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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of E3024, a Novel and Selective Dipeptidyl Peptidase-IV Inhibitor, in Healthy Japanese Male Subjects: Rash Development in Men and Its Possible Mechanism

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Pharmacology & Pharmacy 2013年第9期4卷 663-678页

作者： Yutaka Takeuchi Masayuki Namiki Yasumi Kitahara Setsuo Hasegawa Akihiro Ohnishi Nobuyuki Yasuda Takashi Inoue Richard Clark Kazuto Yamazaki clinical Development Japan/Asia Clinical Research PCU Eisai Co. Ltd. Tokyo Japan clinical Development Japan/Asia Clinical Research PCU Eisai Co. Ltd. Tokyo Japan clinical Pharmacology Clinical Science SOCS CFU Eisai Co. Ltd. Tokyo Japan Department of Laboratory Medicine Daisan Hospital Jikei University School of Medicine Tokyo Japan Sekino clinical Pharmacology Clinic Tokyo Japan Present Address: Pharmaspur Inc. Tokyo Japan Tsukuba research laboratories Eisai Co. Ltd. Tsukuba Japan.

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that was expected to be an antidiabetic agent. Its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) were investigated in a randomized, double-blind, placebo-controlled, ascending single-dose study in 48 healthy Japanese male subjects. Fasted subjects were orally administered E3024 (5, 10, 20, 40, or 80 mg) or placebo. E3024 was rapidly absorbed, with tmax values ranging between 0.33 and 3 h after dosing. The mean t1/2 ranged from 5.34 to 11.68 h. AUC0-inf and Cmax increased dose-proportionately. PK-PD relationship of E3024 was evaluated by using an Imax model, indicating that plasma E3024 concentrations and inhibitory effects of plasma DPP-IV activity were well correlated. The IC50 value was calculated as 33.7 ng/mL, which was consistent with in vitro data. Thus, E3024 showed a good PK profile and inhibited DPP-IV dose-dependently. Of 30 subjects administered E3024, 12 (40%) experienced adverse events (AEs). Dose escalation to 160 mg was abandoned owing to undesired subjective/objective findings in 4 of 6 subjects receiving 40 mg and 5 of 6 subjects receiving 80 mg. The most prominent AE was rash, but there were no serious AEs or deaths. The maximum tolerated dose was considered to be 20 mg. We hypothesized that histamine was a cause of the rash induction, and examined blood histamine levels of normal Fischer rats treated with E3024. Blood histamine levels were increased significantly by E3024 at 500 mg/kg (p < 0.001), but not by vildagliptin or valine-pyrrolidide (DPP-IV inhibitors) at the same dose. No blood histamine increases were observed in genetically mast cell-deficient Ws/Ws rats treated with E3024 at 500 mg/kg. In in vitro assays, E3024 induced histamine release from normal rat peritoneal mast cells in a concentration-dependent manner, but not from basophils. The structure-activity relati

关键词： Dipeptidyl Peptidase-IV Inhibitor Rash Histamine Structure-Activity Relationship

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Exosomes secreted from cardiomyocytes suppress the sensitivity of tumor ferroptosis in ischemic heart failure

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Signal Transduction and Targeted Therapy 2023年第4期8卷 2007-2021页

作者： Ye Yuan Zhongting Mei Zhezhe Qu Guanghui Li Shuting Yu Yingqi Liu Kuiwu Liu Zhihua Shen Jiaying Pu Yanquan Wang Changhao Wang Zhiyong Sun Qian Liu Xiaochen Pang Ao Wang Zijing Ren Tong Wang Ying Liu Jinhuan Hong Jiajie Xie Xin Li Zhonghua Wang Weijie Du Baofeng Yang Department of Pharmacology(The State-Province Key laboratories of Biomedicine Pharmaceutics of China Key Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbinChina Department of Pharmacy(The University Key Laboratory of Drug research Heilongjiang Province)The Second Affiliated Hospital of Harbin Medical UniversityHarbinChina research Unit of Noninfectious Chronic Diseases in Frigid Zone Chinese Academy of Medical Sciences2019RU070 HarbinChina Department of clinical Pharmacology College of PharmacyHarbin Medical UniversityHarbinChina Department of Cardiology The First Affiliated Hospital of Harbin Medical UniversityHarbinChina Translational Medicine research and Cooperation Center of Northern China Heilongjiang Academy of Medical SciencesHarbinChina

