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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 2, May 2006
Contents
Contrast Media: Induction of Side Effects
and Pharmacological Treatment
Guest Editors: Ingrid Böhm & Hans H.
Schild
Editorial Pp. 97
Histamine-Dependent and –Independent Hypersensitivity
Reactions to Contrast Media: The Impact of Antihistamines
Pp. 99-104
Esther A. Coors and Ingrid Böhm
[Abstract]
Immediate and Late Adverse Reactions to Iodinated
Contrast Media: A Pharmacological Point of View Pp.
105-117
Pascale Dewachter ,Dominique Laroche, Claudie
Mouton Faivre and Olivier Clément
[Abstract]
Life Threatening and Fatal Contrast Media Reactions: Pathomechanisms,
Diagnosis, Prevention and Drug Management Pp. 119-128
S.K. Morcos
[Abstract]
Vascular Reactions of Iodinated X-Ray Contrast Media:
Mechanisms and Possible Therapeutic Interventions Pp.
129-137
Michael Uder and Marc Heinrich
[Abstract]
Role of Apoptosis in the Pathogenesis of Contrast
Media-induced Nephropathy and Hints for its Possible Prevention
by Drug Treatment Pp. 139-146
J.-M. Idee, J. Boehm, P. Prigent, S. Ballet and
C. Corot
[Abstract]
Phospholipases: A Target for “New Leads”
in the Modulation of Inflammation Processes
Guest Editor: D. Hadjipavlou-Litina
Editorial Pp. 147
Inhibitors of Cytosolic Phospholipase A2α
as Potential Anti Inflammatory Drugs Pp. 149-161
Matthias Lehr
[Abstract]
Group II Secretory PLA2:
A New Cardiovascular Risk Factor Pp. 163-173
Paul A.J. Krijnen, Remco Nijmeijer, C. Erik Hack and Hans
W.M. Niessen
[Abstract]
3D QSAR Study of Human PLA2
Inhibitors. A Modeling Approach to Select New and Specific
Anti-Inflammatory Drugs Pp.175-187
Marco Pintore, Enrico Mombelli, Christophe Wechman
and Jacques R. Chretien
[Abstract]
Synthetic Inhibitors of Group IVA and Group VIA Phospholipase
A2
Pp. 189-203
Victoria Magrioti and George Kokotos
[Abstract]
Abstracts
[Back to top]
Editorial
Contrast medium (CM)-enhanced X-ray examinations are indispensable
in clinical medicine. This is reflected by approximately 40-50
million CM-administrations per year worldwide. This number
will probably increase due to increasing prevalence/incidence
rates of malignant and cardio-vascular diseases, the need
to monitor new therapeutic approaches (e.g. gene therapy),
and last but not least, due to new technical approaches for
early detection of disease.
It is known that CM can induce allergic/pseudoallergic and
inflammatory side effects, cell damage such as apoptosis,
and cardio-vascular reactions. The cell-biologic, immunologic
and allergic basis of these reactions are investigated world-wide.
Knowing the molecular-biologic background may serve to explain
the rationale for side effect prevention and treatment.
The review of Dr. E.A. Coors and Dr. Ingrid Böhm describes
“Histamine-dependent and -independent hypersensitivity
reactions to contrast media: the impact of antihistamines”.
It highlights that adverse CM-induced events seem to depend
in the great majority upon (mainly non-IgE mediated) histamine
release. These reactions promptly and completely respond to
antihistaminics, while in some cases these drugs show little
if any effect. In such circumstances other non-histamine mediators
(e.g. leukotrienes) seem to play a pathophysiological role.
The paper of Drs. Pascale Dewachter, Dominique Laroche, Claudie
Mouton-Faivre, and Olivier Clément entitled “Immediate
and late adverse reactions to iodinated contrast media: A
pharmacological point of view” presents the current
knowledge concerning the risk, pathophysiological mechanisms,
clinical picture, diagnostic approaches and treatment modalities.
