Journal Mobile Options
Table of Contents
Vol. 158, No. 1, 2012
Issue release date: April 2012

The Efficacy and Tolerability of Two Novel H1/H3 Receptor Antagonists in Seasonal Allergic Rhinitis

Daley-Yates P. · Ambery C. · Sweeney L. · Watson J. · Oliver A. · McQuade B.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: A therapeutic role for histamine H3 receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H1 receptor antagonism. Combined H1/H3 blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage. Methods: Two novel H1/H3 dual receptor antagonists were investigated in phase I and II safety and efficacy studies. One molecule (GSK1004723) was designed for intranasal administration as a suspension or solution and the other molecule (GSK835726) for oral administration. In phase I and II studies, both molecules were compared with an active control and/or placebo in randomised studies. In phase II studies, efficacy was assessed in an environmental allergen challenge chamber (ECC). Subjects with seasonal allergic rhinitis were exposed to allergen to induce symptoms. Efficacy and safety was measured over 4, 7 and 20–24 h post-dose. The endpoints included total nasal symptom score and nasal blockage. Results: Intranasal suspension of GSK1004723 and oral GSK835726 were well tolerated. Single-dose intranasal suspensions of GSK1004723 (220, 1,100 µg) failed to demonstrate clinically significant attenuation of symptoms of allergic rhinitis induced in the ECC. Single (10, 50, 100 mg) and 3-day repeat (10 mg) dose oral GSK835726 demonstrated clinically significant attenuation of symptoms in the ECC comparable to cetirizine 10 mg. Three-day repeat dosing of the intranasal solution GSK1004723 1,000 µg also demonstrated a statistically significant attenuation of nasal symptoms, but was less than seen with cetirizine and GSK835726 and caused initial nasal discomfort. Conclusions: Combined H1/H3 antagonism did not show differentiation from H1 antagonism in reducing total nasal symptom score or nasal blockage.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Naclerio RM: Allergic rhinitis. N Engl J Med 1991;325:860–869.
  2. Naclerio R: Clinical manifestations of the release of histamine and other inflammatory mediators. J Allergy Clin Immunol 1999;103:S382–S385.
  3. Doyle WJ, Boehm S, Skoner DP: Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy. J Allergy Clin Immunol 1990;86:924–935.
  4. Howarth PH, Salagean M, Dokic D: Allergic rhinitis: not purely a histamine-related disease. Allergy 2000;55:(suppl 64)7–16.
  5. Kirkegaard J, Secher C, Borum P, Mygind N: Inhibition of histamine-induced nasal symptoms by the H1 antihistamine chlorpheniramine maleate: demonstration of topical effect. Br J Dis Chest 1983;77:113–122.
  6. Hilberg O, Grymer LF, Pedersen OF: Nasal histamine challenge in nonallergic and allergic subjects evaluated by acoustic rhinometry. Allergy 1995;50:166–173.
  7. Babe KS, Serafin WE: Histamine bradykinin and their antagonists; in Hardman G, Limbind LE (eds): Goodman and Gilman, The Pharmacological Basis of Therapeutics, ed 9. New York, McGrawHill, 1996, pp 581–600.
  8. Prenner BM, Schenkel E: Allergic rhinitis: treatment based on patient profiles. Am J Med 2006;119:230–237.
  9. Spector S: Ideal pharmacotherapy for allergic rhinitis. J Allergy Clin Immunol 1999;103:S386–S387.
  10. Scadding GK, Durham SR, Mirakian R, Jones NS, Leech SC, Farooque S, Ryan D, Walker SM, Clark AT, Dixon TA, Jolles SRA, Siddique N, Cullinan P, Howarth PH, Nasser SM: BSACI guidelines for the management of allergic and non-allergic rhinitis. Clin Exp Allergy 2009;38:19–42.

