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https://www.readbyqxmd.com/read/28213532/susceptibility-and-pk-pd-relationships-of-staphylococcus-aureus-strains-from-ovine-and-caprine-with-clinical-mastitis-against-five-veterinary-fluoroquinolones
#1
J M Serrano-Rodríguez, C Cárceles-García, C M Cárceles-Rodríguez, M L Gabarda, J M Serrano-Caballero, E Fernández-Varón
Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of veterinary fluoroquinolones as enrofloxacin, its metabolite ciprofloxacin, danofloxacin, difloxacin and marbofloxacin against Staphylococcus aureus strains (n=24) isolated from milk of sheep and goats affected by clinical mastitis were evaluated. The authors have used the MIC and MPC, as well as the pharmacokinetic-pharmacodynamic relationships in plasma and milk. MIC values were significantly different between drugs, unlike MPC values...
February 17, 2017: Veterinary Record
https://www.readbyqxmd.com/read/28211169/a-first-in-human-study-of-ds-1040-an-inhibitor-of-the-activated-form-of-thrombin-activatable-fibrinolysis-inhibitor-in-healthy-subjects
#2
Jin Zhou, Jarema Kochan, Ophelia Yin, Vance Warren, Cynthia Zamora, George Atiee, Joseph Pav, Yasushi Orihashi, Vijay Vashi, Victor Dishy
BACKGROUND: Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low-molecular weight compound inhibiting the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), developed as a fibrinolysis enhancer for treatment of thromboembolic diseases. OBJECTIVES: This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-1040 in healthy subjects...
February 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28209351/an-indirect-stereoselective-analysis-of-nebivolol-glucuronides-in-plasma-by-lc-ms-ms-application-to-clinical-pharmacokinetics
#3
Carolina Pinto Vieira, Daniel Valente Neves, Evandro José Cesarino, Adriana Rocha, Séverine Poirier, Vera Lucia Lanchote
Nebivolol is a racemate of the d-isomer responsible for β1 adrenergic receptor antagonism and the l-isomer responsible for the release of nitric oxide from endothelial cells. Nebivolol is mainly metabolized to nebivolol glucuronide, which also contribute to the nebivolol β1 adrenoreceptor antagonism. This study reports the development and validation of an indirect stereoselective method of analysis of nebivolol glucuronides in plasma by LC-MS/MS. The method was applied to the investigation of stereoselectivity in the glucuronidation of nebivolol in elderly hypertensive patients (n=11) CYP2D6 phenotyped as EM and treated with a single oral dose of the racemate...
February 3, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28202680/cross-talk-between-lrrk2-and-pka-implication-for-parkinson-s-disease
#4
REVIEW
Elisa Greggio, Luigi Bubacco, Isabella Russo
Evidence indicates that leucine-rich repeat kinase 2 (LRRK2) controls multiple processes in neurons and glia cells. Deregulated LRRK2 activity due to gene mutation represents the most common cause of autosomal dominant Parkinson's disease (PD). Protein kinase A (PKA)-mediated signaling is a key regulator of brain function. PKA-dependent pathways play an important role in brain homeostasis, neuronal development, synaptic plasticity, control of microglia activation and inflammation. On the other hand, a decline of PKA signaling was shown to contribute to the progression of several neurodegenerative diseases, including PD...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202670/mechanisms-of-lrrk2-dependent-neurodegeneration-role-of-enzymatic-activity-and-protein-aggregation
#5
REVIEW
Md Shariful Islam, Darren J Moore
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202667/lrrk2-from-kinase-to-gtpase-to-microtubules-and-back
#6
REVIEW
Marian Blanca Ramírez, Antonio Jesús Lara Ordóñez, Elena Fdez, Sabine Hilfiker
Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are intimately linked to both familial and sporadic Parkinson's disease. LRRK2 is a large protein kinase able to bind and hydrolyse GTP. A wealth of in vitro studies have established that the distinct pathogenic LRRK2 mutants differentially affect those enzymatic activities, either causing an increase in kinase activity without altering GTP binding/GTP hydrolysis, or displaying no change in kinase activity but increased GTP binding/decreased GTP hydrolysis...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28198656/fungicidal-activity-and-pk-pd-of-caspofungin-as-tools-to-guide-antifungal-therapy-in-a-fluconazole-resistant-c-parapsilosis-candidemia
#7
Carlo Tascini, Emanuela Sozio, Antonello Di Paolo, Giancarlo Tintori, Alessandro Leonildi, Giacomo Bertolino, Franco Carmassi, Enrico Tagliaferri, Francesco Menichetti, Francesco Barchiesi
Candida parapsilosis may be responsible for bloodstream infections (BSI) and it is characterised by an increased incidence of fluconazole resistance. A 75-year old woman with severe comorbidities received the insertion of a peripherally inserted central venous catheter. Fluconazole did not prevent a C. parapsilosis BSI hence caspofungin was started after a nephrotoxic first-line treatment with amphotericin B. The ratio of peak plasma concentration over the minimum inhibitory concentration (Cmax/MIC) was adopted to maximise efficacy of caspofungin...
