Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 13, 2008


Contents

New Therapeutic Options in Central Nervous System Involvement of Rheumatologic Diseases
Executive Editor: Ali Gur


Editorial: Pp. 1240-1241


Proinflammatory Cytokines and Sickness Behavior in Rheumatic Diseases Pp. 1242-1260
D. Lorton, C.L. Lubahn, A.J. Zautra and D.L. Bellinger
[Abstract] [Purchase Article]


Neuropsychiatric Involvement in Systemic Lupus Erythematosus: Current Therapeutic Approach Pp. 1261-1269
G. Sanna, M.L. Bertolaccini and M.A. Khamashta
[Abstract] [Purchase Article]


Treatment of Central Nervous System Involvement Associated with Primary Sjögren’s Syndrome Pp. 1270-1273
S. Ozgocmen and A. Gur
[Abstract] [Purchase Article]


Central Nervous System Abnormalities in Fibromyalgia and Chronic Fatigue Syndrome: New Concepts IN Treatment Pp. 1274-1294
A. Gur and P. Oktayoglu
[Abstract] [Purchase Article]


Central Nervous System Involvement in Pediatric Rheumatic Diseases: Current Concepts in Treatment Pp. 1295-1301
A. Duzova and A. Bakkaloglu
[Abstract] [Purchase Article]


General Articles


Erythropoietin: New Approaches to Improved Molecular Designs and Therapeutic Alternatives Pp. 1302-1310
N. Debeljak and A.J. Sytkowski
[Abstract] [Purchase Article]


Recent Advances in Drugs and Prodrugs Design of Chitosan Pp. 1311-1326
J. Vinsova and E. Vavrikova
[Abstract] [Purchase Article]


The Design of Vectors for RNAi Delivery System Pp. 1327-1340
Q.Z. Wang, Y.H. Lv, Y. Diao and R. Xu
[Abstract] [Purchase Article]




Abstracts


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Editorial: New Therapeutic Options in Central Nervous System Involvement of Rheumatologic Diseases

It is clear that disorders of the nervous system continue to burden the planet's population with not only increasing morbidity and mortality, but also with a significant financial drain through increasing medical care costs coupled to a progressive loss in economic productivity.

Causes underlying the pain and inflammation in rheumatologic diseases are interactive effects between tissues, the extracellular environment and the nervous system, complex interactions within the nervous system itself, and changes in the properties of nerve cells. The central nervous system (CNS) modulates immune functions by signaling target cells of the immune system through autonomic and neuroendocrine pathways. These immune cells relay information back to autonomic, limbic and cortical areas of the CNS to affect neural activity and consequently modify behavior, hormone release and autonomic functions.

The entire neuraxis may be affected by rheumatologic conditions. CNS manifestations may vary according to the location of the lesion and range from focal findings (eg,stroke-like presentations) to global dysfunction (eg, encephalopathy or psychiatric symptoms).

Most rheumatologic and vasculitic syndromes are characterized by pathologic changes in systemic organs and can affect the CNS. However, involvement of the nervous system may be a striking early or presenting feature with a wide variety of manifestations. Some of these diseases in both child and adult, including rheumatoid arthritis, systemic lupus erythematosus (SLE), primary Sjögren's syndrome (PSS), Behcet syndrome, cryoglobulinemia and lymphomatoid granulomatoses can present with CNS findings in the absence of any peripheral evidence of the underlying process.

Central nervous system involvement in rheumatic diseases may occur in 4 forms: 1) CNS involvement of a systemic rheumatic disease, 2) primary CNS vasculitis, 3) indirect involvement secondary to hypertension, hypoxia and metabolic changes, and 4) drug associated adverse events.

There have been advances in understanding the mechanisms behind the initiation and perpetuation of inflammatory processes in vasculitic neuropathy. Clinically relevant data have been obtained on the predictive criteria for a positive biopsy result in giant cell arteritis, the imaging characteristics of primary angiitis of the central nervous system, and Behçet disease, and the clinical and radiologic features of neuro–Behçet disease. There is more clarity about the central nervous system syndromes attributable to systemic lupus erythematosus and new insights into the central mechanisms involved in the manifestations of Sjögren syndrome and rheumatoid arthritis.

