Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

ISSN: 1871-5230

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Volume 8, Number 1, March 2009

Contents

Anti-Inflammatory Strategy: Old Ally or New Promise in Therapy
Guest Editor: Marcella Reale


Editorial Pp. 1-2


UV Induced Skin Immunosuppression Pp. 3-13
P. Amerio, A. Carbone, M. Auriemma, S. Varrati and A. Tulli
[Abstract] [Full text article]


The Antinflammatory Effect of Alpha-MSH in Skin: A Promise for New Treatment Strategies Pp. 14-21
M. Auriemma, T. Luger, K. Loser, P. Amerio and A. Tulli
[Abstract] [Full text article]


Analytical Procedure for Determination of Cyclooxygenase-2 Inhibitors in Biological Fluids by High Performance Liquid Chromatography: A Review Pp. 22-37
G. Carlucci
[Abstract] [Full text article]


Corticoisteroid-Induced Apoptosis in Hematological Malignancies Pp. 38-46
G. D’Arena, N. Cascavilla, G. Rossi, A. Giudice, C. Arra, V. De Feo and B.M. Fusco
[Abstract] [Full text article]


Tumor Necrosis Factor Inhibitors as Therapeutic Choice in Psoriasis Pp. 47-50
D. Digiuseppe and C. Feliciani
[Abstract] [Full text article]


Biotechnological Approaches for the Treatment of Inflammatory Diseases Pp. 51-71
V. Iansante, D. Capece, S. Murgo, M.M. Mancarelli, F. Zazzeroni and E. Alesse
[Abstract] [Full text article]


Anti-Inflammatory Agents in Parkinson’s Disease Pp. 72-84
C. Iarlori
[Abstract] [Full text article]


Anti-Inflammatory Properties of Acetylcholinesterase Inhibitors Administred in Alzheimer’s Disease Pp. 85-100
M.A. Kamal, N.H. Greig and M. Reale
[Abstract] [Full text article]


Anti-Inflammatory and Anti-Allergy Drugs in Rhinosinusitis Pp. 101-113
A. Moretti, A. Augurio and A. Croce
[Abstract] [Full text article]




Abstracts


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Editorial: Anti-Inflammatory Strategy: Old Ally or New Promise in Therapy

The inflammatory response is a complex cascade of non-specific events resulting in excessive generation of inflammatory mediators such as cytokines, C-reactive protein and nitric oxide by cells of the innate (macrophages, monocytes, neutrophils) and adaptive (T-lymphocytes) arms of the immune system. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. Acute inflammation may lead to a systemic reaction known as the acute phase response in which stimulated macrophages secrete TNF-a, IL-1 and IL-6 which act on the hypothalamus to produce fever and on the liver to induce production of acute phase proteins. Inflammation participates importantly in host defences against infectious agents and injury, and it also contributes to the pathophysiology of many chronic diseases. The magnitude of the inflammatory response is crucial: insufficient responses result in immunodeficiency, which can lead to infection and cancer; excessive responses cause morbidity and mortality in diseases such as rheumatoid arthritis, Crohn’s disease, atherosclerosis, diabetes, Alzheimer’s disease, multiple sclerosis, and cerebral and myocardial ischemia. If inflammation spreads into the bloodstream, as occurs in septic shock syndrome, sepsis, meningitis and severe trauma, the inflammatory responses can be more dangerous than the original inciting stimulus.

Mastery of the inflammatory response should aid the development of novel strategies to predict disease susceptibility, target and monitor therapies, and ultimately develop new approaches to the prevention and treatment of chronic diseases. Homeostasis and health are restored when inflammation is limited by anti-inflammatory responses that are redundant, rapid, reversible, localized, and adaptive to changes in input and integrated by the nervous system.

There is still a high medical need for better therapy for many inflammatory diseases, such as eczema and psoriasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and others. Many well established drugs on the market fail in patients with severe disease or have major side effects. Recently, significant progress has been made with the launch of some biologics such as cytokine neutralising antibodies (e.g. Anti-TNF alpha).

