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Bypassing agent

Bharathkumar Inturi, Gurubasavaraj V Pujar, Madhusudhan N Purohit
Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB)...
October 24, 2016: Archiv der Pharmazie
Gabor Nagy, Viktoria Baksa, Alexandra Kiss, Melinda Turani, Gaspar Banfalvi
The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd(3+) ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd(3+) treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time...
October 22, 2016: Apoptosis: An International Journal on Programmed Cell Death
Wenyan Xu, Daniel Kool, Derek K O'Flaherty, Ashley Keating, Lauralicia Sacre, Martin Egli, Anne Marietta Noronha, Christopher James Wilds, Linlin Zhao
DNA interstrand cross-links (ICLs) are cytotoxic DNA lesions derived from reactions of DNA with a number of anti-cancer reagents as well as endogenous bifunctional electrophiles. Deciphering the DNA repair mechanisms of ICLs is important for understanding the toxicity of DNA cross-linking agents and for the development of effective chemotherapies. Previous research has focused on ICLs cross-linked with the N7 and N2 atoms of guanine as well as those formed at the N6 atom of adenine; however, little is known about the mutagenicity of O6-dG-derived ICLs...
October 21, 2016: Chemical Research in Toxicology
J N Mahlangu, T A Andreeva, D E Macfarlane, C Walsh, N S Key
INTRODUCTION: Development of inhibitors to human FVIII (hFVIII) significantly complicates the control of bleeding events in patients with haemophilia A. AIM: This prospective, multicentre, open-label, non-comparative, Phase II study evaluated the haemostatic activity of a recombinant B-domain-deleted porcine FVIII (r-pFVIII), in the treatment of non-life/non-limb-threatening bleeding in individuals with haemophilia A and FVIII inhibitors. METHODS: Acute bleeding episodes in patients with pFVIII inhibitor titres <0...
October 20, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
C Michael White, Elaine Nguyen
OBJECTIVE: To review the limitations of current antiarrhythmic drugs in atrial fibrillation (AF) and discuss the rationale and clinical trials supporting the use of ranolazine in AF. DATA SOURCES: MEDLINE was searched from 1980 to September 2016 using the terms ranolazine, atrial fibrillation, coronary artery bypass grafting, and valve surgery STUDY SELECTION AND DATA EXTRACTION: English-language studies and reviews assessing antiarrhythmic drugs, including ranolazine, were incorporated...
October 6, 2016: Annals of Pharmacotherapy
S K Zyryanov, D Yu Belousov, E V Afanas'eva, E V Dumchenko
AIM: Clinical and economic examinations were made to study whether it is appropriate to use antiplatelet therapy (APT) with ticagrelor in combination with acetylsalicylic acid (ASA) versus a combination of clopidogrel and ASA in patients with acute coronary syndrome (ACS) following coronary artery bypass surgery (CABS). MATERIAL AND METHODS: A budget impact analysis was used. Data on the efficiency and safety of APT were taken from a relevant analysis in the subgroups of the randomized controlled trial PLATO...
2016: Terapevticheskiĭ Arkhiv
Kazuya Shirato, Kazuhiko Kanou, Miyuki Kawase, Shutoku Matsuyama
: Human coronavirus 229E (HCoV-229E), a causative agent of the common cold, enters host cells via two distinct pathways: one is mediated by cell surface proteases, particularly transmembrane protease serine 2 (TMPRSS2), and the other by endosomal cathepsin L. Thus, specific inhibitors of these proteases block virus infection. However, it is unclear which of these pathways is actually utilized by HCoV-229E in the human respiratory tract. Here, we examined the mechanism of cell entry used by a pseudotyped virus bearing the HCoV-229E spike (S) protein in the presence/absence of protease inhibitors...
October 12, 2016: Journal of Virology
Wenda Zhang, Ting Ma, Shanshan Li, Yanwei Yang, Jianpeng Guo, Wenying Yu, Lingyi Kong
STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC50 range in 0.33-0.75 μM in various cancer cell lines...
September 22, 2016: European Journal of Medicinal Chemistry
Amritaj Patra, Qianqian Zhang, F Peter Guengerich, Martin Egli
O6-Methyl-2(prime)-deoxyguanosine (O6-MeG) is a ubiquitous DNA lesion, formed not only by xenobiotic carcinogens but also by the endogenous methylating agent S-adenosylmethionine. It can introduce mutations during DNA replication, with different DNA polymerases displaying different ratios of correct or incorrect incoporation opposite this nucleoside. Of the "translesion" Y-family human DNA polymerases (hpols), hpol η is most efficient in incorporating equal numbers of correct and incorrect C and T bases. However, the mechanistic basis for this specific yet indescriminate activity is not known...
September 30, 2016: Journal of Biological Chemistry
Rajendra Prasad, Vladimir Poltoratsky, Esther W Hou, Samuel H Wilson
Rev1 is a member of the Y-family of DNA polymerases and is known for its deoxycytidyl transferase activity that incorporates dCMP into DNA and its ability to function as a scaffold factor for other Y-family polymerases in translesion bypass events. Rev1 also is involved in mutagenic processes during somatic hypermutation of immunoglobulin genes. In light of the mutation pattern consistent with dCMP insertion observed earlier in mouse fibroblast cells treated with a base excision repair-inducing agent, we questioned whether Rev1 could also be involved in base excision repair (BER)...