Heart failure(HF)patients in general have a higher risk of developing *** animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression,highlighting a cause-and-effect relationship between these two disease *** ferroptosis,a prevailing form of non-apoptotic cell death,has been considered a promising therapeutic strategy for human *** critically contribute to proximal and distant organ-organ communications and play crucial roles in regulating diseases in a paracrine ***,whether exosomes control the sensitivity of cancer to ferroptosis via regulating the cardiomyocyte-tumor cell crosstalk in ischemic HF has not yet been ***,we demonstrate that myocardial infarction(MI)decreased the sensitivity of cancer cells to the canonical ferroptosis activator erastin or imidazole ketone erastin in a mouse model of xenograft ***-MI plasma exosomes potently blunted the sensitivity of tumor cells to ferroptosis inducers both in vitro in mouse Lewis lung carcinoma cell line LLC and osteosarcoma cell line K7M2 and in vivo with xenograft tumorigenesis *** expression of miR-22-3p in cardiomyocytes and plasma-exosomes was significantly upregulated in the failing hearts of mice with chronic MI and of HF patients as *** of tumor cells with the exosomes isolated from post-MI mouse plasma or overexpression of miR-22-3p alone abrogated erastin-induced ferroptotic cell death in ***-enriched miR-22-3p was packaged in exosomes and transferred into tumor *** of cardiomyocyte-specific miR-22-3p by AAV9 sponge increased the sensitivity of cancer cells to ***4,a pro-ferroptotic gene,was experimentally established as a target of miR-22-3p in tumor *** together,our findings uncovered for the first time that MI suppresses erastin-induced ferroptosis through releasing miR-22-3p-enriched exosomes derived from ***

关键词： Exosomes enriched prevailing

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Antidiabetic effect of combination of fractionated-extracts of Andrographis paniculata and Centella asiatica: In vitro study

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Asian Pacific Journal of Tropical Biomedicine 2018年第11期8卷 527-532页

作者： LOM.Fitrawan R.Ariastuti RR.TjANDrawinata AE.Nugroho S.Pramono Master Program of Pharmaceutical Sciences of Faculty of Pharmacy Universitas Gadjah Mada Faculty of Pharmacy Universitas Halu Oleo Dexa laboratories of Biomolecular Sciences Department of Pharmacology and clinical Pharmacy Faculty of Pharmacy Universitas Gadjah Mada Department of Pharmaceutical Biology Faculty of Pharmacy Universitas Gadjah Mada

Objective: To examine the effect of combination of Andrographis paniculata herb fraction(AHF) and Centella asiatica herb fraction(CHF) on PPAR γ and GLUT4 mRNA expression in 3 T3-L1 adipocyte, and its effect on insulin-stimulated glucose uptake. Methods: 3 T3 L1 adipocyte cells were used to investigate gene expression of PPARy reverse transcription-polymerase chain reaction method. The γ and GLUT4 protein b adipocyte cells were differentiated by using insulin, dexamethasone and 3-isobutyl-1-methylxanthine from 3 T3-L1 cells. Pioglitazone, AHF, CHF and the combination of both herbs were evaluated on glucose uptake activity, PPAR γ and GLUT4 mRNA expressions in 3 T3-L1 adipocyte. Results: The results showed that combination of AHF at 30 μg/mL and CHF at 10 μg/mL could enhance insulin-stimulated glucose uptake. The combination also increased PPAR γ and GLUT4 mR NA expressions significantly in comparison to those of negative control(DMSO). These effects were equal in comparison to those of pioglitazone(0.02 μM) and its single extracts Conclusions: The combination of AHF and CHF can increase glucose uptake and insulin sensitivity through up-regulation of PPAR γ and GLUT4 mRNA expressions in 3 T3-L1 adipocyte.