Here we focus our attention on the anti-inflammatory drugs and the diversity and complexity of the inflammatory and immulogical mechanisms in same disease, and have assembled a superb group of articles that deal with the broad issue of inflammatory and immunological disease mechanisms, processes that have relevance in psoriasis, scleroderma, polyposis, neurodegenerative disease and in other areas of pathology. Of necessity, these reviews deal with selected topics but the mixture of articles on specific antiinflammatory therapy with articles addressing different inflammatory diseases provides a broad overview of the field.

Amerio et al. discuss how we can be protected from the harmful effect of solar light. Summing up the actual rate of new results in photoimmunology and the great abundance of new works on the protective effects of sunscreens and UV protective substances.

Auriemma et al. focus on the aMSH and the related C-terminal tripeptide KPV and K (D) PT as the promising molecules against inflammation processes in vitro as well as in vivo. aMSH anti-inflammatory activity on the dermal endothelium seems to be an interesting field of research to the development of new antiinflammatory drugs to be used in vasculitis. Thanks to them anti-microbial effects αMSH and the related C-terminal tripeptide seems to be more prone to prolonged therapy than corticosteroids or other immunosuppressant. The small volume of the C-terminal peptides of aMSH seems to be more prone to the development of new drugs class for topic therapy.

The anti-inflammatory, analgesic, and antipyretic drugs are a heterogeneous group of compounds, often chemically unrelated (although most of them are organic acids), which nevertheless share certain therapeutic actions and side effects. The principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production. Inhibition of cyclooxygenase (COX), the enzyme responsible for the biosynthesis of the prostaglandins and certain related autacoids, generally is thought to be a major facet of the mechanism of NSAIDs. High-performance liquid chromatographic methods for the analysis of cyclooxygenase 2 inhibitors (COX-2) in biological fluids are reviewed by Carlucci. In particular, sample preparation and handling procedures, chromatographic conditions and detection methods are discussed.

D’Arena et al. have considered the possible mechanisms of the glucocorticosteroid-induced apoptosis in hematological ma-lignancies such as leukemia and lymphomas. The emerging knowledge of the molecular mechanisms of apoptotic machinery leads several researchers to point out the apoptosis-based therapies for hematological malignancies targeting several proteins of both extrinsic and intrinsic apoptotic pathways. Though the exact mechanism of corticosteroids-induced apoptosis is not fully understood, glucocorticoids are extensively used in the therapy of leukemia and lymphomas.

Feliciani et al. have developed the theme of inflammatory mediators by discussing current data on the role of tumour necrosis factor (TNF) in inflammatory disease. The wide-ranging role of TNF has become all the more apparent with the increasing use of anti-TNF treatments in the management of patients with Psoriasis, the roles and effects of these treatments are also discussed.

Recent advances in understanding the immunopathogenetic mechanisms of inflammatory diseases have led to the development of biological therapies, which selectively inhibit crucial mediators of the inflammatory process. Iansante et al. have reviewed the state of the art of biological therapies developed for the treatment of different inflammatory diseases, with examples of several drugs designed and tested for targeting molecules involved in the inflammatory cascade, and underlines their principal advantages in comparison with conventional therapies.

Neuroinflammation and oxidative stress may contribute to the pathogenesis of Parkinson’s disease (PD). Nonsteroidal anti-inflammatory drugs (NSAIDs) best known as inhibitors of cyclooxygenase enzyme, which are induced by cytokines or inflammatory stimuli and generate important mediators in inflammatory reactions. NSAIDs are able to prevent neuronal death, possibly through their anti-inflammatory properties, antioxidant properties, or both. The Iarlori’s article address involvement of an inflammatory process in the pathogenesis of PD and include reviews that provide detailed information on the effectiveness of the NSAIDs as therapeutic agents against parkinsonism and as neuroprotective agents against dopaminergic neurotoxicity in the parkinsonian models.

