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Y Dargaud, X Delavenne, D P Hart, S Meunier, P Mismetti
Over the past decades, haemophilia management has continually evolved, with prophylaxis now considered the treatment of choice. Prophylaxis primarily seeks to prevent bleeding and haemarthrosis episodes from occurring and avert the otherwise inevitable haemophilic arthropathy. Yet, numerous unanswered issues remain. These concern dose levels, dosing intervals, ways of integrating variability in bleeding phenotype, patient age, joint status, lifestyle, physical activity, treatment adherence and individual responses to FVIII or FIX concentrates...
March 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Shuyu Zhan, Baoyue Ding, Yu-Er Ruan, Xuan Huang, Guoqiang Liu, Xiaoqing Lv, Xiong Huang, Mingjuan Li, Ninghua Jiang, Qing Shao
Microdialysis is a powerful in vivo sampling technique for pharmacokinetic-pharmacodynamic (PK-PD) modeling of drugs in pre-clinical and clinical studies. However, the noticeable limitations of previous studies using microdialysis were that animals anesthesia in the whole experiment and the combination of microdialysis and blood sampling for drug and (or) effect detection, which can obviously influence PK and PD behavior of drugs. In this study, a simple blood microdialysis sampling system in freely-moving rats was established for simultaneous study of PK and PD of Shengmai injection (SMI) effect on inducing real-time nitric oxide (NO) release on isoproterenol (ISO) induced myocardial ischemia rats...
March 9, 2018: Journal of Pharmaceutical and Biomedical Analysis
Tomas Majtan, Erez M Bublil, Insun Park, Erland Arning, Teodoro Bottiglieri, Frank Glavin, Jan P Kraus
AIMS: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. Here we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice and wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials...
March 8, 2018: Life Sciences
Nicolas Houy, François Le Grand
PURPOSE: We compare the Maximum Tolerated Dose (MTD) and Metronomic Chemotherapy (MC) protocols for temozolomide administration. We develop an innovative methodology for characterizing optimal chemotherapy regimens. METHODS: We use a PK/PD model based on Faivre and coauthors (Faivre et al., 2013) for the pharmacokinetics of temozolomide, as well as the pharmacodynamics of its efficacy. For toxicity, which is measured by the nadir of the normalized absolute neutrophil count, we formalize the myelosuppression effect of temozolomide with the physiological model of Panetta and coauthors (Panetta et al...
March 8, 2018: Journal of Theoretical Biology
Yan Weng, Tetsuya Ishino, Annette Sievers, Saswata Talukdar, Jeffrey R Chabot, Amy Tam, Weili Duan, Kelvin Kerns, Eric Sousa, Tao He, Alison Logan, Darwin Lee, Dongmei Li, Yingjiang Zhou, Barbara Bernardo, Alison Joyce, Mania Kavosi, Denise M O'Hara, Tracey Clark, Jie Guo, Craig Giragossian, Mark Stahl, Roberto A Calle, Ron Kriz, Will Somers, Laura Lin
Pharmacological administration of FGF21 analogues has shown robust body weight reduction and lipid profile improvement in both dysmetabolic animal models and metabolic disease patients. Here we report the design, optimization, and characterization of a long acting glyco-variant of FGF21. Using a combination of N-glycan engineering for enhanced protease resistance and improved solubility, Fc fusion for further half-life extension, and a single point mutation for improving manufacturability in Chinese Hamster Ovary cells, we created a novel FGF21 analogue, Fc-FGF21[R19V][N171] or PF-06645849, with substantially improved solubility and stability profile that is compatible with subcutaneous (SC) administration...
March 9, 2018: Scientific Reports
Jeffrey Baron, Shuntao Cai, Natalie Klein, Burke A Cunha
OBJECTIVE: The clinical effectiveness of tigecycline depends on appropriate use, and PK/PD (pharmacokinetic/pharmacodynamic) parameters related to dose and dosing interval. METHODS: In our 600-bed university-affiliated teaching hospital, we conducted a tigecycline efficacy review over a three-month period in 34 evaluable patients. Parameters assessed included clinical response, cure or treatment failure, once daily as q12h dosing, maintenance dosing, high dose vs...
March 9, 2018: Journal of Clinical Medicine
Alexia F Kalogeropulou, Jing Zhao, Marc F Bolliger, Anna Memou, Shreya Narasimha, Tyler P Molitor, William H Wilson, Hardy J Rideout, R Jeremy Nichols
Autosomal dominant, missense mutations in the Leucine Rich Repeat protein Kinase 2 ( LRRK2 ) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations [N1437H, R1441C/G/H, Y1699C, G2019S], implicating hyperphosphorylation of a substrate in the pathogenesis of disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and substrate of LRRK2...
March 8, 2018: Biochemical Journal
W J van den Brink, T Hankemeier, P H van der Graaf, E C M de Lange
Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man...
March 8, 2018: Expert Opinion on Drug Discovery
Sushant Shengule, Kalyani Kumbhare, Dada Patil, Sanjay Mishra, Kishori Apte, Bhushan Patwardhan
Nisha Amalaki (NA), formulation with Curcuma longa Linn (Turmeric, Haridra, Nisha in Sanskrit; Family: Zingiberaceae) and Phyllanthus emblica Linn (Indian gooseberry, Amlaki in Sanskrit; Family: Phyllanthaceae) which is described for various diseases including diabetes in ayurvedic texts and Nighantus. The aim of the present study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of chemically standardized NA and Curcuminoids (CE) with metformin (MET) in normal and diabetic animals...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jason N Moore, Marc R Gastonguay, Chee M Ng, Susan C Adeniyi-Jones, David E Moody, Wenfang B Fang, Michelle E Ehrlich, Walter K Kraft
Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure...
