Antipruritic Effect Research Articles

26887 Effect of ruxolitinib cream on sleep disturbance and sleep impairment: Pooled analysis from two randomized phase 3 studies

Atopic dermatitis (AD) is a chronic, inflammatory skin disease. Patients’ quality of life is significantly impacted by pruritus leading to sleep disturbances. Ruxolitinib is a Janus kinase (JAK) 1/JAK2 inhibitor, and a cream formulation of ruxolitinib has demonstrated potent anti-inflammatory and antipruritic effects in patients with AD. Two phase 3 randomized studies (TRuE-AD1 [NCT03745638]; TRuE-AD2 [NCT03745651]) enrolled patients aged ≥12 years with AD for ≥2 years, an Investigator’s Global Assessment score of 2 or 3, and 3%–20% affected body surface area. Patients (N = 1249 in both studies combined; median age, 32 years) were randomized (2:2:1) to 0.75% ruxolitinib, 1.5% ruxolitinib, or vehicle cream (all twice daily) for 8 weeks of double-blind treatment. Sleep quality was assessed using the previously validated Patient-Reported Outcome Measures Information System (PROMIS) Sleep-Related Impairment (SRI [8a]) and Sleep Disturbance (SD [8b]) Short Form questionnaires, which were modified to be completed daily with a 24-hour recall; patients with missing postbaseline values were imputed as nonresponders. At Week 2, more patients treated with ruxolitinib achieved ≥6-point improvement from baseline (clinically meaningful) vs vehicle for SRI (0.75% ruxolitinib, 13.6%; 1.5% ruxolitinib, 13.3%; vehicle, 8.0%) and SD (0.75% ruxolitinib, 14.1%; 1.5% ruxolitinib, 16.3%; vehicle, 7.5%). Responses increased over time, indicating progressive sleep improvement at Week 8 in SRI (0.75% ruxolitinib, 20.1%; 1.5% ruxolitinib, 22.3%; vehicle, 13.3%; both P ˂ .05) and SD (0.75% ruxolitinib, 20.9%; 1.5% ruxolitinib, 23.8%; vehicle, 14.2%; both P ˂ .05). In summary, ruxolitinib cream demonstrated early and progressive improvements in SRI and SD in patients with AD.

28200 Effects of ruxolitinib cream on work productivity and activity impairment in patients with atopic dermatitis: Pooled results from two phase 3 studies

Atopic dermatitis (AD) is a chronic inflammatory skin disease that can negatively impact work productivity and daily activities. Ruxolitinib cream is a Janus kinase (JAK) 1/JAK2 inhibitor in development for AD. In two randomized phase 3 studies (TRuE-AD1 [NCT03745638]; TRuE-AD2 [NCT03745651]) that enrolled patients aged ≥12 years with AD for ≥2 years, an Investigator’s Global Assessment score of 2 or 3, and 3%–20% affected body surface area, ruxolitinib cream was well tolerated and showed anti-inflammatory and antipruritic effects. Here, patient-reported outcomes using the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem version 2.0 (WPAI:SHP v2.0) are reported for all employed patients. Patients (N = 1249 total; median age, 32 years) were randomized (2:2:1) to twice-daily 0.75% ruxolitinib, 1.5% ruxolitinib, or vehicle cream for 8 weeks of double-blind treatment. At Week 8, patients on ruxolitinib (0.75%/1.5%) reported less mean percentage of work time missed (absenteeism) due to AD (7.7%/7.5%; 7.9%/3.9% at baseline) vs vehicle (12.7%; 5.2% at baseline) and significantly greater reductions (mean change from baseline) in impairment while working with AD (presenteeism; –19.2/–19.8) vs vehicle (–12.3; both P ˂ .0001). The percentage of overall impairment due to AD (absenteeism and presenteeism) was also lower for 0.75%/1.5% ruxolitinib (14.3%/15.5%; 33.6%/31.8% at baseline) vs vehicle (31.0%; 36.4% at baseline) at Week 8. Ruxolitinib treatment (0.75%/1.5%) also resulted in significantly greater reductions in daily activity impairment scores (–20.6/–21.5) vs vehicle (–10.6; both P ˂ .0001) at Week 8. In summary, ruxolitinib cream brought about substantial improvements in daily activity and work productivity.

