ABSTRACT-In guinea pigs passively sensitized to ovalbumin, sustained (6 days) subcutaneous infusion of (±)salbutamol (1 mg/kg/day) induced significant airway obstruction and heightened responsivity to airway spasmogens. Of these animals, a substantial proportion (78/235) were too responsive to injected spasmogens to permit infusion of ovalbumin or died following infusion of ovalbumin; yet there were few deaths (2/166) amongst the sensitized animals not exposed to (±)salbutamol.In comparison to the animals not exposed to (± )salbutamol, infusion of ovalbumin led to exaggerated responsivity of the airways to leukotriene C4, leukotriene E4, histamine, serotonin and acetylcholine, but not to prostaglandin F2a or bradykinin. The capacity of sustained exposure to high doses of (±)salbutamol to induce airway hyperreactivity to allergic mediators may account for an association between asthma death and regular, excessive use of sympathomimetics.

The inhalation of cyclosporin (Cs)A to the lung is limited by its hydrophobic properties. In order to improve the poor solubility of CsA, cyclodextrin (CD) was evaluated for its suitability for dry powder inhaler formation, and the benefit of an inhaled CsA/CD complex in vivo was demonstrated.The solubilising effect of CDs on CsA was measured by high-performance liquid chromatography. Ciliostatic activity and haemolysis were determined to assess some safety profiles of CDs. The efficacy of an inhaled CsA/CD complex was evaluated by eosinophil infiltration into the bronchoalveolar lavage fluid in actively sensitised mice.CDs markedly improved the poor solubility of CsA. The ciliostatic and haemolytic activities of maltosyl-a-CD were the weakest of all the tested CDs. CsA inhaled alone showed inhibitory effects on allergen-induced eosinophilia. Inhalation of the complex of CsA with maltosyl-a-CD, where the dose of CsA was approximately nine-times less than that of CsA inhaled alone, also inhibited eosinophil accumulation significantly, with a longer duration of action in comparison with the response to CsA alone.Thus the effective dose of cyclosporin A could be reduced by formation of a complex with maltosyl-a-cyclodextrin, and a wider therapeutic safety margin by inhalation of cyclosporin A as a complex with maltosyl-a-cyclodextrin could be expected. Eur Respir J 2003; 22: 213-219.

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ABSTRACT-In passively sensitized guinea pigs, slow infusion of an amount of ovalbumin insufficient to evoke airway obstruction induces hyperreactivity of the airways. A wide range of changed responsivity was observed for different test spasmogens, with leukotriene C4 > histamine > prostaglandin Fl, > bradykinin > leukotriene E4> serotonin > acetylcholine. Injection of ovalbumin as a bolus produced pronounced airway obstruction without hyperreactivity. Airway obstruction due to vascular engorgement (dextran infusion) or edema (histamine infusion) did not result in hyperreactivity. Infusion of PAF induced pronounced airway obstruction together with hyperreactivity, but with a rank order of histamine>leukotriene C4> serotonin > bradykinin > leukotriene E4 > acetylcholine. It can be concluded that allergic airway hyper reactivity in the guinea pig is spasmogen-selective and largely independent of airway obstruction. These observations question the presumption of non-selective hyperreactivity in allergic asthma and cast doubt upon the proposal that airway hyperreactivity is secondary to airway obstruction.

The airways' pharmacology of DNK333 ((1R,3R,2E)-N-[3,4-dichlorobenzyl)]-4-[(hexahydro-2-oxo-1H-azepin-3-yl)amino]-N-methyl-3,5bis(trifluoromethyl) benzamide), a potent and selective dual NK 1 / NK 2 neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK 1 and NK 2 receptors. In guinea-pig isolated trachea, DNK333 induced concentrationdependent blockade of the contractile responses to NK 1 -or NK 2 -receptor agonists. In anaesthetized guineapigs, DNK333 shifted the bronchoconstrictor dose-response curves induced by NK 1 -and NK 2 -receptor agonists by 21.8-(3 mg/kg) and 6.8-fold (10 mg/kg), respectively. At 10 mg/kg, a 12-h duration of action was observed. Nasal perfusion of substance P and capsaicin to anaesthetized guinea-pigs induced extravasation, which was inhibited dose-dependently by DNK333 (ED 50 values 72 and 70 mg/kg, respectively). Exposure of conscious guinea-pigs to 0.6 M citric acid resulted in cough and an increase in enhanced pause of respiratory function (Penh). Oral administration of DNK333 (0.3, 3, or 10 mg/kg, À2 h) inhibited cough by 62, 63, and 82%, respectively and the increase in Penh by 85.5 and 77.2% (3 and 10 mg/kg, respectively). Bronchoconstrictor responses in anaesthetized guinea-pigs to intravenous injections of methacholine and substance P were increased 60 min after LPS challenge (1 mg/kg, i.v.). DNK333 (1 and 10 mg/kg) dosed intraduodenally 30 min prior to LPS challenge inhibited airway hyperreactivity in a dose-dependent manner.In conclusion, DNK333 is a potent, orally bioavailable, dual NK 1 /NK 2 receptor antagonist with a long duration of action. It inhibits bronchoconstriction, extravasation, cough, and airway hyperreactivity induced by endogenous release of neuropeptides, which renders DNK333 suitable for exploring the role of tachykinins in respiratory disease.