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https://www.readbyqxmd.com/read/27925651/model-based-dose-selection-for-intravaginal-ring-formulations-releasing-anastrozole-and-levonorgestrel-intended-for-the-treatment-of-endometriosis-symptoms
#1
Isabel Reinecke, Marcus-Hillert Schultze-Mosgau, Rüdiger Nave, Heinz Schmitz, Bart A Ploeger
Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects...
December 7, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27919590/rebuttal-to-the-manuscript-by-r-j-porter-epires-d-16-00150
#2
D G A Kasteleijn-Nolst Trenité
Development of new effective medicines for patients, who continue to have seizures or experience unwanted side-effects, is an important goal. The human "Photosensitivity Model", a POC study, helps to achieve this goal by providing accurate PharmacoKinetic / PharmcoDynamic (PK/PD) data in epilepsy patients at a very early stage and in a highly controlled, standardized and safe setting (in- hospital video-EEG photic stimulation tests and single-dose AED administration). All information referred to in this rebuttal is based on evidence and not on personal communication...
November 27, 2016: Epilepsy Research
https://www.readbyqxmd.com/read/27917692/once-daily-high-dose-tigecycline-pharmacokinetic-pharmacodynamic-based-dosing-for-optimal-clinical-effectiveness-dosing-matters-revisited
#3
Burke A Cunha, Jeffrey Baron, Cheston B Cunha
Tigecycline has emerged as first line therapy for serious systemic infections due to important pathogens (except P. aeruginosa and Proteus sp.), including multi-drug resistant (MDR) and Gram negative bacilli (GNB), including carbapenem resistant Enterobacteriae. Tigecycline has a "low resistance potential," is protective against C. difficile, and is often the only antibiotic effective against MDR GNB, e.g., Klebsiella sp. Areas covered: Standard dose tigecycline therapy has been used for intra-abdominal infections, complicated skin/skin structure infections (cSSSIs), and CAP...
December 3, 2016: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/27917367/the-role-of-interaction-model-in-simulation-of-drug-interactions-and-qt-prolongation
#4
REVIEW
Barbara Wiśniowska, Sebastian Polak
Computational modelling is a cornerstone of Comprehensive In Vitro Proarrhythmia Assay and is re-increasingly being used in drug development. Electrophysiological effects of drug-drug interactions can be predicted in silico, e.g. with the use of in vitro cardiac ion channel data, PK profiles and human ventricular cardiomyocyte models. There are, however, several approaches with different assumptions used to assess the combined effect of multiple drugs, and there is no agreed standard interaction model. The aim of this study was to assess whether the choice of the drug-drug interaction (DDI) model (Bliss independence, Loewe additivity, or simple sum) influences the results of QT interval simulation trial...
2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/27916558/role-of-carvacrol-in-cardioprotection-against-myocardial-ischemia-reperfusion-injury-in-rats-through-activation-of-mapk-erk-and-akt-enos-signaling-pathways
#5
Yunping Chen, Lina Ba, Wei Huang, Yan Liu, Hao Pan, E Mingyao, Pilong Shi, Ye Wang, Shuzhi Li, Hanping Qi, Hongli Sun, Yonggang Cao
Carvacrol (CAR) is a compound isolated from some essential oils, many studies have demonstrated its therapeutic potential on different diseases. This study aims to evaluate the protective effect of CAR against myocardial ischemia/reperfusion (I/R) injury in rats. Male adult rats underwent ligation of the left anterior descending coronary artery (LAD) in I/R models. Rats were treated with CAR after LAD. The levels of I/R- induced infarct size, cardiomyocyte apoptosis and cardiac functional impairment were examined...
December 1, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27910712/development-of-a-nanogel-formulation-for-transdermal-delivery-of-tenoxicam-a-pharmacokinetic-pharmacodynamic-modeling-approach-for-quantitative-prediction-of-skin-absorption
#6
Mohammed H Elkomy, Shahira F El Menshawe, Hussein M Eid, Ahmed M A Ali
This study investigates potentials of solid lipid nanoparticles (SLN) based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetics-pharmacodynamics (PK-PD) modeling approach for predicting concentration-time profile in skin. A 2(3) factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan induced rat paw edema test...
