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Pharmaceutical Research

Minjee Kim, Sani H Kizilbash, Janice K Laramy, Gautham Gampa, Karen E Parrish, Jann N Sarkaria, William F Elmquist
The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously "leaky" BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents...
July 12, 2018: Pharmaceutical Research
Witold Jamróz, Joanna Szafraniec, Mateusz Kurek, Renata Jachowicz
Growing demand for customized pharmaceutics and medical devices makes the impact of additive manufacturing increased rapidly in recent years. The 3D printing has become one of the most revolutionary and powerful tool serving as a technology of precise manufacturing of individually developed dosage forms, tissue engineering and disease modeling. The current achievements include multifunctional drug delivery systems with accelerated release characteristic, adjustable and personalized dosage forms, implants and phantoms corresponding to specific patient anatomy as well as cell-based materials for regenerative medicine...
July 11, 2018: Pharmaceutical Research
Daniela Monti, Silvia Tampucci, Erica Zucchetti, Carlotta Granchi, Filippo Minutolo, Anna Maria Piras
PURPOSE: The inhibitors of the human isoform 5 of lactate dehydrogenase (hLDH5) have attracted growing interest as efficient anti-cancer agents. In the present paper, the interactions between an efficient hLDH5 inhibitor (N-hydroxyindole-2-carboxylic derivative) and lipid bilayers based on dipalmitoylphosphatidylcholine (DPPC) were investigated. Additionally, since interstitial acidification plays a key role in tumor pathogenesis and tumor drug therapy, the effect of acidic pH was assessed and correlated to DPPC/drug interaction...
July 9, 2018: Pharmaceutical Research
Hua He, Can Liu, Yun Wu, Xinyuan Zhang, Jianghong Fan, Yanguang Cao
PURPOSE: The mechanisms underlying doxorubicin cytotoxicity and cardiotoxicity were broadly explored but remain incompletely understood. A multiscale physiologically-based pharmacokinetic (PBPK) model was developed to assess doxorubicin dispositions at levels of system, tissue interstitial, cell, and cellular organelles. This model was adopted to explore the mechanisms-of-action/toxicity of doxorubicin in humans. METHODS: The PBPK model was developed by analyzing data from mice and the model was verified by scaling up to predict doxorubicin multiscale dispositions in rats and humans...
July 9, 2018: Pharmaceutical Research
Shirley A Aguirre, Hovhannes J Gukasyan, Husam S Younis, Wenhu Huang
PURPOSE: Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety. METHODS: Forty-two Dutch Belted rabbits were anesthetized, and the eyes received a single intravitreal injection of the excipient formulation. Clinical signs and ocular irritation responses were recorded twice daily for 7 days and microscopic evaluation of the eyes, optic nerve, and eyelids was completed at 1-week post treatment. RESULTS: Saline (≥ 300 mOsm and ≤ 592 mOsm at pH 7...
July 9, 2018: Pharmaceutical Research
J Lederhofer, J van Lent, F Bhoelan, Z Karneva, A de Haan, J C Wilschut, T Stegmann
PURPOSE: Characterization of virosomes, in late stage preclinical development as vaccines for Respiratory Syncytial Virus (RSV), with a membrane-incorporated synthetic monophosphoryl lipid A, 3D-PHAD® adjuvant. METHODS: Virosomes were initially formed by contacting a lipid film containing 3D-PHAD® with viral membranes solubilized with the short chain phospholipid DCPC, followed by dialysis, later by adding solubilized 3D-PHAD to viral membranes, or to preformed virosomes from DMSO...
July 3, 2018: Pharmaceutical Research
Giulia Fanesi, Michela Abrami, Francesca Zecchin, Irina Giassi, Elena Dal Ferro, Anja Boisen, Gabriele Grassi, Paolo Bertoncin, Mario Grassi, Paolo Marizza
PURPOSE: This paper is based on the characterization of the rheological and Low Field NMR (LF-NMR) properties of an interpenetrated hydrogel made up by poly(N-vinyl-2-pyrrolidone) and sodium alginate. The final aim is to use the hydrogel as a delivery matrix for liposomes, widely used tools in the drug delivery field. METHODS: Rheology, LF-NMR, TEM, cryo-TEM, confocal laser scanning microscopy and release test were employed to characterize the interpenetrated hydrogel...
July 2, 2018: Pharmaceutical Research
Alexander L Perryman, Jimmy S Patel, Riccardo Russo, Eric Singleton, Nancy Connell, Sean Ekins, Joel S Freundlich
PURPOSE: To advance translational research of potential therapeutic small molecules against infectious microbes, the compounds must display a relative lack of mammalian cell cytotoxicity. Vero cell cytotoxicity (CC50 ) is a common initial assay for this metric. We explored the development of naïve Bayesian models that can enhance the probability of identifying non-cytotoxic compounds. METHODS: Vero cell cytotoxicity assays were identified in PubChem, reformatted, and curated to create a training set with 8741 unique small molecules...
June 29, 2018: Pharmaceutical Research
Felix Weber, Daniel Breustedt, Sonja Schlicht, Claas A Meyer, Jens Niewoehner, Martin Ebeling, Per-Ola Freskgard, Peter Bruenker, Thomas Singer, Michael Reth, Antonio Iglesias
PURPOSE: Administration of therapeutic monoclonal antibodies (mAbs) is frequently accompanied by severe first infusion reactions (FIR). The mechanism driving FIR is still unclear. This study aimed to investigate the cellular and molecular mechanisms causing FIR in humanized mouse models and their potential for evaluating FIR risk in patients. METHODS: Mice humanized for Fc gamma receptors (FcγRs) were generated by recombination-mediated genomic replacement. Body temperature, cytokine release and reactive oxygen species (ROS) were measured to assess FIR to mAbs...
