The
mainstay of current drug therapy for asthma is the combination of inhaled
corticosteroids with long-acting2-agonists (LABAs).. Several improved
inhaled corticosteroids, longer-acting LABAs and LAMAs (and combinations) are
now in clinical development. The first biologic agent to be licensed for the
treatment of severe allergic asthma is a monoclonal antibody directed against
IgE (anti-IgE), while a variety of approaches involving allergen
immunotherapy, T cells and pattern recognition receptors are being developed.
Specifi c biological antagonists of individual cytokines (IL-5, IL-4, IL-13,
IL-9, TNF) have generally been disappointing in asthma, although anti-IL-5 has recently
been found to be effective in various conditions with high levels of eosinophils
and for severe eosinophilic asthma. Oral
CCR3 antagonists have been studied in mild eosinophilic asthma, while in
more severe neutrophilic asthma and
COPD, therapies such as CXCR2 antagonists, p38 mitogen-activated protein
kinase, nuclear factor-B and phosphoinositide 3 kinase inhibitors are being
developed. Cilomilast (Arifl o, GlaxoSmithKline) and roflumilast (Daxas,
Nycomed/ Merck) are oral inhibitors of the enzyme phosphodiesterase type 4 and have been assessed in large phase III
studies, and roflumilast is under regulatory review by the European
Medicines Agency. Amongst the new
generation of nucleic acid-directed therapies, inhaled anti-sense and
small-interfering RNA approaches have recently been assessed in asthma. Hence,
as a result of the considerable ongoing efforts by clinicians, scientists and
the pharmaceutical industry to develop new therapies for asthma andCOPD,
progress is gradually being made.
BRONCHODILATORS
1.INDACETROL: A NEW
ONCE DAILY LONG ACTING β2ADRENOCEPTOR AGONIST
(LABA)
Indacaterol is a novel
once-daily long-acting -adrenoceptor agonist in development for the treatment
of obstructive airway disease, namely chronic obstructive pulmonary disease
(COPD) and (in combination withan
inhaled corticosteroid) asthma. Clinical studies suggest that indacaterol
produces rapid and sustained bronchodilation
in patients with COPD or asthma in a range of different severities. Until now,
clinical studies (PHASE 2) with durations of up to 28 days have been published,
and these studies confirmed suitability of indacaterol for once-daily dosing, along with a favorable overall safety and
tolerability profile.
2
|
.ACLIDINIUM BROMIDE: A NOVEL LONG-ACTING
MUSCARINIC ANTAGONIST (LAMA)
Aclidinium
bromide (Almirall/Forest, previously LAS-34273), a novel, long-acting
muscarinic antagonist, administered
via a new multidose dry powder inhaler, is currently (March 2008) in phase III development for the
maintenance treatment of patients with chronic obstructive pulmonary disease
(COPD) and asthma. Preclinical studies have demonstrated that aclidinium is a
potent, competitive muscarinic receptor antagonist with kinetic selectivity for M3over M2receptors.
Aclidinium has a long residency at M3receptors
and results of preclinical and early clinical studies in healthy subjects
indicate that aclidinium provides long-lasting protection against
bronchoconstriction. This has been confirmed in a phase IIa study of patients
with moderate to severe COPD where aclidinium produced sustained bronchodilation over 24 hours, demonstrating
suitability for once-daily dosing.
In human plasma, aclidinium is rapidly hydrolyzed to two major inactive
metabolites. The very low and
transient systemic exposure to aclidinium is consistent with an excellent tolerability profile, as
demonstrated thus far in the clinical trial program.
Inhaled bronchodilators such β2-adrenoceptor
agonists (BAs) and muscarinic receptor antagonists (MAs)
are commonly used in the treatment of chronic obstructive pulmonary disease
(COPD). Combinations comprised of one agent from each group are recommended
for aggressive treatment of more severe disease. Dual
pharmacology, where a single small
molecule is able to act via two pharmacological mechanisms, is a novel
approach to bronchodilation that could provide equivalent or possibly
superior treatment for patients with COPD. Compounds with both MA and BA
activity (MABAs) offer a single
pharmacokinetic profile for both pharmacological activities, potential
for maximizing the synergy between the two mechanisms, and a simpler
technical and clinical development pathway compared to co-formulation of two
compounds. In addition, the MABA approach may offer a unique opportunity for combination with an
antiinflammatory drug (such as an inhaled corticosteroid) to provide “triple therapy” in a single
inhalation device. Several prototypic MABA molecules, including GSK-961081 (TD-5959), are in
preclinical or clinical phases of development.