December 2, 2016: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/27906179/pink1-dependent-phosphorylation-of-pink1-and-parkin-is-essential-for-mitochondrial-quality-control
#7
Na Zhuang, Lin Li, She Chen, Tao Wang
Mitochondrial dysfunction has been linked to the pathogenesis of a large number of inherited diseases in humans, including Parkinson's disease, the second most common neurodegenerative disorder. The Parkinson's disease genes pink1 and parkin, which encode a mitochondrially targeted protein kinase, and an E3 ubiquitin ligase, respectively, participate in a key mitochondrial quality-control pathway that eliminates damaged mitochondria. In the current study, we established an in vivo PINK1/Parkin-induced photoreceptor neuron degeneration model in Drosophila with the aim of dissecting the PINK1/Parkin pathway in detail...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27905842/airway-smooth-muscle-cells-from-ovalbumin-sensitized-mice-show-increased-proliferative-response-to-tgf%C3%AE-1-due-to-up-regulation-of-smad3-and-tgf%C3%AE-rii
#8
Jianting Shi, Ming Chen, Lihua Ouyang, Linjie Huang, Xiaoling Lin, Wei Zhang, Ruiyun Liang, Zhiqiang Lv, Shanying Liu, Shanping Jiang
Transforming growth factor (TGF)-β1 is an important cytokine in airway remodeling in asthma. However, results of studies focusing on the effect of TGFβ1 on proliferation of airway smooth muscle cells (ASMCs) are controversial. This study aimed to elucidate the role of TGFβ1 signaling in the proliferation of ASMCs by establishing an allergic model that mimics airway remodeling in chronic asthma and cell culture. Cell proliferation was detected by viable cell counting and Cell Counting Kit (CCK)-8 analysis...
December 1, 2016: Journal of Asthma: Official Journal of the Association for the Care of Asthma
https://www.readbyqxmd.com/read/27904098/relationship-between-pk-pd-of-cefepime-and-clinical-outcome-in-febrile-neutropenic-patients-with-normal-renal-function
#9
Yoshiko Yamashita, Hidekazu Kamiyama, Asuka Yamamoto, Hiroki Kanoh, Yoshimitsu Yuhki, Akira Ueda, Yukari Kawamoto, Yoshikazu Gotoh, Satoshi Yamamoto
 The efficacy of cefepime (CFPM) is known to depend on the ratio of the time that the serum levels exceed the minimum inhibitory concentration (MIC) to the dosing interval (%T>MIC). The objective of this study was to clarify the relation between %T>MIC and clinical outcome of CFPM, and to identify the optimal dosage regimen. We investigated the outcome of CFPM treatment for febrile neutropenia (FN) patients with normal renal function. Treatment success was defined as the completion of FN therapy with CFPM only...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/27902884/synthesis-and-biological-evaluation-of-new-triazolo-and-imidazolopyridine-ror%C3%AE-t-inverse-agonists
#10
Samuel Hintermann, Christine Guntermann, Henri Mattes, David A Carcache, Juergen Wagner, Anna Vulpetti, Andreas Billich, Janet Dawson, Klemens Kaupmann, Joerg Kallen, Rowan Stringer, David Orain
Retinoic-acid-related orphan receptor γt (RORγt) is a key transcription factor implicated in the production of pro-inflammatory Th17 cytokines, which drive a number of autoimmune diseases. Despite diverse chemical series having been reported, combining high potency with a good physicochemical profile has been a very challenging task in the RORγt inhibitor field. Based on available chemical structures and incorporating in-house knowledge, a new series of triazolo- and imidazopyridine RORγt inverse agonists was designed...
November 30, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27900601/rna-seq-expression-analysis-of-enteric-neuron-cells-with-rotenone-treatment-and-prediction-of-regulated-pathways
#11
Qiang Guan, Xijin Wang, Yanyan Jiang, Lijuan Zhao, Zhiyu Nie, Lingjing Jin
The enteric nervous system (ENS) is involved in the initiation and development of the pathological process of Parkinson's disease (PD). The effect of rotenone on the ENS may trigger the progression of PD through the central nervous system (CNS). In this study, we used RNA-sequencing (RNA-seq) analysis to examine differential expression genes (DEGs) and pathways induced by in vitro treatment of rotenone in the enteric nervous cells isolated from rats. We identified 45 up-regulated and 30 down-regulated genes...
November 30, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27895516/a-prospective-observational-study-comparing-the-pk-pd-relationships-of-generic-meropenem-mercide-%C3%A2-to-the-innovator-brand-in-critically-ill-patients
#12
Mervyn Mer, Jacques Rene Snyman, Constance Elizabeth Jansen van Rensburg, Jacob John van Tonder, Ilze Laurens
INTRODUCTION: Clinicians' skepticism, fueled by evidence of inferiority of some multisource generic antimicrobial products, results in the underutilization of more cost-effective generics, especially in critically ill patients. The aim of this observational study was to demonstrate equivalence between the generic or comparator brand of meropenem (Mercide(®)) and the leading innovator brand (Meronem(®)) by means of an ex vivo technique whereby antimicrobial activity is used to estimate plasma concentration of the active moiety...
