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https://www.readbyqxmd.com/read/29338251/delivery-of-oxytocin-to-the-brain-for-the-treatment-of-autism-spectrum-disorder-by-nasal-application
#1
Akiko Tanaka, Tomoyuki Furubayashi, Mari Arai, Daisuke Inoue, Shunsuke Kimura, Akiko Kiriyama, Kosuke Kusamori, Hidemasa Katsumi, Reiko Yutani, Toshiyasu Sakane, Akira Yamamoto
Oxytocin (OXT) is a cyclic nonapeptide, two amino acids of which are cysteine, forming an intramolecular disulfide bond. OXT is produced in the hypothalamus and is secreted into the blood stream from the posterior pituitary. As recent studies have suggested that OXT is a neurotransmitter exhibiting central effects important for social deficits, it has drawn much attention as a drug candidate for the treatment of autism. Although human-stage clinical trials of the nasal spray of OXT for the treatment of autism have already begun, few studies have examined the pharmacokinetics and brain distribution of OXT after nasal application...
January 16, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29329091/determination-of-imm-h004-and-its-active-glucuronide-metabolite-in-rat-plasma-and-ringer-s-solution-by-ultra-performance-liquid-chromatography-tandem-mass-spectrometry
#2
Jianwei Jiang, Ziqian Zhang, Xiaowen Zou, Rui Wang, Jie Bai, Shengyu Zhao, Xiaoqing Fan, Li Sheng, Yan Li
IMM-H004 is a novel neuroprotective agent and its glucuronide metabolite IMM-H004G has similar protective effects against cerebral ischemic injury in vivo and in vitro. A specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was established and validated for determination of IMM-H004 and IMM-H004G simultaneously in rat plasma and Ringer's solution. Plasma samples containing IMM-H004, IMM-H004G and internal standard propranolol were prepared by direct protein precipitation in a sample-to-solvent ratio of 1:2:6 (plasma: water: acetonitrile), whereas no protein precipitation was required for Ringer's solution samples...
December 29, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29319897/application-of-a-physiologically-based-pharmacokinetic-model-for-the-prediction-of-bumetanide-plasma-and-brain-concentrations-in-the-neonate
#3
Maria D Donovan, Khaled Abduljalil, John F Cryan, Geraldine B Boylan, Brendan T Griffin
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and pediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data...
January 10, 2018: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29311093/characterization-of-the-preclinical-pharmacology-of-the-new-2-aminomethylphenol-jpc-3210-for-malaria-treatment-and-prevention
#4
Geoffrey W Birrell, Gavin D Heffernan, Guy A Schiehser, John Anderson, Arba L Ager, Pablo Morales, Donna MacKenzie, Karin van Breda, Marina Chavchich, Laura R Jacobus, G Dennis Shanks, David P Jacobus, Michael D Edstein
The new 2-aminomethylphenol JPC-3210 has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and in vitro screening assays including the inhibition of cytochrome (CYP) P450 isozymes. In mice JPC-3210 is rapidly absorbed, has extensive tissue distribution with a brain tissue to plasma concentration ratio of about 5.4 and a lengthy plasma elimination half-life of about 4...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29305823/semi-mechanistic-population-pharmacokinetic-modeling-of-l-histidine-disposition-and-brain-uptake-in-wildtype-and-pht1-null-mice
#5
Xiao-Xing Wang, Yang-Bing Li, Meihua R Feng, David E Smith
PURPOSE: To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. METHODS: L-[14C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected...
January 5, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29300135/non-clinical-pharmacokinetic-profiles-of-rovatirelin-an-orally-available-thyrotropin-releasing-hormone-analogue
#6
Kaoru Kobayashi, Yoshikazu Abe, Hiroshi Harada, Emiko Oota, Takuro Endo, Hiroo Takeda
The non-clinical pharmacokinetic profiles of rovatirelin, a novel thyrotropin releasing hormone (TRH) analogue, were investigated in vivo and in vitro. Rovatirelin orally administered to rats and dogs was rapidly absorbed and bioavailability was estimated to be 7.3% and 41.3%, respectively. The extent of plasma protein binding of rovatirelin in rats, dogs, and humans was low in all species (∼15%). The permeability of rovatirelin from blood to brain (permeability-surface area) ranged from 1.04 ± 0.14 to 1...
January 4, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29285548/preclinical-evaluation-of-an-18f-trifluoroborate-methionine-derivative-for-glioma-imaging
#7
Xiangyu Yang, Zhibo Liu, Huimin Zhang, Zhu Li, Jeeva P Munasinghe, Gang Niu, Gaojun Teng, Xiaoyuan Chen
PURPOSE: 11C-methionine (MET) is one of the most commonly used amino acid tracers for PET imaging of brain tumors. In this study, we report an 18F-labeled boron-derived methionine analogue, denoted as 18F-B-MET, as a potential substitute of 11C-MET for glioma PET imaging. METHODS: 19F-B-MET was synthesized from readily available chemicals according to our previous publication. For kit development, 19F-B-MET was aliquoted in quantities of 10 nmol for on-demand one-step labeling...
