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.[1]

The global market for TNF inhibitors in 2007 was $10Bn , and in 2008 it was $13.5Bn[2] and $22Bn in 2009.[3]

Contents

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 [4] (e.g. pentoxifylline [5]) and Bupropion.[6] 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.[7][8][9]

Therapeutic applications

Skin disease

Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are currently (2009) ongoing.[10]

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.[11] In the January 15, 2008 issue of the Journal of Immunology, a team from the University of Rochester observed[12] 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."[13]

Side effects

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[14]

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.[15]

Tuberculosis

In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab.[16] 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.[17]

Anti-TNF agents in nature

TNF or the effects of TNF are also inhibited by a number of natural compounds, including curcumin[18][19][20][21] (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.[22]

References

  1. ^ Scheinfeld N (September 2004). "A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab". J Dermatolog Treat 15 (5): 280–94. doi:10.1080/09546630410017275. PMID 15370396. 
  2. ^ Pappas DA, Bathon JM, Hanicq D, Yasothan U, Kirkpatrick P (September 2009). "Golimumab". Nat Rev Drug Discov 8 (9): 695–6. doi:10.1038/nrd2982. PMID 19721444. 
  3. ^ http://knol.google.com/k/top-ten-twenty-best-selling-drugs-2009#Best_selling_therapeutic_categoriesBest_selling_therapeutic_categoriesef>
  4. ^ Essayan DM. (2001). "Cyclic nucleotide phosphodiesterases.". J Allergy Clin Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087. 
  5. ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. PMID 9927365. http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=9927365. 
  6. ^ Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB (June 2006). "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice". Int. Immunopharmacol. 6 (6): 903–7. doi:10.1016/j.intimp.2005.12.007. PMID 16644475. 
  7. ^ Miller KJ, Gonzalez HA (December 1998). "Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells". Annals of the New York Academy of Sciences 861: 169–73. doi:10.1111/j.1749-6632.1998.tb10188.x. PMID 9928254. 
  8. ^ Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD (November 2008). "Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency". The Journal of Pharmacology and Experimental Therapeutics 327 (2): 316–23. doi:10.1124/jpet.108.143461. PMID 18708586. 
  9. ^ Pelletier M, Siegel RM (December 2009). "Wishing Away Inflammation? New Links between Serotonin and TNF Signaling". Molecular Interventions 9 (6): 299–301. doi:10.1124/mi.9.6.5. PMC 2861806. PMID 20048135. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2861806. 
  10. ^ Haslund P, Lee RA, Jemec GB (November 2009). "Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors". Acta Derm Venereol. 89 (6): 595–600. doi:10.2340/00015555-0747. PMID 19997689. 
  11. ^ Feldmann M, Maini RN (October 2003). "Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases". Nat. Med. 9 (10): 1245–50. doi:10.1038/nm939. PMID 14520364. 
  12. ^ Anolik JH, Ravikumar R, Barnard J, et al. (January 15, 2008). "Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks". J. Immunol. 180 (2): 688–92. PMID 18178805. 
  13. ^ A new view of drugs used to treat rheumatoid arthritis
  14. ^ http://www.drugs.com/fda/tumor-necrosis-factor-tnf-blockers-azathioprine-mercaptopurine-update-reports-hepatosplenic-t-cell-12945.html
  15. ^ http://www.drugs.com/fda/tumor-necrosis-factor-alpha-tnf-alpha-blockers-label-change-boxed-warning-updated-risk-infection-13023.html
  16. ^ Keane J, Gershon S, Wise RP, et al. (October 2001). "Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent". N. Engl. J. Med. 345 (15): 1098–104. doi:10.1056/NEJMoa011110. PMID 11596589. 
  17. ^ "FDA: Manufacturers of TNF-Blocker Drugs Must Highlight Risk of Fungal Infections" (Press release). U.S. Food and Drug Administration (FDA). September 4, 2008. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116942.htm. Retrieved 2009-11-15. 
  18. ^ Siddiqui AM, Cui X, Wu R, et al. (July 2006). "The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma". Crit. Care Med. 34 (7): 1874–82. doi:10.1097/01.CCM.0000221921.71300.BF. PMID 16715036. 
  19. ^ Okunieff P, Xu J, Hu D, et al. (July 2006). "Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines". Int. J. Radiat. Oncol. Biol. Phys. 65 (3): 890–8. doi:10.1016/j.ijrobp.2006.03.025. PMID 16751071. 
  20. ^ Gulcubuk A, Altunatmaz K, Sonmez K, et al. (February 2006). "Effects of curcumin on tumour necrosis factor-alpha and interleukin-6 in the late phase of experimental acute pancreatitis". J Vet Med a Physiol Pathol Clin Med 53 (1): 49–54. doi:10.1111/j.1439-0442.2006.00786.x. PMID 16411910. 
  21. ^ Lantz RC, Chen GJ, Solyom AM, Jolad SD, Timmermann BN (June 2005). "The effect of turmeric extracts on inflammatory mediator production". Phytomedicine 12 (6–7): 445–52. doi:10.1016/j.phymed.2003.12.011. PMID 16008121. 
  22. ^ Gertsch Jürg et al. (2004). “Alkylamides from Echinacea are a New Class of Cannabinomimetics”. J. Biol. Chem. 281 (20), pp. 14192–14206. http://www.jbc.org/content/281/20/14192.full.pdf
Intracellular
(initiation)
Macrolides/
other IL-2 inhibitors
TNF-α inhibitor
Intracellular
(reception)
Extracellular
Serum target
(noncellular)
Cellular target
Unsorted
-cept (Fusion)

M: LMC

cell/phys/auag/auab/comp, igrc

imdf/ipig/hyps/tumr

proc, drug(L3/4)