title: Pharmacodynamic evaluation of RP3128, a novel and potent CRAC channel inhibitor in guinea pig models of allergic asthma.
abstract: The increase in intracellular Ca(2+) levels through the activation of Ca(2+) release-activated Ca(2+) (CRAC) channels is essential for mediating a wide scale of immune cell responses. Emerging evidence indicates an involvement of abnormal CRAC channel activity in human diseases such as certain types of immunodeficiency, autoimmunity and allergic disorders. This objective of this study was to evaluate the therapeutic potency of a novel CRAC channel inhibitor, RP3128, in experimental models of allergic asthma using guinea pigs. Ovalbumin-induced allergic airway inflammation was determined upon acute and long-term (14 days) oral administration of RP3128. In vivo changes in specific airways resistance (sRaw) and amplitude of isometric contraction (mN) of ASM (in vitro) were estimated to evaluate bronchodilatory effect upon acute and long-term administration of RP3128 or salbutamol. Exhaled nitric oxide (eNO), immunohistochemical and histological analysis of cellular infiltration in airways tissue, and levels of cytokines in plasma as well as bronchoalveolar lavage fluid (BALF), were determined using Bio-Plex® 200 System (BIO-RAD, USA). Ciliary beat frequency (CBF, in Hz) was estimated using a high-speed video camera and LabVIEW™ Software. Additionally, the impact of RP3128 and budesonide on mucociliary clearance was determined. Acute and long-term administration of RP3128 resulted in significant bronchodilation. Long-term administration of RP3128 exceeded the bronchodilatory effect of salbutamol and significantly decreased eNO and cytokine levels in plasma and BALF, which together with histological and immunohistochemical analysis validated its anti-inflammatory effect compared to budesonide. Data demonstrate the therapeutic potential of RP3128 in respiratory diseases causally associated with allergic inflammation.
authors.affiliation: Department of Pharmacology, Jessenius Faculty of Medicine, Comenius University, Martin's Biomedical Center (BioMed) Malá Hora, 11161 4D Martin, Slovakia.
authors.forename: Martina
authors.initials: M
authors.lastname: Sutovska
authors.affiliation: Department of Pharmacology, Jessenius Faculty of Medicine, Comenius University, Martin's Biomedical Center (BioMed) Malá Hora, 11161 4D Martin, Slovakia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kocmalova
authors.affiliation: Department of Pharmacology, Jessenius Faculty of Medicine, Comenius University, Martin's Biomedical Center (BioMed) Malá Hora, 11161 4D Martin, Slovakia.
authors.forename: Sona
authors.initials: S
authors.lastname: Franova
authors.affiliation: Rhizen Pharmaceuticals SA, La Chaux-de-Fonds, Switzerland.
authors.forename: Swaroop
authors.initials: S
authors.lastname: Vakkalanka
authors.affiliation: Incozen Therapeutics Pvt. Ltd., 450, Alexandria Knowledge Park, Shameerpet, Hyderabad, India. Electronic address: srikantv@incozen.com.
authors.forename: Srikant
authors.initials: S
authors.lastname: Viswanadha
mesh_terms: D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D006168:Guinea Pigs; D006801:Humans; D006967:Hypersensitivity / Q000150:complications*; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D012018:Reflex / Q000187:drug effects
chemical_list: D000577:Amides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016207:Cytokines; D011720:Pyrazoles; D009569:Nitric Oxide
keywords: Airway epithelium; Allergic asthma; CRAC channels; Guinea pigs; Immunohistochemistry