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https://www.readbyqxmd.com/read/29329581/microrna-124-regulates-the-expression-of-mekk3-in-the-inflammatory-pathogenesis-of-parkinson-s-disease
#1
Longping Yao, Yongyi Ye, Hengxu Mao, Fengfei Lu, Xiaozheng He, Guohui Lu, Shizhong Zhang
BACKGROUND: Parkinson's disease (PD) is the most prevalent neurodegenerative disorder that is characterised by selective loss of midbrain dopaminergic (DA) neurons. Chronic inflammation of the central nervous system is mediated by microglial cells and plays a critical role in the pathological progression of PD. Brain-specific microRNA-124 (miR-124) expression is significantly downregulated in lipopolysaccharide (LPS)-treated BV2 cells and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD...
January 12, 2018: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29325762/assessment-of-in-vivo-efficacy-of-eravacycline-against-enterobacteriaceae-exhibiting-various-resistance-mechanisms-a-dose-ranging-study-and-pk-pd-analysis
#2
Abrar K Thabit, Marguerite L Monogue, Joseph V Newman, David P Nicolau
After the pharmacokinetic (PK) profile of eravacycline as a novel fluorocycline was defined, understanding its pharmacodynamic (PD) profile became essential. The aim of this study was to assess the correlation of the PK/PD index of the area under free drug concentration-time curve above the minimum inhibitory concentration (fAUC/MIC) and its magnitude with eravacycline's efficacy against Enterobacteriaceae isolates using the immunocompetent murine thigh infection model to resemble the immunocompetent environment in eravacycline's clinical trials...
January 8, 2018: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29317432/in-silico-evaluation-of-pharmacokinetic-optimization-for-antimitogram-based-clinical-trials
#3
Skerdi Haviari, Benoît You, Michel Tod
Antimitograms are prototype in vitro tests for evaluating chemotherapeutic efficacy using patient-derived primary cancer cells. These tests might help optimize treatment from a pharmacodynamic (PD) standpoint by guiding treatment selection. However, they are technically challenging and require refinements and trials to demonstrate benefit in order to be widely used. In this study, we performed simulations aimed at exploring how to validate antimitograms and how to complement them by pharmacokinetic (PK) optimization...
January 9, 2018: Cancer Research
https://www.readbyqxmd.com/read/29316830/use-of-monte-carlo-simulation-to-evaluate-the-efficacy-of-tigecycline-and-minocycline-for-the-treatment-of-pneumonia-due-to-carbapenemase-producing-klebsiella-pneumoniae
#4
Wentao Ni, Guobao Li, Jin Zhao, Junchang Cui, Rui Wang, Zhancheng Gao, Youning Liu
BACKGROUND: Pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-KP) are increasingly encountered in hospitals worldwide, causing high mortality due to lack of treatment options. The goal of this study was to assess the efficacy of tigecycline and minocycline for CP-KP hospital-acquired pneumonia (HAP) by using Monte Carlo simulation. METHODS: A total of 164 non-duplicated CP-KP strains were collected from sputum or blood in patients with HAP. The MICs for antimicrobials were determined by the agar dilution method...
January 9, 2018: Infectious Diseases
https://www.readbyqxmd.com/read/29313863/pharmacokinetics-of-high-dose-extended-infusion-meropenem-during-pulmonary-exacerbation-in-adult-cystic-fibrosis-patients-a-case-series
#5
Emanuele Delfino, Carmen Fucile, Valerio Del Bono, Anna Marchese, Valeria Marini, Erika Coppo, Rosaria Casciaro, Laura Minicucci, Daniele Roberto Giacobbe, Antonietta Martelli, Claudio Viscoli, Francesca Mattioli
This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography...
January 9, 2018: New Microbiologica
https://www.readbyqxmd.com/read/29310479/therapies-for-multidrug-resistant-and-extensively-drug-resistant-non-fermenting-gram-negative-bacteria-causing-nosocomial-infections-a-perilous-journey-toward-molecularly-targeted-therapy
#6
Nadim G El Chakhtoura, Elie Saade, Alina Iovleva, Mohamad Yasmin, Brigid Wilson, Federico Perez, Robert A Bonomo
Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of "serious" by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients...
January 9, 2018: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/29305429/back-to-the-future-new-target-validated-rab-antibodies-for-evaluating-lrrk2-signalling-in-cell-biology-and-parkinson-s-disease
#7
Patrick A Eyers
The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD...
January 5, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29304211/we-can-do-better-a-fresh-look-at-echinocandin-dosing
#8
Justin C Bader, Sujata M Bhavnani, David R Andes, Paul G Ambrose
First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally...
