The <scp>CRTH</scp>2 antagonist <scp>OC</scp>000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo‐controlled, double‐blind trial

Horak, Friedrich; Zieglmayer, Petra; Zieglmayer, René; Lemell, Patrick; Collins, Lisa Pearce; Hunter, Michael; Steiner, Jan; Lewis, Toby C.; Payton, Mark; Perkins, Christopher; Pettipher, Roy

doi:10.1111/all.12042

Cited by 69 publications

(66 citation statements)

References 18 publications

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“…This delayed effect raised the possibility of a carryover effect, as has been seen in prior studies with CRTh2 antagonists [39]. The UAS7 also decreased in the placebo group from baseline to the end of treatment, but this did not reach statistical significance.…”

Section: Resultsmentioning

confidence: 72%

“…During the same time period, AZD1981-treated subjects experienced a 35.9% decline in itch component scores. This suggests the possibility of a carryover effect, as has been seen in other diseases targeted by a CRTh2 antagonist [39]. In the placebo group, decreases were observed in UAS7 and itch scores from baseline to the end of treatment which did not reach statistical significance.…”

Section: Discussionmentioning

confidence: 92%

“…Preclinical studies have shown that AZD1981 blocks CRTh2-mediated shape change in human eosinophils and basophils in vitro, inhibits CRTh2-mediated chemotaxis of human Th2 cells and eosinophils, and blocks PGD 2 -mediated eosinophil release from bone marrow in guinea pigs [37]. In clinical trials, oral CRTh2 antagonists have reduced esophageal eosinophils in eosinophilic esophagitis [38] and provided an improvement in airway function and protection against allergen-induced symptoms in patients with allergic rhinoconjunctivitis and asthma [39-43]. Here we report the results of the first study to examine the safety and efficacy of the selective oral CRTh2 antagonist AZD1981 as add-on therapy to standard antihistamines in CSU.…”

Section: Introductionmentioning

confidence: 99%

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Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Oliver

Chichester

Devine

et al. 2019

Int Arch Allergy Immunol

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Background: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. Objective: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H₁-antihistamines. Methods: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D₂ (PGD₂)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. Results: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD₂-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. Conclusions: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD₂-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD₂/CRTh2 pathway will be an effective treatment for CSU.

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Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Oliver

Chichester

Devine

et al. 2019

Int Arch Allergy Immunol

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“…Considering previous reports, the onset of the effect of CRTH2 antagonist might be slow. Repetitive dosing of OC000459 for 8 days was required to obtain the maximum effect (Horak et al, 2012). Ramatroban showed a significant effect on sneezing after administration for 29 days (Nomiya et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…MK-0524 (Takahashi et al, 2015) and OC000459 ((5-fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid) (Horak et al, 2012;Pettipher et al, 2012) were synthesized in our laboratories. Cetirizine dihydrochloride was purchased from the Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), fluticasone propionate (FP) was from Glaxo Smith Kline K.K.…”

Section: Methodsmentioning

confidence: 99%

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice

Nakano

Kidani

Goto

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Although we previously demonstrated the contribution of the DP 1 receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP 1 receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC: Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP 1 receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP 1 receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP 1 receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP 1 receptor signaling to sneezing was demonstrated using this model, suggesting that DP 1 receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

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Eicosanoid Pathway Modulators: Prostaglandins, Prostacyclin, and Thromboxane

Mazaleuskaya

Ricciotti

2021

Burger's Medicinal Chemistry and Drug Discovery

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Prostanoids (prostaglandins, prostacyclin, and thromboxane) are bioactive lipids, members of the eicosanoid class of compounds, derived from arachidonic acid (AA). They are involved in controlling homeostatic and pathophysiological processes. Their biosynthesis is the result of the coordinated actions of several enzymes. Cyclooxygenases (COXs) catalyze the committed step in the conversion of AA into prostanoids. There are two COX isozymes: the constitutive COX‐1 and the inducible COX‐2, both of which have different patterns of expression and biological functions. COX‐1 and COX‐2 are the targets of traditional nonsteroidal anti‐inflammatory drugs (tNSAIDs), which are used to relieve pain, fever and inflammation. Despite their clinical efficacy, tNSAIDs cause side effects, particularly in the gastrointestinal (GI) tract. NSAIDs selective for COX‐2 inhibition (coxibs) were purposefully designed to spare GI side effects, but predisposed patients to increased cardiovascular (CV) risks. The GI and CV complications from existing NSAIDs prompted interest in the downstream effectors of the COX enzymes as novel drug targets. This article describes various safety issues with tNSAIDs and coxibs, and discusses the current development of novel classes of drugs targeting the AA pathway, including nitric oxide‐releasing and hydrogen sulfide‐releasing NSAIDs, inhibitors of prostanoid synthases, dual inhibitors, and prostanoid receptor agonists and antagonists.

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The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo‐controlled, double‐blind trial

Abstract: Treatment with OC000459 was well tolerated and led to a significant and persistent reduction in the symptoms of rhinoconjunctivitis.

Cited by 69 publications

References 18 publications

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice

Eicosanoid Pathway Modulators: Prostaglandins, Prostacyclin, and Thromboxane

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