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Indian Journal of Pharmacology, Vol. 36, No. 4, August, 2004, pp. 265-266 Molecules of the Millennium A novel therapeutic approach in rheumatoid arthritis Rashmi S, Verma Ujala Postgraduate department of pharmacology and therapeutics, Govt. Medical College, Jammu Code Number: ph04092 Efforts to develop safer and more effective treatments for rheumatoid arthritis (RA) that are based on an improved understanding of the role of inflammatory mediators are being investigated. With the development of biologic agents our therapeutic approach to RA and inflammatory diseases in general, has dramatically changed within the last few years. ′Biologic′ technically means a substance as the product of biologic system and functionally as an agent that targets specific biologic molecule. Rheumatologists and other practitioners are facing a remarkable wave of new therapies for RA like infliximab, etanercept, and leflunomide. Recently FDA has approved some of the following biologic agents for the management of rheumatoid arthritis. Anakinra1: Anakinra is a recombinant form of nonglycosylated human interleukin-1 receptor antagonist expressed in Escherichia coli. The recombinant compound differs from naturally-occurring nonglycosylated human interleukin-1 receptor antagonist by addition of one N-terminal methionine. Natural interleukin-1 receptor antagonist is produced primarily by macrophages and activated monocytes in response to various stimuli e.g., endotoxin and interleukin-1. Anakinra competitively binds to both type I and type II interleukin-1 receptors, at least partially blocking cellular responses mediated by interleukin-1-alpha and interleukin-1-beta; although the binding affinity of natural interleukin-1 receptor antagonist is similar to that of interleukin-1, it lacks interleukin-1 agonist activity. Maximum plasma concentration reaches 3 to 7 h after subcutaneous administration of 1 to 2 mg/kg of the drug with absolute bioavailability up to 95% after subcutaneous injection and approximately 80% of drug gets excreted in urine over 24 h. Its mean plasma clearance decreases by 70 to 75% in severe or end-stage renal disease (creatinine clearance less than 30 ml/min). However, small amounts also get excreted via the hepatobiliary route and the terminal half-life ranges from 4 to 6 h. Anakinra has shown moderate efficacy in severe rheumatoid arthritis when given alone as well as in combination with methotrexate. The requirement of daily 100 mg/day subcutaneous doses of anakinra is a disadvantage, other delivery mechanisms need exploration (eg, depot injection, microspheres, implants), which may enhance efficacy. Prior hypersensitivity to anakinra or E-coli derived proteins and active infection are the important contraindications with the use of anakinra. However, it should be used with caution in patients who have neutropenia, immunosuppression, moderate to severe renal impairment, pregnancy or breastfeeding period, concomitant use of tumor necrosis factor blocking agents. Adalimumab2: FDA has approved adalimumab (marketed by Abbott Laboratories as HUMIRA) to treat rheumatoid arthritis (RA). It is produced by recombinant DNA technology. It is a human-derived antibody that binds to human tumor necrosis factor alpha (TNF alpha). By working against the inflammatory process, adalimumab, like other TNF blockers has been shown to be effective in controlling symptoms of the disease. Adalimumab is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Adalimumab can be used alone or in combination with methotrexate or other DMARDs. The efficacy and safety of adalimumab were assessed in four randomized, double-blind studies in adult patients. Adalimumab was found to reduce signs and symptoms of rheumatoid arthritis in over half the patients. In one of the four studies, patients were treated for a year and then evaluated radiographically. Patients treated with adalimumab plus methotrexate (MTX) demonstrated less joint deterioration than patients receiving MTX alone. It is administered as a single subcutaneous injection every other week. The most serious adverse events associated with adalimumab are, as with other TNF blockers, serious infections, neurologic effects, and certain malignancies of the lymphoid system. Atlizumab3: Interleukin-6 is a pleotropic inflammatory cytokine that is involved in the activation of T-cells, induction of the acute-phase response, stimulation of growth, differentiation of hematopoietic precursor cells and proliferation of synovial fibroblasts. Atlizumab is a humanized anti-interleukin-6 receptor monoclonal antibody. It is efficacious in management of RA in a dose of 2-8 mg/kg/dose intravenously once every 2 weeks. It is a well tolerated drug without any increase in antinuclear, anti-DNA or antiatlizumab antibody. However, increase in blood cholesterol levels has been reported after its use for 24 weeks . CTLA4-Ig4: After activation T-cell expresses CTLA4, which is homologous to CD28, but has high affinity. CTLA4-Ig binds B7 and blocks the second signal. T-cell activation without the co-stimulatory signals leads to inhibition of proliferation and production of cytokines. Controlled trials of CTLA4-Ig are currently underway in RA in early development. ISIS1048385is an antisense recently under phase II clinical trial. It has been reported to decrease TNF-alpha mRNA expression at a dose of 100-300 mg six times a month. Rituximab, a chimeric monoclonal antibody that depletes B cells and Pegsunercept, a PEGylated soluble TNF receptor type-1 are in early stage of clinical trials in RA[6]. REFERENCES
Copyright 2004 - Indian Journal of Pharmacology |
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