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ID PMID Title PublicationDate abstract
16496975 Synthesis of a C-glycoside analogue of beta-D-galactosyl hydroxylysine and incorporation i 2006 Mar 3 A stereoselective synthesis of the C-glycoside analogue of beta-D-galactosyl-(5R,2S)-hydroxylysine (1) has been achieved starting from tetra-O-benzyl-D-galactopyranosyl lactone. The synthesis involved establishment of three stereogenic centers in an unambiguous manner. A facially selective Grignard reaction followed by a silane reduction was used for the anomeric position of the C-galactose residue. An Evans allylation established the configuration of the delta-aminomethylene group of the hydroxylysine moiety, whereas an asymmetric hydrogenation utilizing Burk's catalyst was used for the alpha-amino acid moiety itself. The synthesis was completed in 17 steps with an overall yield of 18%, resulting in the most complex and functionalized C-glycoside analogue of a naturally occurring glycosylated amino acid prepared to date. In addition, amino acid 1 was incorporated in a glycopeptide from type II collagen known to be crucial for the response of autoimmune T cells obtained in models of rheumatoid arthritis. A preliminary immunological study revealed that four out of five members in a panel of T cell hybridomas were able to recognize this C-linked glycopeptide when presented by A(q) class II MHC molecules.
16230774 Tumor necrosis factor as a pharmacological target. 2005 Nov As indicated by its name, tumor necrosis factor (TNF), cloned in 1985, was originally described as a macrophage-derived endogenous mediator that can induce hemorrhagic necrosis of solid tumors and kill some tumor cell lines in vitro. Unfortunately, its promising use as an anticancer agent was biased by its toxicity, which was clear soon from the first clinical trials with TNF in cancer. Almost at the same time TNF was being developed as an anticancer drug, it became clear that TNF was identical to a mediator responsible for cachexia associated with sepsis, which was termed cachectin. This research led to the finding that TNF is, in fact, the main lethal mediator of sepsis and to the publication of a huge number of articles showing that TNF inhibits the toxic effects of bacterial endotoxins, which are now described as systemic inflammatory response. Although the clinical trials with anti-TNF in sepsis have not been successful thus far, undoubtedly as a result of the complexity of this clinical setting, these studies ultimately led to the identification of TNF as a key inflammatory mediator and to the development of anti-TNF molecules (soluble receptors and antibodies) for important diseases including rheumatoid arthritis and Crohn's disease. On the other side, the mechanisms by which TNF and related molecules induce cell death have been studied in depth, and their knowledge might, in the future, suggest means of improve the therapeutic index of TNF in cancer.
16204945 Antinociceptive anti-inflammatory effect of Monotropein isolated from the root of Morinda 2005 Oct The root of Morinda officinalis (Rubiaceae) is used to treat rheumatoid arthritis and impotence in the traditional Oriental medicine. To identify the antinociceptive anti-inflammatory components of this crude drug, we adopted an activity-directed fractionation approach. The active fraction of the BuOH extract of M. officinalis root was subjected to silica gel and ODS column chromatography to yield two diterpenes, compounds 1 and 2 and these were identified as monotropein and deacetylasperulosidic acid, respectively. The iridoid glycoside, monotropein, was tested for its anti-inflammatory antinociceptive effects using hot plate- and writhing antinociceptive assays and by using carrageenan-induced anti-inflammatory assays in mice and rats. Pretreatment with monotropein (at 20, 30 mg/kg/d, p.o.) significantly reduced stretching episodes and prolonged action time in mice. It also significantly reduced acute paw edema by carrageenan in rats. These results indicate that monotropein contributes to the antinociceptive and anti-inflammatory action of Morinda officinalis root.