27595 Neurokinin-1 receptor antagonist tradipitant improves itch associated with mild atopic dermatitis: Results from EPIONE, a randomized clinical trial

Atopic dermatitis (AD) is a relapsing disease affecting 4.9% of the US population and is characterized by intense pruritus that can lead to eczematous lesions in varying severity. EPIONE was a randomized, double-blind, placebo-controlled study in adults with chronic pruritus associated with AD. Participants were men and women (18-70 years), who were refractory to treatment, had a ≥ 7 average daily pruritus intensity by the Worst Itch Numerical Rating Scale (WI-NRS), and ≥ 1% body surface area of AD. All enrolled patients (N = 375) were randomly assigned to twice-daily placebo (n = 187) or tradipitant (n = 188) for 8 weeks. EPIONE did not meet its primary endpoint of mean improvement in WI-NRS (baseline to Week 8) (P = .567). However, robust antipruritic effect was observed in mild AD patients (rated 1 or 2 at baseline by the validated Investigator Global Assessment for Atopic Dermatitis, P = .015). This result was confirmed by daily diary (P = .001) and observed after one full day of treatment (P = .0457). During 8 weeks of treatment, tradipitant was well-tolerated by all participants and although worst itch was not improved over placebo in the overall study population, there was a large and rapid antipruritic effect in the subset of patients with mild AD. These data support the role of neurokinin-1 antagonism in chronic pruritus related to mild AD. Tradipitant may represent a new oral systemic option for mild AD patients based on the well-tolerated safety profile and immediate robust improvement in itch.

Topical treatment with mastic (resin from Pistacia lentiscus) elicits anti-inflammatory and anti-pruritic responses by modulating keratinocyte activation in a mouse model of allergic dermatitis

BackgroundAs the number of patients with skin allergies, including atopic dermatitis, has increased rapidly, therapeutic options such as anti-IL-31 antibody and Janus kinase inhibitor have been developed recently. However, many concerns remain regarding the adverse effects and cost of these drugs; therefore, development of supplements that could support the effect of therapeutic agents is always required. PurposeThe aim of this study was to develop preventive and supportive options for skin allergies by focusing on a natural product called “Mastic”. Methods: Initially, the anti-inflammatory and anti-pruritic responses of 3% and 30% Mastic topical treatment were investigated in a mouse model of allergic contact dermatitis, generated by topical application of toluene-2,4-diisocyanate (TDI), a hapten that induces type 2 helper T cells. After itch behaviour and ear-swelling response were monitored, serum, auricular lymph nodes, and skin tissues were collected to analyse immunocyte differentiation, cytokine determination, and histological changes. ResultsOur findings indicated that topical treatment with mastic significantly ameliorated ear swelling, itch behaviour, immunocyte infiltration, and cytokine production. Histological evaluation confirmed the occurrence of anti-inflammatory responses. The anti-inflammatory and anti-pruritic effects of topical treatment with mastic (3% and 5%) were further confirmed in a mouse model of atopic dermatitis which was generated by topical application of TDI in NC/Nga mice. Thickness of the back skin, AD score, transepidermal water loss (TEWL), and itch behaviour were measured weekly, and immunocyte differentiation, cytokine determination, and histological changes were also analysed. Mastic treatment significantly attenuated the skin thickness, AD score, TEWL, and itch behaviour. Corroborated reduction was observed in the numbers of T cells and IgE-B cells, as well as in pro-inflammatory cytokine production. The reproducibility of the effects of mastic was confirmed with 1% mastic ointment in a setting similar to the AD mouse model. In vitro evaluation of keratinocytes indicated that mastic pre-exposure induced a significant dose-dependent decrease in cytokine production. ConclusionOur findings thus demonstrate that topical treatment with mastic significantly ameliorate inflammatory and pruritic responses in a mouse model of allergic dermatitis.

Hypochlorous Acid Versus Saline Nasal Irrigation in Allergic Rhinitis: A Multicenter, Randomized, Double-Blind, Placebo-controlled Study.