IgE- AND EPITHELIAL-DIRECTED APPROACHES
4. IgE-directed
approaches: A general strategy for the treatment of atopic diseases
Immunoglobulin
E (IgE) is now generally recognized as a key
mediator in the pathogenesis of atopic diseases such as allergic asthma
and rhinitis. Therapeutic strategies targeting IgE resulted in the
development of humanized neutralizing
monoclonal anti-IgE antibodies. They attach to an epitope which overlaps
with a region within the IgE molecule that also interacts with its high- and
low-affinity receptors expressed on mast cells, basophils and dendritic
cells. Thus, these anti-IgE antibodies have the capacity to bind to and
neutralize free serum IgE and membrane-bound IgE on B cells but do not
recognize receptor-bound IgE. Omalizumab (Xolair®)
is the most advanced therapeutic anti-IgE antibody. By removing free IgE from
the circulation it also markedly downregulates the density of high-affinity
IgE receptors on the surface of effector cells. After having been studied in
more than 20 phase II and phase III clinical trials for various atopic
indications, omalizumab has been approved
to treat patients with moderate to severe asthma.
5.Therapy directed
against thymic stromal lymphopoietin (TSLP)
Thymic
stromal lymphopoietin (TSLP) is an interleukin
(IL)-7-like cytokine and has been shown to be one of the factors released
by epithelial cells following allergen contact with an important role instructing dendritic cells (DCs) to
induce a T-helper type 2 (Th2) response. These TSLP-DC stimulate CD4+T
cells to induce a proallergic cytokine profile, suggesting TSLP plays a
crucial role in the initiation of the allergic cascade. Recently, evidence
has also accumulated that TSLP could play a role in enhancement of the
effector stages of the allergic response, with TSLP in synergy with IL-1 and
tumor necrosis factor (TNF)- shown to amplify cytokine secretion from mast
cells. Also, the clinical relevance of TSLP has been demonstrated by both high levels of TSLP in skin biopsies from
lesional atopic dermatitis patients and also increased expression of TSLP
in asthmatic airway epithelial cells which correlated with reduced lung
function. These studies suggest a critical role for TSLP as a driving factor
in the emerging concept of tissue-specific control of immunity with TSLP
secretion at the epithelial–DC interface acting as an initial factor in the
proallergic cascade.
T-cell co-stimulator blockade
6.ICOS and B7RP-1: Novel targets
for monoclonal antibodies
The inducible co-stimulatory molecule (ICOS) receptor is one of several co-stimulators expressed on T cells. ICOS interacts with a distinct cell surface ligand, B7 related protein-1 (B7RP-1 or ICOSL), to regulate Th1- and Th2-dependent immune responses, as well as T-dependent B-cell activation. ICOS expression is increased on T cells from patients with a variety of autoimmune diseases and is linked to increased levels of proinflammatory cytokines. Thus, blocking ICOS/ICOSL signaling is a promising new approach for therapeutic intervention in a number of diseases, including asthma. PATTERN RECOGNITION RECEPTORS
7.Toll-like
receptor 2 as therapeutic target in lung disease
Toll-like
receptor 2 (TLR2) is activated by pathogens and nonpathogen insults leading
to innate immune responses and inflammation. TLR2 is a promiscuous receptor
being activated by a variety of
pathogen- associated molecular patterns (PAMPs), but especially by those
expressed by Gram-positive bacteria.
TLR2 functions in heterodimers with either TLR1 or TLR6, and there is some
evidence for tissue-specific preferences for TLR1 versus TLR6 in the
activation of TLR2-mediated responses. Activation of TLR2 has now been
implicated in a number of respiratory-based conditions including asthma and
chronic obstructive pulmonary disease.
8. Toll-like receptor 3
Toll-like
receptors (TLRs) form a key part of innate immunity as they detect conserved microbial pathogen-associated molecular
patterns and trigger theproduction
of proinflammatory cytokines and interferons leading to pathogen
elimination. TLR3 is an important member of this family as it detects double-stranded RNA of viral
origin and therefore TLR3 function is important in the outcome to viral
infection. Intriguingly, in some viral
infections, TLR3 contributes to the pathogenesis of infection, either by
using TLR3 for cell entry or by the deleterious effects of excessive
proinflammatory cytokines. However, in other viral infections, TLR3 mediates
an important host antiviral response. Given their central role in mediating
inflammation, TLRs have emerged as exciting therapeutic targets in a number
of disease states such as cancer, sterile inflammation and autoimmunity, in
addition to the use of TLR agonists as adjuvants. The therapeutic
opportunities in both cancer and in particular respiratory viral infection
where TLR3 may be manipulated to provide a clinical benefit.
9.Toll-like receptor 4
The biology of Toll-like receptor 4 (TLR4) is extremely complex. Signaling via endotoxins or endogenous molecules revealed by tissue damage can drive inflammatory responses and have profound effects on the establishment and nature of adaptive immunity. Depending on the context and desired outcome, agonists and antagonists of TLR4 are likely to serve important roles, and safe therapeutics achieving both of these pharmacological aims have been developed. TLR4 agonists are now incorporated as adjuvants in licensed therapeutics; the final place of TLR4 antagonists has yet to be determined.
