British Medical Bulletin (1991) Vol. 48, No. 1, pp. 231-247 © The British Council 1992
P J Barnes Department of Thoracic Medicine, National Heart and Lung Institute, London, UK
New therapeutic approaches to asthma involve either improvements in existing classes of drug, or the development of novel drugs. Over the last 20 years there have been no new types of drug introduced, although several new classes of compound are now under development. Improvements in existing bronchodilators include long-acting inhaled p2-agonists, methyl xanthines with a reduced side effect profile and M3-selective anticholinergics. New bronchodilators include K+ channel activators and selective phosphodiesterase inhibitors. Corticosteroids are the most effective anti-inflammatory drugs and there are attempts to develop inhaled steroids with greater topical potency or increased systemic metabolism, or to develop drugs which retain the antiinflammatory effects of steroids without side effects. Steroids are probably effective in asthma by inhibiting the synthesis of cytokines and drugs which inhibit cytokine synthesis or receptors are now being sought. Inhibitors of mediator synthesis and receptors currently under development and leukotriene D4-antagonists are promising. Immunomodulatory drugs such as methotrexate, cyclosporin A and gold may be useful in more severe asthma, but drugs which modulate the immune abberation of asthma more specifically may be of more widespread use in the future. There is no immediate prospect of a cure for asthma and a drug which may be taken orally once daily and has no side effects would be ideal.
There are several indications that the severity and mortality of asthma may be increasing, despite greater use of antiasthma therapy. This raises the possibility that current therapy may not be
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
New therapeutic approaches
232
ASTHMA
NEW BRONCHODILATORS Bronchodilators are presumed to act by reversing contraction of airway smooth muscle, although some may have additional effects on mucosal oedema or inflammatory cells. The biochemical basis of airway smooth muscle relaxation has been studied extensively, yet few new classes of bronchodilator have had any clinical impact. The molecular basis of bronchodilation may involve an increase in intracellular cyclic AMP and a reduction in cytosolic calcium ion concentration ([Ca2 + ]), and both may be amenable to pharmacological manipulation. p2-Agonists (32-Agonists remain the most widely used and effective bronchodilators in clinical practice (see Tattersfield, this issue). This is because they act as functional antagonists and reverse airway smooth muscle contraction irrespective of the spasmogen. They are equally effective on large and small airways, and may have effects on cells other than airway smooth muscle, such as mast cells, to prevent mediator release, or microvascular leak, on cholinergic neurotransmission and on release of epithelial factors. Many selective P2-agonists are now available and there has been a search for |3-agonists which have even greater selectivity for P2receptors. However it is unlikely that any greater selectivity would be an advantage clinically, since a high degree of functional p 2 selectively is obtained using the inhaled route. Furthermore, many of the side-effects of P-agonists (tremor, tachycardia, hypokalae-
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
optimal, yet there have been no new types of drug introduced for asthma therapy over the last 20 years. It is important to understand more about the mechanisms of asthma and also how the currently used drugs work before rational improvements in therapy can be expected. Advances in smooth muscle and receptor pharmacology have opened the way to the development of new classes of bronchodilator, and the further understanding of inflammatory mechanisms in asthma has encouraged exploration of new mediator antagonists, anti-inflammatory and immunomodulatory drugs. Advances in delivery systems are also important for inhaled drugs. There are two main approaches to the development of new antiasthma treatments—either improvement in an existing class of effective drug, or development of novel compounds.
NEW THERAPEUTIC APPROACHES
233
Drugs which increase cyclic AMP Further understanding of the molecular mechanism of P-agonists has prompted a search for other drugs which might increase intracellular cyclic AMP concentrations in airway smooth muscle (Fig. 1). Of course such drugs might also be effective in inhibiting the activation and secretion of inflammatory cells. Several other receptors on airway smooth muscle, other than P-receptors, may activate adenylyl cyclase via a stimulatory G-protein (Gs).
