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https://www.readbyqxmd.com/read/28527958/treadmill-exercise-produces-neuroprotective-effects-in-a-murine-model-of-parkinson-s-disease-by-regulating-the-tlr2-myd88-nf-%C3%AE%C2%BAb-signaling-pathway
#1
Jung-Hoon Koo, Yong-Chul Jang, Dong-Ju Hwang, Hyun-Seob Um, Nam-Hee Lee, Jae-Hoon Jung, Joon-Yong Cho
Parkinson's disease (PD) is characterized by progressive dopamine depletion and a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Treadmill exercise is a promising non-pharmacological approach for reducing the risk of PD and other neuroinflammatory disorders, such as Alzheimer's disease. The goal of this study was to investigate the effects of treadmill exercise on α-synuclein-induced neuroinflammation and neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD...
May 17, 2017: Neuroscience
https://www.readbyqxmd.com/read/28518053/effects-of-genetic-variants-in-ugt1a1-slco1b3-abcb1-abcc2-abcg2-orm1-on-pk-pd-of-telmisartan-in-chinese-patients-with-mild-to-moderate-essential-hypertension%C3%A2
#2
Qi Pei, Liu Yang, Hong-Yi Tan, Shi-Kun Liu, Yang Liu, Lu Huang, Rong-Hui Li, Qian Wan, Jie Huang, Cheng-Xian Guo, Xiao-Cong Zuo, Jingle Li, Guo-Ping Yang
PURPOSE: This study aimed to understand the effects of single nucleotide polymorphisms (SNPs) in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, and ORM1 on the pharmacokinetics (PK) (plasma concentration) and pharmacodynamics (PD) (blood pressure) of telmisartan in Chinese patients. METHODS: 58 Han Chinese patients (aged 45 - 72 years) with mild to moderate essential hypertension were included and received 80 mg/day telmisartan for 4 weeks. The plasma concentration and genetic variants were determined by LC/MS/MS and MALDI-TOF mass spectrometry, respectively...
May 18, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28516358/mechanistic-modeling-of-the-pharmacodynamic-and-pharmacokinetic-relationship-of-tissue-factor-pathway-inhibitor-neutralizing-antibody-bay-1093884-in-cynomolgus-monkeys
#3
Jian-Ming Gu, Xiao-Yan Zhao, Thomas Schwarz, Joachim Schuhmacher, Andreas Baumann, Elena Ho, Babu Subramanyan, Kathy Tran, Timothy Myles, Chandra Patel, Maria Koellnberger
BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28510738/pharmacokinetic-pharmacodynamic-model-for-unfractionated-heparin-dosing-during-cardiopulmonary-bypass
#4
X Delavenne, E Ollier, S Chollet, F Sandri, J Lanoiselée, S Hodin, A Montmartin, J-F Fuzellier, P Mismetti, L Gergelé
Background: High-dose heparin is used during cardiopulmonary bypass (CPB) to prevent thrombosis in the circuits used for extracorporeal circulation. The aim of this study was, initially, to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess the variability of PK/PD parameters and their correlation with the results of the routine haemostatic test activated clotting time (ACT) and thereafter to develop a Bayesian estimator enabling an individualized dosing strategy...
May 1, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/28508378/population-pharmacokinetic-and-pharmacodynamic-modeling-of-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-receiving-hemodialysis
#5
Ping Chen, Adimoolam Narayanan, Benjamin Wu, Per Olsson Gisleskog, John P Gibbs, Andrew T Chow, Murad Melhem
INTRODUCTION: Etelcalcetide is a novel calcimimetic that binds and activates calcium-sensing receptors (CaSRs) for the treatment of secondary hyperparathyroidism (SHPT). METHODS: To assess titrated dosing regimens, population pharmacokinetic (PK) and PK/pharmacodynamic (PKPD) modeling of etelcalcetide was performed using NONMEM 7.2. In this analysis, plasma etelcalcetide, serum parathyroid hormone (PTH) and calcium (Ca) concentration-time data were collected from five phase I, II, and III clinical trials following single or multiple intravenous doses of etelcalcetide ranging from 2...
May 15, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28507715/a-quantitative-mechanistic-pk-pd-model-directly-connects-btk-target-engagement-and-in-vivo-efficacy
#6
Fereidoon Daryaee, Zhuo Zhang, Kayla R Gogarty, Yong Li, Jonathan Merino, Stewart L Fisher, Peter J Tonge
Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery. Previously we described a mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model that used drug-target binding kinetics to successfully predict the in vivo efficacy of antibacterial compounds in models of Pseudomonas aeruginosa and Staphylococcus aureus infection. In the present work we extend this model to quantitatively correlate the engagement of Bruton's tyrosine kinase (Btk) by the covalent inhibitor CC-292 with the ability of this compound to reduce ankle swelling in an animal model of arthritis...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28507517/the-role-of-unfolded-protein-response-and-mitogen-activated-protein-kinase-signaling-in-neurodegenerative-diseases-with-special-focus-on-prion-diseases
#7
REVIEW
Syed Zahid Ali Shah, Deming Zhao, Tariq Hussain, Lifeng Yang
Prion diseases are neurodegenerative pathologies characterized by the accumulation of a protease-resistant form of the cellular prion protein named prion protein scrapie (PrP(Sc)) in the brain. PrP(Sc) accumulation in the endoplasmic reticulum (ER) result in a dysregulated calcium (Ca(2+)) homeostasis and subsequent initiation of unfolded protein response (UPR) leading to neuronal dysfunction and apoptosis. The molecular mechanisms for the transition between adaptation to ER stress and ER stress-induced apoptosis are still unclear...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28507117/pharmacokinetics-of-levofloxacin-in-multidrug-and-extensively-drug-resistant-tuberculosis-patients
#8
Natasha Van't Boveneind-Vrubleuskaya, Tatiana Seuruk, Kai van Hateren, Tridia van der Laan, Jos G W Kosterink, Tjip S van der Werf, Dick van Soolingen, Susan van den Hof, Alena Skrahina, Jan-Willem C Alffenaar
Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily...
