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https://www.readbyqxmd.com/read/29048389/discovery-of-novel-n-substituted-prolinamido-indazoles-as-potent-rho-kinase-inhibitors-and-vasorelaxation-agents
#1
Yangyang Yao, Renze Li, Xiaoyu Liu, Feilong Yang, Ying Yang, Xiaoyu Li, Xiang Shi, Tianyi Yuan, Lianhua Fang, Guanhua Du, Xiaozhen Jiao, Ping Xie
Inhibitors of Rho kinase (ROCK) have potential therapeutic applicability in a wide range of diseases, such as hypertension, stroke, asthma and glaucoma. In a previous article, we described the lead discovery of DL0805, a new ROCK I inhibitor, showing potent inhibitory activity (IC50 6.7 μM). Herein, we present the lead optimization of compound DL0805, resulting in the discovery of 24- and 39-fold more-active analogues 4a (IC50 0.27 μM) and 4b (IC50 0.17 μM), among other active analogues. Moreover, ex-vivo studies demonstrated that 4a and 4b exhibited comparable vasorelaxant activity to the approved drug fasudil in rat aortic rings...
October 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29048285/high-level-fosfomycin-resistance-in-vancomycin-resistant-enterococcus-faecium
#2
Yan Guo, Adam D Tomich, Christi L McElheny, Vaughn S Cooper, Amelia Tait-Kamradt, Minggui Wang, Fupin Hu, Louis B Rice, Nicolas Sluis-Cremer, Yohei Doi
Of 890 vancomycin-resistant Enterococcus faecium isolates obtained by rectal screening from patients in Pittsburgh, Pennsylvania, USA, 4 had MICs >1,024 μg/mL for fosfomycin. These isolates had a Cys119Asp substitution in the active site of UDP-N-acetylglucosamine enolpyruvyl transferase. This substitution increased the fosfomycin MIC >4-fold and rendered this drug inactive in biochemical assays.
November 2017: Emerging Infectious Diseases
https://www.readbyqxmd.com/read/29046464/screening-for-neuraminidase-inhibitor-resistance-markers-among-avian-influenza-viruses-of-the-n4-n5-n6-and-n8-neuraminidase-subtypes
#3
Won-Suk Choi, Ju Hwan Jeong, Jin Jung Kwon, Su Jeong Ahn, Khristine Kaith S Lloren, Hyeok-Il Kwon, Hee Bok Chae, Jungwon Hwang, Myung Hee Kim, Chul-Joong Kim, Richard J Webby, Elena A Govorkova, Young Ki Choi, Yun Hee Baek, Min-Suk Song
Several subtypes of avian influenza viruses (AIVs) are emerging as novel human pathogens, and the frequency of related infections has increased in recent years. Although neuraminidase (NA) inhibitors (NAIs) are the only class of antiviral drugs available for therapeutic intervention for AIV-infected patients, studies on NAI resistance among AIVs have been limited and markers of resistance are poorly understood. Previously, we identified unique NAI-resistance substitutions in AIVs of N3, N7, and N9 NA subtypes...
October 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29045762/synthesis-determination-of-the-lipophilicity-anticonvulsant-activity-and-preliminary-safety-of-new-derivatives-of-n-4-arylpiperazin-1-yl-alkyl-pyrrolidine-2-5-dione
#4
Sabina Rybka, Jolanta Obniska, Paweł Żmudzki, Paulina Koczurkiewicz, Katarzyna Wójcik-Pszczoła, Elżbieta Pękala, Adrian Bryła, Anna Rapacz
A new series of derivatives of 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents are described in this paper. Initial pharmacological screening for these compounds was performed using acute models of seizures (MES and scPTZ tests) in mice after intraperitoneal administration. A quantitative pharmacological research revealed that the most promising compound were N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-propyl]-3-benzhydryl-pyrrolidine-2,5-dione monohydrochloride (11) with ED50=75...
