Abstracts


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Anti-Inflammatory Therapy for Alzheimer's Disease from Epidemiological Fact to New Mechanisms of Action
Kiminobu Sugaya

While the exact causes or mechanisms of Alzheimer’s disease (AD) are still not known, the most critical risk factor is aging. Cellular oxidative stress is known to occur in the brain during aging and some pathology of AD could be explained by the oxidative stress, including senile plaques, deposition of amyloid peptide (Aβ) and tangles (deposition of an abnormally phosphorylated tau). Also gliosis, which may release inflammatory molecules and cause oxidative stress, is a feature of aging and AD. Epidemiological analysis indicates that people with severe arthritis and who are subjected to leprosy therapy have significantly lower rates of AD. Since both arthritis and leprosy therapy involves high doses of non-steroidal anti-inflammatory drugs (NSAIDs), and the fact that inflammation is involved in AD pathology, NSAID-therapy might prevent or delay the onset of AD. More recently NSAIDs were found to reduce production of Aβ peptide. Therefore, we should revisit NSAIDs as potential treatment for AD therapy. There are clinical studies showing the beneficial effects of NSAIDs treatments in AD patients, in contrast, other studies show a lack of benefit. This article discusses the role of inflammation and oxidative stress in AD and the role of drugs preventing them.


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Editorial [Hot topic: Role of Inflammation in Neurological and Psychiatric Disorders] (Guest Editor: Mohtashem Samsam)
Mohtashem Samsam

Neuroinflammation is believed to be the common pathological process in many neurodegenerative diseases, and what was believed to be a naive housekeeping process, as a result of neurodegeneration, can be a hostile contributor of the disease. Several primary neurological disorders are associated with inflammatory responses, in many cases they aggravate the initial problem and lead to acute symptoms and disability or permanent damage due to neuronal death. Most of the anti-inflammatory treatment strategies in neurological disorders aim to reduce the symptoms of the disease leading to a rapid recovery in many cases due to blocking the immune response by inhibiting the pro-inflammatory mediators. There are evidences that inflammatory mediators including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding [1]. Moreover, elevation of soluble tumor necrosis factor (TNF), a potent pro-inflammatory/ pro-apoptotic cytokine is one of the hallmarks of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and demyelinating disease such as multiple sclerosis (MS), as well as the ischemic stroke [2, 3].

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS) characterized by inflammation, demyelination and variable loss of axons [4-6]. The recurrent relapses of CNS inflammation in MS patients cause disability. The Th17 cell response has been indicated in experimental allergic encephalomyelitis (EAE, a model to study MS) [7]. Treatment strategies include the acute treatment of relapses, symptomatic relief, and immunomodulation by constraining the inflammation, stimulation of remyelination and neuroprotection. Relapses have long been treated with anti-inflammatory drugs including the steroids [8]. Interferon beta (IFNß)-1b was the first immunomodulatory drug used for MS [9]. Several other anti-inflammatory or immunomodulatory drugs are currently used in the treatment of MS [10]. A new treatment approach to reduce or prevent the ROS by Dr. Michel Geffard in France and Dr. Rafael Covenas in Spain and colleagues suggests using fatty acids linked to poly-L-Lysine (PL), such as antioxidants linked to PL, free radical scavengers linked to PL, and amino acids linked to PL inhibits brain leukocyte infiltration in EAE, the animal model of MS, and abolishes the episodes of the disease and preserves myelin integrity [11, 12].

In this issue, the article: endotherapia, will discuss how fatty acids, anti-oxidants, amino acids and their derivatives linked to the polymer poly-L-lysine have a better efficiency as anti-inflammatory drugs, an approach that prevents metabolic degradation of the linked small molecules, improves the kinetics and increases the half-life of the product, as well as allowing it to reach the site of the lesion. The result of an open study in treatment of MS patient is presented using this new approach.

