Inhibition of Allergic Histamine Release by Azelastine and Selected Antiallergic Drugs from Rabbit Leukocytes

Chand, N.; Pillar, J.; Diamantis, W.; Sofia, R. D.

doi:10.1159/000233825

Cited by 55 publications

(17 citation statements)

References 3 publications

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“…Azelastine possesses calm odulin [12] and Ca2+ [15] antagonistic activities. It has also been shown to inhibit the form ation of su peroxide radicals (•O2) [16] as well as allergic and nonallergic histamine secretion [13,17]. It exerts anti inflam m atory activity, i.e., it inhibited an antigen-in duced increase in capillary perm eability in experi mental anim al model systems [9,18].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Allergic and Nonallergic Leukotriene C4 Formation and Histamine Secretion by Azelastine: Implication for Its Mechanism of Action

Chand¹,

Pillar²,

Nolan³

et al. 1989

Int Arch Allergy Immunol

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Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C₄/D₄ synthesis. We have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC₄ formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC₄ formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC₄ synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC₄ generation may contribute to its mode of action and its therapeutic efficacy.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Allergic and Nonallergic Leukotriene C4 Formation and Histamine Secretion by Azelastine: Implication for Its Mechanism of Action

Chand¹,

Pillar²,

Nolan³

et al. 1989

Int Arch Allergy Immunol

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“…Azelastine [4-(/?-chlorobenzyl)-2-(hexahydro-1 -me thyl-1 H-azepine-4-yl)-l-(2H)-phthalazinone hydro chloride] has been shown to inhibit immunologically and nonimmunologically provoked histamine release from rat peritoneal mast cells [3][4][5][6] and rabbit leuko cytes [7], The drug showed a potent and long-acting antiallergic effect in several animal models of allergic hypersensitivity reactions, such as bronchospasm in guinea pigs [8], passive cutaneous anaphylaxis (PCA) in guinea pigs [3] and rats [3,9], and passive Arthus reactions in guinea pigs [3,10]. It is well established that azelastine has potent histamine HI receptor blocking properties in vitro and in vivo [3,8,9,11].…”

Section: Introductionmentioning

confidence: 99%

Effect of Azelastine on the Release and Action of Leukotriene C4 and D4

Katayama¹,

Tsunoda²,

Sakuma³

et al. 1987

Int Arch Allergy Immunol

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The effect of azelastine on the release of leukotriene C₄ and D₄ (LTC₄ and LTD₄), and the antagonistic action of the drug against the leukotrienes were determined by using in vitro tests and compared with those of ketotifen and chlorpheniramine. Azelastine inhibited LTC₄ and LTD₄ release from guinea pig lung fragments passively sensitized with homologous anti-ovalbumin IgG1-b antibody. The 50% inhibitory concentration (IC₅₀) of azelastine was 6.4 × 10^––⁵M for a 15-min preincubation or 4.7 × 10^––5M for a 30-min preincubation. Ketotifen and chlorpheniramine were inhibitory only at the highest concentration tested (3 × 10^––4M), giving inhibitions of 35.6 and 21.3%, respectively. Azelastine also inhibited calcium ionophore A23187-induced release of leukotrienes from human polymorphonuclear leukocytes; the IC₅₀ values were 3.6 × 10^––5M for 15 min and 2.3 × 10^––6M for 30 min of preincubation. Ketotifen and chlorpheniramine were inhibitory only after a 30-min preincubation, with IC₅₀ values of 2.1 × 10^––5 and 5.9 × 10^––5M, respectively. The potent inhibition by azelastine might be partly a result of the inhibition of 5-lipoxygenase, since 5-hydroxyeicosatetraenoic acid formation in rat basophilic leukemia cell homogenate was inhibited by azelastine. Pretreatment of guinea pig ileum with azelastine antagonized LTC₄- and LTT-Vinduced contraction of the ileum with IC₅₀ values of 7.0 × 10^––6 and 1.1 × 10^––5M, respectively. Azelastine (with a 50% relaxation concentration of 6.0 × 10^––6M) relaxed the ileum contracted by LTC₄. These antagonistic actions of azelastine were 2–3 times more potent than those of ketotifen. The present results suggest that the anti-allergic action of azelastine may be based on not only inhibition of the release of mediators (including LTC₄/D₄ and histamine), but also antagonism against leukotrienes and histamine.

