Life Sciences & Biotechnology
Title : | Mechanism based approach comprising concomitant administration of chlorogenic acid, a natural JAK/STAT inhibitor with leflunomide (DMARD) for the management of adverse drug reactions and improved efficacy in the treatment of rheumatoid arthritis |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Pharmacology, Immunology |
Principal Investigator : | Dr. Gurleen Kour, CSIR-Indian Institute Of Integrative Medicine (CSIR-IIIM), Jammu and Kashmir |
Timeline Start Year : | 2024 |
Timeline End Year : | 2026 |
Contact info : | gurleen.kour@iiim.res.in |
Details
Executive Summary : | Leflunomide (LEF), a de novo pyrimidine synthesis inhibitor, is a conventional DMARD (Disease-modifying anti-rheumatic drug) with excellent efficacy and is considered in rheumatoid arthritis (RA) patients responding inadequately to methotrexate monotherapy. The predominant adverse effect associated with its use is hepatotoxicity. In 2010, FDA placed a black-boxed warning on LEF for severe liver injury and placed recommendations on its use. It was suggested that the patients to be put on LEF therapy should be pre-evaluated for liver diseases, hepatitis B, C and LEF should not be administered in combination with another hepatotoxic drug. A recent study published in JAMA suggested that the decision to initiate biological DMARD therapy in RA should be carefully considered while keeping in mind the complexity of using biological DMARDs including intravenous routes to administration, serious adverse effects, high cost and increased risks of bacterial and viral infections. Small molecule JAK/STAT inhibitors including baricitinib and tofacitinib is another recent development in the treatment of RA because of their targeted approach and ease of oral administration. However, there is rising concern over the cost-aspects and risks of adverse effects and serious infections associated with their use. According to British National Formulary, yearly cost of tofacitinib (5mg) is 68 times the cost of MTX therapy. Keeping in mind the above-mentioned limitations, a new vision is to increase the therapeutic efficacy of existing conventional DMARDs by combining them with phytochemicals targeting JAK/STAT pathway while also decreasing the adverse effects. Chlorogenic acid (CGA) is a phytochemical abundantly found in tea, coffee and exhibits numerous pharmacological properties. The JAK/STAT inhibition potential of CGA has been seen in rat synoviocytes induced with IL-1β. Additionally, the hepatoprotective effect of CGA has been demonstrated in MTX-induced liver injury in rats wherein CGA decreased the expression of COX-2, iNOS while inhibiting apoptosis. Thus, the current hypothesis aims to investigate the combination of LEF + CGA for its synergistic anti-arthritic potential by targeting two different pathways with the possible potential to limit hepatotoxicity of LEF therapy. The anti-inflammatory potential of the combination will be investigated in SW982 culture model induced by TNF-α/IL-1β. Further validation of the efficacy will be explored using collagen induced arthritic model (DBA/1J mice) with CGA and sub-therapeutic dose of LEF while investigation its hepatoprotective potential. Thus, the project aims to investigate the combination of LEF + CGA for its increased efficacy and synergistic anti-arthritic potential. The synergistic anti-arthritic effect of the combination therapy can possibly reduce the dose of LEF without compromising the efficacy in RA treatment thus reducing its toxic repercussions. |
Total Budget (INR): | 30,47,320 |
Organizations involved