Cell/structure
Effects of SP/NK1R
Potential translational importance
References
Epidermal dendritic cells
Increased migration to skin-draining lymph nodes; inhibition of IL-10 synthesis and secretion
NK1R agonists: potential adjuvant for enhancing the efficiency of DC vaccines
Fibroblast
Production of IFN-gamma, IL-1beta, and IL-8
NK1R antagonists: suppression of SP-induced inflammation
Liu et al. (2008)
Hair follicle
Stress-induced hair growth termination (catagen induction) accompanied by neurogenic inflammation in connective tissue sheath
NK1R antagonists: interruption of stress-mediated hair loss
Peters et al. (2007)
Keratinocyte
Production of NGF, leukotriene B4, IFN-gamma, IL-1beta, and IL-8
NK1R antagonists: suppression of SP-induced inflammation
Mast cell (MC)
Release of histamine, leukotriene B4, prostaglandin D2, or tumor necrosis factor-α
Increased expression of NK1R on MCs in mastocytosis
Degranulation, activation, accumulation in CRPS
NK1R antagonists: suppression of mast cell degranulation in mastocytosis, atopic dermatitis
NK1R antagonists: management of CRPS
Melanoma cells
Suppression of melanogenesis, cell growth of melanoma cells
NK1R agonists: management of skin pigmentation
NK1R antagonists: cell growth inhibition and apoptosis of melanoma cells
Next to its sensory function, SP has abundant efferent function after release from sensory nerve fibers upon activation of C- and Aδ-fibers by a pain or itch signal. SP is a mediator of inflammation in the skin which is terminated after release by cutaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). A major role of SP in the skin is the induction of neurogenic inflammation, which is induced by SP binding on MC and blood vessels. After release from nerve fibers, SP induces vasodilatation of short duration (Weidner et al. 2000) and leads to MC degranulation with release of histamine, leukotriene B4, prostaglandin D2, tumor necrosis factor-α, and vascular endothelial growth factor (VEGF) (Hägermark et al. 1978; Andoh et al. 1998; Kawana et al. 2006). Histamine binds to histamine 1 (H1) receptors on CMi fibers and induces pruritus (Ikoma et al. 2006). Clinically, the neurogenic inflammation results in erythema, whealing, and pruritus. It was shown experimentally several times by intradermal injection of SP (10(-5) and 10(-6) mol/l) in healthy skin of volunteers, in inflamed skin of volunteers pretreated with 1 % sodium lauryl sulfate, and in psoriasis patients. This led to pruritus (in all groups) of the same intensity, flare, and wheal reaction (Thomsen et al. 2002; Amatya et al. 2010). In mice, cutaneous SP injections resulted in a dose-dependent increase in scratching of the injected site (Andoh et al. 1998). Cutaneous thermal hyperemia by local heating has an axon reflex-mediated component and a vascular component (production of local vasodilators), too, both of which are based on cutaneous SP effects and, accordingly, can be blocked by NK1R antagonists (Wong and Minson 2011). Interestingly, also in pain such as complex regional pain syndrome (CRPS), the efferent function of SP plays a role. In CPRS, release of SP into the tissue induces mast cell degranulation, accumulation, and activation that can be inhibited by NK1R antagonist (Li et al. 2012). In mastocytosis, characterized by increased numbers of MCs in the skin and pruritus, there is increased expression of NK1R on cutaneous MCs; furthermore, increased levels of SP have been shown in the serum of patients (Maintz et al. 2011). Moreover, SP increases corticotropin-releasing hormone receptor-1 (CRHR-1) expression on MCs as well as release of IL-8, tumor necrosis factor (TNF), and VEGF by mast cells, which can be blocked by NK1R antagonists (Asadi et al. 2012). Corticotropin-releasing hormone (CRH) induces NK-1 gene expression in mast cells. CRH is released, for example, as a stress response and can induce mast cell degranulation and augment skin vascular permeability. This suggests a link between SP, CRH, and inflammatory diseases that worsen with stress, such as psoriasis or atopic dermatitis (AD), as well as associated pruritus (Singh et al. 1999; Alysandratos et al. 2012). This was also demonstrated in an AD animal model. Stress primarily exacerbates AD (e.g., increased eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, and epidermal thickness) via SP-dependent cutaneous neurogenic inflammation. This was inhibited in NK1R knockout mice (Pavlovic et al. 2008). Interestingly, SP shifted the cytokine profile toward TH2 in skin (Pavlovic et al. 2008) and thus may have additional influence on inflammation.
