| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 25, 2006
Contents
Strategies for the Improvement of Asthma Therapy
Executive Editor: Andreas Pahl
Editorial Pp. 3173-3174
Current Animal Models of Bronchial Asthma Pp. 3175-3194
I. Kurucz and I. Szelenyi
[Abstract]
Pharmacogenomics of Asthma Pp. 3195-3206
A. Pahl, E. Benediktus and L. Chialda
[Abstract]
Phosphodiesterase 7A: A New Therapeutic Target
for Alleviating Chronic Inflammation? Pp. 3207-3220
M.A. Giembycz and S.J. Smith
[Abstract]
Nitric Oxide in Asthma Therapy Pp. 3221-3232
G. Folkerts and F.P. Nijkamp
[Abstract]
Biopharmaceutical Therapeutics for Asthma Remodeling
Pp. 3233-3240
A.M. Das, D.E. Griswold, T.J. Torphy and L. Li
[Abstract]
Corticosteroid Design for the Treatment of Asthma:
Structural Insights and the Therapeutic Potential of Soft
Corticosteroids Pp. 3241-3260
N. Bodor and P. Buchwald
[Abstract]
Advances in Asthma and COPD Treatment: Combination
Therapy with Inhaled Corticosteroids and Long-Acting β2-Agonists
Pp. 3261-3279
A. Miller-Larsson and O. Selroos
[Abstract]
Immune Stimulatory Strategies for the Prevention
and Treatment of Asthma Pp. 3281-3292
G. Wohlleben and K.J. Erb
[Abstract]
Treatment of Allergic Asthma by Targeting Transcription
Factors Using Nucleic-Acid Based Technologies Pp.
3293-3304
S. Sel, W. Henke, A. Dietrich, U. Herz and H. Renz
[Abstract]
Abstracts
[Back
to top]
Editorial
Strategies for the Improvement of Asthma Therapy
Asthma bronchiale, affecting 155 millions people worldwide,
has emerged as a major public health problem worldwide over
the past 20 years. Although data indicate that current asthma
therapies led to limited decreases in death rates, it continues
to be a significant health care problem. As we head into the
21st century doctors have a vast arsenal of drugs and treatments
at their disposal allowing asthmatics to lead normal fulfilled
lives. Can we improve asthma therapy available at present?
Indeed, despite a large number of drugs available to clinicians,
up to 15% of patients suffer from uncontrollable disease symptoms,
increasing the demand for novel therapies that possess new
modes of action. Despite considerable efforts by the pharmaceutical
industry, it has been difficult to develop novel therapeutic
agents; the leukotrien modifiers are the only new class of
asthma treatments that has been approved. Fortunately, omelizumab
(an anti-IgE) has very recently been introduced and appears
to be effective and an addition to the currently available
therapeutics. In addition, there are numerous therapies in
clinical development that combat the inflammation found in
asthma.
This issue of “Current Pharmaceutical Design”
contains the text of nine invited review articles. The selection
of topics and authors was made with the intention to cover
various areas of ongoing drug development efforts for asthma
therapy.
Asthma is not a natural disease in the animal kingdom. Debates
come up from time to time whether mice can develop asthma
or not. Therefore the variety of artificially established
animal models is quite wide. Animal experimentation has been
indispensable not only in establishing or verifying the safety
and the effectiveness of a given drug candidate but animal
models have been crucial in providing basic information about
the physiological and pathological processes associated with
the disease. Kurucz and Szelenyi [1] review the current
state of the art of animal models used to investigate asthma.
They analyse how these different models contributed to our
understanding of the disease and how successfully they helped
to recognize or to introduce new, more effective pharmacons
that can be used for the treatment of asthma.
Great variability in patient responses to current asthma therapy
is observed in the clinic. Whereas, for example, a lot of
patients respond well to steroid treatment, some patients
are resistant to this kind of therapy. The review by Pahl
et al. [2] deals with various aspects of genetic and
genomic variability as one source for this observed variability.
For many years phosphodiesterases (PDEs) attracted little
attention in drug discovery efforts. However, the success
of viagra and new generation PDE5 inhibitors reinforced interest
in targeting other PDEs for chronic airway diseases. Meanwhile,
PDE4 inhibitors such as roflumilast are close to market approval.