January 1, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29303785/mechanisms-of-disordered-neurodegenerative-function-concepts-and-facts-about-the-different-roles-of-the-protein-kinase-rna-like-endoplasmic-reticulum-kinase-perk
#9
Yasmeen M Taalab, Nour Ibrahim, Ahmed Maher, Mubashir Hassan, Wael Mohamed, Ahmed A Moustafa, Mohamed Salama, Dina Johar, Larry Bernstein
Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis...
January 5, 2018: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29298798/phase-1-trial-of-m7824-msb0011359c-a-bifunctional-fusion-protein-targeting-pd-l1-and-tgf-%C3%AE-in-advanced-solid-tumors
#10
Julius Strauss, Christopher Heery, Jeffrey Schlom, Ravi A Madan, Liang Cao, Zhigang Kang, Elizabeth Lamping, Jennifer L Marte, Renee N Donahue, Italia Grenga, Lisa M Cordes, Olaf Christensen, Lisa Mahnke, Christoph Helwig, James L Gulley
PURPOSE: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-β (TGF-β) "trap." Experimental DesignIn the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0...
January 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29296862/brafv600e-accelerates-disease-progression-and-enhances-immune-suppression-in-a-mouse-model-of-b-cell-leukemia
#11
Yo-Ting Tsai, Aparna Lakshmanan, Amy Lehman, Bonnie K Harrington, Fabienne McClanahan Lucas, Minh Tran, Ellen J Sass, Meixiao Long, Alan D Flechtner, Florinda Jaynes, Krista La Perle, Vincenzo Coppola, Gerard Lozanski, Natarajan Muthusamy, John C Byrd, Michael R Grever, David M Lucas
Mutated mitogen-activated protein kinase (MAPK) pathway components promote tumor survival, proliferation, and immune evasion in solid tumors. MAPK mutations occur in hematologic cancers as well, but their role is less clear and few models are available to study this. We developed an in vivo model of disseminated BRAFV600E B-cell leukemia to determine the effects of this mutation on tumor development and immune evasion. Mice with B-cell-restricted BRAFV600E expression crossed with the Eµ-TCL1 model of chronic lymphocytic leukemia (CLL) developed leukemia significantly earlier (median, 4...
November 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290237/antibiotic-pharmacokinetic-and-pharmacodynamic-parameters-in-pediatric-clinical-practice
#12
R Cohen, E Grimprel
Progress in the knowledge of antibiotic mechanisms of action allows to determine the pharmacodynamics/pharmacokinetic (PK/PD) parameters predictive of antibiotic efficacy in bacterial infections. According to the antibiotic compound, the bacterial species implicated, the location of the infection, and the severity of the disease, these parameters may vary. The PK/PD parameters described in this paper, focus only on blood compartments. These PK/PD parameters best predict efficacy in the most frequent infections (e...
December 2017: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
https://www.readbyqxmd.com/read/29288045/elevated-nuclear-phosphatase-and-tensin-homolog-pten-and-altered-insulin-signaling-in-substantia-nigral-region-of-patients-with-parkinson-s-disease
#13
Sathiya Sekar, Changiz Taghibiglou
Studies showed that 50-80% of Parkinson's disease (PD) patients have been reported with abnormal glucose tolerance. Alterations in glucose and energy metabolism serve as the early molecular event in PD. Although evidences support that the insulin resistance plays a major role in motor and non-motor complications of PD, the underlying mechanism in the pathogenesis of PD is unclear. To address this issue, we investigated the alterations in major components of insulin signaling in nuclear fraction (NF) and whole tissue homogenate (TH) of substantia nigral (SN) region obtained from postmortem PD brain and their age-matched controls...
December 26, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29286084/petasites-japonicus-bakkenolide-b-inhibits-lipopolysaccharide%C3%A2-induced-pro%C3%A2-inflammatory-cytokines-via-ampk-nrf2-induction-in-microglia
#14
Sun Young Park, Min Hyun Choi, Geuntae Park, Young-Whan Choi
Abnormal neuroinflammatory responses have diverse roles in neuronal death, oxidative stress and neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Microglia regulate these responses via molecular signaling cascades that involve inflammatory cytokines and complement proteins. Bakkenolide B from Petasites japonicus exhibits significant anti‑inflammatory and anti‑allergic bioactivities. The present study investigated the anti‑neuroinflammatory effects and underlying molecular mechanisms of bakkenolide B on the lipopolysaccharide (LPS)‑mediated neuroinflammatory response in microglia...
December 28, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29282364/mir-pharmacogenetics-of-vincristine-and-peripheral-neurotoxicity-in-childhood-b-cell-acute-lymphoblastic-leukemia
#15
Ángela Gutierrez-Camino, Maitane Umerez, Idoia Martin-Guerrero, Nagore García de Andoin, Borja Santos, Ana Sastre, Aizpea Echebarria-Barona, Itziar Astigarraga, Aurora Navajas, Africa Garcia-Orad
Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function...
