Eur Resplr J

1992, 5, 1126-1136 REVIEW

New drugs for asthma

P.J. Barnes

New drugs for asthma. P.J. Barnes. Correspondence: P.J. Barnes

ABSTRACT: Several new drugs are now under development for the treatment Dept of Thoracic Medicine, National
of asthma, either as improvements to existing classes of therapy or as novel Heart and Lung Institute, Dovehouse St,
London SW3 6LY, UK
agent.s.
Amongst bronehodilators, long-acting Inhaled ~ 1 -agonlsts (salmeterol and Keywords: ~-agonists, corticosteroids,
formoterol) look very promising and there is also interest in selective phosphodi· cromoglycate, cyclosporin A, frusemide,
esterase inhibitors, K• channel-openers and nltrodilators. immunomodulators, leukotriene antago-
There are several new inhaled corticosteroids under development and more nists, 5-lipoxygenase inhibitors, nedo-
selective agents include leukotriene antagonists, 5-lipoxygenase Inhibitors, brady- cromil sodium, phosphodiesterase
kinin and tachykinln antagonists and immunomodulators. inhibitors, phospholipase A 2, potassium
channel-openers, tachykinin antagonists.
In the future, adhesion molecule inhibitors and cytokine inhibitors may be
developed. Received: April 8 1992
Eur Respir J., 1992, 5, 1126-1136. Accepted after revision July 25 1992

There is evidence for increased morbidity and mor-
tality from asthma, despite an increase in the amount
of treatment prescribed. This suggests that currently
available therapy may be contributing to these statis-
tics, or that it is not being used optimally. Despite
considerable efforts by the pharmaceutical industry,
there have been no new classes of drug introduced for
asthma therapy over the last 20 yrs. It is clearly im-
portant to understand more about the underlying
mechanisms of asthma and also about how the cur-
rently used drugs work before rational improvements
in therapy can be expected. Advances in smooth mus-
cle and receptor pharmacology have opened the way
to the development of new classes of bronchodilator,
and the further understanding of inflammatory mecha-
nisms in asthma has encouraged exploration of new
mediator antagonists, anti-inflammatory and immuno-
modulatory drugs. Advances in delivery systems are
also important for inhaled drugs.
There are two main approaches to the development
of new anti-asthma treatments: improvement in an ex-
isting class of effective drug; or development of novel
compounds, based either on rational developments (e.g.
mediator antagonists) or from chance observations (e.g.
frusemide).
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.
However, no new types of bronchodilator have had
any clinical impact. The molecular basis of
bronchodHatation involves an increase in intracellular
cyclic adenosine 3'5' monophosphate (cAMP) and a
reduction in cytosolic calcium ion concentration
([Ca++]). Recent studies suggest that the rise in cAMP
is linked to the opening of Ca++-activated K• channels
(maxi-K channels) in animal and human airway
smooth muscle [1, 2). However, ~-agonists may open
maxi-K channels via a direct G-protein coupling to the
channel, and this may occur at low concentrations of
/3-agonist that do not involve any increase in cAMP
concentration [3]. The molecular mechanisms under-
lying bronchodilatation may be exploited in the devel-
opment of new bronchodilators, several of which are
under development (table 1).
Table 1. - New Bronchodilators
Existing
~ 2-agonists: long-acting (salmeterol, formoterol)
Methylxanthines: less side-effects (enprofylline)
Anticholinergics: more selective (M3-antagonists)
Novel
VIP/VIP analogues
Selective phosphodiesterase (type III, IV, V) inhibitors
K• channel openers
Nitrodilators (nitroprusside, ANP)
VIP: vasoactive intestinal peptide; ANP: atrial natriuretic
peptide.
{32 -agorzists
/3 2-agonists remain the most widely used and effec-
tive bronchodilators in clinical practice. They act as
functi onal 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; also, on microvascular leak and
 NEW DRUGS FOR AS'rnMA
cholinergic neurotransmission [4). Many selective B2 -
agonists are now available and there has been a search
for ~ - agonists which have even greater selectivity for
1}2-receptors. However, it is unlikely that any greater
selectivity would be an advantage clinically, since,
when the drugs are given by inhalation a high degree
of functional ~2 -receptor selectivity is obtained. Fur-
thermore, many of the side-effects of ~-agonists
(tremor, tachycardia, hypokalaemia) are mediated via
B2-receptors.
Long-acting {32 -agonists. The most important recent
advance has been the introduction of inhaled 132-
agonists with a long duration of action, such as
salmeterol and formoterol, that give bronchodilatation
and protection against bronchoconstriction for over 12
h [5]. Clinical trials show that both of these long-
acting B2 -agonists are highly effective in controlling
chronic asthma and have no significant side-effects.
Perhaps surprisingly, tolerance does not appear to
develop to their bronchodilator action [6, 7], although
there is some evidence for tolerance to their protec-
tive action against constrictor challenge [8).
