Adrenomedullin Therapy in Patients with Refractory Ulcerative Colitis: A Case Series

Abstract

Background and AimsAdrenomedullin (AM) is a multifunctional biologically active peptide that has an ameliorative effect against inflammatory bowel disease in several experimental models. We reported the first case where AM infusion dramatically improved symptoms and colonoscopy findings in patients with refractory ulcerative colitis (UC). To confirm the reproducibility of the efficacy and safety of AM infusion, this pilot study evaluated the clinical feasibility of intravenous administration of AM in patients with refractory UC.MethodsSeven patients with active refractory UC participated and received intravenous infusion of AM (1.5 pmol/kg/min) for 8 h daily for 14 days, and their Disease Activity Index (DAI) were evaluated before and 2 and 12 weeks after beginning AM administration.ResultsDAI were improved in all patients after AM administration. Within 2 weeks, marked declines in DAI (≥3 points and ≥30 %) were observed in six patients (85.7 %), while a more modest decline was observed in one patient (14.3 %). Overall mean DAI improved from 9.3 ± 0.6 at baseline to 4.6 ± 0.8 at 2 weeks, and then to 1.2 ± 0.5 at 12 weeks. Endoscopic examination revealed substantial amelioration of ulcers, with mucosal healing and scarring. Four patients remained in clinical remission 12 months after AM treatment. AM administration produced significant increases in plasma AM concentrations (approximately 2.5-fold) that had a mild effect on blood pressure and heart rate, but with no serious adverse effects.ConclusionAM is a potentially useful agent that acts via a novel mechanism to safely induce mucosal healing and clinical remission in patients with refractory UC.

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

“…Indeed, the safety of hemodynamic parameters was confirmed in a previous exploratory clinical study, where AM was infused at a dose of 9 ng/kg/ min for 8 h in patients with UC. 11 In the single-dose administration study, significant increases in PR were observed in the medium-and high-dose AM groups, but this did not appear to be dose-dependent (Table 2). SBP and DBP were decreased during the latter half of the infusion process, but similar decreases were observed in the placebo group.…”

“…[5][6][7][8][9][10] Furthermore, AM previously displayed considerable effects in seven patients with UC in an exploratory clinical study. 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.…”

“…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.…”

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice

“…AM has a protective role in gastrointestinal diseases, including IBD, and its administration in rodents (Ashizuka et al, 2009) and humans (Ashizuka et al, 2013, 2016) ameliorates the severity of these gut pathologies, emerging as a new promising therapeutic alternative. However, these results should be considered with care since IBD patients have an elevated risk of developing colitis-associated CRC, and the involvement of AM in tumor progression has become evident in the last years (Larráyoz et al, 2014).…”

Adrenomedullin – new perspectives of a potent peptide hormone

“…Additionally, a first clinical trial on the intravenous injection of ADM in patients suffering from acute myocardial infarction showed an improvement of wall motion and infarct size, suggesting a beneficial treatment in combination with percutaneous coronary intervention [203]. Recently, intravenous infusion of ADM has also been reported to exhibit powerful effects in the treatment of ulcerative inflammatory bowel disease [204].…”