various small molecule metabolites in RBCs stored in commercially used MAP for 49 days using ultra-high performance liquid chromatography quadruple time-of-flight mass spectrometry (UPLC-QTOF-MS). These alterations indicated that RBC storage lesion is related to multiple pathways including glycolysis, pentose phosphate pathway, glutathione homeostasis, and purine metabolism. Thus, our findings might be useful for understanding the complexity of metabolic mechanisms of RBCs in vitro aging and encourage the deployment of systems biology methods to blood products in transfusion medicine.
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http://dx.doi.org/10.3390/molecules23040923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017316PMC
April 2018

Application of ultra high-performance liquid chromatography tandem mass spectrometry to investigate the regioselective glucuronidation of icaritin in vitro.

J Pharm Biomed Anal 2018 May 13;154:444-453. Epub 2018 Feb 13.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, 27, Taiping Road, Beijing 100850, China. Electronic address:

Icaritin is one of the Epimedium products with various biological activities. In the present study, we developed a rapid, reliable and robust UHPLC-MS/MS method to simultaneously determine unconjugated icaritin and its multiple glucuronides (icaritin-3-glucuronide, icaritin-7-glucuronide and icaritin-3,7-diglucuronide) in microsomal incubation systems, and applied it to study icaritin regioselective glucuronidation in vitro. We identified the involvement of human UDP-glucuronosyltransferase (UGT) isoforms in icaritin metabolism and further studied the kinetic profiles of icaritin glucuronidation using pooled human liver microsomes (HLMs), pooled rat liver microsomes (RLMs), pooled human intestine microsomes (HIMs) and UGTs, respectively. We also evaluated regioselective glucuronidation of icaritin by UGT isoforms and conducted time-dependent experiment to elucidate the metabolic pathways for icaritin clearance. Catalytic efficiency of microsomes is determined according to rank orders of total intrinsic clearance (CL): CL (24.19 mL/mg/min) > CL (13.15 mL/mg/min) > CL (6.43 mL/mg/min). Besides, icaritin glucuronidation is mediated by multiple enzymes, with UGT1A1 the principal metabolizing enzyme (total CL = 6.38 mL/mg/min). As for the regioselectivity, except for UGT1A8 and UGT2B7, most UGT isoforms exhibit preference for the position of 3-OH on icaritin structure. Moreover, time-dependent conversion from monoglucuronides to diglucuronide indicate that icaritin-3,7-diglucuronide may be the final metabolite from icaritin elimination.
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http://dx.doi.org/10.1016/j.jpba.2018.02.029DOI Listing
May 2018

Development, validation, and clinical pharmacokinetic application of ultra-performance liquid chromatography/tandem mass spectrometry method for simultaneously determining a novel recombinant hirudin derivative (Neorudin) and its active metabolite in human serum.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Sep 24;1063:204-213. Epub 2017 Aug 24.

State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, PR China. Electronic address:

Recombinant Neorudin (EPR-hirudin, EH), a novel, low-bleeding anticoagulant fusion protein, has been developed as an inactive prodrug that is converted to an active metabolite, hirudin variant 2-Lys47 (HV2), at the thrombus site and is undergoing Phase I clinical trials in China. The goal of our present research was to establish a novel ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for simultaneously quantifying EH and HV2 in human serum. Furthermore, the method was used in clinical pharmacokinetic study after validation. The stock and dilute working solutions were dissolved in methanol/water (1/1, v/v) to avoid their adsorption. The internal standard (IS) used, had a similar structure to that of EH. The serum sample pretreatment involved protein precipitation with methanol. The volume ratio of the precipitating solvent to the serum sample was 3:1 (300μL methanol: 100μL serum sample). The chromatographic separation was performed using a 300Å C18 column using a multi-step gradient with a mobile phase consisting of acetonitrile:water containing 0.1% formic acid. The detection was carried out using an ESI source in the positive multiple reaction monitoring (MRM) mode. The within and between run precision were in the range of 3.5%-10.3% for EH and 3.3%-8.8% for HV2, and the accuracy of both EH and HV2 was between -4.6% and 2.1%. The extraction recoveries and matrix effect at three quality control (QC) levels for EH and HV2 were satisfactory. The stabilities of EH and HV2 during the storage, preparation, and analysis were confirmed, and the carryover also proved to be acceptable. This technique was efficiently used in Phase I clinical pharmacokinetic trials of EH following intravenous administration of 0.2mg/kg to healthy volunteers.
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http://dx.doi.org/10.1016/j.jchromb.2017.08.030DOI Listing
September 2017