Alzheimer's disease (AD) is a neurodegenerative disorder of the CNS associated with progressive cognitive and memory loss, and is characterized by senile plaques and deposition of amyloid beta peptide (Abeta), neurofibrilary tangles in brain tissue, degeneration of cholinergic pathways, and neuronal degeneration in brain including the cerebral cortex and the hippocampus [13]. Amyloid-beta and tau protein make up the plaques and tangles of Alzheimer's disease, where these normally soluble proteins assemble into amyloid-like filaments [14]. Inflammation also plays a role in AD and there are evidences for the convergence of the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators [15, 16]. Gliosis which is known to be induced by oxidative stress and is increased by aging, significantly contributes to the pathophysiology of AD. Several other factors including the genetic, biological and environmental factors play important role in the pathogenesis of AD. Most genes conferring susceptibility to AD are related to amyloid- beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) as well as the inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha) genes [17-21]. Amyloid-beta oligomers and fibrils and their cellular effects can activate the innate immunity defense and induce inflammatory and apoptotic responses in human brain. Several antiinflammatory drugs approved for other conditions, when used in AD counteract the inflammatory responses [22]. The cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, have been tested as potential therapeutics in AD [23, 24], but due to their side effects on stomach by interfering with production of eicosanoids such as prostaglandin (PGs, which have gastroprotective effects), as well as mediating to bronchoconstriction through other eicosanoids including the leukotriense (LTs), the COX-2 inhibitor drugs were proposed. However, the COX-2 inhibitors, which may reduce the production of prostaglandins, may increase the production of LTB4 which is one of the most potent endogenous chemotactic/inflammatory factors....


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Pharmacogenetics of Anti-Inflammatory Therapy in Asthma: Corticosteroids and Leukotriene Antagonists
Ellen S. Koster, Anke-Hilse Maitland-van der Zee, Susanne J. H. Vijverberg, Cornelis K. van der Ent and Jan A.M. Raaijmakers

Asthma is a chronic airway disease with a relatively high prevalence. Although the etiology of asthma is still not fully clear, there are effective treatments available. The treatment strategy for asthma consists of two steps: maintenance therapy with anti-inflammatory agents (inhaled corticosteroids and/or leukotriene antagonists) to reduce airway inflammation and retain proper lung function and secondly, the use of beta-agonists for quick symptomatic relief. Furthermore, oral steroids are used to treat acute exacerbations.

There are large differences in response to drug therapy. This may be due to many factors, such as severity and type of disease, compliance, co-morbidity, co-medication (drug-drug interactions), environmental exposures and age. However, calculations of repeatability of treatment response suggest that part of this variance in response to pharmacotherapy could be due to genetic factors. Pharmacogenetics may explain the inter-individual variability in drug response due to genetic variation.

Pharmacogenetics is a relatively new emerging research field that provides the opportunity to discover associations between genetic variation and response to a variety of drugs. This review will discuss the pharmacogenetics of antiinflammatory agents (corticosteroids and leukotriene antagonists) used in the treatment of asthma.


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Neuropeptides and Other Chemical Mediators, and the Role of Anti-inflammatory Drugs in Primary Headaches
Mohtashem Samsam, Rafael Covenas, Raheleh Ahangari and Javier Yajeya

Primary headaches including the migraine, cluster, and tension headaches are common neurological disorders which cause pain and disability to the patients. The pathomechanism of migraine is not very well understood however, current clinical findings indicate a possible primary brain disorder due to activation of the brain and brainstem as triggers for migraine. The headache phase of migraine may be due to activation of the peripheral nerves including the trigeminal nerve and others innervating the cranial blood vessels and release of vasoactive substances including the calcitonin gene-related peptides (CGRP), possibly leading to vasodilation and brainstem activation. Several of our studies in an experimental model of pain using electrical stimulation of the trigeminal ganglion in rats focused on various neuropeptides release from the peripheral and central trigeminal nerve terminals, however, clinically only the CGRP in migraine and CGRP and vasoactive intestinal peptide (VIP) in cluster headache were found in patient’s blood. Although several drugs are used in the treatment of migraine, the non-steroid anti-inflammatory drugs (NSAIDs) and the triptan family of drugs are the first choice drugs recommended for the treatment of acute migraine headache. Although clinically very few studies detected other vasoactive/inflammatory molecules in the blood of migraine patients, sensitization of peripheral axons can involve many inflammatory mediators affecting the peripheral tissue substrates of pain. Moreover, central sensitization in the trigeminal nucleus can also contribute to additional pain responses. This article reviews neuropeptides and other molecules involved in primary headaches and major drugs proposed for their treatment in recent years.


