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      NYX‐2925, A Novel N‐methyl‐D‐aspartate Receptor Modulator: A First‐in‐Human, Randomized, Double‐blind Study of Safety and Pharmacokinetics in Adults

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          Abstract

          NYX‐2925, a new chemical entity, acts as a co‐agonist to glutamate at the N‐methyl‐D‐aspartate receptor ( NMDAR). At low concentrations of endogenous agonists (glycine/D‐serine), NYX‐2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX‐2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. In this first‐in‐human, phase I, single‐ascending dose (50–1,200 mg) and multiple‐ascending dose (150–900 mg) study, the safety, tolerability, and pharmacokinetics (PKs) of NYX‐2925 were evaluated in 84 healthy adult volunteers. No safety concerns emerged, including no dissociative side effects. NYX‐2925 exhibited dose‐proportional PKs and minimal accumulation following once‐daily dosing for 7 days. Cerebrospinal fluid ( CSF) measurements confirmed that NYX‐2925 crosses the blood brain barrier, with maximum CSF concentrations approximating 6–9% of maximum plasma concentrations at the same dose level. NYX‐2925 was safe and well‐tolerated in healthy volunteers, and the study results support the continued clinical development for chronic pain conditions.

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          Neuropathic pain in the general population: a systematic review of epidemiological studies.

          Most patients with neuropathic pain symptoms present and are managed in primary care, with only a minority being referred for specialist clinical assessment and diagnoses. Previous reviews have focused mainly on specific neuropathic pain conditions based in specialist settings. This is the first systematic review of epidemiological studies of neuropathic pain in the general population. Electronic databases were searched from January 1966 to December 2012, and studies were included where the main focus was on neuropathic pain prevalence and/or incidence, either as part of a specific neuropathic pain-related condition or as a global entity in the general population. We excluded studies in which data were extracted from pain or other specialist clinics or focusing on specific population subgroups. Twenty-one articles were identified and underwent quality assessment and data extraction. Included studies differed in 3 main ways: method of data retrieval, case ascertainment tool used, and presentation of prevalence/incidence rates. This heterogeneity precluded any meta-analysis. We categorised comparable incidence and prevalence rates into 2 main subgroups: (1) chronic pain with neuropathic characteristics (range 3-17%), and (2) neuropathic pain associated with a specific condition, including postherpetic neuralgia (3.9-42.0/100,000 person-years [PY]), trigeminal neuralgia (12.6-28.9/100,000 PY), painful diabetic peripheral neuropathy (15.3-72.3/100,000 PY), glossopharyngeal neuralgia (0.2-0.4/100,000 PY). These differences highlight the importance of a standardised approach for identifying neuropathic pain in future epidemiological studies. A best estimate of population prevalence of pain with neuropathic characteristics is likely to lie between 6.9% and 10%. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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            A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.

            A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
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              Cloned glutamate receptors.

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                Author and article information

                Contributors
                torstenmadsen@aptinyx.com
                Journal
                Clin Transl Sci
                Clin Transl Sci
                10.1111/(ISSN)1752-8062
                CTS
                Clinical and Translational Science
                John Wiley and Sons Inc. (Hoboken )
                1752-8054
                1752-8062
                29 September 2018
                March 2019
                : 12
                : 2 ( doiID: 10.1111/cts.v12.2 )
                : 164-171
                Affiliations
                [ 1 ] Aptinyx Inc. Evanston Illinois USA
                [ 2 ] Spaulding Clinical Research LLC West Bend Wisconsin USA
                Author notes
                [*] [* ]Correspondence: Torsten M. Madsen ( torstenmadsen@ 123456aptinyx.com )
                Article
                CTS12584
                10.1111/cts.12584
                6440576
                30242962
                0c9e06a1-a42a-4773-aa63-903d375c7110
                © 2018 Aptinyx Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 25 May 2018
                : 04 August 2018
                Page count
                Figures: 3, Tables: 3, Pages: 8, Words: 6757
                Funding
                Funded by: Aptinyx Inc
                Categories
                Article
                Research
                Articles
                Custom metadata
                2.0
                cts12584
                March 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:29.03.2019

                Medicine
                Medicine

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