关键词： Andrographis paniculata Centella asiatica GLUT4 PPAR γ 3T3-L1

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Role of 7-methylxanthine in myopia prevention and control: a mini-review

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International Journal of Ophthalmology(English edition) 2023年第6期16卷 969-976页

作者： Lu Lai Klaus Trier Dong-Mei Cui Shenzhen Eye Hospital Jinan UniversityShenzhen Eye InstituteFutian DistrictShenzhen 518040Guangdong ProvinceChina Trier research laboratories Ojenlage Klaus Trier ApSHellerup DK-2900Denmark

·Myopia is becoming increasingly common. By 2050 around 10% of the world’s population is expected to be highly myopic(<-5 diopters) and therefore particularly at risk of suffering from sight-threatening complication... 详细信息

·Myopia is becoming increasingly common. By 2050 around 10% of the world’s population is expected to be highly myopic(clinical studies. The latest findings regarding 7-MX for myopia control and evaluate its potential as a supplement to existing treatment options were reviewed.

关键词： 7-methylxanthine myopia pharmaceutical therapy

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Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity

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Neural Regeneration research 2022年第9期17卷 1861-1866页

作者： Juan Segura-Aguilar Bengt Mannervik JoséInzunza Mukesh Varshney Ivan Nalvarte Patricia Muñoz Molecular and clinical Pharmacology ICBM Faculty of Medicine University of Chile SantiagoChile Department of Biochemistry and Biophysics Arrhenius LaboratoriesStockholm UniversityStockholmSweden Department of Biosciences and Nutrition Karolinska InstitutetStockholmSweden Nucleo de Química y Bioquímica Facultad de Estudios InterdisciplinariosUniversidad MayorSantiagoChile

Astrocytes protect neurons by modulating neuronal function and *** support neurons in several *** provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support,as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine.A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine,such as aminochrome and other o-quinones,were generated under neuromelanin synthesis by oxidizing dopamine catechol *** secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome *** role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.

关键词： aminochrome astrocytes dopamine dopaminergic neurons exosomes glutathione transferase M2-2 neuroprotection Parkinson’s disease

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Application of echocardiography in resynchronization treatment of heart failure patients

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Chinese Medical Journal 2012年第19期125卷 3548-3555页

作者： DAI Hai-long GUANG Xue-feng XIAO Zhi-cheng ZHANG Ming Department of Cardiology Yan' an Affiliated Hospital of Kunming Medical University Yunnan Cardiovascular Hospital Kunming Yunnan 650051 China Institute of Molecular and clinical Medicine Kunming Medical University Kunming Yunnan 650500 China Monash Immunology and Stem Cell laboratories Monash University Clayton V1C 3800 Australia

Objective To review the updated research progress about the application of echocardiography in resynchronization treatment of chronic heart failure patients. Data sources The data used in this review were from PubMed, published in English and using the key terms ＂heart failure＂, ＂echocardiography＂ and ＂cardiac resynchronization therapy＂. Study selection Relevant articles were reviewed and selected to address the stated purpose. Results Increasing numbers of studies have suggested the importance of echocardiography in resynchronization treatment of chronic heart failure patients. Echocardiography can evaluate atdoventricular, inter- and intra-ventdcular mechanical dyssynchrony before cardiac resynchronization therapy （CRT）, as a guidance to assess the optimal left ventricular （LV） pacing location, optimize the atrioventricular and interventricular delays and predict response to CRT. Conclusions Echocardiography is both non invasive and easily repeatable, and plays a crucial role in appraisal of heart synchronism, instruction of actuator placement, optimization of the device procedure, and prediction of the resoonse to CRT.

