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Rational drugs use

Akhil Kumar, Ashish Tiwari, Ashok Sharma
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target...
March 15, 2018: Current Neuropharmacology
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Colin R O'Dowd, Matthew D Helm, J S Shane Rountree, Jakub T Flasz, Elias Arkoudis, Hugues Miel, Peter R Hewitt, Linda Jordan, Oliver Barker, Caroline Hughes, Ewelina Rozycka, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Stephanie Feutren-Burton, Scarlett Dvorkin, Gerald Gavory, Timothy Harrison
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography...
March 8, 2018: ACS Medicinal Chemistry Letters
Matthew Dankner, April A N Rose, Shivshankari Rajkumar, Peter M Siegel, Ian R Watson
The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants...
March 15, 2018: Oncogene
Vasyl Kovalishyn, Julie Grouleff, Ivan Semenyuta, Vitaliy O Sinenko, Sergiy R Slivchuk, Diana Hodyna, Volodymyr Brovarets, Volodymyr Blagodatny, Gennady Poda, Igor V Tetko, Larysa Metelytsia
The problem of designing new anti-tubercular drugs against multiple-drug-resistant tuberculosis (MDR-TB) was addressed using advanced machine learning methods. Since there are only few published measurements against MDR-TB, we collected a large literature dataset and developed models against the non-resistant H37Rv strain. The predictive accuracy of these models had a coefficient of determination q2 = 0.7-0.8 (regression models), and balanced accuracies of about 80% (classification models) with cross-validation and independent test sets...
March 14, 2018: Chemical Biology & Drug Design
Amit Kumar, Francesca Pintus, Amalia Di Petrillo, Rosaria Medda, Paola Caria, Maria João Matos, Dolores Viña, Enrico Pieroni, Francesco Delogu, Benedetta Era, Giovanna L Delogu, Antonella Fais
Alzheimer's disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated...
March 13, 2018: Scientific Reports
Roberta Gualtierotti, Maria Orietta Borghi, Maria Gerosa, Tommaso Schioppo, Paola Larghi, Jens Geginat, Pier Luigi Meroni
OBJECTIVES: B cells play an important role in the initiation and progression of systemic lupus erythematosus (SLE). Accordingly, B cell-targeted therapy has been suggested as a new rational approach for treating lupus. Belimumab, a human monoclonal antibody directed against B lymphocyte stimulator (BLyS), was reported as the first biological treatment effective in reducing mild-to-moderate SLE disease activity by using different scoring systems and endpoints. Conversely clinical trials with rituximab, a chimeric monoclonal antibody directed against the CD20 expressed by B cells, have failed to achieve primary endpoints in spite of a number of reports showing its beneficial effects...
February 27, 2018: Clinical and Experimental Rheumatology
Richard Njouom, Isabelle Siffert, Gaëtan Texier, Guillaume Lachenal, Mathurin Cyrille Tejiokem, Jacques Pépin, Arnaud Fontanet
Cameroon is thought to have one of the highest prevalences of Hepatitis C virus (HCV) infection in the world (4·9% among adults). A marked cohort effect exists in several communities where ≈50% of the elderly are infected. Better assessment of HCV distribution is needed for planning treatment programs. We tested for HCV antibodies 14150 capillary blood samples collected during the 2011 Demographic and Health Survey, whose participants were representative of the Cameroonian population aged 15-49 (both genders) and 50-59 years (men only)...
March 13, 2018: Journal of Viral Hepatitis
Rumina Hasan, Sadia Shakoor, Johanna Hanefeld, Mishal Khan
Many low- and middle-income countries facing high levels of antimicrobial resistance, and the associated morbidity from ineffective treatment, also have a high burden of tuberculosis. Over recent decades many countries have developed effective laboratory and information systems for tuberculosis control. In this paper we describe how existing tuberculosis laboratory systems can be expanded to accommodate antimicrobial resistance functions. We show how such expansion in services may benefit tuberculosis case-finding and laboratory capacity through integration of laboratory services...
March 1, 2018: Bulletin of the World Health Organization
Md Fazlur Rahman, Radhika Raj, Rajgopal Govindarajan
Combination antiretroviral drug treatments depend on 3'-deoxy-nucleoside analogs such as AZT (3'-azido-3'-deoxythymidine) and DDI (2'3'-dideoxyinosine). Despite being effective in inhibiting HIV viral replication, these drugs produce a range of toxicities, including myopathy, pancreatitis, neuropathy and lactic acidosis, that are generally considered as sequelae to mitochondrial damage. While the cell surface localized nucleoside transporters (e.g., human equilibrative nucleoside transporter 2 (hENT2), human concentrative nucleoside transporter 1 (hCNT1)) are known to increase the carrier mediated uptake of 3'-deoxy-nucleoside analogs into cells, another ubiquitously expressed intracellular nucleoside transporter, namely, hENT3, has been implicated in the mitochondrial transport of 3'-deoxy-nucleoside analogs...
March 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
P Nkoli Mandoko, V Sinou, D Moke Mbongi, D Ngoyi Mumba, G Kahunu Mesia, J Losimba Likwela, S Bi Shamamba Karhemere, L Muepu Tshilolo, J-J Tamfum Muyembe, D Parzy
OBJECTIVE: Artemisinin-based combination therapies have been available since 2005 in the Democratic Republic of the Congo to treat malaria and to overcome the challenge of anti-malarial drug resistance as well as to improve access to effective treatments. The private sector is the primary distribution source for anti-malarial drugs and thus, has a key position among the supply chain actors for a rational and proper use of anti-malarial drugs. We aimed to assess access to nationally recommended anti-malarial drugs in private sector pharmacies of the capital-city of Kinshasa...