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Editorial [Hot-Topic:Current Trends in Natural Products as Anti-Inflammatory and Anti-Allergy Agents (Guest Editor: Francesco Epifano)]
Francesco Epifano

In the last years natural products have been re-discovered as valuable and effective pharmacological agents. In particular they were shown to exert positive effects in the therapy of acute and chronic diseases, like cancer and microbial syndromes, for which the use of chemotherapeutics or antibiotics failed due to increasing resistance. To this concern, many examples of natural products were reported in the recent and current literature. The aim of this special issue is to collect reviews from several research groups to get further insights in the up to date knowledge in the field of anti-inflammatory and anti-allergy agents obtained from the natural kingdom. Such an issue would be of great interest for several categories of scientists operating in natural product chemistry, phytochemistry, pharmacology, molecular biology, pharmacognosy, and others.


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Editorial [Hot topic: Alpha-1 Antitrypsin Deficiency: A Disease with Numerous Adverse Effects on Humans (Guest Editors: S. Ghavami, A.J. Halayko and F.J. de Serres)]
Saeid Ghavami, Andrew J. Halayko and Fredrick J. de Serres

Alpha -1 antitrypsin (AAT) deficiency is a severe autosomal recessive hereditary disorder with an incidence second only to cystic fibrosis among inborn diseases of the lungs [1]. AAT deficiency was first described in 1963 [2, 3], but the earliest assumed case of reported AAT deficiency is in an Alaskan girl who was found frozen in the ice 800 years after her death [4]. Moreover, it is now believed that Frederic Chopin's premature death in 1849 was a AAT deficiency case [5].

In 1963 Laurell and Eriksson investigated 5 patients “with a new type of dysproteinemia characterized by very pronounced alpha 1-antitrypsin deficiency” in their first description of AAT deficiency [2, 6]. Later, in 1965 it was concluded in a study of 33 severely affected patients that most PI*ZZ homozygous individuals are predisposed to early-onset emphysema [2, 6, 7]. In 1969, liver cirrhosis was first linked to AAT deficiency as the presence of periodic acid Schiff (PAS)- positive inclusions in the hepatocytes of AAT deficient individuals was described [8]. Liver involvement is now considered as a conformational feature caused by the accumulation of AAT within hepatocytes rather than the result of tissue breakdown from a protease-antiprotease imbalance [9].

In the four decades since the first description of ATT deficiency significant advances in the understanding its pathogenesis and in clinical management have been made, though important questions remain. Interest in the numbers of individuals affected by AAT deficiency began with a survey of the numbers in various European countries by Hutchinson [10]. This was followed by larger studies by de Serres and colleagues [11-13], revealing data on the frequency of each of the 5 phenotypic classes, PI*MS, PI*MZ, PI*SS, P{I*SZ and PI*ZZ, in 55 countries worldwide. Blanco and colleagues also surveyed for individuals at risk in different geographic regions in Spain (2001a) and others studies assessed the number of individuals at risk for AAT deficiency in countries inside and outside of Europe (2001b,c). de Serres published a paper in 2003 entitled “Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed” in which he described environmental factors associated with different occupations that affect the health and well being of genetic carriers and homozygotes for ATT deficiency. Further work by a collaborative of investigators has surveyed the occurrence of AAT deficiency in all major geographic regions worldwide [12-15](de Serres et al. 2003 a,b, 2005, 2006). These data were summarized in two review papers, the first on 69 countries [16] and another on 98 countries worldwide [17]. The database in the latter paper provides the reader with the following numbers of those at risk in these 98 countries; PI*MS (144,814,982), PI*MZ (37,259,100), PI*SS (4,159,102), PI*SZ (1,467,429), and PI*ZZ (238,161).

Collectively, these studies on the genetic epidemiology demonstrate that AAT deficiency is not a “rare” disease, rather with the exception of countries in the Far East, it affects many people worldwide.

This special issue of Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry will address the latest progress in AAT biology, its deficiency, and emerging therapies.

Besides lung disease, AAT deficiency has been associated with many different diseases like psoriasis [18-20], gasterointestinal disease [21, 22], and ocular inflammation [23, 24]. In their article, Hashemi et al. (pp. 279-288) address multiple aspects of AAT deficiency-induced diseases. They also address the latest detection method and nomenclature rules for AAT alleles.