10.Toll-like receptor 7 and 8
agonists
The
Toll-like receptors (TLR) 7 and 8 are mediators
of the innate immune response to viral infections. They recognize single-stranded RNAs, but also
a variety of small-molecular-weight compounds, such as the
imidazoquinoline compounds imiquimod and resiquimod, as well as guanosine
analogues and adenine derivatives. While TLR7
is predominantly expressed in plasmacytoid dendritic cells (pDC) and B
lymphocytes, TLR8 is mainly expressed by myeloid dendritic cells and
monocytes. Activation of TLR7 by agonists induces production of
interferon-(IFN-) by pDCs, but also inflammatory cytokines, such as
interleukin-12 (IL-12),tumor necrosis factor- (TNF-), IFN-, and also IL-10. TLR8 activation
results mainly in the induction of inflammatory cytokines such as IL-12,
TNF-and IFN-. Moreover, agonists can induce dendritic cell maturation and
B-cell proliferation. Allergic asthma is characterized by a biased Th2-type
immune response, and thus activation
of TLR7/8 could be effective in treatment of atopic disease by modulation
towards a Th0/Th1-type immune response. Indeed, in several preclinical
animal models it was demonstrated that TLR7/8 activation by an agonist can
inhibit development of experimental asthma, and cause a shift from a Th2-type
towards a Th0/Th1-type immune activation.
11.TOLL-LIKE RECEPTOR 9 ACTIVATION
WITH CpG OLIGO DEOXY NUCLEOTIDES FOR ASTHMA THERAPY
Prokaryotic DNA has long been recognized as
immunostimulatory. In the last decade the role played
by CpG motifs (nucleotide sequence motifs centered on a cytosine-guanine
dinucleotide) in bacterial and viral DNA has been elucidated. CpG motifs are detected by the innate
immune pattern recognition receptor Toll-like receptor (TLR) 9, the
ligation of which activates multiple signal cascades in responding cells. A
restricted pattern of TLR9 expression to certain dendritic cells and B cells
appears to provide relative specificity in responses, especially in
comparison to other TLR ligands. TLR9 activation induces aTh1-like pattern of
cytokine release which led to interest in the use of synthetic CpG
oligodeoxynucleotides (CpG ODN) for the prevention and treatment of
Th2-associated atopic disorders such as asthma. Interestingly, Th1 cytokines
do not appear to be necessary for a
therapeutic response in preclinical models of atopic asthma. Additional
potential mechanisms of action include induction of regulatory-type responses
(involving interleukin-10 release), and expression of indoleamine
2,3-dioxygenase. CpG ODN have been
shown to prevent and reverse antigen-induced eosinophilic airway inflammation
in animal models; human trials are ongoing with encouraging early results
when used as a ragweed vaccine
adjuvant in allergic upper airway disease.
Cytokines
12.IL-5-directed
approaches in the treatment of eosinophil-driven disease
Eosinophils
are involved in the initiation and propagation of diverse inflammatory
responses that may result in tissue damage and dysfunction. A number of
diseases such as eosinophilic bronchitis, hypereosinophilic syndrome,
eosinophilic esophagitis and eosinophilic gastroenteritis are currently
considered to be predominantly eosinophil-driven. In atopic disease, their
role has been less clear. Eosinophils are critically dependent on the
cytokine interleukin-5 (IL-5), for their maturation in bone marrow, and also
influence eosinophil migration and survival. Recent clinical data with
monoclonal antibodies (mAbs) directed against IL-5 support this assumption. Mepolizumab (SB-240563, GlaxoSmithKline)
is a humanized mouse anti-human IL-5 mAb and has been shown to be safe
and effective in the treatment of
patients with hypereosinophilic syndrome. Most recently, clinical trials
in severe asthma and nasal polyposis have also reported positive data
increasing our understanding of the role eosinophils play in these disorders.
13.Monoclonal
antibody therapy directed against interleukin-5 receptor a: MEDI-563
MEDI-563,
which has also been known as
BIW-8405, is a humanized anti-human IL-5 receptor a (IL-5Ra) antibody
that not only inhibits the interaction of IL-5 with its high-affinity receptor,
but also depletes IL-5Ra-expressing
cells through enhanced antibody-dependent cell-mediated cytotoxicity. Therefore, quantitative depletion of
eosinophils and basophils in bone marrow, blood and lung tissue by MEDI-563
might result in enhanced clinical efficacy in diseases characterized by
eosinophilic and/or basophilic inflammation.