A sharp, robust, and quantitative method by liquid chromatography tandem mass spectrometry for the measurement of EAD for acute radiation syndrome and its application.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Jun 15;1055-1056:45-50. Epub 2017 Apr 15.

Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing 100850, China. Electronic address:

17-Ethinyl-3,17-dihydroxyandrost-5-ene (EAD) is an agent designed for the treatment of acute radiation syndrome (ARS). Given its vital role played in the prevention and mitigation of ARS, the development of a sharp, sensitive and robust liquid chromatography tandem mass spectrometry (LC-MS/MS) method to monitor the metabolism of EAD in vivo was crucial. A new method was constructed and validated for the determination of EAD with the internal standard of androst-5-ene-3β,17β-diol (5-AED). The blood samples were precipitated with methanol, centrifuged, from which the supernatant was separated on UPLC with C18 column and eluted in gradient with acetonitrile and Milli-Q water both containing 0.1% formic acid (FA). Quantification was performed by a triple quadrupole mass spectrometer with electro spray ionization (ESI) in multiple reactive monitoring (MRM) positive mode. A good linearity was obtained with R>0.99 for EAD within its calibration range from 5 to 1000ngmL with a lowest limit of quantification (LLOQ) of 5ngmL. Inter- and intra-day accuracy and precision of three levels of quality control (QC) samples were within the range of 15%, while the LLOQ was within 20%. Samples were stable under the circumstances of the experiments. The method was simple, accurate and robust applied to determine the concentrations of EAD in Wistar rat after a single administration of EAD orally at the dose of 100mgkg.
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http://dx.doi.org/10.1016/j.jchromb.2017.03.045DOI Listing
June 2017

The improved efficacy of Sifuvirtide compared with enfuvirtide might be related to its selectivity for the rigid biomembrane, as determined through surface plasmon resonance.

PLoS One 2017 16;12(2):e0171567. Epub 2017 Feb 16.

State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.

Most mechanistic studies on human immunodeficiency virus (HIV) peptide fusion inhibitors have focused on the interactions between fusion inhibitors and viral envelope proteins. However, the interactions of fusion inhibitors with viral membranes are also essential for the efficacy of these drugs. Here, we utilized surface plasmon resonance (SPR) technology to study the interactions between the HIV fusion inhibitor peptides sifuvirtide and enfuvirtide and biomembrane models. Sifuvirtide presented selectivity toward biomembrane models composed of saturated dipalmitoylphosphatidylcholine (DPPC) (32-fold higher compared with unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine [POPC]) and sphingomyelin (SM) (31-fold higher compared with POPC), which are rigid compositions enriched in the HIV viral membrane. In contrast, enfuvirtide showed no significant selectively toward these rigid membrane models. Furthermore, the bindings of sifuvirtide and enfuvirtide to SM bilayers were markedly higher than those to monolayers (14-fold and 23-fold, respectively), indicating that the inner leaflet influences the binding of these drugs to SM bilayers. No obvious differences were noted in the bindings of either peptide to the other mono- and bilayer models tested, illustrating that both peptides interact with these membranes through surface-binding. The bindings of the inhibitor peptides to biomembranes were found to be driven predominantly by hydrophobic interactions rather than electrostatic interactions, as determined by comparing their affinities to those of positively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (EPC) to zwitterionic membrane models. The improved efficiency of sifuvirtide relative to enfuvirtide might be related to its ability to adsorb on rigid lipidic areas, such as the viral envelope and lipid rafts, which results in an increased sifuvirtide concentration at the fusion site.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171567PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312942PMC
August 2017

Connexin 32-mediated cell-cell communication is essential for hepatic differentiation from human embryonic stem cells.