The liver is chiefly responsible for AAT synthesis (several grams per day), but AAT is also produced by leukocytes, enterocytes, and other tissues [25-27]. AAT deficiency can induce chronic liver disease [28-30], cirrhosis [31-34], and hepatocellular carcinoma [35, 36]. Over one-third of genetically susceptible adult patients with the most severe phenotype, PiZZ, exhibit severely depleted plasma levels of AAT [35, 37] because it is not effectively secreted from the hepatocytes. The clinical presentation of liver disease is variable, and the genetic and environmental factors that predispose some individuals to liver disease while sparing others are unknown. In his article, Teckman (pp. 289-298) reviews the latest understanding of mechanisms for AAT deficiency-induced-liver disease, with focus on the Z homo and heterozygote AAT phenotypes and their clinical and biochemical features. He also describes how the endoplasmic reticulum (ER) retention of unfolded Z AAT protein can trigger ER-stress induced liver pathogenesis in these patients.

Neutrophil elastase (NE) plays a central role in tissue destruction in the lungs of patients with AAT deficiency, and is the major target proteinase of AAT [38]. AAT can also bind irreversibly to proteinase 3 and cathepsin G and inhibit their function [39]. Point mutations in the AAT mobile domain can prevent its effective secretion from the liver [39], leading to the low local levels of this protein within the lung and susceptibility to NE-induced damage [40]. Chronic obstructive pulmonary disease (COPD) is the most important lung disease that is induced by AAT deficiency [41, 42]. In his article Kalsheker (pp. 299-303) focuses on mechanisms of AAT deficiency in the pathogenesis of respiratory diseases. In particular the effect of cigarette smoking on AAT deficiency-induced lung disease states (COPD, emphysema and asthma). Enzymes play an essential role in the regulation of immunologic and inflammatory responses [23, 24, 43]. This often involves the regulation of cell function and the activation of inflammatory mediators such as the complement and kinin systems, as well as the coagulation and fibrinolytic pathways [43, 44]. Many of these mediators are themselves enzymes, and their activity is in most instances regulated by inhibitors [23, 24]. Some inhibitors are highly specific for one enzyme, but others, such as Pi and α2 macroglobin have a broad range of activity.. In their article Leonardi et al. (pp. 304-313) consider the importance of AAT and its deficiency in ocular allergy and inflammation, emphasizing the role of AAT in uveitis and vernal keratoconjunctivitis (VKC). They describe their recent research focused on the role of metalloproteinase enzymes and immune response, and contrast their results with previous findings in this field [23, 24].

Local concentrations of AAT are reduced in many AAT deficiency-related diseases, and appears to be a key event in the development of emphysema. Thus a logical therapeutic strategy, as used for immunoglobulin deficiency, appeared to be to use replacement treatment (augmentation therapy) in AAT deficiency therapy, in particular for AAT deficiency related pulmonary diseases [45]. A guiding principal for such therapy, using research evidence-based clinical data, is that serum AAT concentration of ≥11 μmol are likely to be protective against AAT deficiency-induced pulmonary diseases. Several studies show it is possible to infuse AAT into the plasma, resulting in an increase in the concentration of AAT in the lung lining fluid [46]. On this basis, the United States Food and Drug Administration (FDA) approved the use of pooled human plasma on a weekly basis for patients with genetic deficiency associated with the PIZ or PI-null phenotypes [47, 48]. The therapy has also been licensed in Canada and some European countries. In their articles, Mahajan et al. and Reeves et al. (pp. 314-329) describe new improvements in AAT deficiency therapy, focusing on augmentation therapy. Moreover, Reeves et al. (pp. 330-335) describe the importance of strategies to rescue protease-antiprotease imbalance on AAT deficiency-dependent diseases, and describe alternate therapeutic approaches for AAT deficiency, such as naturally occurring antiproteases, synthetic and semi-synthetic engineered elastase inhibitors, and gene therapy.

Accumulation of mutant AAT (Z) in the endoplasmic reticulum (ER) leads to liver injury by activating the ER-UPR pathway. It has been theorized that disease pathogenesis is linked with alteration in pathways responsible for removal of mutant AAT (Z) [49, 50]. Therefore genetic traits or environmental factors that can alter the function of a putative AAT disposal pathway may increase or decrease the risk of liver disease [9]. In their article, Carroll et al. (pp. 336-346) describe the mechanism for ER-stress induction and characterize UPR involvement in the ER-stress process. In this context they discuss recent research focusing on the role of the ER-UPR pathway in AAT Z phenotype-induced liver damage.