In both keratinocytes and fibroblasts, SP induces proliferation and the production of interferon gamma, interleukin (IL)-1beta, and IL-8 and fibroblast migration (Tanaka et al. 1988; Kähler et al. 1993; Liu et al. 2008). Interestingly, cetirizine, the H1 antihistamine, significantly inhibited the expression of NK1R and SP-induced IL-1beta and IL-8 production in HaCaT cells and fibroblasts (Liu et al. 2008). These results suggest a link between histamine and SP-induced inflammation in keratinocytes and fibroblasts. In keratinocytes, SP can directly induce nerve growth factor (NGF) mRNA expression and the secretion of bioactive NGF protein (Burbach et al. 2001). Topical capsaicin application results in significant upregulation of keratinocyte NGF expression in the epidermis (Burbach et al. 2001). SP further leads to an increased expression of leukotriene B4 in keratinocytes (Andoh et al. 2001) that can be blocked by azelastine, the H1 antihistamine (Andoh and Kuraishi 2002). The release of SP-mediated pro-inflammatory mediators from mast cells and keratinocytes attracts inflammatory cells to invade into the skin. This pro-inflammatory action of SP can be blocked by addressing NK1R as demonstrated in animal models. NK1R knockout mice displayed a significantly reduced allergic contact dermatitis (ACD) in response to dinitrofluorobenzene (DNFB) with histological evidence of less edema and 50 % fewer infiltrating leukocytes compared with the ACD response in wild-type animals (Scholzen et al. 2004). In addition, administration of a NK1R antagonist before sensitization, significantly inhibited the augmented effector phase of ACD in mice with a heterozygous deletion of somatic ACE (Scholzen et al. 2003).
1.4 Role of SP in Pruritus
By promoting the production of NGF in keratinocytes and the release of histamine and other pro-inflammatory mediators from mast cells, SP leads to sensory nerve fiber sprouting and augmentation of skin inflammation. This contributes to the development and maintenance of cutaneous pruritus. In fact, in AD, prurigo nodularis (PN; pruritus with chronic persistent scratch lesions), and normal looking skin of chronic pruritus patients, an increased density of dermal SP-positive nerve fibers was found (Abadía Molina et al. 1992; Järvikallio et al. 2003; Haas et al. 2010). In addition, one of the key pruritogenic factors in dermatoses is the worsening of pruritus by stress as also mediated by SP (Hosokawa et al. 2009).
Accordingly, SP is reported to be involved in the pathogenesis of pruritus in several entities such as pruritus in psoriasis (Nakamura et al. 2003; Chang et al. 2007), AD (Hosokawa et al. 2009), and cholestatic pruritus (Trivedi and Bergasa 2010). In patients with pruritic psoriasis, an increase in SP-positive nerve fibers in perivascular areas, decreased expression of NEP in the epidermal basal layer, and increased expression of epidermal NK1R were observed compared to patients with non-pruritic psoriasis, suggesting a role of SP and epidermal NK1R-positive keratinocytes in the induction of itch (Nakamura et al. 2003; Chang et al. 2007). Another study demonstrated increased expression of SP and NK1R in dermal inflammatory cells (lymphocytes, mast cells) in involved, compared to noninvolved, psoriatic skin that was not related to pruritus but to stress levels (Remröd et al. 2007). SP plasma levels do not seem to be related to psoriasis-associated pruritus as a negative correlation between pruritus intensity and levels of SP has been found (Reich et al. 2007).
Animal models demonstrated a role for SP in AD. Administration of an NK1R antagonist (BIIF 1149 CL) significantly decreased scratching behavior in NC/Nga mice (Ohmura et al. 2004). Induction of a DNFB-mediated allergic contact dermatitis in mice could be inhibited by depleting substance P by tacrolimus with resulting reduced scratching behavior (Inagaki et al. 2010). In the same study, DNFB-induced ear swelling and scratching behavior were significantly inhibited by FK888, a NK1R antagonist (Inagaki et al. 2010). In another study, oral application of aprepitant reduced the serum IgE level, tissue substance P levels, and the infiltration of Treg cells but not the inflammation as assessed by a total clinical severity score and ear thickness in NC/Nga mice (Lee and Cho 2011).