The aim of this review is to report, from a pharmacological
point of view, the most frequent types of immediate and delayed
reactions following CM administrations, their incidence and
their pathophysiological mechanisms.
Dr. Sameh K. Morcos refers to “Life threatening and
fatal contrast media reactions: pathomechanisms, diagnosis,
prevention and drug management”. He addresses that although
very severe CM-induced reactions occur very rarely (ranging
from 0.004% to 0.04%), they still pose a challenge. Patients
with risk factors (e.g. history of a serious reaction to CM,
bronchial asthma or multiple allergies) have an increased
incidence of serious reactions, which however are unpredictable.
The review presents the underlying patho-physiological mechanisms
(such as direct activation of basophils and mast cells, IgE
mediated reaction, activation of the kinin system, and the
complement cascade) that may be involved, and the adequate
therapy options. The ability to assess and treat serious CM
reactions effectively is an essential skill that the radiologist
should have and maintain.
The paper “Vascular reactions of iodinated x-ray contrast
media: mechanisms and possible therapeutic interventions”
by Drs. Michael Uder and Marc Heinrich provides an interesting
review of the CM-induced mechanisms of vasodilation and vasoconstriction.
It explains that changes in vessel tone depend on the type
of contrast medium, species, vascular territory and contractile
state of the vessels. The authors describe the effects of
high osmolar ionic, low osmolar non-ionic and isotonic contrast
media on different vascular beds in humans and animals. Data
from clinical and in vivo studies as well as from
in vitro investigations on isolated organs and isolated
vessel segments will be discussed.
The review “Role of apoptosis in the pathogenesis of
contrast media-induced nephropathy and hints for its possible
prevention by drug treatment” by Drs. J.M. Idee, J.
Boehm, P. Prigent, S. Ballet, and C. Corot refers to the pro-apoptotic
effect of different iodinated and gadolinium-based contrast
media. Proposed treatment modalities are highlighted.
In addition, to the authors who have contributed to this issue,
we would like to thank the members of the Editorial Advisory
Board who reviewed the articles. We also would like to thank
Bentham Science for their assistance, in particular Dr. Bahar
Tunctan and Ms. Saima Rao.
Dr. Ingrid Böhm
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in
Medicinal Chemistry
Department of Radiology
University of Bonn
Sigmund-Freud Str. 25
53105 Bonn
Germany
Phone: +49-228-2879631
Fax: +49-228-2874457
E-mail: ingrid.boehm@ukb.uni-bonn.de
Prof. Dr. Hans H. Schild
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in
Medicinal Chemistry
Chairman of the Department of Radiology
University of Bonn
Sigmund-Freud Str. 25
53105 Bonn
Germany
[Back to top]
Histamine-Dependent and –Independent Hypersensitivity
Reactions to Contrast Media: The Impact of Antihistamines
Esther A. Coors and Ingrid Böhm
Contrast media (CM) are widely used substances that may lead
to hypersensitivity reactions. Those adverse events can be
classified as immediate reactions that occur within the first
hour after administration of CM or delayed reactions that
develop after more than one hour and during the following
7 days. The pathomechanisms for both types of reactions are
still not fully clear. Only in a minority of cases with immediate
reactions an IgE-mediated pathway has been shown. In most
cases, different mechanisms lead to the release of histamine
and other mediators, thus provoking the symptoms of anaphylaxis.
These reactions may either occur immediately after CM-injection
or delayed. Moreover, some of the delayed reactions seem to
be mainly T-cell mediated. Antihistamines are used in the
treatment of adverse reactions as well as in the prophylaxis
for patients with a history of a hypersensitivity reaction.
Although the clinical aspect of frequently occurring reactions
like urticaria, and angioedema (type I-reactions and type
I-like reactions) implicates a first line application for
antihistamines, the clinical experience shows that some cases
do not respond to these agents. Therefore, it seems likely
that other mediators such as leukotrienes might be involved
in mediating CM-induced reactions.
