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pharmacokinetics, brain, plasma

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https://www.readbyqxmd.com/read/28941624/the-biodistribution-and-pharmacokinetics-of-the-oxime-acetylcholinesterase-reactivator-rs194b-in-guinea-pigs
#1
Michael A Malfatti, Heather A Enright, Nicholas A Be, Edward A Kuhn, Saphon Hok, M Windy McNerney, Victoria Lao, Tuan H Nguyen, Felice C Lightstone, Timothy S Carpenter, Brian J Bennion, Carlos A Valdez
Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al...
September 20, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28940353/repeated-dose-oral-n-acetylcysteine-in-parkinson-s-disease-pharmacokinetics-and-effect-on-brain-glutathione-and-oxidative-stress
#2
Lisa D Coles, Paul J Tuite, Gülin Öz, Usha R Mishra, Reena V Kartha, Kathleen M Sullivan, James C Cloyd, Melissa Terpstra
Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3)...
September 22, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28940203/combination-of-cheminformatics-and-bioinformatics-to-explore-the-chemical-basis-of-the-rhizomes-and-aerial-parts-of-dioscorea-nipponica-makino
#3
Xu-Zhao Li, Shuai-Nan Zhang, Xu-Yan Yang
OBJECTIVES: This study was aimed to explore the chemical basis of the rhizomes and aerial parts of Dioscorea nipponica Makino (DN). METHODS: The pharmacokinetic profiles of the compounds from DN were calculated via ACD/I-Lab and PreADMET program. Their potential therapeutic and toxicity targets were screened through the DrugBank's or T3DB's ChemQuery structure search. KEY FINDINGS: Eleven of 48 compounds in the rhizomes and over half of the compounds in the aerial parts had moderate or good human oral bioavailability...
September 21, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28933097/-pharmacokinetics-and-brain-distribution-of-nmd-tmp-nanoparticles
#4
Wen-Jie He, Qian Hong, Jing Liang, Xiao-Wei He, Feng-Jia Zhu
This study aims to prepare nimodipine/tetramethylpyrazine-loaded poly(D, L-lactide-co-glycolide) dual-drug nanoparticles (NMD/TMP-NPs) and investigate pharmacokinetics and brain distribution to evaluate the possibility of enhancing the drug effect of dual-drug nanoparticles. NMD/TMP-NPs were prepared via W/O/W emulsion solvent evaporation. Entrapment efficiency and drug loading of NMD/TMP-NPs were investigated by ultracentrifugation, and drug release behavior in vitro was studied by dialysis method. The pharmacokinetic and brain distribution were studied in SD mice administered intravenously with NMD/TMP-NPs in comparison with NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension...
November 2016: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/28928160/quantitative-and-mechanistic-understanding-of-azd1775-penetration-across-human-blood-brain-barrier-in-glioblastoma-patients-using-an-ivive-pbpk-modeling-approach
#5
Jing Li, Jianmei Wu, Xun Bao, Norissa Honea, Youming Xie, Seongho Kim, Alex Sparreboom, Nader Sanai
PURPOSE: AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). EXPERIMENTAL DESIGN: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems...
September 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28926513/pharmacokinetics-and-safety-profile-of-single-dose-administration-of-an-estrogen-receptor-%C3%AE-selective-phytoestrogenic-phytoserm-formulation-in-perimenopausal-and-postmenopausal-women
#6
Gerson Hernandez, Liqin Zhao, Adrian A Franke, Yu-Ling Chen, Wendy J Mack, Roberta D Brinton, Lon S Schneider
OBJECTIVE: Selected estrogen receptor β-selective phytoestrogen (phytoSERM), a preparation of genistein, daidzein, and S-equol, has an 83-fold selective affinity for estrogen receptor (ER) β, and may promote neuronal survival and estrogenic mechanisms in the brain without exerting feminizing activity in the periphery. The aim of this study was to assess the safety, tolerability, and single-dose pharmacokinetics of the phytoSERM formulation in perimenopausal and postmenopausal women...
September 18, 2017: Menopause: the Journal of the North American Menopause Society
https://www.readbyqxmd.com/read/28921565/the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-pharmacokinetics-and-pharmacodynamics-of-a-panel-of-mek-inhibitors
#7
Mark C de Gooijer, Ping Zhang, Ruud Weijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28916907/pharmacokinetic-study-of-piracetam-in-focal-cerebral-ischemic-rats
#8
Pankaj Paliwal, Debabrata Dash, Sairam Krishnamurthy
BACKGROUND AND OBJECTIVE: Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion...
