Positive interaction of the novel β₂-agonist carmoterol and tiotropium bromide in the control of airway changes induced by different challenges in guinea-pigs

Abstract

This study evaluated the bronchodilating activity of the β₂-agonist carmoterol and the muscarinic M₃-antagonist tiotropium, given intratracheally alone or in combination in anaesthetized artificially ventilated normal and actively sensitized guinea-pigs. Carmoterol (0.3–100 pmol) and tiotropium (10–1000 pmol) were superfused (0.01 ml/min) for 5 min before challenges with acetylcholine (20 μg/kg i.v.), histamine (10 μg/kg i.v.) or ovalbumin (5 mg/kg i.v.).

Both compounds given alone were markedly active against all the challenges. Tiotropium resulted more effective towards cholinergic challenge and carmoterol was very potent against histamine and ovalbumin-induced reaction, being effective already at 1 pmol. In the presence of tiotropium, the bronchodilating activity of carmoterol was significantly augmented. The ED₅₀ value of carmoterol on the acetylcholine challenge was reduced by about 10 and 28 times (0.1 and 0.3 pmol of tiotropium), that on the histamine one by 4.5 and 13 times (1 and 3 pmol of tiotropium) and that on the ovalbumin-induced one by 8 and 25 times (10 and 30 pmol of tiotropium).

A positive interaction was also evident when other parameters were evaluated. The histamine-induced release of thromboxane B₂ was markedly reduced (56%, $P<0.001$) by combining completely ineffective doses of the two drugs (0.3 and 3 pmol for carmoterol and tiotropium, respectively). In ovalbumin-challenged animals the time to death, amounting in control animals to 7.2±0.9 min, was dose-dependently prolonged up to achieve complete protection from death with combination of 1 and 30 pmol of carmoterol and tiotropium, respectively.

The favorable interaction between carmoterol and tiotropium can represent a good option in the control of bronchopulmonary diseases marked by an increase of airway resistances.

Introduction

The combination of more than one class of inhaled bronchodilators in a single metered dose inhaler has been employing for many years to halt the decline in lung function in obstructive airways diseases. The combined formulation of short-acting anticholinergic agents such as ipratropium with short-acting β-agonists such as fenoterol has been widely used since the 1970s with many advantages including patient compliance.

Tiotropium bromide (thereafter tiotropium) is a new once-a-day anticholinergic drug, recently introduced for the treatment of chronic obstructive pulmonary disease (COPD). It has unique kinetic selectivity for M₁ and M₃ muscarinic receptors, as it dissociates slowly from M₁ and M₃ receptors but rapidly from M₂ receptors, producing long-term blockade of cholinergic neural bronchoconstriction in airway smooth muscle [1], [2].

There is increasing evidence that long-acting β₂-adrenergic receptor agonists, such as salmeterol or formoterol, may represent the most effective option for combined treatment with tiotropium [3] in patients with stable COPD and asthma, but the once-daily administration of these combinations is inadvisable due to the different pharmacokinetic profile of the drugs. Actually, formoterol and salmeterol are given on a twice daily regimen, while tiotropium is required once daily.

Carmoterol (8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(p-methoxyphenyl)-1-methylethyl]amino]ethyl] carbostiryl hydrochloride, previously named TA-2005 and CHF 4226.01) is a new long-acting β₂-agonist under clinical development for the once-daily treatment of asthma and COPD. It is very potent and, as indicated by competition and binding experiments, it can form a very stable ternary complex with the β₂-receptor [4], [5]. In animal models of asthma, carmoterol was significantly more potent and long-lasting than formoterol in preventing decline in lung function [6], [7]. Thus, carmoterol seems to possess pharmacodynamic features suitable for once daily contemporaneous administration with new long acting antimuscarinic agents in patients suffering from diseases characterized by an increased lung resistance.

Cell signaling through muscarinic M₃ receptors in airway smooth muscle cells is well detailed at a molecular level, and is distinct to those of β₂-adrenoceptor agonists [8], [9]. Thus, there is potential for the two drugs to combine additively.

The aim of the present paper was to characterize the functional impact of adding carmoterol to tiotropium in animal models of airway obstruction. In particular, we investigated the potential for the two drugs to exert additive or supra-additive interactions against bronchoconstriction induced by different challenges, i.e. acetylcholine and histamine in normal guinea-pigs and ovalbumin in actively sensitized animals.