Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphocyte infiltration into the intestinal tract in Crohn's disease is mediated by the interaction between alpha(4) integrin, expressed on lymphocytes, and its ligand mucosal vascular addressin cell-adhesion molecule-1 (MADCAM-1), expressed on the endothelial cells of the microvasculature in inflamed intestinal tract. Natalizumab, a recombinant, humanised monoclonal antibody against alpha(4) integrin was effective in Crohn's disease in a Phase II, randomised, controlled trial. The highest response rate and remission rates were 71 and 44% at 6 weeks, respectively, after two infusions of 3 mg of natalizumab administered 4 weeks apart. Natalizumab was well-tolerated in this study. The Phase III trial results are awaited.
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PMID:Therapeutic value of alpha-4 integrin blockade in inflammatory bowel disease:the role of natalizumab. 1294 58

Natalizumab is a humanized monoclonal antibody to alpha 4 beta 1 integrin (VLA-4) currently under development by Elan and Biogen for the treatment of Crohn's disease and multiple sclerosis. Phase II trials in both indications have been completed, and by December 2002 phase III trials in Crohn's disease and multiple sclerosis had been initiated.
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PMID:Natalizumab. Elan/Biogen. 1475 75

Natalizumab [AN 100226, anti-alpha4 integrin monoclonal antibody, Antegren] is a humanised monoclonal antibody that blocks alpha4beta1 integrin-mediated leukocyte migration. Natalizumab is in phase III trials for the treatment of multiple sclerosis in North America and the UK, and for the treatment of Crohn's disease also in the UK. It may have potential in the treatment of other immune-related inflammatory disease. Elan Corporation intends to examine the potential of natalizumab in rheumatoid arthritis and ulcerative colitis. 4beta1 integrin on circulating leukocytes binds to vascular cell adhesion molecule-1, which is expressed at high levels in the blood vessels in the CNS during exacerbations of multiple sclerosis. This allows leukocytes expressing alpha4beta1 integrin (very late antigen-4) to move from the peripheral blood into the CNS. Inflammatory proteins and other factors released from lymphocytes in the brain lead to the progression of symptoms. A limitation of natalizumab is that it must be injected and cannot be administered orally. Scientists have transformed the large anti-alpha4 monoclonal antibody into much smaller, drug-like molecules suitable for oral administration. Protein Design Labs has granted a worldwide nonexclusive licence under its antibody humanisation patents to Elan Pharmaceuticals for natalizumab. Biogen Inc. has entered into an agreement with Elan for a worldwide exclusive collaboration to develop, manufacture and commercialise natalizumab for multiple sclerosis and Crohn's disease and rheumatoid arthritis. Development of natalizumab is also being funded, in part, by Axogen (acquired by Elan in 1999). In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Elan repurchased royalty rights on a package of products, including natalizumab, from Autoimmune Disease Research Company. Elan and Genzyme Transgenics Corporation signed an agreement to produce natalizumab in GTC's genetically engineered goats, which will express the compound in their milk. Genzyme Transgenics Corporation changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. Following discussions with the US FDA, Elan completed enrolment in a second phase III trial, involving approximately 420 patients with Crohn's disease. This Evaluation of Natalizumab as Continuous Therapy-2 (ENACT-2) trial evaluated the effect of natalizumab on duration of response and remission in patients with Crohn's disease. In January 2004, Elan Corporation and Biogen Idec announced that the phase III, ENACT-2 maintenance trial of natalizumab in Crohn's disease met the primary endpoint of maintenance of response. Elan and Biogen Idec will discuss these data with regulatory authorities in both the US and Europe and determine the appropriate path forward for natalizumab in Crohn's disease. An NDA for Antegren in Crohn's disease was expected to be filed at the end of 2003; however, due to failing to meet the primary endpoint in the induction trial, Elan is unable to predict when and if a regulatory filing will be made. Earlier, on 23 January 2001, the Wall Street Journal reported that the Biogen CEO expects Antegren to become a blockbuster drug, with sales of at least $US1 billion. He also predicted that Antegren could be on the market as early as 2003 for the indication of Crohn's disease and in 2004 for multiple sclerosis. The Journal stated that Biogen is under pressure to develop new drugs since its flagship product Avonex will be losing its US Orphan Drug Act protection in 2003. Antegren has a different mechanism to that of Avonex and could be used either alone or as a combination therapy.
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PMID:Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody. 1529 71

