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ID PMID Title PublicationDate abstract
12839111 Neuroimmunology and inflammation: implications for therapy of allergic and autoimmune dise 2003 Jun OBJECTIVES: To review concepts of neuroendocrinoimmunology and provide an overview of the role of immune dysregulation, stress, and the understanding of the pathogenesis and treatment of allergic and autoimmune diseases. DATA SOURCES: Articles include original research papers, review articles, and references identified from the bibliographies of pertinent articles. RESULTS: Neuroendocrine hormones triggered during stress may lead to immune dysregulation or altered or amplified cytokine production, resulting in atopic, autoimmune diseases or decreased host defense. Various types of transmitter substances of the neuroendocrine-immune (NEI) network include epinephrine, norepinephrine, acetylcholine, substance P, vasoactive intestinal peptide, glucagon, insulin, cytokines, growth factors, and numerous other mediators. The stress response and induction of a dysregulation of cytokine balance can trigger the hypothalamic-pituitary-adrenal axis and sympathetic nervous system. Disorders in which abnormalities in immune function are mediated by the NEI network include allergic diseases: allergic rhinitis, atopic dermatitis, and gastro-intestinal allergies and asthma through overproduction of neuropeptides and cytokines. The multiple roles of Th2 cells in maintaining allergic inflammation and altering the balance between Th1 and Th2 responses are important mechanisms for allergic inflammation and tissue damage. In addition, several autoimmune diseases mediated by NEI network such as rheumatoid arthritis, systemic lupus erythematosus, and diabetes mellitus can be attributable to immune dysregulation. CONCLUSIONS: Understanding the NEI network will contribute to novel treatments for immediate and late allergic reactions. Chronic stress or depression could lead to decreased host defenses, decreased response to vaccines, viral susceptibility, or malignancy. Treatment of allergic, autoimmune diseases and asthma should include stress management and behavioral intervention to prevent stress-related immune imbalances.
12777060 Adenoviral-mediated delivery of a viral chemokine binding protein blocks CC-chemokine acti 2003 Chemokines are important mediators of leukocyte recruitment and activation that play critical roles in the pathology of inflammatory diseases such as atherosclerosis, rheumatoid arthritis and asthma. The vaccinia virus (strain Lister) expresses a 35 kDa soluble protein ('35K') that binds and inactivates a wide range of CC chemokines. We generated a recombinant adenovirus encoding soluble 35K (Ad35K). Ad35K-infected cell culture medium, containing recombinant 35K, potently reduced migration of CCR5-transfected 293 cells by 95% in response to the CC-chemokine RANTES, but had no effect on cells transfected with the CX3CR1 fractalkine receptor. Delivery of Ad35K to mice in vivo via tail vein injection resulted in expression of recombinant 35K in plasma and increased serum RANTES and MIP-1alpha levels when quantified by ELISA. However, chemotaxis of both CCR5-transfected cells and primary macrophages was inhibited by more than 90% by plasma from Ad35K-infected animals compared with control plasma from animals injected with AdGFP. Furthermore, 35K delivered by intra-peritoneal injection more than halved biogel-induced inflammatory cell recruitment in peritoneal exudates compared to AdGFP medium. These studies identify broad-spectrum CC-chemokine blockade using in vivo adenoviral-mediated recombinant 35K expression as a promising strategy to reduce local and systemic inflammation.
