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.

Pathogenesis and Treatment of Pruritus Associated with Chronic Kidney Disease and Cholestasis.

Itching is an unpleasant sensation that provokes the desire to scratch. In general, itching is caused by dermatologic diseases, but it can also be caused by systemic diseases. Since itching hampers patients' quality of life, it is important to understand the appropriate treatment and pathophysiology of pruritus caused by systemic diseases to improve the quality of life. Mechanisms are being studied through animal or human studies, and various treatments are being tested through clinical trials. We report current trends of two major systemic diseases: chronic kidney disease and cholestatic liver disease. This review summarizes the causes and pathophysiology of systemic diseases with pruritus and appropriate treatments. This article will contribute to patients' quality of life. Further research will help understand the mechanisms and develop new strategies in the future.

Darier Disease with Psoriasis.

Darier disease is an autosomal dominant disorder with dark crusty patches and is classified as hereditary acantholytic dermatosis. Keratotic papules and crust are often present on the scalp, forehead, chest, back, upper arms, elbows, groin, and behind the ears, predominantly in seborrheic areas. A 48-year-old male patient presented skin lesions with pruritus on the trunk and both upper and lower extremities. He first noticed the lesion 15 years before. On physical examination, there were multiple erythematous papules with crust on the trunk and red-brown colored keratotic plaque on both extremities. The suspected histopathological diagnosis was psoriasis vulgaris. The patient's skin lesions and pruritus were significantly improved after the psoriasis treatment. While continuing psoriasis treatment, the patient showed sudden worsening of the skin lesions on the scalp, abdomen, and fingernails (V-shaped nicks) with pruritus. Punch biopsy was performed on the abdominal lesion again and the final diagnosis was Darier disease. The patient was then treated using alitretinoin while maintaining the use of guselkumab for psoriasis. There are only a few cases that we found in which patients with Darier disease also had psoriasis. We report this rare case of Darier disease with psoriasis and propose that an additional biopsy might be necessary for accurate diagnosis and proper treatment.

Moisturizer in Patients with Inflammatory Skin Diseases.

As interest in skin increases, the cosmetic market is also growing. It is difficult to choose between the numerous types of basic cosmetics on the market. This article aims to provide advice and guidance on which products to recommend according to a patient's skin condition. Appropriate application of a moisturizer attempts not only to improve the dryness, but also improve the skin's natural barrier function to protect the skin from internal and external irritants to keep the skin healthy. Moisturizers consist of various ingredients, including occlusive agents, emollients, humectants, lipid mixture, emulsifiers, and preservatives. Pathophysiology of dry skin is also discussed to provide readers with the background they need to choose the right moisturizer for themselves. As moisturizers play an important role as adjuvant in the treatment of common skin diseases, such as atopic dermatitis, contact dermatitis, psoriasis, acne and rosacea, which type of moisturizer is appropriate for each disease was also dealt with. Basic cosmetics, especially moisturizers, should be recommended in consideration of the ingredients, effectiveness and safety of each product, and the skin condition of each patient.

Aryl Hydrocarbon Receptor Repressor Is Hypomethylated in Psoriasis and Promotes Psoriasis-like Inflammation in HaCaT Cells.

It is known that DNA hypomethylation of aryl hydrocarbon receptor repressor (AhRR), one of the epigenetic markers of environmental pollutants, causes skin diseases. However, the function and mechanisms are still unknown. We aimed to determine whether AhRR is hypomethylated in PBMC of psoriasis patients, as well as to examine the expression of psoriasis-related inflammatory cytokines and antimicrobial peptides after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment in HaCaT cells overexpressing or silencing AhRR. AhRR was determined by qPCR, Western blot, immunohistochemistry, and immunocytochemistry in skin tissue and HaCaT cells. DNA methylation of AhRR was performed by Infinium Human Methylation450 BeadChip in PBMC of psoriasis patients and methylation-specific PCR (MSP) in HaCaT cells. NF-κB pp50 translocation and activity were performed by immunocytochemistry and luciferase reporter assay, respectively. We verified AhRR gene expression in the epidermis from psoriasis patients and healthy controls. AhRR hypomethylation in PBMC of psoriasis patients and pAhRR-HaCaT cells was confirmed. The expression level of AhRR was increased in both TCDD-treated HaCaT cells and pAhRR-HaCaT cells. NF-κB pp50 translocation and activity increased with TCDD. Our results showed that AhRR was hypomethylated and overexpressed in the lesional skin of patients with psoriasis, thereby increasing AhRR gene expression and regulating pro-inflammatory cytokines through the NF-κB signaling pathway in TCDD-treated HaCaT cells.

