Predicting and Establishing the Clinical Efficacy of a Histamine H1-Receptor Antagonist

Desloratadine, the Model Paradigm

Glenis Scadding


Clin Drug Invest. 2005;25(3):153-164. 

In This Article

Abstract and Introduction


Antihistamines are well established as a mainstay for treating allergic diseases, including seasonal and perennial allergic rhinitis as well as other conditions, such as chronic idiopathic urticaria. The development of new antihistamines is a multistage process that includes in vitro and in vivo assessments of the antihistaminic, anti-inflammatory and antiallergic properties of new therapies. Results of these assessments are critical for predicting and establishing the clinical efficacy of an antihistamine. The focus of this article is to review the investigational methods used to assess the efficacy, safety and tolerability of newer histamine H1-receptor antagonists. Desloratadine, a new-generation H1-receptor antagonist, was chosen to illustrate the use of this model paradigm. Data obtained from two large observational studies are presented, confirming results obtained from clinical trials that the in vitro inhibition of release of inflammatory mediators such as histamine, prostaglandins, leukotrienes and the reduction of secretion of cytokines such as IL-4 and IL-13 at physiological concentrations is reflected in increased efficacy, particularly upon nasal obstruction. A recent discovery that desloratadine inhibits nuclear factor-κB may be the underlying explanation for much of this extra anti-inflammatory activity.


Histamine was noted as a mediator of allergic reactions in the early 1900s; the search for effective histamine H1-receptor agonists continues. Antihistamines are considered first-line treatment for immunoglobulin E (IgE)-related allergic conditions, including mild, intermittent seasonal or perennial allergic rhinitis (SAR/PAR), and are also useful in other disorders involving mast cell degranulation, such as chronic idiopathic urticaria (CIU).[1] In the past, evaluation of the efficacy, safety and tolerability of antihistamines was based on intensive development programmes, consisting of numerous stages ranging from preclinical pharmacological experiments to large, post-approval clinical observational trials. In accordance with this established paradigm, the potency, antiallergic effects and anti-inflammatory properties of H1-receptor antagonists have been evaluated using a variety of methods, including in vitro and animal model testing, the histamine-induced skin wheal-and-flare model, controlled allergen chamber trials, and pivotal clinical efficacy and safety trials.

Each investigational method in the programme provides some insight into the absolute and relative efficacy of agents in this therapeutic class. In vitro testing of H1-receptor antagonists determines the binding characteristics of antihistamines at the receptor level, as well as their antiallergic effects on key effector cells and inhibitory effects on inflammatory mediators. Testing in animal models provides additional preclinical data on their antihistaminic, antiallergic and anti-inflammatory activities and may offer evidence of their mechanism of action in humans. The histamine-induced skin wheal-and-flare model - often used in early clinical efficacy and potency studies - assesses the antihistaminic activity of these antagonists. Allergen chamber models evaluate the activity of an antihistamine on allergic rhinitis symptoms due to pollen and dust-mite aeroallergens under controlled conditions. Although each of these methods may be useful in predicting the efficacy and safety of H1-receptor antagonists, large well controlled multicentre clinical trials remain the primary indicator of the effectiveness of an agent in the treatment of allergic disease. Before or simultaneously with the performance of these clinical studies, pharmacokinetic analyses and specialised clinical safety data (e.g. cardiovascular toxicity) are being collected.

The purpose of this article is to review the key features of various investigational methods used for documenting the antihistaminic, antiallergic and anti-inflammatory mechanisms of action of H1-receptor antagonists and to predict their clinical efficacy. This model paradigm was used to evaluate the most recently available H1-receptor antagonist, desloratadine, and explains its efficacy in the treatment of allergic diseases.