TNF inhibitor
Encyclopedia
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 $22Bn in 2009.
(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.
are currently (2009) ongoing.
(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."
, and/or mercaptopurine
. See FDA web site for warnings and details
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.
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.
(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.
Tumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
(TNF) promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, ankylosing spondylitis
Ankylosing spondylitis
Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...
, Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, hidradenitis suppurativa
Hidradenitis suppurativa
Hidradenitis suppurativa is a skin disease that most commonly affects areas bearing apocrine sweat glands or sebaceous glands, such as the underarms, breasts, inner thighs, groin and buttocks.-Overview:...
and refractory asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
. 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 $22Bn in 2009.
Examples
This inhibition can be achieved with a monoclonal antibody such as infliximabInfliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
(Remicade), adalimumab
Adalimumab
Adalimumab is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab...
(Humira), certolizumab pegol
Certolizumab pegol
Certolizumab pegol is a therapeutic monoclonal antibody produced by UCB for the treatment of Crohn's disease and rheumatoid arthritis.-Method of action:...
(Cimzia), and golimumab
Golimumab
Golimumab is a human monoclonal antibody which is used as an immunosuppressive drug and marketed under the brand name Simponi. Golimumab targets tumor necrosis factor alpha , a pro-inflammatory molecule and hence is a TNF inhibitor....
(Simponi),
or with a circulating receptor fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
such as etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
(Enbrel).
While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such as xanthine derivatives
Xanthine
Xanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....
(e.g. pentoxifylline ) and Bupropion
Bupropion
Bupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
. Bupropion
Bupropion
Bupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
is the active ingredient in the smoking cessation aid Zyban and the antidepressant Wellbutrin.
Several 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
agonist hallucinogens including (R)-DOI
2,5-Dimethoxy-4-iodoamphetamine
2,5-dimethoxy-4-iodoamphetamine is a psychedelic drug and a substituted amphetamine of the phenethylamine family. It is also a powerful anti-inflammatory that is effective at doses on the order of 100 micrograms in humans, far below its effective dose as a psychedelic. Despite being a substituted...
, TCB-2
TCB-2
TCB-2 is a hallucinogen, discovered in 2006 by a team at Purdue University where it has been named 2C-BCB. It is a conformationally-restricted derivative of the phenethylamine 2C-B, also a hallucinogen, and acts as a potent agonist for the 5-HT2A and 5-HT2C receptors with a Ki of 0.26nM at the...
, LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
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 suppurativaHidradenitis suppurativa
Hidradenitis suppurativa is a skin disease that most commonly affects areas bearing apocrine sweat glands or sebaceous glands, such as the underarms, breasts, inner thighs, groin and buttocks.-Overview:...
are currently (2009) ongoing.
Rheumatoid arthritis
This potential applicability of anti-TNF therapies in the treatment of rheumatoid arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(RA) is based on the recognition of the role of TNF-alpha as the "master regulator" (as coined by Marc Feldmann
Marc Feldmann
Sir Marc Feldmann is an Australian immunologist, and a professor at the Imperial College School of Medicine where he is a head of the Kennedy Institute of Rheumatology.-Biography:...
and Ravinder N. Maini
Ravinder N. Maini
Sir Ravinder Nath Maini is rheumatology professor at the Kennedy Institute, part of Imperial College London. Maini was born in Ludhiana in the Punjab region of India but has lived most of his life in the UK...
, recipients of the 2003 Lasker Award
Lasker Award
The Lasker Awards have been awarded annually since 1946 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, founded by advertising pioneer Albert Lasker and his wife Mary...
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
Journal of Immunology
The Journal of Immunology is a peer-reviewed academic journal that publishes basic and clinical studies in all aspects of immunology. It was founded by Arthur Fernandez Coca in 1915 . It is the official journal of The American Association of Immunologists and published by The American Association...
, a team from the University of Rochester
University of Rochester
The University of Rochester is a private, nonsectarian, research university in Rochester, New York, United States. The university grants undergraduate and graduate degrees, including doctoral and professional degrees. The university has six schools and various interdisciplinary programs.The...
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 azathioprineAzathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
, and/or mercaptopurine
Mercaptopurine
Mercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:...
. 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, LegionellaLegionella
Legionella is a pathogenic Gram negative bacterium, including species that cause legionellosis or Legionnaires' disease, most notably L. pneumophila. It may be readily visualized with a silver stain....
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 tuberculosisMycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
infection, active tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
(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
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
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 curcuminCurcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
(a compound present in turmeric
Turmeric
Turmeric is a rhizomatous herbaceous perennial plant of the ginger family, Zingiberaceae. It is native to tropical South Asia and needs temperatures between 20 °C and 30 °C and a considerable amount of annual rainfall to thrive...
), and catechins (in green tea
Green tea
Green tea is made solely from the leaves of Camellia sinensis that have undergone minimal oxidation during processing. Green tea originates from China and has become associated with many cultures throughout Asia. It has recently become more widespread in the West, where black tea is traditionally...
). Also activation of cannabinoid CB1 or CB2 receptors by cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
or Echinacea purpurea
Echinacea purpurea
Echinacea purpurea is a species of flowering plant in the genus Echinacea. Its cone-shaped flowering heads are usually, but not always purple. It is native to eastern North America and present to some extent in the wild in much of the eastern, southeastern and midwest United States...
seem to have anti-inflammatory properties through TNF-alpha inhibition.