Strategic approach to developing a self-microemulsifying drug delivery system to enhance antiplatelet activity and bioavailability of ticagrelor

Na, Young-Guk,Byeon, Jin-Ju,Wang, Miao,Huh, Hyun Wook,Son, Gi-Ho,Jeon, Sung-Hoon,Bang, Ki-Hyun,Kim, Sung-Jin,Lee, Hye-Jin,Lee, Hong-Ki,Cho, Cheong-Weon Dove Medical Press 2019 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.14 No.-

<P><B>Background</B></P><P>Ticagrelor (TCG) is used to inhibit platelet aggregation in patients with acute coronary syndrome, but its poor solubility and low bioavailability limit its in vivo efficacy. The purpose of this study was to manufacture an optimized TCG-loaded self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability and antiplatelet activity of TCG.</P><P><B>Materials and methods</B></P><P>Solubility and emulsification tests were conducted to determine the most suitable oils, surfactants, and cosurfactants. Scheffé’s mixture design was applied to optimize the percentage of each component applied in the SMEDDS formulation to achieve optimal physical characteristics, ie, high solubility of TCG in SMEDDS, small droplet size, low precipitation, and high transmittance.</P><P><B>Results</B></P><P>The optimized TCG-loaded SMEDDS (TCG-SM) formulation composed of 10.0% Capmul MCM (oil), 53.8% Cremophor EL (surfactant), and 36.2% Transcutol P (cosurfactant) significantly improving the dissolution of TCG in various media compared with TCG in Brilinta<SUP>®</SUP> (commercial product). TCG-SM exhibited higher cellular uptake and permeability in Caco-2 cells than raw TCG suspension. In pharmacokinetic studies in rats, TCG-SM exhibited higher oral bioavailability with 5.7 and 6.4 times higher area under the concentration–time curve and maximum plasma concentration, respectively, than a raw TCG suspension. Antiplatelet activity studies exhibited that the TCG-SM formulation showed significantly improved inhibition of platelet aggregation compared with raw TCG at the same dose of TCG. And, a 10 mg/kg dose of raw TCG suspension and a 5 mg/kg dose of TCG-SM had a similar area under the inhibitory curve (907.0%±408.8% and 907.8%±200.5%⋅hours, respectively) for antiplatelet activity.</P><P><B>Conclusion</B></P><P>These results suggest that the developed TCG-SM could be successfully used as an efficient method to achieve the enhanced antiplatelet activity and bioavailability of TCG.</P>

Polyphyllin I combined with doxorubicin shows chemosensitization effect in vivo and reduces immunotoxicity of doxorubicin

Zhu Xiang,Na Xin,Zeng Yueqin,Xu Yangantai,Chai Dongya,Yang Huanzhi,Miao Jingqian,Zhang Yuan,Yang Fenghua,Wang Yuehu,Zhou Yiping 대한독성 유전단백체 학회 2022 Molecular & cellular toxicology Vol.18 No.3

Background Polyphyllin I (PPI), a steroidal saponin, exhibits antitumor activity and chemosensitization effect for a broad spectrum of cancer cells, however, its toxicity and chemosensitization effect in vivo is still unknown. Objective We investigated PPI’s cytotoxic activity, toxicity and chemosensitization effect and in vitro and in vivo . Results The IC 50 values of PPI on MCF-7, H22, and S180 tumor cells were 4.37 μmol/L, 1.71 μmol/L, and 0.92 μmol/L, respectively. The LD 50 of PPI was found to be 47.9 mg/kg using ip. injection. PPI at concentrations of 0.3 mg/kg, 0.6 mg/ kg, 1.2 mg/kg, and 2.4 mg/kg (1/80 LD 50 –1/20 LD 50 ) were synergized with DOX of 0.5 mg/kg to inhibit the H22 and S180 tumor growth in vivo by inducing apoptosis without obvious immunotoxicity. PPI exhibited a remarkable hemolytic effect on rabbit erythrocytes (EC 50 = 4.3 μM), while it had no impact in mice. Conclusion Our study revealed that the PPI-sensitized chemotherapeutic effect, when used in safe doses, circumvents immunotoxic side effects of DOX in vivo; thus, helping future clinical research.

