icatibant and Asthma

Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Humans; Quinolines; Receptor, Bradykinin B2; Respiratory System; Tissue Kallikreins

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

Bradykinin (BK) has been identified as a mediator in human bronchial asthma. The current phase II study was designed as a multicentered, double blinded, randomized, placebo-controlled, parallel-group pilot study to investigate the efficacy of the B2 BK receptor antagonist Icatibant in adult patients with chronic asthma. Patients were treated t.i.d. with 900 micrograms or 3000 micrograms of nebulized Icatibant, or placebo. Treatment was for 4 weeks, followed by a 2-week placebo run-out. Icatibant was very well tolerated, and led to a dose-dependent improvement in objective pulmonary function tests (PFTs) measured by the investigators (e.g. FEV1 and PEFR). At 3 mg t.i.d., a statistically significant difference (p < 0.001) between Icatibant and placebo of about 10% was achieved after 4 weeks of treatment for all PFTs. At 900 micrograms t.i.d., the improvement in PFTs was smaller. By contrast, no clinically relevant improvement in global symptom score (nor a reduction of rescue medication) was found when compared with placebo. The observed improvement in objective PFTs started between weeks one and two, gradually increased until the end of active treatment, and slowly decreased during the placebo run-out phase, suggesting an anti-inflammatory effect. No acute bronchodilator effect was found. In conclusion, Icatibant showed a profile expected for an anti-inflammatory asthma drug.

Topics: Adult; Asthma; Bradykinin; Bradykinin Receptor Antagonists; Bronchodilator Agents; Double-Blind Method; Drug Tolerance; Humans; Receptor, Bradykinin B2; Respiratory Function Tests

The present study was designed to evaluate the potential role of bradykinin antagonists (R-715; bradykinin B1 receptor antagonist and icatibant; bradykinin B2 receptor antagonist) in treatment of allergic airway inflammation in comparison to dexamethasone and montelukast. R-715 as dexamethasone significantly decreased peribronchial leukocyte infiltration, bronchoalveolar lavage fluid (BALF) albumin and interleukin 1β as well as serum OVA-specific IgE level. Also, R-715 like montelukast significantly decreased BALF cell count (total and eosinophils). Icatibant showed negative results. The current findings suggest that selective bradykinin B1 receptor antagonists may have the therapeutic potential for the treatment of allergic airway inflammation.

Topics: Animals; Asthma; Bradykinin; Bradykinin Receptor Antagonists; Guinea Pigs; Immunoglobulin E; Inflammation; Interleukin-1beta; Lung; Male; Ovalbumin; Receptors, Bradykinin

Airway hyperresponsiveness is a cardinal feature of asthma. Lung C-fiber activation induces central and local defense reflexes that may contribute to airway hyperresponsiveness. Initial studies show that substance P (SP) activates C fibers even though it is produced and released by these same C fibers. SP may induce release of other endogenous mediators. Bradykinin (BK) is an endogenous mediator that activates C fibers. The hypothesis was tested that SP activates C fibers via BK release. Guinea pigs were anesthetized, and C-fiber activity (FA), pulmonary insufflation pressure (PIP), heart rate, and arterial blood pressure were monitored before and after intravenous injection of capsaicin (Cap), SP, and BK. Identical agonist challenges were repeated after infusion of an antagonist cocktail of des-Arg9-[Leu8]-BK (10(-3) M, B1 antagonist), and HOE-140 (10(-4) M, B2 antagonist). After antagonist administration, BK increased neither PIP nor FA. Increases in neither PIP nor FA were attenuated after Cap or SP challenge. In a second series of experiments, Cap and SP were injected before and after infusion of indomethacin (1 mg/kg iv) to determine whether either agent activates C fibers through release of arachidonic acid metabolites. Indomethacin administration decreased the effect of SP challenge on FA but not PIP. The effect of Cap on FA or PIP was not altered by indomethacin. In subsequent experiments, C fibers were activated by prostaglandin E2 and F2alpha. Therefore, exogenously applied SP stimulates an indomethacin-sensitive pathway leading to C-fiber activation.