December 29, 2017: European Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/29282567/demonstration-of-direct-nose-to-brain-transport-of-unbound-hiv-1-replication-inhibitor-db213-via-intranasal-administration-by-pharmacokinetic-modeling
#8
Qianwen Wang, Yufeng Zhang, Chun-Ho Wong, H Y Edwin Chan, Zhong Zuo
Intranasal administration could be an attractive alternative route of administration for the delivery of drugs to the central nervous system (CNS). However, there are always doubts about the direct transport of therapeutics from nasal cavity to the CNS since there are only limited studies on the understanding of direct nose-to-brain transport. Therefore, this study aimed to (1) investigate the existence of nose-to-brain transport of intranasally administered HIV-1 replication inhibitor DB213 and (2) assess the direct nose-to-brain transport of unbound HIV-1 replication inhibitor DB213 quantitatively by a pharmacokinetic approach...
December 27, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29278694/non-clinical-assessment-of-safety-and-gadolinium-deposition-after-cumulative-administration-of-gadobenate-dimeglumine-multihance%C3%A2-to-neonatal-and-juvenile-rats
#9
Simona Bussi, Laure Penard, Roberta Bonafè, Catherine Botteron, Roberto Celeste, Alessandra Coppo, Roberta Queliti, Miles A Kirchin, Fabio Tedoldi, Federico Maisano
To determine the impact of single and cumulative doses of MultiHance on toxicity, pharmacokinetics, tissue gadolinium presence, behavior and neurological function in juvenile rats. Juvenile male and female rats received either physiological saline or MultiHance at 0.6, 1.25 or 2.5 mmol/kg bodyweight. Animals received either single or six consecutive MultiHance administrations and were sacrificed the day after the last administration or after a 60-day treatment-free period. Animals were assessed for behavior, cognitive function, grip strength, gait, pupillary reflex, and auditory reflex, as well as for physical development, sexual maturation and histopathology...
December 23, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29248595/quantification-of-11b-hydroxysteroid-dehydrogenase-1-kinetics-and-pharmacodynamic-effects-of-inhibitors-in-brain-using-mass-spectrometry-imaging-and-stable-isotope-tracers-in-mice
#10
D F Cobice, D E W Livingstone, A McBride, C L MacKay, B R Walker, S P Webster, R Andrew
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11β-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11 β -HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11 β -HSD1 inhibitor that accesses the brain...
December 14, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29229228/factors-influencing-norvancomycin-concentration-in-plasma-and-cerebrospinal-fluid-in-patients-after-craniotomy-and-dosing-guideline-a-population-approach
#11
Xingang Li, Yuanxing Wu, Shusen Sun, Qiang Wang, Zhigang Zhao
PURPOSE: Antibacterial spectrum and activity of norvancomycin are comparable with vancomycin, and it has been widely used in China. Norvancomycin can penetrate into the cerebrospinal fluid (CSF) through the damaged blood-brain barrier in patients after craniotomy. Because higher inter-individual variability was observed, we aimed to identify factors related to drug concentration to guide clinicians with norvancomycin dosing. METHODS: After craniotomy, patients with an indwelling catheter in the operational area/ventricle were intravenously administered norvancomycin...
December 8, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/29228824/development-of-novel-bioadhesive-granisetron-hydrochloride-spanlastic-gel-and-insert-for-brain-targeting-and-study-their-effects-on-rats
#12
Rehab Abdelmonem, Mohamed El Nabarawi, Alshaimaa Attia
The aim of this study was to formulate granisetron hydrochloride (GH) spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve GH bioavailability and brain targeting. Carpapol 934 and HPMC were incorporated in GH spanlastic in nasal gels (GHSpNGs). Gelatin and HPMC as matrix former, glycine as a collapse protecting and mannitol as an insert filler and sweeting agent were used to prepare GH spanlastic loaded in lyophilized inserts (GHSpNIs). The prepared GHSpNGs were characterized for pH measurement, drug content, rheology, and in vitro drug release...