February 15, 2017: Journal of Chemotherapy
https://www.readbyqxmd.com/read/28193651/in-vivo-pharmacodynamic-evaluation-of-omadacycline-ptk-0796-against-streptococcus-pneumoniae-in-the-murine-pneumonia-model
#8
Alexander J Lepak, Miao Zhao, Karen Marchillo, Jamie VanHecker, David R Andes
Omadacycline is a novel aminomethylcylcine antibiotic in clinical development for community acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the in vivo pharmacodynamic activity of omadacycline against Streptococcus pneumoniae Four strains with varying phenotypic resistance to other antimicrobials including tetracyclines were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28190476/neuroprotective-properties-of-icariin-in-mptp-induced-mouse-model-of-parkinson-s-disease-involvement-of-pi3k-akt-and-mek-erk-signaling-pathways
#9
Wen-Fang Chen, Lin Wu, Zhong-Rui Du, Lei Chen, Ai-Li Xu, Xiao-Han Chen, Ji-Jun Teng, Man-Sau Wong
BACKGROUND: Epimedium sagittatum is a traditional Chinese herb normally which is used to treat the osteoporosis, cardiovascular dysfunction, and to improve neurological and sexual function in China, Korea and Japan. Icariin is the major active ingredient in Epimedium sagittatum. In the present research, we examined the neuroprotective effects of icariin on dopaminergic neurons and the possible mechanisms in a mouse model of Parkinson's disease (PD). METHODS: Ovariectomized PD mice were treated with vehicle or icariin (3 days before MPTP injections) with or without the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or mitogen-activated protein kinase kinase (MEK) inhibitor PD98059...
February 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28183350/pharmacokinetic-and-pharmacodynamic-modeling-of-sarafloxacin-against-avian-pathogenic-escherichia-coli-in-muscovy-ducks
#10
Yang Yu, Yu Feng Zhou, Jian Sun, Wei Shi, Xiao Ping Liao, Ya Hong Liu
BACKGROUND: This study focused on utilizing pharmacokinetics/pharmacodynamics (PK/PD) modeling to optimize therapeutic dosage regimens of sarafloxacin against avian pathogenic Escherichia. coli O78 strain in Muscovy ducks. The ex vivo PK/PD study of sarafloxacin was conducted in Muscovy ducks after intravenous (i.v.) and oral (p.o.) administrations at a single dose of 10 mg/kg bodyweight (BW). The serum samples were analyzed by reverse phase high-performance liquid chromatography (RP-HPLC) using a fluorescence detection method...
February 10, 2017: BMC Veterinary Research
https://www.readbyqxmd.com/read/28182273/association-of-time-varying-clearance-of-nivolumab-with-disease-dynamics-and-its-implications-on-exposure-response-analysis
#11
Chao Liu, Jingyu Yu, Hongshan Li, Jiang Liu, Yuan Xu, Pengfei Song, Qi Liu, Hong Zhao, James Xu, Virginia E Maher, Brian P Booth, Geoffrey Kim, Atiqur Rahman, Yaning Wang
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between post-treatment effects and drug exposure may lead to a biased steep estimate of exposure-response (E-R) relationship for efficacy...
February 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28181260/a-mechanism-based-pharmacokinetic-pharmacodynamic-model-for-bococizumab-a-humanized-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9-and-its-application-in-early-clinical-development
#12
Chandrasekhar Udata, Pamela D Garzone, Barry Gumbiner, Tenshang Joh, Hong Liang, Kai-Hsin Liao, Jason H Williams, Xu Meng
Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies...
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28180234/pharmacokinetics-and-pharmacodynamics-of-tecarfarin-a-novel-vitamin-k-antagonist-oral-anticoagulant
#13
Detlef Albrecht, David Ellis, Daniel M Canafax, Daniel Combs, Pascal Druzgala, Peter G Milner, Mark G Midei
Tecarfarin is a vitamin K antagonist (VKA) with reduced propensity for drug interactions. To evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety of tecarfarin, we performed single ascending dose (SAD) (n=66), multiple ascending dose (MAD) (n=43), and tecarfarin versus warfarin (n=28) studies in human volunteers. In the SAD, tecarfarin was administered to 5 of 6 subjects (1 received placebo) in each of 11 cohorts. AUC0-∞ exhibited linearity and dose proportionality. Elimination T1/2 ranged from 87-136 hours (h) across all doses...
February 9, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28178895/repetitive-urine-and-blood-sampling-in-neonatal-and-weaned-piglets-for-pharmacokinetic-and-pharmacodynamic-modelling-in-drug-discovery-a-pilot-study
#14
Elke Gasthuys, Stijn Schauvliege, Thomas van Bergen, Joske Millecam, Ilaria Cerasoli, Ann Martens, Frank Gasthuys, Tim Vandecasteele, Pieter Cornillie, Wim Van den Broeck, Filip Boyen, Siska Croubels, Mathias Devreese
Piglets are considered to be suitable animal models for predicting the pharmacokinetics and pharmacodynamics (PK/PD) of test drugs for potential use in the paediatric population. Such PK/PD studies require multiple blood and urine samplings. The goal of the present study was to determine a suitable blood collection strategy applicable in the youngest age categories of six days, four weeks and eight weeks of age, as well as a urine collection technique for male piglets in the same age categories. Blood was collected either by a surgically-placed jugular vein catheter (six days old [ n = 4] and four weeks old [ n = 2] piglets) or by direct venepuncture of the jugular vein (four weeks old [ n = 2] and eight weeks old [ n = 4] piglets)...
