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ID PMID Title PublicationDate abstract
19210152 Gastroprotection among new chronic users of non-steroidal anti-inflammatory drugs: a study 2009 Jan OBJECTIVE: To describe the use of gastroprotection (GP) among new chronic users of NSAIDs in the Netherlands by gastrointestinal (GI) risk factor (RF) score. METHODS: Data for this retrospective follow-up study were extracted from the PHARMO database. We selected new chronic users of COX-2 inhibitors (coxibs) or traditional NSAIDs (tNSAIDs) between 1st January 2000 and 31st December 2004. GP strategies were defined as: use of proton pump inhibitors (PPI), coxibs or both. GI RF score at index date was based on: history of GI drug use, high dose of NSAIDs, age > 60 years, use of corticosteroids/anticoagulants/SSRIs, rheumatoid arthritis, heart failure or diabetes, with each condition accounting for one factor. Switching was assessed among those with > or = 1 GI RF during the first year of follow-up. RESULTS: Among 58,770 new chronic NSAID users at index date, 80% used tNSAIDs alone, 8% used tNSAID + PPI, 10% used a coxib alone and 2% used coxib + PPI. Mean (SD) number of GI RF among these groups was 1.6 (2.1), 3.1 (1.3), 1.5 (1.5) and 2.8 (1.3), respectively. Among 48 390 patients (82.3%) with a GI RF score of > or = 1, 20.9% used a GP strategy, this increased with number of GI RFs. Within the first year, 5.3% (n = 2067) and 4.8%(n = 1 843) of tNSAID users with > or = 1 GI RF switched to tNSAID+PPI and coxib alone, respectively. CONCLUSIONS: Gastroprotection in users of tNSAIDs was inadequate. Over 80% of NSAID users with > or = 1 GI RF did not receive any gastroprotection, and even when prescribed, a PPI is used only half the time. More research should show if gastroprotection was used for prevention.
19181509 Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases. 2009 Jun BACKGROUND: Acute exacerbation (AE) is currently established as a distinct condition with acute deterioration of respiratory status in idiopathic pulmonary fibrosis (IPF). Recently, several studies have reported that AE also occurred in interstitial pneumonias other than IPF, such as collagen vascular disease-associated interstitial pneumonia (CVD-IP). However, the incidence of AE in CVD-IP and its clinical characteristics remain to be fully determined. This study was conducted to elucidate cumulative incidence of AE in CVD-IP and its clinical features. METHODS: We reviewed 83 biopsy-proven CVD-IP patients, estimated cumulative incidence of AE, and examined its clinical characteristics. RESULTS: Among 83 CVD-IP patients, six patients with a mean age of 65.7 years developed AE (overall incidence, 7.2%; 1-year incidence, 1.25%). Underlying CVDs included rheumatoid arthritis (RA) (n=5; overall incidence, 20.0%) and primary Sjögren syndrome (n=1; overall incidence, 5.9%). Patients with AE showed acute respiratory deterioration with severe hypoxemia (mean PaO(2)/FiO(2) ratio, 131). Radiologically, ground-glass opacity was superimposed on the underlying reticular abnormalities. Preexisting histological patterns included three usual interstitial pneumonia (UIP) and two non-specific interstitial pneumonia (NSIP). Five (83.3%) of six patients died of respiratory failure despite intensive therapy. Univariate Cox's proportional hazards analysis showed that age and RA diagnosis were significantly associated with AE. Multivariate Cox's proportional hazards analysis indicated that age was an independent significant factor predicting AE. CONCLUSIONS: These data suggest that AE can occur in CVD-IP, and this condition is closely similar to that of IPF with poor prognosis. AE is most common in RA, and associated with higher ages.
18845662 Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of mul 2009 Jan Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.
