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https://www.readbyqxmd.com/read/29054922/protein-turnover-measurements-in-human-serum-by-serial-immunoaffinity-lc-ms-ms
#1
Vahid Farrokhi, Xiaoying Chen, Hendrik Neubert
BACKGROUND: The half-life of target proteins is frequently an important parameter in mechanistic pharmacokinetic and pharmacodynamic (PK/PD) modeling of biotherapeutics. Clinical studies for accurate measurement of physiologically relevant protein turnover can reduce the uncertainty in PK/PD model-based predictions, for example, of the therapeutic dose and dosing regimen in first-in-human clinical trials. METHODS: We used a targeted mass spectrometry work flow based on serial immunoaffinity enrichment of multiple human serum proteins from a [5,5,5-(2)H3]-L-leucine tracer pulse-chase study in healthy volunteers...
October 20, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/29053231/effects-of-common-cold-and-concomitant-administration-of-nasal-decongestant-on-the-pharmacokinetics-and-pharmacodynamics-of-nasal-glucagon-in-otherwise-healthy-participants-a-randomized-clinical-trial
#2
Cristina B Guzman, Helene Dulude, Claude Piché, Marianne Rufiange, Aziz A Sadoune, Emmanouil Rampakakis, Dolores Carballo, Myriam Triest, Michelle Xiaotian Zhang, Shuyu Zhang, Maryam Tafreshi, Eric Sicard
AIMS: Nasal glucagon (NG) is a nasally-administered glucagon powder, absorbed through the nasal mucosa, designed for treatment of severe hypoglycaemia. This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics (PD) of NG in otherwise healthy participants with common colds and after recovery from cold symptoms, with and without concomitant nasal decongestant. MATERIALS AND METHODS: This was a single-centre, open-label study. Cohort 1 participants (N=18) received two NG doses: one while experiencing nasal congestion and another after recovery from cold symptoms...
October 20, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/29038284/evaluation-of-the-microbiological-efficacy-of-a-single-2-g-dose-of-an-extended-release-azithromycin-by-population-pharmacokinetics-and-simulation-in-japanese-patients-with-gonococcal-urethritis
#3
Midori Soda, Shin Ito, Naoki Matsumaru, Sakiko Nakamura, Izumi Nagase, Hikari Takahashi, Yuta Ohno, Mitsuru Yasuda, Miho Yamamoto, Katsura Tsukamoto, Yoshinori Itoh, Takashi Deguchi, Kiyoyuki Kitaichi
The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2 g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy on gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, AZM minimum inhibitory concentration (MIC) values for Neisseria gonorrhoeae isolates were determined, and microbiological outcomes were assessed...
October 16, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29038275/in-vivo-bioluminescent-monitoring-of-therapeutic-efficacy-and-pharmacodynamic-target-assessment-of-antofloxacin-against-escherichia-coli-in-a-neutropenic-murine-thigh-infection-model
#4
Yu-Feng Zhou, Meng-Ting Tao, Yu-Zhang He, Jian Sun, Ya-Hong Liu, Xiao-Ping Liao
Antimicrobial resistance among uropathogens has increased infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli such as Escherichia coli This study monitored the in vivo efficacy of antofloxacin using bioluminescence imaging and determined pharmacokinetic/pharmacodynamic (PK/PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were performed after subcutaneous antofloxacin administration of 2...
October 16, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29035547/pharmacokinetics-and-pharmacodynamics-of-the-triterpenoid-ursolic-acid-in-regulating-the-anti-oxidant-anti-inflammatory-and-epigenetic-gene-responses-in-rat-leukocytes
#5
Chengyue Zhang, Chao Wang, Wenji Li, Renyi Wu, Yue Guo, David Cheng, Yuqing Yang, Ioannis P Androulakis, Ah-Ng Kong
The triterpenoid ursolic acid (UA) has been proposed as a potential cancer chemopreventive agent in many preclinical and clinical studies. In the present work, we aimed to characterize the pharmacokinetics (PK) of UA and to quantitatively assess the anti-oxidative and anti-inflammatory effects of UA, which are potentially linked to its chemopreventive efficacy. UA was administered intravenously (i.v., 20 mg/kg) or by oral gavage (100 mg/kg) to male Sprague-Dawley rats, and blood samples were collected at a series of designated time points...
