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Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
ISSN: 1871-5230
Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
Volume 5, Number 4, November 2006
Contents
Trends in Inflammation – Leads in
Immunopharmacology
Guest Editor: Ekaterini Tiligada
Editorial Pp. 287-288
Therapeutic Exploitation of Endogenous Anti-Inflammatory
Mechanisms: Old and New Leads Pp. 289-305
D. Renshaw, P. Urquhart and M. Perretti
[Abstract]
Development and Chemistry of Histamine H4
Receptor Ligands as Potential Modulators of Inflammatory and
Allergic Responses Pp. 307-322
J.D. Venable and R.L. Thurmond
[Abstract]
The Mast Cell Pathway to Inflammation and Homeostasis:
Pharmacological Insights Pp. 323-334
S. Kakavas, E. Zampeli, K. Papamichael, B. Delitheos and
E. Tiligada
[Abstract]
Evaluation of the Risk/Benefit Ratio of Old and New
Anti Inflammatory Drugs Pp. 335-352
P.F. Mannaioni, V. Fabbroni, R. Mastroianni and E. Masini
[Abstract]
New Therapeutic Interventions in Airway Inflammatory
and Allergic Diseases Pp. 353-356
M. Ennis
[Abstract]
Trends in the Pharmacology of Inflammatory and Allergic
Eye Disorders Pp. 357-363
R. Sgrulletta, M. Coassin and S. Bonini
[Abstract]
Anti-Inflammatory Agents in Ageing and Age-Associated
Diseases Pp. 365-373
S. Bonovas and N.M. Sitaras
[Abstract]
Genomic Targets in Inflammation and in Allergic Reactions:
A Patient-oriented Approach Pp. 375-381
H. Saito
[Abstract]
Genomic Strategies in Pharmacology of Asthma and Autoimmunity
Pp. 383-399
C. Szalai , E.I. Buzás, A.K. Fülöp, L.
K hidai and A. Falus
[Abstract]
Abstracts
[Back to top]
Editorial
Inflammatory reactions have attracted wide interest
lately, as a consequence of their contribution to abnormalities
additional to the long-established immune system-related diseases.
The advancements in molecular biology and genomic/post-genomic
sciences point to a comprehensive synthesis of information
on the physiology and the pharmacological interventions of
“inflammation-related” conditions. Without excluding
the decisive character of inflammatory mediators, such as
histamine and cytokines, and the latest significant developments
in atopy/allergy, autoimmunity and infections, recent evidence
provides insights into the participation of related mechanisms
in a variety of other common human conditions, including cardiovascular
and endocrine diseases, neurological disorders, and cancer;
thus expanding the endeavours of immunopharmacological investigation.
Interestingly, inflammation and the implicated cells and mediators,
nowadays are regarded as “double-edged swords”;
a characterization derived from their remarkable duality in
favoring immune system function as well as in eliciting inflammatory
and pro-inflammatory responses [1-4]. The multi-system modulatory
pathways implicated in the polarization of T helper (TH)
lymphocytes of the TH1 and TH2 type
[5], which are basically considered as regulators of immunostasis
in health and disease [6]; and the organ and tissue specific,
sometimes unexplained and paradoxical responses of prostaglandins
[2] may serve as mere paradigms of the dual character of related
endogenous circuits. The basis for these phenomena is not
understood adequately, thereby urging the need to identify
the homeostatic and self-regulating feedback mechanisms. In
this concept, the efficacy, toxicity and drug interactions
in therapeutic regiments, involving old and new agents [2,
5], need thorough evaluation, aiming at optimally exploiting
the latest data for the development of beneficial end-points.
Regarding pharmacological intervention in the endogenous cross-talk,
prototype drugs, already under phase II clinical trials, have
been directed towards a specific molecular target; yet simultaneously
modulating multiple signaling cascades in highly conserved
homeostatic pathways, like the cellular stress response [7-10].