16172568 The present and future role of (111)In pentetreotide in the PET era. 2005 Sep Today, positron emission tomography (PET) using F-18 Fluoro-deoxyglucose (FDG) is, when available, the most important nuclear medicine procedure applied to oncology. Nevertheless, 2 main reasons for the clinical use of somatostatin analogues labeled with single photon emitting radionuclides are: a) the low accuracy of PET-FDG in neuroendocrine tumors (NET); b) the expression of somatostatin receptors (sstr) in most cells deriving from so-called neuroendocrine dispersed cells. The latter forms the premise for the use of radiolabeled somatostatin analogues, and (111)In pentetreotide (Octreo-scan) in particular, in the diagnosis of NET and other pathological conditions, including some benign diseases. Alongside diagnosis, staging and follow-up of NET, somatostatin analogues, whether radiolabeled or not, can have a role in evaluating prognosis and predicting therapeutic efficacy in cancer patients. Interesting indications have emerged with radioguided surgery and in diagnosing the activity of disease in patients with Graves' disease (exophthalmos), sarcoidosis, and rheumatoid arthritis. The pathophysiological premises to imaging, starting from an analysis of cells expressing sstr, binding affinity of octreotide for sstr, in vivo uptake of Octreoscan in lesions expressing or not sstr are discussed, as is the possible role of quantitative receptor scintigraphy in improving diagnostic accuracy based on tumor expression of sstr.
15934864 Reactivation of hepatitis B virus with rituximab. 2005 May Rituximab has become a useful drug for the treatment of non-Hodgkin's lymphoma (NHL) and such autoimmune diseases as idiopathic thrombocytopenic purpura and rheumatoid arthritis. When combined with cytotoxic agents, rituximab showed synergistic effects for the treatment of NHL. In such treatment, hepatitis B virus (HBV) reactivation is a crucial complication when patients are treated with immunosuppressive or chemotherapeutic agents. Despite its treatment efficacy, several studies have pointed out unusual viral infections after its administration that resulted in fatal hepatitis due to HBV reactivation. In the cases at the authors' institute, the authors analysed the kinetics of HBV antibodies, HBV-reactivation timing, and the prophylactic efficacy of lamivudine. The authors reviewed their cases and the previous literature to clarify the characteristics of HBV-reactivated patients who were administered rituximab.
15853470 Valdecoxib for the management of chronic and acute pain. 2005 Jan Cyclooxygenase-2 specific inhibitors have anti-inflammatory and analgesic properties, and are effective in managing a wide range of chronic and acute painful conditions such as adult rheumatoid arthritis, osteoarthritis, migraine, primary dysmenorrhea and postoperative pain. Valdecoxib, an orally administered cyclooxygenase-2 specific inhibitor, provides effective pain relief for both chronic and acute conditions, and reduces postoperative opioid use, with a concomitant reduction in opioid-related adverse events. Valdecoxib also has superior gastrointestinal safety compared with nonspecific nonsteroidal anti-inflammatory drugs, and at therapeutic doses, it is generally safe and well tolerated in terms of renal and cardiovascular events. This drug profile reviews the efficacy, safety and tolerability of valdecoxib for the management of chronic and acute pain.
15770393 Pathophysiological roles of macrophage migration inhibitory factor in gastrointestinal, he 2005 Feb Macrophage migration inhibitory factor (MIF) is a unique protein, participating in inflammation, immune response, and cell growth. MIF was first discovered as a lymphokine involved in delayed hypersensitivity and various macrophage functions, including phagocytosis, spreading, and tumoricidal activity. It has been reported that MIF is associated with the pathogenesis of a variety of diseases. MIF expression was increased at inflammatory sites in diseases such as rheumatoid arthritis and glomerulonephritis. In experimental inflammatory disease, blockade of MIF bioactivity inhibited the severity of disease activity. On the other hand, MIF expression is also increased in tumor lesions, and MIF plays a role as a cell growth factor. MIF has been reported to be constitutively expressed in gut, liver, and pancreas. In patients with gastritis, inflammatory bowel disease, hepatitis, and pancreatitis, MIF expression was remarkably increased in both the serum and the local lesions. Blockade of MIF bioactivity inhibited and prevented inflammation in experimental gastritis, colitis, hepatitis, and pancreatitis. On the other hand, MIF expression was higher than that in normal tissues in colonic carcinomas and hepatocellular carcinoma both in vivo and in vitro. Blockade of MIF bioactivity successfully inhibited tumor cell growth in vivo and in vitro. MIF plays important roles in the pathogenesis of gastrointestinal, hepatic, and pancreatic disorders.
