Nursing Research Paper About Drug Target Validation-Infliximab (Research Paper Sample)

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Topic: Drug Target Validation-Infliximab
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A Case Study on Drug Target Validation-Infliximab
Biologic agents use has revolutionized rheumatoid arthritis (RA) management in the past twenty years. Some of these biologic agents are direct targets of molecules and cells which are associated with the pathogenesis of rheumatoid arthritis. Use of biological agents’ results in a better outcome with clinical remission in the patients suffering from rheumatoid arthritis who had a poorly controlled disease with the older disease-modifying antirheumatic drugs (DMARDS). Current therapy includes the use of five Tumor Necrosis Factor (TNF) inhibitors. These are biologic agents which have provided a quality evidence of their effectiveness hence bringing about the transformation of the management of rheumatoid arthritis.
In the 1970’s interleukin-1 was among the first of the cytokines that attracted rheumatologists attention because of its biologic function involving tissue damage and bone resorption. Then in the mid-1980s, the Tumor Necrosis Factor also known as cachectin was found to have some biologic activities similar to the IL-1. Between 1996 and 1997, natural inhibitors of TNF were discovered by various researchers and afterward proven that they were soluble fragments of the TNF receptor,CITATION Jea02 \l 1033 (Dayer, 2002) . In rheumatoid arthritis, the cytokine TNF-α causes an inflammation of the synovial joint. It also supports the growth of systemic effects which include producing acute phase reactant proteins especially the C-reactive proteins, anemia of chronic disease. The pathology of rheumatoid arthritis is complex because the specific trigger of that autoimmune response is not known. However, it is associated with the generation of autoantibodies through the contact of antigen-presenting with the adaptive immune system cluster of differentiation cells (CD4+ T cells, B cells). Joint swelling and damage that is seen in rheumatoid arthritis result from the major inflammatory mediators’ TNF-alpha, Interleukin-1, chemokines, IL-6 etc.
Rheumatoid arthritis is characterized by an infiltration of leukocytes in joints’ synovial fluid with a resultant cartilage and bone destruction. Pro-inflammatory cytokines and chemotactic cytokines are a contributory factor in the pathogenesis underlying rheumatoid arthritis. The pathway of destruction begins with leukocyte linkage and recruitment with tissue destruction, finally angiogenesis. TNF-alpha contributes significantly in arthritis by inducing fever and degeneration which induces intercellular adhesion and relocation. One of the pro-inflammatory cytokine involved is the TNF- α whose production may be temporally or partially regulated. In a study done, CITATION ZOL00 \l 1033 (Szekanecz, June 2000) animal models of rat indicated a plentiful production of TNF-alpha in the sera and, hence the conclusion that TNF-alpha has an involvement in the early progression of the disease,CITATION ZOL00 \l 1033 (Szekanecz, June 2000). It shows a variance temporal and spatial expression in the joints and sera. Removal or inhibition of the TNF- α results in a decline of signs and symptoms of rheumatoid arthritis.
TNF in Rheumatoid Arthritis
In 2011, five TNF-alpha inhibitors were ratified by the Food and Drug Acts to be used. Among these drugs was infliximab.
Infliximab is one of the monoclonal antibodies whose administration to patients with RA has shown effectiveness. Clinical trials of infliximab have been effective to reduce signs and symptoms and in inhibition of the structural damage progression. It has also improved the physical function plus the quality of life. Studies in rodents and in dogs contributed significantly to the isolation and identification of the TNF-alpha. Animal research also contributed to the discovery of its part in the normal immune system and in autoimmune diseases. Some of these studies included transgenic mice that resulted in the evidence that TNF-alpha is central to rheumatoid arthritis development. This also laid a foundation which demonstrated a combination of chimeric human and mouse monoclonal antibodies directed against TNF-alpha was protective against inflammation, CITATION Pau10 \l 1033 (Browne, 2010). Anti-TNF- α lessens the adhesion molecules expression and cellularity in rheumatoid arthritis,CITATION RNM99 \l 1033 (Maini, 1999).
The table 1 below gives a summary of findings of inflammation score on some sections of synovial tissue that were taken before the treatment with infliximab and then tissue taken four weeks after day one of treatment i.e. after treatment with infliximab.
Adapted from Annals of the Rheumatic Diseases (Anti-TNF specific antibody (infliximab) treatment offers understandings into the pathophysiology of rheumatoid arthritis). 1999 pages156-160.
As noted earlier, in the late nineteen-eighties, particular antibodies had been produced for blockage of TNF-alpha. CA2 was the initial of these, it was named infliximab afterward. CA2 was a chimeric mouse antibody, produced in order to lessen the chances of the adverse allergic reactions and the tolerance that resulted from antibodies formation due to a foreign protein. A mouse-human chimeric antibody has variable regions of a mouse antibody which are attached to the human constant regions. The result is an antibody about twenty-five percent mouse and seventy-five percent human. CA2 was initially used as an instrument for additional determination of TNF-alpha significance in the pathogenesis of rheumatoid arthritis.
Adapted from Brennan, F., Jackson, A., Chantry, D., Maini, R. and Feldmann, M., 1989. Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. The Lancet, 334(8657), pp.244-247.
Considering human pannus, antibodies to some diversified cytokines previously found were applied. Then the synthesis of various cytokines was assayed, make an effort to find a hierarchy. In the above diagram, we can see the effect of anti-TNF on the IL-1, and the lack of effect on anti-lymphotoxin. Therefore, that concludes that TNF is made by the pannus. Its inhibition has an effect which is consistent with potential benefit.
According to the clinical trials done byCITATION Gre99 \l 1033 (Harriman, 1999) more than a thousand patients with RA were treated with infliximab. In a large phase three study (ATTRACT), patients were treated for longer than one year in the trials. Follow up for three years. From the clinical trials, infliximab was well tolerated by the patients both in single or multiple dose regimen. The potential adverse reactions from infliximab treatment are easily monitored and respond well to the medical treatment. Long-term treatment with infliximab is needed in RA so as to maximize anti-inflammatory effects on affected joints. The drugs reduce signs and symptoms in moderate to severe RA. These results were confirmed by a large phase 3 study in the ATTRACT trial and the benefits have been consistent in six clinical trials.
The ATTRACT trial was the first phase III trial of an anti-TNF. These figures show the efficacy of the treatment, CITATION Bre89 \l 1033 (Brennan, 1989)
The average change in the total radiographic score from baseline to week 102 for all patients with RA (All) v patients with early RA (ERA) who were randomized to MTX only (MTX) or infliximab plus MTX (Infliximab+MTX) in ATTRACT -disease duration ⩽3 years, CITATION FBr04 \l 1033 (Breedveld, 2004).
T
This diagram shows results of median alteration in erosion scores from the baseline to week 102 for patients with early RA i...