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.

Inclusion Criteria:

1. Healthy male and female volunteers
2. BMI of 18-40 kg/m2
3. Aged 18-45
4. Volunteers who are willing to sign the consent form

Exclusion Criteria:

1. Healthy subjects unwilling to consent
2. Smokers
3. Known sensitivity to Racecadotril
4. History of any serious illnesses, including recent infections or trauma
5. A personal history of keloid scarring, or a family history of keloid scarring in a first degree relative with similar skin pigmentation
6. Subjects taking systemic medication (other than the oral contraceptive pill)
7. 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
8. Women who are breastfeeding
9. Subjects with recent or current antibiotic use
10. Subjects with a history of skins conditions.
11. Subjects with a history of allergic reaction to any topical application or history of angioedema
12. Subjects with any history of a blood-borne infectious disease such Hepatitis B or C virus, or HIV.