March 8, 2018: Clinical Pharmacology and Therapeutics
Peijuan Zhu, Sherwin K B Sy, Andrej Skerjanec
This article provides an overview of four case studies to demonstrate the utility of pharmacometric analysis in biosimilar development to help design sensitive clinical pharmacology studies for the demonstration of biosimilarity. The two major factors that determine the sensitivity of a clinical pharmacokinetic/pharmacodynamic (PK/PD) study to demonstrate biosimilarity are the size of the potential difference to be detected (signal) and the inter-subject variability (noise), both of which can be characterized and predicted using pharmacometric approaches...
March 7, 2018: AAPS Journal
Alireza Mohammadi, Vahid Ghasem Amooeian, Ehsan Rashidi
Brain-derived neurotrophic factor (BDNF) is a dominant neurotrophic factor in the brain which plays a crucial role in differentiation, regeneration and plasticity mechanisms. Binding of the BDNF to its high-affinity tropomyosin-related kinase B (TrkB) receptor leads to phosphorylation of TrkB, thus activating the three important downstream intracellular signaling cascades within the neural cells including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), phospholipase C-γ (PLCγ), and mitogen-activated protein kinase/extracellular signal related kinase (MAPK/ERK) pathways...
March 2, 2018: Current Gene Therapy
Ganesh V Sangle, Mohan Patil, Nitin J Deshmukh, Sushant A Shengule, Shantibhushan Kamble, Kiran Kumar Vuppalavanchu, Sushil Kale, Mirza Layeeq Ahmed Baig, Geetchandra Singh, Javed Shaikh, Jitendra Tripathi, P Aravindababu
PURPOSE: Sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes, is reported to be more efficacious in Indian patients than non-Indian patient population. The objective of the study was to evaluate pharmacokinetic and pharmacodynamic (PK/PD) parameters of single-dose sitagliptin 100 mg (Januvia) in healthy Indian male participants. METHOD: In a randomised, single-dose, open-label, three-treatment, three-period, three-sequence, crossover bioavailability study, 18 healthy male participants received single-dose of sitagliptin under fasted and fed conditions...
March 6, 2018: European Journal of Clinical Pharmacology
Maria Goul Andersen, Anders Thorsted, Merete Storgaard, Anders N Kristoffersson, Lena E Friberg, Kristina Öbrink-Hansen
Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin/tazobactam is often used for empiric treatment but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin 4g every 8h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L) and the following PK/PD targets were evaluated: 50% f T>MIC and 100% f T>MIC...
March 5, 2018: Antimicrobial Agents and Chemotherapy
Hajira Bilal, Anton Y Peleg, Michelle P McIntosh, Ian K Styles, Elizabeth B Hirsch, Cornelia B Landersdorfer, Phillip J Bergen
Objectives: To identify the fosfomycin pharmacokinetic (PK)/pharmacodynamic (PD) index (fT>MIC, fAUC/MIC or fCmax/MIC) most closely correlated with activity against Pseudomonas aeruginosa and determine the PK/PD target associated with various extents of bacterial killing and the prevention of emergence of resistance. Methods: Dose fractionation was conducted over 24 h in a dynamic one-compartment in vitro PK/PD model utilizing P. aeruginosa ATCC 27853 and two MDR clinical isolates (CR 1005 and CW 7)...
March 1, 2018: Journal of Antimicrobial Chemotherapy
Andreas Krause, Jochen Zisowsky, Jasper Dingemanse
BACKGROUND: Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. METHODS: The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. RESULTS: Sex, age, and body weight influenced the PK to a statistically significant extent...
February 28, 2018: Pulmonary Pharmacology & Therapeutics
Caixing Wu, Xiaofei Xiang, Yang Yue, Lin Li, Yesen Li, Chong Zhang, Yuhong Xu
PURPOSE: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs were found to be able to target cells that express Toll-like receptor 9 to modulate innate and adaptive immune reactions. But their in vivo application in immunotherapy against cancer has not been successful. We attempted in this study to examine polyethylene-glycol (PEG) conjugated CpG ODNs and investigated their mechanism of immune modulation in anti-cancer therapy. METHODS: CpG-PEG conjugates with different PEG lengths were synthesized...
March 2, 2018: Pharmaceutical Research
Priyanka Dutta, Leila Dargahi, Kara E O'Connell, Ashini Bolia, Banu Ozkan, Andreas W Sailer, Kumlesh K Dev
Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson's disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (γ-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy...
February 26, 2018: Neuroscience Letters
Pekka Talke, Brian J Anderson
AIMS: Alpha-2 agonists are direct peripheral vasoconstrictors by activation of vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer controlled dexmedetomidine infusion in healthy volunteers. METHODS: After local ethics committee approval, we studied 10 healthy volunteers...
March 1, 2018: British Journal of Clinical Pharmacology
Ann E Herman, Leslie W Chinn, Shweta G Kotwal, Elaine R Murray, Rui Zhao, Marilyn Florero, Alyse Lin, Anita Moein, Rena Wang, Meire Bremer, Serika Kokubu, Adrian P Serone, Eva L Hanze, Anders Viberg, Alyssa M Morimoto, Helen R Winter, Tamiko R Katsumoto
GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and non-covalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well-tolerated with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose [SAD] study; ≤250 mg twice daily [BID] and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study)...
February 27, 2018: Clinical Pharmacology and Therapeutics
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