A TNF inhibitor is a pharmaceutical drug that suppresses response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in clinical problems associated with autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so a TNF inhibitor may be used in their treatment. The important side effects that have been most extensively related to TNF inhibitors include lymphoma, infections (especially tuberculosis reactivation), congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.
History of anti-TNF treatments
Early experiments associated TNF function with the pathogenesis of bacterial sepsis, thus the first preclinical studies using anti-TNF antibodies were performed in animal models of sepsis and showed that anti-TNF antibodies protected mice from sepsis. However, subsequent clinical trials in sepsis patients showed no significant benefit upon anti-TNF treatment. It wasn't until 1991 that studies in more physiological animal models of TNF overexpression, namely the human TNF transgenic mouse model, provided the pre-clinical rational for a causal role of TNF in the development of polyarthritis and that anti-TNF treatments could be effective against human arthritides. This was later confirmed in clinical trials and led to the development of the highly successful first biological therapies for RA.
This inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or with a circulating receptor fusion protein such as etanercept (Enbrel).
While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such as xanthine derivatives (e.g. pentoxifylline) and Bupropion. Bupropion is the active ingredient in the smoking cessation aid Zyban and the antidepressant Wellbutrin.
Several 5-HT2A agonist hallucinogens including (R)-DOI, TCB-2, LSD and LA-SS-Az have unexpectedly also been found to act as potent inhibitors of TNF, with DOI being the most active, showing TNF inhibition in the picomolar range, an order of magnitude more potent than its action as a hallucinogen.
Clinical application of anti-TNF drugs in rheumatoid arthritis was demonstrated by Marc Feldmann and Ravinder N. Maini, who won the 2003 Lasker Award for their work. Anti-TNF compounds help eliminate abnormal B cell activity.
The National Institute of Clinical Excellence (NICE) have issued guidelines for the treatment of severe psoriasis using the Anti-TNF drugs etanercept (Enbrel) and adalimumab (Humira) as well as the Anti-IL12/23 biological treatment ustekinumab. In cases where more conventional systemic treatments such as psoralen combined with ultraviolet A treatment (PUVA), methotrexate and ciclosporin have failed to treat or can not be tolerated, these newer biological agents may be prescribed. Infliximab may be used to treat severe plaque psoriasis if afore mentioned treatments fail or can not be tolerated.
The FDA continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factors (TNF) blockers, as well as with azathioprine, and/or mercaptopurine.
Starting TNF inhibition puts patients at increased risk of opportunistic infections. FDA has warned about the risk of infection from two bacterial pathogens, Legionella and Listeria. People taking TNF blockers are at increased risk for developing serious infections that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens.
In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent TB infection or disease. The anti-TNF monoclonal antibody biologics, Infliximab and adalimumab, and the fusion protein etanercept which are all currently approved by the U.S. Food and Drug Administration (FDA) for human use, have label warnings which state that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with these medications.
The U.S. Food and Drug Administration (FDA) issued a warning on September 4, 2008, that patients on TNF inhibitors are at increased risk of opportunistic fungal infections, such as pulmonary and disseminated histoplasmosis, coccidioidomycosis, and blastomycosis. They encourage clinicians to consider empiric antifungal therapy in all patients at risk until the pathogen is identified.
Anti-TNF agents in nature
TNF or the effects of TNF are also inhibited by a number of natural compounds, including curcumin (a compound present in turmeric), and catechins (in green tea). Also activation of cannabinoid CB1 or CB2 receptors by cannabis or Echinacea purpurea seem to have anti-inflammatory properties through TNF inhibition.
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