User:Selket/Sandbox

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Selket/Sandbox
Therapeutic monoclonal antibody
Source	chimeric mouse/human
Target	TNFα
Identifiers
CAS number	170277-31-3
ATC code	L04AA12
DrugBank	BTD00004
Chemical data
Formula	C₆₄₂₈H₉₉₁₂N₁₆₉₄O₁₉₈₇S₄₆
Mol. mass	144190.3 g/mol
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	reticuloendothelial system
Half life	9.5 days
Excretion	?
Therapeutic considerations
Pregnancy cat.	B
Legal status
Routes	IV

Infliximab (brand name Remicade®) is a drug used to treat auto-immune disorders. Infliximab is known as a "chimeric monoclonal antibody" (the term "chimeric" refers to the use of both mouse (murine) and human components of the drug i.e. murine binding VK and VH domains and human constant Fc domains). The drug reduces the amount of active TNFα (tumour necrosis factor alpha) in the body by binding to it and preventing it from signaling the receptors for TNFα on the surface of cells. TNFα is one of the key cytokines that triggers and sustains the inflammation response. Remicade was developed by Junming Le and Jan Vilcek at New York University School of Medicine and developed by Centocor, a pharmaceutical company owned by Johnson & Johnson.^[1]

Infliximab has been approved by the U.S. Food and Drug Administration for for the treatment of psoriasis, pediatric Crohn's disease, ankylosing spondylitis, Crohn's disease, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. According to the manufacturer's websites, there are more patients world-wide who have been treated with Remicade (the first commercially available TNF antagonist) than Enbrel and Humira combined.

Remicade is administered by intravenous infusion, typically at 2-month intervals, and at a clinic or hospital. It cannot be administered orally, because the digestive system would destroy the drug.

1 Pharmacology
2 Safety
3 Other uses
4 Availability/Affordability
5 See also
6 External links
7 Reference

[edit] Pharmacology

According to product labeling Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble (free floating in the blood) and transmembrane (located on the outer membranes of T cells and similar immune cells) forms of TNFα and inhibits or prevents the effective binding of TNFα with its receptors. Remicade and Humira (another TNF antagonist) are in the subclass of "anti-TNF antibodies" (they are in the form of naturally occurring antibodies), and are capable of neutralizing all forms (extracellular, transmembrane, and receptor-bound) of TNF alpha.^[2] Enbrel, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and because of it's modified form, cannot neutralize receptor-bound TNFa.^[3] Additionally, the anti-TNF antibodies Humira and Remicade have the capability of lysing cells involved in the inflammatory process, whereas the receptor fusion protein apparently lacks this capability.^[4] Although the clinical significance of these differences have not been absolutely proven, they may account for the differential actions of these drugs in both efficacy and side effects.

Infliximab has high specificity for TNFα, and does not neutralize TNF beta (TNFβ, also called lymphotoxin α), a related but less inflammatory cytokine that utilizes the same receptors as TNFα. Biological activities that are attributed to TNFα include: induction of proinflammatory cytokines such as interleukin (IL) 1 and IL 6, enhancement of leukocyte movement or migration from the blood vessels into the tissues by increasing the permeability of endothelial layer of blood vessels; and increasing the release of adhesion molecules. Infliximab prevents disease in transgenic mice (a special type of mice that are biologically engineered to produce a human form of TNFα and which are used to test the results of these drugs that might be expected in humans). These experimental mice develop arthritis as a result of their production of human TNFα, and when administered after disease onset, infliximab allows eroded joints to heal.

[edit] Safety

According to the product labeling of Infliximab, Etanercept, and Adalimumab, these drugs are in the class of immunosuppressants. After a number of studies and reports of adverse reactions in patients receiving anti-TNFα therapy (including serious and sometimes fatal blood disorders, infections, rare reports of lymphoma and solid tissue cancers, rare reports of serious liver injury, and rare reports of demyelinating central nervous system disorders), the FDA issued a warning to doctors appearing in the respective product labeling of these drugs instructing them to screen and monitor potential patients more carefully ([1]).

[edit] Other uses

Case studies have been done into other uses of infliximab, such as to treat skin diseases. Remicade (infliximab) has been approved for treating ankylosing spondylitis, Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and ulcerative colitis. Infliximab is also prescribed for the treatment of Behcet's disease.^[5] and infusions of infliximab have been used successfully in the treatment of sciatica due to slipped discs.^[6]

There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases; psoriasis, in which increased TNFα has been demonstrated, is the most recent indication.^[7]

[edit] Availability/Affordability

Like all of the TNF inhibitors, Remicade is an expensive medication, costing about $1000 for a 100mg dose, and is covered by almost every medical insurance plan. It is administered every 6-8 weeks, with an initial startup requiring smaller time frames between infusions. According to the labeling, the current posology is:

Ankylosing Spondylitis: 5mg per Kg
Crohn's disease: 5mg per Kg
Psoriatic Arthritis: 5mg per Kg
Rheumatoid Arthritis: 3mg per Kg
Psoriasis: 5mg per Kg

[edit] See also

[edit] External links

[edit] Reference

^ Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, Scallon B, Moore MA, Vilcek J, Daddona P, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30:1443-53. PMID 8232330.
^ Choy EH et al. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907-916
^ Etanercept product labeling
^ Etanercept, Adalimumab and Infliximab product labeling
^ Sfikakis PP. Behcet's disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis 2002;61 Suppl 2:ii51-3. PMID 12379622.
^ Korhonen T et al. Efficacy fo infliximab for disc herniation-induced sciatica: a one-year follow-up. Spine 2004;29:2115-9.
^ Gupta AK, Skinner AR. A review of the use of infliximab to manage cutaneous dermatoses. J Cutan Med Surg 2004;8:77-89. PMID 15685387.