[Back to top]
Immediate and Late Adverse Reactions to Iodinated
Contrast Media: A Pharmacological Point of View
Pascale Dewachter ,Dominique Laroche, Claudie
Mouton Faivre and Olivier Clément
Iodinated contrast media (CM) are widely used in radiological
procedures, and carry a risk of adverse reactions with possible
sequelae or death. Various and numerous reactions have been
reported, most of which are transient ones and do not threaten
the patient’s life. Immediate adverse reactions include
adverse effects directly related to the osmotic load or to
the CM chemotoxicity, and immediate hypersensitivity reactions.
The exact incidence of the different types of reactions is
difficult to establish because not all cases are reported
and because a unique severity scale is lacking. All the underlying
mechanisms have not been evidenced yet, as patients are rarely
properly investigated. Allergic immediate hypersensitivity
probably provokes the most severe reactions, whereas non-allergic
hypersensitivity determines moderate reactions. Diagnostic
tools are available and consist in tryptase and histamine
measurements and in skin testing. Late reactions include skin
or systemic reactions due to T-lymphocytes-mediated delayed
hypersensitivity, nephropathy and dysthyroidism. Delayed allergic
hypersentivity can be diagnosed by skin testing with delayed
reading. Allergic hypersensitivity, immediate or delayed,
means immune mechanisms and is a contraindication of further
administration of the culprit CM.
[Back to top]
Life Threatening and Fatal Contrast Media
Reactions: Pathomechanisms, Diagnosis, Prevention and Drug
Management
S.K. Morcos
Serious or fatal reactions to a contrast agent are usually
unpredictable and the majority occurs within 20 min of administration.
Incidence of very severe reactions with the use of low osmolar
non ionic contrast media (CM) is very low (0.004%) and is
reduced by a factor of 10 in comparison to high osmolar CM
(0.04%). Fatality due to CM injection is rare and the incidence
is similar with both types of CM (1 in 170,000 contrast examinations).
History of serious reaction to CM, bronchial asthma or multiple
allergies increases the incidence of serious reactions by
at least a factor of 5 in comparison to subjects with a negative
history. Serious or fatal reaction to CM could be due to direct
effect on basophils and mast cells or IgE mediated (type 1
hypersensitivity reaction). Activation of the kinin system
leading to the formation of bradykinin could also be involved.
Complement activation is probably a secondary phenomenon rather
than a primary factor in initiating a serious reaction to
CM. Measuring serum tryptase is important in diagnosing serious
or fatal reaction to CM. Measuring IgE antibodies remains
not widely available but should be considered in appropriate
cases if the technique is available. Avoiding CM administration
in patients at high risk of serious reaction is advisable
but if the administration is deemed essential all precautions
should be implemented and measures to treat serious reactions
should be readily available. Oxygen supplementation, intravenous
administration of physiological fluids and intramuscular injection
of 0.5ml adrenalin (1:1,000) should be considered in the first
line management of acute anaphylaxis. The ability to assess
and treat serious CM reaction effectively is an essential
skill that the radiologist should have and maintain.
[Back to top]
Vascular Reactions of Iodinated X-Ray Contrast Media:
Mechanisms and Possible Therapeutic Interventions
Michael Uder and Marc Heinrich
Vascular reactions after administration of all classes of
iodinated x-ray contrast media are well known side effects
of these drugs. Both vasodilation and vasoconstriction have
been observed. The manner and extent of the change in vessel
tone depends on the type of contrast medium, species, vascular
territory and contractile state of the vessels. The mechanisms
underlying the vascular reaction induced by contrast media
are currently not completely clear and studies on this question
are partly contradictory or non-conclusive. Even if these
side effects do not vitally compromise the patients, they
are mainly responsible for patients’ discomfort during
examinations. To date, there are only a few possibilities
to treat this type of side effect.
In this review we describe the effects of high osmolar ionic,
low osmolar non-ionic and isotonic contrast media on different
vascular beds in humans and animals. Data from clinical and
in vivo studies as well as from in vitro
investigations on isolated organs and isolated vessel segments
will be discussed. It will give an overview of the mechanistic
explanations of the vascular reactions.