19908283 Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal c 2010 Apr Leukotrienes (LTs) belong to a large family of lipid mediators, termed eicosanoids, which are derived from arachidonic acids and released from the cell membrane by phospholipases. LTs are involved in the pathogenesis of inflammatory diseases, such as asthma, rheumatoid arthritis, and peripheral inflammatory pain. In the present study, we examined whether LTs were implicated in pathomechanism of neuropathic pain following peripheral nerve injury. Using the spared nerve injury (SNI) model in rats, we investigated the expression of LT synthases (5-lipoxygenase; 5-LO, Five lipoxygenase activating protein; FLAP, LTA4 hydrolase; LTA4h and LTC4 synthase; LTC4s) and receptors (BLT1, 2 and CysLT1, 2) mRNAs in the rat spinal cord. Semi-quantitative RT-PCR revealed that 5-LO, FLAP, LTC4s, BLT1, and CysLT1 mRNAs increased following SNI, but not CysLT2 mRNAs. Using double labeling analysis of in situ hybridization with immunohistochemistry, we observed that 5-LO, FLAP, and CysLT1 mRNAs were expressed in spinal microglia. LTA4h and LTC4s mRNAs were expressed in both spinal neurons and microglia. BLT1 mRNA was expressed in spinal neurons. The p38 mitogen-activated protein kinase inhibitor, but not MEK inhibitor, reduced the increase in 5-LO in spinal microglia. Continuous intrathecal administration of the 5-LO inhibitor or BLT1 and CysLT1 receptor antagonists suppressed mechanical allodynia induced by SNI. Our findings suggest that the increase of LT synthesis in spinal microglia produced via p38 MAPK plays a role in the generation of neuropathic pain.
18936772 Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögre 2009 Jan To date, little is known about why exocrine glands are subject to immune cell infiltrations in Sjögren's syndrome (SjS). Studies with SjS-prone C57BL/6.NOD-Aec1Aec2 mice showed altered glandular homeostasis in the submandibular glands (SMX) at 8 weeks before disease onset and suggested the potential involvement of inflammatory caspases (caspase-11 and -1). To determine whether inflammatory caspases are critical for the increased epithelial cell death before SjS-like disease, we investigated molecular events involving caspase-11/caspase-1 axis. Our results revealed concurrent upregulation of caspase-11 in macrophages, STAT-1 activity, caspase-1 activity and apoptotic epithelial cells in the SMX of C57BL/6.NOD-Aec1Aec2 at 8 weeks. Caspase-1, a critical factor for interleukin (IL)-1beta and IL-18 secretion, resulted in an elevated level of IL-18 in saliva. Interestingly, TUNEL-positive cells in the SMX of C57BL/6.NOD-Aec1Aec2 were not colocalized with caspase-11, indicating that caspase-11 functions in a noncell autonomous manner. Increased apoptosis of a human salivary gland (HSG) cell line occurred only in the presence of lipopolysaccharide (LPS-) and interferon (IFN)-gamma-stimulated human monocytic THP-1 cells, which was reversed when caspase-1 in THP-1 cells was targeted by siRNA. Taken together, our study discovered that inflammatory caspases are essential in promoting a pro-inflammatory microenvironment and influencing increased epithelial cell death in the target tissues of SjS before disease onset.
19405952 Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen pr 2009 INTRODUCTION: Lupus patients need alternatives to steroids and cytotoxic drugs. We recently found that apigenin, a non-mutagenic dietary flavonoid, can sensitize recurrently activated, normal human T cells to apoptosis by inhibiting nuclear factor-kappa-B (NF-kappaB)-regulated Bcl-xL, cyclooxygenase 2 (COX-2), and cellular FLICE-like inhibitory protein (c-FLIP) expression. Because sustained immune activation and hyperexpression of COX-2 and c-FLIP contribute to lupus, we treated SNF1 mice that spontaneously develop human lupus-like disease with apigenin. METHODS: SNF1 mice with established lupus-like disease were injected with 20 mg/kg of apigenin daily and then monitored for development of severe nephritis. Histopathologic changes in kidneys, IgG autoantibodies to nuclear autoantigens in serum and in cultures of splenocytes, along with nucleosome-specific T helper 1 (Th1) and Th17 responses, COX-2 expression, and apoptosis of lupus immune cells were analyzed after apigenin treatment. RESULTS: Apigenin in culture suppressed responses of Th1 and Th17 cells to major lupus autoantigen (nucleosomes) up to 98% and 92%, respectively, and inhibited the ability of lupus B cells to produce IgG class-switched anti-nuclear autoantibodies helped by these Th cells in presence of nucleosomes by up to 82%. Apigenin therapy of SNF1 mice with established lupus suppressed serum levels of pathogenic autoantibodies to nuclear antigens up to 97% and markedly delayed development of severe glomerulonephritis. Apigenin downregulated COX-2 expression in lupus T cells, B cells, and antigen-presenting cells (APCs) and caused their apoptosis. Autoantigen presentation and Th17-inducing cytokine production by dendritic cells were more sensitive to the inhibitory effect of apigenin in culture, as evident at 0.3 to 3 muM, compared with concentrations (10 to 100 microM) required for inducing apoptosis. CONCLUSIONS: Apigenin inhibits autoantigen-presenting and stimulatory functions of APCs necessary for the activation and expansion of autoreactive Th1 and Th17 cells and B cells in lupus. Apigenin also causes apoptosis of hyperactive lupus APCs and T and B cells, probably by inhibiting expression of NF-kappaB-regulated anti-apoptotic molecules, especially COX-2 and c-FLIP, which are persistently hyperexpressed by lupus immune cells. Increasing the bioavailability of dietary plant-derived COX-2 and NF-kappaB inhibitors, such as apigenin, could be valuable for suppressing inflammation in lupus and other Th17-mediated diseases like rheumatoid arthritis, Crohn disease, and psoriasis and in prevention of inflammation-based tumors overexpressing COX-2 (colon, breast).
