Disease relevance of C12925

• OBJECTIVE: We compared the efficacy and safety of ebastine 20 mg and 10 mg, loratadine 10 mg, and placebo administered once daily for 4 weeks in controlling the symptoms of seasonal allergic rhinitis (SAR) [1].
• CONCLUSION: Ebastine 20 mg given once daily was significantly superior to loratadine 10 mg given once daily at improving the rhinitis total symptom score throughout the day and at awakening over a 4-week period [1].
• Thus, these results, which show ebastine to be an effective and well tolerated agent, indicated that the drug should be considered for the first-line therapy of chronic urticaria [2].
• Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters [3].
• Furthermore, ebastine showed no clinically relevant effects in a complete set of regulatory-required toxicity tests (including acute, chronic, reproductive, mutagenic and carcinogenic protocols) at doses giving blood concentrations representing high multiples of clinical exposure [4].

Psychiatry related information on C12925

• Ebastine: the effect of a new antihistamine on psychomotor performance and autonomic responses in healthy subjects [5].
• On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014 +/- 0.067 and accuracy ratio; 0.990 +/- 0.146) in a 7 ms task) [6].

High impact information on C12925

• This review focuses on the clinical pharmacology (pharmacokinetics and pharmacodynamics) of the newer oral H1 antihistamines (acrivastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and mizolastine) [7].
• Comparison of once-daily ebastine 20 mg, ebastine 10 mg, loratadine 10 mg, and placebo in the treatment of seasonal allergic rhinitis. The Ebastine Study Group [1].
• Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences [3].
• Ebastine is a useful treatment option for patients with allergic rhinitis or chronic idiopathic urticaria [8].
• Ebastine is a new second generation histamine H1 receptor antagonist that has shown clinical efficacy in the treatment of seasonal and perennial allergic rhinitis and chronic urticaria after once-daily administration [2].

Chemical compound and disease context of C12925

• In this study we have investigated the effects of ebastine and carebastine on the release of eicosanoids and cytokines from human dispersed polyp cells and the effect of these compounds on the release of inflammatory mediators into nasal lavage fluid after allergen challenge [9].
• This double-blind multicentre randomised placebo-controlled study has investigated the long term efficacy of ebastine 10mg once daily in the treatment of chronic urticaria compared with that of terfenadine 60mg twice daily [2].
• Cetirizine was most effective on pruritus but caused more often sedation than ebastine or loratadine [10].
• This trial was designed to study the efficacy and tolerability of azelastine in controlling symptoms of chronic idiopathic urticaria, using ebastine as validation group [11].
• The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers [12].

Biological context of C12925

• Their functional impact toward ebastine hydroxylation was evaluated using heterologous expression in Saccharomyces cerevisiae cells of site-directed mutated cDNA variants [13].
• The electrocardiographic effects of ebastine and its active metabolite, carebastine, have been studied alone and in relevant drug-interaction studies in various patient populations [14].
• The increase in QTcB with ebastine most likely resulted from overcorrection of the small drug-induced increase in heart rate [15].
• The overall effect after single and repeated 5-day dose, expressed as the AUC of reduction of wheal and flare area (%/h), showed the following order of magnitude: ebastine 20 mg>fexofenadine 120 mg>placebo [16].
• A double-blind placebo-controlled study of the efficacy and tolerability of ebastine against hayfever in general practice patients [17].

Anatomical context of C12925

• By contrast, ebastine has negligible activity against acetylcholine (no atropine-like adverse effects on secretions and visual accommodation) and only poorly penetrates the blood-brain barrier (no sedative adverse effects) [4].
• These results demonstrate that CYP2J2 is the predominant ebastine hydroxylase in human intestinal microsomes [18].
• Ebastine inhibits T cell migration, production of Th2-type cytokines and proinflammatory cytokines [19].
• Moreover, ebastine inhibited T cell migration and pro-inflammatory cytokine production by T cells and macrophages, suggesting that ebastine might be useful for the treatment of T cell-mediated allergic inflammatory disorders, including asthma, atopic dermatitis, and Th2-type autoimmune diseases [19].
• Ebastine also suppressed I(Kr) in HERG-expressing X. laevis oocytes with the Kd value of 0.3 microM and a maximal block of 46% at 3 microM [20].

Associations of C12925 with other chemical compounds

• Comparison of the efficacy of ebastine 10mg and 20mg once daily with that of cetirizine 10mg once daily in adults with seasonal allergic rhinitis. A multicentre double-blind study [21].
• Thus, it is clear that ebastine was much better tolerated than terfenadine from a cardiovascular standpoint, since ebastine and its metabolite are devoid of effects on cardiac repolarisation, as measured by the QTc interval in these animal models [22].
• Second-generation antihistamines such as ebastine have increased potency due to greater selectivity for histamine receptors, and improved tolerability due to lack of penetration of the blood brain barrier [23].
• Interaction studies involving ebastine with ketoconazole revealed a significant increase in the serum ebastine concentration and in the elimination half-life of ebastine, with a modest 18.1 msec increase in QTc (approximately 10 msec above ketoconazole alone) and a plateau QTc-ebastine relationship at higher ebastine levels [14].
• Cimetidine coadministration did not induce any effect of ebastine on blood pressure and heart rate or cause sedation [24].

Gene context of C12925

• Although CYP3A4 and CYP2J2 have been implicated in ebastine N-dealkylation and hydroxylation, the enzyme catalyzing the subsequent metabolic steps (conversion of hydroxyebastine to desalkylebastine and carebastine) have not been identified [25].
• Interestingly, CYP4F12 catalyzes the hydroxylation of the antihistamine ebastine with significantly higher catalytic activity relative to CYP4F2 (385 vs 5 pmol/min/nmol P450) [26].
• In addition, T cell migration and the production of such pro-inflammatory cytokines as TNF-alpha and IL-6 by macrophages were inhibited by ebastine [19].
• Therefore, we used human liver microsomes (HLMs) and expressed cytochromes P450 (P450s) to characterize the metabolism of ebastine and that of its metabolites, hydroxyebastine and carebastine [25].
• These results indicate that P450 MI-2 belongs to the CYP4F subfamily and is mainly responsible for hydroxylation of ebastine in monkey small intestinal microsomes [27].

Analytical, diagnostic and therapeutic context of C12925

• Ebastine is without effects on the central nervous and cardiovascular systems, even after oral administration of high doses, and does not interact pharmacologically with a wide range of other drugs covering most areas of potential coadministration [4].
• In 3 randomised double-blind, multicentre clinical trials in patients with SAR, ebastine 10 and 20mg once daily for 2 to 3 weeks significantly reduced symptoms (nasal discharge, stuffiness, sneezing, itchy nose, itchy/watery eyes) when compared with placebo [28].
• Pooled data from clinical efficacy trials of ebastine 1-30 mg/day administered for 2-3 weeks showed no clinically relevant cardiac effects as assessed by serial electrocardiographs and Holter monitoring [29].
• 1. We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a randomized double-blind and crossover study for 1 week each [30].
• Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay [30].

References