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Molecular Pharmaceutics

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https://www.readbyqxmd.com/read/28937226/diblock-terpolymers-are-tunable-and-ph-responsive-vehicles-to-increase-hydrophobic-drug-solubility-for-oral-administration
#1
Swapnil Tale, Anatolii A Purchel, Molly C Dalsin, Theresa M Reineke
Synthetic polymers offer tunable platforms to create new oral drug delivery vehicles (excipients) to increase solubility, supersaturation maintenance, and bioavailability of poorly aqueous soluble pharmaceutical candidates. Five well-defined diblock terpolymers were synthesized via reversible addition-fragmentation chain transfer polymerization (RAFT) and consist of a first block of either poly(ethylene-alt-propylene) (PEP), poly(N-isopropylacrylamide) (PNIPAm), or poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA) and a second hydrophilic block consisting of a gradient copolymer of N,N-dimethylacrylamide (DMA) and 2-methacrylamidotrehalose (MAT)...
September 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28937221/in-vivo-dissolution-and-systemic-absorption-of-immediate-release-ibuprofen-in-human-gastrointestinal-tract-under-fed-and-fasted-conditions
#2
Duxin Sun, Jason R Baker, Bo Wen, Ann Frances, Huixia Zhang, Alex Yu, Ting Zhao, Yasuhiro Tsume, Manjunath Pai, Barry Bleske, Xinyuan Zhang, R Lionberger, Allen Lee, Gordon Amidon, William L Hasler, Mark Koenigsknecht
PURPOSE: In vivo drug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study was to evaluate the in vivo drug dissolution and systemic absorption of the BCS Class IIa drug ibuprofen under fed and fasted conditions by direct sampling of stomach and small intestinal luminal content. Expanding current knowledge of drug dissolution in vivo will help to establish physiologically relevant in vitro models predictive of drug dissolution. METHODS: A multi-lumen GI catheter was orally inserted into the GI tract of healthy human subjects...
September 22, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28933554/rational-targeting-of-cellular-cholesterol-in-diffuse-large-b-cell-lymphoma-dlbcl-enabled-by-functional-lipoprotein-nanoparticles-a-therapeutic-strategy-dependent-on-cell-of-origin
#3
Jonathan S Rink, Shuo Yang, Osman Cen, Tim Taxter, Kaylin M McMahon, Sol Misener, Amir Behdad, Richard Longnecker, Leo I Gordon, C Shad Thaxton
Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1)...
September 21, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28930464/gastric-water-emptying-under-fed-state-clinical-trial-conditions-is-as-fast-as-under-fasted-conditions
#4
Michael Grimm, Elisabeth Scholz, Mirko Koziolek, Jens Peter Kuhn, Werner Weitschies
The Magenstrasse (stomach road) describes the fast emptying of ingested liquids from the postprandial stomach. The occurrence of the Magenstrasse has great importance for drugs administered together with food as it represents a shortcut through the fed stomach and allows rapid onset of plasma levels. In this study, we investigated the effect of different meals, their texture and fat content on the occurrence of the Magenstrasse. Since the administration of water is common 60 min after drug intake in clinical trials, we also investigated the effect of time point of water administration on the Magenstrasse by a second water administration...
September 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28929769/design-and-solidification-of-fast-releasing-clofazimine-nanoparticles-for-treatment-of-cryptosporidiosis
#5
Yingyue Zhang, Jie Feng, Simon A McManus, Hoang D Lu, Kurt D Ristroph, Eugene J Cho, Ellen L Dobrijevic, Hak-Kim Chan, Robert K Prud'homme
Clofazimine, a lipophilic (log P = 7.66) riminophenazine antibiotic approved by the US Food and Drug Administration (FDA) with a good safety record, was recently identified as a lead hit for cryptosporidiosis through a high-throughput phenotypic screen. Cryptosporidiosis requires fast-acting treatment as it leads to severe symptoms which, if untreated, result in morbidity for infants and small children. Consequently, a fast-releasing oral formulation of clofazimine in a water-dispersible form for pediatric administration is highly desirable...
September 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28892400/poly-vinyl-methyl-ether-maleic-anhydride-doped-peg-pla-nanoparticles-for-oral-paclitaxel-delivery-to-improve-bioadhesive-efficiency
#6
Qian Wang, Chan Li, Tianyang Ren, Shizhu Chen, Xiaoxia Ye, Hongbo Guo, Haibing He, Yu Zhang, Tian Yin, Xing-Jie Liang, Xing Tang
Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b-PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 ± 4.0%. The nanoparticles were uniform and spherical in shape and exhibited a sustained drug release compared with Taxol. m-NPs also exhibited favorable bioadhesive efficiency at the same time. Coumarin 6 or DiR-loaded nanoparticles with/without PVMMA (C6-m-NPs/DiR-m-NPs or C6-p-NPs/DiR-p-NPs) were used for cellular uptake and intestinal adhesion experiments, respectively...