19898774 Musculoskeletal manifestations in patients with malignant disease. 2010 Feb To detect and describe the incidence of musculoskeletal manifestations in different malignant diseases as well as their relation to the treatment received whether by chemotherapy or radiation therapy. Sixty patients with different malignant diseases were included in this study, 45 with solid tumors and 15 patients with hematological malignancy. The mean age was 46.55 +/- 11.04 years and the mean disease duration was 2 +/- 0.75 years. The patients were fully examined for any rheumatologic involvement, laboratory investigations were performed as well as dual energy X-ray absorptiometry study for bone densitometry. Treatment strategies were assessed including the chemotherapeutics, radiation therapy, and/or surgery. Myalgias and arthralgias were the most frequent followed by flexor tenosynovitis, frozen shoulder, and fibromyalgia syndrome. Hypertrophic osteoarthropathy was seen in five patients, cutaneous vasculitis in two patients as well as arthritis. Osteonecrosis was present in one of the lunate carpal bones of a patient with non-Hodgkin's lymphoma (1.67%) and receiving high dose steroids. Rheumatoid factor was positive in four patients, three of which had hepatitis C virus positivity and cryoglobulins. Anti-neutrophil cytoplasmic antibody was negative in all the studied patients. The bone mineral density was significantly reduced in the patients with malignancy compared to the control. Mild to moderate osteoporosis was present, being more evident in the spine and forearm. The bone loss was higher in those with solid tumors and even more obvious in those receiving aromatase inhibitors. Musculoskeletal manifestations occurring during malignancies and following the treatment represent a significant percentage of symptoms and signs which may raise a clue to differential diagnosis.
19635059 Synthesis and immunomodulation of human lymphocyte proliferation and cytokine (interferon- 2009 Jun Leflunomide is an immunomodulator drug with applications in the management of arthritis rheumatoid. In this study, four novel analogs (4a-d) of A771726, the active metabolite of leflunomide were synthesized and examined in vitro for their immunomodulation activity by examining human lymphocyte proliferation and determination of the cytokine interferon-gamma concentrations in human lymphocyte cell culture. For this purpose, 5 x 10(4) human lymphocyte cells were incubated at 37 degrees C in 5% CO(2) with phytohemagglutinin and one of the analogs (concentrations 1-100 mM), negative controls or cyclosporine (0.1 mM). Effects of the compounds on lymphocyte proliferation and interferon-gamma production were determined by MTT assay and enzyme-linked immunosorbent assay, respectively. Our results showed that all four compounds dose-dependently suppressed lymphocyte proliferation. Moreover, these compounds at some concentrations reduced interferon-gamma production which is an indicator of the immune response. Generally, the most potent analog was 4b with an amide linkage (X=NH) and the weakest analog was 4a with an ester linkage (X=O). Compound 4a has little similarity with the leflunomide active metabolite which has an amide linkage. In this study, four novel compounds were synthesized that showed considerable immunosuppressive effects that deserve further investigations.