Sci Rep 2016 11 22;6:37388. Epub 2016 Nov 22.

Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing 100850, China.

Gap junction-mediated cell-cell interactions are highly conserved and play essential roles in cell survival, proliferation, differentiation and patterning. We report that Connexin 32 (Cx32)-mediated gap junctional intercellular communication (GJIC) is necessary for human embryonic stem cell-derived hepatocytes (hESC-Heps) during step-wise hepatic lineage restriction and maturation. Vitamin K2, previously shown to promote Cx32 expression in mature hepatocytes, up-regulated Cx32 expression and GJIC activation during hepatic differentiation and maturation, resulting in significant increases of hepatic markers expression and hepatocyte functions. In contrast, negative Cx32 regulator 2-aminoethoxydiphenyl borate blocked hESC-to-hepatocyte maturation and muted hepatocyte functions through disruption of GJIC activities. Dynamic gap junction organization and internalization are phosphorylation-dependent and the p38 mitogen-activated protein kinases pathway (MAPK) can negatively regulate Cxs through phosphorylation-dependent degradation of Cxs. We found that p38 MAPK inhibitor SB203580 improved maturation of hESC-Heps correlating with up-regulation of Cx32; by contrast, the p38 MAPK activator, anisomycin, blocked hESC-Heps maturation correlating with down-regulation of Cx32. These results suggested that Cx32 is essential for cell-cell interactions that facilitate driving hESCs through hepatic-lineage maturation. Regulators of both Cx32 and other members of its pathways maybe used as a promising approach on regulating hepatic lineage restriction of pluripotent stem cells and optimizing their functional maturation.
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http://dx.doi.org/10.1038/srep37388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118817PMC
November 2016

Evaluation of genipin-crosslinked chitosan hydrogels as a potential carrier for silver sulfadiazine nanocrystals.

Colloids Surf B Biointerfaces 2016 Dec 11;148:343-353. Epub 2016 Jun 11.

Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China. Electronic address:

In the present study genipin crosslinked chitosan (CHI) hydrogels, which had been constructed and reported in our previous studies (Gao et al., 2014 [22]), were further evaluated for their advantage as a carrier for silver sulfadiazine (AgSD) nanocrystal systems. Firstly, AgSD nanocrystals with a mean particle size of 289nm were prepared by wet milling method and encapsulated into genipin crosslinked CHI hydrogels. AgSD nanocrystals displayed a uniform distribution and very good physical stability in the hydrogel network. Swelling-dependent release pattern was found for AgSD nanocrystals from hydrogels and the release profile could be well fitted with Peppas equation. When AgSD nanocrystals were encapsulated in hydrogels their fibroblast cytotoxicity decreased markedly, and their antibacterial effects against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa were still comparable to unencapsulated AgSD nanocrystals. In vivo evaluation in excision and burn cutaneous wound models in mice showed that AgSD nanocrystal hydrogels markedly decreased the expression of inflammatory cytokine IL-6, but increased the levels of growth factors VEGF-A and TGF-β1. Histopathologically, the wounds treated by hydrogels containing AgSD nanocrystals showed the best healing state compared with commercial AgSD cream, hydrogels containing AgSD bulk powders and blank hydrogels. The wounds treated by AgSD nanocrystal hydrogels were dominated by marked fibroblast proliferation, new blood vessels and thick regenerated epithelial layer. Sirius Red staining assay indicated that AgSD nanocrystal hydrogels resulted in more collagen deposition characterized by a large proportion of type I fibers. Our study suggested that genipin-crosslinked CHI hydrogel was a potential carrier for local antibacterial nanomedicines.
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http://dx.doi.org/10.1016/j.colsurfb.2016.06.016DOI Listing
December 2016

A phase I trial of an oral subtype-selective histone deacetylase inhibitor, chidamide, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.

