Histamine- and pruritogen-induced itch is inhibited by a TRPM8 agonist: a randomized vehicle-controlled human trial.

BACKGROUND: Allergies often present challenges in managing itch and the effects of histamine. Cooling agents that act via transient receptor potential melastatin 8 (TRPM8) agonism have shown potential in itch management. However, animal studies on itch have limitations, as animals cannot communicate subjective events and their fur-coated skin differs from that of humans. Human studies offer more direct and reliable information. OBJECTIVES: To investigate the effects of a specific TRPM8 agonist gel (cryosim-1) on itch induced by various pruritogens in human skin. METHODS: Calcium imaging experiments determined the binding of cryosim-1 and histamine to their respective receptors. Thirty healthy volunteers underwent skin prick tests with pruritogens and a control vehicle. Itch and pain intensity were measured using a numerical rating scale (NRS) across 10 min. Participants were randomly assigned to pretreatments with vehicle or TRPM8 agonist gel. Tests were repeated at a later date, and skin moisture, transepidermal water loss and mechanical sensitivity were measured. RESULTS: The in vitro study confirmed that histamine is not a TRPM8 agonist and cryosim-1 does not act as an agonist or antagonist on the human histamine 1 receptor. The TRPM8 agonist gel significantly reduced the itch intensity for all pruritogens compared with the vehicle-only gel. It also reduced itch NRS and the integrated itch score. Mechanical sensitivity was also reduced. CONCLUSIONS: The specific TRPM8 agonist gel effectively suppressed human skin itch induced by various pruritogens. These versatile actions suggest that cooling agents may be promising treatments for multiple forms of itch stimuli.

Managing itching and the effects of histamine can be difficult for people with allergies. Cooling the skin or applying menthol provides some relief from itch, but the way they work is not fully understood. Cooling agents interact with a protein called TRPM8 (also known as the 'cold and menthol receptor') and have shown potential for the management of itch. However, much of the research has been done on animals and has limitations when compared with human studies. Antihistamine medications can help with histamine-induced itching, but they may not work for other causes of itch. This study investigated the effects of a specific TRPM8 agonist (a chemical that activates a receptor to produce a biologic response) gel called cryosim-1 on itch in human skin. To do this, we conducted tests on 30 healthy people using five different substances that cause itching. Participants rated the itch intensity and pain using a scale and we measured various aspects of their skin. The results showed that all substances caused significant itching compared to a control substance, but itchiness gradually decreased over time. Histamine and compound 48/80 also caused pain. However, when participants applied the TRPM8 activator gel before exposure, they experienced less itching and lower itch intensity versus the gel without the activator. There were no significant differences in pain between the TRPM8 activator and the gel without it. In summary, our findings showed that activating TRPM8 receptors with a specific substance effectively relieved itching caused by various irritants on human skin. This suggests its potential as a treatment for itch-related conditions. Further research is needed to understand its mechanisms better and evaluate its effectiveness in real-life situations.

Non-Systemic Medication for the Treatment of Prurigo Nodularis: A Systematic Review.

Prurigo nodularis (PN) is a skin disease characterized by firm, itchy, erythematous lesions. Treatment consists of systemic and non-systemic modes of therapy. Non-systemic forms of treatment are first-line and include topical corticosteroids, topical steroid-sparing agents, and phototherapy. The objective was to review the efficacy of non-systemic treatment used to treat PN. A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42023412012). The search consisted of keywords and Medical Subject Heading (MeSH) terms and translated to Ovid MEDLINE, Embase, and Scopus. Google Scholar was also searched for the first 200 articles. Article quality of evidence was scored using GRADE criteria. The search yielded 1151 results; 37 met criteria for inclusion. There were 14 studies on phototherapy, and 11 studies on topical corticosteroids, most of which were also combined with topical antihistamines, antipruritics, and/or phototherapy. There were 2 studies each on topical antipruritics used in isolation, vitamin D analogues, and intralesional triamcinolone acetonide. There was 1 study each on topical pimecrolimus, tacrolimus, 2% dinitrochlorobenzene, cryotherapy, acupuncture, and the Paul Gerson Unna boot. Most were case reports and case series, although 2 randomized controlled trials on phototherapy and topical pimecrolimus were included. Corticosteroids had varying levels of positive response in patients and appeared more effective when used in combination or under occlusive dressing. Phototherapy is likely effective, but the risk of relapse is high. Cryotherapy may also be a lesion-directed agent to circumvent challenges to adherence and avoidance of systemic medication.

