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Pharmaceutical Research

Vaishnavi Rohitkumar Shah, Pardeep K Gupta
PURPOSE: Despite the fact that r-hGH was first approved for use by FDA in 1995 and the conventional dosage form in the market has a limitation of daily subcutaneous injections, there remains a lack of sustained delivery system in the market. Nutropin depot, a long-acting dosage form of r-hGH was approved for marketing by FDA in 1999, however, it was discontinued in 2004. Since then, unabating efforts have been made to develop biodegradable polymer based formulations for r-hGH delivery...
March 15, 2018: Pharmaceutical Research
Omkara Swami Muddineti, Preeti Kumari, Balaram Ghosh, Swati Biswas
PURPOSE: Transferrin receptor (TfR) is up-regulated in various malignant tumors not only to meet the iron requirement, but also to increase the cell survival via participation in various cellular signaling pathways. Here we explored transferrin as ligand for Poly(ethylene Glycol) (PEG)-ylated vitamin-E/lipid (PE) core micelles (VPM). METHODS: Transferrin modified polymer was synthesized and drug loaded micelles were evaluated in 2D Hela and HepG2 cancer cells for cellular uptake and cytotoxicity and in 3D Hela spheroids for growth inhibition, uptake and penetration studies...
March 14, 2018: Pharmaceutical Research
Tanaya Vaidya, Robert M Straubinger, Sihem Ait-Oudhia
PURPOSE: Trastuzumab combined with Doxorubicin (DOX) demonstrates significant clinical activity in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC). However, emergence of treatment resistance and trastuzumab associated cardiotoxicity remain clinical challenges. In an effort to improve patient outcome, we have developed and evaluated novel tri-functional immunoliposomes (TFIL) that target HER2-receptors on BC cells and CD3-receptors on T-lymphocytes, and deliver DOX...
March 13, 2018: Pharmaceutical Research
Hari R Desu, Laura A Thoma, George C Wood
PURPOSE: Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo...
March 13, 2018: Pharmaceutical Research
Biki Gupta, Bijay Kumar Poudel, Shobha Regmi, Shiva Pathak, Hima Bindu Ruttala, Milan Gautam, Gyeong Jin An, Jee-Heon Jeong, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
PURPOSE: Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells. METHODS: PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy...
March 13, 2018: Pharmaceutical Research
Alexis Viel, Jérôme Henri, Salim Bouchène, Julian Laroche, Jean-Guy Rolland, Jacqueline Manceau, Michel Laurentie, William Couet, Nicolas Grégoire
PURPOSE: The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. METHODS: Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software...
March 12, 2018: Pharmaceutical Research
Yoshiyuki Kubo, Ayumi Nakazawa, Shin-Ichi Akanuma, Ken-Ichi Hosoya
PURPOSE: To investigate the blood-to-retina verapamil transport at the blood-retinal barrier (BRB). METHODS: EverFluor FL Verapamil (EFV) was adopted as the fluorescent probe of verapamil, and its transport across the BRB was investigated with common carotid artery infusion in rats. EFV transport at the inner and outer BRB was investigated with TR-iBRB2 cells and RPE-J cells, respectively. RESULTS: The signal of EFV was detected in the retinal tissue during the weak signal of cell impermeable compound...
March 12, 2018: Pharmaceutical Research
Kimberley Span, Ebel H E Pieters, Wim E Hennink, Annette van der Toorn, Vera Brinks, Rick M Dijkhuizen, Geralda A F van Tilborg
PURPOSE: The aim of this study was to determine the potential of magnetic resonance imaging to evaluate the biodistribution of exogenous iron within 24 h after one single injection of Venofer® (iron sucrose). METHODS: Venofer® was evaluated in vitro for its ability to generate contrast in MR images. Subsequently, iron disposition was assessed in rats with MRI, in vivo up to 3 h and post mortem at 24 h after injection of Venofer®, at doses of 10- and 40 mg/kg body weight (n = 2 × 4), or saline (n = 4)...
March 8, 2018: Pharmaceutical Research
Christine Taylor Brew, James F Blake, Anita Mistry, Fengling Liu, Diana Carreno, Deidre Madsen, YongQi Mu, Martha Mayo, Wilhelm Stahl, David Matthews, Derek Maclean, Steve Harrison
PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models...
March 8, 2018: Pharmaceutical Research
Rosa Chan, Tom De Bruyn, Matthew Wright, Fabio Broccatelli
PURPOSE: Volume of distribution at steady state (Vdss ) is a fundamental pharmacokinetic (PK) parameter driven predominantly by passive processes and physicochemical properties of the compound. Human Vdss can be estimated using in silico mechanistic methods or empirically scaled from Vdss values obtained from preclinical species. In this study the accuracy and the complementarity of these two approaches are analyzed leveraging a large data set (over 150 marketed drugs). METHODS: For all the drugs analyzed in this study experimental in vitro measurements of LogP, plasma protein binding and pKa are used as input for the mechanistic in silico model to predict human Vdss ...