17133319 [A special case of thyroid associated ophthalmopathy in the course of Graves-Basedow disea 2006 Sep INTRODUCTION: The exact pathogenesis of Graves' ophthalmopathy and the possibility of causal treatment of this disease still remain unclear. Currently no standard treatment guidelines have been accepted. While treatment procedures have been established in specialized centres, management of complicated and long-lasting cases is always individual. We present an unusual case of Graves' ophthalmopathy accompanied by other autoimmune diseases. CASE REPORT: Our patient, MB, female, born in 1961, was diagnosed with Graves' disease 13 years ago. Recurrent hyperthyroidism and large goitre qualified her for strumectomy (performed twice) and long-term antithyroid treatment. Four years after her initial diagnosis, relapsing severe (ophthalmopathy index: 9 points, CAS: 7 points) occurred which persisted despite continuous administration of glucocorticoids. Due to imminent blindness, orbital decompression had to be performed, three times since. Concurrent autoimmune diseases: ulcerative colitis and seronegative rheumatoid arthritis were also stated. Two years ago, due to loss of vision acuity, rapid progression of exophthalmos and recurrence of hyperthyroidism, immunosuppressive treatment with azathioprine was undertaken over a period of 12 months. The present condition of the patient is satisfactory. CONCLUSION: Judging from the discussed course of treatment, in rare and difficult cases of proliferative ophthalmopathy, early immunosuppressive treatment other than glucocorticoids, should be considered.
17064039 Synthesis of a naphthyridone p38 MAP kinase inhibitor. 2006 Oct 27 Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.
17047110 The role of the sympathetic nervous system in intestinal inflammation. 2006 Nov The nervous system in the intestine controls motility, secretion, sensory perception, and immune function. Peptidergic neurones with neurotransmitters such as substance P and nerve growth factors have been the main focus of neuroimmunomodulation research in the gut. This review summarises the present knowledge concerning the role of the sympathetic nervous system (SNS) in modulating intestinal inflammation. The role of the SNS for gut inflammation is compared with its role in rheumatoid arthritis which demonstrates notable similarities. Nerve fibres of the SNS not only enter the enteric plexuses but also innervate the mucosa and gut associated lymphoid tissue (GALT). The SNS has pro- and anti-inflammatory functions. Neurotransmitters such as norepinephrine, adenosine, and others can evoke remarkably different opposing effects depending on concentration (presence of sympathetic nerve fibres and extent of neurotransmitter release), receptor affinity at different receptor subtypes, expression of adrenoceptors, availability of cotransmitters, and timing of SNS activity in relation to the inflammatory course. This review attempts to integrate the different perspectives of the pro- and anti-inflammatory effects of the SNS on inflammatory disease of the gut.
16901030 The early history of giant cell arteritis and polymyalgia rheumatica: first descriptions t 2006 Aug Giant cell arteritis and polymyalgia rheumatica were described separately more than 100 years ago. However, the original reports of both conditions were neglected for many years. After the article by Horton et al on giant cell arteritis in the 1930s and studies published by others in the 1940s, giant cell arteritis began to be recognized as a specific disease. In the 1950s and 1960s, many of the numerous presentations and complications of giant cell arteritis were recorded. In a somewhat similar fashion, physicians became cognizant of polymyalgia rheumatica only after several independent descriptions in the 1940s and 1950s. The rapid response of both syndromes to glucocorticoid therapy was discovered shortly after cortisone's effect on rheumatoid arthritis was described. The origin of the proximal aching and stiffness in polymyalgia rheumatica was more difficult to understand. The relatively minor findings in the joints on physical examination seemed insufficient to account for the severe discomfort. As the link between polymyalgia rheumatica and giant cell arteritis became apparent, some thought the aching in polymyalgia rheumatica was related to vasculitis. The debate about whether proximal synovitis or vasculitis was the cause of the symptoms continued after 1970. Although the reason these 2 conditions were associated was not considered by 1970, the establishment of the syndromes as clinically linked entities provided the groundwork for further progress in the next decades.
