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drug substitution

Yuan Xu, Yi-Fan Han, Bing Ye, Yin-Long Zhang, Jian-Da Dong, Shao-Jun Zhu, Jiong Chen
Chemotherapy is one of the most effective forms of cancer treatment. It has been widely used in the treatment of various malignant tumors. In order to investigate molecular mechanisms responsible for the chemoresistance of anaplastic thyroid cancer (ATC), we established the doxorubicin (Dox) resistance of human ATC SW1736 and 8305C cells and named them SW1736/Dox and 8305C/Dox, respectively. We evaluated the expression of various micro-RNAs (miRNAs) between control and Dox-resistant ATC cells and found that the expression of miR-27b-3p was significantly increased in Dox-resistant ATC cells...
June 20, 2018: Basic & Clinical Pharmacology & Toxicology
Kamilla Rodrigues Rogerio, Leonardo J M Carvalho, Luiza Helena Pinto Domingues, Bruno Junior Neves, José Teófilo Moreira Filho, Rosane Nora Castro, Cesare Bianco Júnior, Claudio Tadeu Daniel-Ribeiro, Carolina Horta Andrade, Cedric Stephan Graebin
BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years...
2018: Memórias do Instituto Oswaldo Cruz
Zia Ud Din, Marilia Almeida Trapp, Lívia Soman de Medeiros, Danielle Lazarin-Bidóia, Francielle Pelegrin Garcia, Francieli Peron, Celso Vataru Nakamura, Ihosvany Camps Rodríguez, Abdul Wadood, Edson Rodrigues-Filho
Symmetrical and unsymmetrical bis-aryl-α,β-unsaturated ketones were synthesized in moderate to excellent yield by treating cyclohexanone with various aldehydes. Dimethylammonium dimethylcarbamate (DIMCARB) was used as both catalyst and reaction medium for the synthesis of monoarylidenes cycloadduct intermediates, which was further used to produce diarylidene cyclohexanones. All the 34 compounds synthesized were evaluated for their anti-proliferative activity, particularly against promastigote of Leishmania amazonensis, epimastigoteand trypomastigoteof Trypanosoma cruzi...
June 14, 2018: European Journal of Medicinal Chemistry
Elin M Svensson, Robin J Svensson, Lindsey H M Te Brake, Martin J Boeree, Norbert Heinrich, Sarah Konsten, Gavin Churchyard, Rodney Dawson, Andreas H Diacon, Gibson S Kibiki, Lilian T Minja, Nyanda E Ntingiya, Ian Sanne, Stephen H Gillespie, Michael Hoelscher, Patrick P J Phillips, Ulrika S H Simonsson, Rob Aarnoutse
Background: Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods: Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg...
June 18, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Edoardo Sciatti, Michele Senni, Carlo M Lombardi, Mauro Gori, Marco Metra
: The Prospective Comparison of Angiotensin Receptor Antagonist and Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial has shown a reduction in the risk of death and heart failure hospitalizations with sacubitril/valsartan, compared with enalapril, in patients with heart failure and reduced ejection fraction. Guidelines now recommend the substitution of angiotensin-converting enzyme inhibitors or AT1 blockers with sacubitril/valsartan in patients with heart failure and reduced ejection fraction...
June 16, 2018: Journal of Cardiovascular Medicine
Zachary J Zimmermann, David V Gauvin, Alan Poling
BACKGROUND: Levamisole (LVM) is a common adulterant in clandestinely manufactured cocaine (COC), with a range of well-documented deleterious health effects. Although the prevalence of LVM in COC has been widely noted, the subjective effects related to concomitant COC-LVM administration are poorly understood. AIMS: The present study sought to compare the subjective effects of LVM alone and in combination with COC in male and female Sprague-Dawley rats trained to discriminate COC from vehicle injections...
June 1, 2018: Journal of Psychopharmacology
Sunwen Chou, L Elizabeth Satterwhite, Ronald J Ercolani
Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In 8 experiments, UL56 terminase gene mutations were detected beginning at 10 passages, including novel amino acid substitutions V236A, L328V and A365S, in a region previously associated with letermovir resistance...