It is difficult to imagine that any future drug could
be more effective than a 132-agonist as a bronchodilator,
but doubts have recently been expressed about
the role of inhaled B-agonists in the control of asthma
[9]. Regular use of inhaled B-agonists appears to give
worse control of asthma than the use of f3-agonists
"on demand" for symptom control [10], and excessive
use of inhaled 13-agonists has been linked to asthma
mortality [11]. It is probable that whilst 13-agonists
may control the acute inflammatory response, they do
not have an effect on the chronic inflammatory
component of asthma [9). Indeed, the protective
effect of 132-agonists against acute inflammation ap-
pears to desensitize after regular therapy [12). This
suggests that anti-inflammatory treatments should al-
ways be administered when f}-agonists are used regu-
larly or excessively. For long-acting inhaled 132-
agonists it was suggested that there may be additional
anti-inflammatory effects, as evidenced by the protec-
tion against the late response to allergen and the
ensuing increase in airway responsiveness [13], but
this is probably explained by prolonged functional
antagonism, and there is no evidence that either regu-
lar short-acting 13-agonists [14 ], or salmeterol [15),
have any effect on airway inflammation assessed
by bronchial biopsy. This suggests that long-acting
inhaled 132-agonists should always be used with inhaled
anti-inflammatory therapy and should be considered
as an additional bronchodilator when asthma
is not controlled on doses of inhaled steroids of
about 1 mg daily. A combination inhaler with an
inhaled steroid would be the most sensible develop-
ment.
Drugs which increase cAMP
Understanding the molecular mechanism of f3-
agonists has prompted a search for other drugs which
1127
increase intracellular cAMP concentrations in airway
smooth muscle cells. Several receptors on airway
smooth muscle, other than P-receptors, may activate
adenylate cyclase via a stimulatory 0-protein (G.).
Vasoactive intestinal peptide (VIP). VIP is a potent
relaxant of human bronchi in vitro [16). .However, it
has no bronchodilator action in asthmatic subjects
when given by inhalation [17], probably because of
problems with diffusion and degradation by epithelial
enzymes. When given by infusion, the cardiovascu-
lar effects (flushing, tachycardia, headache, hypoten-
sion) preclude the administration of a dose high
enough to bronchodilate [18]. It is unlikely that a VIP
analogue, which is resistant to enzymatic degradation,
would offer any great advantage over {32-agonists al-
ready available, and it would have the disadvantage of
greater cardiovascular effects.
Prostaglandins. Prostaglandin E2 (PGE,) stimulates
adenylate cyclase and relaxes airways in vitro. How-
ever, PGE has not proved to be effective as a
bronchodilator in vivo, and may even lead to constric-
tion and coughing in asthmatics, since PGE 2 also
stimulates afferent nerve endings in airways [ 19).
There is now evidence for subtypes of PGE receptors,
and it is possible that the EP-receptor on sensory
nerves differs from the receptor subtype on airway
smooth muscle, so that a selective agonist may be de-
veloped.
G-protein/adenylate cyclase stimulation. Receptor-
mediated stimulation of adenylate cyclase involves ac-
tivation of 0,, which may be stimulated irreversibly
by cholera toxin. Less toxic compounds which stimu-
late 0, are under investigation. Forskolin directly ac-
tivates the catalytic subunit of adenylate cyclase, and
large increases cAMP concentration in airway smooth
muscle cells, but has not proved to be effective as a
bronchodilator i1J vitro [20]. This may be because ~2 -
agonists are effective as bronchodilators mainly
through direct coupling to maxi-K channels via 0
rather than via a rise in cAMP that is only seen with
very high concentrations of 13-agonists [3].
Selective phosphodiesterase inhibitors
By inhibiting the breakdown of cAMP by phos-
phodiesterase (PDE), it should be possible to
increase intracellular concentrations and thereby relax
airway smooth muscle, and also potentiate the
bronchodilator effect of ~-agonists. It is now
recognized that there are several isoenzyme families of
PDE and several selective inhibitors have recently been
developed [21, 22). The isoenzymes that are involved
in relaxation of airway smooth muscle (types Ill and
IV) make up less than 5% of the total enzyme
activity [23]. Selective inhibitors of these isoenzymes,
such as SK&F 94836, which inhibits type Ill
isoenzyme, may therefore be useful as bronchodilators.
