241 Inhibition of leukotriene (SRS-A)-mediated allergic bronchospasm by azelastine, a novel orally effective antiasthmatic drug

Chand, N.; Nolan, K.; Diamantis, W.; Perhach, James L.; Sofia, R. D.

doi:10.1016/0091-6749(83)90365-2

Cited by 25 publications

(11 citation statements)

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“…Azelastine has also been reported to inhibit aeroallergen-induced immediate [2,5] and late asthmatic responses as well as exercise-induced asthma [2]. It inhibits leukotriene-mediated acute allergic bronchospasm in guinea pigs [11] and passive cutaneous anaphylaxis [12]. Azelastine exerts a strong inhibitory influence on allergic and nonallergic histamine secretion [13] and generation of" O~ in polymorphonuclear cells [14].…”

Section: Introductionmentioning

confidence: 97%

Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum

1986

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The effects of azelastine on histamine- and leukotriene C4 and D4 (LTC4, LTD4)-induced contractile responses in isolated guinea pig ileum were investigated. Following a 2-min contact with the ileum, azelastine produced competitive antagonism of histamine (pA2 = 8.24). Following a 15-min contact, azelastine at 2.5 X 10(-9) M exerted competitive antagonism, but at higher concentrations (10, 40 and 160 X 10(-9) M) it not only shifted histamine concentration-effect curves to the right but also suppressed its maximum. Thus, azelastine exerts a dual (competitive/noncompetitive) antagonism of histamine depending upon the concentration and duration of contact. Azelastine and FPL 55712 (a known LT receptor antagonist) produced concentration-dependent antagonism of LTC4 and LTD4. Azelastine and compound FPL 55712 also exerted concentration-dependent reversal (relaxation) of pre-existing LTC4-induced contractions. In conclusion, the potent H1-histamine and leukotriene receptor blocking activities of azelastine may contribute to its antiasthmatic/antiallergic activities.

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Section: Introductionmentioning

confidence: 97%

Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum

1986

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“…Azelastine [4-(p-chlorobenzyl)-2-(hexahydro-1 -methyl-1 H-azepine-4-yl)-1 -(2H)-phthalazinone hy drochloride] is an orally effective and long-acting anti allergic agent [1][2][3][4][5]. Azelastine is capable of inhibiting allergic and nonallergic release of SRS (SRS-A) [5] and histamine [6][7][8][9], In this investigation, the influ ence of azelastine on IgE-mediated allergic histamine release from mixed leukocytes of rabbits sensitized with ragweed antigen [10] was studied and compared with selected antiallergic drugs.…”

Section: Introductionmentioning

confidence: 99%

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

Chand¹,

Pillar²,

Diamantis³

et al. 1985

Int Arch Allergy Immunol

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The ability of azelastine to inhibit allergic histamine release from rabbit mixed leukocytes was studied and compared with selected antiallergic drugs. Azelastine, ketotifen, diphenhydramine, theophylline and disodium cromoglycate (DSCG) produced concentration-dependent inhibition of allergic histamine release from rabbit basophils. The concentrations inhibiting histamine release by 50% (IC₅₀; μM)were as follows: azelastine = 4.5; ketotifen = 9.5; diphenhydramine = 18.9; theophylline = 56.9; DSCG = >1,000. DSCG was added to the cells immediately prior to antigen challenge. All other drugs were preincubated for a period of 10 min prior to antigen challenge. At the IC₅₀ level, azelastine is about 2, 4, 13 and >200 times as effective as ketotifen, diphenhydramine, theophylline and DSCG, respectively. The IC₅₀ of azelastine following 0, 10 and 30 min preincubation were 2.4, 1.9 and 3.5 μM, respectively. These observations showed: (1) azelastine is capable of acting rapidly on basophils and of inhibiting allergic histamine secretion, and (2) the prolongation of the preincubation time of azelastine up to 30 min with rabbit leukocytes did not exhibit any sign of tachyphylaxis (loss of activity). In conclusion, azelastine is a potent inhibitor of allergic histamine secretion from the leukocytes of ragweed-sensitized rabbits.

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“…Earlier, azelastine has been shown to interfere with the synthesis/release of SRS-A (SRS-leukotrienes) in vivo as well as in in vitro model systems (Diamantis et al, 1982;Chand et al, 1983a (Storms et al, 1985), i.e. antagonism of chemical mediators such as histamine, Ca2+, and leukotrienes , azelastine may also act by inhibiting histamine secretion and the synthesis of leukotrienes and sub-sequent allergic airway responses (this study; Diamantis et al, 1982;1984a,b;Chand et al, 1983a,b;1985a,b,c).…”

Section: Pharmacological Modulation Ofschultz-dale Responses In Guinementioning

confidence: 99%

Modulation of in vitro anaphylaxis of guinea‐pig isolated tracheal segments by azelastine, inhibitors of arachidonic acid metabolism and selected antiallergic drugs

Chand

Diamantis

Sofia

1986

British J Pharmacology

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1 The ability of azelastine to influence antigen-induced contractile responses (Schultz-Dale phenomenon) in isolated tracheal segments of the guinea-pig was investigated and compared with selected antiallergic drugs and inhibitors of arachidonic acid metabolism. 2 Indomethacin produced a significant leftward shift of the antigen concentration-effect curve. 3 The inhibitory activity ofazelastine on anaphylactic responses in guinea-pig trachea was dependent on the duration of exposure (preincubation period). 4 The relative order ofpotency (antianaphylactic activity) at calculated IC50 level was as follows: FPL 55712 (a leukotriene receptor antagonist) > nordihydroguaiaretic acid (a lipoxygenase inhibitor) > pbromophenacyl bromide (a phospholipase A2 inhibitor) > BW 755c (a dual inhibitor of lipoxygenase and cyclo-oxygenase) > theophylline (a phosphodiesterase inhibitor) > azelastine > diphenhydramine (HI histamine-receptor antagonist) > ketotifen > disodium cromoglycate. FPL 55712 (added 5 min before antigen challenge) was about 12 times as potent as azelastine (added 2 h before antigen challenge). 5 The incubation of tracheal segments with azelastine and BW 755c for a period of 30 min was found to inhibit indomethacin-augmented anaphylactic responses. These observations seem to suggest that azelastine and BW 755c interfere with the synthesis/release ofthe products oflipoxygenase/leukotriene synthetase pathway (e.g., leukotrienes) in the mediation of allergic responses in airway smooth muscles.

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241 Inhibition of leukotriene (SRS-A)-mediated allergic bronchospasm by azelastine, a novel orally effective antiasthmatic drug

Cited by 25 publications

References 0 publications

Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum

Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum

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

Modulation of in vitro anaphylaxis of guinea‐pig isolated tracheal segments by azelastine, inhibitors of arachidonic acid metabolism and selected antiallergic drugs

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