EFFECT OF ORAL TERFENADINE ON BRONCHOCONSTRICTOR RESPONSE TO INHALED NEUROKININ-A AND HISTAMINE IN ASTHMATIC SUBJECTS

Neurokinin A (NKA) elicits a potent contractile effect in asthmatic ai rways. Its mechanism of action in bronchial asthma is still unknown. R ecent work supports the view that NKA may stimulate mediator release f rom mast cells. To investigate the relative contribution of mast cell degranulation to the action of NKA, a randomized, double-blind study h as been undertaken, to evaluate the effect of a potent and selective h istamine H-1-receptor antagonist, terfenadine (180 mg q.d., for three days), on bronchoconstriction provoked by inhaled NKA in six asthmatic subjects. Bronchial provocation tests with histamine were included in this study as control challenge. In the subjects studied, oral terfen adine, when compared to placebo, significantly increased the geometric mean (range) provocation dose of inhaled histamine required to reduce forced expiratory volume in one second (FEV1) by 20% of baseline (PD2 0) from 0.05 (0.03-0.08) mg (0.16 (0.10-0.26) mumol) to 1.19 (0.63-2.0 4) mg (3.88 (2.05-6.64) mumol). However, terfenadine failed to increas e the airway responsiveness to NKA in all of the subjects studied, the geometric mean (range) PD15 NKA value being 0.94 (0.47-2.49) mug (8.3 6 (4.14-21.9 nmol) and 0.75 (0.48-1.59) mug (6.62 (4.23-14.0) nmol) af ter placebo and terfenadine, respectively. We conclude that NKA is a p otent bronchoconstrictor agonist in asthma, being approximately 19 tim es more potent than histamine in molar terms. In this study on a small number of subjects, pharmacological intervention with oral terfenadin e failed to achieve significant protection of the airways against the constrictor effect of NKA. Thus, it is unlikely that the bronchoconstr iction provoked by inhaled NKA in asthma is mediated through histamine release from airway mast cells.