October 18, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29044929/anticancer-activity-of-vmct1-analogs-against-mcf-7-cells
#5
Cibele Nicolaski Pedron, Gislaine Patricia Andrade, Roseli Hiromi Sato, Marcelo Der Torossian Torres, Giselle Cerchiaro, Anderson Orzari Ribeiro, Vani Xavier Oliveira Junior
Antimicrobial peptides are considered promising drug candidates due to their broad range of activity. VmCT1 (Phe-Leu-Gly-Ala-Leu-Trp-Asn-Val-Ala-Lys-Ser-Val-Phe-NH2 ) is an α-helical antimicrobial peptide that was obtained from the Vaejovis mexicanus smithi scorpion venom. Some of its analogs showed to be as antimicrobial as the wild type and they were designed for understanding the influence of physiochemical parameters on antimicrobial and hemolytic activity. Some cationic antimicrobial peptides exhibit anticancer activity so VmCT1 analogs were tested in order to verify the anticancer activity of this family of peptides...
October 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29040729/csra-maximizes-expression-of-the-acrab-multidrug-resistance-transporter
#6
Vito Ricci, Victoria Attah, Tim Overton, David C Grainger, Laura J V Piddock
Carbon Storage Regulator A (CsrA) is an RNA binding protein that acts as a global regulator of diverse genes. Using a combination of genetics and biochemistry we show that CsrA binds directly to the 5' end of the transcript encoding AcrAB. Deletion of csrA or mutagenesis of the CsrA binding sites reduced production of both AcrA and AcrB. Nucleotide substitutions at the 5' UTR of acrA mRNA that could potentially weaken the inhibitory RNA secondary structure, allow for more efficient translation of the AcrAB proteins...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29039101/methods-for-analysis-of-nanoparticle-immunosuppressive-properties-in-vitro-and-in-vivo
#7
Timothy M Potter, Barry W Neun, Marina A Dobrovolskaia
Adverse drug effects on the immune system function represent a significant concern in the pharmaceutical industry, because 10-20% of the drug withdrawal from the market is accounted to immunotoxicity. Immunosuppression is one such adverse effect. The traditional immune function test used to estimate materials' immunosuppression is a T-cell-dependent antibody response (TDAR). This method involves a 28 day in vivo study evaluating the animal's antibody titer to a known antigen (KLH) with and without challenge...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29036253/understanding-state-regulation-of-biosimilars-and-effect-on-prescribers
#8
Katerina Yale, Olabola Awosika, Monica Rengifo-Pardo, Alison Ehrlich
Biologics are a mainstay of treatment for many dermatologic conditions, however the high costs can be prohibitive for many patients. A growing market of biosimilar drugs is emerging with the hope of providing patients access to more affordable medications. While the FDA has created an abbreviated licensure pathway for these drugs, states are still in the process of creating regulations regarding their substitution for reference biologics. This article looks to raise awareness of the current federal regulations and the differences among state regulations regarding the use of biosimilars...
October 1, 2017: Journal of Drugs in Dermatology: JDD
https://www.readbyqxmd.com/read/29035734/comparison-of-constitutive-and-thiabendazole-induced-expression-of-five-cytochrome-p450-genes-in-fourth-stage-larvae-of-haemonchus-contortus-isolates-with-different-drug-susceptibility-identifies-one-gene-with-high-constitutive-expression-in-a-multi-resistant
#9
Esra Yilmaz, Sabrina Ramünke, Janina Demeler, Jürgen Krücken
Benzimidazoles (BZs) remain amongst the most widely used anthelmintic drug classes against gastro-intestinal nematode infections, although their efficacy is increasingly compromised by resistance. The primary underlying mechanisms for BZ resistance are single-nucleotide polymorphisms (SNPs) in the isotype 1 β-tubulin gene causing the substitutions F167Y, E198A or F200Y. However, resistance is believed to be multi-genic and previous studies have shown that isolates carrying 90-100% F200Y can vary considerably in their resistance level in the egg hatch assay (EHA)...
October 7, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/29035580/mutation-sensitivity-maps-identifying-residue-substitutions-that-impact-protein-structure-via-a-rigidity-analysis-in-silico-mutation-approach
#10
Michael Siderius, Filip Jagodzinski
Understanding how an amino acid substitution affects a protein's structure can aid in the design of pharmaceutical drugs that aim at countering diseases caused by protein mutants. Unfortunately, performing even a few amino acid substitutions in vitro is both time and cost prohibitive, whereas an exhaustive analysis that involves systematically mutating all amino acids in the physical protein is infeasible. Computational methods have been developed to predict the effects of mutations, but even many of them are computationally intensive or are else dependent on homology or experimental data that may not be available for the protein being studied...