关键词： heart failure echocardiography cardiac resynchronization therapy

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Cytomegalovirus antigen-specific T cell immune responses in patients with autoimmune diseases under different cytomegalovirus infection status

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Chinese Medical Journal 2023年第19期136卷 2386-2388页

作者： Yuting Tan Huimin Ma Xiaoqing Liu Xiaochun Shi Wenjie Zheng Jingtao Cui Lifan Zhang Yaling Dou Baotong Zhou Department of Infectious Diseases Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Center for Tuberculosis research Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China clinical Epidemiology Unit Peking Union Medical CollegeInternational Clinical Epidemiology NetworkBeijing 100730China Peking Union Medical College Hospitals Center for the research of Translational Medicine Beijing 100730China Department of Infectious Diseases State Key Laboratory of Complex Severe and Rare DiseasePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China Department of Rheumatology and clinical Immunology Key Laboratory of Rheumatology and Clinical ImmunologyPeking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100730China Department of clinical laboratories Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

To the Editor:Patients with autoimmune diseases have increased risk of active cytomegalovirus(CMV)infection due to immune dysfunction or the application of glucocorticoid and immunosuppressants.[1]Cui et al[2]found that compared with human immunodeficiency virus(HIV)/acquired immune deficiency syndrome(27%),posttransplant patients(14.8%),and hematological malignancies(5.1%),patients with autoimmune disease had the highest incidence of CMV antigenemia(35.1%).Monitoring CMV antigen-specific T cell immunity is helpful for understanding the protective immunity against CMV infection and identifing the risk of CMV-related ***,the CMV antigen-specific T cell immune responses in patients with autoimmune diseases remains unknown.

关键词： immunity patients autoimmune

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HER2 heterogeneity is a poor prognosticator for HER2-positive gastric cancer

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World Journal of clinical Cases 2019年第15期7卷 1964-1977页

作者： Akio Kaito Takeshi Kuwata Masanori Tokunaga Kohei Shitara Reo Sato Tetsuo Akimoto Takahiro Kinoshita Department of Gastric Surgery National Cancer Center Hospital EastKashiwa 277-8577Japan Department of Pathology and clinical laboratories National Cancer Center Hospital EastKashiwa 277-8577Japan Department of Gastrointestinal Oncology National Cancer Center Hospital EastKashiwa 277-8577Japan Exploratory Oncology research&clinical Trial Center(EPOC) National Cancer Center Hospital EastKashiwa 277-8577Japan Juntendo University Graduate School of Medicine Tokyo 163-8001Japan Department of Radiation Oncology National Cancer Center Hospital EastKashiwa 277-8577Japan

BACKGROUND The clinical significance of intratumoral human epidermal growth factor receptor 2(HER2)heterogeneity is unclear for HER2-positive gastric cancer,although it has been reported to be a significant prognosticator for HER2-positive breast cancer,which has received trastuzumab-based *** To clarify the clinical significance of intratumoral HER2 heterogeneity for HER2-positive gastric cancer,which has received trastuzumab-based *** Patients with HER2-positive unresectable or metastatic gastric cancer who received trastuzumab-based chemotherapy as a first line treatment were *** patients were classified into two groups according to their intratumoral HER2 heterogeneity status examined by immunohistochemistry(IHC)on endoscopic biopsy specimens before treatment,and their clinical response to chemotherapy and survival were *** A total of 88 patients were included in this study,and HER2 heterogeneity was observed in 23(26%)patients(Hetero group).The overall response rate was significantly better in patients without HER2 heterogeneity(Homo group)(Homo vs Hetero:79.5%vs 35.7%,P=0.002).Progression-free survival of trastuzumab-based chemotherapy was significantly better in the Homo group(median,7.9 vs 2.5 mo,HR:1.905,95%CI:1.109-3.268).Overall survival was also significantly better in the Homo group(median survival time,25.7 vs 12.5 mo,HR:2.430,95%CI:1.389-4.273).Multivariate analysis revealed IHC HER2 heterogeneity as one of the independent poor prognostic factors(HR:3.115,95%CI:1.610-6.024).CONCLUSION IHC of HER2 heterogeneity is the pivotal predictor for trastuzumab-based ***,HER2 heterogeneity should be considered during the assessment of HER2 expression.