12757404 CDP 571: anti-TNF monoclonal antibody, BAY 103356, BAY W 3356, Humicade. 2003 CDP 571 [anti-TNF monoclonal antibody, BAY 103356, BAY W 3356, Humicade] is a recombinant humanised antibody directed against tumour necrosis factor (TNF). CDP 571 has an advantage over the mouse/human chimera anti-TNF-alpha antibody, nerelimomab, in that it is suitable for multiple dosing as it is not so immunogenic. Celltech constructed CDP 571 by grafting the section of mouse antibody that recognises TNF onto a human IgG4 antibody. In the third quarter of 1999, Celltech merged with Chiroscience to form Celltech Chiroscience. In January 2000, Medeva was merged into Celltech Chiroscience, which was renamed as Celltech Group. The research division of Celltech Group is now called Celltech R&D (formerly Celltech Chiroscience Discovery) and the manufacturing and marketing division is called Celltech Pharmaceuticals (formerly Celltech Medeva Pharma). Celltech has completed two phase III trials, involving around 670 patients with moderate-to-severe Crohn's disease; however, both these trials failed to meet their primary endpoints. Biogen and Celltech group will review the scope of their collaboration following additional analysis of the phase III data and discussions with regulatory authorities. The Celltech Group intends to devote significant resources towards enhancing the capability of Celltech Pharmaceuticals to market CDP 571 and other new drugs (such as CDP 860 and CDP 870) as specialised hospital products. Phase II trials were underway in the United Kingdom for use of the drug in the treatment of type 2 diabetes mellitus. However, these trials have also been discontinued. Celltech Group is no longer developing CDP 571 for septic shock, based on negative results with the related compound nerelimomab. The compound was in phase III trials for septic shock in France, Belgium, the United Kingdom, Germany and the US. Celltech also plans to investigate the use of CDP 571 in psoriasis via a collaboration with Biogen (USA). In January 2002, AFX (Agence France-Presse and the Financial Times Group) reported that analysts at Morgan Stanley have forecast Humicade trade mark to reach sales of 250 million US dollars in 2008--at that time, the market value for anti-TNF products to treat rheumatoid arthritis and Crohn's disease will exceed 4 billion US dollars, according to Morgan Stanley.
12734896 How "soft" are soft neurological signs? The relationship of subjective neuropsychiatric co 2003 May OBJECTIVE: As part of a longitudinal study of cognitive function in systemic lupus erythematosus (SLE), we documented the range and frequency of subjective neurologic and/or psychiatric (NP) complaints in Never-NP-SLE patients, and related these to cognitive function, using the latter as a primary indicator of nervous system involvement. METHODS: Thirty patients with SLE who did not have major neurologic and psychiatric involvement underwent baseline and followup neuropsychological testing roughly 5 years apart. Within 0-13 months prior to retesting, each patient completed a 42 item questionnaire recording NP symptoms. RESULTS: The group as a whole endorsed 26% of symptoms. Fourteen patients labelled high endorsers (> 35% of items) endorsed, on average, 42% of symptoms. There was a significant association between higher item endorsement and lower cognitive function (r = -0.46, p < 0.02) and significantly poorer cognitive performance in the high compared to low endorser groups (t = -3.07, p < 0.005). In addition, a subset of 8 items was endorsed at least twice as often by SLE patients as by patients with rheumatoid arthritis (n = 12) or healthy controls (n = 10). CONCLUSION: These results suggest that "minor" NP symptoms and, in particular, a small subset of subjective complaints may be sufficient to raise suspicion of subclinical nervous system involvement in the absence of clinically evident NP-SLE.
12699405 Association of stress proteins with autoantigens: a possible mechanism for triggering auto 2003 May Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.
12680478 Thalidomide for erythema nodosum leprosum and other applications. 2003 Apr Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.
12606243 Hypothalamic digoxin--central role in conscious perception, neuroimmunoendocrine integrati 2003 Feb A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows--creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na(+)-K(+) ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na(+)-K(+) ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites - serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na(+)-K(+) ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na(+)-K(+) ATPase inhibition can result in increased intracellular Ca(2+) and reduced Mg(++) levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca(++)/Mg(++) ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles.
