The following is a summary of “Trial of thromboxane receptor inhibition with ifetroban: TP receptors regulate eicosanoid homeostasis in aspirin-exacerbated respiratory disease,” published in the SEPTEMBER 2023 issue of Allergy & Immunology by Laidlaw, et al.
Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. This condition is associated with increased production of cysteinyl leukotrienes and decreased production of prostaglandin E2 (PGE2). Preclinical mouse models have suggested the involvement of the thromboxane-prostanoid (TP) receptor in AERD. For a study, researchers sought to investigate whether ifetroban, a TP receptor antagonist, could alleviate aspirin-induced respiratory symptoms in patients with AERD.
A total of 35 patients with AERD participated in a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome measure was the change in the provocative dose of aspirin that caused a 2-point increase in the Total Nasal Symptom Score. They also assessed changes in lung function, eicosanoid levels, and platelet and mast cell activation. Additionally, human nasal fibroblasts were cultured and stimulated with or without the TP agonist U46619 to assess prostanoid production.
Ifetroban was well tolerated by patients with AERD, but it did not significantly alter the primary outcome measure, the 2-point increase in Total Nasal Symptom Score (P = .763). Interestingly, participants taking ifetroban experienced more severe aspirin-induced nasal symptoms and a greater decline in FEV1 values compared to those receiving placebo (–18.8% ± 3.6% with ifetroban vs –8.4% ± 2.1% with placebo [P = .017]). After four weeks of ifetroban treatment, there was a significant increase in urinary leukotriene E4 levels and a decrease in nasal PGE2 levels compared to placebo. Peak levels of aspirin-induced urinary thromboxane correlated with peak levels of urinary leukotriene E4 and prostaglandin D2 metabolites in participants taking ifetroban. In cultured nasal fibroblasts from subjects with AERD but not in those from controls without sinusitis, U46619 significantly potentiated PGE2 production.
Contrary to the initial hypothesis, TP receptor blockade exacerbated aspirin-induced reactions in AERD patients, potentially by worsening eicosanoid system dysregulation. TP receptor signaling in stromal cells may play a crucial role in maintaining PGE2 production when COX-2 function is low.