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Simultaneous determination of amlodipine,valsartan and hydrochlorothiazide by LC-ESIMS/MS and its application to pharmacokinetics in rats

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Journal of Pharmaceutical Analysis 2014年第6期4卷 399-406页

作者： Shankar Ganesh Gadepalli pragney deme Madhusudana Kuncha Ramakrishna Sistla Pharmacology Division Indian Institute of Chemical Technology Tcirnaka Hyderabad Andhra Pradesh 500007 India National Center for Mass Spectrometry Indian Institute of Chemical Technology Tarnaka HyderabadAndhra Pradesh 500007 India

Polypill is a fixed-dose combination that contains three or more active ingredients used as a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects.A novel and accurate liquid chromatography tandem mass spectrometry method using electrospray ionization mode has been developed and validated for the simultaneous determination of amlodipine（AMD）,valsartan（VAL） using losartan（LOS） as an internal standard（IS）,and hydrochlorothiazide（HCT） using furosemide（FSD） as an *** separation was carried on Aquasil C18（50 mm×2.1 mm,5μm） reversed phase column using acetonitrile and water containing 0.1%formic acid（50：50,v/v） as the mobile *** method was validated in terms of linearity,accuracy and precision over the concentration range of 1-1000 ng/*** intra and inter-day precision and accuracy,stability and extraction recoveries of all the analytes were in the acceptable *** method can be successfully applied to the pharmacokinetic study of AMD,VAL and HCT when given as a polypill.

关键词： Amlodipine Valsartan Hydrochlorothiazide Exforge HCT Polypill

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Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

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Translational Neurodegeneration 2023年第1期12卷 70-89页

作者： Carolyn Tallon Benjamin J.Bell Medhinee M.Malvankar pragney deme Carlos Nogueras-Ortiz Erden Eren Ajit G.Thomas Kristen R.Hollinger Arindom Pal Maja Mustapic Meixiang Huang Kaleem Coleman Tawnjerae R.Joe Rana Rais Norman J.Haughey Dimitrios Kapogiannis Barbara S.Slusher Johns Hopkins Drug Discovery Johns Hopkins University School of MedicineBaltimoreMD 21205USA Neurology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Cell Biology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Oncology Johns Hopkins University School of MedicineBaltimoreMD 21205USA Medicine Johns Hopkins University School of MedicineBaltimoreMD 21205USA Pharmacology and Molecular Sciences Johns Hopkins University School of MedicineBaltimoreMD 21205USA Psychiatry and Behavioral Science Johns Hopkins University School of Medicine855 N.Wolfe StreetRangos 278BaltimoreMD 21205USA Intramural Research Program Laboratory of Clinical InvestigationNational Institute on AgingNational Institutes of Health251 Bayview BlvdSte 8C228BaltimoreMD 21224USA Johns Hopkins University School of Medicine 600 N.Wolfe StreetPathology 517BaltimoreMD 21287USA

Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of *** report,for the first time,that human tau expression elevates brain ceramides and nSMase2 *** To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse ***,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the *** contralateral transfer of the double mutant human tau to the dentate gyrus was *** examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse *** Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC *** PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human *** treatment reduced these *** plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated *** the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral *** PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slo

关键词： Alzheimer’s disease Extracellular vesicles Neutral sphingomyelinase 2 Tau Ceramide

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PNPLA8是调控三阴性乳腺癌磷脂代谢并促进肿瘤增殖和转移的关键分子（英文）

PNPLA8是调控三阴性乳腺癌磷脂代谢并促进肿瘤增殖和转移的关键分...

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2024中国肿瘤标志物学术大会暨CACA整合肿瘤学高峰论坛暨第十七届肿瘤标志物青年科学家论坛暨中国肿瘤标志物产业创新大会

作者：谭哲琼 pragney deme Keerti Boyapati Annet A.M.Duivenvoorden Ron M.A.Heeren Caitlin M.Tressler Norman James Haughey Kristine Glunde

Background Triple-negative breast cancer(TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating *** We sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties. Our studies were performed in a large panel of human breast cancer cell lines and patient *** Comprehensive lipid profiling revealed that phospholipid metabolism is reprogrammed in TNBC cells. We discovered that patatin-like phospholipase domain-containing lipase 8(PNPLA8)is overexpressed in TNBC cell lines and tissues from breast cancer patients. Silencing of PNPLA8disrupted phospholipid metabolic reprogramming in TNBC, particularly affecting the levels of phosphatidylglycerol(PG), phosphatidylcholine(PC), lysophosphatidylcholine(LPC) and glycerophosphocholine(GPC). We showed that PNPLA8 is essential in regulating cell viability,migration and antioxidation in TNBC cells and promoted arachidonic acid and eicosanoid production, which in turn activated PI3K/Akt/Gsk3β and MAPK *** Our study highlights PNPLA8 as key regulator of phospholipid metabolic reprogramming and malignant phenotypes in TNBC, which could be further developed as a novel molecular treatment target.

关键词： PNPLA8 Breast cancer Triple negative Phospholipid Metabolism reprogramming Eicosanoids Migration Invasion Proliferation

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