Autoimmune disease, severe

Unlabeled Uses Prevention of organ rejection in patients receiving allogeneic bone marrow, heart, pancreas, pancreatic island cell, or small-bowel transplant, treatment of autoimmune disease, severe recalcitrant psoriasis... 

Rituximab represents the most important scientific achievement of the past decade. It was the first therapeutic antibody approved for the treatment of cancer and specifically for N H L. The current IWRC for N H L had their origin with the rituximab response criteria. Clinical development was completed in record time. Dossiers were filed simultaneously in the United States and in Europe. The US fihng utilized an electronic format (computer-aided product license application, CAPLA). These and many other achievements during clinical development served to provide tremendous impetus to the monoclonal antibody research area. The renewed enthusiasm in this area has yielded many new Mabs with activity in both hematologic malignancies and in autoimmune diseases. Several of these have been approved (e.g. herceptin, alemtuzumab, mylotarg, others) and many others are under active investigation. 

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS (2009) IL-IR signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyehtis. J Immunol 183(l) 613-620 McEarland HE, Martin R (2007) Multiple sclerosis a complicated picture of autoimmunity. Nat Immunol 8 913-919... 

The anti-DNA antibody has been used as a marker molecule of Systemic Lupus Erthematosus (SLE) which is a severe autoimmune disease. Enzyme immunoassay is the most reliable, widely used method of assay however, the electrochemical detection method reported here should be interesting for the purpose of a rapid and convenient diagnostic tool of SLE. 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Other diseases Autoimmune diseases Amyloidosis Aplastic anemia Paroxysmal nocturnal hemoglobinuria Fanconi s anemia Thalassemia major Sickle cell anemia Severe combined immunodeficiency Inborn errors of metabolism... 

The activation of specihc immune responses involves the proliferation of lymphocytes. For T-cells, the stimulatory agent can be a combination of anti-CD3 and anti-CD28 or mitogens such PHA or ConA. Dysregulation of cell homeostasis may have severe adverse effects on immune functions, increasing susceptibility to infections and cancer, as well as favoring the development of autoimmune diseases. 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

Occupational exposure to silica dust has been identified as a risk factor for several systemic autoimmune diseases. This literature dates back almost 100 years, to the description by Bramwell of diffuse scleroderma in stone masons.26 Rheumatoid arthritis and scleroderma in miners were described in the 1950s, and more formal cohort studies of miners and of granite workers were conducted in the 1980s. Other studies focusing on silicosis patients, and several case-control studies of these diseases and of Wegner... 

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