12592419 Serum adenosine deaminase activity and its isoenzyme pattern in women with normal pregnanc 2003 Feb Adenosine deaminase (ADA) is a purine enzyme which is essential for the proliferation, maturation and function of lymphoid cells, and congenital deficiency of this enzyme is associated with severe combined immunodeficiency disease. The activity of ADA has changed in diseases characterized by the alteration of cell-mediated immunity such as rheumatoid arthritis, systemic lupus erythematosus and tuberculosis, so ADA has been considered as a nonspecific marker of cell-mediated immunity. In this study we examined changes in serum total ADA activity and the patterns of two ADA isoenzymes, ADA1 and ADA2 in normal pregnant women, and evaluated the possible role of the alteration of cell-mediated immunity during normal pregnancy as causes of changes in ADA activity. We measured serum activities of total ADA, ADA1 and ADA2 in normal pregnant women in the third trimester (n=24) and age-matched healthy nonpregnant women (n=24). Peripheral blood lymphocytes and monocytes were also measured. In normal pregnant women, serum total ADA activity averaged 10.5 +/- 0.5 U/L, which was significantly lower than in nonpregnant women (14.0 +/- 0.5 U/L ) (p<0.05), and mean serum ADA2 activity also significantly reduced that of nonpregnant women (p<0.05). There was no significant difference in ADA1 activity in normal pregnant and nonpregnant women. The decrease in total ADA activity was accompanied by the decrease in lymphocyte count. These results suggest that reduced serum total ADA activity reflects decrease in ADA2 activity, and which may be in part associated with depressed cell-mediated immunity during normal pregnancy.
12538161 Molecular characterization of antigen-induced lung inflammation in a murine model of asthm 2002 Dec Asthma is one of the foremost contributors to morbidity and mortality in industrialized countries. Our objective was to characterize the acute response to allergen and to identify potentially novel molecular targets for pharmacological intervention in asthma. We therefore designed a study to identify genes whose regulation was altered following ovalbumin (OVA) challenge in the presence and absence of treatment with glucocorticoids in BALB/c mice. RNA was isolated from lungs for gene profiling from 8-week-old sensitized mice, 3 and 18 hours post OVA challenge on days 1, 4, and 7 of aerosol challenge. Taqman (real time RT-PCR) analysis of marker genes indicative of Th2 (IL-4, IL-13), eosinophil (RANTES, eotaxin), Th1/macrophage (IFNgamma) and epithelial cell (MUC5AC) phenotypes were used to characterize responses to allergen challenge. Histological evaluation of lungs from additional challenged animals revealed inflammatory infiltrates on days 4 and 7, but not on day 1 post challenge. We postulate that expression of IL-4, IL-13 and other genes by OVA at day 1 probably reflects activation of resident cells, whereas the fivefold increase in the number of regulated genes at day 7 reflects the contribution of recruited cells. Of the regulated genes, only a subset was counter-regulated by dexamethasone treatment. Although regulated genes included genes in many protein families, herein we report regulation of two proteases whose role in response to OVA challenge has not been characterized. This model will be used to generate disease hypotheses for which may play an important role in initiating disease pathology in this model.
12434272 [Prevalence of circulating autoantibodies in healthy individuals]. 2002 Nov 15 BACKGROUND AND AIM: Circulating autoantibodies are diagnostic markers for a variety of autoimmune diseases including rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, and autoimmune hepatitis. Since only view studies exist on individuals without known diseases, we analyzed the prevalence of frequently determined autoantibodies in "healthy" individuals. PATIENTS AND METHODS: 111 individuals (43 female, 68 male; mean age 58 +/- 13 years, median 58, range 22-89), in whom either known or actual clinical evidence for autoimmune or internal disease was found, were included. Antinuclear and anti-smooth muscle antibodies (ANA and ASMA, respectively) were detected by immunofluorescence on rat organ sections and Hep 2 cells. Antibodies to liver-kidney-microsomes-1 (anti-LKM-1) and antimitochondrial antibodies (AMA) were detected and semiquantified by immunofluorescence. Additionally, anti-LKM-1 and AMA were determined by ELISA and Western blot. Antibodies against soluble liver antigens (anti-SLA) were quantified by ELISA. Sera with a titer of 1 : 40 or higher were classified as positive. RESULTS AND CONCLUSIONS: Sera of "healthy" adults displayed high frequencies of ANA and ASMA (28/111, 25%, and 48/111, 43%, respectively). Although no sex differences were found for ASMA, sera of healthy women tested more often positive for ANA (p < 0.01). Since at least one in three or four healthy individuals tested positive for ANA or ASMA, the positive predictive value of these autoantibodies is low, and clinical interpretation should include additional information.