March 8, 2018: Pharmaceutical Research
Jasmin Monpara, Chryso Kanthou, Gillian M Tozer, Pradeep R Vavia
PURPOSE: This work explores synthesis of novel cholesterol derivative for the preparation of cationic liposomes and its interaction with Paclitaxel (PTX) within liposome membrane using molecular dynamic (MD) simulation and in-vitro studies. METHODS: Cholesteryl Arginine Ethylester (CAE) was synthesized and characterized. Cationic liposomes were prepared using Soy PC (SPC) at a molar ratio of 77.5:15:7.5 of SPC/CAE/PTX. Conventional liposomes were composed of SPC/cholesterol/PTX (92:5:3 M ratio)...
March 8, 2018: Pharmaceutical Research
Gulzar Ahmad, Florence Gattacecca, Rana El Sadda, Galina Botchkina, Iwao Ojima, James Egan, Mansoor Amiji
PURPOSE: The main purpose of this study was to formulate an oil-in-water nanoemulsion of a next generation taxoid DHA-SBT-1214 and evaluate its biodistribution and pharmacokinetics. METHODS: DHA-SBT-1214 was encapsulated in a fish oil containing nanoemulsion using a high pressure homogenization method. Following morphological characterization of the nanoemulsions, qualitative and quantitative biodistribution was evaluated in naïve and cancer stem cell-enriched PPT-2 human prostate tumor bearing mice...
March 8, 2018: Pharmaceutical Research
Ammar A Y Almulathanon, Elisabetta Ranucci, Paolo Ferruti, Martin C Garnett, Cynthia Bosquillon
PURPOSE: This study aimed to further explore the mechanisms behind the ability of certain linear polyamidoamines (PAAs) to transfect cells with minimal cytotoxicity. METHODS: The transfection efficiency of DNA complexed with a PAA of a molecular weight over 10 kDa or 25 kDa branched polyethyleneimine (BPEI) was compared in A549 cells using a luciferase reporter gene assay. The impact of endo/lysosomal escape on transgene expression was investigated by transfecting cells in presence of bafilomycin A1 or chloroquine...
March 7, 2018: Pharmaceutical Research
Shima Gholizadeh, Emmy M Dolman, Rebecca Wieriks, Rolf W Sparidans, Wim E Hennink, Robbert J Kok
PURPOSE: Sepantronium bromide (YM155) is a hydrophilic quaternary compound that cannot be administered orally due to its low oral bioavailability; it is furthermore rapidly eliminated via the kidneys. The current study aims at improving the pharmacokinetic profile of YM155 by its formulation in immunoliposomes that can achieve its enhanced delivery into tumor tissue and facilitate uptake in neuroblastoma cancer cells. METHODS: PEGylated YM155 loaded liposomes composed of DPPC, cholesterol and DSPE-PEG2000 were prepared via passive film-hydration and extrusion method...
March 7, 2018: Pharmaceutical Research
Jean-François Ghersi-Egea, Elodie Saudrais, Nathalie Strazielle
Drug bioavailability to the developing brain is a major concern in the treatment of neonates and infants as well as pregnant and breast-feeding women. Central adverse drug reactions can have dramatic consequences for brain development, leading to major neurological impairment. Factors setting the cerebral bioavailability of drugs include protein-unbound drug concentration in plasma, local cerebral blood flow, permeability across blood-brain interfaces, binding to neural cells, volume of cerebral fluid compartments, and cerebrospinal fluid secretion rate...
March 7, 2018: Pharmaceutical Research
Betty Gourdon, Xavier Declèves, Jean-Manuel Péan, Caroline Chemin
PURPOSE: Oral drug delivery using NPs is a current strategy for poorly absorbed molecules. It offers significant improvement in terms of bioavailability. However, the encapsulation of proteins and peptides in polymeric NPs is a challenge. Firstly, the present study focused on the double emulsion process in order to encapsulate the OXY peptide. Then the technique was challenged by a one-step simplified process, the simple emulsion. METHODS: In order to study the influence of formulation and process parameters, factorial experimental designs were carried on...
March 5, 2018: Pharmaceutical Research
Sean M McClure, Patrick L Ahl, Jeffrey T Blue
PURPOSE: The purpose was to evaluate DSF for high throughput screening of protein thermal stability (unfolding/ aggregation) across a wide range of formulations. Particular focus was exploring PROTEOSTAT® - a commercially available fluorescent rotor dye - for detection of aggregation in surfactant containing formulations. Commonly used hydrophobic dyes (e.g. SYPRO™ Orange) interact with surfactants, complicating DSF measurements. METHODS: CRM197 formulations were prepared and analyzed in standard 96-well plate rT-PCR system, using SYPRO™ Orange and PROTEOSTAT® dyes...
March 5, 2018: Pharmaceutical Research
Mitchell P McInerney, Irene Volitakis, Ashley I Bush, William A Banks, Jennifer L Short, Joseph A Nicolazzo
PURPOSE: Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown. METHODS: Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in-cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper...
March 5, 2018: Pharmaceutical Research
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
Daniel S Hsieh, Liang Luo, Yan Xu, Joshua D Engstrom, Qi Gao
PURPOSE: To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co-vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlus™ modeling to predict the amount of PVPVA degradation in vivo. METHODS: The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC)...
February 28, 2018: Pharmaceutical Research
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