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AAPS Journal

Daniel F Moraga-Espinoza, Eli Eshaghian, Albert Shaver, Hugh D C Smyth
Although high-speed laser imaging is the current standard to characterize the plume angle of suspension-based pressurized metered dose inhalers (pMDIs), this method is limited by the inability to identify the drug content in a droplet and simulate inhalation flow. The Plume Induction Port Evaluator (PIPE) is a modified induction port for cascade impactors that allows for the calculation of the angle of a plume based on direct drug mass quantification rather than indirect droplet illumination under airflow conditions...
July 12, 2018: AAPS Journal
Nikunjkumar Patel, Barbara Wisniowska, Sebastian Polak
QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine...
July 11, 2018: AAPS Journal
Akhil Srivastava, Katherine Moxley, Rachel Ruskin, Danny Natarajan Dhanasekaran, Yan Daniel Zhao, Rajagopal Ramesh
Exosomes have great potential to serve as a source of diagnostic and prognostic biomarkers for endometrial cancer (EC). Urine-derived exosomes from patients with EC and patients with symptoms of EC, but without established EC, were used to evaluate a unique miRNA expression profile. Of the 84 miRNA studied, 57 were amplified in qPCR, suggesting the differential packaging of miRNA in exosomes. Further, hsa-miR-200c-3p was identified to be enriched the most. Various bioinformatics and in silico tools were used to evaluate the biological significance of hsa-miR-200c-3p in EC...
July 9, 2018: AAPS Journal
Moustafa M A Ibrahim, Rikard Nordgren, Maria C Kjellsson, Mats O Karlsson
The purpose of this study was to investigate if model-based post-processing of common diagnostics can be used as a diagnostic tool to quantitatively identify model misspecifications and rectifying actions. The main investigated diagnostic is conditional weighted residuals (CWRES). We have selected to showcase this principle with residual unexplained variability (RUV) models, where the new diagnostic tool is used to scan extended RUV models and assess in a fast and robust way whether, and what, extensions are expected to provide a superior description of data...
July 2, 2018: AAPS Journal
Emilie A G Molins, William J Jusko
The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term...
June 27, 2018: AAPS Journal
Yankang Jing, Yuemin Bian, Ziheng Hu, Lirong Wang, Xiang-Qun Xie
The name of the corresponding author should be 'Xiang-Qun Xie', rather than 'Xiang-Qun Sean Xie'.
June 25, 2018: AAPS Journal
Marilyn N Martinez, Xiongce Zhao
When in vitro dissolution profile variability prohibits the use of the F2 metric, there currently is no satisfactory alternative available. Published reports evaluating alternative approaches such as Multivariate Statistical Distance and use of a bootstrap F2 identify sources of bias that can limit the utility of these alternatives. Within veterinary medicine, an additional complication is the potential magnitude of interlot variability associated with dosage forms containing "natural" ingredients...
June 25, 2018: AAPS Journal
Chunli Chen, Sebastian G Wicha, Rikard Nordgren, Ulrika S H Simonsson
Quantitative evaluation of potential pharmacodynamic (PD) interactions is important in tuberculosis drug development in order to optimize Phase 2b drug selection and ultimately to define clinical combination regimens. In this work, we used simulations to (1) evaluate different analysis methods for detecting PD interactions between two hypothetical anti-tubercular drugs in in vitro time-kill experiments, and (2) provide design recommendations for evaluation of PD interactions. The model used for all simulations was the Multistate Tuberculosis Pharmacometric (MTP) model linked to the General Pharmacodynamic Interaction (GPDI) model...
June 21, 2018: AAPS Journal
Diane R Mould, Richard N Upton, Jessica Wojciechowski, Becky L Phan, Stacy Tse, Marla C Dubinsky
Inflammatory diseases (ID) are incurable, progressive diseases. Literature evidence cites increasing incidence of these diseases worldwide. When treatments with chemical immunosuppressive agents fail, patients are often treated with monoclonal antibodies (MAbs). However, MAb failure rates are generally high, with approximately half the patients being discontinued within 4 years, necessitating switching to another MAb. One potential cause of treatment failure is subtherapeutic exposure. Several studies demonstrated associations between trough MAb concentrations and clinical response, supporting the notion that improving drug exposure may result in improved outcomes...
June 14, 2018: AAPS Journal
Buyun Chen, Liling Liu, Hoangdung Ho, Yuan Chen, Ze Yang, Xiaorong Liang, Jian Payandeh, Brian Dean, Cornelis E C A Hop, Yuzhong Deng
Liling Liu was not noted as the co-first author in the original article. Buyun Chen and Liling Liu contributed equally to the article.
June 6, 2018: AAPS Journal
Navin Goyal, Khadeeja Mohamed, Katie Rolfe, Satty Sahota, Terry Ernest, Stephan Duparc, Maxine Taylor, Linda Casillas, Gavin C K W Koh
Bioavailability/bioequivalence studies supporting clinical drug development or commercial supply of drug formulations are often time, cost, and resource intensive. The drug's pharmacokinetic (PK) variability, systemic half-life, and safety issues may pose additional challenges. The stable isotope label (SIL) approach provides a useful tool to significantly reduce the study size in clinical PK studies. Tafenoquine (TQ) is an 8-aminoquinoline under development for preventing Plasmodium vivax malaria relapse. This SIL study assessed the impact of differences in the in vitro dissolution profiles on in vivo exposure of TQ tablets...