December 27, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29277489/c-547-a-6-methyluracil-derivative-with-long-lasting-binding-and-rebinding-on-acetylcholinesterase-pharmacokinetic-and-pharmacodynamic-studies
#16
Konstantin Petrov, Irina Zueva, Irina Kovyazina, Igor Sedov, Sofya Lushchekina, Alexandra Kharlamova, Oksana Lenina, Sergei Koshkin, Yurii Shtyrlin, Evgeny Nikolsky, Patrick Masson
C-547, a potent slow-binding inhibitor of acetylcholinesterase (AChE) was intravenously administered to rat (0.05 mg/kg). Pharmacokinetic profiles were determined in blood and different organs: extensor digitorum longus muscle, heart, liver, lungs and kidneys as a function of time. Pharmacokinetics (PK) was studied using non-compartmental and compartmental analyses. A 3-compartment model describes PK in blood. Most of injected C-547 binds to albumin in the bloodstream. The steady-state volume of distribution (3800 ml/kg) is 15 times larger than the distribution volume, indicating a good tissue distribution...
December 22, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29273578/pharmacokinetic-and-pharmacodynamic-characteristics-of-dasiglucagon-a-novel-soluble-and-stable-glucagon-analog
#17
Ulrike Hövelmann, Britta Væver Bysted, Ulrik Mouritzen, Francesca Macchi, Daniela Lamers, Birgit Kronshage, Daniél Vega Møller, Tim Heise
OBJECTIVE: Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes...
December 22, 2017: Diabetes Care
https://www.readbyqxmd.com/read/29273485/a-first-in-man-phase-1-trial-for-long-acting-transcon-growth-hormone
#18
David Gilfoyle, Eva Mortensen, Eva Dam Christoffersen, Jonathan A Leff, Michael Beckert
TransCon growth hormone (GH) is a sustained-release inactive prodrug consisting of unmodified GH transiently bound to an inert carrier molecule designed to release fully active GH over a one-week period. This was a first-in-man phase 1 randomized trial was to evaluate the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics (PD) of a single dose of TransCon GH as compared to equivalent doses of daily GH (Omnitrope) or placebo in healthy adults. Forty-four healthy male adults were randomized to 4 cohorts of 11 subjects, distributed in a 7:2:2 ratio (TransCon GH: Omnitrope: placebo)...
December 5, 2017: Growth Hormone & IGF Research
https://www.readbyqxmd.com/read/29260434/study-of-binding-interaction-of-rivaroxaban-with-bovine-serum-albumin-using-multi-spectroscopic-and-molecular-docking-approach
#19
Tanveer A Wani, Haitham AlRabiah, Ahmed H Bakheit, Mohd Abul Kalam, Seema Zargar
BACKGROUND: Rivaroxaban is a direct inhibitor of coagulation factor Xa and is used for venous thromboembolic disorders. The rivaroxaban interaction with BSA was studied to understand its PK and PD (pharmacokinetics and pharmacokinetics) properties. Multi-spectroscopic studies were used to study the interaction which included UV spectrophotometric, spectrofluorometric and three dimensional spectrofluorometric studies. Further elucidation of data was done by molecular simulation studies to evaluate the interaction behavior between BSA and rivaroxaban...
December 20, 2017: Chemistry Central Journal
https://www.readbyqxmd.com/read/29258821/involvement-of-nitric-oxide-reactive-oxygen-species-signaling-via-8-nitro-cgmp-formation-in-1-methyl-4-phenylpyridinium-ion-induced-neurotoxicity-in-pc12-cells-and-rat-cerebellar-granule-neurons
#20
Kumiko Masuda, Hiroyasu Tsutsuki, Shingo Kasamatsu, Tomoaki Ida, Tsuyoshi Takata, Kikuya Sugiura, Motohiro Nishida, Yasuo Watanabe, Tomohiro Sawa, Takaaki Akaike, Hideshi Ihara
To investigate the role of nitric oxide (NO)/reactive oxygen species (ROS) redox signaling in Parkinson's disease-like neurotoxicity, we used 1-methyl-4-phenylpyridinium (MPP+) treatment (a model of Parkinson's disease). We show that MPP+-induced neurotoxicity was dependent on ROS from neuronal NO synthase (nNOS) in nNOS-expressing PC12 cells (NPC12 cells) and rat cerebellar granule neurons (CGNs). Following MPP+ treatment, we found production of 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), a second messenger in the NO/ROS redox signaling pathway, in NPC12 cells and rat CGNs, that subsequently induced S-guanylation and activation of H-Ras...
December 16, 2017: Biochemical and Biophysical Research Communications
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