Psoriasis is a chronic inflammatory skin disease often accompanied by pruritus and a high risk of secondary infection. To address the limitations of current therapies, we developed a dual-layer microneedle (MN) system that integrates methotrexate-zinc (MTX-Zn) for sustained anti-inflammatory and antibacterial effects with difelikefalin (DFK) for rapid antipruritic action. MTX-Zn was successfully synthesized through coordination chemistry and exhibited enhanced stability, preserved antiproliferative activity, and strong antibacterial effects. The GelMA/PVA-based microneedles showed excellent mechanical strength, efficient skin penetration, and distinct spatial drug compartmentalization. In an IMQ-induced psoriasis model, MTX-Zn/DFK MNs markedly improved clinical symptoms, reduced epidermal hyperplasia, restored immune-cell homeostasis, and decreased Th17/Th1-mediated inflammation. DFK-loaded MNs rapidly alleviated pruritus, reduced epidermal nerve-fiber density, and inhibited Schwann cell migration. Transcriptomic analysis further revealed that DFK suppressed Schwann cell EMT pathways. Together, this dual-functional microneedle platform provides a synergistic therapeutic strategy that combines rapid itch relief with long-term anti-psoriatic and antibacterial effects, representing a promising approach for improving psoriasis management.

MKOP002, a novel bifunctional μ-/κ-opioid decapeptide with G protein-biased μ-opioid agonism, exhibits antinociceptive and antipruritic activities.

The κ-opioid receptor (KOR) is a member of the G protein-coupled receptor (GPCR) family, modulating cellular responses through transducers such as G proteins and β-arrestins. G-protein-biased KOR agonists aim to retain analgesic and antipruritic actions while limiting aversion and sedation. Aiming to inform G-biased KOR agonist design, we analyze signaling-relevant residues from structural and dynamic views. Here we show, using multiple complementary methods, shared residues that determine β-arrestin recruitment by nalfurafine and U-50,488H. Cryo-electron microscopy structures of the KOR-Gi signaling complexes identify the ligand binding mode in the activated state. Vibrational spectroscopy reveals ligand-induced conformational changes. Cell-based mutant experiments pinpoint four amino acids (K2275.40, C2866.47, H2916.52, and Y3127.34; Ballesteros–Weinstein numbering is shown in superscript) that play crucial roles in β-arrestin recruitment. Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced β-arrestin recruitment activity. Our research findings provide a foundation for enhancing KOR-mediated therapeutic effects while minimizing unwanted side effects by targeting specific residues within the KOR ligand-binding pocket, including K2275.40 and Y3127.34, which have previously been implicated in biased signaling.

3-Hydroxydecanoic acid (3-HDA) as one hydroxylated fatty acid in royal jelly has limited research on the potential application. This paper investigated the anti-inflammatory properties of 3-HDA on RAW264.7 murine macrophages, RBL-2H3 rat mast cells and HaCaT human keratinocytes. 3-HDA inhibited lipopolysaccharide (LPS)-induced morphological differentiation of RAW264.7 cells and reduced subsequent expressions on reactive oxygen species (ROS), TNF-α, cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). 3-HDA also inhibited the inflammation/allergic responses of RBL-2H3 cells at exposure to Compound 48/80 (C48/80), as evidenced by reduced degranulation, along with the 45% and 58% reductions in histamine (His) and β-hexosaminidase (β-Hex) expression, respectively. At exposure to either capsaicin (CAP) or 45 °C, 3-HDA also inhibited HaCaT cells, to secrete the inflammatory factor of IL-31, express the transient receptor potential vanilloid 1 (TRPV1) activity and release Ca2+. It seems that 3-HDA has the potential to suppress inflammation and pruritic responses, advancing understanding of its biological activities.

Pharmacological characterization of the novel selective kappa opioid receptor agonists 10-Iodo-Akuammicine and 10-Bromo-akuammicine in mice.

