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https://www.readbyqxmd.com/read/29159344/regioselective-and-enantiospecific-synthesis-of-the-hsp-co-inducer-arimoclomol-from-chiral-glycidyl-derivatives
#1
Benjamin N Atkinson, Hannah L Woodward, James Sipthorp, Paul V Fish
A new efficient chiral synthesis of enantiopure arimoclomol (2) is reported from (R)-(-)-glycidyl nosylate (11) with complete retention of chiral integrity. Off-target pharmacology of arimoclomol (2) was evaluated against a representative set of drug targets and showed modest binding to a few kinases. Pharmacokinetic data was generated in vivo in mouse and showed a low brain : plasma ratio. These studies will be helpful towards a better understanding of the PK-PD relationship of 2 in disease models.
November 21, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29154210/clinical-pharmacokinetic-pharmacodynamic-analyses-a-critical-element-for-developing-antibacterial-agents
#2
REVIEW
Sujata M Bhavnani, Jeffrey P Hammel
In the current of era of developing antibacterial agents, including those for unmet medical need, Sponsors are required to submit a robust pre-clinical pharmacokinetic-pharmacodynamic (PK-PD) data package in exchange for limited clinical data. However, the clinical data package also needs to be as robust as possible. The clinical data package needs to include the Phase 1 pharmacokinetic (PK) studies conducted in the target patient populations and special populations. Additionally, PK data need to be collected from all patients enrolled in the pivotal trial(s)...
November 16, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29149294/pharmacokinetics-pharmacodynamics-of-systemically-administered-polymyxin-b-against-klebsiella-pneumoniae-in-mouse-thigh-and-lung-infection-models
#3
Cornelia B Landersdorfer, Jiping Wang, Veronika Wirth, Ke Chen, Keith S Kaye, Brian T Tsuji, Jian Li, Roger L Nation
Background: The pharmacokinetic/pharmacodynamic (PK/PD) relationship for polymyxin B against Klebsiella pneumoniae infections is not known. Methods: Dose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120 mg/kg/day; lung infection 5-120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later...
November 14, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29147906/regulation-of-signal-transduction-by-dj-1
#4
Stephanie E Oh, M Maral Mouradian
The ability of DJ-1 to modulate signal transduction has significant effects on how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy to adapt to changing environmental stimuli and stresses. Perturbations of DJ-1 levels or function can disrupt the equilibrium of homeostatic signaling networks and set off cascades that play a role in the pathogenesis of conditions such as cancer and Parkinson's disease.DJ-1 plays a major role in various pathways. It mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29143669/considerations-for-using-minocycline-vs-doxycycline-for-treatment-of-canine-heartworm-disease
#5
Mark G Papich
BACKGROUND: Doxycycline has been considered the first drug of choice for treating Wolbachia, a member of the Rickettsiaceae, which has a symbiotic relationship with filarial worms, including heartworms. Wolbachia, is susceptible to tetracyclines, which have been used as adjunctive treatments for heartworm disease. Treatment with doxycycline reduces Wolbachia numbers in all stages of heartworms and improves outcomes and decreased microfilaremia in dogs treated for heartworm disease. The American Heartworm Society recommends treatment with doxycycline in dogs diagnosed with heartworm disease at a dose of 10 mg/kg twice daily for 28 days...
November 9, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/29143334/pk-pd-modeling-of-flunixin-meglumine-in-a-kaolin-induced-inflammation-model-in-piglets
#6
O L Levionnois, T K Fosse, B Ranheim
Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty-two piglets (6-8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand-held algometer was used to determine each piglet's mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut-off value of 24...
November 16, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29140892/proficiency-testing-for-meropenem-and-piperacillin-therapeutic-drug-monitoring-preliminary-results-from-the-belgian-society-on-infectiology-and-clinical-microbiology-pk-pd-working-group
#7
Mieke Carlier, Alexandre Athanasopoulos, Daniëlle Borrey, Pieter Colin, Frédéric Cotton, Raphael Denooz, Hugo Neels, Isabel Spriet, Timothy Ghys, Alain G Verstraete, Veronique Stove
No abstract text is available yet for this article.