The articles in this special issue seek (i) to summarize the
state-of-the-art in newly recognized mediators of homeostatic
mechanisms of the organism; (ii) to explore novel aspects
of well established inflammatory cells and mediators; and
(iii) by classical and genomic pharmacological studies, to
evaluate some current and anticipated anti-inflammatory strategies.
These fundamental approaches integrate immunopharmacological
data, challenging efficient therapeutic intervention.
Commencing with glucocorticoids, the prominent example of
drugs developed on an endogenous anti inflammatory pathway,
the article by Prof. Perretti’s group [11] elaborates
on the most recent research on specific effectors of antiinflammation,
like peptides, polyunsaturated fatty acid derivatives and
the anti-inflammatory short-lived gases nitric oxide (NO)
and carbon monoxide (CO). In order to control inflammatory
pathologies, the authors propose that understanding of a given
anti-inflammatory circuit would be of great help in developing
more efficient drugs that mimic the way our own body assures
the inflammatory response. However, long established inflammatory
mediators, like histamine, have not been ignored by immunopharmacologists.
The discovery of the novel histamine H4 receptor
has lead to a reassessment of the role of histamine in several
pathophysiological conditions and offered to the amine a new
perspective beyond its traditional H1- mediated
immunopharmacological properties [12]. Thus, as described
by Dr Venable and Dr Thurmond in this issue [12], the H4
receptor could be a good medicinal chemistry target for the
rational development of compounds to treat a variety of allergic
and inflammatory conditions. Likewise, our group presents
recent data on the differentially released pro-inflammatory
and antiinflammatory mediators from the somewhat neglected
mast cell, that support additional versatile effector roles
for these phenotypically diverse components of the immune
system, beyond their historical involvement in type I hypersensitivity
reactions [13]. Consequently, Prof. Mannaioni’s group
provides a comprehensive risk-benefit insight not only into
the widely prescribed non-steroidal anti-inflammatory drugs
(NSAIDs, aspirin; Coxibs like celecoxib, rofecoxib) and acetaminophen,
but also into the newly developed NO-NSAIDs or COX-inhibiting
NO donors (CINODs) and CO-releasing molecules (CO-RMs) [14].
Subsequently, two reviews address issues concerning therapeutic
strategies in controlling two conditions with substantial
socioeconomic implications, particularly in developed countries
[15], that appear to have a strong atopic/allergic component:
asthma [16] and ocular allergies [17]. Different formulations
of steroids and 2 agonists, targeting inflammation and asthma,
have been reaching the market for many years. The review by
Prof. Ennis [16] considers briefly the recently licensed antiimmunoglobulin
E (anti-IgE) agent; the promising selective adenosine A2B
receptor antagonists and phosphodiesterase inhibitors, the
statins and ambroxol; and some possible treatment approaches
that are open to investigation, like the H4 receptor antagonists
and the toll-like receptor (TLR) ligands. In the field of
ocular allergies, Prof. Bonini’s group describes a wide
spectrum of topical pharmacological agents, including NSAIDs,
antihistamines, corticosteroids used in the aggressive treatment
of sight-threatening forms of allergic conjunctivitis and
the newer immunosuppressive drugs that have demonstrated a
higher safety profile when tested in the treatment of some
forms of ocular allergy [17]. Since several diseases associated
with ageing comprise a component of chronic inflammation,
which influences their pathogenesis, progression and prognosis,
Dr Bonovas and Prof. Sitaras present a selection of data relating
inflammation, anti-inflammatory agents and the major age associated
diseases [18]. At this point one has to consider the emerging
area of pharmacogenomics, which is growing by the availability
of databases, high-throughput technologies and bioinformatics.
The completion of the human genome project in 2001 [19] signified
the beginning of the post-genomic era and initialized the
promise of transition from evidence-based medicine to genomic,
individualized medicine. By using new approaches and technologies,
the scientific community now attempts to gather information
from genomic and post-genomic studies, thus shifting biomedical
research to the rather remote target of personalized medicine.