Collectively, this volume provides fundamental information on the biological mechanisms associated with AAT-deficiency related diseases. Furthermore, an overview of translational research effort leading to new and improved treatment options, in relation to genotype-specific pathology, for this severe disease is provided. In total, this offers a comprehensive overview of the current state of knowledge that is opening windows and doors for development of new and better treatments for AAT deficiency.

 
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New Strategies in Drug Development Focusing on the Anti-Protease-Protease Balance in Alpha-1 Antitrypsin Deficiency
Emer P. Reeves, Sonya Cosgrove, David A. Bergin, Catherine M. Greene and Noel G. McElvaney

Alpha-1 antitrypsin (AAT) is the most abundant proteinase inhibitor within the circulation and AAT deficiency is a genetic disorder characterised by serum levels of less than 11μmol/L. The Z mutation is the most common AAT allele associated with the disease and causes the most severe plasma deficiency, as the mutant protein polymerizes and accumulates within the endoplasmic reticulum of hepatocytes. The retained polymers are associated with cirrhosis and reduced serum levels of AAT contribute to the development of chronic pulmonary disease in AAT deficient individuals. This article will review the importance of AAT as a serine anti-protease, the clinical manifestations of AAT deficiency and specific treatment of the disease. Current therapies including AAT replacement and treatment with synthetic or alternative protease inhibitors are reviewed, along with possible future therapies including those focusing on targeting AAT polymer formation or based on gene therapy.


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Biologic Agents for Treatment of Rheumatoid Arthritis
Bulent Butun

Rheumatoid arthritis (RA) is a chronic disease characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. Thus, treatment goals should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Conventional (nonbiologic) DMARDs use is the first step of this debilitating disease treatment but in many patients, this is inadequate and other forms of therapy are required.

Advances in the current knowledge of pathogenetic mechanisms of rheumatoid arthritis have contributed to the development of biological therapy, and translated research findings into clinical practice. TNF-alpha (infliximab, etanercept, adalimumab), IL-1 (anakinra) and IL-6 (tocilizumab) inhibitors, a B-cell depleting agent (rituximab) and a drug blocking T-cell costimulation (abatacept) have been approved for rheumatoid arthritis.

In this text, the biologic therapies which are currently used in the patients with RA will be reviewed in the company of latest evidences.

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Editorial [Hot topic: General Aspects of Biologic Agents in Rheumatology (Guest Editor: Omer Faruk Sendur)]
Omer Faruk Sendur

Advances in understanding of the pathology of immune based disorders and especially new developments in the field of biotechnology, have triggered great interest in the development of new therapies for inflammatory rheumatic diseases. Subsequently the treatment spectrum of rheumatic inflammatory diseases have increased by quantity and variety in the last years. Earlier uses of traditional disease modifying antirheumatic drugs, along with the arrival of newer therapies including the biologic agents, have provided better long term outcomes for patients suffering from these illnesses. In recent years our better understanding of these disorders has shifted treatment strategy from a more conservative approach to a much more aggressive one, especially in treatment of rheumatoid arthritis. Although conventional treatment modalities remain the mainstay and are sufficient in many of patients today we have clearly entered the “biologic treatment” era in the field of management of rheumatic diseases [1].

The term of biologic therapy have arised as term to define therapeutic agents with biologic properties and refers to treatment that boosts or restores the ability of the immune system to fight with inflammatory process which seen in arthritis. Efforts to develop new biologic agents for treating patients with refractory rheumatoid arthritis have been accelerated in 90's. Research focused on understanding the pathogenesis of rheumatoid arthritis has resulted in revolution therapeutic advances through the targeting cytokine mediators in the inflammatory cascade from late 1990s to 2005. Finally today a lot of biological agents have been approved for management of a various inflammatory arthritis by FDA [2].