14.IL-4-
and IL-13-directed approaches
Interleukin
4 (IL-4) and IL-13 mediate important
proinflammatory functions in asthma including Th2 lymphocyte
differentiation, induction of IgE production, upregulation of IgE receptors,
expression of vascular cell adhesion molecule-1, promotion of eosinophil
transmigration into the lungs, inhibition of T-lymphocyte apoptosis and mucus
hypersecretion. The role of IL-4 and IL-13 in the pathogenesis of asthma is
further supported by identification of polymorphisms linked to asthma in the
IL-4 and IL-13 promoters, the genes themselves and proteins involved in
signaling for the two cytokines. Several approaches to IL-4 and IL-3 antagonism are or have been in clinical
development.
15.Aerovant
(recombinant human interleukin-4 variant)
Aerovant
is a recombinant interleukin (IL)-4 variant that is in clinical development
for the treatment of asthma and other allergic disease based on its ability
to inhibit both IL-4 and IL-13. Phase II studies of Aerovant
demonstrate inhibition of late-phase response to allergen challenge in
subjects with asthma. The clinical evidence is strong supportive evidence for
a continued interest in the contribution of Th2 immunity to the pathogenesis
of allergic asthma.
16.An anti-interleukin-13 receptor α-1 antibody for the
treatment of asthma
A
key role for the interleukin (IL)-13 pathway in asthma and other allergic
diseases has been supported by multiple animal models and by consistent
genetic associations of IL-13 and its receptor to atopy and asthma in several
patient populations. These findings strongly suggest that blocking the IL-13 pathway could be used
as a therapeutic approach for the treatment of asthma. Targeting the
individual cytokine or components of its receptor complex are currently being
explored by a number of companies in order to block this pathway.
17.Interleukin-7-directed
approaches
Interleukin-7 (IL-7) is a cytokine involved in T-cell development in the thymus and in peripheral T-cell homeostasis. IL-7 mediates its function through a membrane-bound receptor composed of the common J chain (CD132) and the IL-7-specific D chain (IL-7RD, CD127). The common J chain (CD132) is shared by a number of other cytokine receptors, and the IL-7RD chain is also used by the receptor for thymic stromal-derived lymphopoietin (TSLP). The TSLP cytokine is involved in the thymic differentiation of regulatory T cells and peripheral modulation of the Th1/Th2 balance. Others and we have identified five polymorphisms in the gene encoding the IL-7RD chain. Four of these single nucleotide polymorphisms (SNPs)—rs1494558 (exon 2), rs1494555 (exon 4), rs6897932 (exon 6) and rs3194051 (exon 8)—give rise to amino acid substitutions, and we have shown significant association with two SNP alleles, rs1494555 and rs6897932, in inhalation allergic patients. The same risk alleles have been associated with survival after allogeneic stem cell transplantation and multiple sclerosis, respectively. The functional impact of IL-7RD polymorphisms is considered an important step towards the development of new treatments based on the modulation of IL-7 and TSLP activities.
18.Monoclonal
antibody therapy directed against interleukin-9: MEDI-528
With
the identification of T helper 2 (2)-derived cytokines, including interleukin
(IL)-9, as orchestrators of allergic asthma, the profound impact of IL-9 on
both immune cells and structural cells of the lung has received great
attention. Both IL-9 and IL-9 receptor
expression are upregulated in human asthmatics, and genetic linkage
studies have associated IL-9 with the susceptibility to develop airway
hyperresponsiveness. Moreover, preclinical studies highlighting the mast
cell-enhancing activity of IL-9, which is unique among the 2 cytokines,
indicate that IL-9 blockade could
provide a novel approach to the treatment of both noneosinophilic asthma,
which is resistant to inhaled corticosteroid therapy, as well as of
eosinophilic asthma. MEDI-528 is a
humanized immunoglobulin G1 antibody that inhibits the activity of IL-9 and
is currently in clinical development, undergoing evaluation in phase IIa studies in mild to moderate
asthmatics. MEDI-528 is currently the only program in clinical development
directly targeting the IL-9-dependent pathway and may have important
therapeutic possibilities in allergic and nonallergic inflammatory diseases
where mast cell contributions are prominent.