September 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28926716/broadband-acoustic-resonance-dissolution-spectroscopy-bards-a-novel-approach-to-investigate-the-wettability-of-pharmaceutical-powder-blends
#7
Raghu V G Peddapatla, M Rizwan Ahmed, Caroline A Blackshields, M J Sousa-Gallagher, Sean McSweeney, J Krüse, Abina M Crean, Dara Fitzpatrick
The ability of Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) to assess the wettability of powder blends is investigated. BARDS is a novel analytical technology developed based on the change in acoustic phenomenon observed when material is added into a solvent under resonance. Addition of solid material to the solvent results in the introduction of gas (air) into the solvent, changing the compressibility of the solvent system and reducing the velocity of sound in the solvent. As a material is wetted and dissolved, the gas is released from the solvent and resonance frequency is altered...
September 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28926265/tobacco-mosaic-virus-delivered-cisplatin-restores-efficacy-in-platinum-resistant-ovarian-cancer-cells
#8
Christina E Franke, Anna E Czapar, Ravi B Patel, Nicole F Steinmetz
Platinum resistance in ovarian cancer is the major determinant of disease prognosis. Resistance can first appear at the onset of disease or develop in response to platinum-based chemotherapy. Due to poor response to alternate chemotherapies and lack of targeted therapies, there is an urgent clinical need for a new avenue toward treatment of platinum-resistant (PR) ovarian cancer. Nanoscale delivery systems hold potential to overcome resistance mechanisms. In this work, we present tobacco mosaic virus (TMV) as a nanocarrier for cisplatin for treatment of PR ovarian cancer cells...
September 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28922604/a-comparative-study-on-the-performance-of-inert-and-functionalized-spheres-coated-with-solid-dispersions-made-of-two-structurally-related-antifungal-drugs
#9
Naila A Mugheirbi, Peter O'Connell, Dolores R Serrano, Anne Marie Healy, Lynne S Taylor, Lidia Tajber
Fluid bed coating offers potential advantages as a formulation platform for amorphous solid dispersions (ASDs) of poorly soluble drugs, being a one-step manufacturing process which could reduce the risk of phase separation associated with multiple step manufacturing approaches. However, the impact of the physicochemical nature of carrier spheres on the properties and drug release from the ASDs has not been studied in detail. In this work, tartaric acid (TAP) and microcrystalline cellulose (CEL) spheres were chosen as examples of functional and inert beads, respectively...
September 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28921988/interaction-of-food-additives-with-intestinal-efflux-transporters
#10
Noora Sjöstedt, Feng Deng, Oskari Rauvala, Tuomas Tepponen, Heidi Kidron
Breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2) and P-glycoprotein (P-gp) are ABC transporters that are expressed in the intestine, where they are involved in the efflux of many drugs from enterocytes back into the intestinal lumen. The inhibition of BCRP, MRP2 and P-gp can result in the enhanced absorption and exposure of substrate drugs. Food additives are widely used by the food industry to improve the stability, flavor and consistency of food products. Although they are considered safe for consumption, their interactions with intestinal transporters are poorly characterized...
September 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28920690/regional-intestinal-permeability-in-rats-a-comparison-of-methods
#11
Carl Roos, David Dahlgren, E Sjögren, Christer Tannergren, Bertil Abrahamsson, H Lennernas
Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain...
September 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28870080/charge-shielding-prevents-aggregation-of-supercharged-gfp-variants-at-high-protein-concentration
#12
Joshua R Laber, Barton J Dear, Matheus L Martins, Devin E Jackson, Andrea DiVenere, Jimmy D Gollihar, Andrew D Ellington, Thomas M Truskett, Keith P Johnston, Jennifer A Maynard
Understanding protein stability is central to combatting protein aggregation diseases and developing new protein therapeutics. At the high concentrations often present in biological systems, purified proteins can exhibit undesirable high solution viscosities and poor solubilities mediated by short-range electrostatic and hydrophobic protein-protein interactions. The interplay between protein amino acid sequence, protein structure, and solvent conditions to minimize protein-protein interactions is key to designing well-behaved pharmaceutical proteins...
September 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28915351/relaxation-dynamics-vs-crystallization-kinetics-in-the-amorphous-state-the-case-of-stiripentol
#13
Guadalupe N Ruiz, Michela Romanini, Maria Del Barrio, Josep Ll Tamarit, Luis C Pardo, Roberto Macovez
With the aim of finding a correlation between the crystallization kinetics and the molecular dynamics of a substance that would allow to predict its crystallization time as a function of temperature for a given α relaxation time, we have studied Stiripentol, an anticonvulsant drug. Stiripentol has been characterized in its supercooled liquid, and amorphous (glass) and crystalline states by the concurrent use of Broadband Dielectric Spectroscopy (BDS), differential scanning calorimetry, x-ray diffraction and optical microscopy...
