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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 2, 2006
Contents
Autoimmunity
Executive Editors: D. Stahl and W. Sibrowski
Editorial Pp. 129-130
The Dendritic Cell-T Cell Synapse as a Determinant
of Autoimmune Pathogenesis Pp. 131-147
M.I. Iruretagoyena, M. Wiesendanger and A.M. Kalergis
[Abstract]
Mechanisms of CTLA-4-Ig in Tolerance Induction Pp.
149-160
M.-L. Alegre and F. Fallarino
[Abstract]
Lysophospholipid Receptors as Potential Drug Targets in Tissue
Transplantation and Autoimmune Diseases Pp. 161-171
J. Chun and H. Rosen
[Abstract]
Autoantibody-Induced Formation of Immune Complexes
in Normal Human Serum Pp. 173-179
R. Lemieux and R. Bazin
[Abstract]
IgG Dimers in Multidonor-Derived Immunoglobulins:
Aspects of Generation and Function Pp. 181-190
P. Gronski
[Abstract]
General Articles
Antibody-Like Peptides as a Novel Purification Tool
for Drugs Design Pp. 191-203
C. Tozzi and G. Giraudi
[Abstract]
Cyclooxygenases Regulation by Estradiol on Endothelium
Pp. 205-215
C. Hermenegildo, P.J. Oviedo and A. Cano
[Abstract]
The Peripheral Anionic Site of Acetylcholinesterase:
Structure, Functions and Potential Role in Rational Drug Design
Pp. 217-225
G. Johnson and S.W. Moore
[Abstract]
Receptor-Independent Effects of Endocannabinoids on
Ion Channels Pp. 227-241
M. Oz
[Abstract]
Promotion of Remyelination by Immunoglobulins: Implications
for the Treatment of Multiple Sclerosis Pp. 241-249
C. Trebst and M. Stangel
[Abstract]
Aspirin Resistance: Definitions, Mechanisms, Prevalence, and
Clinical Significance Pp. 251-258
L. Macchi, N. Sorel and L. Christiaens
[Abstract]
Abstracts
[Back to top]
Editorial
Regulation of the immune response occurs by the interaction
of very different kinds of molecules and is depending on the
presence of receptors. Receptors are known as specific binding
sites on a cell's surface or interior, but they may also be
present in soluble form. Binding to receptors of their natural
counterparts results in activation or inhibition of immune
functions, and includes – as far as cellular functions
are involved – the activation or inhibition of complex
cellular signalling cascades. Under physiological conditions,
activation and inhibition of immune functions by receptor-dependent
mechanisms follow a carefully regulated balance. Such balance
may be disturbed in the context of autoimmune responses as
well as in the context of alloimmune responses, for example
in the transplantation setting, both of the conditions being
related to the destruction or altered function of cells and
tissues. The understanding of receptor-dependent regulation
mechanisms of the immune response allows the therapeutical
modulation of dysregulated immune processes. The present issue
of Current Pharmaceutical Design – Autoimmunity
summarizes actual knowledge on some essential receptor-ligand
interactions that offer opportunities for the pharmacological
modulation of the outcome of pathological immune responses
in autoimmune conditions and in the transplantation setting.
The contributions consider immunomodulation by interference
with membrane-bound receptors as well as immunomodulation
by interference with soluble receptors (i.e. immunoglobulin
molecules).
In the first article, Mirentxu Iruretagoyena, Margrit
Wiesendanger and Alexis Kalergis focus on the dendritic
cell - T cell synapse as a determinant of autoimmune pathogenesis
[1]. Dendritic cells are professional antigen presenting cells
that play an important role in maintaining peripheral tolerance
by preventing self-reactive T cells from causing autoimmune
damage. Thus, alterations in the physiology of dendritic cells
are likely to be responsible for defective immune regulatory
mechanisms and incomplete tolerance to self. Kalergis and
colleagues focus on the ways in which the immunological synapse
occurring at the dendritic cell - T cell interface can fine-tune
the balance between tolerance and immunity and how alterations
of this synapse can determine induction or perpetuation of
autoimmune responses. Activating/inhibitory receptors expressed
on the surface of dendritic cells and T cells modulate the
function of these cells and influence the course of the immune
response. Pharmacological approaches that can modulate dendritic
cell function are addressed as a potential antigen-specific
strategy in the design of noninvasive therapies to prevent
or to treat chronic inflammatory autoimmune disorders.
