Characteristics of histamine H4 receptor agonist-induced allergic conjunctivitis model in Guinea pigs.

Histamine is strongly associated with the onset of allergic conjunctivitis. The most recent cloned histamine H4 receptor antagonist is highly expected as a new therapeutic drug candidate. As a model for a therapeutic drug targeting the histamine H4 receptor, a mouse model in which conjunctivitis symptoms are induced by instilling 4-methylhistamine, a histamine H4 receptor agonist, has been reported. However, the affinity of the H4 receptor for histamine varies in species, and it is known that the histamine binding affinity for the guinea pig H4 receptor is closer to that for human receptor than mice receptor. In this paper, we investigated a possibility that a guinea pig model would become a drug efficacy evaluation model with higher evaluation accuracy than the mouse model. As a result, hyperemia was observed in the conjunctivae and iris of guinea pigs after instillation of 4-methylhistamine and specifically suppressed by the histamine H4 receptor antagonist. Unlikely to the previously reported mouse model, however, none of edema, increased vascular permeability or scratching behavior was observed, suggesting that there may be differences between mice and guinea pigs not only in the binding affinity of histamine to the H4 receptor but also in the biological reaction to 4-methylhistamine. Although the symptoms of allergic conjunctivitis do not appear comprehensively in the guinea pig model, results of this study indicated a possibility that this model can be used as a simple screening model in the early stages of drug development.

Optimization of a histamine-induced allergic conjunctivitis model in Guinea pigs.

Allergic conjunctivitis is one of the most common immune diseases in the field of ophthalmology. The number of patients suffering from allergic conjunctivitis has been increasing, and there is still a strong need for development of therapeutic agents for this disease. In drug development, the utmost important point to improve the success probability is to accurately single out good compounds in the early stage of drug development. Therefore, drug efficacy evaluations in the nonclinical stage should be conducted with high reliability and accuracy. However, there are no literatures investigating the preparation and evaluation methods of animal models of conjunctivitis in details nor the standardized criteria. In this study, we verified the reproducibility of an animal model in the previous report and made improvements in test methods focusing on a guinea pig model of histamine-induced allergic conjunctivitis. Furthermore, the drug efficacy evaluation was conducted using a commercially available antihistamine drug, levocabastine hydrochloride, to judge the suitability of the improved model. As a result, the dose level of histamine needed to be increased to use the existing model for drug efficacy evaluation, but allergic-like symptoms were induced very easily and stably in this model. For observations of symptoms of conjunctivitis, we eliminated ambiguity of evaluation by adopting the Draize scale and ensured a higher objectivity on the evaluation method. The drug efficacy evaluation of levocabastine hydrochloride in the prepared model revealed that drug efficacy of the antihistamine drug was captured according to the standardized test method and highly-reproducible results were obtained.