Elucidation of Inverse Agonist Activity of Bilastine

Abstract

H1-antihistamines antagonize histamine and prevent it from binding to the histamine H1 receptor (H1R). Some of them also act as inverse agonists, which are more potent than pure antagonists because they suppress the constitutive H1R activity. Bilastine is a non-sedative antihistamine which is one of the most satisfy the requirements for oral antihistamines. However, there is no information to show the inverse agonist activity of bilastine including inositol phosphates accumulation, and its inverse agonist activity is yet to be elucidated. Here we evaluated whether bilastine has inverse agonist activity or not. Intracellular calcium concentration was measured using Fluo-8. Inositol phosphates accumulation was assayed using [3H]myo-inositol. The H1R mRNA level was measured using real-time RT-PCR. At rest, Ca2+ oscillation was observed, indicating that H1R has intrinsic activity. Bilastine attenuated this fluorescence oscillation. Bilastine suppressed the increase in IPs formation in a dose-dependent manner and it was about 80% of the control level at the dose of 3 μM. Bilastine also suppressed histamine-induced increase in IPs formation to the control level. Furthermore, bilastine suppressed basal H1R gene expression in a dose-dependent manner. Data suggest that bilastine is an inverse agonist. Preseasonal prophylactic administration with bilastine could down-regulate basal H1R gene expression in the nasal mucosa and ameliorate the nasal symptoms during the peak pollen period.

Establishment of a human nasal epithelium model of histamine-induced inflammation to assess the activity of fexofenadine as an inverse agonist and its link to clinical benefit

“…The results also show that FEX reduces the constitutive receptor activity of H1R in the absence of HIS, confirming the inverse agonist dual mode of action and its benefit when used with pre-treatment. These data are in agreement with a recent article reporting that FEX works as an inverse agonist able to inhibit the basal activity of H1R, based on a HeLa cell line system that express H1R endogenously (Mizuguchi et al, 2020). Furthermore, side-by-side comparison of the conditions showed higher anti-inflammatory activity of FEX (reduction of IL-6 and IL-8 expression) and a trend of higher downregulation of H1R expression with one-hour FEX pretreatment versus without FEX pre-treatment.…”

“…Some H1-antihistamines act as inverse agonists and reduce constitutive receptor activity by binding with and stabilizing the inactive form of H1R in the absence of HIS, thereby shifting the equilibrium of H1R toward the inactive state ( Leurs et al, 2002 ) ( Figure 1A ). As such, they may have a higher potency than neutral antagonists as they exhibit a dual mode of action: downregulation of constitutive H1R activity as well as prevention of H1R activation by HIS ( Leurs et al, 2002 ; Mizuguchi et al, 2012 ; Mizuguchi et al, 2020 ). Fexofenadine (FEX), a non-sedating antihistamine, is used to relieve AR and urticaria symptoms ( Leurs et al, 2002 ; Meltzer et al, 2021 ; Ansotegui et al, 2022 ).…”

Pharmacokinetics and Safety of Bilastine 10 mg/d in Children Aged 2 to 5 Years With Allergic Rhinoconjunctivitis or Urticaria: A Phase 3 Clinical Trial

“…Bilastine is an effective, well-tolerated, and safe secondgeneration, nonsedating selective inverse H1 histamine receptor agonist authorized for the treatment of allergic disorders such as ARC and urticaria in adults, adolescents, and children [15,16]. Bilastine has been extensively evaluated in pharmacokinetic, efficacy, and safety studies [17][18][19], revealing efficacy [20,21] and an excellent safety and tolerability profile [22][23][24][25][26].…”

Ocular Biodistribution of Once-Daily 0.6% Bilastine Eye Drops Reveals Highest Levels in Conjunctiva Up to 24 h Postadministration

“…Bilastine is a nonsedating second-generation H 1 -antihistamine characterized by a fast onset of action and a prolonged effect, 14 , 15 with inverse agonist activity. 16 To date, bilastine has been administered through the oral route in the symptomatic treatment of seasonal or perennial allergic rhinoconjunctivitis and urticaria. 17 Recently, a new ophthalmic formulation of bilastine has been developed for the treatment of allergic conjunctivitis.…”