The efficacy and tolerability of two novel H(1)/H(3) receptor antagonists in seasonal allergic rhinitis.
BACKGROUND
A therapeutic role for histamine H(3) receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H(1) receptor antagonism. Combined H(1)/H(3) blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage.


METHODS
Two novel H(1)/H(3) 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 H(1)/H(3) antagonism did not show differentiation from H(1) antagonism in reducing total nasal symptom score or nasal blockage.
GlaxoSmithKline, Research and Development, Uxbridge, UK. Peter.T.Daley-Yates@gsk.com
Peter
P
Daley-Yates
Claire
C
Ambery
Lisa
L
Sweeney
Joanna
J
Watson
Amanda
A
Oliver
Barbara
B
McQuade
D000281:Administration, Intranasal; D018926:Anti-Allergic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017332:Cetirizine / Q000009:adverse effects / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D054828:Histamine H3 Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000009:adverse effects / Q000627:therapeutic use*; D015508:Nasal Obstruction / Q000188:drug therapy; D010793:Phthalazines / Q000009:adverse effects / Q000627:therapeutic use*; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy*
D018926:Anti-Allergic Agents; C558853:GSK 1004723; C558852:GSK 835726; D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D009281:Naphthalenes; D010793:Phthalazines; D010880:Piperidines; D017332:Cetirizine