Alternative mechanisms for tiotropium

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Abstract

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Introduction

The long-acting anticholinergic tiotropium is indicated for maintenance treatment for chronic obstructive pulmonary disease (COPD). Clinical trials have consistently shown tiotropium to improve lung function [1], [2], [3], which has been attributed to bronchodilation – considered the orthodox mechanism of action for anticholinergics in COPD. More surprising has been the efficacy of tiotropium in reducing the frequency of exacerbations, which are considered transient inflammatory events. Furthermore, post-hoc analysis of 1-year maintenance treatment data with tiotropium suggested an ability to slow the accelerated decline in forced expiratory volume in 1 second (FEV1) [4] that is associated with COPD. This observation prompted a review of the pharmacologic effects of tiotropium in human biology and, specifically, whether mechanisms other than bronchodilation might account for some of the benefits of treatment with this drug. It also provided the basis for a large 4-year clinical study – the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial [5], [6] – involving approximately 6000 patients, the results of which have now been published, and are summarized below.

This article is a summary of a Boehringer Ingelheim/Pfizer-sponsored round-table discussion held in Chicago, Illinois, USA on 26–27 October 2007 that considered current knowledge on the non-bronchodilator pharmacological mechanisms of tiotropium, their clinical relevance and whether tiotropium is unique in these effects. Inhibition of exacerbations and, in particular, amelioration of progressive loss of lung function are major unmet needs in COPD and the possibility that tiotropium could address these, at least in part, and that novel mechanisms may be responsible, provided the motivation for this review. As clinical evidence for a non-bronchodilator mechanism is sparse, this article first considers the theoretical possibilities suggested from laboratory findings and current clinical experience with this drug.

Section snippets

Function of cholinergic innervation in the lungs – the orthodox mechanism

The innervation of human airways is predominantly by the cholinergic parasympathetic system. This has been well described in previous publications (Fig. 1) [7]. Unlike that of dogs, for example, the sympathetic innervation of the pulmonary system in humans is sparse and this system plays little direct role in regulating airway function. However, since there are sympathetic endings on ganglion cell bodies, the sympathetic system may have a role in modulating cholinergic traffic. Evidence also

Non-neuronal acetylcholine in the airways – a potential unorthodox mechanism

Cholinergic communication and regulation was probably established long before the development of neurons. Acetylcholine as a mediator is present in uni- and multicellular organisms, such as bacteria, algae, protozoa, sponges, primitive plants and fungi [14], [15]. Phylogenetically, the lungs and airways would have been external to the body, similar to the present-day gills of fish or skin of amphibians. Of interest is that the surface secretion of mucin in many marine animals is controlled by

Epithelial cells

The entire respiratory tract is lined by epithelial cells, which are continually exposed to the external environment. In addition to acting as a physicochemical barrier, the epithelium plays a crucial role in initiating and augmenting pulmonary host defence mechanisms [23], [24]. The epithelium is the first site of absorption of inhaled anticholinergics, suggesting that epithelial cells play a role in the pharmacological action of anticholinergic medications. The epithelium can also serve both

Potential effects of tiotropium on airway remodelling

The effect of tiotropium on airway remodelling may be relevant to its hypothesized role in reducing the decline in FEV1 [4]. A number of studies have investigated the potential role that acetylcholine could play in remodelling the airways. ‘Remodelling’ of airways is generally considered to be detrimental to structure and function of the lung. However, this may not be true, since proliferation and fibrosis are normal parts of wound healing. Fibrosis of a collapsing airway may have a stabilizing

The effect of tiotropium on mucus production

Mucus secretion is physiological and contributes to maintaining a hydrated mucosal surface as a first line of defence in the lungs. The mucus barrier assists with the trapping and clearance of inhaled particles and microbes, and has microbicidal properties. In disease, mucus hypersecretion may contribute to airflow obstruction and increase the risk of pulmonary infections, and is associated with troublesome symptoms of cough and expectoration. In such circumstances, reduced mucus secretion

The effect of tiotropium on cough

Acute cough (defined as cough of up to 3 weeks’ duration) is most often caused by a viral upper respiratory tract infection (URI) and is usually transient and self-limited. However, some patients will develop a prolonged postviral cough after resolution of all other symptoms or a URI that is non-responsive to treatment [80]. In spite of very limited evidence of their effectiveness in clinical trials, prescription and non-prescription anti-tussive therapies continue to be widely used [81] and

Clinical perspective of effects of tiotropium on non-neuronal acetylcholine and non-mechanical properties of tiotropium

Overall, no clinical evidence currently exists to demonstrate that tiotropium or any other muscarinic antagonist has either an anti-inflammatory effect or an effect on airway remodelling in asthma or COPD. Similarly, evidence for a clinical effect of tiotropium on mucus clearance and cough is sparse.

There is evidence that patients with lower FEV1 values have a greater degree of inflammation, suggesting that inflammation may increase as disease progresses [49]. The role of endogenous

Summary

Reviewing laboratory studies alone, tiotropium could function in the lung by both mechanical (bronchodilator) and non-mechanical (anti-inflammatory and anti-proliferative) mechanisms (Table 5). These mechanisms could co-exist and could interact.

Bronchodilation could reduce physical stress to the lung and, thereby, reduce the possible resulting damage to epithelium and other cells (e.g. via shearing forces, deformation). In this way, the mechanical effects of tiotropium could also reduce

Acknowledgements

We are grateful to Boehringer Ingelheim GmbH and Pfizer Inc for their support in conceiving and hosting the round table meeting on which this article is based. We acknowledge the writing support of PAREXEL MMS Europe Ltd, which was financed by Boehringer Ingelheim GmbH and Pfizer Incorporated, in editing our individual written contributions into this single article.

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