    External Resources

  11. McLeod RL, Mingo GG, Herczku C, DeGennaro-Culver F, Kreutner W, Egan RW, Hey JA: Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion. Am J Rhinol 1999;13:391–399.
  12. Arrang JM, Garbarg M, Schwartz JC: Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983;302:832–837.
  13. Koss MC, Hey JA: Prejunctional inhibition of sympathetically evoked pupillary dilation in cats by activation of histamine H3 receptors. Naunyn Schmiedebergs Arch Pharmacol 1993;348:141–145.
  14. Ohkubo T, Shibata M, Inoue M, Kaya H, Takahashi H: Regulation of substance P release mediated via prejunctional histamine H3 receptors. Eur J Pharmacol 1995;273:83–88.
  15. Ichinose M, Barnes PJ. Inhibitory histamine H3-receptors on cholinergic nerves in human airways. Eur J Pharmacol 1989;163:383–386.
  16. Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, Schunack W, Levi R, Haas HL: International union of pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 1997;49:253–278.
  17. Nakaya M, Takeuchi N, Kondo K: Immunohistochemical localization of histamine receptor subtypes in human inferior turbinates. Ann Otol Rhinol Laryngol 2004;113:552–557.
  18. Yokota E, Kuyama S, Sugimoto Y, Ogawa M, Kamei C: Participation of Histamine H3 Receptors in Experimental Allergic Rhinitis of Mice. J Pharmacol Sci 2008;108:206–211.
  19. McLeod RL, Egan RW, Cuss FM, Bolser DC, Hey JA: New drugs for Asthma, Allergy and COPD. Prog Respir Res 2001;31:133–136.
  20. Taylor-Clark T, Sodha R, Warner B, Foreman J: Histamine receptors that influence blockage of the normal human nasal airway. Br J Pharmacol 2005;144:867–874.
  21. Varty LM, Gustafson E, Laverty M, Hey JA: Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction. Eur J Pharmacol 2004;484:83–89.
  22. Procopiou PA, Browning C, Buckley JM, Clark KL, Fechner L, Gore PM, Hancock AP, Hodgson ST, Holmes DS, Kranz M, Looker BE, Morriss KML, Parton DL, Russell LJ, Slack RJ, Sollis SL, Vile S, Watts CJ: The discovery of phthalazinone-based human H1 and H3 single-ligand antagonists suitable for intranasal administration for the treatment of allergic rhinitis. J Med Chem 2011;54: 2183–2195.
  23. Romero FA, Allan RJ, Phillips PG, Hutchinson JM, Misfeldt JM, Casale TB: The Effects Of An H3 Receptor Antagonist In A Nasal Allergen Challenge Model. JACI 2010;125(issue 2):supplement:AB191.
  24. Slack RJ, Russell LJ, Hall DA, Luttmann MA, Ford AJ, Saunders KA, Hodgson ST, Connor HE, Browning C, Clark KL: Pharmacological characterisation of GSK1004723, a novel, long acting antagonist at histamine H1 and H3 receptors. Br J Pharmacol 2011, in press.
  25. Ford A, Browning C, Russell L, Saunders K, Hall D, Morrison V, Changani K, Hodgson S, Clark K: Preclincal pharmacology of the novel oral dual histamine H1 and H3 receptor antagonist GSK835726. Allergy 2009; 64(suppl 90):134.
  26. Norman P: New H1/H3 antagonists for treating allergic rhinitis. Expert Opin Ther 2011;21:425–429.
  27. Hohlfeld JM, Holland-Letz T, Larbig M, Lavae-Mokhtari M, Wierenga E, Kapsenberg M, van Ree R, Krug N, Bufe A: Diagnostic value of outcome measures following allergen exposure in an environmental challenge chamber compared with natural conditions. Clin Exp Allergy 2010;40:998–1006.
  28. Badorrek P, Dick M, Schauerte A, Hecker H, Murdoch R, Luettig B, Hohlfeld JM, Krug N: A combination of cetirizine and pseudoephedrine has therapeutic benefits when compared to single drug treatment in allergic rhinitis. Int J Clin Pharmacol Ther 2009;47:71–77.
  29. Daley-Yates PT, Stone S, Allen A, Lambert J: Nasal absorption of fluticasone propionate: influence of formulation, dissolution and breath holding; in Dalby RN, Byron PR, Peart J, Suman JD (eds): Respiratory Drug Delivery Europe. Richmond, Virginia Commonwealth University, 2007, vol 1, pp 271–274.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50