olopatadine-hydrochloride and Asthma

Olopatadine hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002).

Topics: Animals; Anti-Allergic Agents; Asthma; Clinical Trials as Topic; Conjunctivitis, Allergic; Dibenzoxepins; Drug Administration Routes; Histamine H1 Antagonists; Humans; Hypersensitivity; Inflammation Mediators; Olopatadine Hydrochloride; Ophthalmic Solutions; Pruritus; Rhinitis, Allergic, Perennial; Urticaria

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Butyrophenones; Cetirizine; Child; Chlorpheniramine; Dermatitis, Atopic; Dibenzazepines; Dibenzoxepins; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Imidazoles; Japan; Male; Middle Aged; Olopatadine Hydrochloride; Pain Measurement; Piperidines; Population Surveillance; Psychomotor Performance; Pyridines; Quality of Life; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sleep Stages; Surveys and Questionnaires; Terfenadine; Urticaria

Allergen-mediated mast cell activation is a key feature of ocular allergic diseases. Evidence of eosinophil-derived mediators in tears and conjunctival biopsy specimens has been associated with chronic ocular allergic inflammation.. To examine the role of conjunctival mast cell mediators in eosinophil adhesion to conjunctival epithelial cells and eosinophil degranulation.. Conjunctival cells were obtained by enzymatic digestion of cadaveric conjunctival tissues. Eosinophils were obtained from peripheral blood samples using negative magnetic bead selection. The effect of IgE-activated mast cell supernates on eosinophil degranulation and adherence to epithelial cells was compared with supernates obtained from mast cells pretreated with a degranulation inhibitor (olopatadine). Eosinophil adhesion was measured by eosinophil peroxidase assay, and eosinophil degranulation was measured by eosinophil-derived neurotoxin radioimmunoassay.. IgE-activated conjunctival mast cell supernates stimulated adhesion of eosinophils to epithelial cells (20.4% +/- 6.3% vs 3.1% +/- 1.0%; P = .048). Degranulation was not required for this process (no effect of olopatadine). IgE-activated mast cell supernates stimulated eosinophil-derived neurotoxin release (108.89 +/- 8.27 ng/10(6) cells vs 79.45 +/- 5.21 ng/10(6) cells for controls, P = .02), which was significantly inhibited by pretreatment of mast cells with a degranulation inhibitor (79.22 +/- 4.33 ng/10(6) cells vs 61.09 +/- 5.39 ng/10(6) cells for olopatadine pretreated and untreated, respectively, P = .02).. Mediators released from conjunctival mast cells promote eosinophil adhesion to conjunctival epithelial cells and eosinophil degranulation. Degranulation inhibition studies suggest that different mast cell mediators are involved in regulation of these events.

Topics: Adolescent; Adult; Asthma; Cell Adhesion; Cell Degranulation; Conjunctiva; Dibenzoxepins; Eosinophils; Epithelial Cells; Female; Humans; Immunoglobulin E; Male; Mast Cells; Middle Aged; Olopatadine Hydrochloride; Rhinitis, Allergic, Perennial

We investigated the effects of KW-4679, an antiallergic drug, on the development of bronchial hyperresponsiveness, airway inflammation and early and late asthmatic responses following aerosol antigen challenge in guinea pigs actively sensitized by the inhalation of aerosolized ovalbumin. Pretreatment with KW-4679 (10 mg/kg, p.o.) 1 h before antigen challenge prevented the development of bronchial hyperresponsiveness to inhaled methacholine. Examination of the bronchoalveolar lavage fluid 24 h after antigen challenge revealed the inhibitory effect of KW-4679 on the infiltration of eosinophils into the airway. Treatment with KW-4679 significantly inhibited both the immediate and late asthmatic responses. These results indicate that KW-4679 could be useful in the treatment of allergic diseases such as bronchial asthma.

Topics: Administration, Oral; Airway Resistance; Animals; Anti-Allergic Agents; Antibody Formation; Antigens; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Movement; Dibenzoxepins; Guinea Pigs; Male; Olopatadine Hydrochloride; Ovalbumin

The present experiment was carried out to elucidate the antiallergic properties of KW-4679. Oral administration of KW-4679 showed a dose-dependent inhibition on the IgE-mediated 48-hr homologous PCA in rats, with an ID50 value of 0.04 mg/kg. Passive anaphylactic broncho-constriction in guinea pigs mediated by IgE-like homologous antibody against ovalbumin was prevented dose-dependently by treatment with KW-4679 at doses of 0.03-1 mg/kg, p.o. KW-4679 also inhibited the IgE-mediated active anaphylactic bronchoconstriction in rats. In passively sensitized guinea pigs, the inhalation of aerosol antigen decreased the dynamic compliance of the lung and increased the mean pulmonary resistance. Pretreatment with KW-4679 (0.03-1 mg/kg, p.o.) inhibited antigen-induced airway obstructions. Oral administration of KW-4679 significantly protected rats from compound 48/80-induced lethality. These results indicate that KW-4679 might be useful in the treatment of allergic diseases such as asthma.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Asthma; Bronchoconstriction; Depression, Chemical; Dibenzoxepins; Dose-Response Relationship, Drug; Female; Guinea Pigs; Male; Olopatadine Hydrochloride; Passive Cutaneous Anaphylaxis; Rats; Rats, Wistar