Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 5-7
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Advances in the Pharmacology of Chronic Obstructive Pulmonary Disease

E. Morcillo

Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive limitation of airflow that is not fully reversible (1). COPD is one of the most common diseases in the world. It is the fourth leading cause of death in developed countries, including Spain, where the Spanish Society for Pneumology and Thoracic Surgery (Sociedad Española de Neumología y Cirugía Torácica [SEPAR]) has declared the year 2002 the year of COPD. COPD is increasing in prevalence and incidence as well as mortality throughout the world. The World Health Organization predicts that by 2020, COPD will rise from its current ranking to the fifth most prevalent disease worldwide and to the third most common cause of death (2).

The progression of the disease causes a large consumption of health care resources. However, in contrast with its importance, research in COPD has been surprisingly neglected, which translates into few advances in therapy. In fact, there are no drugs available at present that halt the relentless progression of this disease (3). As recently stated by Barnes (3): "a better understanding of the cellular and molecular mechanisms that are involved in the underlying inflammatory and destructive processes has revealed several new targets for which new drugs are now in development, and the prospects for finding new treatments are good."

Because cigarette smoking accounts for most cases of COPD, antismoking measures including nicotine-replacement therapy and new drugs for smoking cessation are important aspects of the management of COPD. However, the focus of the present review will be limited to the advances in the pharmacology of bronchodilation and inflammation in COPD. A number of excellent reviews have been recently published (3-6).

NEW BRONCHODILATORS

Bronchodilators continue to be the mainstay of current COPD management, with anticholinergics being the bronchodilators of choice. The major advances in this section are the development of long-acting anticholinergics and selective M₃ antimuscarinic inhaled agents. Tiotropium bromide is a new long-acting anticholinergic drug with a kinetic selectivity based on a very slow dissociation from M₁ and M₃ muscarinic receptors, which is as effective by inhalation once daily as ipratropium bromide taken four times a day (7). As the balance between the results of the blockade of pre and postjunctional M₂ muscarinic receptors in human airways is not clear (8), the clinical position of a purely selective blocker of M₃ muscarinic receptors is yet to be defined.

INFLAMMATORY-MEDIATOR ANTAGONISTS

Chronic airway inflammation is very significant in COPD, yet markedly different from that observed in asthma. Thus, in contrast to the eosinophilic inflammation of asthma, COPD is characterized by a neutrophilic inflammation in which chemoattractants, such as leukotriene B₄ (LTB₄) and the CXC chemokine IL-8, appear relevant. A number of LTB₄-receptor antagonists have been developed, although there are none currently in the clinics. Alternatively, inhibitors of 5'-lipooxygenase (zileuton and others) may serve the same purpose. Blocking antibodies to IL-8, blockers of CXC receptors, as well as antagonists of CC chemokine receptor 2 (CCR2) are now in development.

Tumor necrosis factor-a (TNF-a) levels are increased in COPD, and this mediator may be involved in the skeletal muscle wasting of these patients. Humanized monoclonal TNF-a antibodies (infliximab) and soluble TNF-a receptors (etanercept) that are effective in other chronic inflammatory diseases should also be effective in COPD. In addition, inhibitors of the
TNF-a converting enzyme (TACE), which is required for the release of soluble TNF-a, are in development.

Prostanoid inhibitors such as COX-2 inhibitors, thromboxane antagonists and isoprostane receptor
antagonists are also potentially useful drugs for COPD.

ANTIOXIDANTS

Oxidative stress appears to be very important in the pathophysiology of COPD, including in acute exacerbations (9). Therefore, antioxidants could potentially play a therapeutic role (10). The mucolytic N-acetylcysteine is the most widely investigated drug with antioxidant properties to be used in experimental and clinical settings relevant to COPD (9). A meta-analyis indicated that oral acetylcysteine significantly reduced the frequency of exacerbations (11) and may have a role in the management of COPD (9). Recent experimental research has demonstrated the protective effect of this thiol compound (12), as well as new activities including the ability to block NF-kB activation and the expression of cell adhesion molecules, which may be the basis of its clinical activity in this disease (13, 14). Other antioxidants such as stable glutathione compounds, selenium-based drugs and spin-trap antioxidants are being studied.

Nitrosative stress resulting from augmented expression of iNOS and peroxynitrite is manifested in COPD, and selective inhibitors of iNOS are now in development.

NEW ANTIINFLAMMATORY DRUGS FOR COPD

Contrary to efficacy in asthma, the disappointing lack of effect of corticosteroids in COPD points towards the need for novel, broad spectrum, nonsteroidal antiinflammatory drugs in this disease. Of the different options which are being explored, the phosphodiesterase (PDE) 4 inhibitors are probably the most advanced. Other targets are NF-kB inhibitors (proteasome inhibitors, IkB kinase inhibitors, IkB-a gene transfer), adhesion molecule inhibitors (antiCD11/CD18, antiICAM-1, E-selectin inhibitors), p38 MAP kinase inhibitors, PI3K-g inhibitors, and antiinflammatory cytokines (recombinant human IL-10 is currently in clinical trials for other chronic inflammatory diseases).

Phosphodiesterase 4 inhibitors

Because PDE 4 is the predominat PDE expressed in neutrophils, CD8⁺ cells and macrophages, the selective inhibitors of this isoenzyme appear very attractive as candidates for the treatment of COPD (4). PDE4 is also present in human airways and PDE 4 inhibitors relax human isolated bronchus (15). PDE 4 inhibitors depress functional responses of human neutrophils and other inflammatory cells (16), inhibit airway microvascular leakage and reduce the entry of inflammatory cells (17). Second-generation PDE 4 inhibitors such as cilomilast and roflumilast are in phase III clinical trials for COPD.

PROTEASE INHIBITORS

There is an imbalance in COPD between the proteases released from neutrophils and macrophages. This causes tissue damage, inflammation and protective endogenous antiproteases. The corresponding strategies are the inhibition of these proteases and/or the enhancement of the antiproteases. Small-molecule inhibitors of proteases such as neutrophil elastase seems to be a promising approach, as do the inhibitors of matrix metalloproteinases MMP-9 and MMP-12, and the inhibitors of macrophage-derived cathepsins K, S and L. Another alternative, perhaps less promising, is to give endogenous antiproteases such as a₁-antitrypsin either secretory leukoprotease inhibitor, elastase-specific inhibitor or tissue inhibitor of MMPs.

IMMUNOMODULATORS

COPD is frequently associated with several immune disturbances, yet the pathogenic relevance is unclear. The argument for the use of immunostimulant and immunomodulators in COPD is supported by clinical evidence of reduced recurrence rates of acute respiratory infections (18). A recent study showed that treatment with glycophosphopeptical (Inmunoferon) stimulated peripheral blood natural-killer cytotoxic activity and increased the phagocytic indices of monocytes and polymorphonuclear leukocytes (19). Thus, the use of immunomodulators may offer a great advantage in the successful management of COPD.

In conclusion, although antismoking measures are essential, their success is variable and inflammation may continue after smoking cessation. Therefore, new antiCOPD drugs are necessary. Identification of predisposing genes and proteins by high-density DNA arrays and proteomics, respectively, may unveil novel therapeutic targets in COPD.

ACKNOWLEDGMENTS

Work in the references of our research group quoted in this presentation was supported by grants from the Regional Development Funds (FEDER), CICYT and FIS (Spanish Government), and the Regional Government (Generalitat Valenciana).

REFERENCES

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Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 5-7
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com