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“…It has been shown that it prevents the synthesis/release of mediators such as histamine (Chand et al, 1985), leukotrienes (Chand et al, 1989;Nishihira et al, 1989), superoxide anions (Busse et al, 1989;Taniguchi & Takanaka, 1989), arachidonic acid (Taniguchi & Takanaka, 1989), and that it antagonizes the effect of some of these mediators on target organs (Rafferty et al, 1989). In addition, Nakamura et al (1988) have shown that azelastine inhibits the release of Ca2+ from intracellular storage sites in guinea-pig peritoneal macrophages stimulated by PAF or by FMLP.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Nakamura et al (1988) have shown that azelastine inhibits the release of Ca2+ from intracellular storage sites in guinea-pig peritoneal macrophages stimulated by PAF or by FMLP. Azelastine was also described as an inhibitor of leukocyte (Chand et al, 1985;Taniguchi & Takanaka, 1989;Busse et al, 1989), and platelet functions (Achterrath-Tuckermann et al, 1988). Azelastine is effective in animals (Chand et al, 1986;AchterrathTuckermann et al, 1988), and has been claimed to reduce allergic rhinitis (Meltzer et al, 1988) and asthma Kemp et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

Interference of anti‐inflammatory and anti‐asthmatic drugs with neutrophil‐mediated platelet activation: singularity of azelastine

Renesto

Balloy

Vargäftig

et al. 1991

British J Pharmacology

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1 The capacity of various drugs (acetylsalicylic acid (ASA), ketoprofen, diclofenac, piroxicam, BW 755C, BW A4C, nedocromil sodium and azelastine) to inhibit human polymorphonuclear neutrophil (PMN)-mediated platelet activation was investigated. In this model, stimulated PMN release cathepsin G (Cat G), a serine proteinase which, in turn, induces platelet activation. 2 Among the different tested drugs, azelastine (100pM for 1 min) was the only one able to prevent platelet aggregation. The cyclo-oxygenase inhibitors were all inactive, although used at effective concentrations as judged by inhibition of thromboxane B2 (TxB2) formation. Inhibition of platelet aggregation by azelastine was concentration-dependent, the range of active concentrations being of 20-70pM. Release from platelets of 5-hydroxytryptamine was also inhibited at 3OpM and above, but never reached 100%. 3 The inhibition by azelastine is due to an effect on both cells. Indeed, f-glucuronidase release from activated PMN and platelet activation by purified Cat G were both affected.4 However, used at high concentrations (>100,UM) azelastine was toxic since it released significant amounts of lactate dehydrogenase (LDH) from PMN and platelets. 5 These results show the capacity of azelastine, an anti-allergic and anti-asthmatic compound, to inhibit the cell-to-cell communication between PMN and platelets, an effect which may be relevant for its therapeutic efficacy or for a new application in diseases in which PMN and platelets are involved.

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Inhibition of Allergic Histamine Release by Azelastine and Selected Antiallergic Drugs from Rabbit Leukocytes

Cited by 55 publications

References 3 publications

Inhibition of Allergic and Nonallergic Leukotriene C<sub>4</sub> Formation and Histamine Secretion by Azelastine: Implication for Its Mechanism of Action

Inhibition of Allergic and Nonallergic Leukotriene C<sub>4</sub> Formation and Histamine Secretion by Azelastine: Implication for Its Mechanism of Action

Effect of Azelastine on the Release and Action of Leukotriene C<sub>4</sub> and D<sub>4</sub>

Interference of anti‐inflammatory and anti‐asthmatic drugs with neutrophil‐mediated platelet activation: singularity of azelastine

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