Giembycz and Smith [3] review the literature of another
phosphodiesterase isoenzyme (PDE7A) as a new drug candidate
for asthma therapy.
Folkerts and Nijkamp [4] will mainly deal with the
possible therapeutic application of the NO concept. Such interventions
might be targeted in various ways, e.g. by using selective
reactive nitrogen- and oxygen-scavengers, selective NO donors
and selective nitric oxide synthase inhibitors. The possible
therapeutical opportunities are reviewed in this paper. Nitric
oxide has already made it from the bench to the bedside, and
it is likely that new developments in this area will drastically
change respiratory medicine during the coming 5-10 years.
Airway remodelling is one of the hallmarks of asthma pathogenesis.
The article by Das et al. [5] will focus on this
aspect. Since the pathological changes are thought to contribute
to the clinical symptoms of the disease new targets may arise
from these changes. It may be feasible to have therapeutics
with disease modifying effects in chronic inflammatory diseases.
Therefore, this raises the possibility of approaching asthma
with the aim of developing disease modifying therapies.
Inhaled corticosteroids still are the most effective treatment
available for allergic airway diseases and are likely to remain
the cornerstone of managing persistent asthma/allergic rhinitis
in the foreseeable future. Bodor and Buchwald [6],
with their article on the pharmacology of soft corticosteroids,
highlight on a group of compounds showing better separation
of local effects from systemic side effects. Soft corticosteroids
are particularly well-suited for this purpose, and because
of their promising airway activity.
Asthma treatment guidelines advocate the use of long-acting
β2-agonists
(LABA) in addition to inhaled corticosteroids (ICS) in patients
whose asthma is uncontrolled by ICS alone, thereby addressing
two processes fundamental to asthma: bronchoconstriction and
inflammation. Superior control of asthma and COPD by ICS/LABA
combination therapy has been demonstrated. Miller-Larsson
and Selroos [7] review results from clinical studies
suggesting additive and potentially synergistic effects when
the two agents are used in combination. The exact mechanisms
for the enhanced efficacy of ICS/LABA combinations are under
investigation but include, among others, possible drug interactions
at the receptor level or interwoven signalling pathways, which
may imply improved function of β2-adrenoceptors
and steroid receptors.
Recent epidemiological and clinical studies have provided
compelling evidence suggesting that infectious diseases, which
induce Th1 responses, influence the development of allergic
disorders. In their review, Wohlleben and Erb [8]
will discuss the data showing that animals can be protected
from developing asthma by immune stimulation leading to Th1
or regulatory T cell responses. Possible future human use
and potential side effects of the described strategies are
also discussed.
In the field of experimental medicine, nucleic-acid based
technologies are most notably applied to cancer and viral
therapy. But several studies recently published in the field
of allergy, especially of asthma, impressively demonstrate
that nucleic-acid based technologies are a new promising approach
for the treatment of allergic diseases. Sel et al.
[9] review the action mechanisms, the design and therapeutic
application of nucleic-acid based technologies especially
in regard to their therapeutic usage in the treatment of allergic
diseases.
All the above reviews will provide an update for researchers
on current progress in the area of current asthma drug design.
We would be gratified if the articles within this issue kindle
innovative ideas among the readers who are involved with the
design and discovery of agents for the therapy of asthma.
I am sincerely grateful to the individuals who contributed
to this body of work. All are experts in their fields. They
devoted a large amount of time to the production of these
in-depth reviews. Thanks to them all.
References
[1] Kurucz I, Szelenyi I. Current Animal Models of Bronchial
Asthma. Curr Pharm Design 2006; 12(25): 3175-3194.
[2] Pahl A, Benediktus E, Chialda L. Pharmacogenomics of Asthma.
Curr Pharm Design 2006; 12(25): 3195-3206.
[3] Giembycz MA, Smith SJ. Phosphodiesterase 7A: A New Therapeutic
Target for Alleviating Chronic Inflammation? Curr Pharm Design
2006; 12(25): 3207-3220.
[4] Folkerts G, Nijkamp FP. Nitric Oxide in Asthma Therapy.
Curr Pharm Design 2006; 12(25): 3221-3232.