A thorough knowledge of the rheumatic diseases and therapy related adverse event is mandatory to evaluate a child or adult with rheumatic disease and CNS manifestations. When vasculitis occurs in the setting of a preexisting connective tissue disorder, it often correlates with disease severity and portends a poorer prognosis. It may involve virtually any organ system and present in a myriad of ways. Prompt recognition and treatment of vasculitis can dramatically improve the outcome for the patient. Specific diagnostic tests are inadequate and early intervention with immunosuppressive therapy is frequently necessary. Therefore knowledge of these CNS complications is essential for early diagnosis and treatment. Current treatments include standard immunosuppressive agents, such as corticosteroids and cyclophosphamide, plasmapheresis, intravenous immunoglobulin, thalidomide, and intratechal treatment; however, more directed therapy, such as tumor necrosis factor-alpha blocking agents may hold promise in rheumatoid vasculitis and Sjögren syndrome.

On the other hand, because of the clinical similarities between fibromyalgia syndrome (FM) and chronic fatigue syndrome (CFS) it was suggested that they share a common pathophysiological mechanism, namely, CNS dysfunction. The etiology and pathophysiology of these diseases remain unclear. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic- pituitary- adrenal axis. Researches suggest that the CNS is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Medical treatments are poorly effective and only helpful for a subset of patients. With further understanding of the pathophysiological abnormalities involved in fibromyalgia-chronic fatigue one may expect to find more effective therapeutic modalities.

From the standpoint of this issue of the Current Pharmaceutical Design, I have been honored by Prof. Banks to be a chooser. I am very pleased with what the authors share in this issue. I have been very fortunate to be able to choose and select an outstanding panel of contributors, each of whom focuses on different segments of the issues that permit us to diagnose with reasonable confidence and to rationally treat the CNS involvement in rheumatologic diseases. It is the purpose of this issue to provide to reader with an understanding of the state-of-the-art and the state-of-the science so that a rational basis for the selection of therapeutic interventions may be chosen and excessive proceeduring or redundant, costly, or potentially hazardous therapeutic interventions may be avoided.

The goal of this issue of the Current Pharmaceutical Design covers a very important and specific topic entitled “New therapeutic options in central nervous system involvement of Rheumatologic Diseases”. Its practical articles will help physicians to provide the best help to patients. I hope you enjoy this issue as much as I do (have). This issue consists of six invited review articles prepared by some of the experts in their field. They represent some of the important current trends in the management of central nervous system involvement of Rheumatologic Diseases. I trust this issue will be of great interest and reveal the advances in management of central nervous system involvement in rheumataologic diseases in both child and adult. The high level of interest within academia and industry for each of the reviewed approaches suggests that there is a high likelihood that some of these approaches may be clinically tested with new pharmacological agents in the near future. I will be gratified if the articles within this issue kindle innovative ideas among the readers who are involved with the design and discovery of agents for the therapy in rheumatologic diseases with CNS involvement.

In their review Drs. Lorton et al. [1] from Sun Health Research Institute discuss mechanisms of immune-to-brain signaling that may contribute to disease-related changes in mood, affect and behavior in chronic inflammatory rheumatic diseases. The next article by Drs. Sanna et al. [2] from Homerton University Hospital reviews the clinical approach to therapy in patients with SLE and neuropsychiatric involvement, followed by that of Drs. Ozgocmen and Gur [3] entitled “Treatment of central nervous system involvement associated with primary Sjögren’s syndrome” mainly emphasing on the current therapeutic options in the primary SS with CNS involvement.

The comprehensive article by Drs. Gur and Oktayoglu [4] from Dicle University is entitled “central nervous system abnormalities in FM and CFS: new concepts in treatment”. This chapter presents comprehensive data demonstrating central nervous system abnormalities, abnormal pain processing and autonomic nervous system dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM. Last article of this issue by Drs. Duzova and Bakkaloglu [5] from Hacettepe University summarizes CNS features of rheumatic diseases (particularly SLE), therapeutic approaches, and neurological adverse affects of therapy in pediatric patients suffering from rheumatic diseases. This article is very important for pediatricians and other physicians.

References

[1] Lorton D, Lubahn CL, Zautra AJ, Bellinger DL. Proinflammatory cytokines and sickness behavior in rheumatic diseases. Curr Pharm Des 2008; 14(13): 1242-1260.