November 14, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29138535/comparable-pharmacokinetics-and-pharmacodynamics-of-two-epoetin-alfa-formulations-eporon-%C3%A2-and-eprex-%C3%A2-following-a-single-subcutaneous-administration-in-healthy-male-volunteers
#8
Sumin Yoon, Su-Jin Rhee, Sun Ju Heo, Tae Young Oh, Seo Hyun Yoon, Joo-Youn Cho, SeungHwan Lee, Kyung-Sang Yu
Purpose: This study aimed to assess and compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties following a single subcutaneous injection of epoetin alfa (Eporon(®)) with those of the comparator (Eprex(®)) in healthy male subjects. Subjects and methods: A randomized, double-blind, two-sequence, crossover study was conducted. Subjects were randomly assigned to receive a single dose, that is, 4,000 IU, of the test or comparator epoetin alfa. After 4 weeks, all subjects received the alternative formulation...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29136767/the-exposure-effect-toxicity-correlation-of-docetaxel-and-magnesium-isoglycyrrhizinate-in-non-small-cell-lung-tumor-bearing-mice
#9
Peijin Li, Suning Li, Hongmei Gu, Qianfeng Lu, Wenjiao Jiang, Xue Pei, Yilin Sun, Hongjiang Xu, Guangji Wang, Kun Hao
To take full advantage of combination therapy of Docetaxel (DTX) and Magnesium isoglycyrrhizinate (MGIG), the pharmacokinetic- pharmacodynamic- toxicodynamics (PK-PD-TD) interaction of DTX and MGIG in non-small cell lung tumor-bearing mice was investigated in the present study. A model, an integrated semi-mechanistic PK-PD-TD, was established for elucidating the exposure-effect-toxicity relationship between DTX and MGIG. A tumor growth and a transit compartmental system were applied to imitate the growth and death of tumor cell...
November 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29136540/the-application-of-in-vitro-surveillance-data-for-antibacterial-dose-selection
#10
REVIEW
Robert K Flamm, Helio S Sader, Mariana Castanheira, Ronald N Jones
In vitro surveillance data, which provide key information to interpret the results of pharmacokinetic/pharmacodynamics (PK-PD) target attainment studies, are used to support dose selection decisions and recommendations for in vitro susceptibility testing criteria for antibacterial agents during drug development. Considerations for designing the in vitro surveillance database to support the development of antibacterial agents include the choice of pathogens to study, the sample size of isolate collections needed, and target patient populations from which clinical isolates should be collected...
November 10, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29136343/pharmacokinetics-pharmacodynamics-and-safety-of-a-long-acting-human-growth-hormone-mod-4023-in-healthy-japanese-and-caucasian-adults
#11
William G Kramer, Michal Jaron-Mendelson, Ronit Koren, Oren Hershkovitz, Gili Hart
Daily injections of growth hormone (GH) as replacement therapy in GH-deficient (GHD) patients may cause poor compliance and inconvenience. C-terminal peptide-modified human GH (MOD-4023) has been developed for once-weekly administration in GHD adults and children. In the present study, the pharmacokinetics (PK) and pharmacodynamics (PD) of a single subcutaneous dose of MOD-4023 were evaluated in healthy Caucasian and Japanese adults, using a phase 1 double-blind, vehicle-controlled, randomized study design...
November 14, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29135584/concomitant-medication-polypharmacy-interactions-and-imperfect-adherence-are-common-in-australian-adults-on-suppressive-art
#12
Krista J Siefried, Limin Mao, Lucette A Cysique, John Rule, Michelle L Giles, Don E Smith, James Mcmahon, Tim R Read, Catriona Ooi, Ban K Tee, Mark Bloch, John de Wit, Andrew Carr
OBJECTIVES: We quantified concomitant medication (CM) polypharmacy, pharmacokinetic (PK) and pharmacodynamic (PD) interactions, adverse effects and adherence in Australian adults on effective ART. DESIGN: Cross-sectional. METHODS: Patients recruited into a nation-wide cohort and assessed for prevalence and type of CM (including polypharmacy, defined as ≥5 CMs), PK or PD interactions, potential CM adverse effects and CM adherence. Factors associated with CM polypharmacy and with imperfect adherence were identified using multivariable logistic regression...
November 10, 2017: AIDS
https://www.readbyqxmd.com/read/29134648/pharmacokinetics-pharmacodynamics-and-proposed-dosing-of-the-oral-jak1-and-jak2-inhibitor-baricitinib-in-pediatric-and-young-adult-candle-and-savi-patients
#13
Hanna Kim, Kristina M Brooks, Cheng Cai Tang, Paul Wakim, Mary Blake, Stephen R Brooks, Gina A Montealegre Sanchez, Adriana A de Jesus, Yan Huang, Wanxia Li Tsai, Massimo Gadina, Apurva Prakash, Jonathan Marcus Janes, Xin Zhang, William L Macias, Parag Kumar, Raphaela Goldbach-Mansky
Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance respectively. The half-life of baricitinib in patients less than 40kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29133566/use-of-pharmacokinetic-and-pharmacodynamic-analyses-to-determine-the-optimal-fixed-dosing-regimen-of-iclaprim-for-treatment-of-serious-gram-positive-infections
#14
Thomas Lodise, John Bosso, Colleen Kelly, Paul J Williams, James R Lane, David B Huang
Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two Phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection models studies suggest that the pharmacokinetic and pharmacodynamics (PK/PD) drivers for efficacy are area under the curve from 0-24 hours at steady state (AUC0-24hss), AUC/minimum inhibitory concentration (MIC), and time above the MIC during the dosing interval (T > MIC) while QTc prolongation was associated to maximal concentration at steady state (Cmaxss) in a thorough QTc Phase 1 study...
