PT  - JOURNAL ARTICLE
AU  - Kasiviswanath Routhu
AU  - Babu Govindrajulu
AU  - Sridhar Veeraraghavan
AU  - Srikant Viswanadha
AU  - Swaroop Vakkalanka
TI  - CRAC channel inhibition by RP3128 ameliorates airway hyper-reactivity in antigen sensitized mice and guinea pigs
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - 4865
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/4865.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/4865.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - 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.