16855160 Predicting and preventing autoimmunity, myth or reality? 2006 Jun Many autoimmune diseases are chronic conditions that progress over the course of years, and are characterized by the presence of autoantibodies that precede the overt disease by months or years. As examples, the presence of two islet cell antibodies (ICA) are associated with a 50% risk of developing diabetes mellitus in 5 years, anticyclic citrullinated (anti-CCP) antibodies are found in the sera of rheumatoid arthritis (RA) patients a median of 4.5 years before the overt disease, and in systemic lupus erythematosus (SLE), patients accrue antibodies throughout a foreseen course during the 3-4 years prior to the clinical symptoms. This ability to predict autoimmune diseases, or rather their clinical manifestations, leads to the prospect of screening healthy individuals for autoantibodies. The importance of such a notion lies not only in the ability to prevent life-threatening manifestations, such as Addisonian's crisis and thyroid storm, but also in the ability to treat and even prevent overt autoimmune diseases. Among such documented treatment modalities are administration of aspirin in antiphospholipid syndrome, ursodeoxycholic acid in primary biliary cirrhosis (PBC), vitamin D in SLE and autoimmune thyroid diseases (AITD), and more. Although additional studies are still needed to fully assess these notions, as well as the appropriate screening strategies to apply them, one cannot ignore the prospect of predicting and preventing autoimmunity.
16771071 Importance of lipids in the nutritional treatment of inflammatory diseases. 2006 May Over the last decades, scientific advances in the knowledge of anti-inflammatory properties of lipids have lead to the development of new formulas for enteral and parenteral nutrition. These products have been utilised as a treatment for a variety of inflammatory diseases. In this review we expose the effects of lipids used in enteral nutriton on different inflammatory pathologies such as inflammatory bowel disease, atherosclerosis, lung fibrosis, rheumatoid arthritis, and others. During inflammatory diseases, eicosanoids are produced from polyunsaturated fatty acids present in cellular membranes. Inflammatory activity of these molecules depends on the nature of their precursors: when arachidonic acid (n-6) is present, pro-inflammatory molecules are released, whereas eicosapentaenoic acid (n-3)-derived eicosanoids are weakly inflammatory. In this way, fish oils, rich in n-3 polyunsaturated fatty acids, increase the content of eicosapentaenoic-eicosanoids and decrease arachidonic acid in immune and endothelial cells leading to a lower inflammatory activity. Likewise, oleic acid exhibits anti-inflammatory effects by preventing the release of particular chemotactic molecules. In summary, enteral diets supplemented with n-3 polyunsaturated fatty acids and oleic acid benefits the treatment of patients with inflammatory pathologies, leading to better outcomes, and decreasing the doses of anti-inflammatory drugs, which exhibit important secondary effects.
16433597 Infliximab for chronic obstructive pulmonary disease: towards a more specific inflammation 2006 Feb Chronic obstructive pulmonary disease (COPD) is a predominantly smoking-related condition in which chronic progressive airways obstruction results because of inflammation that is triggered and maintained by the causative agent and enhanced during exacerbations. Inflammation is dominated by neutrophils, and macrophages and their mediators. TNF-alpha is a proinflammatory cytokine involved in COPD pathogenesis. Treatment of the stable disease is mainly inhalatory with anticholinergics, beta(2) agonsists and inhaled corticosteroids being involved in various stages of the disease. Novel therapeutic agents are currently under investigation for COPD treatment and some of them target various inflammation mediators. Infliximab is a monoclonal anti-TNF-alpha antibody with demonstrated efficacy in other autoimmune diseases, such as Crohn's disease and rheumatoid arthritis. The current study assesses the scientific rationale for the use of infliximab in COPD patients.
16337523 Characterizing the effect of diagnosis on presenting deficits and outcomes after total sho 2005 Nov This study compared self-assessed deficits in comfort, function, and health status before and after total shoulder arthroplasty for 4 different diagnoses: degenerative joint disease (DJD), secondary DJD (2 degrees DJD), rheumatoid arthritis (RA), and capsulorrhaphy arthropathy (CA). Deficits were assessed by the Simple Shoulder Test and Short Form 36 (SF-36) questionnaires. There was a significant difference among diagnoses for preoperative and postoperative functional deficits. The profiles of improvement within the categories of comfort, motion, strength, and function were different for each diagnosis. Patients with DJD and CA were most improved in the category of motion, whereas those with 2 degrees DJD and RA were most improved in the category of comfort. There was also a statistically significant difference in 5 of the 8 domains of the preoperative SF-36 among diagnoses. Factors associated with each diagnosis play a significant role in determining the magnitude of preoperative deficits and postoperative improvement in shoulder function.