Recent studies suggest that in human airway smooth
 1128 P.J. BARNES
muscle PDE Il, Ill, IV and V activity is present [24)
and that PDE III, IV and V inhibitors may be
bronchodilators in human airways in vitro (25). Evi-
dence now suggests that PDE IV may be important in
inflammatory cells such as mast cells, eosinophils and
macrophages (22, 26], and that type IV isoenzyme in-
hibitors, such as rolipram and denbufylline, may be
useful anti-inflammatory drugs in asthma. Drugs
which inhibit both type Ill and type IV enzymes, such
as benzafentrine and zardaverine [27, 28], may be both
bronchodilatory and anti-inflammatory, and are there-
fore of particular interest for future development. The
main problem with PDE inhibitors appears to be the
profile of side-effects. PDE Ill inhibitors are associ-
ated with cardiovascular side-effects, whereas the ma-
jor problem with PDE IV inhibitors is nausea and
vomiting.
Methylxanthines
Theophylline has remained an important treatment in
asthma for over 50 yrs, and yet its mode of action is
still unknown. It now seems unlikely that broncho-
dilatation plays an important role in the anti-asthma
effect of theophylline, and increasingly likely that
some anti-inflammatory or immunomodulatory effect is
important (29]. Several molecular mechanisms have
been proposed to explain the actions of theophylline,
but perhaps the most likely is that it non-selectively
inhibits PDE. There is little doubt that theophylline
has a critical role in the management of more severe
asthma and it is important that its mode of action in
this condition is elucidated. In a study of theophylline
withdrawal in young patients with severe asthma, there
was a marked deterioration of control, despite the fact
that they continued to take nebulized bronchodilators
and oral and inhaled steroids (30]. The currently used
"therapeutic concentration" of plasma theophylline is
derived from the belief that theophylline acts as a
bronchodilator, but it is likely that the other anti-
asthma effects of theophylline might be achieved at
lower plasma concentrations, thereby avoiding the
problems of toxicity and side-effects, which currently
limit the use of this drug.
The major problem with theophylline is the rela-
tively high frequency of adverse effects, several of
which are due to antagonism of adenosine receptors.
The development of enprofylline (3 propylxanthine),
which retains the bronchodilator and PDE inhibitory
effect but is not an adenosine antagonist, was an
important advance. Enprofylline is an effective
bronchodilator [31] and shares other anti-asthma
properties of theophylline, but is not an adenosine
antagonist at therapeutic concentrations [32]. Side-
effects, such as diuresis, seizure and cardiac
arrhythmias, are less common than with theophylline,
although headache is a problem. Although
enprofylline is not being developed, because of toxi-
cological problems, other related drugs are under
development.
Drugs which increase cyclic guanosine 3'5' monophos-
phate (cGMP)
Atrial natriuretic factor (ANF), when given by
intravenous infusion, produces a significant broncho-
dilator response and protects against bronchoconstrictor
challenges [33). It is probable that the effects of ANF
on airways are mediated by stimulation of particulate
guanylate cyclase and subsequent generation of cGMP
[34]. Nitro compounds such as isosorbide dinitrate,
glyceryl trinitrate (GTN) and sodium nitroprusside
are thought to activate soluble guanylate cyclase.
A dose-dependent relaxant effect of various nitro com-
pounds has been demonstrated on airway smooth mus-
cle in a number of animal studies, and this effect
appears to be mediated via stimulation of soluble
guanylate cyclase and subsequent generation of cGMP
[34, 35]. Intravenous GTN relaxes human tracheal
smooth muscle in normal subjects undergoing cardiac
surgery [36]. Sublingual GTN and isosorbide dinitrate
have been reported to have a bronchodilator effect
in patients with asthma [37, 38], although others have
not confirmed these beneficial effects [39].
It has recently been established that the endogenous
neural bronchodilator in human airways is NO (40].
These studies suggest that bronchodilators with an
alternative intracellular mechanism of action to ~ 2 -
agonists may be possible and further investigation is
warranted, particularly with inhaled formulations in
order to avoid vasodilator side-effects.
Selective an ticholinergics
Recently it has been established that there are
several distinct subtypes of muscarinic receptor
(41], with differing physiological roles in the airways
[42] . Muscarinic receptors inhibiting the release of
acetylcholine have been described in airway choliner-
gic nerves of animal and are classified as M2-receptors,
which are clearly different from the receptors which
mediate contraction of airway smooth muscle (M3 -
receptors) . Nonselective antagonists, such as
ipratropium bromide, will inhibit prejunctional M2-
receptors and, thus, increase the amount of acetylcho-
line released on vagal stimulation, which may then
overcome the postjunctional blockade of M3-receptors,
and may therefore not be as effective against reflex
bronchoconstriction. Selective M 3-antagonists which
block only postjunctional receptors on smooth muscle
should be more effective, but have proved difficult to
develop, as the binding site for acetylcholine in the
muscarinic receptor is very similar for each subtype
of receptor [43]. Drugs which block M 1 receptors may
also be useful, since M 1-receptors in parasympathetic
ganglia facilitate ganglionic transmission and would,
therefore, exaggerate cholinergic reflexes;
unfortunately, M 1 blockade is responsible for the dry-
ing of secretions, so that it would be important for any
such drug to be delivered by aerosol.