A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

Unmyelinated tactile (C-tactile or CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here, we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves. The most distal receptive fields were located on the proximal phalanx of the third finger for the superficial branch of the radial nerve and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n = 27), radial (n = 8), and peroneal (n = 4) nerves. Moreover, we found that although CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared with C-nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.NEW & NOTEWORHY Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and are thought to signal features of social affective touch. We show that CTs are also present but are relatively sparse in the lower leg compared with C-nociceptors. CTs display similar physiological properties across the arm and leg nerves. Furthermore, CT afferents do not respond to the cooling agent menthol or the pruritogen histamine, and their mechanical response properties are not altered by these chemicals.

Lactobacillus rhamnosus attenuates Thai chili extracts induced gut inflammation and dysbiosis despite capsaicin bactericidal effect against the probiotics, a possible toxicity of high dose capsaicin.

Because of a possible impact of capsaicin in the high concentrations on enterocyte injury (cytotoxicity) and bactericidal activity on probiotics, Lactobacillus rhamnosus L34 (L34) and Lactobacillus rhamnosus GG (LGG), the probiotics derived from Thai and Caucasian population, respectively, were tested in the chili-extract administered C57BL/6 mice and in vitro experiments. In comparison with placebo, 2 weeks administration of the extract from Thai chili in mice caused loose feces and induced intestinal permeability defect as indicated by FITC-dextran assay and the reduction in tight junction molecules (occludin and zona occludens-1) using fluorescent staining and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the chili extracts also induced the translocation of gut pathogen molecules; lipopolysaccharide (LPS) and (1→3)-ß-d-glucan (BG) and fecal dysbiosis (microbiome analysis), including reduced Firmicutes, increased Bacteroides, and enhanced total Gram-negative bacteria in feces. Both L34 and LGG attenuated gut barrier defect (FITC-dextran, the fluorescent staining and gene expression of tight junction molecules) but not improved fecal consistency. Additionally, high concentrations of capsaicin (0.02-2 mM) damage enterocytes (Caco-2 and HT-29) as indicated by cell viability test, supernatant cytokine (IL-8), transepithelial electrical resistance (TEER) and transepithelial FITC-dextran (4.4 kDa) but were attenuated by Lactobacillus condition media (LCM) from both probiotic-strains. The 24 h incubation with 2 mM capsaicin (but not the lower concentrations) reduced the abundance of LGG (but not L34) implying a higher capsaicin tolerance of L34. However, Lactobacillus rhamnosus fecal abundance, using qRT-PCR, of L34 or LGG after 3, 7, and 20 days of the administration in the Thai healthy volunteers demonstrated the similarity between both strains. In conclusion, high dose chili extracts impaired gut permeability and induced gut dysbiosis but were attenuated by probiotics. Despite a better capsaicin tolerance of L34 compared with LGG in vitro, L34 abundance in feces was not different to LGG in the healthy volunteers. More studies on probiotics with a higher intake of chili in human are interesting.

Formulation and assessment of hydroxyzine HCL solid lipid nanoparticles by dual emulsification technique for transdermal delivery.