20483651 Remittent non-destructive polysynovitis in P-ANCA-positive vasculitis patients with anti-C 2010 Dec Patients with antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AASV) commonly suffer from arthralgias and, sometimes, polyarthritis during disease flares. Although rheumatoid factor (RF) can be detected in up to 37-50% of AASV patients, anti-cyclic citrullinated peptide (anti-CCP) antibodies are rare. Herein, we describe the clinical features of five P-ANCA-positive vasculitis patients, who had persistent and/or high anti-CCP levels and, more importantly, suffered from remittent non-destructive arthralgias and polysynovitis, independently of the vasculitis course and without evidence of RA. Two were initially thought to have RA rather than microscopic polyangiitis and, at AASV diagnosis, all had kidney involvement and three had alveolar hemorrhages. With a median follow-up of 30 months, one suffered vasculitis relapses, preceded by polysynovitis, and others had remittent arthralgias and polysynovitis, while their vasculitides remained in remission. None of these patients had radiological destructive arthritis. We discuss the challenge of diagnosing these patients positive for anti-CCP and ANCA, and with dominant articular manifestations. AASV patients with anti-CCP antibodies may experience relapsing polysynovitis and non-erosive polyarthritis prior to vasculitis flares, but also independently of the vasculitis course, which is uncommon in AASV, and might represent a small subgroup of AASV patients.
19110153 Immediate weight bearing following first metatarsophalangeal joint fusion with Kirschner w 2009 Jan The general consensus regarding the postoperative management of patients who have undergone first metatarsophalangeal joint arthrodesis is to maintain non-weight bearing for 4 to 6 weeks. However, a number of studies indicate that immediate postoperative weight bearing does not result in a higher rate of nonunion. A retrospective case series investigation was performed to evaluate the fusion rate of first metatarsophalangeal joint arthrodesis using various forms of pin and wire fixation, and a postoperative protocol that involved immediate weight bearing with a padded surgical shoe. The impetus behind allowing immediate postoperative weight bearing stems from the desire to avoid difficult non-weight-bearing forms of ambulation in patients at risk for falling, and to enhance postoperative rehabilitation in patients at risk for other joint maladies, as in those suffering with rheumatoid and other polyarticular forms of arthritis. A total of 22 fusions (20 patients) were reviewed. Nonunion developed in 2 feet (9.1%), and a delayed union occurred in 1 additional foot (4.55%), for a total complication rate of 13.64% (3/22 cases) and a fusion rate of 86.36%. The remaining patients demonstrated radiographic consolidation of the arthrodesis. A crude rough comparison to previously published reports, wherein weight bearing was initiated anywhere from immediately to up to 2 weeks postoperative, showed that the rate of fusion observed in the patients described in this report was similar. This study demonstrated that immediate ambulation following first metatarsophalangeal joint fusion with wire fixation was safe and effective. LEVEL OF CLINICAL EVIDENCE: 4.
20937806 Tumor necrosis factor alpha-induced inflammation is increased but apoptosis is inhibited b 2010 Dec 10 Tumor necrosis factor (TNF)-α, a homotrimeric, pleiotropic cytokine, is secreted in response to inflammatory stimuli in diseases such as rheumatoid arthritis and inflammatory bowel disease. TNF-α mediates both apoptosis and inflammation, stimulating an inflammatory cascade through the non-canonical pathway of NF-κB activation, leading to increased nuclear RelB and p52. In contrast, the common food additive carrageenan (CGN) stimulates inflammation through both the canonical and non-canonical pathways of NF-κB activation and utilizes the adaptor molecule BCL10 (B-cell leukemia/lymphoma 10). In a series of experiments, colonic epithelial cells and mouse embryonic fibroblasts were treated with TNF-α and carrageenan in order to simulate the possible effects of exposure to dietary CGN in the setting of a TNF-α-mediated inflammatory disease process. A marked increase in secretion of IL-8 occurred, attributable to synergistic effects on phosphorylated NF-κB-inducing kinase (NIK) in the non-canonical pathway. TNF-α induced the ubiquitination of TRAF2 (TNF receptor-associated factor 2), which interacts with NIK, and CGN induced phosphorylation of BCL10, leading to increased NIK phosphorylation. These results suggest that TNF-α and CGN in combination act to increase NIK phosphorylation, thereby increasing activation of the non-canonical pathway of NF-κB activation. In contrast, the apoptotic effects of TNF-α, including activation of caspase-8 and PARP-1 (poly(ADP-ribose) polymerase 1) fragmentation, were markedly reduced in the presence of CGN, and CGN caused reduced expression of Fas. These findings demonstrate that exposure to CGN drives TNF-α-stimulated cells toward inflammation rather than toward apoptotic cell death and suggest that CGN exposure may compromise the effectiveness of anti-TNF-α therapy.
