Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 5, Issue 2, 2006

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.

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.

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.

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.

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.

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, Nacetylcysteine, 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.

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 Creactive 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.

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 a-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.

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 sPLA 2-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.

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 inhibitorprotein 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.

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.