In this hot theme issue, two articles introduce these topics
in the area of inflammatory and allergic conditions. As in
every innovative approach, in earlier related patient-oriented
studies, only a few projects were, and in many 288 Anti-Inflammatory
& Anti-Allergy Agents in Medicinal Chemistry, 2006, Vol.
5, No. 4 Editorial cases still are, successful. Dr Saito presents
the pros and cons of microarray-based studies in the field
of clinical allergy and inflammation, focusing on the most
recent data using a patient-oriented approach and discussing
ways towards future therapeutic targets [20]. Finally, Prof.
Falus’ group summarizes the recent pharmacogenomic trends
in inflammatory diseases and highlights some genes and genetic
variations implicated in asthma and autoimmune conditions
that are potential new drug targets [21].
In conclusion, by avoiding extensive analysis of the ample
available information, the articles in this issue focused
on the synthesis of significant trends in inflammation,
with the anticipation to expose leads in immunopharmacology.
Thanks are due to all authors for their decisive contributions,
as well as to my Ph.D. students, Evangelia Zampeli and Vassilios
Delitheos, for their participation in editing this issue.
REFERENCES
[1] Aggarwal, B.B.; Shishodia, S.; Sandur S.K.; Pandey, M.K.;
Sethi, G. Biochem. Pharmacol., 2006,
(in Press).
[2] Miller, S.B. Semin. Arthritis Rheum., 2006,
36, 37.
[3] Croll, S.D.; Goodman, J.H.; Scharfman, H.E. Adv. Exp.
Med. Biol., 2004, 548, 57.
[4] Stoll, G.; Jander, S.; Schroeter, M. Adv. Exp. Med.
Biol., 2002, 513, 87.
[5] Salem, M.L. Curr. Drug Targets Inflamm. Allergy,
2004, 3, 97.
[6] Kidd, P. Altern. Med. Rev., 2003,
8, 223.
[7] Papamichael, K.; Vovou, I.; Miligkos, V.; Stavrinidis,
E.; Delitheos, A.; Tiligada, E. Folia Microbiol.,
2006, 51, 33.
[8] Tiligada, E. Curr. Med. Chem. 2006,
13, 1317.
[9] Sharp, S.; Workman, P. Adv. Cancer Res., 2006,
95, 323.
[10] Zhu, F.G.; Pisetsky, D.S. Infect. Immun., 2001,
69, 5546.
[11] Renshaw, D.; Urquhart, P.; Perretti, M. Anti-Inflamm.
Anti-Allergy Agents Med. Chem., 2006
(this issue)
[12] Venable, J.D.; Thurmond, R.L. Anti-Inflamm. Anti-Allergy
Agents Med. Chem., 2006 (this issue)
[13] Kakavas, S.; Zampeli, E.; Papamichael, K.; Delitheos,
B.; Tiligada, E. Anti-Inflamm. Anti-Allergy Agents Med.
Chem., 2006 (this issue)
[14] Mannaioni, P.F.; Fabbroni, V.; Mastroianni, R.; Masini,
E. Anti-Inflamm. Anti-Allergy Agents Med. Chem.,
2006 (this issue)
[15] Bousquet, J.; Bousquet, P.J.; Godard, P.; Daures J.-P.
Bull. World Health Organ., 2005,
83, 548.
[16] Ennis, M. Anti-Inflamm. Anti-Allergy Agents Med.
Chem., 2006 (this issue)
[17] Sgrulletta, R.; Coassin, M.; Bonini, S. Anti-Allergy
Agents Med. Chem., 2006 (this issue)
[18] Bonovas, S.; Sitaras N.M. Anti-Allergy Agents Med.
Chem., 2006 (this issue)
[19] International human genome sequencing consortium. Nature,
2001, 409, 860.
