Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit

Abstract

BackgroundOral antihistamines that target the histamine receptor–1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise.MethodsHerein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post-dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396).ResultsPF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events.ConclusionsPF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls.

Blood and nasal epigenetics correlate with allergic rhinitis symptom development in the environmental exposure unit

“…This study was not designed to capture the time points necessary to fully understand this phenomenon or to imply causation. MUC4 may represent a future therapeutic target, as there is an urgent need for nonsympathomimetic treatments for congestion, the AR symptom that is consistently cited by patients as being the most bothersome …”

Clinical validation of controlled grass pollen challenge in the Environmental Exposure Unit (EEU)

“…The EEU has proven effective in multiple studies evaluating various aspects of seasonal allergic rhinitis and its treatments [ 4 - 17 ]. Previous studies conducted in the EEU using ragweed pollen have shown 3500 grains/m 3 ± 500 to be an optimal concentration to produce symptoms similar to those experienced in the outdoor environment.…”

Imetit Dihydrobromide and Thioperamide Medication in Cough Hypersensitivity Model—The Role of H<sub>3</sub> Receptors

“…On the other hand, other studies suggest therapeutic applications of H 3 R antagonists in treatment of allergic rhinitis. H 3 receptor antagonists showed ability to inhibit nasal congestion in combination with antihistamines that target the H 1 receptor [18]. Combined therapy by SCH 79687 (H 3 R antagonist) and loratadine (H 1 R antagonist) showed anti-allergic and decongestant properties [19].…”

“…Some studies suggest therapeutic applications of H 3 R antagonists in treatment of allergic rhinitis. H 3 receptor antagonists showed ability to supress nasal symptoms of AR, especially nasal congestion in combination with antihistamines that target the H 1 receptor [18]- [23].…”