May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
In vitro Analysis of the Antagonism of the Histamine H1 Receptor by Epinastine: A Kinetic Comparison With Other Marketed Compounds
Author Affiliations & Notes
  • K. Brubaker
    Inspire, Durham, NC
  • B.R. Yerxa
    Inspire, Durham, NC
  • J.L. Boyer
    Inspire, Durham, NC
  • Footnotes
    Commercial Relationships  K. Brubaker, Inspire Pharmaceuticals, Inc., E; B.R. Yerxa, Inspire Pharmaceuticals, Inc., E; J.L. Boyer, Inspire Pharmaceuticals, Inc., E.
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 4975. doi:
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      K. Brubaker, B.R. Yerxa, J.L. Boyer; In vitro Analysis of the Antagonism of the Histamine H1 Receptor by Epinastine: A Kinetic Comparison With Other Marketed Compounds . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4975.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Antagonism of the Histamine H1 Receptor (H1R) is one of the main mechanisms of action of current anti–allergy therapeutics. The purpose of this study is to determine the kinetics of inhibition of the H1R by marketed antihistamines (both, onset and offset of action) using a functional receptor assay.

Methods: : Intracellular calcium mobilization assays in CHO–K1 cells stably expressing the human H1R were used to assess the antihistamine properties of the test compounds.

Results: : The order of potency of histamine agonists for activation of the H1 receptor in CHO cells was: histamine>Nαmethylhistamine>(R)αmethylhistamine=Imetit. This order of potency is consistent with the expected pharmacological profile of the H1 receptor. The inhibition of histamine stimulation of the H1 receptor by four allergic conjunctivitis market leaders (epinastine, olopatadine, azelastine and ketotifen) was also studied. When each of the four marketed compounds was added to the cells simultaneously with histamine, only epinastine produced a concentration–dependent inhibition of the histamine response (IC50 = 1.6µM ) whereas the other antihistamines produced partial or no inhibition up to the highest concentration tested (100µM) . Preincubation of cells with the antihistamines for 2.5 minutes before addition of histamine resulted in an increase in the apparent potency of all antagonists. The calculated IC50 values for epinastine, ketotifen, azelastine and olopatadine were 38nM, 154nM, 273nM, and 1369nM, respectively. Preincubation of antagonists for one hour resulted in a significant change in potency only for olopatadine and ketotifen (10–30–fold increase), whereas epinastine and azelastine developed maximum potency after only 2.5 minutes of pre–incubation. Pretreatment of cells with epinastine for 2.5 min followed by washing with drug–free media resulted in persistent inhibition of the histamine response. This inhibition was observed at 24 hours after the removal of the drug with an IC50 of 6µM and a half life of approximately 2–3 hours.

Conclusions: : Epinastine demonstrated a faster onset of maximal inhibition of the H1R than olopatadine and ketotifen. Full potency of epinastine was reached within 3 minutes of application, and inhibition of histamine was detectable 24 hours after removal of the drug. These results may provide the pharmacological basis for the rapid relief that patients report after administration of Elestat, and provide a potential mechanism for the long lasting effect of the drug on the ocular surface.

Keywords: conjunctivitis • pharmacology • receptors 

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