The size of the peripheral T cell pool remains relatively
constant throughout adult life, but individual populations
undergo expansion and contraction upon antigen encounter due
to signals delivered by members of the B7-CD28 family of costimulatory
molecules. This family includes receptors on T cells that
can provide either activating or inhibitory signals. In general,
activation occurs in response to pathogens, when lymphocyte
expansion and acquisition of effector functions is appropriate.
Conversely inhibitory receptors provide down-modulating signals
that help terminate immune responses and maintain self-tolerance.
The activating receptor CD28 engages the same B7-1 and B7-2
molecules as the inhibitory receptor cytotoxic T lymphocyte
antigen 4 (CTLA-4), although with reduced affinity than CTLA-4.
In addition to this direct competitive mechanism, CTLA-4 can
directly inhibit T cell receptor (TCR) signals independently
of CD28 expression and recent findings indicate that CTLA-4
may also operate through reverse signaling on ligand-expressing
cells. Fusion proteins between the extracellular domain of
CTLA-4 and an immunoglobulin Fc portion have been created
that have potent immunosuppressive properties in animal models
of transplantation and autoimmunity and that show great promise
in clinical trials. Like CTLA-4, CTLA-Ig, is thought to selectively
prevent activation of CD28 by interacting with B7-1 and B7-2.
In addition, CTLA-4-Ig can bind to B7 molecules expressed
on dendritic cells and activate a pathway of tryptophan catabolism
that can lead to indirect inhibition of lymphocyte activation
and T cell death. The current knowledge of the mechanisms
of action of CTLA-4 and CTLA-4-Ig is in the center of the
review by Maria-Luisa Alegre and Francesca Fallarino
[2].
Jerold Chun and Hugh Rosen provide an overview
on receptor-mediated lysophospholipid signalling [3]. A large
range of biological activities has been attributed to the
actions of lysophospholipids. Documented cellular effects
encompass growth-factor-like influences on cells, including
but not limited to survival, migration, adhesion differentiation,
as well as pathophysiological actions associated with cancer.
The mechanisms for these actions can be attributed to a growing
family of cognate, 7-transmembrane G protein-coupled receptors
(GPCRs). Such lysophospholipid receptors are a new group of
molecular targets that may lead to the development of innovative
therapies in autoimmune-related diseases and in transplantation
medicine. In particular, entry into humans of a non-selective
sphingosine 1-phosphate receptor agonist, FTY720, for kidney
transplantation and possibly for other indications has raised
prospects for efficacious treatment of human diseases based
on lysophospholipid receptor targets.
Réal Lemieux and Renée Bazin
concentrate on immunoglobulin dependent mechanisms of immune
regulation [4]. Intravenous immunoglobulins (IVIg) are concentrated
preparations of purified human plasma-derived IgG routinely
used in the treatment of many autoimmune diseases. Their precise
mechanisms of therapeutic action have remained unclear in
most diseases and are attracting much interest due to the
rapidly increasing use of this plasma-derived product. The
presence in IVIg of IgG reactive with various human structures
has been known for many years.Réal Lemieux and Renée
Bazin here discuss autoantibody-induced formation of immune
complexes in normal human plasma. Recent work has shown that
the large IVIg doses infused in many patients could oversaturate
the normal anti-idiotype-dependent inhibition of autoreactive
IgG present in the plasma of all healthy individuals since
the formation of autoimmune complexes could be observed in
normal serum in presence of therapeutic amounts of IVIg. These
autoimmune complexes could have potent in vivo immunomodulatory
effects by interacting with various IgG and complement receptors.
Furthermore the autoreactive IgG can be easily purified from
IVIg by affinity chromatography, raising the interesting possibility
of further fractionating IVIg into different sub-products
for use in the treatment of different diseases.
Peter Gronski focuses on aspects of generation
and function of the varying amounts of dimeric IgG in multidonor-derived
intravenous immunoglobulin preparations [5]. An essential
factor influencing dimer formation is the pool size; in addition,
molecular properties of IgG and a variety of production process-
and formulation-specific parameters are important. Numerous
experimental findings suggest that dimers are predominantly
generated by interactions of idiotypic and anti-idiotypic
antibodies (Ids, anti-Ids). Antibody-inherent crossreactivity,
frequency distribution of both the affinities for particular
Id-anti-Id interactions and the corresponding dimer concentrations
still have to be elucidated. All these parameters influencing
molecular features and functional activity of IgG dimers hamper
the assay-dependent measurement of biological efficacy and
correlation of the total IgG content. A more detailed understanding
may help to better control the dual nature of dimer-dependent
biological activity comprising both undesirable effects of
dimeric IgG such as hypotension and desirable effects of dimeric
IgG such as the efficient blockade of the reticuloendothelial
system in autoimmune diseases.