Beneficial effects of natural Jeju groundwaters on lipid metabolism in high-fat diet-induced hyperlipidemic rats

Yan-chao Wang,Jin-miao Lu,Hui-zi Jin,Ai-niu Ma,Jin-yang Zhang,Nian Gong,Qi Xiao,Bin Zhu,Ying-fang Lv,Na Yu,Wei-dong Zhang,Yong-xiang Wang 한국영양학회 2014 Nutrition Research and Practice Vol.8 No.2

BACKGROUND: Groundwater is believed to possess many beneficial effects due to its natural source of various minerals. In this study, we examined the effects of natural Jeju groundwater S1 (SamdasooTM), S2 and S3 pumped up from different locations of Jeju Island, Korea, along with local tap water, on body weight gain, serum lipids and lipoproteins, and liver histopathology in high-fat diet-induced hyperlipidemic rats. MATERIALS/METHODS: Rats were randomly and equally divided into 6 groups. Different water samples were supplied to the hyperlipidemic rats as their daily drinking water and the widely-used anti-hyperlipidemic drug simvastatin was used as a positive control. Body weight, serum lipids and lipoproteins were measured weekly. Liver weight, liver index and liver histopathology were examined after the execution of the rats. RESULTS: After drinking Jeju groundwaters for two months, S2 but not S3 significantly reduced weight growth and serum triglycerides levels and increased high density lipoprotein-C (HDL-C) without affecting total cholesterol or LDL-C. S1 and particularly S2 significantly reduced the severity of liver hypertrophy and steatosis. All Groundwaters had much higher contents of vanadium (S3>S2>S1>>tap water) whereas S1 and S2 but not S3 markedly blocked autoxidation of ferrous ions. CONCLUSION: Jeju Groundwater S1 and particularly S2 exhibit protective effects against hyperlipidemia and fatty liver and hypothesize that the beneficial effect of Jeju Groundwaters may be contributed from blockade of autoxidation of ferrous ions rather than their high contents of vanadium.

Stability evaluation of H3N2 influenza split vaccine in drying process for solidification

김성진,Young‑Guk Na,Hong‑Ki Lee,Hye‑Jin Lee,Miao Wang,Hyun Wook Huh,Han‑Sol Lee,Jae‑Young Lee,조정원 한국약제학회 2020 Journal of Pharmaceutical Investigation Vol.50 No.1

Purpose Currently, most vaccines have been manufactured in liquid forms that are needed a cold-chain system. However, this system does not guarantee the stability of vaccines always and requires a high cost. Although solidifcation of vaccine can be alternative, vaccine stability is a problem. Recently, infuenza vaccine delivery using microneedle formulation has been studied extensively. Moreover, the stability of the vaccine can be improved since the vaccine is solid form in the microneedle. Therefore, the aim of this study is to screen the suitable stabilizer in the drying process and to compare evaluation methods for H3N2 split vaccine stability. Methods Dried vaccine samples were evaluated by enzyme-linked immunosorbent assay (ELISA), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and circular dichroism (CD). Results Fructose provided stability to the vaccine during the drying process by ELISA (91.1±8.9%) and SDS-PAGE (about 65%). Trehalose was rated as providing stability to the vaccine when evaluated with ELISA and SDS-PAGE but was not when evaluated with CD. Conclusions The stability of the vaccine should be fnally determined by comprehensively evaluating the structure and antigenicity of various proteins.