In human AD skin, dermal contacts between mast cells and sensory nerves were increased in number in both lesional and non-lesional samples of AD when compared to those in normal controls (Järvikallio et al. 2003). SP-positive nerve fibers in the epidermis and in the papillary dermis were markedly increased in lesional AD as compared to non-lesional controls (Järvikallio et al. 2003). In the blood plasma, patients with AD had significant increases in levels of NGF and SP compared with controls (Toyoda et al. 2002; Salomon and Baran 2008; Hosokawa et al. 2009). A significant correlation of plasma NGF and SP levels with disease activity (as measured by the grading system of Rajka and Langeland, objective severity scoring of AD and Eczema Area and Severity Index – EASI) was found (Toyoda et al. 2002). However, another AD study demonstrated that SP plasma levels did not seem to be a sensitive marker for disease severity because the distribution window of actual values of plasma SP levels was relatively small (10 to <500 pg/mL) (Hosokawa et al. 2009). Further, in children, no correlation between plasma SP concentration and the subjective symptoms of pruritus or sleep-loss scores as reported by the parents in the SCORAD (SCORing Atopic Dermatitis) was found (Hon et al. 2007). In sum, cutaneous SP seems to play a role in AD pruritus induction, but it is questionable if SP plasma levels can serve as biomarkers.
Thus, SP is a key mediator of itch induction in the skin. Vice versa, skin scratching may influence SP and NK1R content of the skin. Skin-scratching stimulation in mice resulted in immediate depletion of SP from sensory nerves, while the expression of NK1R was upregulated in basal keratinocytes within days (Yamaoka and Kawana 2007). Interestingly, in some entities such as cholestatic pruritus, increased serum concentrations of SP have been found. This may be related to scratching and thus be a secondary finding, as other mediators such as autotoxin have recently been defined as primary mediators of cholestatic pruritus (Kremer et al. 2012).
2 Neurokinin Receptor Antagonist, Aprepitant
Aprepitant (bis(trifluoromethyl) morpholine, MK-869) is a selective high-affinity, CNS-penetrant, oral NKR1-antagonist with little or no affinity for other neurokinin receptors (Kramer et al. 1998). It was developed for the therapy of pain and depression, but studies failed to demonstrate an effect in a nontoxic dosage range (DeVane 2001). In 2003, aprepitant was approved for the prevention of chemotherapy-induced emesis and is usually administered for 3 days only (Hesketh et al. 2003; Dando and Perry 2004).
2.1 Adverse Events with Aprepitant
Aprepitant is an inducer of cytochrome P450 3A4 isoform (CYP3A4) activity and to a modest extent, activity of CYP2C9 (Shadle et al. 2004; Ruhlmann and Herrstedt 2011). As a consequence, there is a risk of drug-drug pharmacokinetic interactions. Several drugs should not be applied in association with aprepitant such as rifampicin, phenytoin, carbamazepine, phenobarbital, ketoconazole, itraconazole, cyclosporine, and tacrolimus.
In studies investigating the use of aprepitant in patients with depression, the drug was applied for 6–8 weeks (Table 2). Mild to moderate side effects occurred but there were no serious adverse events. In one of the first studies including 213 patients who received 300 mg aprepitant (MK-869) for 6 weeks, the safety and tolerability of MK-869 were generally similar to placebo, except for mild and typically transient somnolence and asthenia (Kramer et al. 1998). The most common clinical adverse events observed in patients receiving MK-869 were headache (32 %), somnolence (20 %), nausea (18 %), and asthenia/fatigue (14 %). In studies investigating potential antidepressant effects, the percentage of patients discontinuing therapy because of adverse effects was greater with paroxetine (19 %) than with MK-869 (9 %) or placebo (9 %) (Kramer et al. 1998). Subsequent studies using aprepitant in a lower dosage (80–250 mg) but for a long period (2–8 weeks) confirmed the safety of the substance (Table 2). In general, it can be concluded that aprepitant may have more adverse events (AEs) than placebo (Green et al. 2006; Tebas et al. 2011), but studies including large numbers of patients (Kramer et al. 1998; Keller et al. 2006) concluded that the substance is generally well tolerated over a long period—up to 8 weeks.
