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AAPS Journal

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https://www.readbyqxmd.com/read/27924615/a-model-for-predicting-the-interindividual-variability-of-drug-drug-interactions
#1
M Tod, L Bourguignon, N Bleyzac, S Goutelle
Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc...
December 6, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27924614/gdf11-treatment-attenuates-the-recovery-of-skeletal-muscle-function-after-injury-in-older-rats
#2
Yu Zhou, Neel Sharma, David Dukes, Maria B Myzithras, Priyanka Gupta, Ashraf Khalil, Julius Kahn, Jennifer S Ahlberg, David B Hayes, Michael Franti, Tracy Criswell
Loss of skeletal muscle mass and function results in loss of mobility for elderly patients. Novel therapies that can protect and/or restore muscle function during aging would have profound effects on the quality of life for this population. Growth differentiation factor 11 (GDF11) has been proposed as a "youthful" circulating factor that can restore cardiac, neural, and skeletal muscle functions in aging animals. However, conflicting data has been recently published that casts doubt on these assertions. We used a complex rat model of skeletal muscle injury that physiologically mimics injuries seen in patients; to investigate the ability of GDF11 and to enhance skeletal muscle regeneration after injury in older rats...
December 6, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27913949/epigenetic-cpg-methylation-of-the-promoter-and-reactivation-of-the-expression-of-gstp1-by-astaxanthin-in-human-prostate-lncap-cells
#3
Yuqing Yang, Francisco Fuentes, Limin Shu, Chao Wang, Doug Pung, Wenji Li, Chengyue Zhang, Yue Guo, Ah-Ng Kong
Astaxanthin (AST), a red dietary carotenoid, has synergistic antioxidant effects with polyunsaturated fatty acids at low concentrations via Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2)/antioxidant response element (ARE) signaling. In addition, chromatin remodeling and DNA methylation-based gene silencing represent a common mechanism in prostate carcinogenesis and tumor progression from normal cells to pre-initiated cells and ultimately to invasive carcinoma. Therefore, the control of epigenetic modification and the transcriptional/translational control of the activation of Nrf2 and Nrf2-target genes, including glutathione S-transferases (GSTs), appear to be an important mechanism that protects cells against injuries from oxidative stress and cancer development...
December 2, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27896684/use-of-spray-dried-dispersions-in-early-pharmaceutical-development-theoretical-and-practical-challenges
#4
Jinjiang Li, Dhaval Patel, George Wang
Spray-dried dispersions (SDDs) have become an important formulation technology for the pharmaceutical product development of poorly water-soluble (PWS) compounds. Although this technology is now widely used in the industry, especially in the early-phase development, the lack of mechanistic understanding still causes difficulty in selecting excipients and predicting stability of SDD-based drug products. In this review, the authors aim to discuss several principles of polymer science pertaining to the development of SDDs, in terms of selecting polymers and solvents, optimizing drug loading, as well as assessing physical stability on storage and supersaturation maintenance after dissolution, from both thermodynamic and kinetic considerations...
November 28, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27896683/population-pharmacokinetics-of-an-extended-release-formulation-of-exenatide-following-single-and-multiple-dose-administration
#5
Brenda Cirincione, Jeffrey Edwards, Donald E Mager
Exenatide is a glucagon-like peptide-1 receptor agonist with both immediate- and extended-release (ER) formulations that are approved for the treatment of type 2 diabetes mellitus. Long-term exposure from the ER formulation is achieved through slow peptide release from a degradable microsphere formulation. The goal of this analysis was to develop a pharmacokinetic model for the ER formulation following single and once-weekly multiple-dose administration. Pharmacokinetic data were collected from two clinical trials-one that evaluated single-dose administration of 2...
November 28, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27882487/delivery-of-small-interfering-rna-to-inhibit-vascular-endothelial-growth-factor-in-zebrafish-using-natural-brain-endothelia-cell-secreted-exosome-nanovesicles-for-the-treatment-of-brain-cancer
#6
Tianzhi Yang, Brittany Fogarty, Bret LaForge, Salma Aziz, Thuy Pham, Leanne Lai, Shuhua Bai
Although small interfering RNA (siRNA) holds great therapeutic promise, its delivery to the disease site remains a paramount obstacle. In this study, we tested whether brain endothelial cell-derived exosomes could deliver siRNA across the blood-brain barrier (BBB) in zebrafish. Natural exosomes were isolated from brain endothelial bEND.3 cell culture media and vascular endothelial growth factor (VEGF) siRNA was loaded in exosomes with the assistance of a transfection reagent. While fluorescence-activated cell flow cytometry and immunocytochemistry staining studies indicated that wild-type exosomes significantly increased the uptake of fluorescence-labeled siRNA in the autologous brain endothelial cells, decreased fluorescence intensity was observed in the cells treated with the tetraspanin CD63 antibody-blocked exosome-delivered formulation (p < 0...