Chin J Cancer Res 2016 Aug;28(4):444-51

Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.

Objective: This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase (HDAC) inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC).

Methods: Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel (175 mg/m(2)) and carboplatin [area under the curve (AUC) 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacokinetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients.

Results: Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response (PR). Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment.

Conclusions: Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2016.04.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018540PMC
August 2016

Pharmacokinetics and bioavailability of tuftsin-derived T peptide, a promising antitumor agent, in beagles.

Drug Metab Pharmacokinet 2016 Feb 28;31(1):51-56. Epub 2015 Aug 28.

State Key Laboratory of Drug Metabolism, Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Beijing 100850, PR China. Electronic address:

Tuftsin, a natural phagocytosis-stimulating tetrapeptide, had aroused much interest in tumor immunotherapy, but the poor pharmacokinetics hampered its clinical developments, for that it was extremely susceptible to degradation by enzymolysis in vivo. T Peptide (TP) was a newly designed tuftsin derivative aimed to enhance stability and was proved to have significant antitumor activity. In this study, the pharmacokinetics and bioavailability of TP was first clarified in beagles with subcutaneous administration, by using a simple and robust competitive ELISA method. Dose-dependency and non-linear dynamics of TP after single-dose (2, 6 and 18 mg kg(-1), respectively) were found, and the half-time of TP was proved to reach 1.3-2.8 h. Multiple dosing of 6 mg kg(-1) once a day for 7 days resulted in a slight accumulation (accumulation index was 1.92 ± 0.43), indicating that the dosing interval in the following clinical trial needs to be extended. The absolute bioavailability of TP was 31.1 ± 6.2% after subcutaneous administration. These results first demonstrated the pharmacokinetics and bioavailability data of TP in vivo, which illustrated the potential druggability of TP and provided useful information for the dosage regimen design in the following clinical trials, as well as a simple and feasible analytical method for clinical sample analysis.
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http://dx.doi.org/10.1016/j.dmpk.2015.08.005DOI Listing
February 2016

New synthetic peptide with efficacy for heparin reversal and low toxicity and immunogenicity in comparison to protamine sulfate.

Biochem Biophys Res Commun 2015 Nov 9;467(3):497-502. Epub 2015 Oct 9.

State Key Laboratory of Drug Metabolism, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, China. Electronic address:

Protamine sulfate (PS), the only clinically approved antidote to unfractionated heparin (UFH), is widely used for cardiopulmonary surgery or other extracorporeal circulation situations. However, the applications of PS have accompanied various severe side-effects. In this study, we presented a novel synthesized peptide compound (RRRRR-RRRRR-RRRRR-sulfate, R15S) served as a safer UFH antidote. Comparison studies were conducted between PS and R15S on efficacy and safety, aided by heparin neutralization studies, drug toxicity studies and anaphylactic analysis. Our research demonstrated that R15S contained comparable UFH neutralization activity in vitro and in rats in vivo as to active partial thromboplastin time (APTT) and anti-FXa assays. There was no cytotoxicity for R15S at 60 μg mg(-1) or below and the median lethal dose (LD50) of R15S in mice was 35.4 mg kg(-1), both of which were similar to that of PS. Furthermore, R15S exhibited no immunogenicity while it was obvious in guinea pigs immunized with PS. The level of cross-reactivity to anti-PS antibodies of R15S was about 30%. Both of which indicated much safer properties of R15S than PS. In conclusion, we presented a promising candidate R15S for UFH reversal, which is effective in neutralizing UFH and potentially safer in use.
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http://dx.doi.org/10.1016/j.bbrc.2015.10.020DOI Listing
November 2015

Development and validation of a sensitive HPLC-MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application.