Hydroxyzine HCL (HHCL) is an antihistamine, used for the treatment of allergic skin conditions. The purpose of this study was to achieve a dual phase drug delivery rate across the intact skin, to enhance HHCL permeation through the stratum corneum, to assess the peripheral H1-antihistaminic activity and the extent to which HHCL was systemically absorbed from transdermal gel loaded with solid lipid nanoparticles (SLNs), as well as to avoid its extreme bitterness. According to 23 factorial design, eight formulations of HHCL-SLNs were prepared by the double emulsification method. Lipid type (XA), surfactant concentration (XB) and co-surfactant concentration (XC) were the independent variables. All formulations were characterized for their surface morphology, particle size, entrapment efficiency and in-vitro drug release study. The optimized formula that provides greater desirability was then incorporated into the transdermal gel. In addition, the efficacy of the developed gel was tested in-vivo using 2,4-Dinitrochlorobenzene induced atopic dermatitis as lesion model in mice. F4 showed an average diameter 111 nm ± 0.03, zeta potential - 30 MV ± 2.4 and EE 75.2% ± 4.4. TEM images showed spherical, smooth morphology with uniform particles distribution. In-vivo study demonstrated potent antipruritic efficacy of transdermal gel in atopic dermatitis such as induced lesions compared to HHCL gel. Hence, HHCL solid lipid nanoparticles transdermal gel may be considered as potential for delivery of HHCL and alternatively to traditional oral use.

Cutaneous microbial biofilm formation as an underlying cause of red scrotum syndrome.

BACKGROUND: Red scrotum syndrome is typically described as well-demarcated erythema of the anterior scrotum accompanied by persistent itching and burning. It is chronic and difficult to treat and contributes to significant psychological distress and reduction in quality of life. The medical literature surrounding the condition is sparse, with the prevalence likely under-recognized and the pathophysiology remaining poorly understood. Formation of a cutaneous microbial biofilm has not been proposed as an underlying etiology. Microbial biofilms can form whenever microorganisms are suspended in fluid on a surface for a prolonged time and are becoming increasingly recognized as important contributors to medical disease (e.g., chronic wounds). CASE PRESENTATION: A 26-year-old man abruptly developed well-demarcated erythema of the bilateral scrotum after vaginal secretions were left covering the scrotum overnight. For 14 months, the patient experienced daily scrotal itching and burning while seeking care from multiple physicians and attempting numerous failed therapies. He eventually obtained complete symptomatic relief with the twice daily application of 0.8% menthol powder. Findings in support of a cutaneous microbial biofilm as the underlying etiology include: (1) the condition began following a typical scenario that would facilitate biofilm formation; (2) the demarcation of erythema precisely follows the scrotal hairline, suggesting that hair follicles acted as scaffolding during biofilm formation; (3) despite resolution of symptoms, the scrotal erythema has persisted, unchanged in boundary 15 years after the condition began; and (4) the erythematous skin demonstrates prolonged retention of gentian violet dye in comparison with adjacent unaffected skin, suggesting the presence of dye-avid material on the skin surface. CONCLUSION: The probability that microorganisms, under proper conditions, can form biofilm on intact skin is poorly recognized. This case presents a compelling argument for a cutaneous microbial biofilm as the underlying cause of red scrotum syndrome in one patient, and a review of similarities with other reported cases suggests the same etiology is likely responsible for a significant portion of the total disease burden. This etiology may also be a significant contributor to the disease burden of vulvodynia, a condition with many similarities to red scrotum syndrome.

Capsaicin attenuates imiquimod-induced epidermal hyperplasia and cutaneous inflammation in a murine model of psoriasis.

