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The potential development of drug resistance in rheumatoid arthritis patients identified with p53 mutations

Genes & Diseases 2023年第6期10卷 2252-2255页

作者： Congling Qiu joyce Tsz Wai Chan David Wei Zhang Io Nam Wong Yaling Zeng Betty Yuen Kwan Law Simon Wing Fai Mok Ivo Ricardo De Seabra Rodrigues Dias Wenfeng Liu Liang Liu Vincent kam Wai Wong Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao SAR 999078China Department of Public Health and Preventive Medicine School of MedicineJinan UniversityGuangzhouGuangdong 510000China Faculty of Medicine Macao University of Science and TechnologyMacao SAR 999078China School of Biotechnology and Health Sciences Wuyi UniversityJiangmenGuangdong 529000China

Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by cartilage and bone damage with the presence of pannus formation which causes uncontrollable proliferation and invasion of fibroblast-like synoviocytes(FLS).Since rheumatoid arthritis is a chronic disorder,the patients normally need to undergo prolonged antirheumatic treatment with the use of disease-modifying antirheumatic drugs(DMARDs),steroids,and nonsteroidal anti-inflammatory drugs(NSAIDs).The efficacy of such long-term pharmaceutical intervention can be significantly affected by the development of drug *** pathological relationship between rheumatoid arthritis and cancer hinted that some chemotherapeutic drugs,such as methotrexate(MTX),could be used for RA *** idea was reinforced by the analysis of mutations in p53 tumor suppressor *** 50%of p53 somatic mutations observed from various cancers are also identified in the synovium of RA patients1(Fig.1A).Of note,the hyperplastic synovium in RA with overexpressed p53 mutants contributed to the destruction of joints in patients with erosive RA.

关键词： patients drugs rheumatoid

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HM30181A,a potent P-glycoprotein inhibitor,potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model

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Cancer Biology & Medicine 2020年第4期17卷 986-1001页

作者： Wu Zeng Betty Yuen Kwan Law Vincent kam Wai Wong Denise So Bik Chan Simon Wing Fai Mok joyce Jia Ying Gao Rebecca Ka Yan Ho Xu Liang Jia Hao Li Ming Tsung Lee Weng Li Yoon Michael P Smolinski Johnson Yiu Nam Lau Christopher Wai Kei Lam Manson Fok State Key Laboratory of Quality Research in Chinese Medicines Macao University of Science and TechnologyMacaoChina At he nex Hong Kong Irmo vative Limited Hong Kong China Faculty of Medici ne Macao Un iversity of Science and TechnologyMacaoChina Athenex Inc. New York 14203USA

Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma,owing to the presence of the blood-brain barrier and the activity of P-gp,which pumps its substrate back into the systemic *** aim of the present study was to develop an intravenous formulation of HM30181 A(HM)to inhibit P-gp in the brain to effectively deliver paclitaxel(PTX)for the treatment of malignant ***:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies:i)spray-drying[polyvinlypyrrolidone(PVP)-HM]and ii)solvent evaporation[HP-β-cyclodextrin(cyclodextrin)-HM].The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer *** and brain pharmacokinetic parameters were also determined,and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse ***:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro,cyclodextrin-HM had a higher maximum tolerated dose in mice than did *** study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg,and the mice began to lose weight at doses above this ***-HM(10 mg/kg)administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model,according to both tumor volume measurement and survival time(P<0.05).Conclusions:In a mouse orthotopic brain tumor model,the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

关键词： HM30181A glioma pharmacokinetics paclitaxel P-glycoprotein

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