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      Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

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          Abstract

          Neuropathy is a serious complication of diabetes that has a significant socioeconomic impact, since it frequently demands high levels of health care consumption and compromises labor productivity. Recently, LASSBio-1471 (3) was demonstrated to improve oral glucose tolerance, reduce blood glucose levels, and display an anti-neuropathy effect in a murine streptozotocin-induced diabetes model. In the present work, we describe the design, synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazone derivatives (referred to herein as compounds 4–9), which were designed by molecular modification based on the structure of the prototype LASSBio-1471 (3). Among the compounds tested, better plasma stability was observed with 4, 5, and 9 in comparison to compounds 6, 7, and 8. LASSBio-1773 (7), promoted not only hypoglycemic activity but also the reduction of thermal hyperalgesia and mechanical allodynia in a murine model of streptozotocin-induced diabetic neuropathic pain.

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          Most cited references 20

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          The burden of neuropathic pain: a systematic review and meta-analysis of health utilities.

          Patients with neuropathic pain (NeuP) experience substantially lower health-related quality of life (HRQoL) than the general population. The aim of this systematic review and meta-analysis is to test the hypothesis that NeuP is associated with low levels of health utility. A structured search of electronic databases (MEDLINE, EMBASE, Cochrane Library and CINAHL) was undertaken. Reference lists of retrieved reports were also reviewed. Studies reporting utility single-index measures (preference based) in NeuP were included. Random effects meta-analysis was used to pool EQ-5D index utility estimates across NeuP conditions. The association of utilities and pre-defined factors (NeuP condition, patient age, sex, duration and severity of pain and method of utility scoring) was examined using meta-regression. Twenty-four studies reporting health utility values in patients with NeuP were included in the review. Weighted pooled utility score across the studies varied from a mean of 0.15 for failed back surgery syndrome to 0.61 for post-herpetic neuralgia and diabetic neuropathy. Although there was substantial heterogeneity (P<0.0001) across studies, we found little variation in utility as a function of patient and study characteristics. The single exception was a significant relationship (P<0.0001) between increasing neuropathic pain severity and a reduction in utility. This study confirms the hypothesis that patients with NeuP experience low utilities and therefore low HRQoL. However, the contribution of non-NeuP co-morbidity remains unclear. Neuropathic pain severity emerged as a primary predictor of the negative health impact of NeuP. Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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            Diabetic neuropathy.

            Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality and resulting in a huge economic burden for diabetes care. The clinical assessment of diabetic peripheral neuropathy and its treatment options are multifactorial. Patients with DN should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications. A review of the clinical assessment and treatment algorithms for diabetic neuropathy, painful neuropathy, and autonomic dysfunction is provided. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy.

              Painful diabetic peripheral neuropathy (pDPN) is prevalent among persons with diabetes and increases over time. Published guidelines recommend a number of medications to treat this condition providing clinicians with a variety of treatment options. This study provides a comprehensive systematic review and meta-analysis of published pharmacologic therapies for pDPN.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                09 September 2016
                : 10
                : 2869-2879
                Affiliations
                [1 ]National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil
                [2 ]Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
                [3 ]Department of Anesthesiology, Fluminense Federal University, Rio de Janeiro, Brazil
                Author notes
                Correspondence: Lídia Moreira Lima, Federal University of Rio de Janeiro, CCS, Bloco B, Sala 14, PO Box 68024, Rio de Janeiro, RJ, 21941-971, Brazil, Tel/fax +55 21 3938 6503, Email lidia@ 123456lassbio.icb.ufrj.br
                Article
                dddt-10-2869
                10.2147/DDDT.S108327
                5024769
                © 2016 Zapata-Sudo et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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