January 1, 2017: Laboratory Animals
https://www.readbyqxmd.com/read/28162982/revival-of-old-antibiotics-needs-the-state-of-evidence-and-expectations
#15
Hiba Zayyad, Noa Eliakim-Raz, Leonard Leibovici, Mical Paul
The gap between the emergence of antibiotic resistance and new antibiotic development has drawn attention to old antibiotics whose spectrum of coverage frequently comprises highly resistant bacteria. However, these antibiotics have frequently not undergone the structured process of antibiotic development of modern antibiotics, from pharmacokinetic/pharmacodynamic (PK/PD) studies establishing safe and effective dosing, establishment of susceptibility breakpoints, to clinical trials establishing clinical safety and effectiveness...
February 2, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28162585/-343-oliceridine-trv130-a-novel-%C3%AE-receptor-g-protein-pathway-selective-modulator-%C3%AE-gps-demonstrates-a-predictable-relationship-between-plasma-concentrations-and-pain-relief-ii-simulation-of-potential-dosing-regimens-using-a-pharmacokinetic-pharmacodynamic-pk
#16
M Fossler, B Sadler, C Farrell, D Burt, M Pitsiu, F Skobieranda, D Soergel
No abstract text is available yet for this article.
April 2016: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28162584/-342-oliceridine-trv130-a-novel-%C3%AE-receptor-g-protein-pathway-selective-modulator-%C3%AE-gps-demonstrates-a-predictable-relationship-between-plasma-concentrations-and-pain-relief-i-development-of-a-pharmacokinetic-pharmacodynamic-pk-pd-model
#17
M Fossler, B Sadler, C Farrell, D Burt, M Pitsiu, F Skobieranda, D Soergel
No abstract text is available yet for this article.
April 2016: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28161807/what-we-may-expect-from-novel-antibacterial-agents-in-the-pipeline-with-respect-to-resistance-and-pharmacodynamic-principles
#18
REVIEW
Karen Bush, Malcolm G P Page
There are some 43 small molecules in the antibiotic development pipeline from late preclinical stage (7 compounds) through Phase 1 (11 molecules), Phase 2 (13 molecules) to Phase 3 (12 molecules). The majority of these are representatives of established antibiotic classes that have been modified to address problems of resistance. In addition, there is considerable activity around the discovery of novel classes of β-lactamase inhibitors with 10 combinations representing 4 inhibitor classes, at different stages of development...
February 4, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28158894/is-the-inhibition-of-dipeptidyl-peptidase-4-ddp-4-enzyme-route-dependent-and-or-driven-by-high-peak-concentration-seeking-answers-with-zydpla1-a-novel-long-acting-dpp-4-inhibitor-in-a-rodent-model
#19
Harilal Patel, Amit A Joharapurkar, Rajesh Bahekar, Prakash Patel, Samadhan G Kshirsagar, Nirav Modi, Ashok Ghoghari, Vishal J Patel, Mukul R Jain, Nuggehally R Srinivas, Pankaj R Patel, Ranjit C Desai
ZYDPLA1 is a long acting enzyme dipeptidyl peptidase-4 (DPP-4) inhibitor. The comparative effect of DPP-4 inhibition after intravenous (IV) and oral administration of ZYDPLA1 in a rat model was evaluated to answer the question of route dependency and/or the need of high plasma levels of ZYDPLA1. The study was conducted using parallel design in male Wistar rats for IV/oral route (n=9 and 6, for IV and oral respectively). A single 30 mg/kg dose of ZYDPLA1 was administered. Plasma samples were analysed for ZYDPLA1 concentration and DPP-4 inhibition...
February 3, 2017: Drug Research
https://www.readbyqxmd.com/read/28158245/protein-kinase-c-theta-is-required-for-efficient-induction-of-il-10-secreting-t-cells
#20
Graham J Britton, Ruth E Mitchell, Bronwen R Burton, David C Wraith
Secretion of interleukin-10 (IL-10) by CD4+ T cells is an essential immunoregulatory mechanism. The work presented here assesses the role of the signaling molecule protein kinase C theta (PKCθ) in the induction of IL-10 expression in CD4+ T cells. Using wildtype and PKCθ-deficient Tg4 T cell receptor transgenic mice, we implemented a well-described protocol of repeated doses of myelin basic protein (MBP)Ac1-9[4Y] antigen to induce Tr1-like IL-10+ T cells. We find that PKCθ is required for the efficient induction of IL-10 following antigen administration...
2017: PloS One
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