[2] Sanna G, Bertolaccini ML, Khamashta MA. Neuropsychiatric involvement in systemic lupus erythematosus: current therapeutic approach. Curr Pharm Des 2008; 14(13): 1261-1269.

[3] Ozgocmen S, Gur A. Treatment of central nervous system involvement associated with primary Sjögren’s syndrome. Curr Pharm Des 2008; 14(13): 1270-1273.

[4] Gur A, Oktayoglu P. Central nervous system abnormalities in fibromyalgia and chronic fatigue syndrome: new concepts in treatment. Curr Pharm Des 2008; 14(13): 1274-1294.

[5] Duzova A, Bakkaloglu A. Central nervous system involvement in pediatric rheumatic diseases: current concepts in treatment. Curr Pharm Des 2008; 14(13): 1295-1301.


Ali Gur
Department of Physical Medicine and Rehabilitation
Medical Faculty of Dicle University
21280 Diyarbakir
Turkey
E- mail: alig@dicle.edu.tr


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Proinflammatory Cytokines and Sickness Behavior in Rheumatic Diseases
D. Lorton, C.L. Lubahn, A.J. Zautra and D.L. Bellinger

This review describes mechanisms of immune-to-brain signaling that may contribute to disease-related changes in mood, affect and behavior in chronic inflammatory rheumatic diseases. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. These immune cells relay information back to autonomic, limbic and cortical areas of the CNS to affect neural activity and consequently modify behavior, hormone release and autonomic function [1,2]. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events relating to infection and injury [3]. Equally important, homeostatic mechanisms are needed at all levels to turn off the immune response when the pathogen and injurious condition are eliminated and the repair process is completed. In individuals with chronic inflammatory diseases, such as rheumatoid arthritis (RA), there is a failure of the homeostatic regulation leading to long-term immune activation that has serious health consequences. Rheumatic disorders constitute a challenge to major psychological adaptation resources leading to higher rates of psychological disorders compared with the general population. Thus the relationship between disease pathology and psychological well being is complex.


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Neuropsychiatric Involvement in Systemic Lupus Erythematosus: Current Therapeutic Approach
G. Sanna, M.L. Bertolaccini and M.A. Khamashta

The involvement of the central nervous system (CNS) is one of the major causes of morbidity and mortality in systemic lupus erythematosus (SLE) patients and the less understood aspect of the disease. Its recognition and treatment continue to represent a major diagnostic and therapeutic challenge. Due to the lack of controlled randomized trials, current therapeutic approach is still empirical and based on clinical experience. The therapeutic choice depends on accurate diagnosis, identification of underlying pathogenic mechanism, severity of the presenting neuropsychiatric symptoms, and on prompt identification and management of contributing causes of CNS disease. Mild neuropsychiatric manifestations may need symptomatic treatment only. In more severe CNS disease it is important to distinguish between thrombotic and non-thrombotic mechanisms. Focal CNS manifestations, particularly TIA and stroke, are associated with the presence of antiphospholipid antibodies (aPL). Anticoagulation is warranted in patients with thrombotic disease, particularly in those with the antiphospholipid (Hughes) syndrome (APS). Other CNS manifestations, such as demyelinating syndrome, transverse myelitis, chorea, seizures, migraine and/or cognitive dysfunction, when associated with persistent positivity for aPL, may also benefit from anticoagulation in selected patients. Severe diffuse CNS manifestations, such as acute confusional state, generalised seizures, mood disorders and psychosis, generally require corticosteroids in the first instance. Pulse intravenous cyclophosphamide therapy may help when more severe manifestations are refractory to corticosteroids and other immunosuppressive agents, generally when response is not seen in 3-5 days. Plasmapheresis may also be added in severe cases of symptoms refractory to conventional treatment. Intravenous immunoglobulins, mycophenolate mofetil, rituximab, intratecal methotrexate and dexametasone deserve further studies to confirm their usefulness in the treatment of neuropsychiatric SLE. This article reviews the clinical approach to therapy in patients with SLE and neuropsychiatric involvement.