20473759 Sinomenine reduces invasion and migration ability in fibroblast-like synoviocytes cells co 2011 Nov CD147 expressed by monocytes, macrophages, and synoviocytes cells can stimulate the production of matrix metalloproteinases (MMPs) associated with the development of rheumatoid arthritis (RA). We investigated the effects of Sinomenine (SIN) on invasion and migration ability and gene expression of CD147, MMP-2, MMP-9 of fibroblast-like synoviocytes cells (FLS) co-cultured with activated human monocytic THP-1 cells (A-THP-1) in vitro. SIN is a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum. FLS cells were co-cultured with THP-1 cells which were induced to differentiate into macrophages with phorbol 12-myristate 13-acetate (PMA). Cells were treated with different concentrations of SIN. Invasion and migration ability of cells was tested by transwell assays. Western blot analysis and zymographic analysis were adopted to detect the expression of CD147 and MMPs, respectively. RT-PCR was used to determine the expression of mRNA of CD147, MMP-2, and MMP-9. The invasion and migration ability of the co-cultured cells was significantly inhibited by SIN in a concentration-dependent fashion, and at the same time, the levels of CD147, MMP-2, MMP-9 were markedly down-regulated. This inhibitory effect was most notable at concentrations of 0.25 and 1.00 mM (P < 0.01). Our results point to a possible mechanism of SIN on treatment of RA is the inhibitory effect of SIN on cell invasion and migration ability, which strongly correlates with repressing the expression of CD147, MMP-2, and MMP-9.
20195410 Ethyl acetate fraction from Cudrania tricuspidata inhibits IL-1beta-stimulated osteoclast 2010 Mar BACKGROUND/AIMS: The present study was performed to determine the effects of the ethyl acetate extract of Cudrania tricuspidata (EACT) on interleukin (IL)-1beta-stimulated receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclast differentiation. METHODS: Bone marrow cells were harvested from 6-week-old male imprinting control region mice, and the differentiation of osteoclasts from these cells was evaluated by tartrate-resistant acid phosphatase and resorption pit formation assay. Phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated p38, phosphorylated c-Jun amino-terminal kinase, NF-kappaB (p65), IkappaBalpha, c-Fos, and nuclear factor of activated T-cells c1 (NFATc1) expression was examined by immunoblotting and quantitative reverse transcription-polymerase chain reaction. RESULTS: EACT inhibits IL-1beta-stimulated RANKL-mediated osteoclast differentiation. EACT also inhibits IL-1beta-stimulated RANKL-mediated phosphorylation of ERK 1/2, p38 mitogen activated protein kinase, and expression of c-Fos and NFATc1. CONCLUSIONS: These results suggest that EACT may be involved in the inhibition of bone loss by preventing osteoclast formation and may be used to manage bone destruction in inflammatory diseases, such as rheumatoid arthritis.
20149311 Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-r 2009 Nov OBJECTIVE: We tried to determine whether calcium/calmodulin-dependent protein kinase II (CaMKII) regulates tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS). METHODS: CaMKII expression in FLS was studied by both western blotting and real time reverse transcription polymerase chain reaction (RT-PCR). TRAIL-mediated apoptosis of FLS was quantified by disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp (IETD) ase activity and DNA degradation. Involvement of CaMKII and other kinases, including extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt during TRAIL-mediated apoptosis of FLS was estimated by the use of specific each kinase chemical inhibitor. RESULTS: Predominant expression of delta and gamma isoform of CaMKII, especially delta isoform, was determined in cultured FLS. TRAIL rapidly induced apoptosis of FLS as well as the phosphorylation of extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt. Chemical kinase inhibitor toward CaMKII and Akt significantly augmented TRAIL-mediated apoptosis of FLS whereas those toward ERK, p38 and JNK did not. Notably, CaMKII chemical inhibitor abrogated TRAIL-induced phosphorylation of Akt. Elevation of Leu-Glu-His-Asp (IETD) ase activity was associated with the apoptotic phenomena, which was almost suppressed by IETD competitive peptides. CONCLUSION: Our results suggest a first observation that CaMKII regulates TRAIL-mediated apoptosis of FLS through Akt, standing an upstream of caspase-8-dependent cascades. Furthermore, CaMKII is suggested to be a new therapeutic target molecule of rheumatoid arthritis (RA).
