TNF inhibitor

Tumor necrosis factor (TNF) promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are sometimes treated by using a TNF inhibitor. The important side effects that have been most extensively related to TNFalpha blockers include: lymphoma, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

The global market for TNF inhibitors in 2007 was $10Bn , and in 2008 it was $13.5Bn. and $22 billion in 2009

Examples
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 TNFα, with DOI being the most active, showing TNFα inhibition in the picomolar range, an order of magnitude more potent than its action as a hallucinogen.

Skin disease
Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are currently (2009) ongoing.

Rheumatoid arthritis
This potential applicability of anti-TNF therapies in the treatment of rheumatoid arthritis (RA) is based on the recognition of the role of TNF-alpha as the "master regulator" (as coined by Marc Feldmann and Ravinder N. Maini, recipients of the 2003 Lasker Award for their anti-TNF research in rheumatoid arthritis) of the inflammatory response in many organ systems. In the January 15, 2008 issue of the Journal of Immunology, a team from the University of Rochester observed that "anti-TNF compounds help eliminate abnormal B cell activity in patients, raising the possibility that the drugs improve the health of patients in a way no one has realized before."

FDA
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. See FDA web site for warnings and details

Opportunistic infections
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 TNFα 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. .

Tuberculosis
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.

Fungal infections
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-alpha inhibition.