2016: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/27895011/evaluation-of-fluoroquinolone-activity-against-emergence-of-resistant-salmonella-enterica-serovar-typhimurium-using-in-vitro-dynamic-models
#13
Seung-Jin Lee, Elias Gebru Awji, Na-Hye Park, Seung-Chun Park
The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) using in vitro dynamic models, and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR) and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug- exposure were quantified...
November 28, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27892793/physiologically-based-modeling-to-predict-the-clinical-behavior-of-monoclonal-antibodies-directed-against-lymphocyte-antigens
#14
Patrick M Glassman, Joseph P Balthasar
Many clinically approved and investigational monoclonal antibody (mAb)-based therapeutics are directed against proteins located in the systemic circulation, including cytokines, growth factors, lymphocyte proteins, and shed antigens. Interaction between mAb and target may lead to non-linear pharmacokinetics (PK), characterized by rapid, target-mediated elimination. Several groups have reported that determinants of target-mediated elimination could include mAb-target binding, target expression, and target turnover...
November 28, 2016: MAbs
https://www.readbyqxmd.com/read/27890708/fbxl18-targets-lrrk2-for-proteasomal-degradation-and-attenuates-cell-toxicity
#15
Xiaodong Ding, Sandeep K Barodia, Lisha Ma, Matthew S Goldberg
Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations...
November 24, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27887963/animal-models-in-the-pharmacokinetic-pharmacodynamic-evaluation-of-antimicrobial-agents
#16
Miao Zhao, Alexander J Lepak, David R Andes
Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials...
November 9, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27879128/local-controllability-and-optimal-control-for-a-model-of-combined-anticancer-therapy-with-control-delays
#17
Jerzy Klamka, Helmut Maurer, Andrzej Swierniak
We study some control properties of a class of two-compartmental models of response to anticancer treatment which combines anti-angiogenic and cytotoxic drugs and take into account multiple control delays. We formulate sufficient local controllability conditions for semilinear systems resulting from these models. The control delays are related to PK/PD effects and some clinical recommendations, e.g., normalization of the vascular network. The optimized protocols of the combined therapy for the model, considered as solutions to an optimal control problem with delays in control, are found using necessary conditions of optimality and numerical computations...
February 1, 2017: Mathematical Biosciences and Engineering: MBE
https://www.readbyqxmd.com/read/27872075/pharmacokinetic-pharmacodynamic-evaluation-of-gepotidacin-against-gram-positive-organisms-using-data-from-murine-infection-models
#18
Catharine C Bulik, Ólanrewaju O Okusanya, Elizabeth A Lakota, Alan Forrest, Sujata M Bhavnani, Jennifer L Hoover, David R Andes, Paul G Ambrose
Gepotidacin (formerly GSK2140944) is a novel triazaacenaphthylene bacterial topoisomerase inhibitor with in vitro activity against conventional and biothreat pathogens, including Staphylococcus aureus and Streptococcus pneumoniae Using neutropenic murine thigh- and lung-infection models, the pharmacokinetics-pharmacodynamics (PK-PD) of gepotidacin against S. aureus and S. pneumoniae were characterized. Single dose PK data from uninfected mice (16-128 mg/kg SC) were fit with candidate models. Dose-fractionation studies (one isolate/organism; 2-512 mg/kg/day) and dose-ranging studies (5 isolates/organism; 2-2048 mg/kg/day; MIC ranges: S...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27872070/estimation-of-the-in-vivo-minimum-inhibitory-concentration-of-cipargamin-in-uncomplicated-plasmodium-falciparum-malaria
#19
Hien Tinh Tran, Nicholas J White, Thuy-Nhien Thanh Nguyen, Hoa Thi Nhu, Thuan Duc Phung, Joel Tarning, François Nosten, Baldur Magnusson, Jay Prakash Jain, Kamal Hamed
The minimum inhibitory concentration (MIC) of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure cure of malaria the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate polymerase chain reaction quantitation of low-density malaria parasitemia enables prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects, and now allows identification of the in-vivo MIC...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27867002/trametinib-plus-4-methylumbelliferone-exhibits-antitumor-effects-by-erk-blockade-and-cd44-downregulation-and-affects-pd1-and-pd-l1-in-malignant-pleural-mesothelioma
#20
Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Ikuko Torii, Takashi Nakano, Primo N Lara, David R Gandara, Hiroshi Date, Seiki Hasegawa
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase (MAPK) pathway plays a critical role in the regulation of tumorigenesis. Hyaluronan (HA) is a major component of the extracellular matrix, and elevated HA levels, with a concurrent increase in malignant properties, are associated with MPM. METHODS: We evaluated the effects of trametinib, a MAPK kinase enzyme (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo...
November 17, 2016: Journal of Thoracic Oncology
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