Vasoactive intestinal peptide ( VIP) VIP is a potent relaxant of human bronchi in vitro,5 yet it has no action in asthmatic subjects, when given by inhalation,6 probably because of problems with diffusion and degradation by airway enzymes, such as mast cell derived tryptase. When given by infusion the cardiovascular effects preclude the giving of a dose which causes bronchodilatation.7
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
mia) are mediated via P2-receptors. The most important recent advance has been the introduction of inhaled P2-agonists with a long duration of action, such as salmeterol and formoterol, which give bronchodilation and protection against bronchoconstriction for over 12 h.1 They are highly effective in preventing nocturnal asthma and in controlling 'brittle' asthma. Clinical trials show that both of these long-acting P2-agonists a r e highly effective in controlling chronic asthma, have no significant side-effects and (perhaps surprisingly) tachyphylaxis (tolerance) does not develop.2 It is difficult to imagine that any future drug could be more effective than a P2-agonist a s a bronchodilator, but doubts have recently been expressed about the role of inhaled P-agonists in the control of asthma. Regular use of inhaled P-agonists appears to give worse control of asthma than the use of P-agonists 'as required' for symptom control.3 It is probable that P-agonists do not have a significant anti-inflammatory effect on the chronic inflammatory component of asthma. It has even been suggested that their mast cell stabilising action may be deleterious by inhibiting the release of heparin, which would counteract the effects of eosinophil basic proteins.4
234
ASTHMA
CHOLERA TOXIN |
O CTP
PDE
AMP«-
cyclic AMP
ATP
PDE INHIBITOR]
Protein kinase
Myosin light chain kinase
llntracellular [Ca ++ ]
RELAXATION Fig. 1 Mechanisms of bronchodilation. Interaction with surface receptors (e.g. (3-adrenergic, VIP, PGE receptors) results in activation of adenylyl cyclase (AC) via a stimulatory G-protein (Gs), leading to a rise in intracellular cyclic AMP. The concentration of intracellular cyclic AMP may be increased by several mechanisms, including inhibition of phosphodiesterases (PDE) which break down cyclic AMP.
Prostaglandins of the E-series
These are also able to stimulate adenylyl cyclase, yet have not proved to be very effective as bronchodilators, and may even lead to constriction and coughing in asthmatics since they also stimulate sensory receptors in airways.8 Receptor-mediated stimulation of adenylyl cyclase involves activation of Gs, which may be stimulated irreversibly by cholera toxin. Less toxic compounds which stimulate Gs are under investigation. Forskolin directly activates the catalytic subunit of
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
Beta-agonist VIP PCE
NEW THERAPEUTIC APPROACHES
235
Selective phosphodiesterase inhibitors By inhibiting the breakdown of cyclic AMP by phosphodiesterase (PDE), it should be possible to increase intracellular concentrations and thereby relax airway smooth muscle and also potentiate the bronchodilator effect of P-agonists. It is now recognised that there are several isozymes of PDE and several selective inhibitors have recently been developed.9'10 The isoenzymes most important in relaxation of airway smooth muscle is type III which make up
P J Barnes Department of Thoracic Medicine, National Heart and Lung Institute, London, UK
New therapeutic approaches to asthma involve either improvements in existing classes of drug, or the development of novel drugs. Over the last 20 years there have been no new types of drug introduced, although several new classes of compound are now under development. Improvements in existing bronchodilators include long-acting inhaled p2-agonists, methyl xanthines with a reduced side effect profile and M3-selective anticholinergics. New bronchodilators include K+ channel activators and selective phosphodiesterase inhibitors. Corticosteroids are the most effective anti-inflammatory drugs and there are attempts to develop inhaled steroids with greater topical potency or increased systemic metabolism, or to develop drugs which retain the antiinflammatory effects of steroids without side effects. Steroids are probably effective in asthma by inhibiting the synthesis of cytokines and drugs which inhibit cytokine synthesis or receptors are now being sought. Inhibitors of mediator synthesis and receptors currently under development and leukotriene D4-antagonists are promising. Immunomodulatory drugs such as methotrexate, cyclosporin A and gold may be useful in more severe asthma, but drugs which modulate the immune abberation of asthma more specifically may be of more widespread use in the future. There is no immediate prospect of a cure for asthma and a drug which may be taken orally once daily and has no side effects would be ideal.
There are several indications that the severity and mortality of asthma may be increasing, despite greater use of antiasthma therapy. This raises the possibility that current therapy may not be
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
New therapeutic approaches
232
ASTHMA
NEW BRONCHODILATORS Bronchodilators are presumed to act by reversing contraction of airway smooth muscle, although some may have additional effects on mucosal oedema or inflammatory cells. The biochemical basis of airway smooth muscle relaxation has been studied extensively, yet few new classes of bronchodilator have had any clinical impact. The molecular basis of bronchodilation may involve an increase in intracellular cyclic AMP and a reduction in cytosolic calcium ion concentration ([Ca2 + ]), and both may be amenable to pharmacological manipulation. p2-Agonists (32-Agonists remain the most widely used and effective bronchodilators in clinical practice (see Tattersfield, this issue). This is because they act as functional antagonists and reverse airway smooth muscle contraction irrespective of the spasmogen. They are equally effective on large and small airways, and may have effects on cells other than airway smooth muscle, such as mast cells, to prevent mediator release, or microvascular leak, on cholinergic neurotransmission and on release of epithelial factors. Many selective P2-agonists are now available and there has been a search for |3-agonists which have even greater selectivity for P2receptors. However it is unlikely that any greater selectivity would be an advantage clinically, since a high degree of functional p 2 selectively is obtained using the inhaled route. Furthermore, many of the side-effects of P-agonists (tremor, tachycardia, hypokalae-
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
optimal, yet there have been no new types of drug introduced for asthma therapy over the last 20 years. It is important to understand more about the mechanisms of asthma and also how the currently used drugs work before rational improvements in therapy can be expected. Advances in smooth muscle and receptor pharmacology have opened the way to the development of new classes of bronchodilator, and the further understanding of inflammatory mechanisms in asthma has encouraged exploration of new mediator antagonists, anti-inflammatory and immunomodulatory drugs. Advances in delivery systems are also important for inhaled drugs. There are two main approaches to the development of new antiasthma treatments—either improvement in an existing class of effective drug, or development of novel compounds.