[5] Das AM, Griswold DE, Torphy TJ, Li L. Biopharmaceutical
Therapeutics for Asthma Remodeling. Curr Pharm Design 2006;
12(25): 3233-3240.
[6] Bodor N, Buchwald P. Corticosteroid Design for the Treatment
of Asthma: Structural Insights and the Therapeutic Potential
of Soft Corticosteroids. Curr Pharm Design 2006; 12(25): 3241-3260.
[7] Miller-Larsson A, Selroos O. Advances in Asthma and COPD
Treatment: Combination Therapy with Inhaled Corticosteroids
and Long-Acting β2-Agonists.
Curr Pharm Design 2006; 12(25): 3261-3279.
[8 Wohlleben G, Erb KJ. Immune Stimulatory Strategies for
the Prevention and Treatment of Asthma. Curr Pharm Design
2006; 12(25): 3281-3292.
[9] Sel Serdar, Henke W, Dietrich A, Herz U, Renz H. Treatment
of Allergic Asthma by Targeting Transcription Factors Using
Nucleic-Acid Based Technologies. Curr Pharm Design 2006; 12(25):
3293-3304.
Andreas Pahl
Department of Experimental and
Clinical Pharmacology and Toxicology,
University of Erlangen-Nürnberg,
Fahrstr. 17, D-91054 Erlangen,
Germany
E-mail: pahl@pharmakologie.uni-erlangen.de
[Back to top]
Current Animal Models of Bronchial Asthma
I. Kurucz and I. Szelenyi
Human asthma is on the rise worldwide. The necessity to develop
effective treatments against it requires an organized effort
which covers every aspect of the disease from the pathological
alterations via the genetic background to the use
and development of active remedies. In these processes animal
experiments have served an indispensable role. As asthma is
not a natural disease in the animal kingdom the variety for
artificially established animal models is quite wide. The
possible selection ranges from the laboratory mouse to the
horse, it includes ferret and sheep and even favorite pets
such as cats and dogs. The large number of the models indicates
that to some extent they might not be appropriate or it means
that there is no generally accepted model of human asthma.
Whatever the reason for this diversity animal models helped
us to understand the detailed pathogenesis of some aspects
of the disease, they helped us to develop compounds which
are more active then previously used ones, and these models
proved to us that human asthma is a unique, possibly species-specific
disease the eradication of which requires a huge effort. This
enormous task should include the collaboration of the clinical
and basic research for the development of improved, advanced
animal models, which in turn could strengthen our understanding
about human asthma.
[Back to top]
Pharmacogenomics of Asthma
A. Pahl, E. Benediktus and L. Chialda
Patient response to asthma therapy is consistently observed
to be heterogeneous. Pharmacogenomics is the study of inherited
differences in interindividual drug disposition and effects,
with the goal of selecting the optimal drug therapy and dosage
for each patient. This review will cover selected examples
of gene polymorphisms that influence the outcome of asthma
therapy, and whole-genome expression studies using microarray
technology that have shown tremendous potential for benefiting
asthma pharmacogenomics. The utility of the mouse as an experimental
system for pharmacogenomic discovery will also be discussed
in the context of asthma therapy.
[Back to top]
Phosphodiesterase 7A: A New Therapeutic Target for
Alleviating Chronic Inflammation?
M.A. Giembycz and S.J. Smith
Over the last fifteen years there has been much excitement
in the idea that targeting phosphodiesterase (PDE) 4 with
small molecule inhibitors could lead to the discovery of novel,
steroid-sparing compounds with utility in treating a multitude
of diseases associated with chronic inflammation. However,
dose-limiting side effects, of which nausea and vomiting are
the most common are worrisome, have hampered their clinical
development. Indeed, a fundamental obstacle that still is
to be overcome by the pharmaceutical industry is to make compounds
that dissociate beneficial from the adverse events. Unfortunately,
both of these activities of PDE4 inhibitors represents an
extension of their pharmacology and improving the therapeutic
ratio has proved to be a major challenge. Several strategies
have been considered, with some degree of success, but compounds
with an optimal pharmacophore still have not been reported.