Psoriasis is one of the most common chronic inflammatory diseases that is characterized by well-defined erythematous plaques, with typical histopathological findings of lymphocytic infiltration and epidermal hyperplasia. Topical treatments of psoriasis are either associated with limited response or with side effects. Up to date, topicals targeting neuroimmune axis in psoriasis or psoriasiform dermatitis have not been explored. Here, we investigated whether percutaneous delivery of capsaicin could attenuate the pathological change of psoriasiform inflammation. Imiquimod-induced psoriasis-like murine model was used to evaluate therapeutic effects from topical application of capsaicin. An additional model of psoriasiform dermatitis induced by direct IL-23 injection was used to identify the level of action from capsaicin in this neuroimmune axis. Cutaneous inflammation was assessed by erythema level and ear thickness change. Key cytokines, infiltrating cells in the skin, and draining lymph node cells were investigated. The results showed that capsaicin administration obstructed the activation of IL-23/IL-17 pathway induced by imiquimod, presenting with significantly reduced psoriasiform dermatitis both in gross appearance and microscopic features. Tissue gene expression of psoriatic core cytokines induced by imiquimod (including IL-23, IL-17A, IL-22, TNF-α, and IL-6) were greatly decreased by capsaicin application. This protective effect from capsaicin could be hampered by direct intradermal injection of IL-23. CONCLUSION: Epicutaneous delivery of capsaicin on imiquimod-treated murine skin could significantly decrease expression of multiple inflammatory cytokines and the severity of prototypic change of psoriasiform inflammation. The beneficial effect imposed by capsaicin reinforces the neuroimmune contribution towards psoriasiform inflammation and provides a potential non-steroidal therapeutic alternative for topical treatment of psoriasiform dermatitis.

Energy-Dependent Endocytosis Is Responsible for Skin Penetration of Formulations Based on a Combination of Indomethacin Nanoparticles and l-Menthol in Rat and Göttingen Minipig.

We previously designed a Carbopol gel formulation (N-IND/MEN) based on a combination of indomethacin solid nanoparticles (IND-NPs) and l-menthol, and we reported that the N-IND/MEN showed high transdermal penetration. However, the detailed mechanism for transdermal penetration of IND-NPs was not clearly defined. In this study, we investigated whether endocytosis in the skin tissue of rat and Göttingen minipig is related to the transdermal penetration of IND-NPs using pharmacological inhibitors of endocytosis. The pharmacological inhibitors used in this study are as follows: 54 µM nystatin, a caveolae-mediated endocytosis (CavME) inhibitor; 40 µM dynasore, a clathrin-mediated endocytosis (CME) inhibitor; and 2 µM rottlerin, a micropinocytosis (MP) inhibitor. The N-IND/MEN was prepared by a bead mill method, and the particle size of solid indomethacin was 79-216 nm. In both rat and Göttingen minipig skin, skin penetration of approximately 80% IND-NPs was limited by the stratum corneum (SC), although the penetration of SC was improved by the combination of l-menthol. On the other hand, the treatment of nystatin and dynasore decreased the transdermal penetration of indomethacin in rats and Göttingen minipigs treated with N-IND/MEN. Moreover, in addition to nystatin and dynasore, rottlerin attenuated the transdermal penetration of IND-NPs in the Göttingen minipigs' skin. In conclusion, we found that l-menthol enhanced the SC penetration of IND-NPs. In addition, this study suggests that the SC-passed IND-NPs are absorbed into the skin tissue by energy-dependent endocytosis (CavME, CME, and/or MP pathways) on the epidermis under the SC, resulting in an enhancement in transdermal penetration of IND-NPs. These findings provide significant information for the design of nanomedicines in transdermal formulations.

Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study.

Background and Purpose: Sphenopalatine ganglion (SPG) electrical stimulation has been studied in the setting of acute ischemic stroke to enhance collateral flow. Capsaicin poses an alternative to chemically stimulate the sphenopalatine ganglion. Therefore, the objective of this study was to determine the safety and effect of increasing doses of capsaicin upon serial transcranial Doppler markers of cerebral blood flow. Methods: We performed serial transcranial Doppler testing in 30 healthy volunteers divided into 5 equal groups. Capsaicin doses ranged from 33 to 165 µMol. We recorded peak systolic and end-diastolic velocities in the middle cerebral artery, arterial pressure, and perceived pungency in 5-minute intervals up to 20 minutes. We then calculated the mean velocity, the pulsatility index, and the cerebral blood flow index. Results: The participants' median age was 21 years (range, 5 years); all reported consumption of capsaicin in their diets. After and during the study, none reported side effects. Perceived pungency peaked at 5 minutes, and by the 20-minute mark, none perceived any pungency. All the tested doses produced the same pattern, consisting of augmentation of the middle cerebral artery mean velocity with the pulsatility index's diminution. The effects peaked between the 5- and the 10-minute measurements and then returned to basal levels except for the 66-µMol doses, which produced a sustained effect. We found no correlation between perceived pungency and dose, but the middle cerebral artery mean velocity was strongly correlated with the dose administered. Conclusions: This study provides evidence supporting the safety and tolerability of oral capsaicin in a population of healthy volunteers. Capsaicin appears to produce effects similar to those of sphenopalatine ganglion electrical stimulation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04545892.