May 15, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28506866/non-maturational-covariates-for-dynamic-systems-pharmacology-models-in-neonates-infants-and-children-filling-the-gaps-beyond-developmental-pharmacology
#9
Karel Allegaert, Sinno H P Simons, Dick Tibboel, Elke Krekels, Catherijne Knibbe, John van den Anker
Pharmacokinetics and -dynamics show important changes throughout childhood. Studies on the different maturational processes that influence developmental pharmacology have been used to create population PK/PD models that can yield individualized pediatric drug dosages. These models were subsequently translated to semi-physiologically or physiology-based PK (PBPK) models that support predictions in pediatric patient cohorts and other special populations. Although these translational efforts are crucial, these models should be further improved towards individual patient predictions by including knowledge on non-maturational covariates...
May 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28502671/integrating-clinical-metabolomics-based-biomarker-discovery-and-clinical-pharmacology-to-enable-precision-medicine
#10
Isabelle Kohler, Thomas Hankemeier, Piet H van der Graaf, Catherijne A J Knibbe, J G Coen van Hasselt
Novel developments in biomarkers discovery are essential in modern health care, notably in treatment individualization and precision medicine. Clinical metabolomics, which aims to identify small molecule metabolites present in patient-derived samples, has attracted much attention to support discovery of novel biomarkers. However, the step from discriminatory features of disease states towards biomarkers that can truly individualize treatments is challenging. Biomarkers used for treatment individualization can either be dynamic or static prognostic biomarkers...
May 11, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28501767/garlic-derived-organosulfur-compound-exerts-antitumor-efficacy-via-activation-of-mapk-pathway-and-modulation-of-cytokines-in-sgc-7901-tumor-bearing-mice
#11
Xiaoyan Jiang, Xiaosong Zhu, Weizhen Huang, Hongya Xu, Zhongxi Zhao, Siying Li, Shanzhong Li, Jianhua Cai, Jimin Cao
Diallyl trisulfide (DATS), a natural agent derived from garlic, has been tested for its antigastric cancer activities in various preliminary studies. However, more systematic pharmacodymatic (PD) and mechanistic evaluations are clearly needed. The aim of this study was to investigate the antitumor effects of DATS in the treatment of human gastric cancer cell SGC-7901 both in vitro and in vivo using widely recommended study procedures. DATS suppressed cancer cells proliferation and induced cell cycle arrest accompanied by an increase in the expressions of cyclin A2 and cyclin B1 in SGC-7901 cancer cells...
May 11, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28497320/accelerating-drug-development-by-efficiently-using-emerging-pk-pd-data-from-an-adaptable-entry-into-human-trial-example-of-lumretuzumab
#12
Georgina Meneses-Lorente, Christine McIntyre, Joy C Hsu, Marlene Thomas, Wolfgang Jacob, Celine Adessi, Martin Weisser
PURPOSE: This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. METHODS: Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens...
June 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28496463/antibacterial-loaded-spray-dried-chitosan-polyelectrolyte-complexes-as-dry-powder-aerosol-for-the-treatment-of-lung-infections
#13
Brahmeshwar Mishra, Madhusmita Mishra, Sarita Kumari Yadav
Inhalation delivery of aerosolized antibacterials is preferred over conventional methods of delivery for targeting lung infection. The present study is concerned with the development and characterization of a novel, spray dried, aerosolized, chitosan polyelectrolyte complex (PEC) based microparticles containing antibacterials for the treatment of lung infections. Chitosan polyelectrolyte complex microparticles were formulated by spray drying process. Prepared spray dried chitosan PEC microparticles were studied for surface morphology, drug encapsulation efficiency, moisture content, Carr's index, solid state interaction by XRD, aerosolization behaviour and in-vitro drug release...
2017: Iranian Journal of Pharmaceutical Research: IJPR
https://www.readbyqxmd.com/read/28488766/brief-isoflurane-anesthesia-regulates-striatal-akt-gsk3%C3%AE-signaling-and-ameliorates-motor-deficits-in-a-rat-model-of-early-stage-parkinson-s-disease
#14
Juuso V Leikas, Samuel Kohtala, Wiebke Theilmann, Aaro J Jalkanen, Markus M Forsberg, Tomi Rantamäki
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3β (GSK3β) and neurodegenerative processes has encouraged investigation into the potential disease modifying effects of novel GSK3β inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3β within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3β signaling in naïve rats and in a rat model of early-stage PD...