June 18, 2018: Antimicrobial Agents and Chemotherapy
Shalini Nair, Xue Li, Grace A Arya, Marina McDew-White, Marco Ferrari, François Nosten, Tim J C Anderson
Fitness costs are key determinants of whether drug resistance alleles establish and how fast they spread within populations. More than 125 different kelch13 alleles, each containing a different amino acid substitution, have arisen in SE Asian malaria parasite ( Plasmodium falciparum ) populations under artemisinin selection over the past 15 years in a dramatic example of a soft selective event. However, just one of these alleles (C580Y) is now outcompeting other alleles in multiple different countries and is spreading towards fixation...
June 18, 2018: Antimicrobial Agents and Chemotherapy
Toyotaka Sato, Tsukasa Shiraishi, Yoshiki Hiyama, Hiroyuki Honda, Masaaki Shinagawa, Masaru Usui, Koji Kuronuma, Naoya Masumori, Satoshi Takahashi, Yutaka Tamura, Shin-Ichi Yokota
Colistin is a last-line drug for multidrug-resistant Gram-negative bacteria. We previously reported four plasmid-mediated colistin resistance ( mcr ) gene-negative colistin-resistant Escherichia coli clinical isolates, including the major pathogenic and fluoroquinolone-resistant strains O25b:H4-ST131- H 30Rx [isolates SRE34 and SRE44, minimum inhibitory concentration (MIC) for colistin = 16 mg/L] and non-x (SME296, MIC = 8 mg/L), and O18-ST416 (SME222, MIC = 4 mg/L). Herein, we investigated the colistin resistance mechanism, and identified novel amino acid substitutions or deletion in the PmrAB two-component system that activates eptA (encoding a phosphoethanolamine transferase) and arnT (encoding an undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase) in all colistin-resistant isolates...
June 18, 2018: Antimicrobial Agents and Chemotherapy
Beate Gaertner, Michael Wagner, Tobias Luck, Amanda K Buttery, Judith Fuchs, Markus A Busch
OBJECTIVE: To provide normative data for the Digit Symbol Substitution Test (DSST) of the Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III) in a population-based sample of community-dwelling older adults in Germany according to age, sex, and level of education. METHOD: The sample comprised 1385 participants aged 65-79 years from the nationwide representative 'German Health Interview and Examination Survey for Adults' (DEGS1, 2008-2011). Participants with known cognitive impairment or dementia, other medical conditions affecting cognition, or currently using psychotropic drugs were excluded...
June 17, 2018: Clinical Neuropsychologist
Sean B Dolan, Ritu A Shetty, Michael J Forster, Michael B Gatch
BACKGROUND: Substituted piperazines comprise a substantial proportion of the novel psychoactive substance market. Among the most widely abused piperazine compounds are meta-chlorophenylpiperazine (mCPP), tri-fluoromethylphenylpiperazine (TFMPP), and, especially, benzylpiperazine (BZP), which are commonly incorporated, either alone or in combination, in illicit "party pills" or "ecstasy" formulations. Illicit synthesis of BZP often results in production of an impure by-product dibenzylpiperazine (DBZP), which frequently appears alongside BZP in these formulations; however, despite its ubiquity, little information exists regarding the abuse liability of DBZP...
June 1, 2018: Journal of Psychopharmacology
Mehrak Javadi-Paydar, Eric L Harvey, Yanabel Grant, Sophia A Vandewater, Kevin M Creehan, Jacques D Nguyen, Tobin J Dickerson, Michael A Taffe
RATIONALE: The synthetic cathinone α-pyrrolidinopentiophenone (α-PVP) has been associated with bizarre public behavior in users. Association of such behavior with extended binges of drug use motivates additional investigation, particularly since a prior study found that half of male rats experience a binge of exceptionally high intake, followed by sustained lower levels of self-administration during the acquisition of intravenous self-administration (IVSA) of a related drug, 3,4-methylenedioxypyrovalerone...
June 16, 2018: Psychopharmacology
Rajiv Kumar, Lalit Vats, Silvia Bua, Claudiu T Supuran, Pawan K Sharma
In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide...