We wish to express our gratitude to the authors who accepted
to contribute to this issue of Current Pharmaceutical
Design – Autoimmunity. The issue has become possible
by their strong commitment to the concern to let the reader
participate in new and original approaches to regulate self-recognition.
For an in-depth understanding of the context of their work,
readers are referred to the detailed up-to-date reference
lists accompanying the reviews. Authors as well as editors
hope that the current issue of Current Pharmaceutical
Design – Autoimmunity might stimulate substantial
discussion regarding the development of new strategies for
the therapeutical regulation of immune responses.
References
[1] Iruretagoyena MI, Wiesendanger M, Kalergis AM. The Dendritic
cell-T cell synapse as a determinant of autoimmune pathogenesis.
Curr Pharm Des 2006; 12(2): 131-147.
[2] Alegre M-L, Fallarino F. Mechanisms of CTLA-4-Ig in Tolerance
Induction. Curr Pharm Des 2006; 12(2): 149-160.
[3] Chun J, Rosen H. Lysophospholipid receptors as potential
drug targets in tissue transplantation and autoimmune diseases.
Curr Pharm Des 2006; 12(2): 161-171.
[4] Lemieux R, Bazin R. Autoantibody-induced formation of
immune complexes in normal human serum. Curr Pharm Des 2006;
12(2): 173-179.
[5] Gronski P. IgG Dimers in Multidonor-Derived Immunoglobulins:
Aspects of Generation and Function. Curr Pharm Des 2006; 12(2):
181-190.
Priv.-Doz. Dr. med. Dorothea Stahl
University of Muenster
Institute for Transfusion Medicine
Domagkstrasse 11
D – 48149 Muenster
Germany
stahld@uni-muenster.de
Prof. Dr. med. Dr. rer. nat. Walter Sibrowski
University of Muenster
Institute for Transfusion Medicine
Domagkstrasse 11
D – 48149 Muenster
Germany
sibrowski@uni-muenster.de
[Back to top]
The Dendritic Cell-T Cell Synapse as a Determinant
of Autoimmune Pathogenesis
M.I. Iruretagoyena, M. Wiesendanger and A.M. Kalergis
Autoimmune diseases occur when the immune response is targeted
to self-antigens, leading to destruction or altered function
of specific cells and tissues. Although the aetiology of these
diseases has not yet been fully elucidated, it is believed
that genetically determined susceptibility and environmental
triggers are both implicated in the detrimental immune response
against the body’s own tissues. Dendritic cells (DCs)
are professional antigen presenting cells that play an important
role in maintaining peripheral tolerance by preventing self-reactive
T cells from causing autoimmune damage. Thus, alterations
in the physiology of DCs are likely to be responsible for
defective immune regulatory mecha-nisms and incomplete tolerance
to self. Here, we will focus specifically on the ways in which
the immunological synapse occurring at the DC-T cell interface
can fine-tune the balance between tolerance and immunity and
how alterations of this synapse can determine induction or
perpetuation of autoimmune responses. Activating/inhibitory
receptors expressed on the surface of DCs and T cells modulate
the function of these cells and influence the course of the
immune response. Pharmacological approaches that can modulate
DC function will be also addressed as a potential antigen-specific
strategy in the design of new, noninvasive therapies to prevent
or to treat chronic inflammatory autoimmune disorders.
[Back to top]
Mechanisms of CTLA-4-Ig in Tolerance Induction
M.-L. Alegre and F. Fallarino
The size of the peripheral T lymphocyte pool remains relatively
constant throughout adult life, but individual populations
undergo expansion and contraction upon antigen encounter due
to signals delivered by members of the B7-CD28 family of costimulatory
molecules. This family includes receptors on T cells that
can provide either activating or inhibitory signals. In general,
activation occurs in response to pathogens, when lymphocyte
expansion and acquisition of effector functions is appropriate.
Conversely inhibitory receptors provide down-modulating signals
that help terminate immune responses and maintain self-tolerance.
The activating receptor CD28 engages the same B7-1 and B7-2
mole-cules as the inhibitory receptor cytotoxic T lymphocyte
antigen 4 (CTLA-4), although with reduced affinity than CTLA-4.