June 4, 2018: AAPS Journal
Rui Zhang, Jake S Kramer, Josiah D Smith, Brittany N Allen, Caitlin N Leeper, Xiaolei Li, Logan D Morton, Fabio Gallazzi, Bret D Ulery
Current vaccine research has shifted from traditional vaccines (i.e., whole-killed or live-attenuated) to subunit vaccines (i.e., protein, peptide, or DNA) as the latter is much safer due to delivering only the bioactive components necessary to produce a desirable immune response. Unfortunately, subunit vaccines are very weak immunogens requiring delivery vehicles and the addition of immunostimulatory molecules termed adjuvants to convey protective immunity. An interesting type of delivery vehicle is peptide amphiphile micelles (PAMs), unique biomaterials where the vaccine is part of the nanomaterial itself...
June 1, 2018: AAPS Journal
Dongwoo Chae, Chung Mo Nam, Joo Hoon Kim, Choong-Kun Lee, Seung-Seob Kim, Hyo Song Kim, Minkyu Jung, Jae Ho Cheong, Hyun Cheol Chung, Sun Young Rha, Kyungsoo Park
The effects of different patient factors and dose levels of chemotherapeutic agents on clinical outcomes in advanced gastric cancer are not as yet fully characterized. We aimed at developing an integrative model that incorporates dose and covariate information to predict tumor growth and patient survival in advanced gastric cancer patients treated with trastuzumab (T), 5-FU(F)/capecitabine (X) (F or X), and cisplatin (P). Sixty-nine patients (training dataset) were used for model building and a separate 86 patients (test dataset) for model validation...
May 29, 2018: AAPS Journal
Alexandros Kourentas, Maria Vertzoni, Vicky Barmpatsalou, Patrick Augustijns, Stefania Beato, James Butler, Rene Holm, Neils Ouwerkerk, Joerg Rosenberg, Tomokazu Tajiri, Christer Tannergren, Mira Symillides, Christos Reppas
The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs...
May 24, 2018: AAPS Journal
Chen Qiu, Hongbin Zhu, Connie Ruzicka, David Keire, Hongping Ye
Penicillins and some non-penicillin β-lactams may cause potentially life-threatening allergic reactions. Thus, possible cross contamination of β-lactams in food or drugs can put people at risk. Therefore, when there is a reasonable possibility that a non-penicillin product could be contaminated by penicillin, the drug products are tested for penicillin contamination. Here, a sensitive and rapid method for simultaneous determination of multiple β-lactam antibiotics using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated...
May 15, 2018: AAPS Journal
Lambertus A Peletier, Johan Gabrielsson
In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target...
May 14, 2018: AAPS Journal
Kristof Vandekerckhove, Andreas Seidl, Hiten Gutka, Manish Kumar, Gyöngyi Gratzl, David Keire, Todd Coffey, Henriette Kuehne
Leading regulatory agencies recommend biosimilar assessment to proceed in a stepwise fashion, starting with a detailed analytical comparison of the structural and functional properties of the proposed biosimilar and reference product. The degree of analytical similarity determines the degree of residual uncertainty that must be addressed through downstream in vivo studies. Substantive evidence of similarity from comprehensive analytical testing may justify a targeted clinical development plan, and thus enable a shorter path to licensing...
May 10, 2018: AAPS Journal
Scott Ferguson, Sera Kim, Christine Lee, Michael Deci, Juliane Nguyen
Exosomes are nano-sized vesicles composed of lipids, proteins, and nucleic acids. Their molecular landscape is diverse, and exosomes derived from different cell types have distinct biological activities. Since exosomes are now being utilized as delivery vehicles for exogenous therapeutic cargoes, their intrinsic properties and biological effects must be understood. We performed miRNA profiling and found substantial differences in the miRNA landscape of prostate cancer (PC3) and human embryonic kidney (HEK) 293 exosomes with little correlation in abundance of common miRNAs (R2  = 0...
April 30, 2018: AAPS Journal
Mohammad Tabrizi, Daping Zhang, Vaishnavi Ganti, Glareh Azadi
With the recent advances in cancer immunotherapy, it is now evident that the antigen-specific activation of the patients' immune responses can be utilized for achieving significant therapeutic benefits. Novel molecules have been developed and promising advances have been achieved in cancer therapy. The recent success of cancer immunotherapy clearly reflects the novelty of the approach and importance of this class of therapeutics. Due to the nature of immunotherapy, i.e., harnessing the patient's immune system, it becomes critical to evaluate the important variables that can guide preclinical development, translational strategies, patient selection, and effective clinical dosing paradigms following single and combination therapies...
April 27, 2018: AAPS Journal
Shannon D Chilewski, Julie Shields, Johanna R Mora, Heather Myler
PEGylation is a modification commonly used to increase the half-life of therapeutic proteins. The strategy for immunogenicity testing of these compounds should include methods to detect both anti-protein and anti-PEG antibodies. We previously reported a method for the detection of anti-PEG antibodies using ProterixBio's (formerly BioScale) acoustic membrane microparticle (AMMP) technology. Our initial method development work showed the assay was capable of detecting antibodies in human serum with a sensitivity of 1 μg/mL with good reproducibility (CV < 7%)...
April 24, 2018: AAPS Journal
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