Abetimus Sodium (Riquent) for the Prevention of Nephritic Flares in Patients with Systemic Lupus Erythematosus
New York University School of Medicine, New York, NY, USA.Rheumatic Disease Clinics of North America (Impact Factor: 2.69). 03/2006; 32(1):149-56, x. DOI: 10.1016/j.rdc.2005.11.001
Abetimus sodium has been under development for the treatment of systemic lupus erythematosus since the early 1990s. Because its administration results in the selective reduction of circulating double-stranded DNA antibodies, La Jolla Pharmaceutical Company has focused on the agent's ability to prolong time to nephritic flare. Fourteen trials have been initiated since 1994, but the two pivotal registration trials failed to meet primary end points. The US Food and Drug Administration issued a letter in October 2004 that stated abetimus sodium was "approvable" pending the successful completion of a trial demonstrating clinical benefit. The fate of this agent lies in the ability of the company to successfully complete a phase III study.
Conference Paper: Implementation of the performance evaluation system for the NTP server[Show abstract] [Hide abstract]
ABSTRACT: Most routers working in the Internet support NTP and register the current accurate time on the NTP control message. But how precisely the time is maintained depends on the topology and/or load of mutual references of NTP. We implemented the application to send continuously NTP control messages with variable time intervals. We experimented to watch the behavior of the NTP daemon and then we can get the following results of the clock offset. First, we extracted effects of the dock offset maintained by different types of stratum servers. We have 0.133 msec/sec drift on the host with no support of NTP. Second, we extracted two cyclic jitters of clock offset on the stratum 1 server. One long cyclic interval is 50 second and the other is 2 second. Finally, we compared between the clock offset on the local stratum 2 server and the remote(long network distance) stratum 2 server and extracted the element of precision of the clock offset.Communications, Computers and signal Processing, 2003. PACRIM. 2003 IEEE Pacific Rim Conference on; 09/2003
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ABSTRACT: Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-alpha, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.Rituximab, a mouse-human chimeric monoclonal antibody against CD20 that specifically depletes B cells, has been studied the most extensively. Although promising open-label data await confirmation in ongoing multicentre placebo-controlled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B-cell depletion depends on achieving high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose and factors that may affect drug clearance, such as human anti-chimeric antibodies. In SLE patients with effective B-cell depletion, the clinical response can be significant, with favourable responses observed in a diverse array of disease manifestations. Moreover, rituximab appears to have the potential to induce clinical remission in severe, refractory disease. B-cell depletion has the potential to induce disease amelioration by inhibiting autoantibody production and/or by interfering with other B-cell pathogenic functions. The fact that clinical improvement correlates with B-cell depletion and precedes by several months any decline in serum levels of relevant autoantibodies suggests a predominant effect of autoantibody-independent functions of B cells, although the subset of patients with disease remission ultimately also experience autoantibody normalisation. Significant questions remain about rituximab therapy in SLE, including the immunological determinants of treatment response and remission, the role of combination therapy, and the safety of repeated courses of rituximab. In addition, the efficacy and role of other B-cell-depleting approaches, such as humanised anti-CD20 antibodies and anti-CD22, remain to be defined. Another B-cell-targeted therapeutic approach is to block costimulatory interactions between T and B cells. Blockade of the CD40-CD40 ligand pathway has met with variable clinical benefit and unfortunate thromboembolic complications, although inhibition of the B7 pathway with cytotoxic T-lymphocyte antigen-4Ig is currently under early investigation in SLE clinical trials. Preliminary data on the treatment of SLE with belimumab, a fully human monoclonal antibody that specifically binds to and neutralises the B-lymphocyte stimulator (BLyS or B-cell-activating factor [BAFF]), are now available. In a phase II double-blind, placebo-controlled trial of the safety and efficacy of three different doses administered in addition to standard therapy, belimumab was well tolerated but reportedly did not meet primary efficacy endpoints. Blockade of BAFF is still viewed as a promising therapeutic approach and additional agents that interfere with the BAFF pathway are under study.Overall, therapies targeting B cells appear to be promising in the treatment of SLE, provide additional evidence for the importance of B cells to disease pathogenesis, and will continue to elucidate the diverse roles of B cells in this disease.Drugs 02/2006; 66(15):1933-48. DOI:10.2165/00003495-200666150-00004 · 4.34 Impact Factor
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ABSTRACT: B cells were first implicated in lupus pathogenesis because of their roles as autoantibody producers. B cells, which play important roles in (auto)immune recognition, are now understood to also have other functional capabilities that contribute to the recruitment and stimulation of T lymphocytes and cells of the innate immune system. Herein, these emerging insights are discussed as well as the newly recognized influence on B cells of the Toll-like receptors, which are postulated to be important sources of costimulation for autoreactive B cells. Also discussed is how B-cell survival factors may contribute to the loss of immune tolerance that leads to pathologic autoimmunity. These findings are part of the rationale for the development of new specific B-cell-targeted therapies.Bulletin of the NYU hospital for joint diseases 02/2006; 64(1-2):51-6.
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