The recent explanation of the inflammatory pathways involved in AD has opened new avenue for researchers to find it cure by thinking from alternative angle that target the cause of the disease rather than the obvious symptoms. In this respect, there are appreciating efforts by various research teams who are working on expression of pro-and anti-inflammatory markers in peripheral blood of AD patients and on anti-inflammatory effects of some acetylcholinesterase inhibitors (AChEI), the FDA-approved drug for treatment of AD. Kamal et al. have reviewed the recent, major progress made in elucidating the neuroinflammation as well as the in vitro and in vivo studies on anti-inflammatory activity of cholinesterase inhibitors

The medical management of rhinosinusitis is related to the duration and severity of symptoms and a variety of general and topical pharmacologic interventions are available, for eliminating causative factors and controlling the inflammatory and infectious components. Moretti et al. make a review of the literature to describe the most useful anti-allergy and anti-inflammatory drugs in the management of rhinosinusitis.

Within this issue an overview is given on recent progress in the field of anti-inflammatory strategy for the treatment of inflammation addressing the opportunities and chances on one hand and the issues and hurdles on the other hand. The aim of this special issue, starting by some old strategy to the recent new promise, was to highlight therapeutic approaches that could be used to mitigate the devastating effects of inflammation, and how they may have a role to play in improving clinical outcome in humans.

I am privileged to have the opportunity to convince experts to contribute to this comprehensive and critical issue. I wish to also express my appreciation to Prof. B Tunctan, Editor-in-Chief, Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry and Bentham Science Publishers for the wonderful opportunity to publish this special issue. I am also grateful to kind assistance of Saima Rao at Bentham for the kind assistance in processing of these manuscripts.


Marcella Reale
Department of Oncology and Neuroscience
Unit of Immunology
University G. D'Annunzio
Via dei Vestini, 31
66123 Chieti
Italy
E-mail: mreale@unich.it


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UV Induced Skin Immunosuppression
P. Amerio, A. Carbone, M. Auriemma, S. Varrati and A. Tulli

[Full text article]

It is well estabilished that ultraviolet radiations from sunlight are carcinogenetic for skin cells. These radiations at different wavelength induce damage in the skin manly through two mechanisms : direct DNA alteration and alteration of the immune system.

The skin immune system is composed by a complex network of cells and soluble mediators that help to maintain the homeostasis of the skin.

UV induced immunosuppression is mediated through different photoreceptors present in the skin that lead to either: the production of immunosuppressive cytokines such as IL-10, TNF-α and TGF-β or the development of suppressive T regulatory cells or to the migration in the skin of CD11+ leukocytes in the skin that ultimately lead to the suppression of immune responses.

The aim of this short review is to summarize the general knowledge in the field of UV-induced immunosuppression. The knowledge of the exact mechanism involved in this mechanism is important in order to develop strategies aimed at reducing skin cancer induction.


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The Antinflammatory Effect of Alpha-MSH in Skin: A Promise for New Treatment Strategies
M. Auriemma, T. Luger, K. Loser, P. Amerio and A. Tulli

[Full text article]

MCs are peptide hormones involved in the regulation of an increasing list of processes: pigmentation, cortisol production, food intake, energy and metabolism homeostasis, sexual behaviour, exocrine gland function and inflammation. One of the most important players of this system is αMSH, a neuroimmunomodulatory tri-decapeptide derived from POMC; while it has been demonstrated in melanocytes, monocytes, B-cells, NK, a subset of cytotoxic T-cells, epithelial cells and in keratinocytes, the skin is one of the most relevant extrapituitary sources of αMSH expression and secretion.

The key role of MCs in skin/hair colour regulation has been widely figured out in man and animal models. UV-light induces the production of MCs; additionally other skin’s produced cytokines and parakrine factors (CRH, IL-1, TNF-α, and TGF-β) regulate MC production and MC-1R activity. Moreover MCs and their autoAbs are involved in grooming behaviour, antipyretic and antinflammatory responses, learning, reproductive function, appetite regulation, eating disorders, energy homeostasis, ethanol consumption and violent conduct. A strong and not well understood association between skin malignancies and the CRH-POMC axis has been shown.

