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AAPS Journal

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https://www.readbyqxmd.com/read/28526963/incorporation-of-the-time-varying-postprandial-increase-in-splanchnic-blood-flow-into-a-pbpk-model-to-predict-the-effect-of-food-on-the-pharmacokinetics-of-orally-administered-high-extraction-drugs
#1
Rachel H Rose, David B Turner, Sibylle Neuhoff, Masoud Jamei
Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q Splanch) was developed to describe the observed data for healthy individuals...
May 19, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28523515/distribution-of-exogenous-and-endogenous-cyp3a-markers-and-related-factors-in-healthy-males-and-females
#2
Jieon Lee, Andrew HyoungJin Kim, SoJeong Yi, SeungHwan Lee, Seo Hyun Yoon, Kyung-Sang Yu, In-Jin Jang, Joo-Youn Cho
Cytochrome P450 (CYP) 3A is an important drug-metabolizing enzyme in humans. Assessing CYP3A activity is necessary for predicting therapeutic outcomes or the potential adverse events of various therapeutics. This study sought to evaluate the distribution of endogenous and exogenous markers reflecting hepatic CYP3A activity and related factors affecting its activity in healthy male and female. Each subject was given a single 1 mg dose of midazolam intravenously. Pharmacokinetics, pharmacometabolomics, and pharmacogenomics analyses were performed to evaluate CYP3A activity...
May 18, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28516359/evolution-of-choice-of-solubility-and-dissolution-media-after-two-decades-of-biopharmaceutical-classification-system
#3
Nadia Bou-Chacra, Katherine Jasmine Curo Melo, Ivan Andrés Cordova Morales, Erika S Stippler, Filippos Kesisoglou, Mehran Yazdanian, Raimar Löbenberg
The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28516358/mechanistic-modeling-of-the-pharmacodynamic-and-pharmacokinetic-relationship-of-tissue-factor-pathway-inhibitor-neutralizing-antibody-bay-1093884-in-cynomolgus-monkeys
#4
Jian-Ming Gu, Xiao-Yan Zhao, Thomas Schwarz, Joachim Schuhmacher, Andreas Baumann, Elena Ho, Babu Subramanyan, Kathy Tran, Timothy Myles, Chandra Patel, Maria Koellnberger
BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively...
May 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28497318/controlled-ion-release-from-novel-polyester-ceramic-composites-enhances-osteoinductivity
#5
Soheila Ali Akbari Ghavimi, Rama Rao Tata, Andrew J Greenwald, Brittany N Allen, David A Grant, Sheila A Grant, Mark W Lee, Bret D Ulery
Due to the growing number of patients suffering from musculoskeletal defects and the limited supply of and sub-optimal outcomes associated with biological graft materials, novel biomaterials must be created that can function as graft substitutes. For bone regeneration, composite materials that mimic the organic and inorganic phases of natural bone can provide cues which expedite and enhance endogenous repair. Specifically, recent research has shown that calcium and phosphate ions are inherently osteoinductive, so controllably delivering their release holds significant promise for this field...
May 11, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28488175/erratum-to-microdialysis-the-key-to-physiologically-based-model-prediction-of-human-cns-target-site-concentrations
#6
Yumi Yamamoto, Meindert Danhof, Elizabeth C M de Lange
No abstract text is available yet for this article.
May 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28488174/characterization-of-apolipoprotein-c3-apo-c3-lna-dna-impurities-and-degradation-products-by-lc-ms-ms
#7
Olga V Friese, Justin B Sperry, Yan He, Liji Joseph, James A Carroll, Jason C Rouse
Apolipoprotein C3 (Apo C3) LNA/DNA gapmer was evaluated under various stress and formulation conditions for the purpose of its development as a potential biotherapeutic for low density lipoprotein (LDL) lowering. Using ion-pairing (IP) reversed-phase (RP) liquid chromatography ultra-high resolution (UHR) tandem mass spectrometry (IP-RPLC-MS/MS), a combination of accurate mass measurements and collision-induced dissociation enabled in-depth characterization of Apo C3 LNA/DNA oligonucleotide, in particular the inherent impurities following synthesis and degradation products after exposure to stress conditions...