19.Targeting
interleukin-17 in the lungs
A
growing body of experimental evidence suggests that interleukin (IL)-17 (also termed IL-17A) is aproinflammatory cytokine
uniquely positioned at the interface of innate and adaptive immunity in
mammals. Currently believed to be predominantly produced by a unique T-helper
(h) subset, the Th17 cells, IL-17 exerts its effects on components of the
innate immune system by contributing in direct as well as indirect
(i.e.,through inducing the release of other, neutrophil-mobilizing cytokines)
ways to the accumulation of inflammatory cells. Thus, IL-17 has been recognized as an important component of the
pulmonary host defense in mice and it has been implicated in lung disorders such as bronchial
asthma, lung allograft rejection and cystic fibrosis in humans. In
addition, recent experimental studies in mouse models of autoimmune diseases
have forwarded evidence for an important role of IL-17 in the pathogenesis of
these disorders. Unfortunately, there are currently no published clinical
trials of the concept of targeting IL-17 in lung disorders. In contrast, there are published clinical trials of
blocking IL-23, an upstream regulator of IL-17, in patients with
inflammatory bowel disease and psoriasis and these have shown promising
results in terms of potentially antiinflammatory effects. Therefore, it now
seems motivated to target IL-17 in human lung disorders such as severe
asthma, lung allograft rejection and, possibly, even in cystic fibrosis, when
conducting new clinical trials.
CHEMOKINES
20.Chemokine
CCR3 antagonists
CCR3
expression was first thought to be limited to eosinophils, in vitro
studies have now demonstrated that CCR3 is more widely expressed on cells involved in inflammation, such as
basophils, mast cells, airway epithelium, smooth muscle cells and T-helper
type 2 (Th2) T lymphocytes. Preclinical studies have established that CCR3 antagonism can be used to control
allergic inflammation. Patents and
literature indicate that major pharma ceutical companies are still active
preclinically in this area and the discovery of second-generation compounds
with which to test robustly the therapeutic potential of CCR3 antagonists is
eagerly anticipated.
21.Therapeutic
potential of CCR4 antagonists
CCR4
is a CC-chemokine receptor which is expressed on a number of T-cell subsets.
Inhibition of this receptor is of potential interest as a target in allergic
diseases due to its selective
expression on Th2 but not Th1 cells and hence the potential to selectively
inhibit the recruitment of Th2 cells to sites of allergic inflammation
while leaving other immune responses unaffected. CCR4 is also expressed on
regulatory T cells and this has led to the hypothesis that CCR4 blockade or a
CCR4-directed cytotoxic antibody may be effective in treating certain .
ADHESION MOLECULES
22.Very
late activation antigen-4 (VLA-4) antagonists
The
integrin VLA-4 (very late activation antigen-4) is a cell surface receptor that mediates cellular adhesion events crucial
to leukocyte trafficking and activation.
Although results from human clinical trials using inhaled formulations
of small-molecule VLA-4 antagonists have been disappointing to date, a recent
trial using an orally available
antagonist has proved promising. Natalizumab
(Tysabri®), a humanized monoclonal antibody directed against the D4integrin
subunit of VLA-4, was successful
in clinical trials of multiple sclerosis (MS) and has been approved for
this indication. Although natalizumab has provided crucial validation of
VLA-4 as a therapeutic target in humans, it
has yet to be evaluated in any respiratory indication. Clinical trials
with natalizumab also unveiled a potential serious side effect of VLA-4
blockade as three patients were diagnosed with progressive multifocal
leukoencephalopathy following treatment. The effectiveness of natalizumab in
clinical trials has led many in the pharmaceutical industry to target MS rather
than asthma as the primary indication for small-molecule antagonists. As more
drugs targeting VLA-4 reach the market, asthma will likely be reconsidered as
a potential alternative indication.
23.Selectin antagonists and their
potential impact for the treatment of inflammatory lung diseases
Selectin
antagonists comprise a heterogeneous group of synthetic molecules, natural
product compounds and biologics. They are targeted against the selectin
family of cell adhesion molecules (selectins), which are located on the surface of endothelial cells (E- and P-selectin),
platelets (P-selectin) and of leukocytes (L-selectin) Selectins play a
crucial role in the adhesion and activation of leukocytes and platelets in
inflammation. They are supposed to be involved in the pathogenesis of
several respiratory diseases such as asthma and chronic obstructive pulmonary
disease (COPD). Selectin antagonists targeting one, two or all three
selectins (pan- selectin antagonists) were developed. Depending on the target
binding site, sialyl Lewis X (sLeX)-mimicking antagonists can be
distinguished from antagonists mimicking more complex natural ligand
structures like, for example, P-selectin glycoprotein ligand-1 (PSGL-1). To
date, the most advanced pan-selectin
antagonist in development is Bimosiamose
mimicking both sLeX and PSGL-1. It has been demonstrated to be effective in
animal models of inflammatory lung diseases and human clinical trials for
asthma and COPD.
MEDIATOR RECEPTOR ANTAGONISTS
24.Histamine
H4receptor antagonistsate
The
histamine H4receptor (H4R) is expressed on multiple cell types involved in the pathology of asthma.
Emerging preclinical data in animal models of allergic airway
inflammation suggest that H4R antagonists may have a therapeutic
effect against inflammation, and against pathological remodeling and changes
in airway function. Novel aspects of H4R biology suggest it may
also contribute to the etiology of other airway disorders such as chronic
obstructive pulmonary disease and cough. Consequently, H4R antagonists
are being actively pursued by the pharmaceutical and biotech industry as
novel therapies for airway diseases.
