TY - JOUR T1 - CRAC channel inhibition by RP3128 ameliorates airway hyper-reactivity in antigen sensitized mice and guinea pigs JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - 4865 AU - Kasiviswanath Routhu AU - Babu Govindrajulu AU - Sridhar Veeraraghavan AU - Srikant Viswanadha AU - Swaroop Vakkalanka Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/4865.abstract N2 - IntroductionCalcium release activated calcium (CRAC) channel inhibitors have a potent role in treatment of respiratory disorders. RP3128 is a novel CRAC channel inhibitor exhibiting nanomolar potency against ICRAC and immune-modulatory activity across relevant pre-clinical assays. The objective of the current study was to explore and elucidate the anti-asthmatic properties of RP3128 in allergen-challenged mice and guinea pigs.MethodsSuppression of antigen-induced asthmatic responses upon oral administration of RP3128 in Balb/c mice and guinea pigs were determined. Changes in ASM reactivity in response to RP3128 in vitro were tested using an organ-bath method.ResultsOral administration of RP3128 to sensitized mice resulted in attenuation of methacholine induced airway hyperresponsivness manifested by dose-dependent reduction in PenH (∼50% @ 3 mg/kg) values as well as eosinophil count (ED50 = 1.9 mg/kg). RP3128 significantly reduced basal (71%) and histamine (86%) or methacholine (87%) induced sRaw values in sensitized guinea pigs. Besides, RP3128 caused a near complete inhibition of ENO levels as well as reduction in serum (IL-4, IL-13, and TNFα) and BALF (IL-4, IL-5, IL-13, and TNFα) cytokines (50-95%). Additionally, contraction amplitude of isolated tracheal or pulmonary smooth muscle in response to cumulative doses of acetylcholine or histamine was significantly reduced in RP3128 treated animals compared to saline control group.ConclusionsData demonstrate the anti-inflammatory and airway remodelling properties of RP3128 upon administration at a low dose thereby indicating the therapeutic potential of this molecule in respiratory disorders. ER -