The MCs bind to five MC-Rs. Each MC-R binds several MCs with the exception of MC-2R, strongly selective for ACTH, unlike the expression of MC-R which is tissue specific, MC-5R being the most widespread.

The discovery of the influence of MC in the inflammation modulation, food intake behaviour, lipid metabolism, sex activities, neoplasm development and autoimmune diseases is attracting more and more attention to define new therapeutic strategies and drugs like αMSH and the related tripeptide KPV and K(D)PT.


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Analytical Procedure for Determination of Cyclooxygenase-2 Inhibitors in Biological Fluids by High Performance Liquid Chromatography: A Review
G. Carlucci

[Full text article]

High-performance liquid chromatographic methods for the analysis of cyclooxygenase 2 inhibitors (COX-2) in biological fluids are reviewed. In particular, sample preparation and handling procedures, chromatographic conditions and detection methods are discussed. A summary of published high-performance liquid chromatographic assays for individual nabumetone, celecoxib, rofecoxib, nimesulide, etoricoxib, etodolac, deracoxib, lumiracoxib, valdecoxib, and meloxicam is included.


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Corticoisteroid-Induced Apoptosis in Hematological Malignancies
G. D’Arena, N. Cascavilla, G. Rossi, A. Giudice, C. Arra, V. De Feo and B.M. Fusco

[Full text article]

Corticosteroids induce apoptosis in both normal and neoplastic lymphocytes. For this reason they are commonly used to treat autoimmune disorders and lymphoid malignancies also.

The exact mechanism of corticosteroid-induced apoptosis is not fully understood despite the fact that much has been found in respect to several supposed involved mechanisms. This process is arbitrarily divided in several phases. Firstly, glucocorticoid enters the cell and binds to the glucocorticoid receptor (GR) in the cytoplasm. The GR changes conformation and the heat shock proteins, normally bound to the receptor in the steady state, fall off. The activated GR-hormone complex enters the nucleus and binds to its specific DNA binding site, the glucocorticoid responsive element (GRE), thus resulting in activating or repressing transcription of genes. The activation of caspases or other proteases and endonucleases finally results in the commitment to cell death.


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Tumor Necrosis Factor Inhibitors as Therapeutic Choice in Psoriasis
D. Digiuseppe and C. Feliciani

[Full text article]

Psoriasis has been for a long time a distressing skin disease difficult to treat. Several topical and systemic drugs have been used successfully in the treatment but the most active drugs are also the most difficult to manage in a long term treatment. Discovering the pathogenesis of this skin disorder has suggested that anti tumor necrosis factors agents could be an alternative treatment. Up to now several manuscripts show data supporting the idea that anti TNF are safe and effective more than other drugs. On the experience of dermatologists using this drug in a large number of patients TNF inhibitors are very effective drugs with a relatively safe management. At the moment several drug companies are developing a second generation of biologic drugs with different targets. This review point out the actual knowledge about anti TNF drugs and their activities on psoriasis both clinically and biologically.


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Biotechnological Approaches for the Treatment of Inflammatory Diseases
V. Iansante, D. Capece, S. Murgo, M.M. Mancarelli, F. Zazzeroni and E. Alesse

[Full text article]

Chronic inflammation represents a key pathogenetic event of many diseases, such as psoriasis, inflammatory bowel diseases, rheumatoid arthritis, asthma, multiple sclerosis, atherosclerosis, cystic fibrosis, and sepsis. Conventional therapies for many of these disorders do not lead to the resolution of the inflammatory disorder, and frequently are associated with limited effectiveness and severe side effects. For these reasons alternative therapies have been developed, in the attempt to ensure a more sustained therapeutic response. Biotechnological approaches for the development of these novel drugs are giving exciting results: several biologic molecules are now tested in preclinical or clinical trials, and several of them are even approved for marketing.