 NEW DRUGS FOR ASTIIMA
Calcium antagonists
Contraction of airway smooth muscle and release of
inflammatory mediators results from an increase in in-
tracellular [Ca++] and subsequent activation of
calmodulin. Several important advances have been
made in understanding the regulation of intracellular
[Ca++J and many new types of drug are under devel-
opment. Drugs which block calcium entry through
voltage-dependent calcium channels (VDC), such as
nifedipine, verapamil and diltiazem, have not proved
effective in asthma. This suggests that Ca++ entry via
VDCs is not important in human airway smooth mus-
cle contraction. Calcium entry via receptor-operated
channels (ROCs) may be more important in airway
smooth muscle [44], and drugs which act on these
channels are currently under development. One such
drug SK&F 96365 has been found to inhibit the sus-
tained contractile response in airway smooth muscle in
vitro, by preventing refilling of the calcium stores [45].
Release of Ca++ from intracellular stores is probably
the most important source of calcium for contraction
of airway smooth muscle. Drugs which inhibit cal-
cium release, such as TMB-8, may have effects in air-
way smooth muscle, but they lack selectivity and will
probably be too toxic for clinical use. Most spas-
mogens contract airway smooth muscle by stimulating
phosphoinositide (PI) hydrolysis [46]. Drugs which
inhibit PI turnover or effects may, therefore, be of
potential use in asthma. Inositol 1, 4, 5-trisphosphate
(IP.) generated by PI hydrolysis, causes release of in-
tracellular calcium by binding to specific binding sites
on the endoplasmic reticulum. Heparin is a potent
competitive inhibitor of IP3 binding in airway smooth
muscle [47], but is not of therapeutic use, since it does
not penetrate cells. Analogues of IP3 are currently
under development.
Breakdown of PI also leads to the formation
of diacylglycerol, which activates protein kinase C
(PKC). This enzyme regulates many cellular events,
including slow contractile responses. Antagonists of
PKC, such as staurosporine lack specificity, but more
selective PKC inhibitors, such as Ro 31-8425, are un-
der development. The recognition that there are sev-
eral isoenzymes of PKC may make it possible to
develop blockers selective to certain cell types or func-
tions in the future [48].
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 [49]. Drugs which
selectively activate a K• channel in smooth muscle,
such as BRL 3491 (cromakalim), have been developed
for the treatment of hypertension. These drugs inhibit
1129
spontaneous and induced tone in airway smooth mus-
cle in vitro and might, therefore, have a role in nor-
malizing "hyperreactive" airway smooth muscle. K+
channel activators are currently under investigation as
potential anti-asthma compounds [50]. The active
enantiomer of cromakalim, BRL 38227 (Jemakalim), is
a relatively effective relaxant of human bronchi in
vitro and appears equally active against several
spasmogens [51]. In vivo it has no bronchodilator ef-
fect or protective effect against bronchoconstrictor
challenge at maximally toletrated oral doses [52], but
cromakalim has been shown to offer a small protec-
tion against the fall in lung function at night in asth-
matic patients [53]. Side-effects include headache,
flushing and postural hypotension, due to vasodilata-
tion. It will, therefore, be necessary to develop these
drugs for inhalational use in order to avoid these ef-
fects, although it may be possible to develop K• chan-
nel 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 (BRL 55834) has already been described [54).
The future success of these compounds in asthma
will probably depend on whether they have any addi-
tional effects not shared with ~-agonists. K+ channel
activators inhibit the release of neuropeptides from
sensory nerves and modulate neurotransmission in the
airways [55], but whether they have effects on inflam-
matory cells is not certain. Many different types of
K• channel have now been characterized; cromakalim
and related drugs appear to open a low affinity
adenosine triphosphate (ATP)-dependent channel
(which opens in response to a fall in intracellular ATP
concentrations). Relaxation of airway smooth muscle
in response to ~-agonists and theophylline appears to
involve another type of channel, a calcium-activated
K• channel which is selectively blocked by
charybdotoxin and iberiotoxin [1, 2, 56]. Development
of activators of this channel may, therefore, be an im-
portant target for future development.
Anti-inflammatory drugs
There are several new approaches to controlling
inflammation in asthmatic airways (table 2).
Corticosteroids
Corticosteroids are the most efficacious treatment
currently available for the long-term management of
asthma. Steroids of high topical potency, such as
beclomethasone dipropionate and budesonide, are
highly effective when given by inhalation. Future ad-
vances will depend upon the development of inhaled
steroids of even higher topical potency or which are
metabolized locally ("hit and run" steroids), so that the
local dose of steroids in the airways will be increased
without the systemic effects, which currently limit the
dose of steroids which are rapidly metabolized in the
 1130 P.J. BARNES
circulation (57]. Several new inhaled steroids, includ-
ing fluticasone, tipredane, mometasone and butixicort
are already in clinical development. Perhaps steroids
which are "targeted" to key inflammatory cells such
as macrophages, would also be useful, and the use of
liposomes to deliver steroids to specific sites may be
considered. Modification of the basic structure of
methylprednisolone led to the development of 21-
aminosteroids or "lazeroids", such as U-74006F, which
appear to have some anti-inflammatory effects, perhaps
acting as anti-oxidants (58].