Pruritus is a distressing symptom associated with various dermatological, systemic and neurological conditions, markedly impairing quality of life. Pruritus arises through histamine-dependent and histamine-independent pathways, involving mediators such as histamine, gastrin-releasing peptide (GRP), interleukin-31 (IL-31) and STAT3 signaling. The present study aimed to investigate the antipruritic effects of Diospyros lotus leaf extract (DLE) and its major constituent, myricitrin (MC), on ICR mice using compound 48/80 (histamine-dependent) and chloroquine (histamine-independent) itch models. Serum levels of histamine and IL-31 were measured by ELISA, and mast cell infiltration was assessed via toluidine blue staining. Furthermore, the expression and activation of GRP receptor (GRPR), IL-31RA and STAT3 in the spinal cord were analyzed using western blotting and immunofluorescence staining. Notably, DLE and MC significantly reduced scratching behavior, serum histamine levels and mast cell infiltration in both models. Immunofluorescence staining and western blot analysis revealed that DLE and MC downregulated GRPR, IL-31 receptor A and phosphorylated STAT3 expression in the spinal cord, indicating modulation of central itch signaling. Additionally, DLE and MC suppressed IL-31 levels in serum and skin tissues. These findings indicated that DLE and MC may alleviate pruritus through multiple mechanisms, including mast cell stabilization, histamine reduction and modulation of central itch pathways. The broad-spectrum antipruritic activity of DLE and MC highlights their potential as natural therapeutic agents for diverse pruritic conditions, offering a safer alternative to synthetic antipruritic drugs. Further research is warranted to validate these findings in clinical settings and to elucidate the molecular mechanisms underlying their efficacy.

Skin dryness is a moderately common symptom, especially in a group of elderly patients. Xerosis can be caused both by age‐associated skin features and chronic diseases, and the use of certain drugs. Retinoids are the drugs used to treat young patients, which are prescribed due to acne and rosacea. Systemic and topical retinoids induce thinning of the stratum corneum, changes in the sebum composition, which becomes the cause of increased transepidermal moisture loss. Antineoplastic drugs can also induce skin dryness. In particular, xerosis is a common side effect that occurs when epidermal growth factor receptor (EGFR) inhibitors are administered. Antihistamines, high blood pressure drugs, for instance diuretics, statins that are used to lower cholesterol levels, can induce xerosis. Therefore, care products with pronounced moisturizing effects should be included in the guidelines on the treatment with drugs inducing skin dryness. Preference should be given to combination drugs, which ingredients will not only restore the normal moisture level of the skin, but also have an antipruritic action, as itching is often observed in xerosis, and repair a damaged skin barrier that inevitably occurs in skin dryness. Care products should have a prolonged action, allowing them to be used 1–2 times a day, a pleasant texture, and be quickly absorbed without leaving a greasy feeling. This will not only eliminate the unpleasant side effect of the backbone therapy, but also improve the patients’ quality of life.

Different symptoms are associated with atopic skin, including dryness, pruritus and pain, and affect patients' quality of life. The environment, microbiota, epidermis, immune and nerve cells are all implicated in the pathogenesis of atopic skin. Staphylococcus aureus is the focus of particular attention. Epidermis is implicated at multiple levels: inflammatory process, barrier, control of moisture and water loss. Sensory neurons that participate in cutaneous neurogenic inflammation and pruritus are seen as a potential new target. Specific management strategies and new treatments for adults and children are needed to help in more refractory cases. As a baseline of management, guidelines recommend a treatment to moisturize the skin and maintain the skin barrier function, such as an emollient. To evaluate a new product in vitro and in vivo in order to validate the potential of its use in people with atopic skin or dry skin. A specific mineral composition, Active Oligo Skin complex™, from seawater was developed and included in a balm. The effects of a solution and balm containing the complex were evaluated in vitro on the growth and biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis in different skin models, and in vivo in adult and young volunteers. In vitro, the complex modulated bacterial biofilm formation and growth, decreased cytokine [interleukin (IL)-1, IL-6, IL-4] and neuropeptide (substance P) release, and increased the expression of CL1 and CL4. On volunteers with dry skin, the complex had a moisturizing effect after 1 h of application. Dryness and roughness were also reduced in young participants with atopic skin. The balm decreased erythema and pruritus after 21 days of topical application on 60 young participants. On 22 adult participants, stinging score was decreased after -application. The Active Oligo Skin complex™ appears to display potent antipruritic and anti-inflammatory activities, both in vitro and in vivo.