[20] Saito H. Anti-Allergy Agents Med. Chem., 2006
(this issue)
[21] Szalai, C.; Buzás, E.; Fülöp, A.K.;
K hidai, L.; Falus, A. Anti-Allergy Agents Med. Chem.,
2006 (this issue)
Ekaterini Tiligada
Guest Editor
Department of Pharmacology
Medical School, University of Athens
M. Asias 75, GR-115 27 Athens, Greece
Tel: +30 2107462575
Fax: +30 2107462554
E-mail: aityliga@med.uoa.
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Therapeutic Exploitation of Endogenous Anti-Inflammatory
Mechanisms: Old and New Leads
D. Renshaw, P. Urquhart and M. Perretti
Understanding the way our body switches off host defence responses
has yielded some of the most innovative recent discoveries
in inflammation research. In reality the concept is not new,
and was already implicit in early publications of the 1970s’
which showed that during inflammation, glucocorticoids are
increased in the circulation and that these protect the host
from over-shooting and ensuing self-inflicted injury. Stemming
from the first example of drugs developed on an endogenous
anti-inflammatory pathway, that of the glucocorticoid, we
have here touched upon other counter-regulatory breakpoints,
such as those centred on melanocortins; the annexin 1 system;
the polyunsaturated fatty acid derivatives lipoxins and resolvins;
galectin-1 and selected others, including novel chemical entities
engineered to release anti-inflammatory gases and factors
originally discovered in the developmental field. We propose
that understanding the molecular mechanisms switched on by
a given anti-inflammatory mediator and the events it modulates
in target cells will be of great help in developing innovative
ways to control inflammatory pathologies. This seems quite
articulated and with a degree of complexity in the group of
developmental axonal guidance factors.
We propose that drugs discovered along this philosophy will
have a better compliance and would be theoretically devoid
of side effects since they will be acting by mimicking the
way our own body assures the inflammatory response is restricted
both spatially and temporally.
[Back to top]
Development and Chemistry of Histamine H4
Receptor Ligands as Potential Modulators of Inflammatory and
Allergic Responses
J.D. Venable and R.L. Thurmond
Histamine, which is known to play a role in most inflammatory
conditions including allergy, asthma and autoimmune diseases,
is a ubiquitous chemical messenger that has numerous functions.
The inflammatory responses of histamine have long been believed
to be mainly mediated by the histamine H1 receptor.
Indeed the importance of histamine in the pathology of many
diseases, like asthma, has been defined by whether traditional
antihistamines, which are H1 receptor antagonists,
are efficacious. The discovery of a fourth histamine receptor
(H4) has prompted the questioning of these assumptions.
The H4 receptor is expressed on mast cells, eosinophils,
basophils, dendritic cells and T cells suggesting that it
may play an important role in inflammatory responses. The
discovery of selective ligands for this receptor has been
crucial in uncovering its function. These tools have been
used to show that the receptor plays a role in mast cell and
eosinophil chemotaxis, as well as cytokine production in dendritic
cells and T cells. In addition H4 receptor antagonists
have efficacy in a variety of inflammatory animal models including
peritonitis, colitis and airway inflammation models. These
data suggest that the H4 receptor is an attractive
medicinal chemistry target for possible treatment of inflammation,
allergy and asthma. Herein we describe the recent advances
regarding the biology of the histamine H4 receptor,
as well as detail the progress in developing imidazole and
non-imidazole based modulators of this receptor as anti-inflammatory
therapies.