Table 2. - Anti-inflammatory agents for asthma
Existing
Corticosteroids: increased topical effect (budesonide,
fluticasone)
Cromoglycate: increased potency/effect (nedocromil,
frusemide)
Novel
Mediator antagonists (LTD 4 , 5-LO, PAF antagonists)
Phospholipase A2/C/D inhibitors
Neurogenic inflammation inhibitors (fl·opiolds, SP antago-
nists)
Immunomodulators (cyclosporin A, FK 506, rapamycin)
Cytokine inhibitors (IL-5 inhibitor)
IgE suppressors (IL-4 inhibitors)
LTD4 : Jeukotrienc 04; 5-LO: 5-lipoxygenase; PAF; plate-
let-activating factors; IL: interleukin.
Because steroids are so effective in the control of
asthma, an important goal of research is to identify the
particular cellular and molecular mechanisms which
are of critical importance in asthmatic inflammation.
This may then lead in the future to non-steroidal drugs
which mimic the beneficial effects, without the side-
effects which are due to the other actions of steroids.
The molecular basis of steroid action involves inter-
action with a cytosolic glucocorticosteroid receptor,
which then interacts with specific nucleotide sequences
on the upstream regulatory elements of certain target
genes to either increase (e.g. lipocortin-1, ~-adreno­
ceptors) or decrease (e.g. cytokines) the rate of tran-
scription (59). It might be possible in the future to
mimic certain aspects of steroid action by developing
agents which selectively influence the transcription of
the same genes. In addition to effects of steroids on
gene transcription, it has recently been recognized that
the activated glucocorticoid receptor may interact di-
rectly with other activated transcription factors in the
cell via a protein-protein interaction [60, 61). Many
cytokines activate a transcription factor called activa-
tor protein-1 (AP-1), which directly interacts with the
activated steroid receptor, and that this interaction
occurs with low concentrations of steroids. Such an
interaction between steroids and transcription factors
has recently been demonstrated in human lung [62).
In the future it may be possible to develop drugs that
also bind to AP-1 or other transcription factors to
prevent their interaction with target genes.
Lipocortin
Steroids stimulate the production of a protein,
lipocortin-1, which inhibits phospholipase ~ (PLA2)
(63], the enzyme which leads to the generation of
arachidonic acid and platelet-activating factor (P AF).
Recombinant human lipocortin-1 is now available, but
there might be problems in delivering such an agent,
and it may be degraded at inflammatory sites. The
presumed advantage of lipocortin might be reduction
in glucocorticoid side-effects. However, there are
doubts as to whether many of the effects of steroids
are mediated via PL~ inhibition [64).
Anti-allergic drugs
Sodium cromoglycate is effective in controlling mild
asthma [65). It appears to have a specific action on
allergic inflammation, and yet its molecular mechanism
of action remains a mystery. Although it was believed
that its primary mode of action was by inhibiting mast
cell mediator release, it has now been demonstrated
that it has effects on several other inflammatory cells
and on sensory nerves. Nedocromil sodium has a very
similar profile of anti-asthma effects, but is more po-
tent and it may be possible to maintain control with
less frequent administration [66). Both cromoglycate
and nedocromil sodium must be given by inhalation
and all attempts to develop orally active drugs of this
type have been unsuccessful, possibly because topical
administration is critical to their efficacy.
Mediator antagonists
Many different inflammatory mediators have now
been implicated in asthma [67), and several specific
receptor antagonists and synthesis inhibitors have been
developed, which will prove invaluable in working out
the contribution of each mediator. As many media-
tors probably contribute to the pathological features of
asthma, it seems unlikely that a single antagonist will
have a major clinical effect, compared with nonspe-
cific agents such as ~-agonists and corticosteroids.
However, until such drugs have been evaluated in
careful clinical studies, it is not possible to predict
their value.
Lipid mediators may play an important role in asth-
matic inflammation. Several potent Jeukotriene, PAF
and thromboxane antagonists have now been developed
and are currently undergoing clinical trials in asthma
[68]. Initial results appear to suggest that potent
leukotriene antagonists, such as MK-571 and ICI 204,
219, have a significant protective effect against some
constrictor challenges, such as exercise and allergen
[ 69, 70], and long- term clinical trials are now
underway, with encouraging preliminary results (71).
