men-11420 and Asthma

Menarini Richerche is developing nepadutant, an NK2 antagonist, for the potential treatment of asthma and irritable bowel syndrome. The compound is in phase IIa trials in Belgium and Sweden for both these indications [359518].

Topics: Animals; Asthma; Bronchodilator Agents; Colonic Diseases, Functional; Humans; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Structure-Activity Relationship

We previously reported that the nonpeptide tachykinin NK(2) receptor antagonist SR48968 (saredutant) significantly inhibits neurokinin A-induced bronchoconstriction in patients with asthma. MEN11420 (nepadutant) is a bicyclic peptide tachykinin NK(2) receptor antagonist. The aim of the trial was to examine the effect of nepadutant on neurokinin A-induced bronchoconstriction in man.. 12 patients with stable, mild to moderate asthma participated in a double-blind, placebo-controlled crossover trial and received, with intervals of 1 week, MEN11420 2 mg, MEN11420 8 mg and placebo (i.v.). Increasing concentrations of NKA (10(-9) to 10(-6) moles/ml) were inhaled immediately after (d1) and 24 hours after (d2) administration of treatment.. On d1 both MEN11420 2 and 8 mg shifted the dose response curve for neurokinin A to the right (log PC(20) FEV(1) neurokinin A [moles/ml]; mean + or = or - SEM -6.38 + or - 0.26 after 2 mg, -6.11 + or - 0.23 after 8 mg, versus -6.95 + or - 0.27 after placebo]. On d2 MEN11420 had no effect on neurokinin A-induced bronchoconstriction.. In conclusion, the tachykinin NK(2) receptor antagonist nepadutant significantly inhibits bronchoconstriction induced by neurokinin A in patients with asthma.

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin A; Peptides, Cyclic; Receptors, Neurokinin-2; Respiratory Function Tests; Young Adult

The effects of the tachykinin NK(2)receptor antagonist, MEN 11420 (300 nmol/kg) and the bradykinin B(2)receptor antagonist, CP 0597 (17.2 and 172 nmol/kg) were studied in a rabbit model of antigen-induced airway responses. Antigen inhalation induced acute bronchoconstriction, airway hyperresponsiveness to histamine, and pulmonary eosinophil infiltration in 3-month-old rabbits immunized with Alternaria tenuis antigen within 24 h of birth. Treatment with MEN 11420 significantly reduced the acute bronchoconstriction induced by antigen, in terms of lung resistance. Antigen-induced changes in dynamic compliance were unaffected. CP 0597 had no effect on antigen-induced changes in lung function. Neither MEN 11420 nor CP 0597 had a significant effect on the antigen-induced increase in airway responsiveness to inhaled histamine or the pulmonary eosinophil infiltration 24 h after antigen challenge. We conclude that blockade of the NK(2)receptor can alter acute airway responses to antigen, but not antigen-induced eosinophilia or hyperresponsiveness to histamine. We also conclude that bradykinin B(2)receptor-mediated responses do not play a role in airway responses to antigen.

Topics: Administration, Inhalation; Airway Resistance; Animals; Asthma; Bradykinin Receptor Antagonists; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage; Bronchodilator Agents; Disease Models, Animal; Female; Intradermal Tests; Male; Oligopeptides; Peptides, Cyclic; Rabbits; Receptors, Tachykinin