[Back to top]
The Mast Cell Pathway to Inflammation and Homeostasis:
Pharmacological Insights
S. Kakavas, E. Zampeli, K. Papamichael, B. Delitheos and
E. Tiligada
Mast cells (MCs) were first described by Paul Ehrlich as well
fed granular cells that stain metachromatically. Today MCs
are regarded as multifunctional, granulated, tissue-dwelling
cells distributed in the perivascular spaces and connective
tissues of every major organ of the body. Their long recognized
phenotypic diversity might be associated not only with their
anatomic distribution and mediator repertoire, but also with
their functional characteristics related to the regulation
of effector pathways. In addition to their historical involvement
in type I hypersensitivity response, MCs have emerged as versatile
effector cells with functional diversity and homeostatic functions
in non-IgE-mediated inflammatory responses, autoimmunity,
bidirectional interactions with the neuroendocrine circuit,
the urinary, gastrointestinal, cardiovascular and endocrine
systems, in metabolism and malignancy. Thus, MCs appear to
receive, integrate and transmit a wide range of signals in
their microenvironment, coordinated by the differential release
of their pro-inflammatory and anti-inflammatory granular mediators.
Understanding the heterogeneity of this complex cellular communication
may provide a tool for selective pharmacological intervention
directed to specific MC subsets.
[Back to top]
Evaluation of the Risk/Benefit Ratio of Old and New
Anti Inflammatory Drugs
P.F. Mannaioni, V. Fabbroni, R. Mastroianni and E. Masini
Non-steroidal anti-inflammatory drugs (NSAIDs) are a structurally
diverse group of similarly acting compounds that are widely
prescribed and used for the management of pain associated
with inflammatory conditions. Our present aim is to choose
a leading drug for each class of NSAIDs, and to discuss the
debated issues still pending about that drug, in order to
weigh the risk/benefit ratio according to the current hypotheses
on its mode of action. The leading compounds of the past and
present which we have selected within this framework are aspirin,
acetaminophen, celecoxib and rofecoxib. The discovery of nitric
oxide (NO) in the last decade has resulted in proposing new
NO-donors. Particularly interesting in this area has been
the synthesis of NO-releasing anti-inflammatory drugs. The
addition of NO to aspirin and to other NSAIDs has resulted
in molecules that maintain their inhibitory effects on the
cyclooxygenases (COX) but are devoid of cardiovascular, renal
and gastrointestinal toxicity. The purpose of this review
is also to update the “state-of-the-art” of new
classes of anti-inflammatory drugs such as COX-inhibiting
nitric oxide donors (CINODs) and carbon monoxide (CO) releasing
molecules (CO-RMs) as future tools in the therapy of inflammation
and cellular proliferation.
[Back to top]
New Therapeutic Interventions in Airway Inflammatory
and Allergic Diseases
M. Ennis
Asthma is a common, chronic condition that is usually treated
by the combination of inhaled steroids and β2
agonists on a when required basis. More recently, two further
agents have been licensed for use: leukotriene receptor antagonists
and very recently anti-IgE. This review describes a number
of other possible treatment modalities. Some are well developed
and already in Phase III clinical trials, others involve the
use of drugs already on the market for other indications and
a number are reasonably speculative.
[Back to top]
Trends in the Pharmacology of Inflammatory and Allergic
Eye Disorders
R. Sgrulletta, M. Coassin and S. Bonini
Ocular allergies are one of the most common diseases presenting
to the general ophthalmologist. Allergic eye disease includes
a spectrum of different clinical entities: the seasonal and
perennial allergic conjunctivitis and the more severe forms
vernal keratoconjunctivitis and atopic keratoconjunctivitis.
A wide spectrum of topical pharmacological agents has been
developed for the treatment of the different forms of ocular
allergy. These include mast cell stabilizers, pure antihistamines,
new dual-acting agents with antihistamine and mast-cell stabilizer
properties and non-steroidal anti-inflammatory drugs (NSAIDs).
All these drugs are very effective in controlling signs and
symptoms of mild and moderate forms of allergic reaction and
are mainly free of adverse reaction in the chronic use. Topical
corticosteroids remain the mainstay in the aggressive treatment
of sight-threatening forms of allergic conjunctivitis, although
their long-term use is limited by the risk of severe ocular
side effects. For this reason, newer immunosuppressive drugs,
such as cyclosporine and tacrolimus, have been tested in the
treatment of some forms of ocular allergy demonstrating an
high safety profile. New potential therapeutic strategies
include the modulation of the immune system through a switch
of the allergic response from a Th2-dominated immune profile
towards a Th1 response.