Although PAF has several properties which suggest
that it may play an important role in asthma [72], re-
cent studies with potent PAF antagonists show no
effect on allergen challenge (73-75). The most
 NEW DRUGS FOR ASTHMA
potent PAF antagonist currently available is UK
74,505, which after a single oral dose inhibits the air-
way effects of inhaled PAF for up to 24 h [76), and
yet is ineffective in allergen challenge [77), indicat-
ing that such drugs will probably have no place in the
future management of asthma.
Bradykinin has also attracted attention as a poten-
tial mediator of asthma symptoms, since bradykinin
appears to be the inflammatory mediator produced in
asthma that is most likely to activate sensory nerves
in the airway [78). A potent and stable bradykinin
BK.z-receptor antagonist HOE 140 has recently been
developed [79] and may have therapeutic potential as
a modulator of asthma symptoms.
It seems rather unlikely that antagonizing a single
mediator will ever be as useful as less specific thera-
pies, but such therapies may have the advantage of
fewer side-effects and oral administration. Certain
types of asthmatic patient may respond much better to
these more specific therapies. For example, it seems
likely that aspirin-sensitive asthmatic patients may
particularly benefit from leukotriene D4 (LTDJ-antago-
nists [80).
Enzyme inhibitors
An alternative to antagonists of mediator receptors
are drugs which inhibit the enzymes involved in me-
diator synthesis. Since PLA2 appears to be of critical
importance in the generation of all lipid mediators, it
is a suitable target for inhibitory drugs. Drugs other
than steroids which inhibit PL~, such as mepacrine,
might be expected to share the beneficial effects of
steroids, but this drug is weak and nonspecific. More
potent PLA2 inhibitors, such as manoalide, derived
from a sponge, are also nonselective [81). It is now
clear that there may be many forms of PLA2 , and a
high molecular weight cytosolic PLA 2 that is
arachidonic acid-selective has recently been cloned
[82]. This may make it more feasible to select inhibi-
tors by random screening, but whether PLA2-inhibitors
would offer any advantage over 5-lipoxygenase inhibi·
tors is uncertain, in the light of the fact that neither
cycle-oxygenase inhibitors nor P AF receptor antago-
nists are effective in asthma. Inhibition of phos-
pholipase C, which is the enzyme leading to PI
breakdown, could also be useful, as discussed above.
Phospholipase D (PLD) appears to play a critical
role in the priming of inflammatory cells and, there-
fore, may be an important target in asthma [83). Al·
though poor inhibitors such as wortmannin are
available, more selective PLD inhibitors are under
development.
Cycle-oxygenase inhibitors, which inhibit the for-
mation of prostaglandins and thromboxane, are of no
obvious therapeutic value in asthma [84, 85), and in
the small group of asthmatics with aspirin-sensitive
asthma they may cause a deterioration.
5-lipoxygenase (5-LO) is the critical enzyme
involved in the generation of leukotrienes. Several
drugs have been developed which inhibit 5-LO,
1131
although most of these compounds are very weak.
Thus zileuton, the most effective of these drugs avail-
able for clinical use, has only a small inhibitory ef-
fect on allergen-induced responses and leukotriene
production [86), although more encouraging results
have been obtained in cold air challenge [87).
Zileuton, like most other 5-LO inhibitors, appears to
work as a redox inhibitor of the enzyme, but more re-
cently a novel inhibitor MK-886 has been developed,
which apparently binds to a 5-LO activating protein
(FLAP) in the cell membrane, to which cytosolic 5-
LO must bind in order to be active [88]. There is a
theoretical advantage to the use of 5-LO inhibitors,
compared with leukotriene antagonists, since the for-
mation of leukotriene B4 (LTB 4) and other 5-LO prod-
ucts, as well as sulphidopeptide leukotrienes, will also
be inhibited.
Inhibitors of neurogenic inflammation
Neuropeptides, which may be released from senso~y
nerves in airways in asthma via an axon reflex might
amplify the inflammatory response [89). There are
several approaches to inhibiting these local reflexes
[90). Antagonists of sensory neuropeptides, 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
neurokinin-! (NK1)-receptors and several selective an-
tagonists have been developed [91]. A potent non-
peptide NK1 -antagonist, CP-96, 345, has recently been
described, which may prove to be a very useful
lead compound, which avoids all the problems asso-
ciated with the development of peptide antagonists
[92). This antagonist is extremely effective in block-
ing the inflammatory effects of tachykinins released
endogenously by nerve stimulation (93).
Another approach is to inhibit the release of these
peptides from C-fibres rather than to block their ef-
fects, since several peptides are likely to be released
from sensory nerves. Opioids markedly inhibit sen-
sory neuropeptide release and have been shown to
block neurogenic plasma exudation, mucus secretion
and bronchoconstriction in guinea-pigs and neurogenic
mucus secretion in human airways [90). Opioids
which act peripherally, such as the opioid peptide BW
443C, may be effective in reducing neurogenic inflam-
mation in asthma (and also the associated sensory
symptoms such as cough) [94]. Inhaled BW 443C has
no effect on resting lung function or on broncho-
constriction induced by metabisulphite (95), although
this peptide is likely to be rapidly degraded by
epithelial enzymes. More stable, peripherally active,
opioid agonists are now under development. Several
other agonists act on pre-junctional receptors on sen-
sory nerves in airways to inhibit neuropeptide release;
these include a 2 -agonists, gamma amino butyric acid,
and histamine H 3-agonists, which all appear to open
a common K+ channel which is blocked by
charybdotoxin [96).
