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Drug diversion

Rama I Mahran, Magda M Hagras, Duxin Sun, Dean E Brenner
Cancer is still a major cause of death all over the world. Its incidence and prevalence are increasing drastically. Cancer treatment imposes high socioeconomic burden with little impact especially on aggressive types of cancer. Reversing or delaying carcinogenesis "cancer chemoprevention" by purified or extracted natural products is a cost-effective alternative. Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects...
October 25, 2016: AAPS Journal
Remigijus Didziapetris, Kiril Lanevskij
A large and chemically diverse hERG inhibition data set comprised of 6690 compounds was constructed on the basis of ChEMBL bioactivity database and original publications dealing with experimental determination of hERG activities using patch-clamp and competitive displacement assays. The collected data were converted to binary format at 10 µM activity threshold and subjected to gradient boosting machine classification analysis using a minimal set of physicochemical and topological descriptors. The tested parameters involved lipophilicity (log P), ionization (pK a ), polar surface area, aromaticity, molecular size and flexibility...
October 25, 2016: Journal of Computer-aided Molecular Design
Beatrice Setnik, Carl L Roland, Glenn C Pixton, Kenneth W Sommerville
OBJECTIVES: To compare the results of two open-label primary care-based studies that examined investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion relative to patient self-reports and urine drug tests (UDTs). METHODS: Risk assessment data from two open-label, multicenter, primary care-based US studies in patients with chronic pain were compared. RESULTS: In one study (n = 1487), 54.4% of patients were at moderate, 24...
October 26, 2016: Postgraduate Medicine
Kristelle Desfossés-Baron, Ian Hammond-Martel, Antoine Simoneau, Adnane Sellam, Stephen Roberts, Hugo Wurtele
The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression...
October 26, 2016: Scientific Reports
Ki-Young Lee, Bong-Jin Lee
Bacterial toxin-antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins...
October 22, 2016: Toxins
Kapileswar Seth, Priyank Purohit, Asit K Chakraborti
The benzazole scaffolds are present in various therapeutic agents and have been recognized as the essential pharmacophore for diverse biological activities. These have generated interest and necessity to develop efficient synthetic methods of these privileged classes of compounds to generate new therapeutic leads for various diseases. The biological activities of the benzazoles and efforts towards their synthesis have been summarized in a few review articles. In view of these, the aim of this review is to provide an account of the developments that have taken place in the synthesis of biorelevant benzazoles under microwave irradiation as the application of microwave heating has long been recognized as a green chemistry tool for speedy generation of synthetic targets...
October 25, 2016: Current Medicinal Chemistry
Mikhail Krasavin, Alexey Lukin, Daria Bagnyukova, Nikolay Zhurilo, Ihor Zahanich, Sergey Zozulya
A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly's advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides)...
October 26, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Ashok Jangra, Chandra Shaker Sriram, Suryanarayan Pandey, Priyansha Choubey, Prabha Rajput, Babita Saroha, Babul Kumar Bezbaruah, Mangala Lahkar
Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype...
October 2016: Annals of Neurosciences
Frank Loganzo, Matthew Sung, Hans-Peter Gerber
Drug resistance limits the effectiveness of cancer therapies. Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents. Antibody-drug conjugates (ADC) are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy; however, recent preclinical studies reveal potential mechanisms of resistance...
October 25, 2016: Molecular Cancer Therapeutics
Yao-Jie Pan, Ying Zhuang, Jun-Nian Zheng, Dong-Sheng Pei
MicroRNAs (miRNAs), which are characterized by highly conserved and small non-coding RNAs, have been a hot spot regarding biological processes such as cellular proliferation, apoptosis and metabolism as well as cellular differentiation, signal transduction and carcinogenesis. MiRNA-106a (miR-106a), a member of the miR-17 family, has been validated to be aberrantly regulated in the diversity of tumors. The purpose of this review is supposed to deliver an intricate overview of miR-106a, including its role in cell proliferation, apoptosis, cell cycle, invasion and metastasis, involvement in drug resistance as well as its interactions with the target proteins and signaling pathways involved...
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
Sebastian Schneeweiss, Wesley Eddings, Robert J Glynn, Elisabetta Patorno, Jeremy Rassen, Jessica M Franklin
BACKGROUND: Data-adaptive approaches to confounding adjustment may improve performance beyond expert knowledge when analyzing electronic healthcare databases and have additional practical advantages for analyzing multiple databases in rapid cycles. Improvements seemed possible if outcome predictors were reliably identified empirically and adjusted. METHODS: In five cohort studies from diverse healthcare databases, we implemented a base-case high-dimensional propensity score algorithm with propensity score decile-adjusted outcome models to estimate treatment effects among prescription drug initiators...
October 21, 2016: Epidemiology
G E B Wright, B Carleton, M R Hayden, C J D Ross
Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (FST>0...
