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Oxaliplatin is a widely used chemotherapeutic drug and represents the cornerstone of colorectal cancer therapy, in combination with 5-fluorouracil and folinic acid. As with many chemotherapeutic agents, its use is associated with a number of side effects, ranging from hypersensitivity reactions to haematological dyscrasias. Oxaliplatin also induces acute and chronic peripheral neuropathy. While it is likely that the haematological side effects are associated with its anti-proliferative effects and with the ability to form DNA adducts, the molecular mechanisms underlying peripheral neuropathy and hypersensitivity reactions are poorly understood, and therefore the choice of adequate supportive therapies is largely empirical. Here we show that an acute low dose oxaliplatin application on DRG neurons is able to induce an increase in intracellular calcium that is dependent on the Histamine 1 receptor (H1). Oxaliplatin-induced intracellular calcium rises are blocked by two selective H1 antagonist, as well as by U73122, a PLC inhibitor, and by 2-APB, a non-specific IP receptor blocker. Moreover, expression of the H1 receptor on HEK293 t cells unmasks an oxaliplatin-induced Ca-rise. Last, activation of H1 via either histamine or oxaliplatin activates TRPV1 receptors, a mechanism that has been associated with itch. These data, together with literature data that has shown that anti-histamine agents reduce the incidence of oxaliplatin-induced hypersensitivity, may provide a molecular mechanism of this side effect in oncological patients.
Learn More >While psychological factors are relevant in many patients with chronic pruritus, not all patients can be offered psychologic, psychosomatic or psychiatric consultation. The aim of this exploratory study was to identify criteria suggestive of psychological factors relevant for the etiology of chronic pruritus and of somatoform pruritus. Routine data from the database of the Center for Chronic Pruritus of the University Hospital Münster were used, including the Neuroderm Questionnaire, Dermatology Life Quality Index and Hospital Anxiety and Depression Scale. chronic pruritus patients (n = 3,391) without a psychiatric diagnosis in their medical history were compared to the 331 chronic pruritus patients with diagnoses of "psychological factors associated with etiology and course of chronic pruritus" (ICD-10:F54) or "somatoform pruritus" (F45.8) confirmed by an expert. The latter reported more pruritus triggers, especially "strain" and "emotional tension" and used more emotional adjectives to describe their pruritus. They reported more often scratching leading to excoriations, higher levels of pruritus, impairment of quality of life, anxiety and depression. These aspects suggest the presence of psychological factors in the etiology of chronic pruritus and somatoform pruritus. Prospective validation, however, needs to be carried out.
Learn More >Little is known about the validity of numeric and verbal rating scales (NRS and VRS) for itch and itch frequency for assessing itch severity in AD. We evaluated the Patient-Reported Outcomes Information System (PROMIS ) Itch Questionnaire (PIQ) – itch severity assessment, including multiple NRS, VRS and frequency of itch assessments, in adults with AD and compared their performance.
Learn More >Interleukin 13 (IL-13) is a central pathogenic mediator driving multiple features of atopic dermatitis (AD) pathophysiology.
Learn More >Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis.
Learn More >Itch is a unique sensation that helps organisms scratch away external threats; scratching itself induces an immune response that can contribute to more itchiness. Itch is induced chemically in the peripheral nervous system via a wide array of receptors. Given the superficial localization of itch neuron terminals, cells that dwell close to the skin contribute significantly to itch. Certain mechanical stimuli mediated by recently discovered circuits also contribute to the itch sensation. Ultimately, in the spinal cord, and likely in the brain, circuits that mediate touch, pain, and itch engage in cross modulation. Much of itch perception is still a mystery, but we present in this review the known ligands and receptors associated with itch. We also describe experiments and findings from investigations into the spinal and supraspinal circuitry responsible for the sensation of itch. Expected final online publication date for the , Volume 43 is July 8, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >: Treatment for chronic pruritus ranges from use of topical formulations to newer biologic agents. Targeting treatment to the underlying etiology is key in reducing the burden of disease while avoiding systemic or adverse effects.: This review details the effective medical treatments used in various etiologies of chronic itch with a focus on the potential adverse effects and safety data available for each.: New drug developments in the areas of neural signaling and immune targeting show great promise for the future of chronic itch treatment. These new therapies broaden the available treatment options but also pose new considerations for safety and adverse effects.
Learn More >: Atopic dermatitis (AD) is a type of allergic/inflammatory dermatitis characterized by itch and an impairment in quality of life.: Herein, the authors review drug discovery efforts for AD, highlighting the clinical efficacy of novel drugs, with a particular focus on the relief of pruritus. Topical agents include emollients, topical antihistamines, corticosteroids, calcineurin inhibitors and herbs. Recently, topical phosphodiesterase E4 (PDE4) inhibitors like crisaborole have become available and are efficacious for mild to moderate AD with few side effects. For more severe AD, monoclonal antibodies like dupilumab are considered as efficacious subcutaneous treatment options. In severe and recalcitrant AD, systemic treatment can ameliorate AD symptoms.: Many topical and systemic medications have demonstrated therapeutic benefits for AD. Indeed, randomized trials have shown that topical PDE4 inhibitors and subcutaneous dupilumab are safe and efficacious. Objective tools to evaluate itch and gauge treatment efficacy is important, but current methodology relies primarily on clinical scores. AD is a systemic atopic disease with a lot of complicated psychosocial issues. Suboptimal efficacy is often due to poor compliance and unrealistic expectation of curative treatment, rendering treatment difficult despite the existence of effective medications.
Learn More >Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (Na) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, Na1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing Na-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in Na channel-mediated itch signalling. Na1.7 showed substantial scratch reduction mainly towards strong pruritogens. Na1.8 impaired histamine and 5-HT-induced scratching while Na1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of Na1.7 and indicated an overall contribution of Na1.9. Beside the proposed general role of Na1.7 and 1.9 in itch signalling, scrutiny of time courses suggested Na1.8 to sustain prolonged itching. Therefore, Na1.7 and 1.9 may represent targets in pruritus therapy.
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