Novel TRPM8 agonist cooling compound against chronic itch: results from a randomized, double-blind, controlled, pilot study in dry skin.

BACKGROUND: Patients suffering from chronic pruritus (CP) due to dry skin with are often applying emollients containing menthol. However, topical menthol may be irritating and of weak potency in severe pruritus. Two TRPM8 agonists, (1R,2S,5R)-N-(2-(2-pyridinyl)ethyl)-2-ispropyl-5-methylcyclohexancarboxamide and menthoxypropanediol, combined as cooling compound (CC) have shown stronger activation of TRPM8 than menthol. OBJECTIVES: Objective of this study was to evaluate the efficacy and safety of CC in alleviating pruritus in patients with dry itchy skin. METHODS: In this vehicle-controlled, double-blind, randomized (1 : 1) study, 70 dry skin patients with pruritus intensity measured by Numerical Rating Scale (NRS) ≥3, were treated twice daily over 4 weeks, either with a lotion containing CC or with its vehicle. RESULTS: At treatment end, pruritus, assessed by a global score, improved significantly more in the CC than in the vehicle group (79.2% vs. 47.1%; P < 0.05; primary endpoint). Also assessed by verbal rating scale (VRS) and percentual improvement, pruritus decreased significantly more in the CC group (P = 0.007/P = 0.015) compared to vehicle arm after treatment. Up to 84% of CC-treated patients reported a significant, sometimes too strong, long-lasting cooling effect. The health-related quality of life improved significantly more in the CC group (P = 0.023). Skin roughness, dryness and hydration improved significantly in both groups without significant differences in-between them. There were no severe adverse events reported. CONCLUSIONS: Treatment of dry and pruritic skin with a lotion containing the TRPM8 agonist combination ameliorates severe pruritus and represents a possible novel treatment for the burdensome symptom. The most suitable treatment concentration needs still to be identified. ClinicalTrials.gov: NCT00669708.

Effective treatment for sensitive skin: 4-t-butylcyclohexanol and licochalcone A.

BACKGROUND: More than 50% of adults report to suffer from sensitive skin. This common condition is characterized by subjective sensations such as prickling, burning, skin tightness or pruritus, and is often accompanied by objective symptoms like inflammation and erythema. OBJECTIVE: The objective of this study was to develop an active ingredient concept for the treatment of sensitive skin. We tested compounds regarding their potential to (i) decrease the release of proinflammatory mediators, which among others induce erythema and (ii) counteract the hyperresponsiveness of nerve fibres and, thus, exert effects on cutaneous neurosensory dysfunction. METHODS: 4-t-butylcyclohexanol, licochalcone A and acetyl dipeptide-1 cetyl ester were analysed in vitro regarding their potential to (i) decrease the release of PGE2 and activation of NFκB and to (ii) inhibit TRPV1 activation or the release of neuronal CGRP. To assess subjective and objective symptoms of skin sensitivity in vivo, two controlled, single-blind, randomized studies were conducted with 4-t-butylcyclohexanol and the combination with licochalcone A. RESULTS: In vitro, 4-t-butylcyclohexanol significantly reduced TRPV1 activation, while acetyl dipeptide-1 cetyl ester had no effect on receptor activation. Licochalcone A significantly decreased NFκB signalling and PGE2 secretion, at lower concentrations than acetyl dipeptide-1 cetyl ester. A formulation containing 4-t-butylcyclohexanol showed a significant immediate anti-stinging/anti-burning effect in vivo, and a cream base containing a combination of 4-t-butylcyclohexanol and a licochalcone A-rich licorice extract reduced shaving-induced erythema. CONCLUSION: In vitro and in vivo data indicate that the combination of the TRPV1 antagonist 4-t-butylcyclohexanol and the potent anti-inflammatory licochalcone A provide an effective active ingredient concept for the treatment of sensitive skin, as the topical application resulted in an immediate relief from symptoms such as erythema and stinging.