Anti-allergic activity of betotastine besilate (TAU-284), a new anti-allergic drug.

Yato, Naoko; Murata, Takashi; Saito, Noriko; Sakai, Atsuko; Kikuchi, Motohiro; Tsuzurahara, Kei; Narita, Hiroshi

doi:10.1254/fpj.110.19

Cited by 24 publications

(10 citation statements)

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“…Bepotastine besilate [(ϩ)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino}butyric acid monobenzenesulfonate, betotastine besilate, TAU-284, Talion] was developed as a second-generation H1-antagonist. Bepotastine showed a high selectivity and potent antagonistic action to H1-receptor and exerted an excellent antiallergic action (Honda et al, 1997;Kato et al, 1997;Sakai et al, 1997;Yato et al, 1997). Nonclinical and clinical studies suggested that bepotastine does not exhibit sedation at the clinical therapeutic dose because of limited distribution into brain (Kadosaka et al, 1997;Ohashi et al, 1997).…”

mentioning

confidence: 99%

Effect of P-Glycoprotein on Intestinal Absorption and Brain Penetration of Antiallergic Agent Bepotastine Besilate

Ohashi

Kamikozawa

Sugiura

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:The antiallergic agent bepotastine besilate is a nonsedating, second-generation H1-antagonist with high oral absorption and negligible distribution into brain. To clarify the role of P-glycoprotein (P-gp) in the pharmacokinetics of bepotastine, intestinal absorption and brain penetration studies were performed. In conclusion, bepotastine is a substrate for P-gp, and P-gp clearly limited the brain distribution of bepotastine, whereas the effect of P-gp on intestinal absorption of bepotastine was minimal, presumably because of high membrane permeability at the upper region of small intestine where P-gp is less expressed. Such intestinal absorption property of bepotastine is distinctly different from the low membrane-permeable P-gp substrate fexofenadine.First-generation H1-receptor antagonists have been used for the treatment of allergic disorders. However, they are problematic because they induce sedation as they penetrate well to the brain (Nicholson 1983, Tagawa et al., 2001. Bepotastine besilate [(ϩ)-(S)-4-{4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino}butyric acid monobenzenesulfonate, betotastine besilate, TAU-284, Talion] was developed as a second-generation H1-antagonist. Bepotastine showed a high selectivity and potent antagonistic action to H1-receptor and exerted an excellent antiallergic action (Honda et al., 1997;Kato et al., 1997;Sakai et al., 1997;Yato et al., 1997). Nonclinical and clinical studies suggested that bepotastine does not exhibit sedation at the clinical therapeutic dose because of limited distribution into brain (Kadosaka et al., 1997;Ohashi et al., 1997). Bepotastine is metabolically stable in dogs and humans and is excreted into urine in an unchanged form Ͼ70% of dose after p.o. administration. Intestinal absorption of bepotastine was Ͼ85%, Ͼ70%, and Ͼ80% in rats, dogs, and humans, respectively, showing high absorption. The variation of drug concentration in plasma after p.o. administration to healthy volunteers was small, and plasma concentration was not significantly affected by food. The tissue distribution studies of [14 C]bepotastine after p.o. administration to rats showed that [ 14 C]bepotastine distributed widely in the whole body, whereas its brain distribution was lower than that of ketotifen, terfenadine, and its carboxylic metabolite (fexofenadine) (Kato et al., 1997).The MDR1 gene (multidrug resistance; ABCB1) product P-glycoprotein (P-gp) plays an important role in pharmacokinetics of drugs. P-gp is well known as an important factor to limit membrane permeability in several tissues and/or the elimination pathways into urine and bile. P-gp is highly expressed in the endothelial cells of brain capillaries and restricts the brain penetration of drugs (Tsuji et al., 1992;Schinkel et al., 1994). Although intestinal P-gp is probably a limiting factor of intestinal absorption of drugs, it is also true that substrates of P-gp exhibit good bioavailability (Varma et al., 2005). Therefore, the effect of P-gp on intestinal drug absorption is controversial compared with ...

