Antimetabolite Benificial in number of c/c inflammatory d/s including crohns d/s, rheumatoid arthritis & in cancer Given orally, subcutaneously or I/M
DHFA Dihydro folate reductase THFA This step is important in production of thymidine and purine
High doses, used in chemotherapy, inhibits cellular proliferation. Low dose is used in treatment of IBD(12-25mg/wk). Interfere with inflammatory actions of interleukin-1. Stimulate increased release of adenosine, an endogenous anti-inflammatory autocoid. Also stimulate apoptosis & death of activated T- lymphocytes
Induce & maintain remission in patients with crohns d/s. Efficacy in ulcerative colitis is uncertain. To induce remission, 15-25mg given once weekly by subcutaneous inj. If satisfactory response in 8-12wks, dose is reduced to 15mg/wk
At high doses, cause BONE MARROW DEPRESSION, MEGAIOBLASTIC ANAEMIA, ALOPACIA & MUCOSITIS Folate supplimentation reduces risk of events without impairing anti inflammatory effect.
Dysregulation of TH1 response is present in IBD. Key proinflammatory cytokine in TH1 response is TNF-alpha. INFLIXIMAB is a chimeric mouse human monoclonal Ab to human TNF- alpha Given I/v, therapeutic dose 5-10mg/kg & plasma t1/2 is 8-10days
TNF-alpha trimers bind to cell-surface TNF-alpha receptors. INFLIXIMAB bind to soluble TNF-alpha trimers with high affinity, preventing cytokine from binding to receptors. It also bind to membrane bound TNF- alpha & neutralises its activity. Also promote compliment activation & Ab-mediated apoptosis & cellular cytotoxicity of activated T- lymphocytes & macrophages.
Used in a/c & c/c treatment of patients with moderate to severe Crohns d/s & Ulcerative colitis. INFLIXIMAB induction therapy – dose 5mg/kg at 0, 2, &6wks. In patients who respond can be treated with repeat infusions every 8wks. Other anti-TNF agent approved are ADALIMUMAB & CERTOLIZUMAB.
Infection due to suppresion of TH1 inflammatory response. Reactivation of latent TB, with dissemination. Other infections include pneumonia, sepsis, pneumosistosis, histoplasmosis, listeriosis & reactivation of hepatits B. May cause severe hepatic reactions leading to a/c hepatic failure. May worsen CHF in cardiac disease.
o INTEGRINS are adhesion molecules on surface of leucocytes that interact with another class of adhesion molecules on the surface of vascular endothelium known as SELECTIN, allowing circulating leucocytes to adhere & subsequently move through the vessel wall into the tissue.o Integrins contain two subunits alpha & beta.o NATALIZUMAB a humanized IgG4 monoclonal Ab targeted against alpha-2 subunit.
Used in patients with moderate to severe Crohns disease. DOSE-300mg every 4 wks by I/V infusion & patient should not be on any immunosuppressive treatment. ADVERSE EFFECTS- a/c infusion reactions & small risk of oppurtunistic infections.