Topics: Action Potentials; Adrenergic beta-Antagonists; Animals; Asthma; Blood Pressure; Bradykinin; Capsaicin; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Guinea Pigs; Heart Rate; Indomethacin; Lung; Nerve Fibers, Unmyelinated; Prostaglandins; Respiratory Hypersensitivity; Substance P

Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid- induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RL value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p = 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B2 receptor antagonist HOE 140 (0.1 micromol x kg-1, intravenous) and abolished by the tachykinin NK2 receptor antagonist SR 48968 (0.3 micromol x kg-1, intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatment with the NO synthase inhibitor, L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increased in an L-arginine-dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced the L-NMMA-potentiated bronchoconstriction to inhaled citric acid. We conclude that citric acid-induced bronchoconstriction is caused by tachykinin release from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests a possible implication of these mechanisms in asthma associated with gastroesophageal acid reflux and a potential therapeutic role of tachykinin and bradykinin antagonists.

Topics: Administration, Inhalation; Adrenergic beta-Antagonists; Airway Resistance; Animals; Asthma; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Citric Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Piperidines; Receptors, Neurokinin-2

Because bradykinin has potent inflammatory actions, this molecule may be involved in the late allergic response (LAR). We investigated the role of the molecule in airway microvascular hyperpermeability during the LAR. Three weeks after ovalbumin (OVA) sensitization, animals were pretreated with bradykinin B2 receptor antagonist HOE 140 or vehicle for 30 min before the OVA inhalation challenge. The occurrence of LAR was judged by a two-fold increase in transpulmonary pressure (Ptp) from the baseline values. The microvascular permeability in the trachea was assessed by an index defined as the ratio of the area of vasculature labeled by the Monastral blue dye (area density percent). Significant microvascular hyperpermeability were observed during the LAR. The bradykinin concentrations in the bronchoalveolar lavage-fluid (BAL-f) were increased during the LAR. HOE 140 (0.1-10 mg/kg, s.c.) inhibited the airway microvascular hyperpermeability during the LAR dose-dependently. These findings suggest that bradykinin may play an important role in microvascular hyperpermeability during the LAR.

Topics: Animals; Asthma; Bradykinin; Bradykinin Receptor Antagonists; Bronchoalveolar Lavage Fluid; Capillary Permeability; Guinea Pigs; Hypersensitivity; Male; Microcirculation; Ovalbumin; Receptor, Bradykinin B2; Trachea

We examined the mechanisms of bradykinin-induced airway microvascular leakage in guinea pig airways by measuring extravasation of Evans blue dye. Animals were pretreated with propranolol (1 mg/kg, intravenous) and atropine (1 mg/kg, intravenous) to block the beta-adrenergic and muscarinic responses, respectively. Bradykinin (250 nmol) instillation into airways significantly increased the leakage of dye in the trachea, main bronchi, and intrapulmonary airways to the same degree. The bradykinin B2-receptor antagonist HOE140 (500 nmol/kg, intravenous) did not alter basal leakage but almost completely inhibited bradykinin-mediated leakage. By contrast, the neurokinin NK1 antagonist FK888 (10 mg/kg, intravenous) partially inhibited bradykinin-induced leakage in trachea (p < 0.01) and main bronchi (p < 0.01), but had no significant effect on intrapulmonary airways. Indomethacin (5 mg/kg, intravenous) had no effect on the plasma leakage after instilled bradykinin. We concluded that the airway inflammatory response to bradykinin administered directly into the airways is mediated by bradykinin B2 receptors and partially mediated by tachykinin release from sensory nerve terminals, whereas cyclooxygenase products have no important role in the response. In the central airways, the contribution of sensory neuropeptides to the bradykinin response is greater than that caused by direct stimulation of the B2 receptor on the endothelium at the postcapillary venule of the bronchial circulation. In contrast, in the peripheral airways, the contribution of direct B2-receptor stimulation on the airway vasculature is greater than that involving sensory neuropeptides.

Topics: Animals; Asthma; Atropine; Bradykinin; Capillary Permeability; Dipeptides; Evans Blue; Guinea Pigs; Indoles; Indomethacin; Inflammation; Male; Neurons, Afferent; Premedication; Propranolol; Substance P; Tachykinins