Dynamic Event-triggered Adaptive Control for Uncertain Nonlinear Switched Systems Based on MDADT Method

Xueliang Wang,Jianwei Xia,Na Zhang,Miao Yu,Xiaoxiao Guo 제어·로봇·시스템학회 2023 International Journal of Control, Automation, and Vol.21 No.1

This article deals with the dynamic event-triggered tracking control problem for nonlinear switched systems with uncertain nonlinearities. By combining neural network control technology, mode-dependent average dwell time (MDADT) switching rule and dynamic event-triggered strategy, a valid adaptive control scheme is established, which guarantees the boundedness of all signals in the resulting closed-loop system and the tracking error eventually converges to a small neighborhood of the origin under a class of switching signals with MDADT property. Unlike the existing tracking control schemes, the proposed dynamic event-triggered strategy reduce some unnecessary transmissions from controller to actuator and thus saving network resources better. Finally, the effectiveness of the proposed control design is verified by a numerical simulation.

A green ultrasound-assisted enzymatic extraction method for efficient extraction of total polyphenols from Empetrum nigrum and determination of its bioactivities

Yuan Gao,Yutong Shi,Na Miao,Wenxin Xing,Cholil Yun,Shengfang Wang,Wenjie Wang,Huimei Wang 한국공업화학회 2022 Journal of Industrial and Engineering Chemistry Vol.109 No.-

In this study, a green and efficient ultrasound-assisted enzymatic extraction (UAEE) method was establishedfor total polyphenols (TPP) extraction from E. nigrum aerial parts. Fractional Factorial design (FFD)was initially implemented for the selection of significant parameters affecting TPP yield and then Box-Behnken design-response surface methodology (BBD-RSM) was employed to optimize the parameters. The optimum extraction conditions for UAEE were as follows: incubation temperature of 38.39 ℃, incubationtime of 3.39 h, tannase of 386.53 U/g of sample (U/g), and cellulase of 224.42 U/g. Under the optimumconditions, the TPP yield was 52.17 ± 0.39 mg/g, which was 1.62 and 1.73 times those of themethods of ultrasound-assisted extraction (UAE) and enzyme-assisted extraction (EAE), respectively. The crude extract was purified by HPD-600 microporous resin, and the purity was improved from8.11% to 22.56%. In addition, the results of antioxidant and antibacterial activity assays showed thatthe purified extract has stronger bioactivities in contrast with the crude extract. This study indicated thatUAEE was an effective technique for the extraction of TPP from the aerial parts of E. nigrum, and TPPextracted by this extraction method could be applied in pharmaceuticals, cosmetics, and food industries.

Effect of Laparoscopic Nerve-sparing Radical Hysterectomy on Bladder Function, Intestinal Function Recovery and Quality of Sexual Life in Patients with Cervical Carcinoma

Chen, Long,Zhang, Wei-Na,Zhang, Sheng-Miao,Yang, Zhi-Hao,Zhang, Ping Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.24

Objective: To investigate bladder and intestinal function recovery and quality of sexual life after laparoscopic nerve-sparing radical hysterectomy (LNRH) for treatment of early invasive cervical carcinoma. Methods: Subjects included patients who underwent radical hysterectomy by laparotomy who were randomly assigned to 2 groups: 30 patients who underwent LNRH and 35 classical laparoscopic radical hysterectomy (LRH). We assessed the patients general clinical information, surgical characteristics, pathological findings, and adjuvant therapies. A urodynamic study was used to assess bladder function. Intestinal function recovery and quality of sexual life were evaluated by questionnaire. Results: No significant differences were found in age, surgery characteristics, pathological findings, adjuvant therapies, and main adverse effects between the 2 groups. The mean duration of the postoperative catheterization (DPC) in group LNRH was shorter than that in group LRH (P < 0.001). The maximum flow rate, maximum cystometric capacity, maximum detrusor pressure and urinary complications in group LNRH were better than those in group LRH. The quality of sexual life evaluated according to the female sexual function index (FSFI) was better in group LNRH than in those who underwent LRH. The intestinal function of patients in group LNRH also recovered better compared with patients in group LRH.