An alternative approach to targeting PDE4 is to inhibit other
cAMP PDE families that are also expressed in immune and pro-inflammatory
cells in the hope that the beneficial activity can be retained
at the expense of side effects. One such candidate is PDE7A.
In this article we review the literature on PDE7A and explore
the possibility that selective small molecule inhibitors of
this enzyme family could provide a novel approach to alleviate
the inflammation that is associated with many inflammatory
diseases including asthma, chronic obstructive pulmonary disease,
atopic dermatitis, psoriasis, lupus, rheumatoid arthritis
and multiple sclerosis.
[Back to top]
Nitric Oxide in Asthma Therapy
G. Folkerts and F.P. Nijkamp
The discovery of the delicate role of endogenous nitric oxide
in the homeostasis of various cellular functions and the dynamic
behaviour of the airways, has led to a new, rapidly progressing
area of physiological science, that has direct bearing for
our understanding of multiple airway diseases.
The potentially protective effects of nitric oxide include:
neuromodulation by mediating inhibitory non-cholinergic non-adrenergic
nerve activity; smooth muscle relaxation, attenuating airway
hyperresponsiveness to bronchoconstrictor stimuli and immun-suppression.
NO itself or SNO can be administerd directly to the airways,
and the development of gene transfer therapy seems to become
a realistic approach in the treatment of airway diseases.
However, NO has also harmfull effects, especially when it
interacts with other molecules. At present, there are novel
opportunities to modulate nitric oxide-synthesis aimed to
restore the balance between the protective and deleterious
effects of nitric oxide. This is potentially beneficial in
both airway and alveolar diseases. Such interventions might
be targeted in various ways, e.g. by using selective reactive
nitrogen- and oxygen- scavengers, selective NO donors and
selective nitric oxide synthase inhibitors. The possible therapeutical
opportunities are reviewed in this paper. Nitric oxide has
already made it from the bench to the bed-side, and it is
likely that new developments in this area will drastically
change respiratory medicine during the coming 5-10 years.
[Back to top]
Biopharmaceutical Therapeutics for Asthma Remodeling
A.M. Das, D.E. Griswold, T.J. Torphy and L. Li
Current asthma therapy is aimed at controlling disease symptoms.
A subset of asthma patients remains symptomatic despite optimal
therapy indicating that an unmet medical need exists for these
patients. Innovative therapeutics are needed to treat the
unmet need in asthma and biopharmaceutical approaches may
provide an opportunity for identifying these agents. It is
proposed that airway remodeling contributes to asthma symptoms
and this feature of disease pathology may be a target for
future therapies. The current review focuses on the contribution
of one feature of airway remodeling, subepithelial fibrosis,
towards disease and highlights some of the mechanisms that
may contribute to this feature of airway remodeling. Further,
some potential molecular targets are identified for consideration
for therapeutic intervention.
[Back to top]
Corticosteroid Design for the Treatment of Asthma:
Structural Insights and the Therapeutic Potential of Soft
Corticosteroids
N. Bodor and P. Buchwald
Inhaled and intranasal corticosteroids (ICSs) still are
the most effective treatment available for allergic airway
diseases and are likely to remain the cornerstone of managing
persistent asthma/allergic rhinitis in the foreseeable future.
Even if the therapeutic index of this class increased significantly
with the introduction of newer corticosteroids, and even if
new therapeutic potentials are beginning to emerge with our
increasing understanding of the mechanisms of asthma, chronic
obstructive pulmonary disease, and rhinitis, corticosteroid
development still remains a very important field for drug
designers. After a brief review of issues related to the structure-activity
relationships of glucocorticoids and the main determinants
of their receptor-binding affinity at the glucocorticoid receptor,
the main focus of the present article will be on the development
of soft corticosteroids, as they are particularly well suited
to separate local activity from systemic side effects, which
still is an important issue for ICSs. Design consideration
required in the search for safe and effective soft drugs on
one hand, and safe and effective ICSs on the other hand, will
be briefly discussed and illustrated with a number of cases,
in particular, with that of loteprednol etabonate and etiprednol
dicloacetate, soft corticosteroids that are being developed
for a full spectrum of therapeutic applications including
asthma and allergic rhinitis.