J Chromatogr B Analyt Technol Biomed Life Sci 2015 Sep 19;1000:181-6. Epub 2015 Jul 19.

State Key Laboratory of Drug Metabolism and Pharmacokinetics, Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, 27, Taiping Road, Haidian District, Beijing 100850, China. Electronic address:

Chidamide (epidaza), a new oral isotype-selective histone deacetylase inhibitor (HDACi), which is just approved in China for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in December 2014, is the first listed benzamide class of HDACi in the world, and is currently undergoing global clinical trials for solid tumor treatments. Here, we report a sensitive, rapid and robust HPLC-MS/MS method for determination of chidamide in human plasma. Plasma sample was subjected to a simple acetonitrile protein precipitation containing MS-275 used as an internal standard (IS). Chromatography was performed on a Hypersil GOLD C18 analytical column, using a gradient methanol/water mobile phase containing 0.1% formic acid. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive-ion mode. Selected reaction monitoring (SRM) using the precursor/ product transitions (m/z) of 391.1/265.1 for chidamide and 377.1/359.2 for IS were used for quantification, respectively. Good linearity was obtained in the range of 1-1000ng/mL. The method gave R.S.D.% values for precision always lower than 13.8% and R.E.% values for accuracy between -3.7 and 9.1%. In addition, the specificity, recovery, stability and matrix effect were satisfactory too. The method is now being successfully applied to plasma samples as part of an ongoing chidamide phase Ib clinical trial in patients with solid tumors, and had demonstrated consistent AUClast and t1/2 results with the published phase I pharmacokinetic data, which was also analyzed by this method, thus further confirming the reproducibility and accuracy during its clinical application. Considering the excellent performance of this method, it will continue being utilized for future clinical developments of chidamide and for routine monitoring of plasma exposure of chidamide during its clinical therapy.
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http://dx.doi.org/10.1016/j.jchromb.2015.07.001DOI Listing
September 2015

Pharmacokinetics of topically applied recombinant human keratinocyte growth factor-2 in alkali-burned and intact rabbit eye.

Exp Eye Res 2015 Jul 16;136:93-9. Epub 2015 May 16.

Key Laboratory Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Chashan University Park, Wenzhou, 325035, China; The Eye Hospital of Wenzhou Medical University, #270 Xueyuan West Road, Wenzhou, 325027, China. Electronic address:

Keratinocyte growth factor-2 (KGF-2), an effective agent in the development of epithelial tissue and regeneration during corneal wound healing, is a potential therapeutic option to treat the corneal diseases with corneal epithelial defects. However the tissue distribution and pharmacokinetics of KGF-2 have not been explored yet in eye upon topical application. Using (125)I-labeled recombinant human KGF-2 ((125)I-rhKGF-2), tissue distribution of rhKGF-2 in alkali-burned and control rabbit eyes was studied. Our results revealed that (125)I-rhKGF-2 was distributed to all eye tissues examined. The highest radioactivity level was found in the cornea, followed by iris, sclera, ciliary body, lens, aqueous humor, vitreous body, and serum in a greatest to least order. The levels of (125)I-rhKGF-2 were higher in corneas of alkali-burned eyes than those in control eyes though without statistical significance. Calculated pharmacokinetic parameters of t1/2, Cmax, and Tmax of rhKGF-2 in the rabbit corneas were 3.4 h, 135.2 ng/ml, and 0.5 h, respectively. In iris, lens, aqueous humor, and tear, t1/2, Cmax, and Tmax values were 6.2, 6.5, 5.2, and 2.5 h; 23.2, 4.5, 24.1, and 29,498.9 ng/ml; and 1.0, 0.5, 0.5, and 1.0 h, respectively. Predominant and rapid accumulation of rhKGF-2 in corneas suggests that therapeutic doses of rhKGF-2 could be delivered by topical application for treatment of corneal diseases.
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http://dx.doi.org/10.1016/j.exer.2015.05.006DOI Listing
July 2015