Antihistaminergics and inverse agonism: Potential therapeutic applications

Monczor, Federico; Fernández, Natalia Cristina; Fitzsimons, Carlos P.; Shayo, Carina; Davio, Carlos

doi:10.1016/j.ejphar.2013.06.027

Cited by 20 publications

(11 citation statements)

References 79 publications

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“…H 1 -Receptor Antagonists H 1 -Antihistamines, or histamine H 1 -receptor antagonists, can also in many instances act as inverse agonists that combine with and stabilize the inactive form of the H 1 -receptor, shifting the equilibrium toward the inactive state (Monczor et al, 2013). In addition, some H 1 -antihistamines can also inhibit muscarinic, a-adrenergic and serotonin receptors, as well as some ion channels.…”

Section: Drugs In Current Use For the Treatment Of Coughmentioning

confidence: 99%

Antitussive Drugs—Past, Present, and Future

et al. 2014

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Section: Drugs In Current Use For the Treatment Of Coughmentioning

confidence: 99%

Antitussive Drugs—Past, Present, and Future

et al. 2014

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“…Inverse agonism describes the ability of certain “antagonists” to reduce the activity of receptor systems that are active in the absence of agonists [35]. However, whether inverse agonism is essential or clinically important for antihistamines has not been clarified yet [35]. Thus far, the published literature indicates that PF-03654764 is a potent and specific H 3 receptor antagonist [17].…”

Section: Discussionmentioning

confidence: 99%

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

North

Walker

Steacy

et al. 2014

All Asth Clin Immun

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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.

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“…Traditionally, antihistamines have been thought of as H 1 receptor antagonists; however, it has recently been demonstrated that they may act as inverse agonists, stabilizing inactive forms of the H 1 and H 2 receptors [43][44][45]. Whether this is essential or clinically important for antihistamines has not yet been clarified [46]. The second-generation antihistamines terfenadine, astemizole, cetirizine, and loratadine and their efficacy against AR symptoms were investigated in the EEU [47•].…”

Section: Oral Antihistaminesmentioning

confidence: 99%

Controlled Allergen Challenge Facilities and Their Unique Contributions to Allergic Rhinitis Research

North

Soliman

Walker

et al. 2015

Curr Allergy Asthma Rep

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The aim of this study is to review advances in basic and clinical allergic rhinitis (AR) research over the past decade that have been conducted using controlled allergen challenge facility (CACF) models of allergen challenge. Databases, including PubMed, Medline, and Web of Science were searched for articles employing an ambient pollen exposure in a controlled facility to study AR, published between 2004 and the present date, using the terms as follows: CACF, Environmental Exposure Unit (EEU), Vienna Challenge Chamber (VCC), Fraunhofer Institute Environmental Challenge Chamber, Atlanta Allergen Exposure Unit, Biogenics Research Chamber, Allergen BioCube, Chiba and Osaka Environmental Challenge Chamber, exposure unit, challenge chamber, or environmental exposure chamber. Articles were then selected for relevance to the goals of the present review, including important contributions toward clinical and/or basic science allergy research. CACFs offer sensitive, specific, and reproducible methodology for allergen challenge. They have been employed since the 1980s and offer distinct advantages over traditional in-season multicentre trials when evaluating new treatments for AR. They have provided clinically applicable efficacy and pharmacologic information about important allergy medications, including antihistamines, decongestants, antileukotrienes, immunotherapies, and nasal steroids. CACF models have also contributed to basic science and novel/experimental therapy research. To date, no direct studies have been conducted comparing outcomes from one CACF to another. Over the past decade, CACF models have played an essential role in investigating the pathophysiology of AR and evaluating new therapies. The future opportunities for this model continue to expand.

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Antihistaminergics and inverse agonism: Potential therapeutic applications

Cited by 20 publications

References 79 publications

Antitussive Drugs—Past, Present, and Future

Antitussive Drugs—Past, Present, and Future

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

Controlled Allergen Challenge Facilities and Their Unique Contributions to Allergic Rhinitis Research

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