25.Antagonists
of the prostaglandin D2receptor CRTH2
Prostaglandin
D2(PGD2) is produced by mast cells, Th2 lymphocytes and
dendritic cells and causes activationOx
of Th2 lymphocytes, eosinophils and basophils through a
high-affinity interaction with the G protein-coupled receptor chemo attractant
homologous receptor expressed on Th2 cells (CRTH2, also known as DP2).
Activation of CRTH2 induces chemotaxis of Th2 lymphocytes and eosinophils and
has the unusual property of promotingTre cytokine
production by Th2 lymphocytes in the absence of allergen or co-stimulation.
The ability of supernatants from immunologically activated mast cells to activate
Th2 cells and eosinophils is mediated by CRTH2. This receptor also plays an
important role in amplifying allergic responses through paracrine activation
-80of Th2 cells. Pharmacological
blockade or genetic ablation of CRTH2 is associated with a reduction in
airways inflammation and reduced levels of mucus, Th2 cytokines and
immunoglobulin E. The central role played by CRTH2 in mediating these
effects suggests that antagonism of this receptor is an attractive approach
to the treatment of chronic allergic disease.
ENZYME INHIBITORS
26.5-Lipoxygenase
inhibition
The
5-lipoxygenase (5-LO) is a key arachidonic acid metabolizing enzyme that generates leukotrienes and other
eicosanoids capable of producing a variety of potent biological functions observed in asthma and other inflammatory
diseases. In spite of the high level of scientific information indicating
a prominent role for the 5-LO pathway in chronic inflammatory diseases, there
is no inhibitor available to effectively test the hypotheses in the clinic.
Novel, nonredox, or iron-ligand
chelators and rather competitive inhibitors of 5-LO are needed. These
agents should provide good efficacy and safety in asthmatics and they may
have a great potential when combined with steroids. Also, new 5-LO inhibitors
may help alleviate patients with a variety of inflammatory diseases.
27.Utility
of cytosolic phospholipase A2D (cPLA2D) inhibitors in
the treatment of asthma
Cytosolic
phospholipase A2α (cPLA2α, PLA type IVA) hydrolyzes arachidonyl phospholipids to initiate
the production of prostaglandins and leukotrienes and generate the
lysophospholipid precursor to platelet activating factor (PAF). Leukotriene
antagonists are approved for the treatment of asthma, and both CRTH2, the
receptor for prostaglandin D2(PGD2), and PAF receptor
have been implicated in asthma. Thus, the concurrent blockade of
prostaglandins, leukotrienes and PAF signaling due to a cPLA2α antagonist
could be beneficial. However, PGE2, another downstream product of
cPLA2α may be
beneficial in asthma. Wyeth has
advanced compounds to phase II clinical trials to evaluate safety and
efficacy of cPLA2αinhibitors in the treatment of osteoarthritis.
These inhibitors are also active in preclinical models of asthma.
ANTIOXIDANTS
28.Antioxidant
therapeutic strategies
In
view of the evidence implicating oxidative stress in the pathogenesis of
several respiratory diseases, one rational approach would be to consider
antioxidant intervention in order to neutralize the increased oxidative
stress, and the subsequent pathology. Several small-molecular-weight
compounds that target oxidant signaling, quench oxidants and the subsequent
reactive aldehydes/carbonyls or boost antioxidant potential in the lung are
currently being tested clinically. Antioxidant agents such as thiol molecules (glutathione/cysteine
and mucolytic drugs, such as N-acetyl-L-cysteine and nacystelyn), dietary polyphenols (curcumin,
resveratrol, greentea, quercetin), erdosteine, fudosteine and carbocysteine
lysine salt, have all been reported to increase
intracellular thiol antioxidant levels and induction of glutathione biosynthesis genes.
PROTEASE INHIBITORS
29.Small-molecule
neutrophil elastase inhibitors as therapies for respiratory disease
There
is significant evidence in the literature to support the concept that inhibition of neutrophil elastase (NE)
will provide antiinflammatory activity, effects on lung remodeling and mucus
hypersecretion, and in addition have a positive impact on host defense.
Therefore, the potential utility of NE inhibitors in respiratory disease is
broad and includes chronic obstructive pulmonary disease, cystic fibrosis and
severe asthma. In addition, NE
inhibitors could provide a replacement therapy for D1-antitrypsin
deficiency. Inhibition of NE should achieve an impact on these diseases
through its multifaceted profile which enhances its probability of success in
the clinic. The potential of oral and inhaled NE inhibitors will be
elucidated in the next decade.
