jnj-7777120 and Rhinitis--Allergic--Perennial

At the turn of the millennium, the DNA sequence encoding the histamine H4 receptor (H4R) was identified in data from human genome databases. Considering the clinical importance of H1R and H2R ligands, and the clinical trials that are ongoing for H3R ligands, the latest addition to the histamine receptor family was noted with interest by the pharmaceutical industry. Initial studies describing the expression of the H4R, and the activity of this receptor in (patho)physiology, suggested that the H4R played a role in the immune system. The introduction of the reference H4R antagonist JNJ-7777120 (Johnson & Johnson Pharmaceutical Research & Development LLC/Abbott Laboratories), and proof of the efficacy of this agent in models of asthma, allergic rhinitis and pruritus, highlighted the H4R as a novel drug target. The first clinical candidates targeting the H4R have been identified, and new H4R antagonists are expected to enter the clinic in the near future.

Topics: Animals; Anti-Allergic Agents; Asthma; Disease Models, Animal; Drug Design; Drug Discovery; Histamine Antagonists; Humans; Indoles; Molecular Structure; Piperazines; Pruritus; Pyrimidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Structure-Activity Relationship

To clarify the effect of histamine H4 receptor antagonist, JNJ 7777120, and histamine H1 receptor antagonist, Loratadine, on allergic rhinitis (AR) in rats and to study the role of histamine H4 receptor antagonist and histamine H1 receptor antagonist in the pathogenesis of allergic rhinitis and therapeutic value of their antagonist.. AR animal model were induced by ovalbumin (OVA) in the Wistar rats, which treated with histamine H4 receptor antagonist and (or) histamine H1 receptor antagonist. The allergic symptoms (sneezing and nasal rubbing), serum total IgE and the levels of cytokines in serum or nasal lavage fluid were measured, the diversity between two groups were observed. Statistical analysis was performed using a SPSS 13.0 software.. Compared with AR group with no treatment, the inhibition of nasal symptoms (P < 0.01), a significant decrease in the levels of IgE, IL-4 in serum and Eotaxin in nasal lavage fluid (P < 0.01), a significant increase in the levels of IFN-γ in serum (P < 0.01) after treatment was found. Compared with group treated with Loratadine, inhibition of nasal symptoms (q value were 3.72, 4.16, P < 0.01), a significant increase in the levels of IgE and IL-4 in serum (q value were 8.01, 4.96, P < 0.05), a significant decrease in the levels of IFN-γ in serum (q = 3.18, P < 0.05) in group treated with JNJ 7777120 also, but no significant differences in the levels of Eotaxin in nasal lavage fluid (P > 0.05). Administration of JNJ 7777120 and Loratadine jointly, neither additive effect nor synergistic action were found (P > 0.05).. Histamine H4 receptor is closely related with allergic rhinitis and is important in the pathogenesis of allergic rhinitis, the same as histamine H1 receptor. Histamine H4 receptor antagonist, JNJ 7777120, could relieve symptoms and inflammatory conditions in allergic rhinitis, the effect was weak compared with Loratadine. Neither additive effect nor synergistic action were found between them.

Topics: Animals; Histamine Antagonists; Indoles; Loratadine; Male; Piperazines; Rats; Rats, Wistar; Receptors, Histamine; Rhinitis, Allergic, Perennial

The aim of this study was to clarify the effect of histamine H(4) receptor antagonist, JNJ7777120 (1-[(5-Chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine) on allergic rhinitis in mice. We measured allergic symptoms (sneezing and nasal rubbing), serum total IgE and the levels of cytokines in nasal lavage fluid. Histamine H(4) receptor antagonist, JNJ7777120, caused the dose-dependent inhibition of nasal symptoms by single and repeated intranasal administrations; however, JNJ7777120 caused no inhibition of serum total IgE by single and repeated intranasal administrations. Therefore, we investigated the effect of JNJ7777120 by oral administration. JNJ7777120 also caused a significant inhibition of nasal symptoms by both single and repeated oral administrations. In addition, repeated oral administration of JNJ7777120 caused significant inhibition of serum total IgE. Furthermore, JNJ7777120 caused a significant decrease in the levels of IL-4 and a significant increase in the levels of IFN-gamma in nasal lavage fluid. These results indicated that histamine H(4) receptor is closely related with allergic rhinitis and is important in the pathogenesis of allergic rhinitis. From these results, it can be concluded that histamine H(4) receptor antagonist might be a new strategy to treat allergic rhinitis with immunomodulatory function.

Topics: Administration, Intranasal; Administration, Oral; Animals; Disease Models, Animal; Female; Histamine Antagonists; Histamine H1 Antagonists; Immunoglobulin E; Indoles; Interferon-gamma; Interleukin-4; Ketotifen; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Rhinitis, Allergic, Perennial