[Back to top]
Role of Apoptosis in the Pathogenesis of Contrast
Media-induced Nephropathy and Hints for its Possible Prevention
by Drug Treatment
J.-M. Idee, J. Boehm, P. Prigent, S. Ballet and
C. Corot
Contrast-induced nephropathy (CIN) is a worrying concern
in at-risk patients. Its pathophysiological mechanism remains
speculative and is possibly modulated according to the risk
factor(s) and clinical presentation of the patients. Overall,
iodinated contrast media (CM) have been shown, in animal models,
to induce medullary hypoxia. Furthermore, numerous studies
have demonstrated that they have a direct cytotoxic potential
on proximal (LLC-PK1) as well as distal (MDCK) tubular cell
lines and mesangial cells. A pro-apoptotic potential of such
molecules has been found on various cell types including renal
tubular and mesangial cells, both in vitro and
in vivo. This pro-apoptotic effect on tubular cells has
been found to be concentration- and time-dependent.
In addition to periprocedural hydration, which is the cornerstone
of CIN, several drugs have been investigated for the pharmacological
prophylaxis of CIN, either on pre-clinical models or in clinical
studies. Some of them (theophylline, N-acetylcysteine, the
prostacyclin analogue beraprost or taurine) are known to interfere
with the apoptosis pathways.
This article reviews and critically discusses the available
data concerning the role of apoptosis in the mechanism of
CIN and its pharmacological prophylaxis. It also reviews the
putative interaction of gadolinium chelates, used as CM for
magnetic resonance imaging, with apoptosis pathways.
[Back to top]
Editorial
Phospholipase A2
constitutes a large and diverse family of enzymes, which catalyze
the hydrolysis of membrane glycerophospholipids at the sn-2
position to release fatty acids and lysophospholipids. When
the fatty acid is the arachidonic acid, a complementary metabolism
leads to pro-inflammatory mediators such as prostaglandins,
leukotrienes, thromboxanes and platelet activating factors.
Thus, modulating pro-inflammatory lipid mediator production
by inhibiting PLA2
activity remains a potential target for the development of
new drugs for the treatment of inflammatory diseases.
Many different PLA2
are present in the mammalian organism. They can be divided
in PLA2s
utilizing a catalytic histidine and in PLA2s
having a serine in the active site. Thus, a problem associated
with the in vitro search for PLA2
inhibitors is the selection of the appropriate enzyme.
All the above facts prompted us to deal with phospholipases
in a thematic issue, as a biomolecule target for “new
leads” in the modulation of inflammation processes.
In their contribution Lehr et al., describe the different
assays applied for the evaluation of cPLA2
inhibitors in vitro and in vivo. Furthermore,
they present the structures and inhibition data of known cPLA2a
inhibitors and discuss the problems associated with the development
of a clinical active drug candidate. Since it is difficult
to compare the in vitro inhibition data of enzyme
inhibitors as far as they are monitored with different assays,
the authors also present such data for some interesting cPLA2a
inhibitors determined with the same assay.
Inflammatory mediators contribute significantly to the induction
and progression of cardiovascular diseases such as atherosclerosis
and acute myocardial infarction (AMI). A mediator that has
been shown to play a crucial role in both cardiovascular events
is group-II secretory phospholipase A2
(sPLA2-II),
as this mediator has been suggested to modulate atherosclerotic
plaque formation, for example by increasing the accumulation
of intracellular lipids in macrophages and stimulating the
formation of foam cells. Furthermore, increased levels of
sPLA2-II
in the blood form a risk marker for the development of complications
of coronary artery disease. In line with this, Krijnen et
al., have recently found that extracellular sPLA2-II
is more abundantly present in the extracellular matrix of
atherosclerotic culprit lesions of coronary arteries in patients
who developed AMI than in those of patients with stable or
unstable angina pectoris. Another important feature of sPLA2-II
is its abilty to bind to and hydrolyze membrane phospholipids.
