Serlopitant for the treatment of chronic pruritus: Results of a randomized, multicenter, placebo-controlled phase 2 clinical trial

Yosipovitch, Gil; Ständer, Sonja; Kerby, Matthew B.; Larrick, James W.; Perlman, Andrew J.; Schnipper, Edward F.; Zhang, Xiaoming; Tang, Jean Y.; Luger, Thomas A.; Steinhoff, Martin

doi:10.1016/j.jaad.2018.02.030

Cited by 101 publications

(95 citation statements)

References 29 publications

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“…The antipruritic efficacy of NK1R antagonism by aprepitant or serlopitant is well documented but not yet understood. 6,21 Superficial spinal dorsal horn neurons that give rise to ascending somatosensory projections, express NK1R. 26 Blocking of NK1R in these neurons leads to suppression of chronic itch in mice and is thus speculated to represent the mechanism underlying the antipruritic effect 26 of aprepitant.…”

Section: Discussionmentioning

confidence: 99%

“…19 However, another clinical trial with the novel NK1R antagonist serlopitant demonstrated high antipruritic effects in PN patients. 20,21 Up to now it is unclear if the antipruritic effects of NK1R antagonists result from receptor binding in the skin or the central nervous system. This study aims to investigate if there are any changes in cutaneous NK1 receptor expression, IL expression or signal cascade activation after NK1R therapy as a parameter of peripheral effects in the skin.…”

Section: Introductionmentioning

confidence: 99%

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264 Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Agelopoulos

Rülander

Dangelmaier

et al. 2019

Journal of Investigative Dermatology

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Background Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN).Objectives To investigate the peripheral effects of NK1R antagonism in PN and cell culture models.Methods Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)-1beta, IL-6, IL-8 and TNFalpha.Results Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up-regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL-expression shown when blocking NK1R.Conclusion Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system. Rolf Dierichs foundation, DFG -Deutsche Forschungsgemeinschaft; grant numbers: STA1159/4-1; AG271/1-1. expressed in various cell types in the skin including keratinocytes, mast cells and fibroblasts. 7 Sensory neurons release SP directly into peripheral tissues, 8,9 where it has an efferent roleThe paper presents partial results of the doctor thesis of FR and JD. JEADV Results Effects of blocking of NK1R in vivoPruritus intensity and scratch symptoms Prurigo nodularis lesions improved slightly after aprepitant treatment (Fig. 1).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

264 Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Agelopoulos

Rülander

Dangelmaier

et al. 2019

Journal of Investigative Dermatology

View full text Add to dashboard Cite

show abstract

“…The antipruritic efficacy of NK1R antagonism by aprepitant or serlopitant is well documented but not yet understood . Superficial spinal dorsal horn neurons that give rise to ascending somatosensory projections, express NK1R .…”

Section: Discussionmentioning

confidence: 99%

“…Blocking the binding of SP by systemic application of the NK1R antagonist aprepitant showed a marked reduction of itch in large series of patients with chronic pruritus including PN, but failed in a recent randomized placebo‐controlled clinical trial . However, another clinical trial with the novel NK1R antagonist serlopitant demonstrated high antipruritic effects in PN patients . Up to now it is unclear if the antipruritic effects of NK1R antagonists result from receptor binding in the skin or the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Agelopoulos

Rülander

Dangelmaier

et al. 2019

Acad Dermatol Venereol

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Background Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). Objectives To investigate the peripheral effects of NK1R antagonism in PN and cell culture models. Methods Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)‐1beta, IL‐6, IL‐8 and TNFalpha. Results Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up‐regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL‐expression shown when blocking NK1R. Conclusion Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system.

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“…In addition, treatment with oral antidepressants, such as mirtazapine, paroxetine and sertraline, have been recommended in patients with pruritus unresponsive to conventional treatment options, and particularly in patients with uraemic pruritus, cholestatic pruritus or paraneoplastic pruritus (21)(22)(23)(24)(25)(26)(27)(28). Other systemic treat-ment options include opioid receptor agonists and antagonists, thalidomide and neurokinin 1 receptor (NKR1) antagonists (29)(30)(31)(32)(33)(34)(35)(36).…”

mentioning

confidence: 99%

Use of Systemic Treatment in Patients with Chronic Pruritus: A Survey of Dermatologists in the Netherlands

Kouwenhoven

Kerkhof²,

Kamsteeg³

2019

Acta Derm Venerol

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This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Acta Derm Venereol 2019; 99: 304-308 304 SIGNIFICANCE This study analysed the prescription of systemic treatment by dermatologists in patients with chronic itch. Overall, 6 out of 10 dermatologists prescribed antidepressants or gaba pentinoids, of which, antidepressants were prescribed most frequently. Reasons not to prescribe systemic treat ment included lack of knowledge or experience, risk of side effects, and lack of available evidence. Only a minority of the clinicians surveyed felt comfortable prescribing these drugs; therefore, we recommend more education on ef fective and safe dosing.Treatment of chronic pruritus can be a challenge for clinicians. Several systemic treatments have been suggested to reduce itch, such as gabapentinoids and antidepressants. The aim of this study was to assess the current practice of dermatologists regarding systemic treatment in patients with chronic pruritus, and to identify possible barriers in the prescription of these treatments. An online survey was sent to all dermatologists and dermatology residents in the Netherlands between July 2017 and April 2018. A total of 193 physi cians completed the questionnaire (response rate 27.0%). Overall, 61.7% prescribed gabapentinoids or antidepressants in patients with chronic pruritus. Amitriptyline was prescribed most frequently, followed by gabapentin, doxepin and mirtazapine. Reasons not to prescribe systemic treatment included lack of knowledge or experience, risk of side-effects, and lack of available evidence. As only a minority of respondents felt comfortable prescribing these drugs, more education on effective and safe dosing is needed. ActaDV ActaDV Advances in dermatology and venereologyActa Dermato-Venereologica 305 Systemic treatment for chronic pruritus Acta Derm Venereol 2019 ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica T. A. Kouwenhoven et al. 306

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Serlopitant for the treatment of chronic pruritus: Results of a randomized, multicenter, placebo-controlled phase 2 clinical trial

Abstract: Serlopitant, 1 mg and 5 mg daily, was associated with a statistically significant reduction in chronic pruritus and was well tolerated (NCT01951274).

Cited by 101 publications

References 29 publications

264 Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

264 Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

Use of Systemic Treatment in Patients with Chronic Pruritus: A Survey of Dermatologists in the Netherlands

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