Low concentrations of hypochlorous acid (HOCl) have proven antipruritic, anti-inflammatory, and antimicrobial effects without toxicity, although the mechanism has not been fully elucidated. The aim of this study was to evaluate the effectiveness of HOCl nasal irrigation to reduce allergic rhinitis (AR) symptoms compared with saline nasal irrigation. This was multicenter, randomized, double-blind, placebo-controlled study. Initially, 139 patients with perennial AR were enrolled; however, 25 did not successfully complete the study. Patients were randomly assigned to the nasal irrigation with low-concentration HOCl (n = 55) or normal saline (n = 59) treatment groups for the 4-week study period. Participants completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at every visit (baseline, Weeks 2 and 4), and Total Nasal Symptom Score (TNSS) was determined before and after nasal irrigation every morning and evening. We found that RQLQ scores significantly decreased after 4 weeks in the HOCl and placebo groups, but the decrement of the RQLQ score was similar between the 2 groups. Additionally, TNSS improved in both groups between baseline and Week 4, whereas there were no significant differences in the change of TNSS between the 2 groups. The HOCl group did not show any clinical side effects related to nasal irrigation. Allergic symptoms significantly decreased with low-concentration HOCl nasal irrigation, without significant adverse events. However, HOCl showed no additional improvement in symptoms compared with saline nasal irrigation for patients with perennial AR.

Rapid Improvement of Itch Associated With Atopic Dermatitis With Abrocitinib Is Partially Independent of Overall Disease Improvement: Results From Pooled Phase 2b and 3 Monotherapy Studies.

Itch, the most bothersome symptom in atopic dermatitis, is largely mediated by pruritogenic cytokines via Janus kinase 1 signaling in cutaneous sensory neurons. The aims of the study were to assess the magnitude and rapidity of itch relief with the Janus kinase 1 selective inhibitor abrocitinib and to evaluate the extent to which the effect of abrocitinib on itch relief is independent of overall disease improvement. Pooled data from 1 phase 2b (NCT02780167) and 2 phase 3 (NCT03349060, NCT03575871) double-blind, randomized, placebo-controlled monotherapy trials in moderate to severe atopic dermatitis (N = 942) were analyzed. Abrocitinib produced significant and clinically meaningful itch relief versus placebo from week 2 through week 12 (end of treatment) that was associated with marked sleep and quality-of-life improvements. Mean percentage reductions in itch scores 24 hours after the first dose were greater for both abrocitinib doses (200 and 100 mg) versus placebo. Itch improvement occurred regardless of baseline itch severity, sex, race, body mass index, or Investigator Global Assessment response, suggesting that abrocitinib-associated itch relief is at least partially independent of overall disease improvement. Abrocitinib showed a rapid and profound antipruritic effect, partially independent of improvement in overall disease.

Riboflavin Inhibits Histamine-Dependent Itch by Modulating Transient Receptor Potential Vanilloid 1 (TRPV1).

Riboflavin, also known as vitamin B2, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.

Itch reduction using immersive virtual reality-An experimental pilot study.

In a previous proof-of-concept study we have demonstrated that visual exposure to specific colors results in pruritic or antipruritic effects. To determine the effect of "antipruritic" colors when using immersive virtual reality (VR) and to assess whether psychometric values correlate with the response to the color exposure. In this cross-sectional interventional single-center study, itch patients were exposed to their subjective "antipruritic color" (defined by the Manchester Color Wheel) in a virtual monochromatic room for 10min using a head-mounted display. Itch intensity rating (0-10 numerical rating scale [NRS]) was repeated at 1-min intervals. Additionally, dermatology life quality index, itch-related quality of life and the Hospital Anxiety and Depression Scale questionnaires were completed. Twenty-two patients (mean age 51.9 ± 23 years, 13 females) participated in the study. Following color exposure for 10min itch intensity was significantly reduced compared to baseline (exact Wilcoxon signed-rank test, mdn-NRS 4.5 vs 3.0; z=-3.025, p=0.001), confirmed by the area under the curve (z=-3.118; p=0.001). No significant correlation between itch reduction and questionnaire scores was found (Spearman's Rho for all questionnaires). Visual exposure to the "antipruritic color" using immersive VR resulted in a significant decrease in itch intensity. This aligns with previous findings on the influence of colors on itch perception. The response of the intervention appeared independent of psychometric values. Thus, color exposure using immersive VR is a promising, low-cost, rapidly-acting, easily-applicable, non-pharmacological experimental antipruritic method.