Notably, sPLA2-II
cannot bind to the tightly packed hydrophobic phospholipids
in the outer leaflet of a normal membrane, but only to the
disarranged or flip-flopped membranes of damaged cells, as
is the case in ischemic jeopardized cardiomyocytes. Interestingly,
Krijnen et al., have recently observed that sPLA2-II
cannot only bind to reversible damaged cardiomyocytes but
also induces these cells to die, partly by potentiating binding
of C-reactive protein and thus inducing an inflammatory response
in the ischemically challenged heart.
From this point of view, Krijnen and co-investigators discuss
in their review the pros and cons of therapy with inhibitors
of sPLA2-II
to prevent complications of the process of atherosclerosis,
and/or to limit the amount of cell death of cardiomyocytes
subsequent to AMI.
Hnps-PLA2
has been crystallized with different ligands and several classes
of inhibitors are known, but the optimization of their therapeutic
properties requires: (i) a better understanding of the inhibitor-protein
interaction mechanism, and (ii) finding a strategy to predict
the activity of new molecules. Approaches related to computational
chemistry may help to resolve these two problems and these
are included in the review of Chretien’s et al.
An automated docking study was performed on a series of 188
competitive hnps-PLA2 inhibitors. The docking data were then
used to establish 3D QSAR models by combining Comparative
Molecular Field Analysis (CoMFA) and PLS modeling. The robustness
and prediction power of the best model were assessed with
the help of cross-validation and test set procedures that
delivered excellent scores. The combination of the two models
generated on hnps-PLA2
and hp-PLA2
offered a global predictive tool able to select new strong
anti-inflammatory drugs with negligible side effects, at least
at pancreatic level.
In the last review, Kokotos et al., summarize the
chemical classes of reversible and irreversible inhibitors
of both GIVA PLA2
and GVIA PLA2.
Structures, synthesis and inhibition data for both enzymes
are presented.
Dr. D. Hadjipavlou-Litina
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Department of Pharmaceutical Chemistry
School of Pharmacy, Aristotelian University of Thessaloniki
Thessaloniki, 54124
Greece
E-mail : hadjipav@pharm.auth.gr
[Back to top]
Inhibitors of Cytosolic Phospholipase A2α
as Potential Anti Inflammatory Drugs
Matthias Lehr
Arachidonic acid derivatives, like prostaglandins and leukotrienes,
and the platelet-activating factor (PAF) are highly active
substances with diverse biological actions. Elevated levels
of these lipid mediators in response to a variety of stimuli
have been implicated in the pathology of many inflammatory
diseases. The rate limiting step in the generation of prostaglandins,
leukotrienes and the PAF, respectively, is the cleavage of
the sn-2-ester of membrane phospholipids by phospholipase
A2.
To date four main groups of phospholipases are known, which
comprise the secretory, the calcium-independent, the cytosolic
and the lipoprotein-associated phospholipases A2.
From these the α
-subtype of cytosolic phospholipases A2
(cPLA2α
) appears to be the most likely candidate to catalyze
this hydrolysis, since the enzyme is highly selective for
arachidonoyl-containing phospholipids and is tightly regulated
by receptor-stimulated mechanisms (calcium influx and phosphorylation).
Moreover, experiments with cPLA2α
knockout mice have provided further evidence for the central
role of this enzyme in inflammation. Therefore, inhibition
of cPLA2α
activity is an attractive approach to the control of inflammatory
disorders.
In this article we describe the different assays applied for
the evaluation of cPLA2α
inhibitors in vitro and in vivo. Furthermore,
we present the structures and inhibition data of known cPLA2α
inhibitors and discuss the problems associated with the development
of a clinical active drug candidate. Since it is difficult
to compare the in vitro inhibition data of enzyme
inhibitors as far as they are monitored with different assays,
we also present such data for some interesting cPLA2α
inhibitors determined with the same assay.
