Rheumatoid arthritis structure

The Structure of the Hyaluronic Acid Component of Synovial Fluid in Rheumatoid Arthritis," S. A. Barker, S. H. I. Bayyuk, J. S. Brimacombe, C. F. Hawkins, and M. Stacey, Clin. Chim. Acta, 9 (1964) 339-343. 

Human chronic inflammatory diseases are characterized by populations of cells with altered regulation and function. A large body of evidence suggests that many of these cellular abnormalities may be linked to an increase in the production of free radicals and/or deficiencies of antioxidant defence systems. Oxygen free radicals attack cell structures, altering their function, and are cytotoxic. They have therefore been implicated in the pathogenesis of rheumatoid arthritis as well as many other human diseases (HaUiwell, 1991). 

Despite the importance of Au(I) thiolates for the treatment of rheumatoid arthritis and inflammatory disorders, little is known of how the structures of these drugs are affected while being biologically active. 

The goals of treatment for rheumatoid arthritis are to (1) reduce or eliminate pain, (2) protect articular structures, (3) control systemic complications, (4) prevent loss of joint function, and (5) improve or maintain quality of life. 

Fig. 5. Structures of (A) CP-481,715, (B) BX 471, and (C) T487. CP-481,715 and BX 471 are specific CCR1 antagonists from Pfizer and Berlex/Schering AG, and both failed to exhibit efficacy for rheumatoid arthritis and multiple sclerosis, respectively, in phase II trials. T487 is a specific CXCR3 antagonist from Amgen/Turalik that failed in phase Ha psoriasis clinical trials due to lack of efficacy.

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

IgM 1-2 (5-10%) Pentameric structure secreted from B cells during primary response potent binder of complement high levels indicative of systemic lupus erythematosus or rheumatoid arthritis cannot cross placenta... 

Figure 1.6 The structures of (a) the MRI contrast agent Gd-DTPA and (b) the orally active anti-rheumatoid arthritis drug Auranofin .

Benorylate (315) [4 -(acetamido)phenyl-2-acetoxybenzoate] is another example. It is the ester between two well-known antiinflamatory drugs, aspirin and paracetamol, and is employed in rheumatoid arthritis therapy. In view of the chemical structure with three photolabile groups (two esters and one amide), its possible phototoxicity has been investigated. From the preparative irradiations, it has been concluded that the PFR takes place with breaking of the central C—O bond to yield 5-acetamido-2 -acetoxy-2-hydroxybenzophenone (316). This product undergoes transacetylation to 5 -acetamido-2 -acetoxy-2-hydroxy-benzophenone (318) (Scheme 80) [300]. 

Rheumatoid arthritis (RA moderate to severe) In combination with methotrexate for reducing the signs and symptoms and inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA who have had an inadequate response to methotrexate. 

Rheumatoid arthritis—Decreased acute phase reactants (ESR, C-reactive protein), pain relief, reduction in number of swollen joints, improved range of motion, less fatigue, greater functional capacity, less structural damage, maintenance of normal lifestyle... 

Mechanism of Action A DMARD that inhibits dihydroorotate dehydrogenase, the enzyme involved in autoimmune process that leads to rheumatoid arthritis. Therapeutic Effect Reduces signs and symptoms of rheumatoid arthritis and slows structural damage. 

Acute phase react ant s for efficacy in rheumatoid arthritis pain, stiffness, number of swollen joints, range of motion, functional capacity, structural damage fecal occult... 

New indication Reducing the signs and symptoms and delaying structural damage in patients with moderately to severely active rheumatoid arthritis, including those who have not previously failed treatment with disease-modifying drugs... 

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