September 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28901776/liposomal-delivery-of-diacylglycerol-lipase-beta-inhibitors-to-macrophages-dramatically-enhances-selectivity-and-efficacy-in-vivo
#14
Myungsun Shin, Helena W Snyder, Giulia Donvito, Lesley D Schurman, Todd E Fox, Aron H Lichtman, Mark Kester, Ku-Lung Hsu
Diacylglycerol lipase-beta (DAGLβ) hydrolyzes arachidonic acid (AA)-containing diacylglycerols to produce bioactive lipids including endocannabinoids and AA-derived eicosanoids involved in regulation of inflammatory signaling. Previously, we demonstrated that DAGLβ inactivation using the triazole urea inhibitor KT109 blocked macrophage inflammatory signaling and reversed allodynic responses of mice in inflammatory and neuropathic pain models. Here, we tested whether we could exploit the phagocytic capacity of macrophages to localize delivery of DAGLβ inhibitors to these cells in vivo using liposome encapsulated KT109...
September 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28863265/structure-property-relationships-in-sodium-muricholate-derivative-bile-salts-micellization-the-effect-of-conformation-of-steroid-skeleton-on-hydrophobicity-and-micelle-formation-pattern-recognition-and-potential-membranoprotective-properties
#15
Mihalj Poša, Kosta Popović
It is known that β-muricholic acid anions prevent membrane toxicity of hydrophobic bile acids, which are being used in therapy for solubilization of the cholesterol type bile stone. Better knowledge of these derivative micelles is very important for understanding their physiological and pharmacological effects. β-Axial (a) oriented hydroxyl group from the steroid skeleton decreases the hydrophobic surface of the convex side of the steroid skeleton. Therefore, the critical micellization concentration (CMC) for steroid surfactants with β-a-OH group should increase, but in the case of OH groups of different orientations forming H-bonds in the hydrophobic phase of the micelle, it has the opposite effect; the CMC decreses, and aggregation is more favored...
September 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28858508/design-synthesis-and-biological-evaluation-of-ester-and-ether-derivatives-of-antisickling-agent-5-hmf-for-the-treatment-of-sickle-cell-disease
#16
Guoyan G Xu, Piyusha P Pagare, Mohini S Ghatge, Ronni P Safo, Aheema Gazi, Qiukan Chen, Tanya David, Alhumaidi B Alabbas, Faik N Musayev, Jürgen Venitz, Yan Zhang, Martin K Safo, Osheiza Abdulmalik
Candidate drugs to counter intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) continue to represent a promising approach to mitigating the primary cause of the pathophysiology associated with sickle cell disease (SCD). One such compound is the naturally occurring antisickling agent, 5-hydroxymethyl-2-furfural (5-HMF), which has been studied in the clinic for the treatment of SCD. As part of our efforts to develop novel efficacious drugs with improved pharmacologic properties, we structurally modified 5-HMF into 12 ether and ester derivatives...
September 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28898584/in-vitro-characterization-of-ritonavir-drug-products-and-correlation-to-human-in-vivo-performance
#17
Hao Xu, Socrates Vela, Yi Shi, Patrick Morroum, Ping Gao
Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro dissolution and supersatuation behaviors of three Norvir® oral products including the Tablet, Powder and Solution were investigated by two biorelevant dissolution methods with pH alteration: a two-stage dissolution test and a biphasic dissolution-partition test. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these products accompanied by the occurrence of RTV LLPS in biorelevant dissolution media...
September 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28895735/reduction-sensitive-paclitaxel-prodrug-self-assembled-nanoparticles-with-tetrandrine-effectively-promote-synergistic-therapy-against-drug-sensitive-and-multidrug-resistant-breast-cancer
#18
Mengjuan Jiang, Ruoshi Zhang, Yingli Wang, Wenna Jing, Ying Liu, Yan Ma, Bingjun Sun, Menglin Wang, Peizhuo Chen, Hongzhuo Liu, Zhonggui He
Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE co-loaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells...
September 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28885847/regulation-of-reduced-folate-carrier-rfc-by-vitamin-d-receptor-at-the-blood-brain-barrier
#19
Camille Alam, Md Tozammel Hoque, Richard H Finnell, I David Goldman, Reina Bendayan
Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate transport systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT) and folate receptor alpha (FRα), known to be regulated by ligand-activated nuclear receptors such as vitamin D receptor (VDR). Folate uptake at the choroid plexus, which requires the actions of both FRα and PCFT, is critical to cerebral folate delivery. Inactivating FRα or PCFT mutations cause severe cerebral folate deficiency resulting in early childhood neurodegeneration...
September 8, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28881141/elongated-plant-virus-based-nanoparticles-for-enhanced-delivery-of-thrombolytic-therapies
#20
Andrzej Stanislaw Pitek, Yunmei Wang, Sahil Gulati, Huiyun Gao, Phoebe L Stewart, Daniel I Simon, Nicole F Steinmetz
Thrombotic cardiovascular disease, including acute myocardial infarction, ischemic stroke, and venous thromboembolic disease, is the leading cause of morbidity and mortality worldwide. While reperfusion therapy with thrombolytic agents reduces mortality from acute myocardial infarction and disability from stroke, thrombolysis is generally less effective than mechanical reperfusion and is associated with fatal intra-cerebral hemorrhage in up to 2-4% of patients. To address these limitations, we propose the tobacco mosaic virus (TMV)-based platform technology for targeted delivery of thrombolytic therapies...
September 7, 2017: Molecular Pharmaceutics
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