Table 2
Adverse events of aprepitant as reported in long-term treatment trials
Indication | Number of patients | Duration of treatment | Oral dosage of aprepitant | Adverse events (AE) | Authors |
|---|---|---|---|---|---|
HIV infection | 30 | 2 weeks | 125 mg (n = 9) 250 mg (n = 8) | Aprepitant induced more grade 2–4 AEs than placebo (p = 0.042) | Tebas et al. (2011) |
Overactive bladder | 125 | 8 weeks | 160 mg | Aprepitant induced more AEs than placebo (p = 0.001), although AEs were mild and unlikely to be of clinical significance | Green et al. (2006) |
Depression | 2,526 (summary of five studies) | 8 weeks | 160 mg (n = 806) 80 mg (n = 479) | No significant differences versus placebo in any of the five studies. Aprepitant 80 mg showed no significant differences versus placebo on any of the summary safety measures | Keller et al. (2006) |
Depression | 213 | 6 weeks | 300 mg | No significant differences versus placebo | Kramer et al. (1998) |
3 Antipruritic Effects of Aprepitant
Given the important function of SP in skin inflammation and peripheral and central pruritus transmission, aprepitant was applied in acute and chronic pruritus patients.
3.1 Acute Pruritus (Table 3)
Table 3
Current evidence of an antipruritic effect of aprepitant
Indication | Number of patients | Dosage of aprepitant | References |
|---|---|---|---|
Acute pruritus (n = 50) | |||
Drug-induced pruritus (with or without skin rash) | |||
Erlotinib-induced acneiform pruritic rash in stage IV non-small cell lung cancer | 2 | 125 mg (day 1), 80 (day 2–3); then altering dosage of 125 mg and 80 mg for 2 months | Vincenzi et al. (2010b) |
Erlotinib-induced pruritic rash in lung adenocarcinoma | 1 | 80 mg for 1 week (therapy still ongoing) | Mir et al. (2011) |
Antineoplastic drug-induced pruritus in metastatic solid tumors | 45 | 125 mg (day 1), 80 mg (day 3; day 5) for one cycle | Santini et al. (2012) |
Paraneoplastic pruritus | |||
Metastatic soft tissue sarcoma, metastatic breast carcinoma | 2 | 125 mg (day 1), 80 mg (day 2–3) | Vincenzi et al. (2010a) |
A 54-year-old patient with lung adenocarcinoma received aprepitant (80 mg per day) for erlotinib-induced pruritic rash. Rash and pruritus regressed during an 8-day therapy (Mir et al. 2011). The authors mention that the patient still receives aprepitant (80 mg per day) and erlotinib (150 mg per day) without recurrence of pruritus, but the precise duration of therapy as well as occurrence of side effects was not mentioned.
In an open-label, uncontrolled, and non-randomized pilot study (Santini et al. 2012), 45 patients with solid tumors were treated with aprepitant for acute pruritus due to the application of an antineoplastic drug (erlotinib, n = 16; cetuximab, n = 23; sunitinib, n = 3; lapatinib, imatinib, gefitinib, each n = 1). Patients were grouped into a refractory group (for patients with pruritus refractory to standard treatment with prednisone 25 mg/day or fexofenadine 180 mg/day) or a naive group (for patients who had not been previously treated for pruritus). Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after the first onset of severe pruritus (Santini et al. 2012). Forty-one (91 %) patients responded to aprepitant. Median VAS dropped from 8 to 1 (in the refractory group; p < 0.0001) and from 8 to 0 (in the naive group; p < 0.0001). No side effects related to aprepitant occurred (Santini et al. 2012).
Given that aprepitant is a CYP3A4 inhibitor, there is risk of an increase in erlotinib concentrations and decrease in erlotinib clearance upon continuous administration of aprepitant (Levêque 2010; Mir et al. 2011; Mir and Coriat 2012). An accumulation of mast cells in the lesional skin of patients treated with erlotinib might be responsible for the induction of pruritus; prevention of SP-induced degranulation of mast cells by aprepitant might explain the antipruritic effect of the NK1R antagonist in these patients (Gerber et al. 2011).
In two patients with potential paraneoplastic pruritus (a male with metastatic soft tissue sarcoma and a female with metastatic breast carcinoma) receiving systemic chemotherapy, pruritus (duration not provided) occurred without clear correlation to chemotherapy or any other origin (Vincenzi et al. 2010b). These patients received aprepitant during chemotherapy (125 mg for 1 day, 80 mg for 2 days) and both reported a drop of 8 VAS points from initial 8 and 9, respectively. After interruption of aprepitant, pruritus recurred within 3 days. No relevant side effects related to aprepitant administration were observed in the two patients (Vincenzi et al. 2010b).
3.2 Chronic Pruritus (Table 4)
Table 4
Current evidence of an antipruritic effect of aprepitant in chronic pruritus
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