1132 P.J. BARNES
The surface enzyme, neutral endopeptidase (NEP),
is important in degrading several peptides with bron-
choconstrictor and inflammatory effects in the airways,
including tachykinins, bradykinin and endothelins.
There is circumstantial evidence from animal studies
that it may be deficient in asthmatic airways [97].
Recombinant human NEP is capable of reversing any
induced deficiency of the enzyme and, therefore, has
some potential in asthma, although delivery is a prob-
lem, as it is a relatively large protein.
Another possibility is to inhibit activation of sensory
nerves. This may be achieved by drugs such as
sodium cromoglycate and nedocromil sodium, which
appear to stabilize unmyelinated nerves in airways
[98]. Another drug which has a similar profile of
activity is the loop diuretic frusemide.
A more radical solution is to deplete sensory nerves
of neuropeptides using capsaicin. This approach has
been successful in vasomotor rhinitis and local appli-
cation of capsaicin markedly reduces symptoms of
rhinitis for several months [99].
Frusemide
Inhaled frusemide protects against "indirect "
bronchoconstrictor challenges, such as exercise, fog,
allergen, sodium metabisulphite and adenosine, but has
no effect against direct bronchoconstrictor challenges
such as histamine, methacholine and prostaglandin
F2 " (PGF2Cl) [100-102]. These effects mimic those
of sodium cromoglycate but, in addition, inhaled
frusemide inhibits certain types of induced cough
[103). The mechanism of action of frusemide
in asthma is not certain, but it is ineffective systemi-
cally, suggesting that it is acting at the airway surface.
Frusemide works as a diuretic by inhibiting the
Na•tK•/Cl· eo-transporter in renal tubular cells, but the
more potent inhibitor bumetanide is ineffective in the
same challenges [104]. 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 neces-
sary for the activation of inflammatory cells
and sensory nerves. Indeed frusemide is effective
in blocking eosinophil activation and airway sensory
nerves, and its actions are mimicked by Cl· channel
blocking drugs [105). Frusemide itself causes diure-
sis when inhaled in high concentrations, but it is
possible that derivatives with less diuretic potency or
that selective Cl· channel blockers may, in the future
be developed for use in asthma.
lmmunomodulators
T-lymphocytes may play a critical role in initiating
and maintaining the inflammatory process in asthma
via the release of cytokines. Methotrexate has a ster-
oid-sparing effect in asthma, probably acting as a
nonspecific immunosuppressive or anti-inflammatory
agent [106, 107]. The side-effects of methotrexate
(particularly nausea and blood dyscrasia) 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 control-
ling asthma, and there is evidence that low dose
cyclosporin A improves lung function or has a ster-
oid-sparing effect in steroid-dependent asthmatic pa-
tients [108, 109]. Its efficacy is not very impressive
in most patients, and the nephrotoxicity of cyclosporin
A would limit its widespread use. The possibility of
using inhaled cyclosporin A should be explored, since
in animal studies it is effective in inhibiting the in-
flammatory response [110). In experimental models
of asthma, whilst cyclosporin A inhibits the
eosinophilic inflammation in the airways, it fails to
reduce airway hyperresponsiveness, whereas steroids
are effective in inhibiting both responses [111].
Immunomodulators, such as FK506 and rapamycin
appear to be more potent and less toxic (112].
Cytokine inhibitors
There is increasing evidence that cytokines may par-
ticipate in the inflammatory response in asthma.
Interleukin (IL)-1, IL-8 tumour necrosis factor and
granulocyte-macrophage colony-stimulating factor
(GM-CSF) from macrophages, and IL-3, IL-4 and
IL-5 from CD4+ T-lymphocytes may all be involved
in the chronic inflammation in asthmatic airways,
together with additional cytokines (GM-CSF, IL-6, IL-
8), which may be released from epithelial cells of the
airways. Drugs which interfere with the production or
action of these cytokines may, therefore, prove to be
of benefit in asthma. Indeed, corticosteroid& may be
effective in asthma by suppressing cytokine synthesis
in inflammatory cells [113). It may prove difficult to
develop specific receptor antagonists for cytokines,
since they are large peptides and have a very high af-
finity for their receptors. Strategies such as antisense
nucleotides, which would inactivate the specific
messenger ribonucleic acid (mRNA) encoded by
cytokine genes, may be a more optimistic approach
(114]. A naturally occurring antagonist of IL-l has
been isolated [ 115), and in experimental allergic
inflammation of the airways IL-l receptor antagonist
has some inhibitory effect [116). Studies of human
recombinant IL-1ra in asthma are currently underway.