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confidence: 99%

Effect of P-Glycoprotein on Intestinal Absorption and Brain Penetration of Antiallergic Agent Bepotastine Besilate

Ohashi

Kamikozawa

Sugiura

et al. 2006

Drug Metabolism and Disposition

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“…In the in vitro experiments, a practically high dose of betotastine (1 mmol/l) inhibited the release of histamine, leukotriene B 4 and 5-HETE from the rat peritoneal cells stimulated with ionophore A23187 [1]. Thus, betotastine scarcely affects the release of mediators from the mast cells within attainable blood and tissue concentrations.…”

Section: Discussionmentioning

confidence: 88%

“…Betotastine also inhibited homologous passive cutaneous anaphylaxis (PCA) in rats and guinea pigs [1,2], anaphylactic shock in guinea pigs [3], and histamine-induced bronchoconstriction in guinea pigs and dogs [4]. In addition, betotastine inhibited the release of histamine, leukotriene B 4 and 5-HETE from rat peritoneal cells stimulated with calcium ionophore A23187 [1]. Recently, a new histamine H 1 -receptor antagonist, cetirizine, has been reported to inhibit infiltration of eosinophils in animals [5][6][7] and in humans [8][9][10][11][12][13].…”

Section: Betotastine Besilate ((+)-(S)-4-[4-[(4-chlorophenyl)-2-pyridmentioning

confidence: 99%

Antiallergic Action of Betotastine Besilate (TAU-284) in Animal Models: A Comparison with Ketotifen

et al. 1998

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The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (R_rs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3–10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.

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“…In vivo studies suggest that bepotastine besilate stabilizes mast cell function and inhibits IL-5 production, leukotriene B 4 (LTB 4 ) and leuko triene D 4 (LTD 4 ) activity, PAF activity and eosinophil migration [27,[29][30][31]. Hence, the antiallergic and anti-inflammatory actions of bepotastine besilate occur at both the early and late phase of the allergic response [27].…”

Section: Pharmacologymentioning

confidence: 99%

Clinical safety and efficacy of bepotastine besilate ophthalmic solution to treat allergic conjunctivitis

Berdy

Oliff

2010

Expert Review of Ophthalmology

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The mast cell-stabilizer-antihistamine class of medications has become physicians' first choice for treating seasonal allergic conjunctivitis owing to the rapid onset of action, long duration of effect and improved comfort. Bepotastine besilate ophthalmic solution 1.5% (Bepreve™, ISTA Pharmaceuticals, Inc., CA, USA) has recently been approved by the US FDA for the treatment of itching associated with the signs and symptoms of allergic conjunctivitis. Bepotastine besilate has multiple mechanisms of action, selectively inhibiting histamine H 1 receptors, stabilizing mast cells, inhibiting eosinophil infiltration, and inhibiting production of inflammatory cytokines or chemokines. Although not approved for other indications, a clinical study has shown that bepotastine besilate reduces nonocular (principally nasal) symptoms and thus may be particularly helpful for people with rhinoconjunctivitis. As per FDA approval, bepotastine besilate is well tolerated and safe for subjects as young as 2 years of age. Bepotastine besilate ophthalmic solution provides an alternative choice of treatment for allergic conjunctivitis. Keywords: allergic conjunctivitis • antihistamine • conjunctival allergen challenge • mast cell stabilizer • ocular allergy • rhinoconjunctivitis Clinical safety and efficacy of bepotastine besilate ophthalmic solution to treat allergic conjunctivitis Expert Rev. Ophthalmol. 5(5), 595-602 (2010) For reprint orders, please contact reprints@expert-reviews.com Expert Review of Ophthalmology Downloaded from informahealthcare.com by Nyu Medical Center on 07/30/15 For personal use only.

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Anti-allergic activity of betotastine besilate (TAU-284), a new anti-allergic drug.

Cited by 24 publications

References 2 publications

Effect of P-Glycoprotein on Intestinal Absorption and Brain Penetration of Antiallergic Agent Bepotastine Besilate

Effect of P-Glycoprotein on Intestinal Absorption and Brain Penetration of Antiallergic Agent Bepotastine Besilate

Antiallergic Action of Betotastine Besilate (TAU-284) in Animal Models: A Comparison with Ketotifen

Clinical safety and efficacy of bepotastine besilate ophthalmic solution to treat allergic conjunctivitis

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