Safety considerations for the management of cholestatic itch.

Introduction: Pruritus is adisabling symptom common to cholestatic liver disorders. Its pathophysiology has not been completely elucidated and although multiple mediators have been identified, only lysophosphatidic acid (LPA) and its synthetizing enzyme autotaxin (ATX) appear to consistently correlate with symptom intensity. This review aims to summarize the most relevant safety and efficacy data regarding both standard and new medications utilized to treat pruritus in cholestatic liver disease.Areas covered: International societies like the AASLD and EASL recommend astepwise approach for the management of cholestatic itch. However, therapeutic response is variable. Cholestyramine is considered first-line, followed by rifampicin, naltrexone and sertraline. When used appropriately, these medications have afavorable adverse events profile with most side effects related to drug class and not to the underlying etiology of liver disease.Expert opinion: Although conventional therapies seem to be effective in aproportion of patients, asizable number of cases remain refractory and require the utilization of experimental treatments. Multiple potential targets, especially in the ATX-LPA axis have yet to be pharmacologically explored, with ongoing translational and clinical research. Novel drugs are currently being developed for the management of cholestatic itching with promising results and afavorable safety profile.

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 STATEMENTWhat 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.

Comprehensive Review of Topical Analgesics for Chronic Pain.

PURPOSE OF REVIEW: Topical analgesics are a non-opioid option for the treatment of chronic pain conditions including neuropathic pain, musculoskeletal pain, and osteoarthritis. There are many topical medications available; however their efficacy is variable. This article reviews the various topical analgesics, their mechanisms of action, and their efficacy. RECENT FINDINGS: Studies have found topical NSAIDs are useful in treating acute musculoskeletal pain syndromes (strains and sprains) and show some efficacy in treating hand and knee osteoarthritis (Derry et al. Cochrane Database Syst Rev 5:CD008609, 2017). Topical capsaicin 8% has been shown to be efficacious in the treatment of postherpetic neuralgia, painful diabetic peripheral neuropathy, and HIV-neuropathy (Derry et al. Cochrane Database Syst Rev 1:CD007393, 2017). Topical lidocaine has been widely studied and found to reduce pain in patients with postherpetic neuralgia (Knezevic et al. Pain Manag 7:537-58, 2017). Although many other topical analgesics are available, there is limited data to support the efficacy of other agents. Topical analgesics are a relatively benign treatment for chronic pain conditions including neuropathic pain, musculoskeletal, and myofascial pain. There is evidence to support the use of topical NSAIDs, high concentration topical capsaicin, and topical lidocaine for various painful conditions.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Impact of menthol on nicotine intake and preference in mice: Concentration, sex, and age differences.