Cimifugin relieves pruritus in psoriasis by inhibiting TRPV4

Psoriasis is an immune-mediated chronic inflammatory skin disease characterized by erythema, scales, and infiltration of the skin, which causes deleterious effects on patient quality of life. TRP channel played important roles in the generation and conductance of itch signal . According to our results, psoriasis induced itch was TRPV4 dependent, and TRPV4 expression in both epidermis and DRG were up-regulated in psoriasis. Thus, TRPV4 is an attractive candidate for treating psoriasis induced itch. Cimifugin is a common compound in antipruritic Chinese medicine. In our study, GSK1016790A, a TRPV4 channel specific agonist, induced acute itch was inhibited by cimifugin in a dose-dependent manner. Furthermore, cimifugin treatment reduced the scratching behavior and reversed the TRPV4 up-regulation induced by psoriasis. In particular, cimifugin decreased GSK1016790A induced calcium response both in HaCaT cells and DRG neurons. Importantly, in TRPV4 transfected HEK293 cells, GSK101 induced calcium response was also significantly inhibited by cimifugin pretreatment. Consistent with our calcium imaging result, cimifugin pretreatment also inhibited GSK101 induced inward currents. Our study delineated a new role of TRPV4 in psoriasis and emphasized the antipruritic effect of cimifugin, which opened a new avenue to itch management in psoriasis.

Itch in Atopic Dermatitis - What Is New?

Atopic dermatitis (AD) is among the most frequent inflammatory skin diseases in humans, affecting up to 20% of children and 10% of adults in higher income countries. Chronic pruritus is a disease-defining symptom of AD, representing the most burdensome symptom for patients. Severe chronic pruritus causes significant sleep disturbances and impaired quality of life, as well as increased anxiety, depression and suicidal behavior. Until recently, skin care, topical corticosteroids, and calcineurin-inhibitors were primarily used to treat mild to moderate AD, while phototherapy and immunosuppressive agents such as corticosteroids, cyclosporine, and methotrexate were used to treat patients with moderate to severe AD. The potential short- and long-term adverse events associated with these treatments or their insufficient therapeutic efficacy limited their use in controlling pruritus and eczema in AD patients over longer periods of time. As our understanding of AD pathophysiology has improved and new systemic and topical treatments have appeared on the market, targeting specific cytokines, receptors, or their intracellular signaling, a new era in atopic dermatitis and pruritus therapy has begun. This review highlights new developments in AD treatment, placing a specific focus on their anti-pruritic effects.

Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies

Ruxolitinib (RUX) cream demonstrated potent anti-inflammatory and antipruritic efficacy in a phase 2 study in adults with atopic dermatitis (AD). To evaluate 8-week efficacy and safety in 2 phase 3 studies of RUX cream in patients with AD. Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 (NCT03745638) and Study 2 (NCT03745651) enrolled patients aged ≥12years with AD for ≥2years, an Investigator's Global Assessment score of 2/3, and 3%-20% affected body surface area. Patients were randomized 2:2:1 to twice-daily 0.75% RUX cream, 1.5% RUX cream, or vehicle cream for 8 continuous weeks. The primary endpoint was Investigator's Global Assessment treatment success at week 8 (Investigator's Global Assessment score of 0/1 and ≥2-grade improvement from baseline). In the Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 and 2, 631 and 618 patients were randomized (631/577 analyzed for efficacy). Significantly more patients achieved Investigator's Global Assessment treatment success with 0.75% RUX cream (50.0%/39.0%) and 1.5% RUX cream (53.8%/51.3%) versus vehicle (15.1%/7.6%; P<.0001) at week 8. Significant itch reductions versus vehicle were reported within 12hours of first application of 1.5% RUX (P<.05). Application site reactions were infrequent (<1%) and lower with RUX versus vehicle; none were clinically significant. Longer-term safety data are not yet available. RUX cream showed anti-inflammatory and prompt antipruritic effects with superior efficacy versus vehicle and was well tolerated.

