jnj-7777120 and Cough

The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30 min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by Pennock's method as baseline, during AR and after JNJ7777120 treatment. Leucocyte count in BAL and blood was analyzed. JNJ7777120 (5mg/kg) significantly suppressed nasal symptoms and the number of coughs. This compound significantly inhibited airway reactivity to histamine, but not methacholine. Pre-treatment with JNJ7777120 5mg/kg did not influence significantly the leucocyte count in BAL and blood except for a significant decrease in monocyte count in blood compared to the control group (p<0.05). We conclude that the antitussive action of JNJ7777120 is peripheral. The primary effect of the compound is anti-inflammatory, and the suppression of cough is a consequence of reduced airway inflammation.

Topics: Airway Resistance; Aluminum Hydroxide; Animals; Bronchoalveolar Lavage Fluid; Citric Acid; Cough; Disease Models, Animal; Dose-Response Relationship, Drug; Guinea Pigs; Indoles; Inflammation; Injections, Intraperitoneal; Nose Diseases; Ovalbumin; Piperazines; Plethysmography; Serotonin Antagonists

Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H₄ receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators.. Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured.. OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid.. Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.

Topics: Animals; Annexin A1; Antigens; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Cough; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Antagonists; Indoles; Inflammation; Lung; Male; Ovalbumin; Piperazines; Tumor Necrosis Factor-alpha; Up-Regulation