June 8, 2018: European Journal of Medicinal Chemistry
N Metrebian, T Weaver, S Pilling, J Hellier, S Byford, J Shearer, L Mitcheson, M Astbury, P Bijral, N Bogdan, O Bowden-Jones, E Day, J Dunn, E Finch, S Forshall, A Glasper, G Morse, S Akhtar, J Bajaria, C Bennett, E Bishop, V Charles, C Davey, R Desai, C Goodfellow, F Haque, N Little, H McKechnie, J Morris, F Mosler, J Mutz, R Pauli, D Poovendran, E Slater, J Strang
There are approximately 256,000 heroin and other opiate users in England of whom 155,000 are in treatment for heroin (or opiate) addiction. The majority of people in treatment receive opiate substitution treatment (OST) (methadone and buprenorphine). However, OST suffers from high attrition and persistent heroin use even whilst in treatment. Contingency management (CM) is a psychological intervention based on the principles of operant conditioning. It is delivered as an adjunct to existing evidence based treatments to amplify patient benefit and involves the systematic application of positive reinforcement (financial or material incentives) to promote behaviours consistent with treatment goals...
June 13, 2018: Contemporary Clinical Trials
Clara T Schoeder, Maria Kaleta, Andhika B Mahardhika, Agnieszka Olejarz-Maciej, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Christa E Müller
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date...
June 1, 2018: European Journal of Medicinal Chemistry
Ales Holoubek, Petr Heřman, Jan Sýkora, Barbora Brodská, Jana Humpolíčková, Markéta Kráčmarová, Dana Gášková, Martin Hof, Kateřina Kuželová
Oligomerization plays a crucial role in the function of nucleophosmin (NPM), an abundant nucleolar phosphoprotein. Two dual-color methods based on modern fluorescence confocal microscopy are applied for tracking NPM aggregates in live cells: cross-correlation Number and Brightness analysis (ccN&B) combined with pulsed interleaved excitation (PIE) and fluorescence-lifetime imaging microscopy (FLIM) utilizing resonance energy transfer (FRET). HEK-293T cells were transfected with mixture of plasmids designed for tagging with fluorescent proteins so that the cells express mixed population of NPM labeled either with eGFP or mRFP1...
June 14, 2018: Methods and Applications in Fluorescence
Fernando Santos-Beneit
BACKGROUND: Glycopeptide antibiotics inhibit bacterial cell-wall synthesis, and are important for the treatment of infections caused by multi drug-resistant strains of enterococci, streptococci and staphylococci. The main mechanism by which bacteria resist the action of glycopeptides is by producing a modified cell-wall in which the dipeptide D-Alanine-D-Alanine is substituted by D-Alanine-D-Lactate or D-Alanine-D-Serine. Recently, it has been shown that inorganic phosphate (Pi) induces hypersensitivity to vancomycin in Streptomyces coelicolor (which is highly resistant to the antibiotic in low-Pi media)...
June 14, 2018: BMC Genomics
Anthony Nash, Thomas Sewell, Rhys A Farrer, Alireza Abdolrasouli, Jennifer M G Shelton, Matthew C Fisher, Johanna Rhodes
Summary: The increase of antifungal drug resistance is a major global human health concern and threatens agriculture and food security; in order to tackle these concerns, it is important to understand the mechanisms that cause antifungal resistance. The curated Mycology Antifungal Resistance Database (MARDy) is a web-service of antifungal drug resistance mechanisms, including amino acid substitutions, tandem repeat sequences and genome ploidy. MARDy is implemented on a Linux, Apache, MySQL and PHP web development platform and includes a local installation of BLASTn of the database of curated genes...
April 20, 2018: Bioinformatics
Sheng Wang, Yiyang Qin, Zhongmin Wang, Junjian Xiang, Yu Zhang, Meng Xu, Baiyong Li, Yu Xia, Peng Zhang, Hong Wang
Compelling evidence implicates that overexpression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) drives tumor progression, can serve as prognostic biomarkers or therapeutic targets for NSCLC patients. But at present, we still lack of effective drugs for bFGF. The preparation of monoclonal antibodies against bFGF or to understand its mechanism of action is urgently need. Previously, we used hybridoma technology to produce a murine anti-bFGF monoclonal antibody (E12)...
2018: Journal of Cancer
Nilce M Martinez-Rossi, Tamires A Bitencourt, Nalu T A Peres, Elza A S Lang, Eriston V Gomes, Natalia R Quaresemin, Maíra P Martins, Lucia Lopes, Antonio Rossi
Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance...
2018: Frontiers in Microbiology
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