October 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29033841/pharmacodynamic-evaluation-and-pk-pd-based-dose-prediction-of-tulathromycin-a-potential-new-indication-for-streptococcus-suis-infection
#6
Yu-Feng Zhou, Hui-Min Peng, Ming-Xiao Bu, Ya-Hong Liu, Jian Sun, Xiao-Ping Liao
Tulathromycin is the first member of the triamilide antimicrobial drugs that has been registered in more than 30 countries. The goal of this study is to provide a potential new indication of tulathromycin for Streptococcus suis infections. We investigated the pharmacokinetic and ex vivo pharmacodynamics of tulathromycin against experimental S. suis infection in piglets. Tulathromycin demonstrated a relatively long elimination half-life (74.1 h) and a mean residence time of 97.6 h after a single intramuscular administration...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29024493/pharmacokinetics-and-pharmacodynamics-of-meloxicam-in-east-asian-populations-the-role-of-ethnicity-on-drug-response
#7
T Aoyama, Y Ishida, M Kaneko, A Miyamoto, Y Saito, M Tohkin, S Kawai, Y Matsumoto
We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population pharmacokinetic (PK) analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 Caucasian) under strictly controlled trial conditions with regulated meals and a single lot of the drug...
October 12, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28993331/evaluation-of-pk-pd-model-based-optimized-combination-regimens-against-multidrug-resistant-pseudomonas-aeruginosa-in-a-murine-thigh-infection-model-using-humanized-dosing-schemes
#8
Rajbharan Yadav, Jürgen B Bulitta, Jiping Wang, Roger L Nation, Cornelia B Landersdorfer
We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical P. aeruginosa isolate using in vitro infection models, mechanism-based PK/PD modeling (MBM) and Monte Carlo simulations. The current study aimed to evaluate these regimens in a neutropenic murine thigh infection model and to characterize the time-course of bacterial killing and regrowth via MBM. We studied monotherapies and combinations of imipenem with tobramycin in vivo against the double-resistant clinical P...
October 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28993326/a-dynamic-stress-model-explains-the-delayed-drug-effect-in-artemisinin-treatment-of-plasmodium-falciparum
#9
Pengxing Cao, Nectarios Klonis, Sophie Zaloumis, Con Dogovski, Stanley C Xie, Sompob Saralamba, Lisa J White, Freya J I Fowkes, Leann Tilley, Julie A Simpson, James M McCaw
Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimisation of dosing regimens and the development of strategies to prolong the lifespan of current first-line treatment options. Recent short drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic(PK-PD) paradigm in which the killing rate depends only on drug concentration...
October 9, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28988505/clinical-and-pharmacokinetic-drug-evaluation-of-delafloxacin-for-the-treatment-of-acute-bacterial-skin-and-skin-structure-infections
#10
Matteo Bassetti, Davide Pecori, Piergiorgio Cojutti, Federico Pea
In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin...
October 9, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28988277/a-physiologically-based-pharmacokinetic-and-pharmacodynamic-pbpk-pd-model-of-the-histone-deacetylase-hdac-inhibitor-vorinostat-for-pediatric-and-adult-patients-and-its-application-for-dose-specification
#11
Daniel Moj, Hannah Britz, Jürgen Burhenne, Clinton F Stewart, Gerlinde Egerer, Walter E Haefeli, Thorsten Lehr
PURPOSE: This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach. METHODS: A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes...
October 7, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28982547/hm10660a-a-long-acting-hifn-%C3%AE-2b-is-a-potent-candidate-for-the-treatment-of-hepatitis-c-through-an-enhanced-biological-half-life
#12
Sungmin Bae, Taehoon Sim, Chaemin Lim, Daejin Kim, Jongsoo Lee, Youngjin Park, Sungyoub Jung, Inyoung Choi, Sechang Kwon, Kyung Taek Oh
Interferon-α (IFN-α) has been widely used for the treatment of infections due to the hepatitis C virus (HCV). Because of the short half-life of IFN-α in serum, it must be administered three times per week. To increase the half-life of IFN-α, the immunoglobulin G4 (IgG4) Fc fragment (HMC001) was conjugated with human IFN-α-2b to develop a long-acting IFN-α-2b, HM10660A. An analysis of the antiviral efficacy of HM10660A in a human hepatocyte-engrafted mouse model found that HM10660A reduced serum HCV titers more effectively than a commercially available peginterferon α-2a (PEGASYS(®)) and IFN-α-2b...
October 2, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28982394/leishmania-and-other-intracellular-pathogens-selectivity-drug-distribution-and-pk-pd
#13
Simon L Croft
New drugs and treatments for diseases caused by intracellular pathogens, such as leishmaniasis and the Leishmania species, have proved to be some of the most difficult to discover and develop. The focus of discovery research has been on the identification of potent and selective compounds that inhibit target enzymes (or other essential molecules) or are active against the causative pathogen in phenotypic in vitro assays. Although these discovery paradigms remain an essential part of the early stages of the drug R & D pathway, over the past two decades additional emphasis has been given to the challenges needed to ensure that the potential anti-infective drugs distribute to infected tissues, reach the target pathogen within the host cell and exert the appropriate pharmacodynamic effect at these sites...