[Back to top]
Anti-Inflammatory Agents in Ageing and Age-Associated
Diseases
S. Bonovas and N.M. Sitaras
Ageing and inflammation might be considered as natural partners.
Numerous mechanisms of an inflammatory basis for several age-associated
diseases have been identified. Some markers of inflammation
are already being integrated into clinical medicine. Furthermore,
existent anti-inflammatory drugs and novel candidates have
been found to specifically target inflammation pathways in
the ageing processes. In this review, we focus on the current
knowledge on the field, from the molecular and cellular level
to the therapeutic potential of anti-inflammatory agents.
First, we present several theories of ageing, in order to
explore the involvement of inflammation and to define targets
of intervention. Then, we discuss the current approaches and
applications as well as the future trends in research regarding
the involvement of anti-inflammatory agents in the ageing
processes.
[Back to top]
Genomic Targets in Inflammation and in Allergic Reactions:
A Patient-oriented Approach
H. Saito
Along with advances in the genome sequencing and microarray
technologies, many attempts have been made to understand the
human diseases systemically. Here, literatures regarding genomic
studies on allergic diseases are reviewed, especially by focusing
on microarray-based transcriptome studies. In earlier patient-oriented
transcriptome studies related to allergy and inflammation,
only a few projects seem to be successful considering the
amounts of time, labor and research grants. Most frequently
observed among the problems in such studies are contamination
by a different cell type having a certain highly expressed
transcript that may cause a virtual increase in the transcript
number in the whole population even where the major cell type
lacks it. The successful transcriptome studies are therefore
commonly obtained by using cell lines, highly purified cells
or gene-targeting cell lines for microarray analysis as the
first screening. A cell-type specific transcriptome database
is also useful for determining whether an increase of a certain
transcript in inflammatory tissues reflects an increase in
its expression level or an increase in the number of inflammatory
cells. Nevertheless, high quality RNA samples are necessary
for obtaining reproducible results in the present transcriptome
assays using clinical samples. In this context, analysis for
genome-wide chromatin structure will be useful to understand
the transcriptome more precisely. Considering the rapid development
of microarray and data mining technologies, it is well expected.
[Back to top]
Genomic Strategies in Pharmacology of Asthma and Autoimmunity
C. Szalai , E.I. Buzás, A.K. Fülöp, L.
K hidai and A. Falus
Pharmacogenomics, a fascinating, emerging area of biomedical
research is strongly influenced by growing availability of
genomic databases, high-through-put genomic technologies,
bioinformatic tools and artificial computational modeling
approaches. Multinational clusters, such as the regional and
internet-driven pharmaco-grids generated an entirely new environment
for research and development in pharmacology. Although the
field of pharmacogenomics is in its infancy, the promise of
pharmacogenomics lies in its potential to predict genomic
sources of interindividual variability in drug response (both
efficacy and toxicity), thus allowing individualization of
therapy to maximize effectiveness and minimize risk. Thus,
pharmacogenomics holds the promise for individualized medicine
adapted to each person's own genetic makeup. Environmental
factors including diet, age, and lifestyle as well as infection
can influence a person's response to medicines, but understanding
an individual's genetic background is thought to be the key
to creating personalized drugs with greater efficacy and safety.
Similar to other biomedical fields, in allergic and autoimmune
diseases pharmacogenomics combines traditional pharmaceutical
sciences such as biochemistry with annotated knowledge of
genes, proteins, and single nucleotide polymorphisms (SNP).
One of the major challenges now are developing and applying
the statistical and computational capacity to store, manage,
analyze and interpret the wealth of data being generated.
This review summarizes the recent pharmacogenomic trends in
inflammatory diseases with particular attention to autoimmune
conditions and asthma.
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