Influence of NEP Inhibition on Vascular Leak and Inflammation (NEPi-INFLAMMATION)

Assessment of the Effect of Neutral Endopeptidase Inhibition on Vascular Leak and Leukocyte Accumulation in a Human Cantharidin Blister Model

Acute Respiratory Distress Syndrome (ARDS) is a severe type of lung injury that affects 10% of patients admitted to Intensive Care Units worldwide, with an unacceptably high mortality of up to 48% in those with the most severe form of the condition. It is a complex and poorly understood syndrome that results in progressive failure of the lungs. Crucially, the inflamed lungs allow fluid to leak from the circulation into the airspace, so that patients' lungs fill with fluid - "drowning from the inside". As this condition progresses, the patient typically requires increasing amounts of oxygen and eventually, support from a ventilator. To date, there are no effective treatments for ARDS that can limit, stop or repair this process. This research study is aiming to look at a naturally occurring substance produced by blood vessels, C-type natriuretic peptide (CNP). The investigators have evidence suggesting that CNP plays a role in maintaining the barrier provided by blood vessels that stops fluid leaking out into tissues. This is based on various studies done on CNP by the investigators research group that have established its widespread role in maintaining cells that line blood vessels and play a vital role in lungs' barrier function: the endothelium. CNP is broken down in part by an enzyme called Neutral endopeptidase and therefore, drugs that inhibit this enzyme would result in increased CNP concentration and activity. If CNP does in fact strengthen the lungs' endothelial barrier, then this class of drug may benefit patients with ARDS. The aim of this experimental medicine study is to assess the effect of using the licensed NEP inhibitor Racecadotril, in a well-established, safe model of inflammation-induced skin blisters in healthy human volunteers to determine primarily whether the fluid accumulation i.e. leak, in these blisters is reduced by treatment with this drug.

Powered unpaired inter-patient comparison of change in blister fluid volume following Racecadotril or placebo administration.

Powered paired intra-patient comparison of change in blister fluid volume following Racecadotril or placebo admininstration.

Powered comparison of sex differences in change in blister volume following Racecadotril or placebo administration.

Difference in concentration of blister fluid cytokines; specifically Interleukin (IL) -1β, IL-6, IL-8, IL-10, CXCL1, CXCL2, CCL5 and CCL2 in volunteers receiving Racecadotril compared to placebo.

Comparison of change in blister fluid leukocyte count following Racecadotril or placebo administration

Comparison of change in pro and anti-inflammatory mediators from blister fluid following Racecadotril or placebo administration

Inclusion Criteria: Healthy male and female volunteers BMI of 18-40 kg/m2 Aged 18-45 Volunteers who are willing to sign the consent form Exclusion Criteria: Healthy subjects unwilling to consent Smokers Known sensitivity to Racecadotril History of any serious illnesses, including recent infections or trauma A personal history of keloid scarring, or a family history of keloid scarring in a first degree relative with similar skin pigmentation Subjects taking systemic medication (other than the oral contraceptive pill) Subjects who are pregnant or any possibility that a subject may be pregnant, unless in the latter case a pregnancy test is performed with a negative result Women who are breastfeeding Subjects with recent or current antibiotic use Subjects with a history of skins conditions. Subjects with a history of allergic reaction to any topical application or history of angioedema Subjects with any history of a blood-borne infectious disease such Hepatitis B or C virus, or HIV.

Fully anonymised data will be shared with fellow researchers via conference presentation and via publication of the results in scientific journals. Data will be shared between the research team directly undertaking the research