12237470 Mapping and characterization of the functional epitopes of tissue inhibitor of metalloprot 2002 Oct Tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE/ADAM-17) is responsible for the release of TNF-alpha, a potent proinflammatory cytokine associated with many chronic debilitating diseases such as rheumatoid arthritis. Among the four variants of mammalian tissue inhibitor of metalloproteinases (TIMP-1 to -4), TACE is specifically inhibited by TIMP-3. We set out to delineate the basis for this specificity by examining the solvent accessibility of every epitope on the surface of a model of the truncated N-terminal domain form of TIMP-3 (N-TIMP-3) in a hypothetical complex with the crystal structure of TACE. The epitopes suspected of interacting with TACE were systematically transplanted onto N-TIMP-1. We succeeded in transforming N-TIMP-1 into an active inhibitor for TACE (K(i)(app) 15 nM) with the incorporation of Ser4, Leu67, Arg84, and the TIMP-3 AB-loop. The combined effects of these epitopes are additive. Unexpectedly, introduction of "super-N-TIMP-3" epitopes, defined in our previous work, only impaired the affinity of N-TIMP-1 for TACE. Our mutagenesis results indicate that TIMP-3-TACE interaction is a delicate process that requires highly refined surface topography and flexibility from both parties. Most importantly, our findings confirm that the individual characteristics of TIMP could be transplanted from one variant to another.
12070680 Stress fractures in rheumatological practice: clinical significance and localizations. 2002 Jun The objective of this study was to analyze the clinical characteristics, associated disorders, and the most common sites of stress fractures in rheumatological patients. Over a 3-year period, 35 patients with 44 stress fractures were prospectively recruited from an outpatient rheumatological department (32 postmenopausal women and three men aged 47 to 86 years, mean 70+/-10.6 years). Clinical diagnosis was established by compatible clinical and radiological data. In addition, previous skeletal fractures were recorded in all patients. Bone mass assessment was performed in 23 patients and spinal X-ray in 21. The diagnosis of osteoporosis was defined by the presence of atraumatic vertebral fractures and/or densitometric criteria (lumbar or femoral bone mass <-2.5 T score). The most frequent stress fractures were: pelvic ring (13 sacrum and eight pubic) and metatarsal (11 fractures), followed by tibia (seven fractures), calcaneus (three fractures), femur (one), and tarsal (one). Nine patients (26%) presented simultaneous stress fractures. Twenty-four patients (69%) suffered previous osteoporotic fractures, vertebral and Colles' fractures being the most frequent. Most of the evaluated patients (25 out of 30) had osteoporosis (83%). Six patients had associated disorders (glucocorticoids use in three patients, neurologic disorders in two, and rheumatoid arthritis in one). Except for the patient with a femur fracture which required internal fixation, no other clinical complications were observed after conservative treatment. In conclusion, fractures of the pelvic ring, especially sacrum, and metatarsal are the most frequent stress fractures in rheumatological practice. The association with osteoporosis and the history of prior low-trauma fractures are common in these patients.