Feeding Cannabidiol (CBD)-Containing Treats Did Not Affect Canine Daily Voluntary Activity.

Growing public interest in the use of cannabidiol (CBD) for companion animals has amplified the need to elucidate potential impacts. The purpose of this investigation was to determine the influence of CBD on the daily activity of adult dogs. Twenty-four dogs (18.0 ± 3.4 kg, 9 months−4 years old) of various mixed breeds were utilized in a randomized complete block design with treatments targeted at 0 and 2.5 mg (LOW) and at 5.0 mg (HIGH) CBD/kg body weight (BW) per day split between two treats administered after twice-daily exercise (0700–0900 and 1,700–1,900 h). Four hours each day [1,000–1,200 h (a.m.) and 1,330–1,530 h (p.m.)] were designated as times when no people entered the kennels, with 2 h designated as Quiet time and the other 2 h as Music time, when calming music played over speakers. Quiet and Music sessions were randomly allotted to daily a.m. or p.m. times. Activity monitors were fitted to dogs' collars for continuous collection of activity data. Data were collected over a 14-day baseline period to establish the activity patterns and block dogs by activity level (high or low) before randomly assigning dogs within each block to treatments. After 7 days of treatment acclimation, activity data were collected for 14 days. Data were examined for differences using the MIXED procedure in SAS including effects of treatment, day, session (Quiet or Music), time of day (a.m. or p.m.), and accompanying interactions. CBD (LOW and HIGH) did not alter the total daily activity points (P = 0.985) or activity duration (P = 0.882). CBD tended (P = 0.071) to reduce total daily scratching compared with the control. Dogs were more active in p.m. sessions than in a.m. sessions (P < 0.001). During the p.m. session, dogs receiving HIGH tended (P = 0.091) to be less active than the control (CON). During the a.m. and p.m. sessions, CBD reduced scratching compared with CON (P = 0.030). CBD did not affect the activity duration during exercise periods (P = 0.143). These results indicate that, when supplemented with up to 4.5 mg CBD/kg BW/day, CBD does not impact the daily activity of adult dogs, but may exert an antipruritic effect.