Menthol has been shown to contribute to the appeal of tobacco products in humans. However, factors such as sex, age and menthol concentration remain unclear in the interaction between menthol and nicotine. To understand these factors, we utilized a mouse model to determine the impact of menthol on oral nicotine consumption. A range of menthol concentrations (oral and systemic) were tested with or without oral nicotine using the two-bottle choice paradigm in adolescent and adult female and male C57BL/6J mice. Moreover, genetically modified mice were used to investigate the role of α7 nicotinic acetylcholine receptors (nAChRs) on the effects of menthol. Menthol addition to nicotine solution increased oral nicotine consumption in C57BL/6J mice in a sex- and menthol concentration-dependent manner. At lower menthol concentrations, female mice demonstrated an enhancement of nicotine consumption and male mice showed a similar behavior at higher menthol concentrations. Menthol drinking alone was only significantly different by sex at 60 µg/ml menthol concentration where female mice had higher menthol intake than males. Menthol administered both orally and systemically (intraperitoneal) increased oral nicotine consumption. Adolescent female mice had a higher nicotine intake at lower menthol concentrations compared to their adult counterparts. While α7 nAChR wild type mice consumed more mentholated nicotine solution than nicotine only solution, this effect was abolished in KO mice. Effects of menthol are concentration-, sex-, age-, and α7 nAChR-dependent. Oral and intraperitoneal menthol increases nicotine intake, suggesting that sensory, peripheral, and/or central mechanisms are involved in effects of menthol on oral nicotine consumption.

Serotonin and noradrenaline modulate chronic itch processing in mice.

The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and noradrenaline to chronic itch, the effects of the administration of antidepressants or noradrenaline reuptake inhibitors were evaluated in the present study. A pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of spontaneous scratching behavior in mice with chronic itch. The administration of a serotonin reuptake inhibitor, such as fluvoxamine and paroxetine, but not escitalopram, or a noradrenaline reuptake inhibitor, such as atomoxetine and nisoxetine, ameliorated the induction of spontaneous scratching behavior in mice with chronic itch. Furthermore, this attenuation was reversed by the administration of yohimbine, a selective α2-adrenoceptor antagonist, or methysergide, a non-selective serotonin receptor antagonist. These results suggest that elevated serotonin and noradrenaline levels are involved in the attenuation of scratching behavior induced by chronic itch, and serotonin receptors and an α2-adrenoceptor play a crucial role in chronic pruriceptive processing.

Topical Application of ASN008, a Permanently Charged Sodium Channel Blocker, Shows Robust Efficacy, a Rapid Onset, and Long Duration of Action in a Mouse Model of Pruritus.

The sensation of pruritus, or itch, is associated with a variety of skin and medical disorders. Itch is transmitted through afferent C-fibers, and sodium channels play a key role in the transmission process. Local anesthetics, which block sodium channels, are used topically to treat itch but generally have a short duration of action and are not selective for afferent nerves underlying the itch sensation. Accordingly, there is a substantial unmet need for safe, efficacious, long-acting treatments for chronic pruritus, including nonhistaminergic itch. We investigated the dose-response, time to onset, and duration of action of ASN008 topical gel, which targets small afferent sodium channels, in a murine model of pruritus in which scratching behavior is induced by intradermal injection of chloroquine into the nape of the neck of C57BL/6 mice. Topical application of ASN008 gel resulted in a concentration-dependent reduction of scratching behavior. Onset of action was ≤1 hour, and duration of scratching inhibition was 15-24 hours. In a further study involving once-daily application for 5 days with chloroquine challenge on day 5, treatment with ASN008 gel again resulted in a concentration-dependent reduction of chloroquine-induced scratching, even when the gel was removed 3 hours after each daily application. In conclusion, topical ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once-daily treatment of a variety of pruritic conditions in humans, including nonhistaminergic itch. SIGNIFICANCE STATEMENT: ASN008 gel produces a dose-dependent reduction of scratching in a mouse model of pruritus, with a rapid onset and long duration of action, and may prove to be an effective, once- or twice-daily treatment for a variety of pruritic conditions in humans. ASN008 gel has demonstrated good safety and tolerability in healthy volunteers and is currently under investigation in a phase 1b clinical study to evaluate safety, tolerability, pharmacokinetics, and preliminary antipruritic efficacy in atopic dermatitis patients (ClinicalTrials.gov ID: NCT03798561).

Emerging drugs for the treatment of chronic pruritic diseases.