[Back to top]
Advances in Asthma and COPD Treatment: Combination
Therapy with Inhaled Corticosteroids and Long-Acting β2-Agonists
A. Miller-Larsson and O. Selroos
Asthma treatment guidelines advocate the use of long-acting
β2-agonists
(LABA) in addition to inhaled corticosteroids (ICS) in patients
whose asthma is uncontrolled by ICS alone, thereby addressing
two processes fundamental to asthma: bronchoconstriction and
inflammation. Superior control – including a reduction
in severe exacerbations – of asthma and COPD by ICS/LABA
combination therapy has been demonstrated. Results from clinical
studies suggest additive and potentially synergistic effects
when the two agents are used in combination. No new safety-related
issues have been identified with ICS/LABA compared with the
monocomponents.
The exact mechanisms for the enhanced efficacy of ICS/LABA
combinations are under investigation but likely include drug
interactions at the receptor level and interwoven signalling
pathways, which may result in improved function of β2-adrenoceptors
and steroid receptors. Data from preclinical studies provide
evidence of additive, compensatory, complementary and synergistic
effects of ICS and LABA in the control of inflammation and
airway and lung remodelling. These effects may contribute
to the improved efficacy seen when treating asthma and COPD
with ICS/LABA combinations in clinical studies.
Two ICS/LABA combination products are available: budesonide/formoterol
(Symbicort®)
and salmeterol/fluticasone propionate (Seretide™).
An ICS/LABA combination in a single inhaler represent safe,
effective and convenient treatment options for the management
of patients with asthma and COPD. Clinical results also suggest
that adjustable dosing with budesonide/formoterol provides
better asthma control than fixed dosing. Further elucidation
of the underlying mechanisms responsible for this superior
disease control is needed.
[Back to top]
Immune Stimulatory Strategies for the Prevention and
Treatment of Asthma
G. Wohlleben and K.J. Erb
The severity and incidence of asthma has dramatically increased
in the developed nations over the last decades. Although the
reason for this development is unknown, epidemiological studies
and experimental data have lead to the suggestion that this
phenomenon is associated with the decline of infectious diseases,
which induce T helper 1 and/or T regulatory responses. Supporting
this view are recent publications showing that animals can
be protected from developing asthma by using different immune
stimulatory strategies. One approach is based on vaccinations
using live or killed bacteria or their components, CpG-ODNs
or DNA vaccination, which all induce allergen-specific or
unspecific Th1 responses. Th1 responses lead to the production
of IFN-γ,
IL-12, IL-18 and IL-23, thereby inhibiting Th2 responses and
thus the development of asthma. A further strategy both for
the prevention and therapy of asthma is the induction of Tr
cells. Tr cells have also been shown to suppress allergic
Th2 responses, however, in contrast to Th1 cells through a
cell/cell contact mediated mechanism or by the secretion of
the anti-inflammatory cytokines IL-10 and/or TGF-β.
Furthermore, there is growing information on how to induce
Tr cells both in animals and humans. Here we review the data
showing that animals can be protected from developing asthma
by immune stimulation leading to Th1 or Tr responses. Possible
future human use and safety of the described strategies are
also discussed.
[Back to top]
Treatment of Allergic Asthma by Targeting Transcription
Factors Using Nucleic-Acid Based Technologies
S. Sel, W. Henke, A. Dietrich, U. Herz and H. Renz
There is considerable evidence that T-helper 2 (Th2)
cells play a central role in the pathogenesis of allergic
diseases such as bronchial asthma, hay fever or food allergy.
The differentiation of naïve T cells into Th2 cells producing
a specific pattern of cytokines is tightly controlled and
regulated by transcription factors. Thus down-regulation of
mRNA-levels of a single transcription factor leads to a “knock-down”
of several mediators simultaneously, representing an advantage
compared to earlier approaches involving down-regulation of
one intercellular inflammatory mediator, which is unlikely
to influence all pathophysiological aspects of the disease.
We review the impact of specific and master transcription
factors involved in Th2 cell commitment and evaluate approaches
for the down-regulation of these proteins by degradation of
their mRNA using nucleic-acid based technologies including
antisense oligonucleotides, ribozymes, DNAzymes, decoys oligonucleotides
and RNA interference.
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