October 16, 2017: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
https://www.readbyqxmd.com/read/29035049/exceptionally-high-proton-and-lithium-cation-gas-phase-basicity-of-the-anti-diabetic-drug-metformin
#11
Ewa Daniela Raczynska, Jean-Francois Gal, Pierre-Charles Maria, Piotr Michalec, Marcin Zalewski
Substituted biguanides are known for their biological effect and a few of them are used as drugs, the most prominent example being metformin (1,1-dimethylbiguanide, IUPAC name: N,N-dimethylimidodicarbonimidic diamide). Owing to the presence of hydrogen atoms at the amino groups, biguanides exhibit a multiple tautomerism. This aspect of their structures was examined in detail for unsubstituted biguanide and metformin in the gas phase. At the DFT level {essentially B3LYP/6-311+G(d,p)}, the most stable structures correspond to the conjugated, push-pull, system (NR2)(NH2)C=N-C(=NH)NH2 (R= H, CH3), further stabilized by an internal hydrogen bond...
October 16, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/29034683/a-budding-defective-m2-mutant-exhibits-reduced-membrane-interaction-insensitivity-to-cholesterol-and-perturbed-interdomain-coupling
#12
Alice Lydia Herneisen, Indra Dev Sahu, Robert M McCarrick, Jimmy B Feix, Gary A Lorigan, Kathleen P Howard
Influenza A M2 is a membrane-associated protein with a C-terminal amphipathic helix that plays a cholesterol-dependent role in viral budding. An M2 mutant with alanine substitutions in the C-terminal amphipathic helix is deficient in viral scission. With the goal of providing atomic-level understanding of how the wild-type protein functions, we used a multi-pronged site-directed spin labeling electron paramagnetic spectroscopy (SDSL-EPR) approach to characterize the conformational properties of the alanine mutant...
October 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/29034185/ashtawarga-plants-suffering-a-triple-standardization-syndrome
#13
REVIEW
Jaswinder Kaur Virk, Vikas Gupta, Sanjiv Kumar, Ranjit Singh, Parveen Bansal
Ayurveda is one of the oldest known holistic health care systems recommending diverse medicinal uses of plants for prevention and cure of diseases and illness. World Health Organization (WHO) estimates that the holistic system is gaining more popularity due to its easy availability, low cost, congeniality, better accessibility and higher safety than allopathic medicine. Demand of herbal drugs is increasing day-by-day because of increasing popularity of herbal drugs; however market fails to meet this supply due to numerous factors, one of the important factors being the extinction of these plants from local flora...
October 2017: Journal of Traditional and Complementary Medicine
https://www.readbyqxmd.com/read/29031225/cube-shaped-theranostic-paclitaxel-prodrug-nanocrystals-with-surface-functionalization-of-spc-and-mpeg-dspe-for-imaging-and-chemotherapy
#14
Fuqiang Guo, Jiajia Shang, Hai Zhao, Kangrong Lai, Yang Li, Zhongxiong Fan, Zhenqing Hou, Guanghao Su
As one of nanomedicine delivery systems (NDSs), drug nanocrystals exhibited an excellent anticancer effect. Recently, differences of internalization mechanisms and subcellular localization of both drug nanocrystals and small molecular free drug have drawn much attention. In this paper, paclitaxel (PTX) as a model anticancer drug was directly labeled with 4-chloro-7-nitro-1, 2, 3-benzoxadiazole (NBD-Cl) (a drug-fluorophore conjugate Ma et al. (2016) and Wang et al. (2016) [1,2] (PTX-NBD)). PTX-NBD was synthesized by nucleophilic substitution reaction of PTX with NBD-Cl in high yield and characterized by fluorescence, XRD, ESI-MS, and FT-IR analysis...
October 5, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/29030430/direct-binding-to-integrins-and-loss-of-disulfide-linkage-in-il-1%C3%AE-are-involved-in-the-agonistic-action-of-il-1%C3%AE
#15
Yoko K Takada, Jessica Yu, Masaaki Fujita, Jun Saegusa, Chun-Yi Wu, Yoshikazu Takada
There is a strong link between integrins and IL-1β, but the specifics of the role of integrins in IL-1β signaling are unclear. We describe that IL-1β specifically bound to integrins αvβ3 and α5β1. The E128K mutation in the IL1R-binding site enhanced integrin binding. We studied if direct integrin binding is involved in IL-1β signaling. We compared sequences of IL-1β and IL-1 receptor antagonist (IL1RN), which is an IL-1β homologue but has no agonistic activity. Several surface-exposed Lys residues are present in IL-1β, but not in IL1RN...