30.The
role of MMP-9 and MMP-12 inhibitors in inflammation
Since
the discovery of the first matrix metalloproteinase (MMP), this ever growing
family of proteinases has been the subject of intense research. Although it
was initially believed that MMPs were solely involved in the turnover and
degradation of the extracellular matrix, there is now data suggesting MMPs act on cytokines, chemokines and
protein mediators to regulate various aspects of inflammation and immunity.
For these reasons, there has been great interest in the development of MMP
inhibitors as novel therapeutics for the treatment of inflammatory diseases
such as asthma and chronic obstructive pulmonary disease.
31. α1-Antitrypsin
therapyt
Currently,
there are a number of approved therapies for the treatment of panacinar
emphysema, a disease that results from severe deficiency of circulating D1-antitrypsin
(AAT). The adoption of AAT therapy in the treatment of hereditary emphysema
and the well-known activity of AAT as an inhibitor of human neutrophil
elastase (HNE) has suggested its use in other indications where
-133unregulated HNE may be a causative factor. These include cystic fibrosis,
chronic lung disease of prematurity and other, more common forms of chronic
obstructive pulmonary disease, such as smoking-related . Other inhibitory
pathways that are known for AAT have suggested its further potential in
asthma therapy. A growing understanding of global mechanisms involved in
respiratory disease progression, together with advances in the inhalation
delivery of AAT, suggest that AAT therapy may expand beyond its current use
as an infusion therapy for AAT deficiency.
INHIBITORS OF FIBROSIS AND VESSELS
32.Proteinase-activated
receptor-1 inhibitors
Proteinase-activated
receptor-1 (PAR1) is the major high-affinity thrombin receptor and
belongs to a unique family of seven transmembrane domain G-coupled receptors.
The discovery of this family of receptors heralded the establishment of a new
paradigm for ligand-receptor interaction mechanisms leading to cellular
signaling in that these receptors are activated by proteolysis rather than
classical ligand binding. PAR1is
widely distributed in the human lung,
and recent evidence indicates a role for this receptor in the pathophysiology
of lung inflammatory and fibrotic responses. The recent development of
potent orally available PAR1antagonists may provide novel
opportunities for therapeutic intervention in conditions, such as acute lung
injury/acute respiratory distress syndrome and pulmonary fibrosis.
33.Small-molecule
inhibitors of transforming growth factor-E type I receptor kinase (ALK5)
Transforming
growth factor Es (GF-E1, TGF-E2 and TGF-E3) are members of a large
superfamily of growth factors required for normal biological functions. As a
consequence of this pleitrophy, dysregulation of this inhibiting TGF-E
signaling has become an attractive strategy for drug discovery. There are
several modes of inhibiting TGF-E signaling: reducing the production of TGF-E
using antisense technology (1), inhibiting the extracellular activation of
latent TGF-E by blocking integrin-mediated activation , and sequestering
circulating TGF-E using soluble TGF-E receptor or monoclonal antibodies. In
addition, a major effort has been invested in inhibiting receptor-mediated
signaling using small-molecule inhibitors of the TGF- E type I receptor
(TGF-ERI) kinase.
34. Serum
amyloid P: A novel antifibrotic agent with therapeutic potential
Serum
amyloid P (SAP) is a highly conserved, naturally circulating serum protein
and a soluble pattern recognition receptor of the innate immune system. The
unique binding activities of SAP suggest that it may localize specifically to
sites of injury and function to aid in the removal of damaged tissue. Recent
discovery of its ability to regulate
certain monocyte differentiation states has identified SAP as a novel and potentially powerful antifibrotic agent,
which warrants testing in human clinical trials.
INHIBITORS OF CELL SIGNALING AND TRANSCRIPTION
35.Phosphodiesterase type 4 (PDE4) inhibition:
Phosphodiesterase
type 4 (PDE4) inhibition remains a seductive target for new drugs for
treatment of a variety of diseases. In many of the cells thought to play a central role in the pathology and
symptomatology of asthma, chronic obstructive pulmonary disease and allergic
rhinitis, increases in the level of intracellular cAMP leads to
suppression of a range of unwanted activities. Since hydrolysis of this key
intracellular mediator is controlled primarily by the action of a family of
PDE4 isoenzymes, suitable inhibitors should deliver the sought-after
efficacy. However, oral agents, including those selective for one isoform or
another, have been hampered by mechanism-based adverse effects. Furthermore,
inhaled agents though well-tolerated have not delivered the promised
benefits. We consider what has been learned from decades of research on PDE4,
and consider whether there is promise for new PDE4 inhibitors.
