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      Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial

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          Abstract

          Background

          Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial.

          Methods

          This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20–65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed.

          Findings

          All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached C max at the end of administration. Plasma AM rapidly returned to baseline concentrations after termination, with a T 1/2 of under 60 min.

          Interpretation

          This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.

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          Most cited references 24

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          Inflammatory bowel disease in Asia: a systematic review.

          The incidence and prevalence of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are lower in Asia than in the West. However, across Asia the incidence and prevalence of IBD has increased rapidly over the last two to four decades. These changes may relate to increased contact with the West, westernization of diet, increasing antibiotics use, improved hygiene, vaccinations, or changes in the gut microbiota. Genetic factors also differ between Asians and the Caucasians. In Asia, UC is more prevalent than CD, although CD incidence is rapidly increasing in certain areas. There is a male predominance of CD in Asia, but a trend towards equal sex distribution for UC. IBD is diagnosed at a slightly older age than in the West, and there is rarely a second incidence peak as in the West. A positive family history is much less common than in the West, as are extra-intestinal disease manifestations. There are clear ethnic differences in incidence within countries in Asia, and an increased incidence in IBD in migrants from Asia to the West. Research in Asia, an area of rapidly changing IBD epidemiology, may lead to the discovery of critical etiologic factors that lead to the development of IBD. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
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            Acute and chronic responses associated with adrenomedullin administration in experimental colitis.

            Adrenomedullin (AM) is a 52 amino acid peptide and member of the calcitonin gene-related peptide (CGRP) super family. Given that AM has emerged as a potential immuno-regulatory and anti-inflammatory agent in various experimental models, this study has deepened into its possible therapeutic effect in intestinal inflammation analyzing the responses in both acute and chronic (14 and 21 days) phases of TNBS-induced colitis in rats. In the acute model, AM treatment reduced the incidence of diarrhea and the severity of colonic damage, and improved the survival rate at the three doses assayed (50, 100, and 200ng/kg animal). AM administration was able to reduce the early production of TNF-alpha and collaborated to maintaining basal levels of IFN-gamma and IL-10. In the chronic studies the peptide attenuated the extent of the damage with lesser incidence of weight loss and diarrhea (50 and 100ng/kg animal). Cellular neutrophil infiltration, with the subsequent increase in myeloperoxidase (MPO) levels caused by TNBS, was reduced after chronic AM administration. The peptide played a role in the evolution of Th1/Th2 cytokines balance and chronic disease recuperation: levels of proinflammatory TNF-alpha and IFN-gamma decreased and anti-inflammatory IL-10 increased significantly. Cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) protein expression were not modified by AM administration, although a reduction of nitric oxide (NO) production could be detected in the chronic model. These results support a role of AM as an anti-inflammatory factor with beneficial effects in intestinal inflammatory colitis.
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              Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn's disease.

              Urocortin 1 (UCN) and adrenomedullin (AM) are two recently discovered neuropeptides that, due to their distribution and binding to receptors in immune cells, have emerged as potential endogenous anti-inflammatory factors. Crohn's disease is a chronic debilitating disease characterised by a Th1 driven severe inflammation of the gastrointestinal tract. This study investigated the therapeutic effect of UCN and AM in a murine model of colitis. Treatment with UCN or AM ameliorated significantly the clinical and histopathological severity of the inflammatory colitis, abrogating body weight loss, diarrhoea, and inflammation, and increased the survival rate of colitic mice. The therapeutic effect was associated with downregulation of both inflammatory and Th1 driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. In addition, partial involvement of interleukin 10 secreting regulatory cells in this therapeutic effect was demonstrated. Importantly, UCN or AM treatments were therapeutically effective in established colitis and avoided recurrence of the disease. This work identifies UCN and AM as two potent anti-inflammatory factors with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, both peptides represent novel multistep therapeutic approaches for the treatment of Crohn's disease and other Th1 mediated inflammatory diseases.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                06 January 2020
                2020
                : 14
                : 1-11
                Affiliations
                [1 ]Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki , Miyazaki, Japan
                [2 ]Souseikai Hakata Clinic , Fukuoka, Japan
                Author notes
                Correspondence: Toshihiro Kita Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki , 5200 Kihara, Miyazaki889-1692, JapanTel +81-985-85-0872Fax +81-985-85-6596 Email toshihiro_kita@med.miyazaki-u.ac.jp
                Article
                225220
                10.2147/DDDT.S225220
                6955635
                © 2020 Kita 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 5, References: 25, Pages: 11
                Funding
                Health Labour Sciences Research Grant and Research Fund from the Japanese Agency for Medical Research and Development (AMED).
                Categories
                Clinical Trial Report

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