June 27, 2018: Pharmaceutical Research
Indu Javeri, Kaliappanadar Nellaiappan, Charles McNemar, Kirill Yakovlevsky, Amina Soukrati, Phanindra Velisetty, Bijay Misra
PURPOSE: Accurate quantification of the intact proteins, antibodies or peptides and their impurities without interaction to silanols of HPLC column. METHODS: Hydroxypropyl ß Cyclodextrin (HPCD) is added in the mobile phase at different concentrations. Different commercial SEC-HPLC columns and biologics with a molecular weight ranging from 5.8 kDa to 150kDa were assessed with and without cyclodextrin. RESULTS: Addition of non-ionic sugars such as Hydroxypropyl ß Cyclodextrin in the mobile phase, resulted improved peak performance such as theoretical plates, peak resolution, peak width, peak height, and improved quantification of aggregates in biologics such as antibodies Humira and Actemra, and peptides such as insulin...
June 26, 2018: Pharmaceutical Research
Adrian Schmidt, Hans de Waard, Peter Kleinebudde, Markus Krumme
PURPOSE: It was investigated if continuous wet granulation and drying could be combined in a twin-screw granulator with the aim to provide (pre-)dried granules in a single-step process, i.e. in-barrel-drying. METHODS: To have a consistent and robust material propulsion mechanism, a twin-screw granulator was divided into two compartments. One compartment was operated at lower temperature to granulate and to pre-heat the material, while another compartment was operated at very high temperature to evaporate the granulation liquid as rapidly as possible...
June 25, 2018: Pharmaceutical Research
James W McBlane, Parvinder Phul, Michaela Sharpe
PURPOSE: This article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical...
June 25, 2018: Pharmaceutical Research
Christina Karavasili, Emmanuel Panteris, Ioannis S Vizirianakis, Sotirios Koutsopoulos, Dimitrios G Fatouros
PURPOSE: Localized chemotherapy has gained significant impetus for the management of malignant brain tumors. In the present study, we appraised the versatility of an in-situ gel forming self-assembling peptide, ac-(RADA)4 -CONH2 , as a biocompatible delivery depot of the chemotherapeutic drug doxorubicin (DOX) and the anticancer agent curcumin (CUR), respectively. METHODS: The morphology and mechanical properties of ac-(RADA)4 -CONH2 were assessed with scanning electron microscopy (SEM) and rheological studies...
June 25, 2018: Pharmaceutical Research
Xiaobei Wang, Zhenshan Jia, Yosif Almoshari, Subodh M Lele, Richard A Reinhardt, Dong Wang
PURPOSE: Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity...
June 25, 2018: Pharmaceutical Research
Lucija Vuletić, M Zahirul I Khan, Drago Špoljarić, Maja Radić, Biserka Cetina-Čižmek, Jelena Filipović-Grčić
PURPOSE: The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC). METHODS: Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively...
June 22, 2018: Pharmaceutical Research
Ninad Varkhede, Nita Patel, William Chang, Kenneth Ruterbories, M Laird Forrest
PURPOSE: To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. METHODS: Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data...
June 21, 2018: Pharmaceutical Research
Konstantin Tsinman, Oksana Tsinman, Ram Lingamaneni, Saijie Zhu, Bernd Riebesehl, Arnaud Grandeury, Michael Juhnke, Bernard Van Eerdenbrugh
PURPOSE: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature. METHOD: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus...
June 20, 2018: Pharmaceutical Research
Hamdy Abdelkader, Zeinab Fathalla
BACKGROUND: The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need. PURPOSE: In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed. METHODS: Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability...
June 18, 2018: Pharmaceutical Research
Anura S Indulkar, Yi Gao, Shweta A Raina, Geoff G Z Zhang, Lynne S Taylor
PURPOSE: The overall purpose of this study was to understand the impact of different biorelevant media types on solubility and crystallization from supersaturated solutions of model compounds (atazanavir, ritonavir, tacrolimus and cilnidipine). The first aim was to understand the influence of the lecithin content in FaSSIF. As the human intestinal fluids (HIFs) contain a variety of bile salts in addition to sodium taurocholate (STC), the second aim was to understand the role of these bile salts (in the presence of lecithin) on solubility and crystallization from supersaturated solutions, METHODS: To study the impact of lecithin, media with 3 mM STC concentration but varying lecithin concentration were prepared...
June 18, 2018: Pharmaceutical Research
Guangqing Xiao, Christopher Rowbottom, Carri Boiselle, Liang-Shang Gan
PURPOSE: The renal clearance of fampridine (Fampyra®, or Ampyra®) significantly exceeds the glomerular filtration rate, suggesting active renal secretion is likely the major elimination pathway. The goal of this study was to identify the renal transporters that are involved in the renal active secretion, and elucidate the active renal secretion mechanism of fampridine. METHODS: The uptake of fampridine to HEK-293 cells overexpressing human OCT2, MATE1 or MATE2K was determined in the absence and presence of Cimetidine, the prototypical inhibitor of the transporters...
June 18, 2018: Pharmaceutical Research
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