November 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29128853/use-of-monte-carlo-simulation-and-considerations-for-pk-pd-targets-to-support-antibacterial-dose-selection
#15
REVIEW
Michael Trang, Michael N Dudley, Sujata M Bhavnani
Monte Carlo simulation is used to generate data for pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses to assess antibacterial dosing regimens in early and late stage drug development. Careful consideration of the quality of data for pharmacokinetics, non-clinical PK-PD targets for efficacy, the choice of the bacterial reduction endpoint upon which the PK-PD target is based, variability in the PK-PD target, and effect site exposures ensures optimal dose selection. Relationships between drug exposure and efficacy and/or safety endpoints based on clinical data can also be applied to simulated data to support dose selection...
November 9, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29127502/piperacillin-tazobactam-as-alternative-to-carbapenems-for-icu-patients
#16
REVIEW
Benoit Pilmis, Vincent Jullien, Alexis Tabah, Jean-Ralph Zahar, Christian Brun-Buisson
Several studies suggest that alternatives to carbapenems, and particulary beta-lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-related infections in non-ICU patients. Little is known concerning ICU patients in whom achieving the desired plasmatic pharmacokinetic/pharmacodynamic (PK/PD) target may be difficult. Also, in vitro susceptibility to beta-lactamase inhibitors might not translate into clinical efficacy. We reviewed the recent clinical studies examining the use of BL/BLI as alternatives to carbapenems for therapy of bloodstream infection, PK/PD data and discuss potential ecological benefit from avoiding the use of carbapenems...
November 10, 2017: Annals of Intensive Care
https://www.readbyqxmd.com/read/29127256/development-of-phospho-specific-rab-protein-antibodies-to-monitor-in-vivo-activity-of-the-lrrk2-parkinson-s-disease-kinase
#17
Pawel Lis, Sophie Burel, Martin Steger, Matthias Mann, Fiona Brown, Federico Diez, Francesca Tonelli, Janice L Holton, Philip Winglok Ho, Shu-Leong Ho, Meng-Yun Chou, Nicole K Polinski, Terina N Martinez, Paul Davies, Dario R Alessi
Mutations that activate the LRRK2 protein kinase, predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector binding Switch-II motif. In this study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against 9 different LRRK2 phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43)...
November 10, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29119968/time-dependent-pharmacokinetics-of-dexamethasone-and-its-efficacy-in-human-breast-cancer-xenograft-mice-a-semi-mechanism-based-pharmacokinetic-pharmacodynamic-model
#18
Jian Li, Rong Chen, Qing-Yu Yao, Sheng-Jun Liu, Xiu-Yun Tian, Chun-Yi Hao, Wei Lu, Tian-Yan Zhou
Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect...
November 9, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29115479/overexpression-of-mir%C3%A2-185-inhibits-autophagy-and-apoptosis-of-dopaminergic-neurons-by-regulating-the-ampk-mtor-signaling-pathway-in-parkinson-s-disease
#19
Zhi Wen, Jie Zhang, Peng Tang, Ning Tu, Ke Wang, Guangyao Wu
Parkinson's disease (PD) is an age‑associated neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta. Activation of 5'‑adenosine monophosphate‑activated protein kinase (AMPK) has been suggested to be associated with PD pathogenesis. The aim of the present study was to investigate the effects of the aberrant expression of microRNA‑185 (miR‑185) in PD. A 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑induced in vitro model of PD was generated using the human SH‑SY5Y dopaminergic neuroblastoma cell line, in order to examine the potential molecular mechanisms underlying the roles of miR‑185 in PD...
October 26, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29114473/immunohistochemistry-for-predictive-biomarkers-in-non-small-cell-lung-cancer
#20
REVIEW
Mari Mino-Kenudson
In the era of targeted therapy, predictive biomarker testing has become increasingly important for non-small cell lung cancer. Of multiple predictive biomarker testing methods, immunohistochemistry (IHC) is widely available and technically less challenging, can provide clinically meaningful results with a rapid turn-around-time and is more cost efficient than molecular platforms. In fact, several IHC assays for predictive biomarkers have already been implemented in routine pathology practice. In this review, we will discuss: (I) the details of anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) IHC assays including the performance of multiple antibody clones, pros and cons of IHC platforms and various scoring systems to design an optimal algorithm for predictive biomarker testing; (II) issues associated with programmed death-ligand 1 (PD-L1) IHC assays; (III) appropriate pre-analytical tissue handling and selection of optimal tissue samples for predictive biomarker IHC...
October 2017: Translational Lung Cancer Research
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