In addition to this direct competitive mechanism, CTLA-4 can
directly inhibit T cell receptor (TCR) signals inde-pendently
of CD28 expression and recent findings indicate that CTLA-4
may also operate through reverse signaling on ligand-expressing
cells. Fusion proteins between the extracellular domain of
CTLA-4 and an immunoglobulin Fc portion have been created
that have potent immunosuppressive properties in animal models
of transplantation and autoimmunity and that show great promise
in clinical trials. Like CTLA-4, CTLA-Ig, is thought to selectively
prevent activation of CD28 by interacting with B7-1 and B7-2.
In addition, CTLA-4-Ig can bind to B7 molecules expressed
on dendritic cells and activate a pathway of tryptophan catabolism
that can lead to indirect inhibition of lymphocyte activation
and T cell death. In this review, we will focus on the current
knowledge of the mechanisms of action of CTLA-4 and CTLA-4-Ig.
[Back to top]
Lysophospholipid Receptors as Potential Drug
Targets in Tissue Transplantation and Autoimmune Diseases
J. Chun and H. Rosen
New therapies directed at ameliorating or altering autoimmune
diseases represent an area of significant medical need. Included
amongst autoimmune diseases are problems related to transplantation
rejection, as well as a number of neurological diseases such
as Multiple Sclerosis (MS). A new group of molecular targets
that may lead to novel therapies are lysophospholipid (LP)
receptors. A large range of biological activities has been
attributed to the actions of these simple phospholipids that
include well-studied members lysophosphatidic acid (LPA) and
sphingosine 1-phosphate (S1P). Documented cellular effects
of these lipid molecules encompass growth-factor-like influences
on cells, including but not limited to survival, migration,
adhesion differentiation, as well as pathophysiological actions
associated with cancer. In turn, these cellular effects have
roles in developing and adult organ systems such as the nervous
system, cardiovascular system, reproductive system and, of
relevance here, the immune system. The mechanisms for these
actions can be attributed to a growing family of cognate,
7-transmembrane G protein-coupled receptors (GPCRs), with
documented validation through studies utilizing pharmacology,
molecular genetics and an enlarging repertoire of chemical
tools having agonist or antagonist properties. The growing
literature on immunological effects of LP receptors, particularly
those mediating the effects of S1P, has suggested possible
therapeutic roles for this class of receptors. In particular,
entry into humans of a non-selective S1P receptor agonist,
FTY720, for kidney transplantation and possibly other indications
(e.g., Multiple Sclerosis), has raised prospects for efficacious
treatment of human diseases based on LP receptor targets.
Here we provide a brief introduction to receptor-mediated
lysophospholipid signaling and discuss its basic and potential
therapeutic roles in autoimmune-related diseases.
[Back to top]
Autoantibody-Induced Formation of Immune Complexes
in Normal Human Serum
R. Lemieux and R. Bazin
Intravenous immunoglobulins (IVIg) are concentrated preparations
of purified human plasma-derived IgG routinely used in the
treatment of many autoimmune diseases. Their precise mechanisms
of therapeutic action have remained unclear in most diseases
and are attracting much interest due to the rapidly increasing
use of this precious plasma-derived product. The presence
in IVIg of IgG reactive with various human structures has
been known for many years. In this review, we first briefly
discuss the formation and role of natural autoreactive human
IgG in healthy individuals. A role for IgG autoantibodies
in the in vivo immunomodulatory effects of IVIg has
been proposed several years ago but the underlying mechanism
has remained unclear. Recent work has shown that the large
IVIg doses infused in many patients could oversaturate the
normal anti-idiotype-dependent inhibition of autoreactive
IgG present in the plasma of all healthy individuals since
the formation of autoimmune complexes could be observed in
normal serum in presence of therapeutic amounts of IVIg. These
autoimmune complexes could have potent in vivo immunomodulatory
effects by interacting with various IgG and complement receptors.
Furthermore the autoreactive IgG can be easily purified from
IVIg by affinity chromatography, raising the interesting possibility
of further fractionating IVIg into different sub-products
for use in the treatment of different diseases. These results
indicate that natural autoantibodies have important in
vivo roles not only for the protection of the body against
infectious agents but also for the efficiency of passive immunotherapy
procedures used in the treatment of many diseases.