16318992 Recombinant immunoglobulin-based epitope delivery: a novel class of autoimmune regulators. 2005 Sep Over the past decades, there has been significant progress in understanding the mechanisms of autoimmune diseases at a molecular level. Diseases such as juvenile diabetes, multiple sclerosis, celiac disease, rheumatoid arthritis, and others appear to be mediated by pathogenic T cells that recognize self-epitopes and escape natural tolerance. Seminal observations correlating autoimmunity with HLA and disease-associated epitopes, in conjunction with recent characterization of T regulatory (Treg) cells, promoted a renewed interest in antigen or epitope-based methods of interfering with pathogenic autoimmune reactions. Recombinant immunoglobulin-peptides encompassing disease-associated self-epitopes (IgPP) integrate effective targeting of antigen-presenting cells (APCs) with a potential to generate Treg cells and thus are being developed for treatment of selected autoimmune disorders. In the current review, we outline the main features of this new class of active immunotherapeutics and directions of future development.
16011450 Methotrexate pulmonary toxicity. 2005 Jul Methotrexate is a commonly prescribed antineoplastic and immune modulating compound that has gained wide acceptance in the management of rheumatoid arthritis, psoriasis, sarcoidosis and a number of neoplastic disorders. Although generally considered safe and easy to use, methotrexate has been associated with a number of adverse reactions. Pulmonary toxicity has been well-described and may take a variety of forms. Pulmonary infiltrates are the most commonly encountered form of methotrexate pulmonary toxicity and these infiltrates resemble hypersensitivity lung disease. This discussion focuses primarily on low-dose methotrexate pulmonary toxicity and will discuss the diagnosis using clinical, pulmonary function, radiographical and pathological manifestations. Suggestions for clinical monitoring to detect adverse effects are given. In addition, management of pulmonary toxicity through discontinuation of the methotrexate, support and possibly the administration of corticosteroids is discussed.
15861789 Determination of triptolide in root extracts of Tripterygium wilfordii by solid-phase extr 2005 Apr 8 Extracts of Tripterygium wilfordii roots have a long history of use in traditional Chinese medicine and have shown great promise in recent clinical trials as a treatment for rheumatoid arthritis. The major active component of Tripterygium root extracts is the diterpenoid triptolide. This paper describes a method for the determination of triptolide in root extracts that is suitable for the analysis of many small samples simultaneously. Extracts are applied to aminopropyl solid-phase extraction (SPE) tubes that are then eluted with dichloromethane-methanol (49:1, v/v). The eluate is chromatographed on a pentafluorophenyl HPLC column using an acetonitrile:water gradient. Triptolide is quantified by ultraviolet detection at 219 nm. Using this method, it was shown that smaller diameter roots with secondary growth contained higher triptolide concentrations than larger roots. This suggests that roots to be used for production of the drug extract could be harvested while still small, which would reduce the growing time necessary and thus be economically beneficial for the growers.
15853687 Targeting kinin receptors for the treatment of neurological diseases. 2005 Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B(1) receptor antagonists as antiepileptic agents, and for B(2) receptor antagonists (and/or B(1) agonists) in the treatment of stroke. Functional B(1) receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.
15771586 Network communications: lymphotoxins, LIGHT, and TNF. 2005 Lymphotoxins (LT) provide essential communication links between lymphocytes and the surrounding stromal and parenchymal cells and together with the two related cytokines, tumor necrosis factor (TNF) and LIGHT (LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells), form an integrated signaling network necessary for efficient innate and adaptive immune responses. Recent studies have identified signaling pathways that regulate several genes, including chemokines and interferons, which participate in the development and function of microenvironments in lymphoid tissue and host defense. Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens. Pharmacological disruption of this network in human autoimmune diseases such as rheumatoid arthritis alleviates inflammation in a significant number of patients, but not in other diseases, a finding that challenges our molecular paradigms of autoimmunity and perhaps will reveal novel roles for this network in pathogenesis.