September 15, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28916482/disposition-of-treosulfan-and-its-active-monoepoxide-in-a-bone-marrow-liver-lungs-brain-and-muscle-studies-in-a-rat-model-with-clinical-relevance
#9
Michał Romański, Anna Kasprzyk, Mateusz Walczak, Agnieszka Ziółkowska, Franciszek Główka
For the recent years, the application of treosulfan (TREO)-based conditioning prior to hematopoietic stem cell transplantation (HSCT) has been increasing as an alternative to busulfan-based therapy, especially for patients presenting high risk of developing hepato-, pulmo-, and neurotoxicity. So far, the penetration of TREO and its epoxy-derivatives into central nervous system and aqueous humor of the eye has been investigated. However, lacking knowledge on the compounds distribution into the other key tissues precludes comprehensive understanding and assessment of TREO clinical efficacy and toxicity...
September 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28910706/pharmacokinetics-and-tissue-distribution-of-five-major-triterpenoids-after-oral-administration-of-rhizoma-alismatis-extract-to-rats-using-ultra-high-performance-liquid-chromatography-tandem-mass-spectrometry
#10
Wen Xu, Xiaoyan Li, Na Lin, Xue Zhang, Xiaoqiang Huang, Tingting Wu, Yanni Tai, Shuyun Chen, Chieh-Hsi Wu, Mingqing Huang, Shuisheng Wu
Rhizoma Alismatis (RA) was wildly used for treatment of dysuria, pyelonephritis, hyperlipidemia, enteritis diarrhea, diabetes, inflammation, and cancer. Triterpenoids are the major active components of RA, and its extract is mainly composed of alisol A (ALA), alisol B (ALB), alisol C 23-acetate (ALC-23A), alisol A 24-acetate (ALA-24A), and alisol B 23-acetate (ALB-23A). In this study, a simple, reliable, and sensitive ultra high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) method was created and validated for the quantification of the five major triterpenoids in rat plasma and various tissues biosamples (including intestine, stomach, liver, kidney, fat, muscle, brain, heart, lung, spleen, and testes)...
September 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28905934/conversion-and-pharmacokinetics-profiles-of-a-novel-pro-drug-of-3-n-butylphthalide-potassium-2-1-hydroxypentyl-benzoate-in-rats-and-dogs
#11
Jiang Li, Shao-Feng Xu, Ying Peng, Nan Feng, Ling Wang, Xiao-Liang Wang
Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a novel pro-drug of 3-n-butylphthalide (dl-NBP) that is used to treat ischemic stroke. Currently, dl-PHPB is in phase II-III clinical trials in China. In this study, we investigated the conversion and pharmacokinetics profiles of dl-PHPB in vitro and in vivo. The conversion of dl-PHPB to dl-NBP was pH- and calcium-dependent, and paraoxonase was identified as a major enzyme for the conversion in rat plasma. The pharmacokinetics, tissue distribution and excretion of dl-PHPB were studied and compared with equal-molar doses of dl-NBP in rats and dogs...
September 14, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28891201/predicting-drug-concentration-time-profiles-in-multiple-cns-compartments-using-a-comprehensive-physiologically-based-pharmacokinetic-model
#12
Yumi Yamamoto, Pyry A Välitalo, Dymphy R Huntjens, Johannes H Proost, An Vermeulen, Walter Krauwinkel, Margot W Beukers, Dirk-Jan van den Berg, Robin Hartman, Yin Cheong Wong, Meindert Danhof, Johan G C van Hasselt, Elizabeth C M de Lange
Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically-based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, two cerebrospinal fluid sites, and total brain tissue...
September 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28882765/multivariate-pharmacokinetic-pharmacodynamic-pkpd-analysis-with-metabolomics-shows-multiple-effects-of-remoxipride-in-rats
#13
W J van den Brink, J Elassaiss-Schaap, B Gonzalez-Amoros, A C Harms, P H van der Graaf, T Hankemeier, E C M de Lange
The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride...
September 4, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28880966/the-prolyl-4-hydroxylase-inhibitor-gsk360a-decreases-post-stroke-brain-injury-and-sensory-motor-and-cognitive-behavioral-deficits
#14
Jin Zhou, Jie Li, Daniel M Rosenbaum, Jian Zhuang, Carrie Poon, Pu Qin, Katrina Rivera, John Lepore, Robert N Willette, Erding Hu, Frank C Barone
There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes...
2017: PloS One
https://www.readbyqxmd.com/read/28864277/neolignans-from-leaves-of-nectandra-leucantha-lauraceae-display-in%C3%A2-vitro-antitrypanosomal-activity-via-plasma-membrane-and-mitochondrial-damages
#15
Simone S Grecco, Thais A Costa-Silva, Gerold Jerz, Fernanda S de Sousa, Vinicius S Londero, Mariana K Galuppo, Marta L Lima, Bruno J Neves, Carolina H Andrade, Andre G Tempone, João Henrique G Lago
Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries especially in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane extract from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi. Using several chromatographic steps, four related neolignans were isolated and chemically characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-[3'-methoxy-1'-(8-propenyl)-phenoxy]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene (3), and 1-[(7S)-hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4,5-dimethoxybenzene (4)...