Determination of clemastine by the HPLC method in the blood

Topicality. Сlemastine fumarate (tavegil)-1-methyl-2 [2-α-methyl-p-chlorobenzhydryloxy)-ethyl]-pyrrolidine fumarate is the first generation H1-histamine receptor blocker. Сlemastine fumarate selectively inhibits histamine H1 receptors and reduces capillary permeability. The drug has a pronounced anti-allergic and antipruritic effect. Clemastine prevents the development of vasodilation and the smooth muscle contraction induced by histamine. Сlemastine fumarate has an isignificant anticholinergic activity, causes sedation. The drug is used to treat pruritus in psoriasis, multiple sclerosis and optic neuritis. Clemastine is characterized by the following side effects: increased fatigue, drowsiness, sedation, weakness, lethargy, impaired coordination of movements; nausea, vomiting, decreased blood pressure, palpitations, hemolytic anemia, skin rash, anaphylactic shock. In case of an overdose, the drug has a neurotoxic effect, which manifests itself in impaired consciousness with the development of generalized anticholinergic convulsive syndrome. The urgent task for monitoring the treatment effectiveness of the population with сlemastine fumarate and diagnosis of drug intoxication is the choice of highly sensitive and selective research methods of its analysis in pharmaceuticals and biological matrices during the treatment. Aim. To develop an algorithm for directed analysis of clemastine in biological extracts from the blood using a unified method of the HPLC research. Materials and methods. The extraction of clemastine was performed with chloroform at Ph 9.0. The extracts were purified from impurities by a combination of TLC and extraction with hexane. The TLC purification and identification of clemastine were carried out under optimal conditions: the system of organic solvents – methanol – 25 % solution of ammonium hydroxide (100 : 1.5) and chromatographic plates – Sorbfil PTLC-AF-A, Rf сlemastine = 0.60 ± 0.03. To detect clemastine, the most sensitive location reagents were used –UV light (λ = 254 nm) and Dragendorff’s reagent modified by Mounier. The chromatographic analysis was performed on a “Milichrome A-02” microcolumn liquid chromatograph (EkoNova, Closed Joint-Stock Company, Russia) under standardized HPLC conditions: the reversed-phase variant using a metal column with a non-polar absorbent Prontosil 120-5C 18 AQ, 5 μm; the mobile phase in the linear gradient mode – from eluent А (5 % acetonitrile and 95 % buffer solution – 0.2 М solution of lithium perchlorate in 0.005 М solution of perchloric acid) to eluent B (100 % acetonitrile) for 40 min. Regeneration of the column was conducted for 2 min with the mixture of solvents; the flow rate of the mobile phase was 100 μl/min, the injection volume – 4 μl. The multichannel detection of the substance was performed using a two-beam multi-wave UV spectrophotometer at 8 wavelengths of 210, 220, 230, 240, 250, 260, 280, and 300 nm; the optimal value of the column temperature – 37-40 °С and the pump pressure – 2.8-3.2 MPa. Results and discussion. Isolation of clemastine from the blood was performed according to the method developed, including the extraction with chloroform at pH 9.0; the extraction purification of extracts with hexane from impurities; the TLC purification and identification of clemastine. Using the unified HPLC method clemastine was identified by retention parameters and spectral ratios. For the quantitative determination, a calibration graph or the straight line equation corresponding to this graph were used. The results obtained indicated the reliability and reproducibility of the method. It was found that the relative uncertainty of the average result in the analysis of clemastine in the blood was ε = ± 4.63 %, the relative standard deviation of the average result was RSDx = 1.67 %. Conclusions. Clemastine was extracted with chloroform at pH 9.0 from the blood. Purification of extracts from co-extractive compounds was performed by combining TLC and extraction with hexane. It has been found that when isolating сlemastine from the blood according to the methods developed it is possible to determine 36.05-39.55 % of the substance (ε = ± 4.63 %, RSDx = 1.67 %). The method of TLC purification and identification of сlemastine in biogenic extracts was tested under the optimal conditions: the system of organic solvents – methanol – 25 % solution of ammonium hydroxide (100 : 1.5), the use of reagents – UV light, Dragendorff’s reagent modified by Mounier, Rf сlemastine = 0.60 ± 0.03 (Sorbfil PTLC-AF-A). The unified HPLC method for identification and quantification of сlemastine was tested in biogenic extracts from the blood according to the algorithm of the directed analysis developed. It has been found that сlemastine can be identified by the retention time – 25.997-26.011 min; the retention volume – 2599.7-2601.1 μl; spectral ratios – 0.741; 0.536; 0.096; 0.023; 0.027; 0.005; 0.003. The сlemastine content was determined by the equation S = 0.15 · 10-3 С + 0.14 · 10-3; the correlation coefficient was equal to 0.9998. Chromatographic methods can be recommended for implementation in practice of the Bureau of Forensic Medical Examination, poison control centers, clinical laboratories regarding the study of medicinal substances in biological objects.

Crisaborole prevents infiltration of neutrophils to suppress itch in a mouse model of atopic dermatitis

The phosphodiesterase-4 inhibitor crisaborole exerts an antipruritic effect and is effective for the treatment of mild-to-moderate atopic dermatitis. However, the mechanisms underlying the antipruritic effect of crisaborole are not completely understood. In this study, we tested whether crisaborole affects spontaneous itch-related behavior as well as neutrophil infiltration and epidermal nerve fiber density (ENFD) in the ovalbumin (OVA)-induced mouse model of atopic dermatitis. OVA treatment resulted in atopic-like skin lesions and spontaneous scratching, which was significantly inhibited by crisaborole treatment. OVA treatment significantly increased neutrophil infiltration and nonpeptidergic ENFD compared with vehicle-treated mice. Crisaborole significantly inhibited neutrophil infiltration without a significant effect on nonpeptidergic ENFD. In a cytokine array, crisaborole significantly decreased neutrophil chemokines, such as CXCL1, CXCL2, and CXCL5. Crisaborole may inhibit atopic dermatitis itch through inhibition of neutrophil infiltration and chemokine expression.

Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study

BackgroundThe pathophysiology of uremic pruritus (UP), which is characterized by systemic and intractable itching, remains unclear. As interleukin (IL)-31 may be involved, we conducted a phase II, randomized, controlled study to evaluate nemolizumab (anti-IL-31 receptor A antibody) in Japanese hemodialysis patients with UP.MethodsPatients were randomly assigned (1:1:1:1:1) to one of four double-blind groups (receiving a single subcutaneous injection of nemolizumab 0.125, 0.5, or 2.0 mg/kg, or placebo on Day 1) or an open-label reference group (receiving oral nalfurafine hydrochloride 2.5–5 μg once daily for 12 weeks). The primary endpoint was the difference in the absolute change in pruritus visual analog scale (VAS) at Week 4 between placebo and each nemolizumab group.ResultsThe primary efficacy endpoint was not met. The mean change from baseline with all three nemolizumab doses at Week 1, and with 0.5 mg/kg at Week 4, was greater than with placebo. Least square mean differences (95% confidence intervals) in the absolute changes between the placebo arm and each nemolizumab arm were − 2.4 (− 19.7, 14.9) for 0.125 mg/kg, − 8.7 (− 26.6, 9.2) for 0.5 mg/kg, and 0.4 (− 17.0, 17.8) for 2.0 mg/kg. Secondary efficacy parameters including the Shiratori severity score and 5-D itch score failed to show between-group differences. Patients with higher serum IL-31 levels at screening tended to have greater pruritus VAS reductions following nemolizumab treatment.ConclusionsIn this phase II study in patients with UP, the primary efficacy parameter was not met. Nemolizumab was generally well tolerated with no clinically significant safety concerns.Clinical trial registrationJAPIC: JapicCTI-152961, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152961.

Ondansetron versus ondansetron with dexamethasone to prevent intrathecal-morphine pruritus for caesarean patients: randomised double-blind trial

The objective of this randomised, double blinded clinical trial was to evaluate the efficacy of prophylactic administration of 4 mg ondansetron as monotherapy versus combination therapy of 4 mg ondansetron plus 8 mg dexamethasone for the prevention of intrathecal morphine-associated pruritus in caesarean section within 24 h. A total of 194 patients were included, 96 patients in the monotherapy group and 98 in the combination group. One hour after the operation, 11.5% of patients in ondansetron group had failure of prophylaxis for pruritus compared to 13.5% of patients in the combination group (p = .66). This decreased throughout the follow-up to reach 0.0% and 1.0% at 24 h in the ondansetron vs. the combination groups respectively. There was no superiority of combining ondansetron with dexamethasone over the use of ondansetron as prophylactic antipruritic in parturients receiving intrathecal morphine for caesarean section. IMPACT STATEMENT What is already known on this subject? The incidence of pruritus has been reported to be between 36% and 60% in patients undergoing caesarean section with intrathecal morphine. Ondansetron has been identified as possible antipruritic agent while the antipruritic effect of dexamethasone is inconclusive. What do the results of this study add? The study demonstrated that there was no superiority of combining ondansetron with dexamethasone over the use of ondansetron as prophylactic antipruritic in parturients receiving intrathecal morphine for caesarean section. Moreover, it seems that there is no effect of combining ondansetron with dexamethasone over ondansetron alone on antiemetic consequences. What are the implications of these findings for clinical practice and/or further research? Ondansetron could be an effective antipruritic if used solely for patients undergoing caesarean section.