May 9, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28484963/blood-brain-barrier-protection-as-a-therapeutic-strategy-for-acute-ischemic-stroke
#8
Ali Ehsan Sifat, Bhuvaneshwar Vaidya, Thomas J Abbruscato
The blood-brain barrier (BBB) is a vital component of the neurovascular unit (NVU) containing tight junctional (TJ) proteins and different ion and nutrient transporters which maintain normal brain physiology. BBB disruption is a major pathological hallmark in the course of ischemic stroke which is regulated by the actions of different factors working at different stages of cerebral ischemia including matrix metalloproteinases (MMPs), inflammatory modulators, vesicular trafficking, oxidative pathways, and junctional-cytoskeletal interactions...
May 8, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28484962/controlled-release-of-second-generation-mtor-inhibitors-to-restrain-inflammation-in-primary-immune-cells
#9
Emily A Gosselin, Lisa H Tostanoski, Christopher M Jewell
Autoimmune disease occurs when the immune system incorrectly targets the body's own tissue. Inflammatory CD4(+) T cell phenotypes, such as TH1 and TH17, are key drivers of this attack. Recent studies demonstrate treatment with rapamycin-a key inhibitor of the mTOR pathway-can skew T cell development, moving T cell responses away from inflammatory phenotypes and toward regulatory T cells (TREGS). TREGS are important in inducing and maintaining tolerance to self-antigens, creating new potential to treat autoimmune diseases more effectively and specifically...
May 8, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28474310/minipig-and-human-metabolism-of-aldehyde-oxidase-substrates-in-vitro-in-vivo-comparisons
#10
David J Wilkinson, Rosalind L Southall, Mingguang Li, Lisa M Wright, Lindsay J Corfield, Thomas A Heeley, Benjamin Bratby, Ranbir Mannu, Sarah L Johnson, Victoria Shaw, Holly L Friett, Louise A Blakeburn, John S Kendrick, Michael B Otteneder
The importance of aldehyde oxidase (AOX) is becoming increasingly recognized in the prediction of human pharmacokinetic parameters from animal data. The objectives of these studies were to ascertain whether an in vitro-in vivo correlation existed in the clearance and metabolic pathways of AOX substrates and to establish whether the minipig represented an appropriate non-rodent model for man in the pre-clinical development of drugs metabolized by AOX. Using the AOX substrates carbazeran, 6-deoxypenciclovir and zaleplon, clearance was estimated from in vitro depletion experiments with minipig and human liver cytosol and microsomes and scaled before comparison with data generated in parallel in vivo studies in minipigs...
May 4, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28462473/neurovascular-alterations-in-alzheimer-s-disease-transporter-expression-profiles-and-cns-drug-access
#11
Mitchell P McInerney, Jennifer L Short, Joseph A Nicolazzo
Despite a century of steady and incremental progress toward understanding the underlying biochemical mechanisms, Alzheimer's disease (AD) remains a complicated and enigmatic disease, and greater insight will be necessary before substantive clinical success is realised. Over the last decade in particular, a large body of work has highlighted the cerebral microvasculature as an anatomical region with an increasingly apparent role in the pathogenesis of AD. The causative interplay and temporal cascade that manifest between the brain vasculature and the wider disease progression of AD are not yet fully understood, and further inquiry is required to properly characterise these relationships...
May 1, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28455676/metabolic-profile-of-synthetic-cannabinoids-5f-pb-22-pb-22-xlr-11-and-ur-144-by-cunninghamella-elegans
#12
Shimpei Watanabe, Unnikrishnan Kuzhiumparambil, My Ann Nguyen, Jane Cameron, Shanlin Fu
The knowledge of metabolic profile of synthetic cannabinoids is important for the detection of drugs in urinalysis due to the typical absence or low abundance of parent cannabinoids in human urine. The fungus Cunninghamella elegans has been reported to be a useful tool for metabolism study and thus applicability to synthetic cannabinoid metabolism was examined. In this study, 8-quinolinyl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5F-PB-22), 8-quinolinyl 1-pentyl-1H-indole-3-carboxylate (PB-22), [1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (XLR-11) and (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144) were incubated with C...
April 28, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28447295/functional-expression-of-p-glycoprotein-and-organic-anion-transporting-polypeptides-at-the-blood-brain-barrier-understanding-transport-mechanisms-for-improved-cns-drug-delivery
#13
Wazir Abdullahi, Thomas P Davis, Patrick T Ronaldson
Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain...