October 25, 2016: Pharmacogenomics Journal
Hyung Suk Chung, Jeong-Heui Choi, A M Abd El-Aty, Young-Jun Lee, Han Sol Lee, Sangdon Kim, Hee-Jung Jung, Tae-Woo Kang, Ho-Chul Shin, Jae-Han Shim
A simultaneous determination method using solid-phase extraction and liquid chromatography with tandem mass spectrometry was developed to detect and quantify the presence of seven multiclass veterinary antibiotics (13 compounds in total) in surface water samples, which included the effluents of livestock wastewater and sewage treatment plants, as well as the reservoir drainage areas from dense animal farms. The pH of all water samples was adjusted to 2 or 6 before solid-phase extraction using Oasis HLB cartridges...
October 24, 2016: Journal of Separation Science
James A McCubrey, Kvin Lertpiriyapong, Timothy L Fitzgerald, Alberto M Martelli, Lucio Cocco, Dariusz Rakus, Agnieszka Gizak, Massimo Libra, Melchiorre Cervello, Guiseppe Montalto, Li V Yang, Stephen L Abrams, Linda S Steelman
TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation...
October 6, 2016: Advances in Biological Regulation
P Noufi, E Khoury, E Ayoub, N Naccache, S Richa
OBJECTIVES: Use of chronic opioid therapy has increased substantially over the past few years, even though opioid therapy is associated with potentially serious harms, including opioid-related adverse effects and outcomes. Prescription of opioids for chronic pain, particularly nonmalignant chronic pain, remains controversial. In the midst of this controversy, patterns of actual prescription and influences on these patterns are not well understood. This study aims to describe the frequency of prescription of opioid analgesics in a university hospital, the attitudes of doctors towards this category of drugs, and the follow-up modalities of patients taking these drugs...
October 21, 2016: L'Encéphale
Raquel Girardello, Marina Visconde, Rodrigo Cayô, Regina Célia Bressan Queiroz de Figueiredo, Marcelo Alves da Silva Mori, Nilton Lincopan, Ana Cristina Gales
Polymyxins have become drugs of last resort for treatment of multi-drug resistant (MDR) Gram-negative infections. However, the mechanisms of resistance to this compound have not been completely elucidated. In this study, we evaluated the mechanisms of resistance to this antimicrobial in two A. baumannii clinical isolates, respectively, susceptible (A027) and resistant (A009) to polymyxin B before and after polymyxin B exposure (A027(ind) and A009(ind)). The pmrAB and lpxACD were sequenced and their transcriptional levels were analyzed by qRT-PCR...
October 8, 2016: Diagnostic Microbiology and Infectious Disease
Charlene Muscat Galea, Debby Mangelings, Yvan Vander Heyden
Defining a method development methodology for achiral drug impurity profiling in SFC requires a number of steps. Initially, diverse stationary phases are characterized and a small number of orthogonal or dissimilar phases are selected for further method development. In this paper, we focus on a next step which is the investigation of the modifier composition on chromatographic selectivity. A solvent-triangle based approach is used in which blends of organic solvents, mainly ethanol (EtOH), propanol (PrOH), acetonitrile (ACN) and tetrahydrofuran (THF) mixed with methanol (MeOH) are tested as modifiers on six dissimilar stationary phases...
October 18, 2016: Journal of Pharmaceutical and Biomedical Analysis
Monika B Dolinska, Nicole Kus, Katie Farney, Paul T Wingfield, Brian P Brooks, Yuri V Sergeev
: Oculocutaneous albinism Type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intra-melanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities- tryptophan fluorescence, and Gibbs free energy changes...
October 24, 2016: Pigment Cell & Melanoma Research
Lu Liu, Georg Pohnert, Dong Wei
Industrial microalgae, as a big family of promising producers of renewable biomass feedstock, have been commercially exploited for functional food, living feed and feed additives, high-value chemicals in nutraceuticals, cosmeceuticals, and chemical reagents. Recently, microalgae have also been considered as a group that might play an important role in biofuel development and environmental protection. Almost all current products of industrial microalgae are derived from their biomass; however, large amounts of spent cell-free media are available from mass cultivation that is mostly unexploited...
October 20, 2016: Marine Drugs
Marie E Jetté, Kimberly A Dill-McFarland, Alissa S Hanshew, Garret Suen, Susan L Thibeault
Prolonged diffuse laryngeal inflammation from smoking and/or reflux is commonly diagnosed as chronic laryngitis and treated empirically with expensive drugs that have not proven effective. Shifts in microbiota have been associated with many inflammatory diseases, though little is known about how resident microbes may contribute to chronic laryngitis. We sought to characterize the core microbiota of disease-free human laryngeal tissue and to investigate shifts in microbial community membership associated with exposure to cigarette smoke and reflux...
October 24, 2016: Scientific Reports
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