[Back to top]
IgG Dimers in Multidonor-Derived Immunoglobulins:
Aspects of Generation and Function
P. Gronski
Immunoglobulin G (IgG) concentrates for therapeutic purposes,
like passive immunotherapy, supplementation in inherited or
aquired deficiencies or immunomodulation, are prepared from
multidonor-derived plasma pools. They usually contain varying
amounts of dimeric IgG. The essential factor influencing dimer
formation is the pool size; in addition, molecular properties
of IgG and a variety of production process- and formulation-specific
parameters are important. Numerous experimental findings suggest
that dimers are predominantly generated by interactions of
idiotypic and anti-idiotypic antibodies (Ids, anti-Ids). Ab-inherent
crossreactivity, frequency distribution of both the affinities
for particular Id-anti-Id interactions and the corresponding
dimer concentrations still have to be elucidated. All these
pa-rameters influencing molecular features and functional
activity of IgG dimers hamper the assay-dependent measurement
of biological efficacy and correlation of total IgG content.
A more detailed understanding may help to better control the
dual nature of dimer-dependent biological activity comprising
both undesirable (e.g., hypotension) and desirable effects
of dimeric IgG (blockade of the reticuloendothelial system,
RES, in immune thrombocytopenic purpura, ITP). These ef-fects
are detectable in in vitro and in vivo models
and are thought to be of relevance for humans.
[Back to top]
Antibody-Like Peptides as a Novel Purification Tool
for Drugs Design
C. Tozzi and G. Giraudi
New pharmaceutical approaches, such as biotechnology industry,
genomic and proteomic studies, require the development of
new analytical and preparative tools that should allow the
resolution and the characterisation of complex sets of molecule
mixtures in a high-throughput mode with the isolation of a
single substance from complex matrices in a high degree of
purity, low costs and wide availability. In this review we
discuss the design of a tailor-made peptide by focusing our
attention on the bioinformatic techniques and combinatorial
approaches. Then synthesis, purification and characterisation
of peptides with recognition properties are discussed by considering
different approaches and their fitness to drug design. Moreover,
the development of affinity devices and the discussion of
their characteristics to optimise the purification phase are
reported. Applications of peptide ligands that bind pharmaceutical
compounds (i.e. therapeutic proteins, monoclonal antibodies,
hormones) are described and analytical tools mentioned and
evaluated. Future perspectives, in particular alternative
applications of peptide ligands and their substitution with
peptidomimetic compounds, are described.
[Back to top]
Cyclooxygenases Regulation by Estradiol on Endothelium
C. Hermenegildo, P.J. Oviedo and A. Cano
Estrogen and hormone replacement therapies are being tested
to prevent the incidence of cardiovascular disease in postmenopausal
women. In spite of the evidence from several epidemiological
studies suggesting that estrogens protect against atherosclerosis
and associated diseases, controversy exists. Moreover, it
is important to develop synthetic compounds that achieve the
beneficial effects of estrogens on the cardiovascular system
while minimizing such undesirable effects on other tissues
as the increased risk of endometrial and breast cancer. Some
drugs that modulate estrogen function in a tissue-specific
manner (Selective Estrogen Receptor Modulators; SERMs) have
been discovered and are currently being used in clinical practice.
An example of these is raloxifene.
Clinical and experimental data support the consideration
of endothelium as a target for estradiol and other sexual
hormones. Among other actions, estradiol has been implicated
in the control of prostacyclin production through cyclooxygenases
(COX) regulation in endothelial cells. Prostacyclins are powerful
vasodilators and potent inhibitors of platelet aggregation
which are produced from free arachidonic acid through the
catalytic activity of two COX: COX-1 and COX-2. Together,
these COX represent the main control mechanism for prostacyclin
production. Although several non-specific COX inhibitors have
been available for decades (aspirin, indomethacin, ibuprofen),
COX-2 selective inhibitors have been commercialized only within
the last few years, thus making it possible to increase the
study and treatment of different disorders.
This review will discuss clinical and experimental data that
document the endothelial effects of estradiol and SERMs on
prostacyclin production and COX regulation, their vascular
consequences, and their possible interactions with COX inhibitors.
[Back to top]
The Peripheral Anionic Site of Acetylcholinesterase:
Structure, Functions and Potential Role in Rational Drug Design
G. Johnson and S.W. Moore
The peripheral anionic site of acetylcholinesterase lies
at the entrance to the active site gorge. It is composed of
five residues (Tyr 70, Asp 72, Tyr 121, Trp 279 and Tyr 334;
Torpedo numbering); associated with it are a number of surface
loops, conferring a high degree of conformational flexibility
on the area. The site is involved in the allosteric modulation
of catalysis at the active centre and is the target of various
anti-cholinesterases. It is also implicated in a number of
non-classical functions, in particular, amyloid deposition,
cell adhesion and neurite outgrowth. A number of peptide and
protein ligands for the site have been identified. In this
review, the structure and multiple functions of the peripheral
anionic site are discussed, together with its potential as
a target in rational drug design for the development of novel
and improved inhibitors and of therapeutics for the treatment
of neural cancers, nerve regeneration and neurodegenerative
disorders such as Alzheimer’s disease.