November 23, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27873119/validation-of-a-drug-resistant-anti-adalimumab-antibody-assay-to-monitor-immunogenicity-in-the-presence-of-high-concentrations-of-adalimumab
#7
Sumin Bian, Marc Ferrante, Ann Gils
With respect to patient safety and long-term efficacy, immunogenicity of therapeutic antibodies remains an important issue. Pre-treatment of samples using either higher temperature or acidification in order to separate drug/anti-drug antibody complexes has been implemented in the traditional bridging assay and an in-house-developed affinity capture elution assay but only a limited drug tolerance was obtained. In this study, we aim to apply a drug-resistant anti-drug antibody assay to adalimumab through a combination of adalimumab/anti-adalimumab antibody complex precipitation and acid dissociation...
November 21, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27873118/current-update-of-a-carboxymethylcellulose-peg-conjugate-platform-for-delivery-of-insoluble-cytotoxic-agents-to-tumors
#8
Yang Yang, Joseph Bteich, Shyh-Dar Li
Cytotoxic chemotherapeutic agents are used as the standard therapy for a range of significant cancers, but many of these drugs suffer from poor water solubility and low selectivity, limiting their clinical efficacy. To overcome these shortcomings, Cellax™ drug delivery platform was developed. Cellax™ is a polymer-based nanoparticle drug delivery system designed to solubilize hydrophobic drugs and target them to solid tumors, thereby enhancing the efficacy and reducing the side effects. Cellax-docetaxel (Cellax-DTX) displayed improved pharmacokinetic, safety, and efficacy profiles compared to native DTX (Taxotere®) and Nab-paclitaxel (Nab-PTX, Abraxane®) in multiple animal models...
November 21, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27873117/mitigation-of-pre-existing-antibodies-to-a-biotherapeutic-in-non-clinical-species-when-establishing-anti-drug-antibody-assay-cutpoint
#9
Seema C Kumar, Jason A DelCarpini, Qiang Qu, Martin Kane, Boris Gorovits
Biotherapeutics are known for their potential to induce drug specific immune responses, which are commonly evaluated by the detection of anti-drug antibodies (ADAs). For some biotherapeutics, pre-existing ADAs against drug have been observed in drug-naïve matrix. The presence of pre-existing drug specific antibodies may significantly complicate assessment of the screening ADA assay cutpoint value, which is usually established based on the statistical analysis of signal distribution from the drug-naïve individuals...
November 21, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27844404/erratum-to-intra-articular-injection-of-urinary-bladder-matrix-reduces-osteoarthritis-development
#10
Heather N Jacobs, Sona Rathod, Matthew T Wolf, Jennifer H Elisseeff
No abstract text is available yet for this article.
November 14, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27834047/physiologically-based-pharmacokinetic-pbpk-modeling-of-pharmaceutical-nanoparticles
#11
Min Li, Peng Zou, Katherine Tyner, Sau Lee
With the great interests in the discovery and development of drug products containing nanoparticles, there is a great demand of quantitative tools for assessing quality, safety, and efficacy of these products. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches provide excellent tools for describing and predicting in vivo absorption, distribution, metabolism, and excretion (ADME) of nanoparticles administered through various routes. PBPK modeling of nanoparticles is an emerging field, and more than 20 PBPK models of nanoparticles used in pharmaceutical products have been published in the past decade...
November 10, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27822601/nanomaterial-drug-products-manufacturing-and-analytical-perspectives
#12
Christie M Sayes, Grace V Aquino, Anthony J Hickey
The increasing use of nanotechnology, including nanoparticles, in the preparation of drug products requires both manufacturing and analytical considerations in order to establish the quality metrics suitable for performance and risk assessment. A range of different nanoparticle systems exists including (but not limited to) nano-drugs, nano-additives, and nano-carriers. These systems generally require more complex production and characterization strategies than conventional pharmaceutical dosage forms. The advantage of using nanoparticle systems in pharmaceutical science is that the effective and desired function of the material can be designed through modern manufacturing processes...
November 7, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27822600/clarithromycin-midazolam-and-digoxin-application-of-pbpk-modeling-to-gain-new-insights-into-drug-drug-interactions-and-co-medication-regimens
#13
Daniel Moj, Nina Hanke, Hannah Britz, Sebastian Frechen, Tobias Kanacher, Thomas Wendl, Walter Emil Haefeli, Thorsten Lehr
Clarithromycin is a substrate and mechanism-based inhibitor of cytochrome P450 (CYP) 3A4 as well as a substrate and competitive inhibitor of P-glycoprotein (P-gp) and organic anion-transporting polypeptides (OATP) 1B1 and 1B3. Administered concomitantly, clarithromycin causes drug-drug interactions (DDI) with the victim drugs midazolam (CYP3A4 substrate) and digoxin (P-gp substrate). The objective of the presented study was to build a physiologically based pharmacokinetic (PBPK) DDI model for clarithromycin, midazolam, and digoxin and to exemplify dosing adjustments under clarithromycin co-treatment...