May 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28485503/role-of-small-interfering-rna-silencing-protein-kinase-c-%C3%AE-gene-on-the-occurrence-of-ultrafiltration-failure-in-peritoneal-dialysis-rats
#15
Zhi-Wei Sun, Jian Wang, Min Weng, Jian-Zhong Tang, Jun-Feng Wang, Jian Xu, Ling Lin, Hong-Ling Yuan
This study aims to explore the effect of PKC-α gene silencing on the occurrence of ultrafiltration failure (UFF) in peritoneal dialysis (PD) rats. Forty-eight male SD rats were collected to establish 5/6 renal resection uremic and uremic PD rats models. Rats were assigned into control, sham operation, uremia, PD-2 W (peritoneal dialysis for 2 weeks), PD-4 W (peritoneal dialysis for 4 weeks), negative control (NC) (peritoneal dialysis for 4 weeks, and injected 0.1 mg/kg blank plasmid into abdominal cavity) and PKC-α siRNA (peritoneal dialysis for 4 weeks, and injected 0...
May 9, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28484287/mir-135b-plays-a-neuroprotective-role-by-targeting-gsk3%C3%AE-in-mpp-intoxicated-sh-sy5y-cells
#16
Jianlei Zhang, Wei Liu, Yabo Wang, Shengnan Zhao, Na Chang
miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson's disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP(+)-intoxicated SH-SY5Y cells in a dose- and time-dependent manner...
2017: Disease Markers
https://www.readbyqxmd.com/read/28476536/translational-pharmacokinetic-pharmacodynamic-analysis-in-the-pharmaceutical-industry-an-iq-consortium-pk-pd-discussion-group-perspective
#17
Harvey Wong, Tonika Bohnert, Valeriu Damian-Iordache, Christopher Gibson, Cheng-Pang Hsu, Anu Shilpa Krishnatry, Bianca M Liederer, Jing Lin, Qiang Lu, Jerome T Mettetal, Daniel R Mudra, Marjoleen J M A Nijsen, Patricia Schroeder, Edgar Schuck, Satyendra Suryawanshi, Patrick Trapa, Alice Tsai, Haiqing Wang, Fan Wu
With inadequate efficacy being the primary cause for the attrition of drug candidates in clinical development, the need to better predict clinical efficacy earlier in the drug development process has increased in importance in the pharmaceutical industry. Here, we review current applications of translational pharmacokinetic-pharmacodynamic (PK-PD) modeling of preclinical data in the pharmaceutical industry, including best practices. Preclinical translational PK-PD modeling has been used in many therapeutic areas and has been impactful to drug development...
May 2, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28473732/anti-inflammatory-and-neuroprotective-role-of-natural-product-securinine-in-activated-glial-cells-implications-for-parkinson-s-disease
#18
Dmitri Leonoudakis, Anand Rane, Suzanne Angeli, Gordon J Lithgow, Julie K Andersen, Shankar J Chinta
Glial activation and subsequent release of neurotoxic proinflammatory factors are believed to play an important role in the pathogenesis of several neurological disorders including Parkinson's disease (PD). Inhibition of glial activation and inflammatory processes may represent a therapeutic target to alleviate neurodegeneration. Securinine, a major natural alkaloid product from the root of the plant Securinega suffruticosa, has been reported to have potent biological activity and is used in the treatment of neurological conditions such as amyotrophic lateral sclerosis, poliomyelitis, and multiple sclerosis...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28472247/pharmacodynamics-of-isavuconazole-for-invasive-mold-disease-role-of-galactomannan-for-real-time-monitoring-of-therapeutic-response
#19
Laura L Kovanda, Ruwanthi Kolamunnage-Dona, Michael Neely, Johan Maertens, Misun Lee, William W Hope
Background.: The ability to make early therapeutic decisions when treating invasive aspergillosis using changes in biomarkers as a surrogate for therapeutic response could significantly improve patient outcome. Methods.: Cox proportional hazards model and logistic regression were used to correlate early changes in galactomannan index (GMI) to mortality and overall response, respectively, from patients with positive baseline GMI (≥0.5) and serial GMI during treatment from a phase 3 clinical trial for the treatment of invasive mold disease...
June 1, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28470723/pharmacokinetics-milk-penetration-and-pk-pd-analysis-by-monte-carlo-simulation-of-marbofloxacin-after-intravenous-and-intramuscular-administration-to-lactating-goats
#20
A M Lorenzutti, N J Litterio, M A Himelfarb, M D P Zarazaga, M I San Andrés, J J De Lucas
The main objectives of this study were (i) to evaluate the serum pharmacokinetic behaviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regimen on steady-state conditions, (ii) to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady-state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emergence of resistance...
May 4, 2017: Journal of Veterinary Pharmacology and Therapeutics
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