[Back to top]
Receptor-Independent Effects of Endocannabinoids on
Ion Channels
M. Oz
Endogenous cannabinoids (endocannabinoids), produced from
membrane-bound precursors via calcium and/or G-protein dependent
processes, mimic the effects of cannabinoids by activating
cannabinoid CB1 and/or CB2 receptors.
Several reports however, also indicate that endocannabinoids
can produce effects that are independent of cannabinoid receptors.
Thus, in pharmacologically relevant concentrations, endocannabinoids
have been demonstrated to modulate the functional properties
of voltage-gated ion channels including Ca2+ channels,
Na+ channels and various types of K+
channels, and ligand-gated ion channels such as 5-HT3,
and nicotinic ACh receptors. In addition, the functional modulations
by endocannabinoids of other ion-transporting membrane proteins
such as transient potential receptor-class channels, gap junctions,
and neurotransmitter transporters have also been reported.
These findings indicate that additional molecular targets
for endocannabinoids exist and that these targets may represent
important sites for cannabinoids to alter either the excitability
of the neurons or the response of the neuronal systems. This
review focuses on the results of recent studies indicating
that beyond their receptor-mediated effects, endocannabinoids
alter the function of ion channels directly.
[Back to top]
Promotion of Remyelination by Immunoglobulins: Implications
for the Treatment of Multiple Sclerosis
C. Trebst and M. Stangel
During the last decade immunomodulatory treatments have
been shown to influence the natural course of multiple sclerosis
(MS). However, demyelination in the central nervous system
(CNS) still occurs and repair mechanisms are incomplete leading
to neurological deficits. Currently, there is no therapy available
to promote remyelination and thus enhance repair mechanisms.
Both immunoglobulins directed against spinal cord homogenate
and polyclonal immunoglobulins for intravenous use (IVIg)
have been shown to support remyelination in the animal model
of Theiler’s virus encephalomyelitis (TMEV). Further
studies have identified monoclonal antibodies that lead to
remyelination in TMEV and a toxic demyelination model using
lysolecithin. The shared characteristics of these monoclonal
antibodies are an IgM isotype and the capacity to bind oligodendrocytes,
independent of epitope specificity. Recently, two human monoclonal
antibodies with remyelinating properties were described. Clinical
trials with IVIg have so far failed to dem-onstrate clinical
improvement in MS patients, but these studies only employed
IgG preparations. However, recent experimental data both
in vivo and in vitro underline the importance
of IgM for remyelination. Thus future clinical trials are
needed to evaluate the remyelination potential of IgM in human
diseases. The design of monoclonal antibodies capable of promoting
remyelination is a telling example for the design of new specific
therapies derived from biological products like polyclonal
immunoglobulins.
[Back to top]
Aspirin Resistance: Definitions, Mechanisms,
Prevalence, and Clinical Significance
L. Macchi, N. Sorel and L. Christiaens
Aspirin is the most commonly used therapeutic agent in prevention
of vascular ischemic events. Aspirin exerts its antithrombotic
effect primarily by interfering with the biosynthesis of thromboxane
A2 (TXA2) and inhibition of TXA2 -dependent platelet aggregation.
A meta-analysis of secondary prevention trials indicated that
aspirin reduced major cardiovascular or cerebral events by
25%. This led to the widespread use of aspirin for prevention
of cardiovascular events. However, it appears that aspirin
antiplatelet effect is not uniform in all patients and previous
studies estimated that 8–45% of the population were
aspirin resistant. Furthermore, (i) the optimal dosage of
aspirin for complete inhibition of platelet aggregation by
physiological agonists (i.e arachidonic acid) is subject to
great interindividual variability, (ii) the tests to detect
aspirin resistance in vitro are subject to debate
and (iii) the mechanisms by which some patients are resistant
to aspirin in vitro remain to be determined. Despite
these unresolved questions, recent clinical studies provide
the reliable evidence that aspirin resistance correlates with
confirmed clinical unresponsiveness, highlighting the clinical
interest of determining the aspirin inhibitory effects on
patients’ platelets.
In conclusion, discovery of aspirin resistance in individuals
might be important in order to devise better anti-platelet
strategies and improve our ability to prevent acute thrombotic
complication.
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