12052464 Glucocorticoid-induced osteopenia in the mouse as assessed by histomorphometry, microcompu 2002 Jun Glucocorticoids are potent anti-inflammatory molecules used in the treatment of asthma, rheumatoid arthritis, inflammatory bowel disease, and other inflammatory and dermatological diseases, as well as in posttransplantation immunotherapy. Although glucocorticoids have been prescribed for many years, their potential side effects, when administered orally, can prevent their long-term use. The most serious side effect observed in the clinic is glucocorticoid-induced osteoporosis (GIOP). To develop a small animal model to characterize glucocorticoid-induced bone loss, we carried out a series of experiments using BALB/c mice given daily intraperitoneal doses of the synthetic glucocorticoid, dexamethasone. Following dexamethasone treatment, the mice became osteopenic, with highly significant decreases in bone formation rate and mineral apposition rate, as assessed by standard histomorphometry. Moreover, 3 week treatment with dexamethasone resulted in a decrease in trabecular thickness and trabecular number with an increase in surface-to-volume ratio of trabeculae in the distal femur, as measured using microcomputed tomography (micro-CT). The serum bone formation marker, osteocalcin, was dose-dependently decreased in all mice treated with dexamethasone and showed a parallel extent of regulation to the bone formation rate changes. In addition, serum levels of leptin, recently identified as playing a role in the regulation of bone mass, increased following dexamethasone treatment. BALB/c mice therefore represent a useful model system in which the detrimental effects of glucocorticoids on bone can be studied.
11987980 Millennium Award. Proteomics for the development of DNA tolerizing vaccines to treat autoi 2002 Apr Autoimmune disease affects 3% of the world population, yet current therapies that globally suppress immune function are inadequate. Tremendous need exists for specific and curative therapies, and we describe a strategy for development of antigen-specific therapies that inactivate pathogenic lymphocytes causing tissue injury. Major barriers to development of antigen-specific therapies for T-cell-mediated autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and autoimmune diabetes, include (i) lack of knowledge of the specificity of autoimmune responses, for which proteomic technologies represent powerful tools to identify the self-protein targets of the autoimmune response, and (ii) lack of methods to induce specific immune tolerance, for which DNA tolerizing vaccines represent a promising strategy. We termed our approach Reverse Genomics: use of the proteomics-determined specificity of the autoantibody response to develop and select DNA tolerizing vaccines. Studies performed using animal models for multiple sclerosis and autoimmune diabetes support our Reverse Genomics approach. Through integration of proteomics with specific tolerizing therapies, we are developing a comprehensive approach to treat human autoimmune disease.
11841839 Effects of a new anti-rheumatic drug KE-298 and its active metabolite: KE-758 on secretion 2002 Feb Thioredoxin (TRX) and glutathione (GSH) are key regulators of the cellular balance of reduction/oxidation (redox). The impaired redox balance in joint cellular circumstances participates in immune dysfunctions seen in patients with rheumatoid arthritis (RA). We analyzed effects of a newly developed anti-rheumatic drug, KE-298 (2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid) and it is active metabolite; KE-758 (2-mercaptomethyl-4-(4-methylphenyl)-4-oxobutanoic acid) on the secretion of TRX and the level of intracellular GSH in THP-1 cells, a human monocytic cell line and in Jurkat cells, a human T cell leukemia cell line, then we compared their effects with N-acetyl-L-cysteine (NAC). KE-298 (10-100 microg/ml) and KE-758 (10-100 microg/ml) as well as a high concentration of NAC (10mM) dose-dependently inhibited the secretion of TRX by THP-1 and Jurkat cells. RT-PCR analysis indicated that the suppressive effects of KE-298 and KE-758 on TRX secretion could be partly explained by the inhibition of TRX mRNA expression. On the other hand, KE-758 as well as a high concentration of NAC significantly increased the level of intracellular GSH. Thus, KE-298 is a novel sulphydryl drug which regulates the redox state of cellular circumstances. The potential of KE-298 to suppress the secretion of TRX and to increase the level of intracellular GSH may partly explain the efficacy in cases of RA.