New biological agents developed for treatment of inflammatory joint diseases in the last decade have proven to be effective for a majority of patients unresponsive to traditional therapies. As pathogenesis of rheumatoid arthritis becomes clear the proinflammatory role of cytokines, the involvement of different cell types and their surface molecules, provides the rationale for the development of highly specific therapeutics by targeting these molecules. These can be achieved by; first, the cytokines of interest may be prevented from binding to its cell surface receptors by soluble receptors, natural antagonists, or monoclonal antibodies. Second, anti-inflammatory cytokines such as IL-4, IL-10 or IL-13, can inhibit the production or expression of inflammatory cytokines. Third, biological agents targeted against differentiation or functionally associated cell surface antigens can lead to either elimination of the targeted cells or interference with cell function [3].

Most of the approved biologics explore the first strategy mentioned above; they impair the binding of proinflammatory cytokines to their receptors. Among them, tumor necrosis factor (TNF) and IL-1 have been the most intensively investigated. These biological agents are mostly product of recombinant DNA technology, also known as bioengineered replicas of human proteins, which should be administered by subcutaneous injection or intravenous infusion. These agents has quicker onset of action than traditional disease modifying anti-rheumatic drugs , produced rapid and sustained therapeutic responses, and did not require regular laboratory monitoring [2].

TNF-α antagonist are highly effective in the treatment of many chronic inflammatory diseases, as demonstrated in several randomized clinical trials, showing clinical and radiological improvement in treated patients. The different mechanism of action between monoclonal antibodies (infliximab and adalimumab) and soluble receptor (etanercept) for TNF-α is proved by the results of the switching in case of inefficacy and adverse events.

IL-1 is a proinflammatory cytokine that shares many properties similar with TNF- α and is associated with the characteristic inflammatory joint destruction of rheumatoid arthritis (RA). Anakinra is a recombinant form of IL-1 receptor antagonist, a naturally occurring IL-1 receptor ligand that competes with IL-1 for binding to cell surface-bound IL-1 receptor, but does not induce intracellular signaling.In many controlled studies has been shown that Anakinra reduce signs and symptoms of synovitis and slow radiographic progression of joint damage in RA [3].

The development of new agents and widespread use of existing agents continues to be a highly active area of investigation among the rheumatic diseases. In the future, improved versions of existing drugs will become available. Already anti TNF- α preparations that are given as monthly subcutaneous injections are currently being developed. Other targets for therapy such as IL6, CD22, CD40-CD40L, lymphostat B and many others are under study. Currently there is no doubt of improving outcomes for patients with rheumatic diseases by biological agents. As is known most of the clinical studies carried out with biologics are designed in RA patients. Biologics bring new hope to those patients that do not respond adequately to traditional DMARDs in the treatment of RA signs and symptoms and beyond that also ameliorate radiographic progression. But how to establish of these agents most safe, efficient, cost-effective means of delivering is needed to be explicated in well designed trials [4]. “Fear of the unknown should not preclude progress, but caution must be essential”

I hope in this issue the reviews will guide the readers the appropriate way of use biologics and answer of most questions of curiosity about these new agents in treatment fields of rheumatology.

Many thanks to all authors for their efforts and contributions.


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Treatment of Ankylosing Spondylitis with Biologic Agents
Mehmet Tuncay Duruoz

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of the spine that can lead to significant disability if left untreated. Although conventional treatments can be successful in alleviating symptoms, they have not been shown to stop progression of the disease. The proinflammatory cytokine tumor necrosis factor (TNF) is central to the pathogenesis of AS. Several TNF-α blocker drugs such as infliximab, adalimumab, etanercept and golimumab have been developed and shown to control symptoms effectively, possibly preventing both clinical and radiographic progression of the disease in patients with AS. Acute inflammatory lesions in the spine and sacroiliac joints can be effectively suppressed by the TNF-α blockers in AS, suggesting that bone destruction and bone proliferation might be prevented.


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Bioactivities of Iridoids
Irene M. Villasenor

Iridoids discussed in this review were chosen based on their anti-inflammatory activity and their having various different bioactivities. Harpagoside is the major iridoid glycoside (0.5-1.6%) in Harpagophytum procumbens, an herbal medicine for rheumatologic conditions. The stem bark of C. ovata is used as an anti-inflammatory drug and catalposide is the main constituent. Geniposide is a main iridoid glucoside of Gardenia jasmoides, 56.2 mg / 500 mg extract. Gardenia fruits are used for the treatment of anti-inflammatory, hepatic and gall bladder diseases. Catalpol, known for its neuroprotective activity, is the major constituent of the roots of Rehmannia glutinosa, which are traditionally used for the treatment of auditory diseases such as tinnitus. Aucubin, which is frequently found as a natural constituent of many traditional medicinal plants, is used in the alleviation of chronic allergic inflammatory disease. PicroLiv, an anti-inflammagen, is a standardized fraction from the root and rhizome of Picrorhiza kurroa containing picrosides I and II and kutkoside. Both aucubin and PicroLiv have potent hepatoprotective activity.


