The effect of MK-0524, a prostaglandin D(2) receptor antagonist, on prostaglandin D (2)-induced nasal airway obstruction in healthy volunteers.
BACKGROUND
Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D(2) is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD(2) reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD(2) (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD(2) can be a useful tool for evaluating DP-receptor antagonists.


OBJECTIVE
The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD(2) induced nasal congestion in healthy volunteers.


METHODS
To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD(2) were performed to determine the PD(75), which is the intranasal dose of PGD(2) that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry.


RESULTS
Following treatment with MK-0524, the PD(75) (mean+/-SD) was significantly shifted from 15.8 +/- 18.3 mug/nostril during the placebo period to more than 512 mug/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen.


CONCLUSIONS
Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.
Van Hecken
A
A
Center for Clinical Pharmacology, UZ Gasthuisberg, (K.U.Leuven), Herestraat 49, 3000 Leuven, Belgium. Anne.VanHecken@uz.kuleuven.ac.be
Depré
M
M
De Lepeleire
I
I
Thach
C
C
Oeyen
M
M
Van Effen
J
J
Laethem
T
T
Mazina
K
K
Crumley
T
T
Wenning
L
L
Gottesdiener
K M
KM
Deutsch
P
P
Clement
P
P
Lai
E
E
de Hoon
J N
JN
D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D015508:Nasal Obstruction / Q000139:chemically induced / Q000188:drug therapy*; D015230:Prostaglandin D2 / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy*; D025363:Rhinomanometry
D007211:Indoles; C518174:MK-0524; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor