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Safety issues
As steroids are used at an earlier stage in therapy and larger inhaled doses are available there are an increasing number of reports about systemic side effects of inhaled steroids. These side effects include easy bruising and skin thinning, reduced bone density,"°biochemical markers of increased bone metabolism and cataracts. It is difficult to evaluate the importance of these changes since the patients have usually also taken courses of oral steroids. It is not yet clear whether sensitive biochemical indices of bone metabolism such as serum osteocalcin indicate a long-term effect on bone structure, however. At daily doses of 800 micron (µ)g or less, systemic effects are uncommon with either beclomethasone diproprionate (BDP) or budesonide. There may also be inter-individual susceptibility to systemic effects. Systemic effects of inhaled steroids arise from the gastrointestinal absorption of the fraction of inhaled steroid which is swallowed after oropharyngeal deposition, and from the fraction absorbed from the lower respiratory tract. Oropharyngeal deposition is reduced by the use of a large volume spacer and therefore systemic effects may be reduced. Mouth washing has a similar (but lesser) beneficial effect. Budesonide is more efficiently degraded by hepatic metabolism than BDP and therefore the fraction absorbed from the gut is less likely to reach the systemic circulation. There is some evidence that at high doses systemic effects of inhaled budesonide are less than those of BDP at high doses, but the appropriate long-term comparative studies in asthmatic patients have not yet been done. There has been particular concern about the effect of inhaled steroids on growth in children. A sensitive measurement of growth may be the length of the lower leg measured by knemometry. With this technique it has been observed that a daily inhaled dose of 800 micron(µ)g budesonide and 400 micron(µ)g BDP have an inhibitory effect, whereas 400 micron(µ)g budesonide does not. This is a very sensitive technique since 2 mg prednisolone orally has an even greater suppressive effect, yet it is known that such a dose of oral steroids does not affect overall height of children. These studies indicate that it is important to use as low a dose of inhaled steroids as possible in controlling asthma, and to minimize systemic effects by using a large volume spacer and by mouth rinsing when high doses are required.
New anti-asthma drugs
Although no new classes of anti-asthma drug have yet reached the clinic, several drugs are in clinical development and there have been improvements in existing classes of drug.
Long-acting inhaled beta2-agonists
Inhaled beta2-agonists with a long duration of action, such as salmeterol and formoterol, which give broncho dilatation and protection against broncho-constriction for over 12 hours have recently been introduced. Clinical trials show that both of these long-acting beta2-agonists are highly effective in controlling chronic asthma, have no significant side effects and (perhaps surprisingly) tolerance does not develop. These drugs are effective in controlling nocturnal symptoms. There is little to suggest that these drugs have any anti-inflammatory effect which is different from short-acting beta-agonists and the protective effect against the late response to allergen and subsequent airway hyper-responsiveness, is likely to be explained by functional antagonism. The exact place of long-acting beta2-agonists in the management of asthma is still not certain, but it is probably wise to administer them only in combination with inhaled steroids.
Selective phosphodiesterase inhibitors
By inhibiting the breakdown of cAMP by phosphodiesterase (PDE), it should be possible to increase intracellular concentrations and thereby relax airway smooth muscle and also potentiate the bronchodilator effect of beta-agonists. It is now recognized that there are several isoenzyme families of PDE and several selective inhibitors have recently been developed. The isoenzymes which are involved in relaxation of airway smooth muscle (types III and IV) make up <5% of the total enzyme activity. Selective inhibitors of these isoenzymes, such as SK&F 94836 which inhibits type III isoenzyme, may therefore be useful as bronchodilators. Evidence now suggests that PDE IV may be important in inflammatory cells suchas mast cells, eosinophils, macrophages and lymphocytes, and that PDE IV inhibitors, such as rolipram and denbufylline, may be useful anti-inflammatory drugs in asthma. Drugs which inhibit both PDE III and PDE IV enzymes, such as AH21-132 (benzafentrine) and zardaverine, may be both bronchodilator and anti-inflammatory, and are therefore of particular interest for future development. The main problem with PDE inhibitors appears to be the profile of side effects. PDE III inhibitors are associated with cardio vascular side effects, whereas the major problem with PDE IV inhibitors is nausea and vomiting.
K+ channel openers
K+ channels play an important role in the recovery of excitable cells after activation and in maintaining cell stability. Opening of K+ channels therefore results in relaxation of smooth muscle and inhibition of secretion. Many different types of K+ channel have now been recognized electrophysiologically and with several selective toxins and drugs. Drugs which selectively activate a K+ channel in smooth muscle, such as BRL 34915 (cromakalim), have been developed for the treatment of hypertension. These drugs inhibit spontaneous and induced tone in airway smooth muscle in vitro and might, therefore, have a role in normalizing 'hyperreactive' airway smooth muscle. K+ channel activators are currently under investigation as potential anti-asthma compounds. The active enantiomer of cromakalim, BRL 38227 (lemakalim), is a relatively effective relaxant of human bronchi in vitro and appears equally active against several spasmogens. In vivo it has no bronchodilator effect or protective effect against bronchoconstrictor challenge at maximally tolerated oral doses, but cromakalim has been shown to have a small protective effect against the fall in lung function at night in asthmatic patients.
Side effects include headache, flushing and postural hypotension, due to vasodilatation. It will therefore be necessary to develop these drugs for inhalational use in order to avoid these effects, although it may be possible to develop K+ channel openers which are more selective for airway than vascular smooth muscle, in view of the diversity of K+ channels. One such airway selective K+ channel opener (BRL55834) has already been described. The future success of these compounds in asthma will probably depend on whether they have any additional effects not shared with, beta-agonists. K+ channel activators inhibit the release of neuro peptides from sensory nervesand modulate neuro transmission in the airways, but whethert hey have effects on inflammatory cells is not certain. Many different types of K+ channel have now been characterized; cromakalim and related drugs appear to open a low affinity ATP-dependent channel (which opens in response to a fall in intracellular ATP concentrations). The K+ channel involved in airway smooth muscle relaxation and neuro modulation of airway nerves is the maxi-K channel, but no openers of this channel have so far been identified.
Mediator antagonists
Many different mediators are implicated in the pathophysiology of asthma and it is therefore some what unlikely that blocking the effects of a single mediator would have a major clinical impact. Anti histamines have minimal effects in asthma and are not useful in therapy, but recently lipid mediators have received more attention. Several potent leukotriene, PAF and thromboxane antagonists have now been developed and are currently undergoing clinical trials in asthma. Initial results appear to suggest that potent leukotriene antagonists, such asMK-571, ICI 204, 219 and SKF 104,353, have a significant protective effect against some constrictor challenges, such as exercise, allergen and aspirin, and long-term clinical trials are now underway, with preliminary encouraging results. Although AFP has several properties which suggest that it may play an important role in asthma, but recent preliminary studies with potent PAF antagonists show no effect on allergen challenge. Similarly thromboxane receptor antagonists have proved disappointing.
Enzyme inhibitors
An alternative to antagonists of mediator receptors are drugs which inhibit the enzymes involved in mediator synthesis. 5-Lipoxygenase (5-LO) is the critical enzyme involved in the generation of leukotrienes.Several drugs have been developed which inhibit 5-LO, although most of these compounds are very weak. Thus zileuton, the most effective of these drugs available for clinical use, has only a trivial inhibitory effect on allergen-induced responses and leukotriene production, although it has proved to be more effective in some other challenges. Zileuton, as most other 5-LO inhibitors, appears to work as a redox inhibitor of the enzyme, but more recently a novel inhibitor MK-886 has been developed, which appears to bind to a 5-LO activating protein (FLAP) in the cell membrane, towhich cytosolic 5-LO must bind in order to be active. There is a theoretical advantage to the use of 5-LO inhibitors compared with leukotriene antagonists since the formation of LT B4 and other 5-LO products, as well as sulphido peptide leukotrienes will also be inhibited.
Inhibitors of neurogenic inflammation
Neuropeptides, which may be released from sensory nerves in airways in asthma via an axon reflex might amplify the inflammatory response. There are several approaches to inhibiting these local reflexes. Antagonists of sensory neuro peptides, such as substance P, neurokinin A and calcitonin gene-related peptide, are currently under development. Most of the inflammatory effects of tachykinins are mediated by NK,-receptors and several selective antagonists have been developed. A potent non-peptide NKI-antagonist, CP96,345, has recently been discovered, which may prove to be a very useful lead compound which avoids all the problems associated with the development of peptide antagonists.' This antagonist is extremely effective in blocking the inflammatory effects of tachykinins released endogenously by nerve stimulation. Another approach is to inhibit the release of these peptides from C fibres than to block their effects, since several peptides are likely to be released from sensory nerves. Opioids markedly inhibit sensory neuropeptide release and have been shown to block neurogenic plasma exudation, mucus secretion and broncho constriction in guinea pigs and neurogenic mucus secretion in human airways. Several other agonists inhibit neuropeptide release, including M2-agonists, gamma-amino-butyric acid, and histamine H3-agonists, which all appear to open a common K+ channel which is blocked by charybdotoxin.
Frusemide
Inhaled frusemide protects against 'indirect' broncho constrictor challenges, such as exercise, fog, allergen, sodium metabisulphite and adenosine, but has no effect against direct broncho constrictor challenges such as histamine, methacholine and PGF 2alpha,. These effects mimic those of sodium cromoglycate but, in addition, inhaled frusemide inhibits certain types of induced cough. The mechanism of action of frusemide in asthma is not certain, but it is ineffective systemically, suggesting that it is acting at the airway surface. Frusemide works as a diuretic by inhibiting the Na+/K+/Cl-cotransporter in renal tubular cells, but the more potent inhibitor bumetanide is ineffective in the same challenges. Some effects of frusemide are mediated by the release of PGE 2, but cyclo-oxygenase inhibition does not abolish the anti-asthma effect. The most likely possibility is that frusemide blocks a certain type of Cl-channel which is necessary for the activation of inflam-matory cells and sensory nerves.
Immunomodulators
T-lymphocytes may play a critical role in initiating and maintaining the inflammatory process in asthma via the release of cytokines. Methotrexate has a steroid-sparing effect in asthma, probably acting as a non-specific immuno suppressive or anti-inflammatory agent. The side effects of methotrexate (particularly nausea and blood dyscrasias) preclude its use in all but the most severe asthmatic patients who have problems with oral steroids.
More specific immunomodulators, such as cyclosporin A, which have an inhibitory effect on T-lymphocyte function, might be more useful in controlling asthma, and there is some evidence that low-dose cyclosporin A improves lung function in steroid-dependent asthmatics. The
nephrotoxicity of cyclosporin A would limit its widespread use but derivatives with less nephrotoxicity are now being developed and the possibility of using inhaled cyclosporin is being explored. Other immunomodulators such as FK 506 and rapamycin appear to be more potent and less toxic.
In the future it may be possible to develop more specific inhibitory drugs. There is particular interest in the development of an inhibitor of IL-5 synthesis or receptor antagonist, since blocking IL-5 with a monoclonal antibody appears to inhibit eosinophil infiltration into the airways completely after allergen exposure. An endogenous IL-1 antagonist (IL-1ra) has recently been cloned, which competes with IL-1 for binding to IL-1 receptors. This antagonist has an inhibitory effect on the hyper responsiveness and leukocyte infiltration following allergen challenge in guinea pigs, suggesting that it may have therapeutic potential in asthma.
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