Brihati (~Solanum indicum), Haridra (~Curcuma longa) and Daruharidra (~Berberis aristate) Brihatiphala Haridradwaya are easily accessible traditional herbal drugs and renowned for their pharmacotherapeutic properties and actions. Brihatiphala Haridradwaya are indicated in Pruritus vulva with special reference to Kaphaja Yonivyapada (Vulvovaginitis). Yonidhoopana (~vulvovaginal fumigation) and Yonipoorana (~ vaginal filling) are the important local procedure (~Sthanika Chikitsa) to treat Yonikandu (~pruritus vulva). Sthanika Chikitsa is the speciality of Ayurveda gynaecological Panchakarma procedures to treat vaginal infections with immediate effect. Literature search was done through different bibliographic databases such as PubMed, Ayush Research Portal, Google Scholar to search peer reviewed clinical, experimental and fundamental research studies. Ayurvedic pharmacopeia of India, Quality Standards of Indian Medicinal Plants, Ayurvedic text books of Dravya Guna, different Samhitas (Brihatrayi) and Ayurvedic literature of Striroga & Prasuti Tantra were studied thoroughly. After datamining it is found that Pharmacologically Brihati Haridradwaya possess a range of biological active phytoconstituents which exhibit anti-inflammatory, analgesic, antipruritic, antimicrobial, antioxidant, anticancer and hepatoprotective activity. Synergistically these drugs are available in different feasible herbal forms like powders, granules, decoction, oils, ointments, herbal Gel and volatile fumes used for fumigation to treat genital infections as per individual health requirements. Thus, integration of traditional medicines when used for clinical and experimental studies provide a comprehensive prospective of effectiveness and application in current medical practice. Accurate taxonomical identification, phytochemical consistency, pharmacological properties, traditional uses are the important consideration to explore pharmaceutical and therapeutic actions of herbal drugs. In present review active phytoconstituents, pharmacological, pharmacotherapeutic activities of Brihatiphala Haridradwaya are explored for better holistic evidence-based management of diseases.

Background/Objective: Senile pruritus (SP) is a prevalent disease that occurs in elderly individuals over the age of 60 and is characterized by the primary symptom of pruritus. The disease's pathogenesis is complex, and clinical practice mainly uses symptomatic treatment drugs. YGZ223 is a traditional Chinese medicine currently in clinical trials for treatment of SP. However, its chemical composition and pharmacological mechanism remain unclear. The purpose of this inquiry is to investigate the workings of YGZ223 in managing SP using network pharmacology, UPLC-MS, and molecular docking. Materials and Method: This investigation employs network pharmacology to anticipate the mode of operation of YGZ223 in alleviating SP, and UPLC-MS is applied to identify the chemical constituents. Molecular docking provides the binding strengths between principal constituents and targets, while animal experiments are performed to validate the antipruritic activity of YGZ223. Results: The compound prescription for SP contains formononetin and erysodienone as effective ingredients. These ingredients have the potential to impact pathways related to cancer, endocrine resistance, and the PI3K/AKT signaling pathway by regulating targets such as AKT1, EGFR, and mTOR. Formononetin and erysodienone have a considerable binding capacity with various targets, the former displaying the strongest binding with AKT1. Animal test results show that the YGZ223 group can significantly reduce the number of tickles in mice compared to the 4-Aminopyridine induced model group, and has a good anti-itch effect. Conclusion: This study demonstrates that YGZ223 has potential anti-SP activity due to multiple constituents, targets, and pathways, and thus lays the groundwork for development of novel therapeutic approaches for SP.

This article discusses the immediacy of the problem of rising incidence of common mycoses that dermatovenerologists deal with at outpatient visits, the reasons for their occurrence, conversion from one course of the disease to another and the use of etiological effective treatments. The author described the mechanisms of development of different mycoses according to their etiology, comorbid disorders accompanying mycoses and the features of the clinical picture based on etiological factors and sites of infection. The article places special emphasis on the reasons for infection with fungal invasions in humans, conditions and numerous contact routes. Modern features of the course of fungal skin diseases include formation of biofilms in the sites of infection, multicentricity, extension of the pathological process, frequent formation of granulomas, follicles, occurrence of numerous mycoides, as well as the low virulence of dermatophytes. The publication also presents various clinical cases of somatically healthy patients suffering from various mycoses caused by variant factors, which have pathological processes located in different sites. According to the doctor’s prescription, patients used conventional treatment regimens that included external/ topical treatment and general therapy, strictly in accordance with clinical guidelines – the use of highly active broad-spectrum antifungal drugs with fungicidal, fungistatic, antibacterial, anti-inflammatory and antipruritic action. These properties ensure a low probability resistance of microorganisms or relapses during treatment with topical dosage forms of antifungal drugs for cutaneous application. Upon completion of the course of treatment, patients reported a significant improvement in their skin condition resulting in minimization of disease symptoms, disappearance of skin rashes, skin itching, and elimination of exfoliation.

