Characterization of a pruritus challenge model

In many dermatological diseases, pruritus (or itch will be used interchangeably) is one of the impactful and burdensome symptoms patients face every day. Although pruritus by itself is seen as a benign symptom, pruritus can have adverse effects on the patients’ wellbeing and daily life. In addition, chronic itch is often accompanied by several unpleasant sensations such as pain or a burning sensation. The mechanisms that underlie pruritus are not well known and are compounded by the subjective nature of itch. In dermatological conditions, itch is mainly caused by inflammation or skin damage. Changes in barrier function of the skin can lead to itch by endogenous mediators or exogenous allergens that come into contact with the skin.
The primary sensory nerve fibers that innervate the skin are categorized into three groups based on the degree of myelination, diameter, and conduction velocity. The thick myelinated Aβ fibers transmit tactile sensation, whereas the thinly myelinated Aδ and unmyelinated C-fibers are mainly involved in the conduction of thermal and pain/itch sensation. Itch is transmitted predominately by these unmyelinated, slow conducting C-fibers. These fibers extend to the dermo-epidermal junction with free endings penetrating into the epidermis where sensation is detected. The cell bodies for these fibers are in the dorsal root ganglia (DRG), just outside the spinal cord. From here, both sensations involve secondary transmission neurons that ascend via the contralateral spinothalamic tract to the thalamus (Garibyan et al 2013).
Pruritogens interact with receptors or ion channels on the nerve fibers. The receptors that are often involved are G-protein coupled receptors (GPCR). GPCRs detect and respond to a diverse range of ligands or stimuli and are the target of many drugs. GPCRs that are relevant to itch respond to histamine, prostaglandins, neuropeptides, and proteases. The ion channels that appear to be primarily involved are members of the transient receptor potential (TRP) family. As an example, TRPV1 detects capsaicin, the active ingredient in chili peppers.
Various drugs with different mechanisms of action are currently in development. These drugs have the potential to lead to targeted therapy of peripheral itch independent of blocking inflammation. For clinical drug development efficient and effective pruritus provoking challenge models in humans are needed. For these purposes a variety of different compounds including cowhage, capsaicin and histamine have been tested. Ample experience has been obtained with histamine also being used as positive control of the skin prick test in allergy testing sued routinely in clinical practice. However, hardly any bioquantitative measurements have been performed to characterize the itch response following histamine injection.
The aim of this study is to characterize the dose-pruritogenic response upon intradermal histamine injection in healthy volunteers and patients with atopic dermatitis. This setup will create a challenge model that temporarily induces skin itch which enables future application as proof-of-pharmacology or drug profiling in drug developmental programs. As histamine is known as low potent pruritogenic agent the study will also enroll atopic dermatitis patients where lesional site will be evaluated to study the difference in pruritus response in patients. With the application oral antihistamine, the reversal of a fixed histamine-dose effect can be investigated in both populations.

This is a set-up for a challenge pruritus model. We expect to initiate a local, reversible itch- response

Screening: up to 35 days before dosing, Day 1, Day 3, EOS

Investigational product: Histamine phosphate
Non-investigational product: Cetirizine 10 mg or placebo