icatibant and Rhinitis

The kallikrein-kinin system plays an important role in many physiological and pathophysiological conditions such as homeostasis of circulation, inflammation/allergy, pain, shock, etc. Two types of kinin receptor are known, bradykinin (BK) B1 receptor and BK B2 receptor. B2 receptors are constitutively expressed and mediate most physiological actions of kinins, whereas B1 receptors are highly inducible upon inflammatory stimulation or tissue injury, suggesting that they are involved in inflammation and/or nociception. Only three peptide type B2 antagonists, NPC 567, CP-0127 and HOE-140, have been evaluated in clinical studies so far, and some beneficial effects of B2 antagonists have been shown for rhinitis, asthma, systemic inflammatory response syndrome/sepsis and brain injury. However, the results were less convincing than expected. Now several potent and orally active nonpeptide B2-receptor antagonists have been found, which are expected to overcome the weak point of the peptide type antagonists and clarify the therapeutic potential of the B2-receptor antagonist for novel indications as well as those mentioned above. As for B1 receptors, no antagonist has been tested in a clinical trial. The important role of B1 receptors is just being elucidated by use of peptide type antagonists or B1 receptor gene knockout mice. The further development of newer B1 antagonists and clinical evaluation is desired.

Topics: Asthma; Bradykinin; Bradykinin Receptor Antagonists; Humans; Hypersensitivity; Peptides; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Rhinitis; Systemic Inflammatory Response Syndrome

1. Over the past decade, data have been obtained showing that the potent vasoactive peptides known as kinins are generated in airway secretions during a variety of inflammatory airway diseases, such as allergic rhinitis, viral rhinitis and asthma. Kinin generation involves release of tissue kallikrein from airway glands, as well as increased vascular permeability and activation of the plasma kallikrein system. The activity of generated kinins is regulated by a number of cell-associated, as well as plasma-derived, peptidases. 2. Kinins can induce relevant symptoms when applied to the surface of human airways. Moreover, the effects of kinins are more pronounced in the setting of chronic inflammation. In the upper airways, kinins can stimulate glandular secretion, increase vascular permeability and stimulate sensory nerves to produce symptoms of nasal obstruction, rhinorrhea, and nasal and throat irritation. In the lower airways of asthmatics, kinins are potent inducers of edema and cause bronchoconstriction by a mechanism that involves, at least in part, neural reflexes. 3. Definitive proof of a role for kinins in human airway diseases has been difficult to obtain because receptor antagonists that have been available to date have suffered from problems of potency or duration of action. Studies are continuing, however, to understand the mechanisms by which kinins exert their effects and to delineate their importance in airway diseases.

Topics: Asthma; Bradykinin; Humans; Kallikreins; Kinins; Rhinitis; Vascular Patency

Icatibant, a bradykinin B(2) receptor antagonist, inhibits the reduction in nasal patency after challenge with house dust mite antigen in sensitive subjects and abolishes the nasal hyperresponsiveness induced by platelet-activating factor in nonatopic subjects.. We sought to investigate the effect of icatibant on the response to nasal antigen challenge in subjects with seasonal allergic rhinitis.. Patients allergic to grass pollen antigen (n = 9-13) were included in a double-blind, randomized-block, placebo-controlled, crossover study outside the pollen season. Subjects first received an intranasal spray of icatibant (200 microg per nostril) or a saline control. Subjects were then challenged with antigen or diluent (control), and their responses were monitored by using acoustic rhinometry. Six hours later, nasal lavage fluid was collected and quantified for inflammatory cells and various inflammatory mediators (kinin, eosinophil cationic protein, IL-5, and IL-8). At 24 hours, the response of the nasal airways to 200 microg of histamine was assessed, and a further nasal lavage was carried out.. Antigen challenge caused a significant increase in nasal obstruction and albumin extravasation, which was not affected by icatibant. Nasal hyperresponsiveness to histamine was present 24 hours after antigen and was abolished by pretreatment with icatibant. Icatibant also reduced the antigen-induced increase in eosinophils, eosinophil cationic protein, kinin, and IL-8 in nasal lavage fluid.. Pretreatment with icatibant does not affect the acute inflammatory response in seasonal allergic rhinitis. However, our results imply the involvement of kinins and the bradykinin B(2) receptor in the development of antigen-induced hyperresponsiveness and the associated eosinophilia in the human nasal airway.

Topics: Adult; Aerosols; Antigens; Bradykinin; Bradykinin Receptor Antagonists; Bronchial Hyperreactivity; Cross-Over Studies; Eosinophilia; Humans; Kinins; Middle Aged; Nasal Cavity; Nasal Provocation Tests; Rhinitis; Rhinitis, Allergic, Seasonal; Time Factors

The present studies were undertaken as a first step to evaluate the potential usefulness of the bradykinin antagonist HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis. Intranasal single-dose administration of HOE-140, at doses up to 500 micrograms, was safe and well tolerated. Bradykinin-induced symptoms and increased vascular permeability could be inhibited, in a dose-dependent manner, by preadministration of HOE-140 5 min prior to kinin challenge. The results of dose-ranging experiments suggested that bradykinin and HOE-140 were approximately equipotent at bradykinin receptors. Preadministration of HOE-140 2 h before kinin challenge caused a significant but much weaker level of inhibition than that seen with 5-min preadministration. Comparison of data with those obtained during dose-ranging studies suggested that more than 90% of the administered HOE-140 was lost during this 2-h period. We conclude that topical HOE-140 is an effective inhibitor of the effects of bradykinin on the nasal mucosa but that the short duration of action of this drug may severely limit the utility of HOE-140 in delineating the role of kinins in the pathogenesis of chronic rhinitis.

Topics: Adolescent; Adult; Bradykinin; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Nasal Mucosa; Nasal Provocation Tests; Rhinitis; Time Factors