11754745 Crystal structure of the antigen-binding fragment of apoptosis-inducing mouse anti-human F 2002 Jan Binding of Fas ligand to Fas induces apoptosis. The Fas-Fas ligand system plays important roles in many biological processes, including the elimination of autoreactive lymphoid cells. The mouse anti-human Fas monoclonal antibody HFE7A (m-HFE7A), which induces apoptosis, has been humanized based on a structure predicted by homology modeling. A version of humanized HFE7A is currently under development for the treatment of autoimmune diseases such as rheumatoid arthritis. For a deeper understanding of the protein engineering aspect of antibody humanization, for which information on the three-dimensional structure is essential, we determined the crystal structure of the m-HFE7A antigen-binding fragment (Fab) by X-ray crystallography at 2.5 A resolution. The main-chain conformation of the five loops in the six complementarity-determining regions (CDRs) was correctly predicted with root-mean-square deviations of 0.30-1.04 A based on a comparison of the crystal structure with the predicted structure. The CDR-H3 conformation of the crystal structure, which was not classified as one of the canonical structures, was completely different from that of the predicted structure but adopted the conformation which followed the "H3-rules." The results of charge distribution analysis of the antigen-binding site suggest that electrostatic interactions may be important for its binding to Fas.
15971575 [The OPG/RANKL/RANK system and bone resorptive disease]. 2003 Nov The OPG/RANKL/RANK system plays an important role in osteoclastogenesis and represents a great progress in bone biology. RANKL, which expresses on the surface of osteoblast/stromal cells and activated T cells, binds to RANK on the osteoclastic precursors or mature osteoclasts, and promotes osteoclastogenesis and bone resorption. While osteoprotegerin (OPG), which is expressed by osteoblasts/stromal cells, strongly inhibits bone resorption by binding to its ligand RANKL and thereby blocks the interaction between BANKL and RANK. A number of cytokines and hormones exert their effects on bone metabolism by regulating the OPG/RANKL ratio in the bone marrow microenvironment. RANK is also expressed on mammary epithelial cells and RANKL expression in these cells is induced by pregnancy hormones, RANKL and RANK are essential for the formation of the lactating mammary gland and the transmission of maternal calcium to neonates in mammalian species. Modulation of these systems provides a unique opportunity to develop novel therapeutics to inhibit bone loss in osteoporosis, rheumatoid arthritis, and bone metastasis of cancer. Further research should be focused on the cooperation of OPG/RANKL/RANK system with other signal pathways and the interactions among bone remodeling, immune system and endocrinology system. Currently, the development of OPG analogues or compounds which may stimulate OPG expression is becoming an attractive industry which may be profitable to both patients and manufacturers.
15324530 Oxaprozin: kinetic and dynamic profile in the treatment of pain. 2004 Aug Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal anti-inflammatory drug (NSAID) which is effective in models of inflammation, pain and pyrexia. It is effective and well tolerated in the clinical management of adult rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis, soft tissue disorders and post operative dental pain. Oxaprozin has a high oral bioavailability (95%), with peak plasma concentrations at 3 to 5 hours after dosing. It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes. Oxaprozin's strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder, since it exhibits actions such as inhibition of COX-1 and COX-2 isoenzymes, inhibition of nuclear translocation of NF-kappaB and of metalloproteases, and modulates the endogenous cannabinoid system. This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain, in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period. Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain. Oxaprozin and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component. The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin, diclofenac, ibuprofen, indomethacin etc. in several different painful musculoskeletal conditions.
15287234 Reported medication errors associated with methotrexate. 2004 Jul 1 PURPOSE: Medication errors reported to FDA as adverse events in which methotrexate was identified as a possible contributor were studied. METHODS: All adverse-event reports submitted to FDA between November 1997 and December 2001 indicating potential medication errors involving methotrexate were analyzed to determine the indication for use, the type of error, and the point in the medication-use process where the error occurred. RESULTS: A total of 106 cases of reported medication errors associated with methotrexate were identified, including errors resuiting in 25 deaths (24%) and 48 other serious outcomes (45%). The most common types of errors involved confusion about the once-weekly dosage schedule (30%) and other dosage errors (22%). The most frequently involved indication for use was rheumatoid arthritis (42%). Of the errors, 39 (37%) were attributable to the prescriber, 21 (20%) to the patient, 20 (19%) to dispensing, and 18 (17%) to administration by a health care professional. CONCLUSION: A review of medication errors involving methotrexate revealed that errors occurred during all phases of use, often resulted from confusion about dosage, and often caused death or other serious adverse effects.
15247881 Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other 2004 May Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.