Similar antagonists of other cytokines may be discov-
ered which could lead to the development of future
antagonists. Specific antibodies to various cytokines
have now been developed, but while these may be
suitable for revealing the roles of various cytokines
[117), they would not be suitable for chronic admin-
istration. An antibody to IL-5 is effective in
controlling eosinophilic inflammation after allergen in
guinea-pigs [ 118], suggesting that IL-5 antagonism
may be a promising target for more specific therapy.
 NEW DRUGS FOR ASTHMA
Cell adhesion b/ockers
It is now recognized that the infiltration of inflam-
matory cells into tissues is dependent on adhesion of
blood-borne inflammatory cells to endothelial cells
prior to migration to the inflammatory site [119]. This
depends upon specific glycoprotein adhesion molecules
on leucocytes and on endothelial cells, which may be
upregulated, or expressed on the cell surface, in
response to various stimuli, such as cytokines, or
mediators, such as PAF, or leukotrienes. Monoclonal
antibodies which inhibit these adhesion molecules,
therefore may prevent inflammatory cell infiltration.
Thus, a monoclonal antibody to intercellular adhesion
molecule-1 (ICAM-1) on endothelial cells prevents
eosinophil infiltration into airways and increase in
bronchial reactivity after allergen exposure in sensi-
tized primates (120}. Synthetic peptides, with the
sequence which is critical for adhesion, may have
therapeutic potential. Thus, some integrins bind to a
tripeptide sequence Arg-Gly-Asp (RGD), which
may therefore inhibit leucocyte adhesion. Another
possibility is to inhibit the expression of adhesion
molecules on the cell surface. For example, 3-
deazoadenosine inhibits cytokine-mediated induction of
ICAM-1 [121]. Whilst inhibition of adhesion
molecules is an attractive new approach to the treat-
ment of inflammatory disease, there may be potential
dangers in inhibiting immune responses, leading
to increased infections and increased risks of
neoplasia. If some selectivity of effect could be
achieved then this would be of less concern. Adhesion
of eosinophils appears to involve an interaction be-
tween vascular cell adhesion molecule-1 (VCAM-1) on
endothelial cells and very late activation antigen-4
(VLA4) on eosinophils (122], either of which may be
a more specific target than ICAM-1.
Immunoglobulin E (lgE) suppression
Since release of mediators in asthma may be IgE-
dependent, an alternative approach may be to inhibit
the synthesis of IgE. Suppressor factors which inhibit
IgE synthesis, and which are related in structure to the
IgE receptor, have been described, but have proved
disappointing in vivo. IgE synthesis by B-lymphocytes
is dependent on IL-4, so that IL-4 synthesis inhibitors
or receptor antagonists would be useful in allergy
suppression [123].
Immunotherapy
Although immunotherapy, as currently practised, has
been disappointing in the therapy of asthma, it is likely
that more effective vaccines will be developed in the
future. As the complex mechanisms of antigen pres-
entation and the interaction between antigen-
presenting cells and T -lymphocyte receptors are elu-
cidated this may lead to the development of peptides
which will block allergen-induced immune reactions
[124, 125).
1133
Conclusions
Many different therapeutic approaches to the treat-
ment of asthma may be possible, yet there have
been few new drugs which have reached the clinic.
13 -agonists are by far the most effective bronchodila-
t~r drugs and lead to rapid symptomatic relief. Now
that inhaled ~ -agonists with a long duration of action
have been de~eloped, it is difficult to imagine that
more effective bronchodilators could be discovered.
Similarly, inhaled corticosteroids are extremely effec-
tive as chronic treatment in asthma and suppress the
underlying inflammatory process. For most patients,
a short-acting ~-agonist on demand and regular inhaled
steroids are sufficient to give excellent control of
asthma [126]. For some patients, a fixed combination
~-agonist and steroid inhaler may be a useful devel-
opment, since they will improve the compliance of
inhaled steroids (which is poor because of the lack of
immediate bronchodilator effect). The ideal drug for
asthma would probably be a tablet which can be
administered once daily to improve compliance. It
should have no side-effects and this means that it
should be specific for the abnormality of asthma (or
allergy).
Future developments in asthma therapy should be
directed towards the inflammatory mechanisms and
perhaps more specific therapy may one day be devel-
oped. The possibility of developing a "cure" for
asthma seems remote, but when more is known about
the genetic abnormalities of asthma it may be possi-
ble to search for such a therapy. Advances in mo-
lecular biology may aid the development of drugs
which can specifically switch off relevant genes, but
more must be discovered about the basic mechanisms
of asthma before such advances are possible.
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