INTRODUCTION: Chronic pruritus is non-histaminergic and mediated through a complex interplay of peripheral and central immune and neural pathways. Significant developments in the understanding of chronic pruritus have emerged and paved the way for new, emerging therapies. AREAS COVERED: This review details the emerging drug landscape for chronic pruritus treatment, focusing on monoclonal antibody agents that target key cytokines and their receptors as well as small molecule agents that inhibit mediators of the immune and neural pathways. The article provides background regarding the currently available therapies and the rationale for the development of new agents based on the current market and recent scientific developments. EXPERT OPINION: Identification of new targets along neuroimmune itch pathways has allowed for the development of targeted drugs which can be utilized for effective therapy. As we enter a new era of chronic itch treatments, we face exciting prospects and challenges.

Small molecule drugs for the treatment of pruritus in patients with atopic dermatitis.

Chronic pruritus is a cardinal symptom of the inflammatory skin disease atopic dermatitis (AD). Pathogenic mechanisms in the periphery, spinal cord and the brain have been implicated in AD-related pruritus. Therefore, both systemic and topical administration of drugs could potentially provide relief. Despite efforts to elucidate the mechanisms behind AD-related pruritus and the relative contribution of peripheral nervous system and central nervous system (CNS), specific and successful treatment options have not yet been developed. Several small molecule drugs are currently being investigated to treat AD and AD-related pruritus. These small molecule drugs can be applied systemically but also topically, as they are able to penetrate into the skin due to their small size. Small molecule drugs specifically targeting peripheral itch transmission, e.g. peripherally selective κ-opioid receptors agonists and neurokinin 1 receptors antagonists, have so far been unable to improve AD-related pruritus when applied systemically, possibly because of the lack of CNS activity. Current evidence from clinical and preclinical trials with centrally acting or peripherally selective oral κ-opioid receptors agonists implies that CNS activity is required for an antipruritic effect. CNS activity is, however, directly associated with CNS-mediated side-effects. On the other hand, topical application of small molecules with anti-inflammatory activity such as Janus kinase inhibitors and phosphodiesterase 4 inhibitors, and also of κ-opioid receptor agonists, has shown promising results regarding their ability to reduce AD-related pruritus. In conclusion, topical application of anti-inflammatory compounds appears to be a highly promising strategy for the treatment of AD-related pruritus.

Comparison of gabapentin and hydroxyzine in the treatment of pruritus in patients on dialysis.

BACKGROUND: Pruritus is one of the most common problems in patients with chronic renal failure. Of all patients with end-stage renal disease (ESRD), 60-80% report pruritus during their life. AIM: To compare the effect of gabapentin (GBP) and hydroxyzine (HYDZ) in treating pruritus in patients on dialysis. METHODS: In a double-blind, randomized, crossover clinical trial, 32 patients on dialysis who reported pruritus were assigned randomly to receive either GBP or HYDZ for 6 weeks; the first group received GBP 100 mg/day orally and the second group received HYDZ 25 mg/day orally for 6 weeks. After this 6-week period (Period 1) there was a washout period of 2 weeks then patients were crossed over to the other drug (the first group receiving HYDZ and second group receiving GBP) and followed up for a further 6 weeks (Period 2). A visual analogue scale was used to measure pruritus intensity in the groups before and after the first and second period. RESULTS: In Period 1, pruritus severity decreased from 7.1 ± 1.46 at baseline to 2.17 ± 1.82 at 6 weeks in the GBP group (P = 0.001) and from 6.83 ± 2.11 to 2.86 ± 1.67 in the HYDZ group (P = 0.001). In Period 2, pruritus severity decreased from 5.1 ± 1.61 at baseline to 1.56 ± 0.82 at 6 weeks in the GBP group (P < 0.01) and from 5.23 ± 2.11 to 2.1 ± 1.87 in the HYDZ group (P = 0.001). CONCLUSION: Results showed that both HYDZ and GBP significantly improved and controlled pruritus in patients on dialysis, with no significant difference observed between the two drugs.