Dermatophytosis is a major health burden worldwide and is now increasing day by day. Dermatophytosis is also becoming increasingly unresponsive to topical conventional antifungals now a day. Newer topical antifungals may be more effective in these patients. Sertaconazole is a new, broad spectrum, fungicidal and fungistatic imidazole with added antipruritic and anti-inflammatory activity that may be effective and beneficial in improving the quality of life for the patient with dermatophytoses. It is indicated in the European Union(EU) for the treatment of superficial skin mycoses such as dermatophytosis (including tinea corporis, tinea cruris, tinea manus, tinea barbae and tinea pedis), cutaneous candidiasis, pityriasis versicolor and seborrhoeic dermatitis of the scalp, and in the US for tinea pedis only. Sertaconazole has broad-spectrum antifungal activity against dermatophytes of the Trichophyton, Epidermophyton and Microsporum genera, and yeasts of the genera Candida and Cryptococcus; additionally, it is effective against opportunistic filamentous fungi and Gram-positive bacteria. Moreover, the antifungal activity of sertaconazole is maintained in clinical isolates of dermatophytes that show reduced susceptibility to other azoles. While the drug has good dermal penetration, this is not associated with systemic absorption. In clinical trials in patients with superficial mycoses, 2% sertaconazole cream applied twice daily was effective in the eradication of a range of dermatophytoses, and a significantly greater proportion of patients were cured compared with those receiving 2% miconazole cream twice-daily treatment. Both as a topical cream and suppository preparation, sertaconazole was generally well tolerated. Sertaconazole is a well-established antifungal agent, which is now available in a variety of formulations, and remains a useful treatment option particularly in patients with fungal infections resistant to other azoles. Medicine Today 2023 Vol.36 (1): 62-66

A biochip assay provides high-throughput and multiplexed analysis of biological samples, chemicals, and natural products. Pruritus is itchiness due to several causes, such as allergy, dry skin, pregnancy, liver disease, kidney disease, and thyroid disease. Treatment of pruritus is associated with reduced immunoglobulin (IgE) and FcεRI levels in sera. Treatment of pruritus include corticosteroid creams or ointment. However, they have side effects, so we need a safer treatment using natural products. Here, we developed an assay using protein chip technology to identify natural products with antipruritic activity that inhibit IgE-FcεRI binding. Of the 28 tested natural product extracts, Corni Fructus extract inhibited human IgE-FcεRI binding and also showed anti-histamine effects in MC/9 mast cells. These results suggest that this protein biochip assay system can be used to identify promising natural product extracts for the treatment of pruritus.

Various disorders are accompanied by histamine‐independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch‐sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack‐activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on‐target antipruritic activity in multiple mouse models of acute histamine‐independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.

In the early stages of the development of psychiatry, all new psychotropic drugs, without any exception, came to it from other areas of medicine. Examples are chlorpromazine (came from anesthesiology, where it was used for so-called potentiated anesthesia), reserpine (came from cardiology, where it was used as a treatment for arterial hypertension), lithium (came from rheumatology, where it was used to treat gout, long before John Cade), iproniazid (originally a promising anti-tuberculosis drug), methylene blue (came from parasitology, where it was used to treat malaria), sulpiride (was discovered in the process of searching for a new antiarrhythmic among procainamide analogues). Now the situation has turned 180 degrees. The arsenal of psychotropic drugs at the disposal of psychiatrists today had expanded unimaginably, compared to the 1950s. And many of these drugs, in addition to their main psychotropic activity, have a number of additional somatotropic properties that are of genuine interest to researchers from various fields of medicine. Within the framework of this article, we decided to focus not on rather banal and already widely known properties of some psychotropic drugs, such as analgesic, antiemetic, prokinetic, antipruritic or antimigraine activity, but on unexpected and sometimes surprising properties, such as their antitumor activity against some tumors of the central nervous system, their antifungal, antibacterial, antiviral activities.

Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or μ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood-brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter with anti-inflammatory actions that also reduces itching. To test whether a combination of an antihistamine with a H2S donor has improved antipruritic efficacy, bifunctional molecules with antihistamine and H2S-releasing pharmacophores were synthesized and tested in vitro and in vivo. H2S release from the hybrid molecules was evaluated with the methylene blue and lead acetate methods, and H1-blocking activity was assessed by determining tissue factor expression inhibition. All new compounds released H2S in a dose-dependent manner and retained histamine blocking activity. Two compounds with the highest potency were evaluated in vivo for their antipruritic as well as sedative action; they proved to possess higher efficacy in inhibiting histamine-induced pruritus and decreased sedative effects compared to the parent compounds (hydroxyzine and cetirizine), suggesting that they exhibit superior antipruritic action and limited side effects that likely arise from the H2S-releasing moiety.

Psoriasis is one of the most widespread dermatological diseases, having a strong influence on the quality of human life. About 70% of patients require external therapy at that. The aim of this work is evaluation of the efficiency of combination therapy of psoriatic patients by solidol in combination with application of greater celandine (Chelidonii majoris L.) extract. The areas of the skin, affected by psoriasis, were treated by celandine infusion 2 times a week during the first month of cure, and solidol was applied on plaque after drying. The same procedure was carried out in the second month once a week. The course of treatment was 2 months. The efficiency of described combination therapy was proved in a resulting keratolytic, antiphlogogenic, emollient and antipruritic action.

BACKGROUND: Transcranial electrostimulation (TES therapy) is a physiotherapeutic non-invasive technology that allows painlessly, selectively and strictly dosed activation of certain brain structures producing endogenous opioid peptides by modulating activity in these brain regions that are involved in the processing of pain and itching signals. Originally, this technique was used as an electronarcosis, then the scope of TES therapy in medicine expanded and began to be used in neurology, gynecology, urology, gastroenterology. The efficacy of its use in dermatology as an antipruritic action remain poorly understood.
 AIM: the purpose of the pilot study was to evaluate the effectiveness and acceptability of the use of non-invasive TES therapy in patients with atopic dermatitis.
 MATERIAL AND METHODS: According to the existing concept, itching is considered as a kind of pain sensation caused by an altered threshold level of nerve endings in the skin that perceive pain. Given this similarity of the mechanisms of pain and itching, noninvasive brain stimulation can simultaneously reduce itching, which opens up broad prospects for its further use in itchy dermatoses.
 A pilot controlled study was conducted, the object of the study was patients with moderate atopic dermatitis (9 women and 6 men) aged 19 to 48 years. TES therapy was carried out by a pulsed bipolar electrical stimulator with acoustic effect "TRANSAIR-07" according to the standard method. All patients who received a course of TES monotherapy underwent 10 procedures, 1 time a day, lasting 3040 minutes, with a current of 13 mA. To assess the dynamics of clinical manifestations of atopic dermatitis and the severity of the disease, the following scales were used: SCORAD, EASI, IGA, DLQI, HADS, BDI. The assessment was carried out twice: the first time on the day of diagnosis verification and again on the 10th day of treatment.
 RESULTS: As a result of the treatment, there was a decrease in itching from 5 to 2 points, an improvement in mood from 5 to 1 point, an increase in performance from 4 to 1 point, a decrease in anxiety and depression from 4 to 2 points. With a general assessment of the dynamics of the indicators of the applied clinical scales (SCORAD, EASI, IGA, DLQI, HADS, BDI), the total average effectiveness in the form of parameter improvement amounted to 66.25% reduction by the end of the 10-day course.
 CONCLUSION: The work presents the modern aspects of the application of non-invasive hardware transcranial electrical stimulation technique. The positive results of our own pilot study are presented and data confirming the clinical efficacy of transcranial electrical stimulation in patients with atopic dermatitis are presented, which determines the prospect of developing a combined application of TES therapy for this persistent disease.

A novel broad-spectrum (anti-inflammatory, anti-pruritic and anti-S. aureus/MRSA) topical drug compound for mild to moderate atopic dermatitis