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Treatment of Central Nervous System Involvement Associated with Primary Sjögren’s Syndrome
S. Ozgocmen and A. Gur

Sjögren’s syndrome (SS) is a chronic autoimmune disease that mainly affects the exocrine glands and usually presents with sicca symptoms of the main mucosal surfaces. The prevalence and the type of central nervous system (CNS) tissue damage caused by SS are debatable. The wide spectrum of CNS manifestations, different classification criteria used and unclear inclusion or exclusion criteria pose some difficulty reviewing these studies. Careful examination of the SS patients and to be aware of neurological findings which may be associated with suspicious CNS involvement is highly important. Central nervous system may also hypothetically have a role in the pathophysiology of SS. The wide spectrum of CNS involvement includes focal (sensorial and motor deficits, brain stem, cerebellar lesions, seizure, migraine etc.) or non-focal (encephalomyelitis, aseptic meningitis, neuropsychiatric dysfunctions), spinal cord (myelopathy, transverse myelitis, motor neuron disease etc.) findings or multiple sclerosis-like illness and optic neuritis. Evolving imaging techniques such as single photon emission computed tomography (SPECT), magnetic resonance spectroscopy or magnetization transfer imaging are promising for better understanding the nature of CNS involvement in SS. Treatments usually comprise symptomatic approach in milder cases however, pulse cyclophosphamide and steroids or other immunosuppressants (chlorambucil or azathioprine) are required in cases with progressive symptoms leading to neurological impairment. Anti-TNF agents (infliximab and etanercept) and B cell targeted therapies (rituximab and epratuzumab) are used in primary SS however their efficacy on CNS manifestation is still unclear. Randomized, multicenter studies are warranted to confirm the efficacy of treatment regimes which were reported to be effective in anecdotal reports or in small uncontrolled series. This article reviews the clinical approach to current therapy of CNS involvement in patients with primary SS.


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Central Nervous System Abnormalities in Fibromyalgia and Chronic Fatigue Syndrome: New Concepts IN Treatment
A. Gur and P. Oktayoglu

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are poorly understood disorders that share similar demographic and clinical characteristics. The etiology and pathophysiology of these diseases remain unclear. Because of the similarities between both disorders it was suggested that they share a common pathophysiological mechanisms, namely, central nervous system (CNS) dysfunction. Current hypotheses center on atypical sensory processing in the CNS and dysfunction of skeletal muscle nociception and the hypothalamic- pituitary-adrenal (HPA) axis. Researches suggest that the (CNS) is primarily involved in both disorders in regard to the pain, fatigue and sleep disturbances. Many patients experience difficulty with concentration and memory and many others have mood disturbance, including depression and anxiety. Although fibromyalgia is common and associated with substantial morbidity and disability, there are no US Food and Drug Administration (FDA)-approved treatments except pregabalin. Recent pharmacological treatment studies about fibromyalgia have focused on selective serotonin and norepinephrine (NE) reuptake inhibitors, which enhance serotonin and NE neurotransmission in the descending pain pathways and lack many of the adverse side effects associated with tricyclic medications. CFS is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function. To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms and minimising impediments to recovery. This chapter presents data demonstrating CFS, abnormal pain processing and autonomic nervous system (ANS) dysfunction in FM and CFS and concludes by reviewing the new concepts in treatments in CFS and FM.


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Central Nervous System Involvement in Pediatric Rheumatic Diseases: Current Concepts in Treatment
A. Duzova and A. Bakkaloglu

Central nervous system (CNS) manifestations are not rare in pediatric rheumatic diseases. They may be a relatively common feature of the disease, as in systemic lupus erythematosus (SLE) and Behçet’s disease. Direct CNS involvement of a systemic rheumatic disease, primary CNS vasculitis, indirect involvement secondary to hypertension, hypoxia and metabolic changes, and drug associated adverse events may all result in CNS involvement. We have reviewed the CNS manifestations of SLE, Behçet’s disease, Henoch-Schönlein purpura, polyarteritis nodosa, juvenile idiopathic arthritis, juvenile ankylosing spondylitis, familial Mediterranean fever, scleroderma, sarcoidosis, Wegener’s granulomatosis, Takayasu’s arteritis, CINCA syndrome, Kawasaki disease, and primary CNS vasculitis; and adverse CNS effects of anti-rheumatic drugs in pediatric patients. The manifestations are diverse; ranging from headache, seizures, chorea, changes in personality, depression, memory and concentration problems, cognitive impairment, cerebrovascular accidents to coma, and death. The value of cerebrospinal fluid (CSF) examination (pleocytosis, high level of protein), auto-antibodies in serum and CSF, electroencephalography, neuroimaging with computerized tomography, magnetic resonance imaging, SPECT, PET, and angiography depends on the disease. Brain biopsy is gold standard for the diagnosis of CNS vasculitis, however it may be inconclusive in 25% of cases. A thorough knowledge of the rheumatic diseases and therapy-related adverse events is mandatory for the management of a patient with rheumatic disease and CNS involvement. Severe CNS involvement is associated with poor prognosis, and high mortality rate. High dose steroid and cyclophosphamide (oral or intravenous) are first choice drugs in the treatment; plasmapheresis, IVIG, thalidomide, and intratechal treatment may be valuable in treatment-resistant, and serious cases.