Silencing of Fanconi Anemia Complementation Group F Exhibits Potent Chemosensitization of Mitomycin C Activity in Breast Cancer Cells

Jiankun Yu,Lin Zhao,Yanlin Li,Na Li,Miao He,Xuefeng Bai,Zhaojin Yu,Zhihong Zheng,Xiaoyi Mi,En-Hua Wang,Minjie Wei 한국유방암학회 2013 Journal of breast cancer Vol.16 No.3

Purpose: Fanconi anemia complementation group F (FANCF) is a key factor to maintaining the function of Fanconi anaemia/BRCA (FA/BRCA) pathway, a DNA-damage response pathway. However,the functional role of FANCF in breast cancer has not been elucidated. In the present study, we evaluated the chemosensitization effect of FANCF in breast cancer cells. Methods: We performed specific knockdown of the endogenous FANCF in breast cancer cells by transfecting the cells with an FANCF short hairpin RNA (shRNA) vector. Cell viability was measured with a Cell Counting Kit-8, and DNA damage was assessed with the alkaline comet assay. The apoptosis, cell cycle, and drug accumulation were measured by flow cytometric analysis. Protein expression levels were determined by Western blot analysis, using specific antibodies. Results: The analyses of two breast cancer cell lines (MCF-7 and MDA-MB-435S) demonstrated that the FANCF shRNA could effectively block the FA/BRCA pathway through the inhibition of Fanconi anemia complementation group D2ubiquitination. Moreover, FANCF silencing potentiated the sensitivity of cells to mitomycin C (MMC), where combined FANCF shRNA/MMC treatment inhibited cell proliferation, induced Sphase arrest, apoptosis, and DNA fragmentation, and reduced the mitochondrial membrane potential, compared with MMC treatment alone. Conclusion: Taken together, this study demonstrates that the inhibition of FANCF by its shRNA leads to a synergistic enhancement of MMC cytotoxicity in breast cancer cells. These results suggest that the inhibition of the FA/BRCA pathway is a useful adjunct to cytotoxic chemotherapy for the treatment of breast cancer.

A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability

Kim, Sung-Jin,Lee, Hong-Ki,Na, Young-Guk,Bang, Ki-Hyun,Lee, Hye-Jin,Wang, Miao,Huh, Hyun-Wook,Cho, Cheong-Weon Elsevier 2019 International journal of pharmaceutics Vol.555 No.-

<P><B>Abstract</B></P> <P>The aim of this study is to improve the bioavailability of ticagrelor, BCS class 4 drug, using solid dispersion technique, and to evaluate the potential of ticagrelor loaded-solid dispersion, as a new formulation. The solid dispersion formulation was prepared via solvent evaporation method using ethanol. TPGS and Neusilin® US2 selected via screening studies were used for preparing formulation. The results of scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction showed that the crystallinity of the ticagrelor was completely transformed to an amorphous form and maintained in the solid dispersion formulation. The released amount of the optimized solid dispersion significantly increased by 2.2- and 34-fold in comparison with physical mixture (Ticagrelor:TPGS:Neusilin® US2 = 1:2:2, w/w/w) and commercial product (Brilinta®) in distilled water at 90 min, respectively. The absorptive permeability was improved (1.4-fold) and the efflux ratio was decreased (0.45-fold) by formulation containing TPGS acting as a P-gp inhibitor compared to pure drug. The solid dispersion formulation improved the peak plasma concentration (C<SUB>max</SUB>) and relative bioavailability compared to that of pure drug as 238.09 ± 25.96% and 219.78 ± 36.33%, respectively, after oral administration in rats. Thus, we successfully prepared the solid dispersion formulation for enhancing oral bioavailability of ticagrelor, and then this formulation would be recommended as a practical oral pharmaceutical product.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

DNA Repair Gene Associated with Clinical Outcome of Epithelial Ovarian Cancer Treated with Platinum-based Chemotherapy

Kang, Shan,Sun, Hai-Yan,Zhou, Rong-Miao,Wang, Na,Hu, Pei,Li, Yan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Objective: The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repair pathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association between single nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy in epithelial ovarian cancer. Method: Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213 patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques. Results: The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Gln genotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overall survival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox's multivariate analysis suggested that patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95% CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-, XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survival of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Conclusion: Our results indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.