September 28, 2016: Nucleic Acids Research
Arman Qamar, Deepak L Bhatt
Thrombotic events such as myocardial infarction or stent thrombosis are the major cause of adverse outcomes in patients undergoing percutaneous coronary intervention (PCI). While current antiplatelet agents, anticoagulants, and PCI techniques have reduced the risk of thrombotic events in PCI-treated patients, a considerable hazard still remains. Cangrelor is an intravenous P2Y12 receptor antagonist that provides a rapid onset and maximal platelet inhibition, which is quickly reversible. In the large-scale CHAMPION PHOENIX trial, cangrelor was shown to reduce ischemic events significantly, including myocardial infarction and stent thrombosis, without increasing the risk of severe bleeding across the full spectrum of patients undergoing PCI, with substantial benefits in all patient subgroups examined...
September 27, 2016: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
Yiling Lu, Shiyun Ling, Apurva M Hegde, Lauren A Byers, Kevin Coombes, Gordon B Mills, Rehan Akbani
The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents...
August 2016: Seminars in Oncology
Braganza Veena, Rajinish Samal, Leeberk R Inbaraj, Carolin Elizabeth George
BACKGROUND: Prostaglandins are popular agents for induction of labour, owing to their dual action of cervical ripening and inducing uterine contractions. Sublingual misoprostol offers high efficacy as it bypasses first-pass metabolism. Researchers have proved that intracervical PGE1 is as effective as PGE2 except for increased caesarean rate and hyperstimulation. Limited knowledge is available on the efficacy of sublingual PGE1 and intracervical PGE2. This study was designed to compare the effectiveness of sublingual PGE1 with intracervical PGE2...
October 2016: Journal of Obstetrics and Gynaecology of India
Michael Losos, Scott Scrape, Sarita Joshi, Aaron Shmookler, Jian Chen
Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents...
September 20, 2016: Journal of Clinical Apheresis
Jesse A Jones, Kristopher G Virga, Giuseppe Gumina, Kirk E Hevener
: This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents...
September 1, 2016: MedChemComm
Mina Golestani, Peyman Eshghi, Hamid Reza Rasekh, Abdoll Majid Cheraghali, Jamshid Salamzadeh, Majid Naderi, Mohammad Reza Managhchi, Hamid Hoorfar, Gholam Reza Toogeh, Ali Imani, Mohammad Taghi Khodayari, Behnaz Habibpanah, Razieh Hantooshzadeh
Nowadays, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCC) are used to treat bleeding episodes in the Hemophilia patients with inhibitors. AryoSeven® is an Iranian biogeneric rFVIIa with homogeneity of efficacy and the nature to NovoSeven in a comparative trial. The current clinical trial aimed to evaluate the cost-effectiveness of FEIBA and AryoSeven® by Decision Analytic Model according to the Iranian healthcare system. An open label, multi-center, cross-over clinical trial was designed...
2016: Iranian Journal of Pharmaceutical Research: IJPR
Maxine Swee-Li Yee, Poi-Sim Khiew, Wee Siong Chiu, Yuen Fen Tan, Yih-Yih Kok, Chee-Onn Leong
Fouling of marine surfaces has been a perpetual problem ever since the days of the early sailors. The tenacious attachment of seaweed and invertebrates to man-made surfaces, notably on ship hulls, has incurred undesirable economic losses. Graphene receives great attention in the materials world for its unique combination of physical and chemical properties. Herein, we present a novel 2-step synthesis method of graphene-silver nanocomposites which bypasses the formation of graphene oxide (GO), and produces silver nanoparticles supported on graphene sheets through a mild hydrothermal reduction process...
September 9, 2016: Colloids and Surfaces. B, Biointerfaces
Timothy A Marlowe, Felicia L Lenzo, Sheila A Figel, Abigail T Grapes, William G Cance
Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms which drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTKs) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397)...
September 16, 2016: Molecular Cancer Therapeutics
Shital Lungare, Keith Hallam, Raj K S Badhan
Central nervous system (CNS) drug delivery is often hampered due to the insidious nature of the blood-brain barrier (BBB). Nose-to-brain delivery via olfactory pathways have become a target of attention for drug delivery due to bypassing of the BBB. The antioxidant properties of phytochemicals make them promising as CNS active agents but possess poor water solubility and limited BBB penetration. The primary aim of this study was the development of mesoporous silica nanoparticles (MSNs) loaded with the poorly water-soluble phytochemicals curcumin and chrysin which could be utilised for nose-to-brain delivery...
September 12, 2016: International Journal of Pharmaceutics
Zdeněk Fryšák, David Karásek
UNLABELLED: Decrease of blood glucose levels below 3 mmol/l is in fully developed cases accompanied by neuroglycopenic symptoms that may even lead to altered state of consciousness. The treating physician frequently faces a complicated situation. This may be due to inappropriately administered drugs including cases motivated by self-harm intentions (insulin, insulin secretagogues), or alcohol abuse. Undernourished people, or those afflicted with a serious systemic infection, end-stage liver or kidney diseases or with a failing heart, belong to a risk group...
2016: Vnitr̆ní Lékar̆ství
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