Topical application of sebacoyl dinalbuphine ester-loaded nanostructured lipid carriers alleviate pruritus in scratching mouse model

Sebacoyl dinalbuphine ester (SDE) is a nalbuphine (NA) prodrug capable of biotransformation in vivo and prolong the duration of NA, maximize its effect in pain and pruritus management. However, the large molecular weight, low skin penetration, and stability concerns of SDE make it difficult to be used in local skin delivery. Nanostructured lipid carrier (NLC) is a lipid-based nanoparticulate system that has the potential for formulating SDE in order to promote drug delivery through the skin. The aim of this study was to develop SDE-loaded NLC formulations (SDE-NLC) with good stability, sustained release characteristics, and sufficient antipruritic effect. SDE was successfully encapsulated into NLC and the formulation increased the stability of SDE, enhanced skin penetration through hair follicles, and sustained SDE release during pruritus management. We also demonstrated that topical application of SDE-NLCs significantly reduced the number of scratches in pruritus-induced mice. Both NA and SDE were found in the skin strata, but only NA was detectable in the plasma, indicating rapid conversion of SDE into NA. All results demonstrated that SDE-NLC formulation protected SDE from degradation in vitro, while the released prodrug was converted into NA in vivo and extended antipruritic effect. The formulation has the potential of improving the life quality of patients with chronic pruritus.

100 Hz Electroacupuncture Alleviated Chronic Itch and GRPR Expression Through Activation of Kappa Opioid Receptors in Spinal Dorsal Horn.

BackgroundClinical studies have shown that electroacupuncture (EA) alleviates chronic itch. Gastrin-releasing peptide receptor (GRPR) and dynorphin (DYN) in the spinal dorsal horn positively or negatively regulate itch, respectively. However, which frequency of EA is effective on relieving chronic itch and reducing the expression of GRPR, whether DYN-A in the spinal cord is involved in the underlying mechanism of the antipruritus effect of EA remains unknown.MethodsThe mixture of acetone and diethyl ether (1:1) [designated as AEW (acetone/diethyl ether and water) treatment] was used to induce the dry skin model of chronic itch. EA was applied to Quchi (LI11) and Hegu (LI4). Western blot was used to detect the expression of GRPR and DYN-A. Immunofluorescence was used to detect the expression of DYN-A.ResultsThe AEW administration induced remarkable spontaneous scratching, enhanced the expression of GRPR, and reduced the expression of DYN-A. Compared with the sham EA, 2 Hz EA, or 15 Hz EA group, 100 Hz EA was the most effective frequency for relieving chronic itch, reducing the expression of GRPR, and increasing the expression of DYN-A in the cervical dorsal horn. Furthermore, intraperitoneal injection of kappa opioid receptors (KORs) antagonist nor-Binaltorphimine dihydrochloride (nor-BNI) significantly reversed the effect of 100 Hz EA on the inhibition of both itching behavior and GRPR expression.ConclusionEA at 100 Hz is the most effective frequency that inhibits chronic itch and GRPR expression through activation of KORs in the spinal dorsal horn, which can effectively guide the clinical treatment and improve the antipruritic effect of acupuncture.

Projections from the lateral parabrachial nucleus to the lateral and ventral lateral periaqueductal gray subregions mediate the itching sensation.

Lateral and ventral lateral subregions of the periaqueductal gray (l/vlPAG) have been proved to be pivotal components in descending circuitry of itch processing, and their effects are related to the subclassification of neurons that were meditated. In this study, lateral parabrachial nucleus (LPB), one of the most crucial relay stations in the ascending pathway, was taken as the input nucleus to examine the modulatory effect of l/vlPAG neurons that received LPB projections. Anatomical tracing, chemogenetic, optogenetic, and local pharmacological approaches were used to investigate the participation of the LPB-l/vlPAG pathway in itch and pain sensation in mice. First, morphological evidence for projections from vesicular glutamate transporter-2-containing neurons in the LPB to l/vlPAG involved in itch transmission has been provided. Furthermore, chemogenetic and optogenetic activation of the LPB-l/vlPAG pathway resulted in both antipruritic effect and analgesic effect, whereas pharmacogenetic inhibition strengthened nociceptive perception without affecting spontaneous scratching behavior. Finally, in vivo pharmacology was combined with optogenetics which revealed that AMPA receptor-expressing neurons in l/vlPAG might play a more essential role in pathway modulation. These findings provide a novel insight about the connections between 2 prominent transmit nuclei, LPB and l/vlPAG, in both pruriceptive and nociceptive sensations and deepen the understanding of l/vlPAG modulatory roles in itch sensation by chosen LPB as source of ascending efferent projections.

A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability

TRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.