19828878 Inhibition of phosphoinositide 3-kinase ameliorates dextran sodium sulfate-induced colitis 2010 Jan The critical role of phosphoinositide 3-kinase gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3Kgamma inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4(+) T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The down-regulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.
19821426 Single dose oral tiaprofenic acid for acute postoperative pain in adults. 2009 Oct 7 BACKGROUND: Tiaprofenic acid is a a non-steroidal anti-inflammatory drug (NSAID). It is widely available around the world, with indications for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, periarticular disorders, and strains and sprains. This review sought to evaluate the efficacy and safety of oral tiaprofenic acid in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. OBJECTIVES: To assess the efficacy of single dose oral tiaprofenic acid in acute postoperative pain, and any associated adverse events. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to June 2009. SELECTION CRITERIA: Randomised, double blind, placebo-controlled trials of single dose orally administered tiaprofenic acid in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We planned to use area under the "pain relief versus time" curve to derive the proportion of participants with tiaprofenic acid experiencing at least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals. MAIN RESULTS: Not one of eleven studies identified by the searches and examined in detail studied oral tiaprofenic acid against placebo in patients with established postoperative pain and therefore no results are available. AUTHORS' CONCLUSIONS: In the absence of evidence of efficacy for oral tiaprofenic acid in acute postoperative pain, its use in this indication is not justified at present. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes which are effective, there is no urgent research agenda for this particular drug.
19563006 [Effects of perioperative administration of celecoxib on pain management and recovery of f 2009 Jan 15 OBJECTIVE: To assess the effect of perioperative administration of a selective cyclooxygenase 2 inhibitor (celecoxib) on pain management and recovery of function after total knee arthroplasty (TKA). METHODS: Randomized, controlled trial conducted from January 2005 through February 2006, 60 patients underwent TKA for osteoarthritis or rheumatoid arthritis were randomly divided into group of perioperative, administration of celecoxib (Study group, n = 30) and postoperative administration of celecoxib (Control group, n = 30). Patients in Study group were given oral celecoxib 3 d before TKA, 200 mg twice daily, and extended to 5 d postoperatively; patients in Control group were given oral celecoxib 2 h after TKA, 200 mg twice daily, and extended to 5 d postoperatively. All operations were finished by the same surgeon group. RESULTS: The postoperative patient-controlled analgesia (PCA) consumption was significantly less in Study group than in Control group [(43 +/- 12) ml vs. (53 +/- 12) ml, P < 0.05]. The pain scores of postoperative 4, 8, 12 h, 1, 2 d in Study group were 6.1 +/- 1.2, 5.0 +/- 1.3, 4.3 +/- 1.1, 3.4 +/- 1.2, significantly less than in Control group (P < 0.05); There were no intergroup significant differences in the pain scores of postoperative 3, 4, 5 d (P > 0.05). There were no intergroup significant differences in respect to the side-effect occurrence, operation time and postoperative drainage, postoperative analgesic consumption (P > 0.05). The time to achieve 90 degrees knee flexion was significantly shorter in Study group than in Control group [(6.2 +/- 1.7) d vs. (8.6 +/- 1.8) d, P < 0.05]. CONCLUSIONS: Perioperative administration of the selective Celecoxib holds the effect of preemptive analgesia. Compared with postoperative administration, perioperative administration of celecoxib can alleviate the early postoperative pain score, reduce the consumption of postoperative analgesic, accelerate the recovery of joint motion and thus increase the patient satisfaction.