November 2018: Drug Delivery
https://www.readbyqxmd.com/read/29228726/tyrosine-kinase-inhibitors-show-different-anti-brain-metastases-efficacy-in-nsclc-a-direct-comparative-analysis-of-icotinib-gefitinib-and-erlotinib-in-a-nude-mouse-model
#13
Jianlong Tan, Min Li, Wen Zhong, Chengping Hu, Qihua Gu, Yali Xie
Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29225107/comparison-of-blood-brain-barrier-penetration-efficiencies-between-linear-and-cyclic-all-d-enantiomeric-peptides-developed-for-the-treatment-of-alzheimer-s-disease
#14
Elena Schartmann, Sarah Schemmert, Tamar Ziehm, Leonie H E Leithold, Nan Jiang, Markus Tusche, N Joni Shah, Karl-Josef Langen, Janine Kutzsche, Dieter Willbold, Antje Willuweit
Alzheimer's disease (AD), until now, is an incurable progressive neurodegenerative disease. To target toxic amyloid β oligomers in AD patients' brains and to convert them into non-toxic aggregation-incompetent species, we designed peptides consisting solely of d-enantiomeric amino acid residues. The original lead compound was named D3 and several D3 derivatives were designed to enhance beneficial properties. Here, we compare four d-peptides concerning their efficiencies to pass the blood-brain barrier (BBB)...
December 7, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29211812/a-simulation-study-on-the-impact-of-the-blood-flow-dependent-component-in-18f-av45-suvr-in-alzheimer-s-disease
#15
Julie Ottoy, Jeroen Verhaeghe, Ellis Niemantsverdriet, Sebastiaan Engelborghs, Sigrid Stroobants, Steven Staelens
BACKGROUND: Increased brain uptake on [18F]AV45 PET is a biomarker for Alzheimer's disease (AD). The standardised uptake value ratio (SUVR) is widely used for quantification but is subject to variability. Here we evaluate how SUVR of a cortical target region is affected by blood flow changes in the target and two frequently used reference regions. METHODS: Regional baseline time-activity curves (TACs) were simulated based on metabolite-corrected plasma input functions and pharmacokinetic parameters obtained from our previously acquired data in healthy control (HC; n = 10), amnestic mild cognitive impairment (aMCI; n = 15) and AD cohorts (n = 9)...
2017: PloS One
https://www.readbyqxmd.com/read/29197298/pharmacokinetics-and-tissue-distribution-study-of-10-methoxycamptothecin-in-rats-following-intragastric-administration
#16
Jian Zheng, Yong Ji, Changmin Shao, Lijia Jing, Yang Wang
Natural bioactive derivatives of camptothecin (CPT), 10-methoxycamptothecin (MCPT) and 10-hydroxycamptothecin (HCPT) have been confirmed to possess high antitumor activities. MCPT could be metabolized to HCPT in vivo. The HPLC method for the quantification of MCPT and HCPT was established and validated, and the pharmacokinetics and the tissue distribution of MCPT in rats after i.v. administration have been well carried out in our previous studies. To improve the further understanding of the in vivo behavior of MCPT, a rapid and sensitive UPLC-MS/MS method was developed and validated for the quantification of MCPT and HCPT in plasma and tissue samples, and the pharmacokinetics and tissue distribution as well as the bioavailability of MCPT after i...
November 29, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29194416/melatonin-pharmacokinetics-following-oral-administration-in-preterm-neonates
#17
Silvia Carloni, Fabrizio Proietti, Marco Rocchi, Mariangela Longini, Lucia Marseglia, Gabriella D'Angelo, Walter Balduini, Eloisa Gitto, Giuseppe Buonocore
Melatonin possesses potential efficacy in perinatal brain injuries, and has been proposed as adjunctive pharmacological therapy in combination with hypothermia in the clinical setting. However, the pharmacokinetics of melatonin in preterm and term newborns is still unknown. The aim of this study was to analyze the pharmacokinetics of melatonin after intragastric administration in preterm infants. Preterm newborns were enrolled 24-72 h after birth, and randomly assigned to three groups receiving a single bolus of 0...
December 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29189941/vortioxetine-clinical-pharmacokinetics-and-drug-interactions
#18
REVIEW
Grace Chen, Astrid-Maria Højer, Johan Areberg, George Nomikos
Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed...
November 30, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29181488/preclinical-and-clinical-development-of-abbv-8e12-a-humanized-anti-tau-antibody-for-treatment-of-alzheimer-s-disease-and-other-tauopathies
#19
T West, Y Hu, P B Verghese, R J Bateman, J B Braunstein, I Fogelman, K Budur, H Florian, N Mendonca, D M Holtzman
Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies...
2017: Journal of Prevention of Alzheimer's Disease
https://www.readbyqxmd.com/read/29180684/systemic-clearance-and-brain-distribution-of-carbazole-based-cyanine-compounds-as-alzheimer-s-disease-drug-candidates
#20
Wei Zhou, Xiaohui Hu, Kin Yip Tam
SLM and SLOH, two analogues of carbazole-based cyanine compounds, have been shown to inhibit β-amyloid peptide aggregation in vitro and in Alzheimer's disease model mice, which could be potentially developed into drugs for disease treatment. To pave the way for further pharmacokinetics-pharmacodynamics study, we set to investigate these compounds' systemic clearance pathways and their brain exposure. We found that they generally exhibited relatively low plasma clearance which comprised of hepatic clearance and biliary clearance...
November 27, 2017: Scientific Reports
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