August 31, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28862650/pharmacokinetics-of-jaspine-b-and-enhancement-of-intestinal-absorption-of-jaspine-b-in-the-presence-of-bile-acid-in-rats
#16
Min-Koo Choi, Jihoon Lee, So Jeong Nam, Yun Ju Kang, Youjin Han, Kwangik Choi, Young A Choi, Mihwa Kwon, Dongjoo Lee, Im-Sook Song
We aimed to investigate the pharmacokinetics and the underlying mechanisms of the intestinal absorption, distribution, metabolism, and excretion of Jaspine B in rats. The oral bioavailability of Jaspine B was 6.2%, but it decreased to 1.6% in bile-depleted rats and increased to 41.2% (normal) and 23.5% (bile-depleted) with taurocholate supplementation (60 mg/kg). Consistent with the increased absorption in the presence of bile salts, rat intestinal permeability of Jaspine B also increased in the presence of 10 mM taurocholate or 20% bile...
September 1, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28842351/screening-of-pharmacokinetic-properties-of-fifty-dihydropyrimidin-thi-one-derivatives-using-a-combo-of-in-vitro-and-in-silico-assays
#17
Mariana Matias, Ana Fortuna, Joana Bicker, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, but their pharmacokinetic properties remain almost unknown. Herein, fifty dihydropyrimidin(thi)ones were submitted to in vitro screening tests using parallel artificial membrane permeability assays (PAMPA) to evaluate their apparent permeability (Papp) through intestinal membrane and blood-brain barrier models, and cell-based assays to assess their interference on the efflux transporter P-glycoprotein (P-gp). Moreover, a set of kinetic and toxicological parameters was also estimated employing a new computational tool, the pkCSM...
August 24, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28841776/cholera-toxin-subunit-b-enabled-multifunctional-glioma-targeted-drug-delivery
#18
Juan Guan, Zui Zhang, Xuefeng Hu, Yang Yang, Zhilan Chai, Xiaoqin Liu, Jican Liu, Bo Gao, Weiyue Lu, Jun Qian, Changyou Zhan
Glioma is among the most formidable brain cancers due to location in the brain. Cholera toxin subunit B (CTB) is investigated to facilitate multifunctional glioma-targeted drug delivery by targeting the glycosphingolipid GM1 expressed in the blood-brain barrier (BBB), neovasulature, and glioma cells. When modified on the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CTB-NPs), CTB fully retains its bioactivity after 24 h incubation in the fresh mouse plasma. The formed protein corona (PC) of CTB-NP and plain PLGA nanoparticles (NP) after incubation in plasma is analyzed using liquid chromatography tandem massspectrometry (nano-LC-MS/MS)...
August 25, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28836583/pharmacokinetic-and-metabolomic-analyses-of-the-neuroprotective-effects-of-salvianolic-acid-a-in-a-rat-ischemic-stroke-model
#19
Si-Qi Feng, Nan Aa, Jian-Liang Geng, Jing-Qiu Huang, Run-Bin Sun, Chun Ge, Zhi-Jian Yang, Lian-Sheng Wang, Ji-Ye Aa, Guang-Ji Wang
Salvianolic acid A (SAA), a water-soluble phenolic acid isolated from the root of Dan Shen, displays distinct antioxidant activity and effectiveness in protection against cerebral ischemia/reperfusion (I/R) damage. However, whether SAA can enter the central nervous system and exert its protective effects by directly targeting brain tissue remains unclear. In this study, we evaluated the cerebral protection of SAA in rats subjected to transient middle cerebral artery occlusion (tMCAO) followed by reperfusion...
August 24, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28828691/pharmacokinetics-of-mephedrone-and-its-metabolites-in-human-by-lc-ms-ms
#20
Eulàlia Olesti, Magí Farré, Esther Papaseit, Aristotelis Krotonoulas, Mitona Pujadas, Rafael de la Torre, Óscar J Pozo
Mephedrone is a synthetic cathinone consumed as a recreational drug. Recently, it was identified several of its metabolites in vivo in humans but there is little information about its pharmacokinetics in plasma and urine. Although several analytical methods have been proposed for mephedrone quantification in different matrices, none are available for its metabolites. Therefore, the aim of the study was to develop and validate an analytical method using liquid chromatography-tandem mass spectrometry for the quantification of mephedrone, nor-mephedrone, N-succinyl-nor-mephedrone, 1'-dihydro-mephedrone, and 4'-carboxy-mephedrone...
August 21, 2017: AAPS Journal
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