19210159 Pooled analysis of GI tolerability of 21 randomized controlled trials of celecoxib and non 2009 Mar OBJECTIVE: To compare the gastrointestinal (GI) tolerability of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at approved doses in patients with common musculoskeletal conditions. RESEARCH DESIGN AND METHODS: This was a retrospective, pooled analysis of studies selected from the Pfizer Corporate Clinical Trials Registry. Study selection criteria were: (1) Data available as of October 31, 2004; (2) Randomized, parallel-group study design and planned treatment duration of >or= 2 weeks; (3) At least one nonselective NSAID (naproxen, ibuprofen, or diclofenac) as a comparator; (4) At least one arm with 200 mg or 400 mg celecoxib per day; (5) Patients with osteoarthritis (OA), adult rheumatoid arthritis (RA), or ankylosing spondylitis (AS). Data were pooled by treatment and by subject from the safety analysis population of each included study. Joint primary end points were the combined incidence of tolerability-related GI adverse events (AEs) (abdominal pain, dyspepsia, nausea, diarrhea, and flatulence), and time to study discontinuation due to any GI AE. RESULTS: In all, 21 studies met the selection criteria. Across the safety analysis populations of the included studies, 7797 patients received celecoxib total daily dose 200 mg/day, 6653 received celecoxib total daily dose 400 mg/day, 2953 received naproxen, 499 received ibuprofen, and 5643 received diclofenac. Tolerability-related GI AEs were reported by significantly fewer celecoxib-treated patients (16.0%) than by those treated with naproxen (24.3%), ibuprofen (24.2%), or diclofenac (19.9%) (p < 0.0001 vs. each comparator). Time to study discontinuation due to any GI AE was significantly longer for celecoxib than for naproxen (p < 0.0001), ibuprofen (p = 0.002), or diclofenac (p = 0.048). In the RA subpopulation (n = 2857), there was no significant difference between the celecoxib and naproxen or ibuprofen groups in incidence of tolerability-related GI AEs and GI AEs. LIMITATIONS: The limitations are inherent to the retrospective analysis design. CONCLUSIONS: In this pooled analysis of celecoxib at approved doses in OA, RA, and AS, fewer celecoxib-treated patients in the overall population had tolerability-related GI AEs than patients treated with naproxen, ibuprofen, or diclofenac. In addition, celecoxib-treated patients had a significantly longer time to study discontinuation due to GI AEs.
20642000 (99m)Tc-Diamine dioxime-Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys-polyethylene glycol. 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues (6, 8, 9). The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) integrin (50% inhibition concentration (IC(50)), 7–40 nM) but no inhibition of binding to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Of these developments, [(18)F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) integrin in cancer patients (14-19). Both α(v)β(3) and α(v)β(5) integrins bind to vitronectin (20). However, while the α(v)β(3) integrin is required for basic fibroblast growth factor–mediated angiogenesis, the α(v)β(5) integrin is required for vascular endothelial growth factor–induced angiogenesis (21, 22). The peptide Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys (NC100717) was identified with phage display screening to be a potent and selective binder to both α(v)β(3) and α(v)β(5) integrins (23). A new peptide, NC100692, was derived from NC100717 with addition of diamine dioxime to the ε-amine of Lys and the N-terminal end modified with a short polyethylene glycol unit. Hua et al. (24) reported the development of (99m)Tc-NC100692 for single-photon emission computed tomography (SPECT) imaging of α(v)β(3) and α(v)β(5) integrins in mice with hindlimb ischemia. Bach-Gansmo et al. (25) has performed a preliminary study in patients with breast cancer.
20181891 TNF activates a NF-kappaB-regulated cellular program in human CD45RA- regulatory T cells t 2010 Apr 1 Emerging data suggest that regulatory T cell (Treg) dysfunction and consequent breakdown of immunological self-tolerance in autoimmunity can be mediated by factors that are not Treg-intrinsic (e.g., cytokines). Indeed, recent studies show that in rheumatoid arthritis the proinflammatory cytokine TNF reduces the suppressive function of Tregs, whereas in vivo TNF blockade restores this function and accordingly self-tolerance. However, until now a coherent mechanism by which TNF regulates the Treg has not been described. In this paper, we show that TNF induces preferential and significant activation of the canonical NF-kappaB pathway in human Tregs as compared with CD25(-) conventional T cells. Furthermore, TNF induced primarily in CD45RA(-) Tregs a transcription program highly enriched for typical NF-kappaB target genes, such as the cytokines lymphotoxin-alpha and TNF, the TNFR superfamily members FAS, 4-1BB, and OX-40, various antiapoptotic genes, and other important immune-response genes. FACS analysis revealed that TNF also induced upregulation of cell surface expression of 4-1BB and OX40 specifically in CD45RA(-)FOXP3(+) Tregs. In contrast, TNF had only a minimal effect on the Treg's core transcriptional signature or on the intracellular levels of the FOXP3 protein in Tregs. Importantly, TNF treatment modulated the capacity of Tregs to suppress the proliferation and IFN-gamma secretion by conventional T cells, an effect that was fully reversed by cotreatment with anti-TNFR2 mAbs. Our findings thus provide new mechanistic insight into the role of TNF and TNFR2 in the pathogenesis of autoimmunity.