October 6, 2017: Parasitology
https://www.readbyqxmd.com/read/28980026/-bacterial-sepsis-diagnostics-and-calculated-antibiotic-therapy
#14
REVIEW
D C Richter, A Heininger, T Brenner, M Hochreiter, M Bernhard, J Briegel, S Dubler, B Grabein, A Hecker, W A Krüger, K Mayer, M W Pletz, D Störzinger, N Pinder, T Hoppe-Tichy, S Weiterer, S Zimmermann, A Brinkmann, M A Weigand, Christoph Lichtenstern
The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment...
October 4, 2017: Der Anaesthesist
https://www.readbyqxmd.com/read/28975652/pharmacological-versus-classical-approaches-in-the-design-of-first-in-man-clinical-drug-trials
#15
Cornelis A van den Bogert, Adam F Cohen, Hubert G M Leufkens, Joop M A van Gerven
AIMS: To investigate the role of pharmacology in the design of first in man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015. METHODS: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources. The design elements preclinical information, dose calculation, endpoints and dose escalation were assessed on the justification of the chosen approaches...
October 4, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28974368/correlation-of-pharmacokinetics-and-brain-penetration-data-of-adult-zebrafish-with-higher-mammals-including-humans
#16
Pushkar Kulkarni, Raghavender Medishetti, Nagaraju Nune, Swapna Yellanki, Vijaykumar Sripuram, Pallavi Rao, Dharmarajan Sriram, Uday Saxena, Srinivas Oruganti, Perumal Yogeeswari
INTRODUCTION: Adult zebrafish pharmacology is evolving rapidly for creating efficacy and safety models for drug discovery. However, there is very limited research in understanding pharmacokinetics (PK) in adult zebrafish. Methods for understanding PK will help in conducting pharmacokinetic - pharmacodynamic (PK-PD) correlations and improving the quality and applicability of data obtained using zebrafish. METHODS: We conducted adult zebrafish PK and brain penetration studies on two known compounds (irinotecan and lorcaserin) with distinct PK and brain penetration properties using validated LCMS/MS method...
September 30, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28971281/model-informed-pediatric-development-applied-to-bilastine-ontogenic-pk-model-development-dose-selection-for-first-time-in-children-and-pk-study-design
#17
Valvanera Vozmediano, Ander Sologuren, John C Lukas, Nerea Leal, Mónica Rodriguez
PURPOSE: Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years)...
October 2, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28968675/pharmacodynamics-of-the-novel-antifungal-agent-f901318-for-acute-sinopulmonary-aspergillosis-caused-by-aspergillus-flavus
#18
Clara E Negri, Adam Johnson, Laura McEntee, Helen Box, Sarah Whalley, Julie A Schwartz, V Ramos-Martín, Joanne Livermore, Ruwanthi Kolamunnage-Dona, Arnaldo L Colombo, William W Hope
Background: Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics of the lead compound F901318 is required to plan safe and effective regimens for clinical use. Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis...
September 12, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28967873/assessment-of-skin-permeability-to-topically-applied-drugs-by-skin-impedance-and-admittance
#19
Simon Schwingenschuh, Hermann Scharfetter, Orjan Grottem Martinsen, Beate Boulgaropoulos, Thomas Augustin, Katrin Tiffner, Christian Dragatin, Reingard Raml, Christian Hoefferer, Eva-Christina Prandl, Frank Sinner, Martin Hajnsek
<b>Objective </b> Pharmacokinetic and pharmacodynamic studies of topically applied drugs are commonly performed by sampling of interstitial fluid with dermal open flow microperfusion and subsequent analysis of the samples. However, the reliability of results from the measured concentration-time profile of the penetrating drug suffers from highly variable skin permeability to topically applied drugs that is mainly caused by inter- and intra-subject variations of the stratum corneum. Thus, statistically significant results can only be achieved by performing high numbers of experiments...
October 2, 2017: Physiological Measurement
https://www.readbyqxmd.com/read/28964956/in-vivo-infection-models-in-the-pre-clinical-pharmacokinetic-pharmacodynamic-evaluation-of-antimicrobial-agents
#20
REVIEW
David R Andes, Alex J Lepak
Animal infection models serve a critical role in the pre-clinical development of antimicrobials. Thoughtful use of these tools can be useful to design and de-risk subsequent clinical trials. Specifically, pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobials can define the PK/PD driver and target magnitude. In doing so they provide guidance for dosing regimen design and forecast the likelihood of success against target pathogens at the infection site of interest. This review outlines the key design features to consider for successful assessment of experimental output...
September 28, 2017: Current Opinion in Pharmacology
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