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Erythropoietin: New Approaches to Improved Molecular Designs and Therapeutic Alternatives
N. Debeljak and A.J. Sytkowski

Erythropoietin (Epo) is a glycoprotein hormone that is the prime regulator of erythropoiesis. Recombinant Epo is a highly effective pharmaceutical used to correct anemias associated with renal insufficiency, cancer and other diseases. Efforts to increase its efficacy in vivo by manipulating the protein’s structure have met with some success, and novel Epo-like agents are in development. Additionally, efforts to create Epo mimetic agents are underway, as is the design of agents to increase endogenous production. Because Epo has tissue protective actions outside of erythropoiesis, other designs have focused on producing erythropoietically inactive molecules that still retain extra-hematopoietic activity. The demonstration that Epo can trigger signaling in some cancer cells with, potentially, adverse effects on patient health has raised warning signs in the medical community and has gained the attention of regulatory authorities.


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Recent Advances in Drugs and Prodrugs Design of Chitosan
J. Vinsova and E. Vavrikova

The aim of this review is to outline the recent advances in chitosan molecular modeling, especially its usage as a prodrug or drug in a field of antibacterial, anticarcinogenic and antioxidant activity.

Polymeric materials like peptides, polysaccharides and other natural products have recently attracted attention as biodegradabile drug carriers. They can optimize clinical drug application, minimize the undesirable drug properties and improve drug efficiency. They are used for the slow release of effective components as depot forms, to improve membrane permeability, solubility and site-specific targeting.

Chitosan is such a prospective cationic polysaccharide which has shown number of functions in many fields, including bio medicinal, pharmaceutical, preservative, microbial and others. This article discusses the structure characteristics of chitosan, a number of factors such as degree of polymerization, level of deacetylation, types of quarternisation, installation of various hydrophilic substituents, metal complexation, and combination with other active agents. Biodegradable, non-toxic and non-allergenic nature of chitosan encourages its potential use as a carrier for drug delivery systems in all above mentioned targets. The use of chitosan prodrug conjugates is aimed at the site-specific transport to the target cells use, for example, a spacer tetrapeptide Gly-Phe-Leu-Gly, promotion of drug incorporation into cells via endocytosis, hybridization or synergism of two types of drugs or a drug with a bioactive carrier. The design of chitosan macromolecule prodrugs is also discussed.


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The Design of Vectors for RNAi Delivery System
Q.Z. Wang, Y.H. Lv, Y. Diao and R. Xu

RNA interference (RNAi) is a process of double-stranded RNA-dependent post-transciptional gene silencing that occurs mainly in the mRNA processing bodies (P-bodies) of cells. It has become the most powerful and widely used gene strategy for genetic analysis and molecular therapeutics, based on the highly specific and efficient silencing of target genes. The key challenge for achieving effective RNAi in vitro and in vivo is its delivery to the desired organs and into the target cells. The RNAi delivery systems can be either non-viral or viral vectors. The main candidate for RNAi as a therapeutical tool is the viral-based vectors, including retroviruses, adenoviruses, adeno-associated viruses (AAV), lentiviruses and herpes simplex virus-1 (HSV-1). There is a high potential for clinical use of RNAi in treatment of a wide variety of human diseases, including genetic disorders, infectious diseases and cancer. This paper reviews the designs of inducible, tissue specific, hybrid, oncolytic and high-throughput RNAi vectors based on plasmids or viruses, and discusses their specificity, efficiency and safety.