关键词： Human epidermal growth factor receptor 2 Heterogeneity Trastuzumab Gastric cancer Chemotherapy

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A Duplex Real-Time PCR Assay for the Simultaneous Detection of Porcine Circovirus 2 and Circovirus 3

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Virologica Sinica 2018年第2期33卷 181-186页

作者： Xiangdong Li Mingming Qiao Ming Sun Kegong Tian National research Center for Veterinary Medicine High-Tech District Luoyang 471003 China Beijing Anheal laboratories Co. Ltd. Beijing 100094 China College of Animal Science and Veterinary Medicine Henan Agricultural University Zhengzhou 450002 China

Porcine circoviruses(PCV) include PCV1, PCV2, and the new-emerging PCV3. PCV2 is pathogenic to pigs, but the pathogenicity of PCV3 in pigs is debatable. Recently, there have been frequent reports of PCV2 and PCV3 co-infections in clinical samples. Thus, it would be practical to develop a duplex PCR method to detect PCV2 and PCV3 simultaneously. In this study, specific primers and probes were designed to target PCV2 cap and PCV3 rep genes. A duplex real-time PCR method was then developed to detect the two viruses. The assay was found to be highly specific, sensitive, and reproducible for PCV2/3 without cross-reactions with other swine pathogens. The sensitivity of this assay was 2.9 copies for the PCV2 plasmid and 22.5 copies for the PCV3 plasmid. The established assay was then used to detect PCV2/3 infection in 340 clinical samples collected in the first half of 2017. The results showed that the co-infection rate of PCV2/3 in the samples was 27.6%. Our study provides an important tool that can be used to perform urgently needed surveys for the two porcine circoviruses to evaluate their impact on the swine industry.

关键词： Porcine circovirus 2(PCV2) Porcine circovirus 3(PCV3) Co-infection Real-time PCR

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Blue LED promotes the chemosensitivity of human hepatoma to Sorafenib by inducing DNA damage

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BIOCELL 2023年第8期47卷 1811-1820页

作者： TONG WANG JINHUAN HONG JIAJIE XIE QIAN LIU JINRUI YUE XUTING HE SHIYU GE TAO LI GUOXIN LIU BENZHI CAI LINQIANG LI YE YUAN Department of Pharmacy(The University Key Laboratory of Drug research Heilongjiang Province)The Second Affiliated Hospital of Harbin Medical UniversityHarbinChina Department of General Surgery The First Affiliated Hospital of Harbin Medical UniversityHarbinChina National Key Laboratory of Frigid Cardiovascular Disease HarbinChina Department of Pharmacology(The State-Province Key laboratories of Biomedicine Pharmaceutics of China Key Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbinChina Department of clinical Pharmacology College of PharmacyHarbin Medical UniversityHarbinChina

Background:Phototherapies based on sunlight,infrared,ultraviolet,visible,and laser-based treatments present advantages like high curative effects,small invasion,and negligible adverse reactions in cancer *** aimed to explore the potential therapeutic effects of blue light emitting diode(LED)in human hepatoma cells and decipher the underlying cellular and molecular ***:Wound healing and transwell assays were employed to probe the inhibition of the invasion and migration of hepatocellular carcinoma cells in the presence of blue *** sphere-forming test was used to evaluate the effect of LED blue light irradiation on cancer stem cell *** and western blotting were used to detect the changes inγ-*** Cell Counting Kit-8 assay,5-ethynyl-2′-deoxyuridine staining,and colony formation assay were used to detect the combined effect of blue LED and sorafenib on cell proliferation ***:We demonstrated that the irradiation of blue LED light in hepatoma cells could lead to cell proliferation reduction along with the increase of cell ***,blue LED irradiation also markedly suppressed the migration and invasion ability of human hepatoma *** formation analysis further revealed the decreased cancer stemness of hepatoma cells upon blue LED ***,blue LED irradiation significantly promoted the expression of the phosphorylation of the core histone protein H2AX(γ-H2AX),a sensitive molecular marker of DNA *** addition,we found that the combined treatment of blue LED irradiation and sorafenib increased cancer cell sensitivity to ***:Collectively,we demonstrated that blue LED irradiation exhibited anti-tumor effects on liver cancer cells by inducing DNA damage and could enhance chemosensitivity of cancer cells,which represents a potential approach for human hepatoma treatment.

关键词： Blue LED Irradiation Liver cancer DNA damage Chemotherapy resistance

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