Adrenomedullin: A Novel Therapy for Intractable Crohn's Disease with a Loss of Response to Infliximab

Ashizuka, Shinya; Kuroishi, Nobuko; Nakashima, Kenichiro; Inatsu, Haruhiko; Kita, Toshihiro; Kïtamura, Kazuo

doi:10.2169/internalmedicine.1791-18

Cited by 10 publications

(13 citation statements)

References 15 publications

(15 reference statements)

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“…11 AM has also shown high efficacy in the treatment of intractable Crohn's disease with a loss of response to infliximab. 12 These data strongly suggest that AM is a novel potent therapeutic agent for IBD. 13 Additionally, AM is an endogenous peptide; thus, it is expected to be safe for patients without the need for excessive immune-suppression and antibody production.…”

Section: Introductionmentioning

confidence: 92%

“…An important factor for developing the phase 1 protocol is that AM showed anti-inflammatory and wound healing effects in IBD patients within subdepressor dose. 11,12 Therefore, the development of an AM formulation as a therapeutic agent for IBD, and confirmation of the upper safe and tolerable limits of AM, particularly the limit for an acceptable vasodilating influence, are crucial. This paper reports the results of the phase 1 trial, which included single-dose and multipledose administration tests using AM in healthy males through a placebo-controlled double-blinded study.…”

Section: Introductionmentioning

confidence: 99%

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

Kita¹,

Kaji²,

Kïtamura³

2020

DDDT

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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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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Kita¹,

Kaji²,

Kïtamura³

2020

DDDT

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“…We observed a decrease in serum IL-6 and TNF-α 8 h after AM administration (Figure 5, case A-C) [45]. In patients with refractory Crohn's disease with secondary failure of infliximab, continuous intravenous infusion of AM resulted in marked improvement in clinical symptoms and mucosal healing of longitudinal ulcers of the colon, as well as a re-elevation of IFX levels in the blood (Figure 5, case D) [46]. Wide and deep ulcers were observed in the colon before the AM therapy.…”

Section: Translational Research With Adrenomedullinmentioning

confidence: 75%

“…Significant mucosal regeneration and reddening with neovascularization were observed after AM therapy (middle figures). Eight to 12 weeks after treatment with AM, the ulcers had disappeared, and ulcer scars were observed (each right figure) (modified and redrawn from [32,45,46]). UC, ulcerative colitis; CD, Crohn's disease.…”

Section: Translational Research With Adrenomedullinmentioning

confidence: 99%

Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

et al. 2021

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Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment.

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“…10) Therefore, we conducted a clinical study in patients with inflammatory bowel disease (IBD). 11,12) However, in these studies, long-term intravenous infusion of AM was necessary because it has a half-life of approximately 20 min. 13) To overcome this issue, we investigated AM derivatives to increase the half-life of AM.…”

Section: Introductionmentioning

confidence: 99%

Activation of Calcitonin Gene-Related Peptide and Adrenomedullin Receptors by PEGylated Adrenomedullin

Akashi

Nagata

Yamasaki

et al. 2020

Biological & Pharmaceutical Bulletin

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Adrenomedullin (AM) improves colitis in animal models and patients with inflammatory bowel disease. We have developed a PEGylated AM derivative (PEG-AM) for clinical application because AM has a short half-life in the blood. However, modification by addition of polyethylene glycol (PEG) may compromise the function of the original peptide. In this paper, we examined the time course of cAMP accumulation induced by 5 and 60 kDa PEG-AM and compared the activation of calcitonin gene-related peptide (CGRP), AM1 and AM2 receptors by AM, 5 and 60 kDa PEG-AM. We also evaluated the effects of antagonists on the action of 5 and 60 kDa PEG-AM. PEG-AM stimulated cAMP production induced by these receptors; the increase in cAMP levels resulting from application of PEG-AM peaked at 15 min. Moreover, PEG-AM activity was antagonized by CGRP (8-37) or AM (22-52) (antagonists of CGRP and AM receptors, respectively) and the maximal response was not suppressed. These findings indicate that the effects of PEG-AM are similar to those of native AM.

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Adrenomedullin: A Novel Therapy for Intractable Crohn's Disease with a Loss of Response to Infliximab

Cited by 10 publications

References 15 publications

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

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

Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

Activation of Calcitonin Gene-Related Peptide and Adrenomedullin Receptors by PEGylated Adrenomedullin

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