[Back to top]
Group II Secretory PLA2:
A New Cardiovascular Risk Factor
Paul A.J. Krijnen, Remco Nijmeijer, C. Erik Hack and Hans
W.M. Niessen
Inflammatory mediators contribute significantly to the induction
and progression of cardiovascular diseases such as atherosclerosis
and acute myocardial infarction (AMI). A mediator that has
been shown to play a crucial role in both cardiovascular events
is group-II secretory phospholipase A2
(sPLA2-II),
as this mediator has been suggested to modulate atherosclerotic
plaque formation, for example by increasing the accumulation
of intracellular lipids in macrophages and stimulating the
formation of foam cells. Furthermore, increased levels of
sPLA2-II
in the blood form a risk marker for the development of complications
of coronary artery disease. In line with this, we recently
found that extracellular sPLA2-II
is more abundantly present in the extracellular matrix of
atherosclerotic culprit lesions of coronary arteries in patients
who developed AMI than in those of patients with stable or
unstable angina pectoris. Another important feature of sPLA2-II
is its ability to bind to and hydrolyze membrane phospholipids.
Notably, sPLA2-II
cannot bind to the tightly packed hydrophobic phospholipids
in the outer leaflet of a normal membrane, but only to the
disarranged or flip-flopped membranes of damaged cells, as
is the case in ischemic jeopardized cardiomyocytes. Interestingly,
we recently have observed that sPLA2-II
cannot only bind to reversible damaged cardiomyocytes but
also induces these cells to die, partly by potentiating binding
of C-reactive protein and thus inducing an inflammatory response
in the ischemically challenged heart.
This review will discuss the pros and cons of therapy with
inhibitors of sPLA2-II
to prevent complications of the process of atherosclerosis,
and/or to limit the amount of cell death of cardiomyocytes
subsequent to AMI.
[Back to top]
3D QSAR Study of Human PLA2
Inhibitors. A Modeling Approach to Select New and Specific
Anti-Inflammatory Drugs
Marco Pintore, Enrico Mombelli, Christophe Wechman
and Jacques R. Chretien
High concentrations of human non pancreatic secretory phospholipase
A2
(hnps-PLA2)
have been reported as inducing factors in different inflammatory
diseases. Thus, hnps-PLA2
inhibitors would be potential drugs against disorders generated
by high levels of this enzyme. The latter has been crystallized
with different ligands and several classes of inhibitors are
known, but the optimization of their therapeutic properties
requires: (i) a better understanding of the inhibitor-protein
interaction mechanism, and (ii) finding a strategy to predict
the activity of new molecules. Approaches related to computational
chemistry may help to resolve these two problems.
An automated docking study was performed on a series of 188
competitive hnps-PLA2 inhibitors. The docking data were then
used to establish 3D QSAR models by combining Comparative
Molecular Field Analysis (CoMFA) and PLS modeling. The robustness
and prediction power of the best model were assessed with
help of cross-validation and test set procedures that delivered
excellent scores. The search for the best inhibitors against
hnps-PLA2
has to be associated with a high specificity of the molecules
selected, minimizing possible human side effects. This requires
keeping at an extremely low level the inhibitor’s activity
against human pancreatic phospholipase A2
(hp-PLA2)
which is in negligible concentration in all tissues except
in pancreatic ones. Then, the above mentioned modeling procedure
was applied also on a series of hp-PLA2
inhibitors and, once more, the 3D QSAR model thus generated
showed an excellent robustness and prediction power.
Finally, the combination of the two models generated on hnps-PLA2
and hp-PLA2
offered a global predictive tool able to select new strong
anti-inflammatory drugs with negligible side effects, at least
at pancreatic level.
[Back to top]
Synthetic Inhibitors of Group IVA and Group VIA Phospholipase
A2
Victoria Magrioti and George Kokotos
PLA2
is an important signaling enzyme that generates multiple downstream
effectors, such as arachidonic acid and PAF, which are key
mediators of inflammation as well as other pathophysiological
conditions. Inhibition of PLA2
is potentially an effective therapy for several inflammatory
diseases. In this review, we discuss the various classes of
synthetic inhibitors of Group IVA and Group VIA phospholipase
A2.
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