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      Identification and characterization of related substances in EVT-401 by hyphenated LC–MS techniques

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          Abstract

          A sensitive and selective method was developed for the separation and characterization of related substances (RSs) in EVT-401 by hyphenated LC–MS techniques. Complete separation of the RSs was achieved with an Inertsil ODS-SP column (250 mm×4.6 mm, 5 µm) by linear gradient elution using a mobile phase consisting of 0.2% formic acid solution, methanol and acetonitrile. EVT-401 was found to be susceptible to acid, alkaline and oxidative stresses, while relatively stable under photolytic and thermal dry stress conditions. Fourteen RSs including six process-related substances and eight degradation products were detected and identified in EVT-401 with positive ESI high-resolution TOF-MS analysis of their parent ions and the corresponding product mass spectra elucidation, and some of them were further verified by chemical synthesis and NMR spectroscopy. The specific LC–MS method developed for separation, identification and characterization of RSs is valuable for EVT-401 manufacturing process optimization and quality control.

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          Most cited references 6

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          The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease.

          The P2X7 receptor is a trimeric ATP-gated cation channel found predominantly, but not exclusively, on immune cells. P2X7 activation results in a number of downstream events, including the release of proinflammatory mediators and cell death and proliferation. As such, P2X7 plays important roles in various inflammatory, immune, neurologic and musculoskeletal disorders. This review focuses on the use of P2X7 antagonists in rodent models of neurologic disease and injury, inflammation, and musculoskeletal and other disorders. The cloning and characterization of human, rat, mouse, guinea pig, dog, and Rhesus macaque P2X7, as well as recent observations regarding the gating and permeability of P2X7, are discussed. Furthermore, this review discusses polymorphic and splice variants of P2X7, as well as the generation and use of P2X7 knockout mice. Recent evidence for emerging signaling pathways downstream of P2X7 activation and the growing list of negative and positive modulators of P2X7 activation and expression are also described. In addition, the use of P2X7 antagonists in numerous rodent models of disease is extensively summarized. Finally, the use of P2X7 antagonists in clinical trials in humans and future directions exploring P2X7 as a therapeutic target are described. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
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            A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases.

            The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R knockout mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases. We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as anti-inflammatory agents. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in Phase I and II clinical trials of P2X7R antagonists are covered. Recent studies using gene knockout mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of development. Future challenges include: identifying potential toxicity and side effects of treatment, timing of treatment initiation and its duration in chronic inflammatory conditions, optimum dosage and development of a functional assay for P2X7R that would help to guide treatment.
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              Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states.

              ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Both the localization and functional consequences of P2X(7) receptor activation indicate a role in inflammatory processes. The phenotype of P2X(7) receptor gene-disrupted mice also indicates that P2X(7) receptor activation contributes to ongoing inflammation. More recently, P2X(7) receptor knockout data has also suggested a specific role in inflammatory and neuropathic pain states. The recent discovery of potent and highly selective antagonists for P2X(7) receptors has helped to further clarify P2X receptor pharmacology, expanded understanding of P2X(7) receptor signaling, and offers new evidence that P2X(7) receptors play a specific role in nociceptive signaling in chronic pain states. In this review, we incorporate the recent discoveries of novel P2X(7) receptor-selective antagonists with a brief update on P2X(7) receptor pharmacology and its therapeutic potential.
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                Author and article information

                Contributors
                Journal
                J Pharm Anal
                J Pharm Anal
                Journal of Pharmaceutical Analysis
                Xi'an Jiaotong University
                2095-1779
                2214-0883
                31 March 2017
                August 2017
                31 March 2017
                : 7
                : 4
                : 223-230
                Affiliations
                [a ]Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education; Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
                [b ]Department of Chemical Drug Control, Hubei Institute for Food and Drug Control, Wuhan 430074, China
                [c ]Department of Pharmacy, Taizhou First People's Hospital, Taizhou 318200, China
                Author notes
                [* ]Corresponding author. hangtj@ 123456cpu.edu.cn
                Article
                S2095-1779(17)30044-8
                10.1016/j.jpha.2017.03.008
                5790700
                © 2017 Xi'an Jiaotong University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Original Research Article

                degradation products, evt-401, lc–ms, related substances

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