March 9, 2018: Médecine et Maladies Infectieuses
C Ricardo Ramirez, M L Álvarez Gómez, C A Agudelo Vélez, S Zuluaga Penagos, R A Consuegra Peña, K Uribe Hernández, I C Mejía Gil, E M Cano Londoño, M Elorza Parra, J G Franco Vásquez
OBJECTIVE: To evaluate the clinical characteristics, prevalence and factors associated with delirium in critical patients from 5 to 14 years of age. DESIGN: An analytical, cross-sectional observational study was made. Delirium was assessed with the Pediatric-Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU) and motor classification was established with the Delirium Rating Scale Revised-98. SETTING: A pediatric Intensive Care Unit...
March 9, 2018: Medicina Intensiva
Shuyu Zhan, Baoyue Ding, Yu-Er Ruan, Xuan Huang, Guoqiang Liu, Xiaoqing Lv, Xiong Huang, Mingjuan Li, Ninghua Jiang, Qing Shao
Microdialysis is a powerful in vivo sampling technique for pharmacokinetic-pharmacodynamic (PK-PD) modeling of drugs in pre-clinical and clinical studies. However, the noticeable limitations of previous studies using microdialysis were that animals anesthesia in the whole experiment and the combination of microdialysis and blood sampling for drug and (or) effect detection, which can obviously influence PK and PD behavior of drugs. In this study, a simple blood microdialysis sampling system in freely-moving rats was established for simultaneous study of PK and PD of Shengmai injection (SMI) effect on inducing real-time nitric oxide (NO) release on isoproterenol (ISO) induced myocardial ischemia rats...
March 9, 2018: Journal of Pharmaceutical and Biomedical Analysis
Faiza H Waghu, Shaini Joseph, Sanket Ghawali, Elvis A Martis, Taruna Madan, Kareenhalli V Venkatesh, Susan Idicula-Thomas
Antimicrobial peptides (AMPs) are gaining attention as substitutes for antibiotics in order to combat the risk posed by multi-drug resistant pathogens. Several research groups are engaged in design of potent anti-infective agents using natural AMPs as templates. In this study, a library of peptides with high sequence similarity to Myeloid Antimicrobial Peptide (MAP) family were screened using popular online prediction algorithms. These peptide variants were designed in a manner to retain the conserved residues within the MAP family...
2018: Frontiers in Microbiology
Agnieszka Zagorska, Anna Partyka, Adam Bucki, Alicja Gawalska, Anna Czopek, Maciej Pawlowski
BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery...
March 8, 2018: Current Medicinal Chemistry
Vladimir Potemkin, Maria Grishina
Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained at a SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and bioactive probability is described...
March 8, 2018: Current Medicinal Chemistry
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
Adolfo Marican, Fabián Avila-Salas, Oscar Valdés, Sergio Wehinger, Jorge Villaseñor, Natalia Fuentealba, Mauricio Arenas-Salinas, Yerko Argandoña, Verónica Carrasco-Sánchez, Esteban F Durán-Lara
This study describes the in-silico rational design, synthesis and evaluation of cross-linked polyvinyl alcohol hydrogels containing γ-cyclodextrin (γ-CDHSAs) as platforms for the sustained release of prednisone (PDN). Through in-silico studies using semi-empirical quantum mechanical calculations, the effectiveness of 20 dicarboxylic acids to generate a specific cross-linked hydrogel capable of supporting different amounts of γ-cyclodextrin (γ-CD) was evaluated. According to the interaction energies calculated with the in-silico studies, the hydrogel made from PVA cross-linked with succinic acids (SA) was shown to be the best candidate for containing γ-CD...
March 7, 2018: Pharmaceutics
Dirk Theile, Gerd Mikus
Recently, the opioid analgesic D,L-methadone has gained much attention as a potential antineoplastic compound, considerably triggered through lay press and media. In consequence, physicians and pharmacists are currently confronted with numerous patients willing to use D,L-methadone against their malignancies. Well-performed in vitro and in vivo models have in fact shown pro-apoptotic effects of D,L-methadone or other opioids, but also proliferation-stimulating properties. Moreover, the mechanisms of proposed opioid-stimulated apoptosis are incompletely described or contradicting...
March 8, 2018: International Journal of Cancer. Journal International du Cancer
Florence F Wagner, Lina Benajiba, Arthur J Campbell, Michel Weïwer, Joshua R Sacher, Jennifer P Gale, Linda Ross, Alexandre Puissant, Gabriela Alexe, Amy Conway, Morgan Back, Yana Pikman, Ilene Galinsky, Daniel J DeAngelo, Richard M Stone, Taner Kaya, Xi Shi, Matthew B Robers, Thomas Machleidt, Jennifer Wilkinson, Olivier Hermine, Andrew Kung, Adam J Stein, Damodharan Lakshminarasimhan, Michael T Hemann, Edward Scolnick, Yan-Ling Zhang, Jen Q Pan, Kimberly Stegmaier, Edward B Holson
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers...
March 7, 2018: Science Translational Medicine
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