Background: Histamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells.
Objective: During the Ph2b trial in AD, we performed experiments to understand the pharmacology of adriforant in primary murine cells and in vivo models. We assessed its effects on ERK phosphorylation and transcriptional changes in bone marrow-derived mast cells, histamine-dependent Ca flux in neurons and histamine-induced itch response. In addition, its impact on MC903-induced skin inflammation was evaluated.
Results: We show that, contrary to transfectants, adriforant is a competitive antagonist of the murine histamine receptor 4, antagonizes histamine-induced ERK phosphorylation, normalizes histamine-induced transcriptional changes in mast cells and reduces histamine-dependent Ca flux in neurons. Administration to mice reduces acute histamine-induced itch response. In addition, adriforant ameliorates inflammation in the mouse MC903 model.
Conclusions: Our results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models.
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http://dx.doi.org/10.1016/j.ejphar.2023.175533 | DOI Listing |
Can J Kidney Health Dis
January 2025
Division of Nephrology, Department of Medicine, Ottawa Hospital, University of Ottawa, ON, Canada.
Background: Patients with end-stage kidney disease (ESKD) have high rates of gastrointestinal bleeding due to several risk factors including platelet dysfunction, comorbid illness, and use of antiplatelet medications. Proton pump inhibitors (PPIs) reduce gastrointestinal bleeding and are recommended for high-risk patients such as those prescribed dual antiplatelet therapy (DAPT). Whether inappropriate duration of DAPT therapy and/or lack of appropriate PPI use contribute to the known elevated risk of gastrointestinal bleeding in hemodialysis patients is not known.
View Article and Find Full Text PDFExpert Opin Ther Pat
January 2025
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Kraków, Poland.
Introduction: Histamine H receptor antagonists/inverse agonists, since the discovery of histamine H receptor (HR), are important ligands in the search for new potential drugs. The most interesting are CNS diseases as these receptors are mainly there present.
Areas Covered: The current review covers patent applications/patents that were published during the last 6 years (October 2017 - December 2023).
BMC Chem
January 2025
Energy Systems Engineering Department, Engineering Faculty, Adana Alparslan Türkeş Science and Technology University, 01250, Adana, Türkiye.
Although the antiallergic properties of compounds such as CAPE, Melatonin, Curcumin, and Vitamin C have been poorly discussed by experimental studies, the antiallergic properties of these famous molecules have never been discussed with calculations. The histamine-1 receptor (H1R) belongs to the family of rhodopsin-like G-protein-coupled receptors expressed in cells that mediate allergies and other pathophysiological diseases. In this study, pharmacological activities of FDA-approved second generation H1 antihistamines (Levocetirizine, desloratadine and fexofenadine) and molecules such as CAPE, Melatonin, Curcumin, Vitamin C, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiles, density functional theory (DFT), molecular docking, biological targets and activities were compared by calculating.
View Article and Find Full Text PDFFront Immunol
January 2025
Department Integrative Agriculture, College of Agriculture and Veterinary Medicine, United Arab Emirates University, Al Ain, United Arab Emirates.
Surfactant protein D (SP-D) is a C-type lectin that was originally discovered as a lung surfactant associated phospholipid recognising protein. It was originally shown to be of great importance in surfactant turnover and homeostasis in conjunction with another hydrophilic surfactant protein i.e.
View Article and Find Full Text PDFAllergy Asthma Proc
January 2025
From the Section of Allergy, Asthma and Immunology, Medicine and Pediatrics, Pennsylvania State University School of Medicine, Hershey, Pennsylvania and.
Patients with mast cell activation syndrome (MCAS) can be refractory to standard antimediator therapy. Alternative treatment options to reduce disease burden and improve quality of life are needed. To compile the evidence that supports the use of omalizumab for patients with refractory MCAS.
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