April 26, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28444562/infliximab-maintenance-dosing-in-inflammatory-bowel-disease-an-example-for-in-silico-assessment-of-adaptive-dosing-strategies
#14
Jessica Wojciechowski, Richard N Upton, Diane R Mould, Michael D Wiese, David J R Foster
Infliximab is an anti-tumour necrosis factor alpha monoclonal antibody used to treat inflammatory diseases. Many patients fail during induction and others respond initially but relapse during maintenance therapy. Although anti-drug antibodies (ADA) are associated with some clinical failures, there is evidence that some failures may be due to subtherapeutic exposure. Adapting doses based on clinical outcomes and trough concentrations can improve response and reduce the proportion that develop ADA, but identification of appropriate doses in the presence of time-varying patient factors is complicated...
April 25, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28439809/site-selection-a-case-study-in-the-identification-of-optimal-cysteine-engineered-antibody-drug-conjugates
#15
L Nathan Tumey, Fengping Li, Brian Rago, Xiaogang Han, Frank Loganzo, Sylvia Musto, Edmund I Graziani, Sujiet Puthenveetil, Jeffrey Casavant, Kimberly Marquette, Tracey Clark, Jack Bikker, Eric M Bennett, Frank Barletta, Nicole Piche-Nicholas, Amy Tam, Christopher J O'Donnell, Hans Peter Gerber, Lioudmila Tchistiakova
As the antibody drug conjugate (ADC) community continues to shift towards site-specific conjugation technology, there is a growing need to understand how the site of conjugation impacts the biophysical and biological properties of an ADC. In order to address this need, we prepared a carefully selected series of engineered cysteine ADCs and proceeded to systematically evaluate their potency, stability, and PK exposure. The site of conjugation did not have a significant influence on the thermal stability and in vitro cytotoxicity of the ADCs...
April 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28421428/how-has-cder-prepared-for-the-nano-revolution-a-review-of-risk-assessment-regulatory-research-and-guidance-activities
#16
Katherine M Tyner, Nan Zheng, Stephanie Choi, Xiaoming Xu, Peng Zou, Wenlei Jiang, Changning Guo, Celia N Cruz
The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration (FDA) was established to assess the potential impact of nanotechnology on drug products. One of the working group's major initiatives has been to conduct a comprehensive risk management exercise regarding the potential impact of nanomaterial pharmaceutical ingredients and excipients on drug product quality, safety, and efficacy. This exercise concluded that current review practices and regulatory guidance are capable of detecting and managing the potential risks to quality, safety, and efficacy when a drug product incorporates a nanomaterial...
April 18, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28397097/blood-brain-barriers-in-obesity
#17
Elizabeth M Rhea, Therese S Salameh, Aric F Logsdon, Angela J Hanson, Michelle A Erickson, William A Banks
After decades of rapid increase, the rate of obesity in adults in the USA is beginning to slow and the rate of childhood obesity is stabilizing. Despite these improvements, the obesity epidemic continues to be a major health and financial burden. Obesity is associated with serious negative health outcomes such as cardiovascular disease, type II diabetes, and, more recently, cognitive decline and various neurodegenerative dementias such as Alzheimer's disease. In the past decade, major advancements have contributed to the understanding of the role of the central nervous system (CNS) in the development of obesity and how peripheral hormonal signals modulate CNS regulation of energy homeostasis...
April 10, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28382544/in-vitro-and-in-vivo-metabolite-identification-studies-for-the-new-synthetic-opioids-acetylfentanyl-acrylfentanyl-furanylfentanyl-and-4-fluoro-isobutyrylfentanyl
#18
Shimpei Watanabe, Svante Vikingsson, Markus Roman, Henrik Green, Robert Kronstrand, Ariane Wohlfarth
New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoro-isobutyrylfentanyl, and furanylfentanyl. All compounds were incubated at 10 μM with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed...
April 5, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28374319/application-of-a-pk-pd-modeling-and-simulation-based-strategy-for-clinical-translation-of-antibody-drug-conjugates-a-case-study-with-trastuzumab-emtansine-t-dm1
#19
Aman P Singh, Dhaval K Shah
Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861-875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models...
April 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28374318/erratum-to-systematic-verification-of-bioanalytical-similarity-between-a-biosimilar-and-a-reference-biotherapeutic-committee-recommendations-for-the-development-and-validation-of-a-single-ligand-binding-assay-to-support-pharmacokinetic-assessments
#20
Joseph C Marini, Michael Anderson, Xiao-Yan Cai, John Chappell, Todd Coffey, Dominique Gouty, Aparna Kasinath, Vera Koppenburg, Philip Oldfield, Shannon Rebarchak, Ronald R Bowsher
No abstract text is available yet for this article.
April 3, 2017: AAPS Journal
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