Current Medicinal Chemistry - Anti-Allergy Agents, Vol. 1, No. 1, 2002

Ischemia and reperfusion (I/R) injury is a common inflammatory process in living conditions such as shock, organ transplantation and vascular operations in which arteries needed to be clamped. During the process of ischemia, there is cellular accumulation of xanthine oxidase and hypoxanthine because of the lack of oxygen. The more destructive effect of reperfusion is caused by the formation of highly destructive free radicals such as O₂^·, OH^· and H₂0₂, which are produced in large quantities once the oxygen supply is resumed. The damage is magnified by neutrophil infiltration, cytokine activation, cellular apoptosis, and necrosis and microvascular destruction. The role of nitric oxide (NO) in the process of I/R has been controversial mainly because of the difficulty of measuring its concentration. NO is very reactive and has a very short half-life. Measurement of nitrite and nitrate has been used to measure NO concentration indirectly. Electron paramagnetic resonance method has proved to be more accurate and specific for measuring NO. Peroxynitrite (ONOO-), formed as a result of NO reacting with free superoxide radicals in inflammatory bowel disease, has aroused concern about the damaging effect of NO. However, in I/R, NO has been shown to be beneficial because of its ability to protect microvasculature, prevent neutrophil infiltration, maintain vascular permeability and react with free radicals. It also has anti-microbial and anti-platelet-activating-factor properties. Agents that enhance NO formation, such as L-arginine and NO.NSAID, have great therapeutic potential to become effective anti-inflammatory drugs for the living conditions with I/R injury.

[Back to top] Bisphosphonates – Anti-Inflammatory Properties

Walter P. Maksymowych

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Although bisphosphonates have found widespread use in disorders of bone metabolism, there has been no serious examination of published work describing their anti-inflammatory and immune modifying properties. Structurally as well as mechanistically, they have been divided into amino- and non-aminobisphosphonates. The former appear to form toxic ATP analogues within cells whilst the latter inhibit enzymes in the mevalonate pathway thereby leading to impaired prenylation of small GTPases regulating diverse cellular processes such as cell viability and proliferation. In vitro studies indicate that these agents impair the accessory function of antigen-presenting cells in T cell proliferation, proliferation of macrophage precursors, macrophage migration, and induce macrophage cytotoxicity/apoptosis. Their effects on cytokine generation in vitro are complex and dependent on the molecular class of bisphosphonate examined, the concentration employed, the cell type examined, and evaluation of cultured cells versus whole blood assays. In vivo, aminobisphosphonates induce generation of proinflammatory cytokines in the short term although chronic administration may suppress these cytokines. In animal models they ameliorate established antigen and adjuvant induced arthritis although they appear to be less effective in collagen induced arthritis. Liposomal formulations of non-aminobisphosphonates, especially clodronate, induce macrophage cytotoxicity and amelioration of synovitis associated with depletion of synovial lining cells. The limited clinical studies performed to date in patients with rheumatoid arthritis and ankylosing spondylitis, primarily evaluating pamidronate, do not allow firm conclusions but suggest that bisphosphonates exert a dose dependent anti-inflammatory effect in patients with chronic arthritis. Further studies employing the more potent third generation aminobisphosphonates are warranted.

[Back to top] Identification of a Novel Inhibitor of the NF-kB Pathway

A. Misra-Press, M. McMillan, E. Cudaback, M. Qabar, F. Ruan, M. Nguyen, T. Vaisar, H. Nakanishi and M. Kahn

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NF‑kB¹ plays a central role in regulating genes involved in inflammatory responses, and its recently described role in oncogenesis reemphasizes its importance as a critical mediator of cellular function. We describe herein a novel inhibitor (MOL-294) of NF-kB driven transcription that does not inhibit the proteasome complex, does not inhibit IkB² phosphorylation, and does not significantly inhibit nuclear translocation of the p65/RelA subunit of NF-kB. We have identified thioredoxin, a cellular redox protein, which has previously been implicated in the regulation of NF-kB driven transcription, as one of the intracellular targets of MOL-294. The identification of a low molecular weight inhibitor of this type of redox protein represents a novel mechanism of inhibiting the NF-kB signaling pathway.

[Back to top] Strategies for Targeting IL‑4 as a Novel Therapeutic Approach for the Treatment of Atopic Dermatitis

H. Hennekes and K. Asadullah

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Atopic dermatitis (AD) is a chronic inflammatory skin disease, affecting more than 10% of children. It frequently predates the development of allergic rhinitis or asthma and is often difficult to treat. The current therapeutic options are limited, might induce side effects, and are not curative, indicating the need for better drugs. Numerous studies demonstrated the complex interrelationship of genetic, environmental, psychologic, skin barrier, and immunologic factors that contribute to the development and severity of AD. Today, AD is considered to be a T-cell mediated dermatosis, in which cytokines play a crucial role. These insights provide new opportunities for targeted therapeutic intervention. One target candidate is the T-helper (Th)-2 cytokine interleukin (IL)-4. Here we review the rationale and the current strategies for targeting IL‑4, which might lead to novel therapies for atopic dermatitis and other atopic disorders. This includes the development of i) inhibitors of IL‑4 formation, ii) soluble IL‑4 receptors, iii) IL‑4 receptor antagonists and iv) inhibitors of IL‑4 signal transduction. The approaches followed in these areas, their current status and their advantages and disadvantages are discussed.