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Anti-Inflammatory Agents in Parkinson’s Disease
C. Iarlori

[Full text article]

Parkinson’s disease (PD) is a frequent neurological disorder of the basal ganglia, which is characterized by the progressive loss of dopaminergic neurons mainly in the substantia nigra pars compacta (SNpc). Recently, increasing evidence from human and animal studies has suggested that neuroinflammation is a cause or rather a consequence of neurodegeneration. Activated microglia, as well as to a lesser extent reactive astrocytes, are found in the area associated with cell loss, possibly contributing to the inflammatory process by the release of pro-inflammatory prostaglandins or cytokines. Further deleterious factors released by activated microglia or astrocytes are reactive oxygen species. Although dopamine replacement can alleviate symptoms of the disorder, there is no proven therapy to halt the underlying progressive degeneration of dopamine-containing neurons. Furthermore, growing experimental evidence demonstrates that inhibition of the inflammatory response can, in part, prevent degeneration of nigrostriatal dopamine-containing neurons in several animal models of PD, It has been revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have neuroprotective properties based not only on their cyclooxygenase-inhibitory action, but also on other properties including their inhibitory effects on the synthesis of nitric oxide radicals. NSAIDs inhibit prostaglandin H synthase, thus suppressing dopamine oxidation and subsequent dopamine quinone formation.

This study suggests that inhibition of inflammation may become a promising therapeutic intervention for PD.


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Anti-Inflammatory Properties of Acetylcholinesterase Inhibitors Administred in Alzheimer’s Disease
M.A. Kamal, N.H. Greig and M. Reale

[Full text article]

Alzheimer disease (AD) is a frustrating health disorder agitating millions in this era of modern science and technology. AD is a progressive neurodegenerative disorder that damages the memory and cognitive systems of the body, therefore wrecking normal daily activities as well as the communicative skills of the afflicted person. To this regard special attention is required by our researchers to develop better treatment and by the various political social-assistence agencies to grant more funds and aides to better provide for the patients. Consequently, it is worthwhile to examine the role of anti-acetylcholinesterases in reducing the level of inflammatory markers reported in current literature. As of today, AD patients are treated by acetylcholinesterase inhibitors which prolong cognitive function by increasing synaptic activity. Often, new natural as well as synthetic inhibitors are reported by researchers all around the world although this treatment is only symptomatic and provides modest outcomes to the patients. The recent explanation of the inflammatory pathways involved in AD however, has opened new avenues for researchers to find a cure by thinking from alternative angles that target the cause of the disease rather than the obvious symptoms. To this respect, there are appreciating efforts by various research teams, who are working on expressions of pro-and anti-inflammatory markers in peripheral blood mononuclear cells of AD patients to understand their actual mechanisms. There are several links between inflammation and central nervous system disorders like Alzheimer's, Cancer, Huntington's, Multiple Sclerosis, and Parkinson's while the depth of their relationship depends on the timing and extent of anti- or pro-inflammatory gene expressions.


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Anti-Inflammatory and Anti-Allergy Drugs in Rhinosinusitis
A. Moretti, A. Augurio and A. Croce

[Full text article]

Rhinosinusitis constitutes one of the most common respiratory tract diseases affecting up to 15% of the adult population in the Western world.

Sinusitis is almost always accompained by inflammation of the contiguous nasal mucosa, thus the correct terminology is now rhinosinusitis. It can be classified into acute and chronic form by duration, or into acute bacterial rhinosinusitis or viral rhinosinusitis, by symptoms.

This paper describes some aspects about epidemiology, pathophysiology, and predisposing factors in rhinosinusitis and nasal polyps, offering evidence based recommendations on diagnosis and first line and second line treatment.

The medical management of rhinosinusitis is related to the duration and severity of symptoms and a variety of general and topical pharmacologic interventions are available, for eliminating causative factors and controlling the inflammatory and infectious components. The Authors make a review of the literature to describe the most useful anti-allergy and anti-inflammatory drugs in the management of rhinosinusitis.