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Kinases as Drug Targets in Inflammation: In Vitro and In Vivo Target Validation and Expression Profiling
Tatjana Clarissa Gust and Arne v. Bonin

Inflammation seems to be at the beginning of the majority of chronic diseases, and major efforts are dedicated to the development of anti-inflammatory drugs. Chronic inflammatory diseases, such as psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and asthma, are diseases that affect a large segment of our population. Recent evidence suggests that even metabolic diseases, such as type 2 diabetes, and certain cardiovascular diseases, could also be considered to have an inflammatory origin. However, a chronic disorder that in its initial and even more advanced stages is often not life-threatening, presents a challenge for therapeutic intervention: companies have to develop drugs that are efficacious, relatively free of side effects, and can be used effectively for a long time. The identification of suitable targets, thus, depends on better understanding of the signaling pathways involved in the initiation and maintenance of inflammation. The availability of target validation technology, such as targeted mutagenesis in mice, gene silencing mediated by small interfering RNA and protein expression profiling in this context is of utmost importance. Here, we will focus on the latter two technologies.


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Methamphetamine and HIV Infection, Role in Neurocognitive Dysfunction
Katherine Conant, Arun Venkatesan and Avindra Nath

The use of methamphetamine is steadily increasing worldwide. Its use is associated with high-risk sexual behavior and subsequent infection with HIV. Methamphetamine has profound effects on the brain both as an acute intoxicant and following chronic exposure. The combined effects of HIV and methamphetamine appear to result in widespread neuronal and white matter injury. These changes are most prominent in the basal ganglia and frontal lobe, and are not restricted to dopaminergic neurons. Additionally, methamphetamine and HIV proteins disrupt the blood brain barrier, cause glial cell activation and impair the function of neural progenitor cells. Methamphetamine also results in increased HIV replication via activation of chemokine receptors involved in HIV entry. Common pathways in several of these effects seem to involve induction of oxidative stress. Characterization of these subcellular pathways and identification of common targets is essential for development of therapeutic strategies for HIV-infected methamphetamine abusers.


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S100A8/A9 as a Pro-inflammatory Cytokine in Obstructive Airway Disease Via the Multi-Ligand Receptor, RAGE
Andrew J. Halayko and Pawan Sharma

Asthma and chronic obstructive pulmonary disease (COPD) are persistent inflammatory conditions that have exhibited significantly increased prevalence in the past two decades. Though many current medications relieve the symptoms of obstructive airway disease, morbidity can still increase over time in individual patients. With particular respect to asthma, despite satisfactory control of symptoms in most patients with inhaled steroids, a sub-phenotype of subjects, representing ~15% of all asthmatics, do not respond to steroids – these patients can exhibit severe asthma, which accounts for ~50% of asthma health care costs. Moreover, inhaled steroids are not recommended as a sole therapy for COPD, and there is limited evidence for their effectiveness in preventing disease pathogenesis. Thus, it is important to better understand mechanisms for severe asthma and COPD and identify mediators released by cells, such as neutrophils, that are unresponsive to steroid therapy. This review focuses on the probable role of one the most abundant neutrophil proteins, called S100A8/A9, in asthma. S100A8/A9 is released in abundance in rheumatoid arthritis, inflammatory bowel disease and cancer, but there are no definitive studies on its role in obstructive airways disease. A primary receptor for S100A8/A9, which is uniquely expressed in high abundance in the lung, is the multi-ligand receptor for advanced glycated end-products (RAGE) of the immunoglobin-like receptor family. RAGE participates in mediating fibroproliferative lung remodeling in idiopathic pulmonary fibrosis, and in bleomycin-exposed animal models. This review provides an overview of the S100A8/A9-RAGE axis, and discusses its potential in mediating chronic airway inflammation and tissue remodeling in asthma and COPD.