[Back to top] Anti-Inflammatory Adjuvant Agents in Bacterial Meningitis

M. van der Flier, S.P.M. Geelen and J.L.L. Kimpen

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Bacterial meningitis is associated with high morbidity and mortality in both children and adults. The overall mortality rate from bacterial meningitis is 5-10% despite the availability of effective antibiotics and 5-40 % of the survivors has severe sequelae. Work in animal models has demonstrated that the host inflammatory response induced by bacterial products in the subarachnoid space in bacterial meningitis is associated with central nervous system (CNS) injury. This has led to the concept that attenuation of inflammation early in the disease process might improve outcome. The increased understanding of the pathogenesis of inflammation and CNS damage has suggested rational targets to modulate the host inflammatory response and prevent irreversal neuronal injury. This review focuses on the adjuvant use of corticosteroids, pentoxifylline, and other agents in bacterial meningitis. In addition novel potential targets such as transcription factor NFkB and caspases are discussed.

[Back to top] Scintigraphic Imaging of Inflammatory Processes

Huub J.J.M. Rennen, Otto C. Boerman, Wim J.G. Oyen and Frans H.M. Corstens

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Nuclear medicine offers ideal techniques to visualize inflammatory processes using noninvasive methods of whole-body scanning, enabling the determination of both the localization and the number of inflammatory foci. In nuclear medicine, a radiolabeled compound is injected (mostly) intravenously and accumulates in the inflammatory lesion due to the locally changed physiological condition. These changes are enhanced blood flow, enhanced vascular permeability and enhanced influx of leukocytes. Radiopharmaceuticals can be primarily divided into two classes: those accumulating in the inflammatory lesion based on non-specific processes and those accumulating in connection to leukocytes. Nonspecific tracers like ⁶⁷Ga-citrate, radiolabeled non-specific immunoglobulins and radiolabeled liposomes are discussed in detail.Studies using specific tracers mainly focus on radiolabeling leukocytes, either directly or indirectly. Direct labeling of isolated leukocytes and reinjecting them is considered the “gold standard” nuclear medicine technique for imaging inflammation. Labeling leukocytes in vivo (the indirect approach) can be achieved by the use of radiolabeled antibodies or by compounds binding to leukocyte receptors with high affinity. At least three anti-granulocyte antibodies have been tested for infection imaging: anti-NCA-95 IgG (BW250/183), anti-NCA-90 Fab' (Immu-MN3, leukoscan^®: anti-CD66), and anti-SSEA-1 IgM (LeuTech^®: anti-CD15). In addition, a w ide var iety of pe ptide s binding to le ukocyte re ceptors ha s be en inve stiga ted, e.g. chemota ctic pe ptide formyl- Me t-L eu-Phe, cytokines such as inte rleukin-1, inte rleukin-2, inte rleukin-8 and pla te let f actor 4 (deriva tives) a nd complement f ac tor s suc h as C5a. Furthermore, positron emission tomography with 18Ffluorodeoxyglucose takes advantage of the enhanced glucose requirements of leukocytes and macrophages in inflammatory foci. A totally different approach is to target directly micro-organisms, without intervention of leukocytes. This strategy is adopted in radiopharmaceuticals such as Infecton and antimicrobial peptides. The discussed radiopharmaceuticals enable accurate diagnosis of the inflammatory condition and with these agents the effectiveness of anti-inflammatory therapies can be monitored.

[Back to top] Intraarticular Application of Unsealed Beta-Emitting Radionuclides in the Treatment Course of Inflammatory Joint Diseases

W.U. Kampen, W. Brenner, N. Czech and E. Henze

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Intraarticular injection of b-emitting radionuclides, called radiation synovectomy or radiosynoviorthesis, is an effective treatment in patients suffering from inflammatory-rheumatoid and degenerative joint diseases. Since the first description of intraarticular radionuclide therapy in 1952, several gamma- and beta-emitting radionuclides have been used in both experimental and clinical studies. Today, mainly three substances are in clinical use, each of them for special joints regarding to their biophysical characteristics: Yttrium-90 for knee joints, Rhenium-186 for mid-sized joints like shoulder, wrist or ankle joints and Erbium-169 for small joints of fingers and toes. Except for Rhenium, which consists of an additional gamma-radiation, all nuclides are pure beta-emitter with a tissue penetration depth of a few mm to avoid radiation damage to other diarthrodial tissues.

Indication for radiosynoviorthesis is based on both clinical symptoms and on acute synovitis, proven in a pretherapeutic three-phase bone scan. Following intraarticular injection, the radionuclides are taken up by the synovial lining cells. A colloidal preparation with a mean particle size between 100nm and 2µm favors cellular uptake and minimizes extraarticular leakage by lymphatic or venous drainage. The local high energy irradiation results in sclerosis and fibrosis of the inflamed synovial membrane, achieving significant reduction of pain and joint effusion in appr. 70% of the patients.

Present-day studies and future developments do focus in part on radiochemical aspects like new radionuclides with promising biophysical characteristics to optimize therapeutic effects with minimizing radation burden. Clinically oriented studies search for combined therapeutic approaches, e.g. the benefit of endoscopic synovectomy prior to radiosynoviorthesis.

Current Medicinal Chemistry-Anti- Inflammatory & Anti-Allergy Agents, Volume 1, Number 1, 2002

Contents

Abstracts