November 7, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27800573/pharmacokinetic-modeling-and-monte-carlo-simulation-to-predict-interindividual-variability-in-human-exposure-to-oseltamivir-and-its-active-metabolite-ro-64-0802
#14
Mototsugu Ito, Hiroyuki Kusuhara, Atsushi Ose, Tsunenori Kondo, Kazunari Tanabe, Hideki Nakayama, Shigeru Horita, Takuya Fujita, Yuichi Sugiyama
Oseltamivir (Tamiflu®) is a prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. There is a possible relationship between oseltamivir treatment and neuropsychiatric adverse events; although this has not been established, close monitoring is recommended on the prescription label. The objective of this study was to predict interindividual variability of human exposure to oseltamivir and its active metabolite Ro 64-0802. By leveraging mathematical models and computations, physiological parameters in virtual subjects were generated with population means and coefficient of variations collected from the literature or produced experimentally...
October 31, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27796911/accelerating-regulated-bioanalysis-for-biotherapeutics-case-examples-using-a-microfluidic-ligand-binding-assay-platform
#15
Rong Liu, Brian Hoffpauir, Shannon D Chilewski, Janice Gamberdella, Uma Kavita, Jia Duo, Carol Gleason, Yan Zhang, Renuka Pillutla, Binodh DeSilva, Lora Hamuro
The Gyrolab™ xP is a microfluidic platform for conducting ligand binding assays (LBAs) and is recognized for its utility in discovery bioanalysis. However, few reports have focused on the technology for regulated bioanalysis. This technology has the advantage of low reagent consumption, low sample volume, and automated ligand binding methods. To improve bioanalysis testing timelines and increase the speed at which biotherapeutics are delivered to patients, we evaluated the technology for its potential to deliver high-quality data at reduced testing timelines for regulated bioanalysis...
October 27, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27796910/role-of-hla-dp-in-the-presentation-of-epitopes-from-the-truncated-bacterial-pe38-immunotoxin
#16
Ronit Mazor, Selamawit Addissie, Youjin Jang, Chin-Hsien Tai, Jeremy Rose, Fran Hakim, Ira Pastan
Identification of helper T-cell epitopes is important in many fields of medicine. We previously used an experimental approach to identify T-cell epitopes in PE38, a truncated bacterial toxin used in immunotoxins. Here, we evaluated the ability of antibodies to DR, DP, or DQ to block T-cell responses to PE38 epitopes in 36 PBMC samples. We predicted the binding affinities of peptides to DR, DP, and DQ alleles using computational tools and analyzed their ability to predict the T-cell epitopes. We found that HLA-DR is responsible for 65% of the responses, DP 24%, and DQ 4%...
October 27, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27785749/revealing-the-neuroendocrine-response-after-remoxipride-treatment-using-multi-biomarker-discovery-and-quantifying-it-by-pk-pd-modeling
#17
Willem J van den Brink, Yin C Wong, Berfin Gülave, Piet H van der Graaf, Elizatbeth C M de Lange
To reveal unknown and potentially important mechanisms of drug action, multi-biomarker discovery approaches are increasingly used. Time-course relationships between drug action and multi-biomarker profiles, however, are typically missing, while such relationships will provide increased insight in the underlying body processes. The aim of this study was to investigate the effect of the dopamine D2 antagonist remoxipride on the neuroendocrine system. Different doses of remoxipride (0, 0.7, 5.2, or 14 mg/kg) were administered to rats by intravenous infusion...
October 26, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27783266/bringing-curcumin-to-the-clinic-in-cancer-prevention-a-review-of-strategies-to-enhance-bioavailability-and-efficacy
#18
Rama I Mahran, Magda M Hagras, Duxin Sun, Dean E Brenner
Cancer is still a major cause of death all over the world. Its incidence and prevalence are increasing drastically. Cancer treatment imposes high socioeconomic burden with little impact especially on aggressive types of cancer. Reversing or delaying carcinogenesis "cancer chemoprevention" by purified or extracted natural products is a cost-effective alternative. Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects...
October 25, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27778194/intra-articular-injection-of-urinary-bladder-matrix-reduces-osteoarthritis-development
#19
Heather N Jacobs, Sona Rathod, Matthew Wolf, Jennifer H Elisseeff
Micronized porcine urinary bladder matrix (UBM) is an extracellular matrix biomaterial that has immunomodulatory and pro-regenerative properties. The objective of this study was to assess the ability of UBM to alter disease progression in a mouse model of post-traumatic osteoarthritis (OA). Ten-week-old wild-type C57BL/6 male mice underwent anterior cruciate ligament transection (ACLT) to induce OA. Two weeks after ACLT, UBM (50 mg/mL) or saline was injected into the mouse joint. At 4 and 8 weeks post-ACLT, cartilage integrity was assessed using OARSI scoring of histology, pain was evaluated, and joints were harvested for quantitative RT-PCR analysis of cartilage-specific and inflammatory gene expression...
October 24, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27770277/erratum-to-computational-advances-for-the-development-of-allosteric-modulators-and-bitopic-ligands-in-g-protein-coupled-receptors
#20
Zhiwei Feng, Guanxing Hu, Shifan Ma, Xiang-Qun Xie
No abstract text is available yet for this article.
October 21, 2016: AAPS Journal
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