prostaglandin-d2 and azelastine

Allergen challenge of subjects with asthma produces an early asthmatic response, late asthmatic response, and increases bronchial responsiveness. Histamine partly mediates the early asthmatic response, and may play a role in late-phase responses. Azelastine has antiallergic properties and has been proposed as a treatment for asthma. We therefore investigated the contribution of histamine to late-phase responses with the use of the potent H1-receptor antagonist azelastine.. Ten subjects with atopic asthma were studied in a double-blind, randomized, placebo-controlled trial. Azelastine was administered over 4 days before allergen challenge. Changes in airway caliber were followed with measurements of forced expiratory volume in 1 second, and changes in bronchial responsiveness were followed by methacholine and prostaglandin D2 bronchial provocation tests.. Azelastine significantly inhibited the development of the early asthmatic response. Azelastine had no effect on the late asthmatic response or on the development of allergen-induced increases in bronchial responsiveness. The power of the study was sufficient to have had a high probability of detecting any important differences between placebo and azelastine during the late phase.. Azelastine had no significant effect on the late-phase response model of asthma. This study does not support the hypothesis that histamine is an important mediator of the late asthmatic response or allergen-induced increases in bronchial responsiveness.

Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Double-Blind Method; Female; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Male; Methacholine Chloride; Phthalazines; Prostaglandin D2

To study the effect of azelastine on the immediate reaction to nasal allergen challenge, we performed a double blind, placebo-controlled cross-over clinical trial. Thirteen subjects with seasonal allergic rhinitis underwent nasal challenge with antigen 4 hr after a single oral 2 mg dose of azelastine. The response was monitored by counting the number of sneezes and by measuring the levels of histamine, prostaglandin D2, immunoreactive sulphidopeptide leukotrienes, kinis and TAME-esterase activity in recovered nasal lavages. After a single dose of azelastine, there was a significant reduction in sneezing (10 vs 2, P = 0.01) and in the median levels of recovered TAME-esterase activity (63.1 vs 17.5 c.p.m. x 10(-3), P = 0.01), immunoreactive sulphidopeptide leukotrienes (7.5 vs 2.1 ng/ml, P = 0.03) and kinins (1370 vs 251 pg/ml, P = 0.03), with no significant reduction in the median levels of histamine (3.7 vs 1.2 ng/ml, P = 0.2) and prostaglandin D2 (70 vs 70 pg/ml, P = 0.2) compared to placebo (numbers represent total increase over diluent challenge). These results suggest that azelastine does not inhibit mast cell activation but affects the consequences of released histamine, namely sneezing, increased vascular permeability and the generation of kinins. The results further suggest that other cells, in addition to mast cells, might be responsible for the generation of leukotrienes during the early allergic response, and that azelastine reduces their ability to generate this mediator or that inhibition of leukotriene release from mast cells occurs at lower drug concentrations.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Kinins; Male; Nasal Cavity; Nasal Provocation Tests; Peptide Hydrolases; Phthalazines; Prostaglandin D2; Sneezing; Therapeutic Irrigation

Recently, mast cell stabilizers, so called antiallergic drugs, that also have blocking effects on receptors for chemical mediators (CM) have been developed. The present study investigated the effects of a new antiallergic drug, epinastine (3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazol [1,5-a]azepine hydrochloride, WAL 810 CL; CAS 80012-43-7) on the in vivo bronchoconstriction (BC) induced by several CM as compared with those of other antiallergic drugs such as ketotifen, azelastine and oxatomide. Male Hartley guinea pigs were used. The BC was measured with a modified Konzett-Rössler method and expressed as a change in ventilation overflow (VO) under anesthesia. Antiallergic drugs were given orally 1 h before i.v. administration of CM. I.v. administrations of histamine (His), U-46619 (thromboxane A2 mimetic), leukotriene D4 (LTD4), prostaglandin D2 (PGD2), substance P (SP), neurokinin A (NKA), bradykinin (BK) and endothelin-1 (ET-1) increased VO in a dose dependent manner. The potency was as follows; ET-1 greater than LTD4 greater than NKA much greater than U-46619 greater than SP greater than His greater than BK much greater than PGD2. All the antiallergic drugs used markedly inhibited the His-induced BC. Epinastine, ketotifen and azelastine also significantly inhibited the BK-induced BC; epinastine had the strongest anti-BK effect among them. On the other hand, the four antiallergic drugs did not inhibit the BC induced by the other CM except for His and BK. Based on the above results, it is suggested that epinastine possesses anti-His and BK effects, and therefore could be promising as a new antiallergic drug without sedative effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Bronchoconstriction; Dibenzazepines; Guinea Pigs; Histamine; Histamine H1 Antagonists; Imidazoles; Ketotifen; Male; Neurokinin A; Phthalazines; Piperazines; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; SRS-A; Substance P