NEW THERAPEUTIC APPROACHES
233
Drugs which increase cyclic AMP Further understanding of the molecular mechanism of P-agonists has prompted a search for other drugs which might increase intracellular cyclic AMP concentrations in airway smooth muscle (Fig. 1). Of course such drugs might also be effective in inhibiting the activation and secretion of inflammatory cells. Several other receptors on airway smooth muscle, other than P-receptors, may activate adenylyl cyclase via a stimulatory G-protein (Gs).
Vasoactive intestinal peptide ( VIP) VIP is a potent relaxant of human bronchi in vitro,5 yet it has no action in asthmatic subjects, when given by inhalation,6 probably because of problems with diffusion and degradation by airway enzymes, such as mast cell derived tryptase. When given by infusion the cardiovascular effects preclude the giving of a dose which causes bronchodilatation.7
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
mia) are mediated via P2-receptors. The most important recent advance has been the introduction of inhaled P2-agonists with a long duration of action, such as salmeterol and formoterol, which give bronchodilation and protection against bronchoconstriction for over 12 h.1 They are highly effective in preventing nocturnal asthma and in controlling 'brittle' asthma. Clinical trials show that both of these long-acting P2-agonists a r e highly effective in controlling chronic asthma, have no significant side-effects and (perhaps surprisingly) tachyphylaxis (tolerance) does not develop.2 It is difficult to imagine that any future drug could be more effective than a P2-agonist a s a bronchodilator, but doubts have recently been expressed about the role of inhaled P-agonists in the control of asthma. Regular use of inhaled P-agonists appears to give worse control of asthma than the use of P-agonists 'as required' for symptom control.3 It is probable that P-agonists do not have a significant anti-inflammatory effect on the chronic inflammatory component of asthma. It has even been suggested that their mast cell stabilising action may be deleterious by inhibiting the release of heparin, which would counteract the effects of eosinophil basic proteins.4
234
ASTHMA
CHOLERA TOXIN |
O CTP
PDE
AMP«-
cyclic AMP
ATP
PDE INHIBITOR]
Protein kinase
Myosin light chain kinase
llntracellular [Ca ++ ]
RELAXATION Fig. 1 Mechanisms of bronchodilation. Interaction with surface receptors (e.g. (3-adrenergic, VIP, PGE receptors) results in activation of adenylyl cyclase (AC) via a stimulatory G-protein (Gs), leading to a rise in intracellular cyclic AMP. The concentration of intracellular cyclic AMP may be increased by several mechanisms, including inhibition of phosphodiesterases (PDE) which break down cyclic AMP.
Prostaglandins of the E-series
These are also able to stimulate adenylyl cyclase, yet have not proved to be very effective as bronchodilators, and may even lead to constriction and coughing in asthmatics since they also stimulate sensory receptors in airways.8 Receptor-mediated stimulation of adenylyl cyclase involves activation of Gs, which may be stimulated irreversibly by cholera toxin. Less toxic compounds which stimulate Gs are under investigation. Forskolin directly activates the catalytic subunit of
Downloaded from https://academic.oup.com/bmb/article-abstract/48/1/231/337719 by university of winnipeg user on 17 January 2019
Beta-agonist VIP PCE
NEW THERAPEUTIC APPROACHES
235
Selective phosphodiesterase inhibitors By inhibiting the breakdown of cyclic AMP by phosphodiesterase (PDE), it should be possible to increase intracellular concentrations and thereby relax airway smooth muscle and also potentiate the bronchodilator effect of P-agonists. It is now recognised that there are several isozymes of PDE and several selective inhibitors have recently been developed.9'10 The isoenzymes most important in relaxation of airway smooth muscle is type III which make up