October 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29029547/nanoformulations-of-curcumin-an-emerging-paradigm-for-improved-remedial-application
#16
REVIEW
Meeta Gera, Neelesh Sharma, Mrinmoy Ghosh, Do Luong Huynh, Sung Jin Lee, Taesun Min, Taeho Kwon, Dong Kee Jeong
Curcumin is a natural polyphenol and essential curcuminoid derived from the rhizome of the medicinal plant Curcuma longa (L.) is universally acknowledged as "Wonder drug of life". It is a vital consumable and restorative herb, commonly keened for several ailments such as cancer, arthritis, pain, bruises, gastrointestinal quandaries, swelling and much more. Despite its enormous curative potential, the poor aqueous solubility and consequently, minimal systemic bioavailability with rapid degradation are some of the major factors which restrict the utilization of curcumin at medical perspective...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29029317/the-critical-role-of-supply-chains-in-preventing-human-immunodeficiency-virus-drug-resistance-in-low-and-middle-income-settings
#17
Thomas Minior, Meaghan Douglas, Dianna Edgil, Meena Srivastava, John Crowley, Jacqueline Firth, Ilana Lapidos-Salaiz, Jason Williams, Lana Lee
The functioning of the supply chain may be a driving factor behind the development of human immunodeficiency virus (HIV) drug resistance (HIVDR) in many low- and middle-income countries (LMICs). Additionally, the effectiveness of supply chains will likely impact the scale-up of both viral-load monitoring and HIVDR testing. This article describes the complexities of global supply chains relevant for LMICs and presents early data on stock-outs and drug substitutions in several countries supported by the US President's Emergency Plan for AIDS Relief...
October 6, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29028541/tuning-the-structure-of-aminoferrocene-based-anticancer-prodrugs-to-prevent-their-aggregation-in-aqueous-solution
#18
Steffen Daum, Svetlana Babiy, Helen Konovalova, Walter Hofer, Alexander Shtemenko, Natalia Shtemenko, Christina Janko, Christoph Alexiou, Andriy Mokhir
Aminoferrocene-based prodrugs are activated in cancer cells by reactive oxygen species (ROS). They were shown to exhibit high cytotoxicity towards a variety of cancer cell lines and primary cancer cells, but remain not toxic towards non-malignant cells. However, these prodrugs have rather high lipophilicity leading to relatively low water solubility. In particular, an n-octanol/water partition coefficient for the best aminoferrocene-based prodrug (2) was found to be 4.51±0.03. Though the approaches for decreasing lipophilicity are straightforward and include the addition of polar residues to the drug structure, these modifications also lead to dramatic decrease of cell permeability and, correspondingly, lower the activity of the drug...
September 15, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29027562/monomeric-and-dimeric-coordinatively-saturated-and-substitutionally-inert-ru-ii-polypyridyl-complexes-as-anticancer-drug-candidates
#19
REVIEW
Anna Notaro, Gilles Gasser
Due to the increasing impact of cancer on worldwide mortality, more and more attention is being devoted to the investigation of novel anticancer strategies. Among these, chemotherapy plays a key role in fighting cancer. This explains the increasing engagement of both the pharmaceutical industry and academia towards the discovery of new chemotherapeutic agents. In recent years, metal-based drugs have attracted much attention due to their atypical physico-chemical properties compared to organic molecules. After the approval of cisplatin as a chemotherapeutic agent in 1978, several types of metal-based drugs have been explored...
October 13, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/29026839/missing-the-benefit-of-metformin-in-acute-myeloid-leukemia-a-problem-of-contrast
#20
Alice C Ceacareanu, George K Nimako, Zachary A P Wintrob
OBJECTIVE: To evaluate whether metformin's cancer-related benefits reported in patients with solid tumors (ST) are also present in acute myeloid leukemia (AML) patients. METHODS: Baseline demographic and clinical history for all diabetes mellitus patients newly diagnosed with AML or cancer of the breast, ovary, prostate, gastrointestinal tract, lung, or kidney at Roswell Park Cancer Institute in Buffalo, NY (January 2003-December 2010, n = 924) was collected. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan-Meier (KM) analysis and Cox proportional hazards regression (hazard ratio [HR])...
July 2017: Journal of Research in Pharmacy Practice
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