Inhibition of leukocyte trafficking via alpha4-integrin antibody blockade has recently become a validated therapeutic approach for several inflammatory diseases, including multiple sclerosis, ulcerative colitis and Crohn's disease. In the midst of this recent success, 3 patients receiving chronic treatment with the anti-alpha4 antagonist natalizumab (Tysabri) for the treatment of multiple sclerosis or Crohn's disease, developed JC-virus related progressive multifocal leukoencephalopathy (PML). These unforeseen consequences suggest that long term blockade of alpha4-integrins might prevent trafficking of non-pathogenic lymphocytes that are essential for viral immunosurveillance. In the current issue of the European Journal of Immunology Bjursten and colleagues report that long term treatment with anti-alpha4-integrin antibodies results in exacerbation of the murine model of colitis induced by the targeted deletion of the heterotrimeric G protein subunit Galphai2. In order to properly evaluate the efficacy and safety of anti-alpha4-integrin therapy, the relationship between these observations in an immunologically altered animal model and human clinical disease needs to be carefully measured.
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PMID:Therapeutic targeting of alpha 4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit? 1605 10

The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.
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PMID:Novel treatment options for inflammatory bowel disease: targeting alpha 4 integrin. 1682 96

Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn's disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus-host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease.
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PMID:Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? 1686 84

Natalizumab is a humanized monoclonal antibody that is produced in murine myeloma cells. It functions in the body as an antagonist of integrin heterodimers that contain the a4 integrin subunit. These heterodimers include a4b1 integrin and a4b7 integrin, which are expressed on the surface of most leukocytes. When natalizumab binds to the a4-subunit of the integrin, it prevents the a4-mediated adhesion of the leukocytes to their counter-receptor(s) (eg, vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1), thus preventing transmigration of the leukocytes across the endothelium and into the inflamed parenchymal tissue. Clinical trials with natalizumab for the treatment of the relapsing forms of multiple sclerosis have found the drug is capable of delaying the accumulation of physical disability and reducing the frequency of clinical exacerbations. Clinical trials of natalizumab for the treatment of Crohn's disease have found the drug, alone or in combination with infliximab, is effective in improving clinical response and remission rates as well as health-related quality of life in patients with Crohn's disease who have not been able to achieve remission with infliximab therapy alone. Like all drugs, natalizumab is not without risks. The drug was temporarily withdrawn from the market because of 3 reported cases of progressive multifocal leukoencephalopathy. Subsequent evaluations determined that the risk of this severe, but rare, adverse reaction did not justify keeping the drug off the market. When natalizumab was reintroduced, however, a closed prescribing and distribution program (Tysabri Outreach Unified Commitment to Health [TOUCH]) was also introduced. This program requires all patients prescribed natalizumab to be enrolled in and to receive their medication through the TOUCH system. Any serious adverse reactions must be reported to the TOUCH and MedWatch systems.
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PMID:Natalizumab: overview of its pharmacology and safety. 1739 28

Natalizumab (Tysabri) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease. Immune compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued. Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.
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PMID:Expert opinion: guidelines for the use of natalizumab in multiple sclerosis patients previously treated with immunomodulating therapies. 1749 66

In the last 10 years many advances have been achieved in the treatment of patients with Crohn's disease, particularly in the field of biological agents. Infliximab, a tumour necrosis factor alpha antagonist, has been recently added to the therapeutic armamentarium for Crohn's disease and has greatly improved our treatment options. Infliximab has demonstrated efficacy in the induction and maintenance of remission in luminal and fistulizing Crohn's disease both in adults and children. However, the potential development of autoantibodies and the risk of serious adverse events limit the possibility of a wider use of infliximab. Searching for less immunogenicity and higher effectiveness in the last years a number of biological agents have been developed. Adalimumab, a fully human monoclonal antibody anti tumour necrosis factor alpha, has resulted effective and safe in patients with Crohn's disease, both naive and refractory to infliximab, presenting also the advantage of subcutaneous way of administration. Natalizumab also showed promising results in terms of efficacy but its safety is still under investigation. To date no particular advances have been recently appeared in the literature concerning conventional immunosuppressive drugs. Surgery remains a valid resort for refractory patients. Autologous stem cell transplantation represents a new hope as rescue treatment for patients with severe refractory Crohn's disease.
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PMID:Recent advances in the management of Crohn's disease. 1843 Jun 17

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Natalizumab ((R)Tysabri) is a humanized recombinant monoclonal antibody that binds to the alpha (alpha)(4) chain of the alpha(4) beta (beta)(1) integrin (very late activation antigen 4; VLA-4), and alpha(4)beta(7) integrin. Recently, two patients with MS and one patient with Crohn's disease who were treated with natalizumab in the setting of clinical trials developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyoma virus JC. We recently showed that natalizumab decreases the numbers of CD4(+) and CD8(+) T lymphocytes, CD19(+) B cells, and CD138(+) plasma cells in the cerebrospinal fluid (CSF) of patients with MS on natalizumab therapy. In addition, we demonstrated that the cell numbers in CSF remained unchanged even 6 months after cessation of natalizumab treatment.
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PMID:The effects of natalizumab on the innate and adaptive immune system in the central nervous system. 1847 72


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