36. Therapy directed against c-kit
(CD117) and PDGF transmembrane receptor tyrosine kinases
Imatinib, an oral agent licensed for
use in Philadelphia chromosome-positive chronic myeloid leukemia and a variety of other rare conditions, has
activity against a range of receptor and nonreceptor tyrosine kinases. C-kit
(CD117) stem cell factor receptor and platelet-derived growth factor receptor
are transmembrane receptor tyrosine kinases (TMTKs) that are inhibited by
imatinib; inhibition of these TMTKs is expected to modulate mast cells,
eosinophils and airway remodeling. There is a rationale for the use of imatinib in the treatment of severe
allergic and asthmatic disease, and "proof of concept" and
therapeutic clinical trials in humans are required. In addition, a variety of
TMTK inhibitors are in clinical development, and nisotinib and dasatinib represent compounds of interest.
37.Syk
kinase inhibitors
One of the most important kinases in the IgE
signaling pathway is spleen tyrosine
kinase (Syk) which has a critical
function early in the signaling cascade following binding of allergen to receptor
bound IgE on the mast cell. A number of Syk inhibitors have now been
developed which have been shown to effectively inhibit IgE-driven mast cell
degranulation and release of inflammatory cytokines in vitro and
inhibit allergic responses in a variety of in vivo models. In humans,
allergen-driven symptoms were reduced in allergic rhinitic patients exposed
to tree pollen in an outdoor environment following intranasal dosing of the Syk inhibitor R-112. Syk therefore
represents a promising target for therapeutic intervention in allergic
diseases.
38.Targeting
protein kinase C-T for asthma
Protein
kinase C-T (PKC-T) regulates T-cell
receptor (TCR) signaling to interleukin-2 production, with effects on T-cell
effector function but not T-cell development. Using mice deficient in PKC-T,
a critical role has been defined in
Th2-mediated pulmonary inflammation and airway hyperresponsiveness. PKC-T
also regulates Th1 cells in experimental autoimmune encephalomyelitis and
other models of T-cell-mediated autoimmune diseases. Its selective role in
T-cell effector function and the TCR signalosome makes PKC-α an attractive
therapeutic target in T-cell-mediated disease processes. PKC-T is also
expressed in mast cells and may play a role in IgE-mediated signaling.
NUCLEIC ACID THERAPY
39.A multitargeted
antisense therapy directed at CCR3 and the common E-chain of IL-3/IL-5/GM-CSF
TPI ASM8 is an inhaled drug designed to reduce the recruitment and persistence
of chronic inflammatory cells in allergic asthma. TPI ASM8 consists of two RNA-targeted, modified antisense
oligonucleotides directed at the CCR3 chemokine receptor and the common
E-subunit of the interleukin (IL)-3, IL-5 and granulocyte macrophage-colony
stimulating factor (GM-CSF) receptors. TPI ASM8 has a unique mechanism of
action and represents a novel, highly effective approach for respiratory diseases.
40.Antifungal therapy
With up to
60% of patients
with asthma being
atopic to common aeroallergens, sensitization to
fungi appears to be an emerging phenotype conferring an
increased risk of hospital. Several trials in patients with allergic
bronchopulmonary aspergillosis have established the role of antifungal
therapy, but only recently have trials in asthma been undertaken. The Fungal
Asthma Sensitization Trial (FAST)95 studied patients with severe asthma who
were sensitized by a skin prick or radio allergosorbent testing to one or
more fungal allergens and did not fulfill the criteria for allergic
bronchopulmonary mycosis. Treatment
with oral itraconazole 200
mg twice daily/placebo for 32
weeks resulted in clinically significant improvements of
asthma quality of
life scores as
well as rhinitis and morning
peak flows.
Interestingly, the precise mechanisms of antifungal action in asthma
remain unknown. Although generally
accepted to modulate the immunological response, concerns remain about
the azole–corticosteroid interaction. Although active
against some species of Aspergillus, itraconazole is not active
against all of the fungal species that
the human airway is constantly subjected to. Its microbiological activity is
further limited by variable absorption and need for monitoring in contrast to
newer triazoles that have better oral bioavailability. Further trials in this
interesting area are warranted.
41.Thermal
bronchoplasty
Targeted treatment of the airway smooth muscle hypertrophy
seen in chronic asthma, aside from other changes of airway remodeling including
goblet cell hyperplasia, increased mucus secretion,
and increased vascularization, has
been made possible with a novel technique utilizing radiofrequency
ablation. Treatment involves delivering
thermal energy through use of a
standard bronchoscope into which a catheter containing an expandable basket
is inserted. When extended, this comes into circumferential contact with the
walls of targeted airways, thus depleting smooth muscle mass with the hope of
attenuating the bronchoconstrictor response. In clinical studies, thermal
bronchoplasty has been shown to reduce parameters of airways
hyperresponsiveness and minimize exacerbations.
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- Chiranjeevi Venkatesh
BITS Pilani
Tags:
Pharmacology