Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy

Sonja Ständer, Dorothee Siepmann, Ilka Herrgott, Cord Sunderkötter, Thomas A Luger, Sonja Ständer, Dorothee Siepmann, Ilka Herrgott, Cord Sunderkötter, Thomas A Luger

Abstract

Background: Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus.

Methods and findings: Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD +/-1.7) before treatment to 4.9 VAS points (SD +/-3.2) (p<0.001, CI 1.913-5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients.

Conclusions: The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial.

Conflict of interest statement

Competing Interests: On behalf of all authors, Dr. Stander declares that the authors received a part (around 25%) of the medication (aprepitant) from MDS Sharp and Dohme Company. This does not alter their adherence to all the PLoS ONE policies on sharing data and materials. The authors received the samples on demand, for free, without contract or involvement of anybody of the company in in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No author has any other financial or personal relationship to the company such as ownership of stocks or shares, employment or consultancy, board membership, or patent applications. No author received research grants, travel grants for conferences, honoraria for speaking or participation at meetings or any other gifts.

Figures

Figure 1. Distribution of values for pruritus…
Figure 1. Distribution of values for pruritus intensity as scored on the visual analog scale (VAS) from 0 to 10 before (pre) and after (post) aprepitant.
Response is shown for all patients (All, n = 20) as well as for several diagnostic subgroups: patients without (No Prurigo) or with (Prurigo) clinical presence of chronic scratch lesions as well as patients with (AD) and without (No AD) atopic predisposition. Best antipruritic effects were observed in patients with atopic predisposition and prurigo nodularis. Bar: median response in each group.

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