Aryl Hydrocarbon Receptors: Evidence of Therapeutic Targets in Chronic Inflammatory Skin Diseases.

The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is important for xenobiotic metabolism and binds to various endogenous and exogenous ligands present in the skin. AhR is known to be associated with diseases in various organs; however, its functions in chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis (PS), have recently been elucidated. Here, we discuss the molecular mechanisms of AhR related to chronic inflammatory skin diseases, such as AD and PS, and the mechanisms of action of AhR on the skin immune system. The importance of AhR molecular biological pathways, clinical features in animal models, and AhR ligands in skin diseases need to be investigated. In conclusion, the therapeutic effects of AhR ligands are demonstrated based on the relationship between AhR and skin diseases. Nevertheless, further studies are required to elucidate the detailed roles of AhR in chronic inflammatory skin diseases.

Differential Diagnosis and Treatment of Itching in Children and Adolescents.

Itching is prevalent in children with skin disorders and associated with effects on their mood, quality of life, and social functioning. Surprisingly, there are no data on childhood prevalence of pruritus in the general population. The aim of this article is to explore the epidemiology, clinical manifestation, and treatment for itch (pruritus) in the pediatric population (from infancy to adolescence), and to be helpful to primary care physicians who assess and diagnose pediatric patients with itching. In this study, we searched for specific keywords using PubMed and MEDLINE (Ovid) and, then, refined the retrieved searches for each cause and treatment. As a result of reviewing the literature, atopic dermatitis was shown to be the most common cause of itching, especially during infancy and through preschool. Not only skin disorders but also systemic diseases, drugs, and postburn states can predispose an individual to itching in childhood. There are traditional and newly developed treatment modalities for itching in pediatric patients. However, because the pharmacokinetics and pharmacodynamics of childhood are different from those of adults, the medications for itching have to be applied carefully for these age groups. There are many areas to be elucidated regarding the prevalence and objective assessment of pruritus in pediatric patients. Moreover, the safety profiles of medications in the pediatric population need to be better understood. Further studies to investigate itching in childhood are warranted.

An Open Label, Multi-Center, Non-Interventional Post-Marketing Surveillance to Monitor the Safety and Efficacy of ALTARGO® (Retapamulin) Administered in Korean Patients According to the Prescribing Information.

BACKGROUND: With the approval of topical retapamulin ointment in 2011, it was officially required to conduct a post-marketing surveillance (PMS) study to obtain further data of its safety profile and effectiveness, in accordance with the requirement of the Korean Ministry of Food and Drug Safety (MFDS). OBJECTIVE: This study had prospectively designed to monitor safety and tolerability with the effectiveness of topical retapamulin in clinical practices. METHODS: Open label, multi-center, non-interventional observational study was done from May 2011 to October 2015. All subjects had bacterial skin infections of locally approved prescribing information accordingly. The study mainly focused on safety issues in the local target population (3,612 eligible subjects). And, drug effectiveness was also evaluated by physicians. RESULTS: The incidence of adverse events (AEs) and adverse drug reactions (ADRs) were 2.53% and 0.97%, respectively. In terms of the incidence of unexpected AEs and ADRs, 1.45% and 0.33%, and for the incidence of serious AEs, 0.28%, whereas no serious ADRs reported. And, the effectiveness of topical retapamulin rate was 96.1% (1,697 of total 1,765 subjects). CONCLUSION: Topical retapamulin is to be well-tolerated and effective in patients with bacterial skin infections of locally approved prescribing information.

Effects of tacrolimus ointment on the expression of substance P, nerve growth factor, and neurotrophin-3 in atopic dermatitis.

BACKGROUND: There is increasing evidence that neuropeptides may be involved in the pathogenesis of atopic dermatitis (AD). Objectives To investigate the effects of tacrolimus on the neuropeptides substance P (SP), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the skin, and SP and NGF in the serum, of patients with AD. METHODS: Lesional skin specimens were obtained from eight AD patients and eight normal controls. For 8 weeks, AD patients applied 0.03% tacrolimus ointment to all affected areas twice daily. Blood samples and skin biopsies were then repeated. The participants' serum SP and NGF levels, as well as the SP, NGF, and NT-3 immunoreactive cell counts, were evaluated in the epidermal, dermal, and perivascular areas of lesional skin before and after treatment. RESULTS: The immunoreactive cell counts of SP, NGF, and NT-3 in skin were higher in AD patients than in normal controls. Most cell counts decreased significantly after treatment; however, the change in serum SP and NGF was not statistically significant. CONCLUSIONS: We demonstrated semiquantitative differences in neuropeptides in the skin of AD patients. In addition, topical tacrolimus reduced the levels of neuropeptides in the tissues of AD patients.