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					Cyclosporine
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Cyclosporine, Ciclosporin (INN), or cyclosporin (former BAN), is an
immunosuppressant drug. It is widely used post-allogenic organ transplant to
reduce the activity of the patient's immune system and so the risk of organ
rejection. It has been studied in transplants of skin, heart, kidney, lung, pancreas,
bone marrow and small intestine. Cyclosporine is a cyclic nonribosomal peptide of
11 amino acids (an undecapeptide) produced by the fungus Hypocladium inflatum
gams, initially isolated from a Norwegian soil sample.[1]

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Naming
Although the international nonproprietary name is now ciclosporin, it is still
referred to as cyclosporine in most scientific journals and medical publications.

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Commercialisation
The drug is marketed by Novartis under the brand names Sandimmune, the original
formulation, and Neoral for the newer microemulsion formulation. Generic
cyclosporine preparations have been marketed by companies such as Sangstat, Abbott
Laboratories and Gengraf. Since 2002 a topical emulsion of cyclosporine for treating
keratoconjunctivitis sicca has been marketed under the trade name Restasis. Annual
sales of cyclosporine are around $1 billion.

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Uses
The immuno-suppressive effect of Cyclosporine was discovered on January 31, 1972,
by employees of Sandoz (now Novartis) in Basle, Switzerland, in a screening test on
immune-suppression designed and implemented by Hartmann F. Stähelin.
Cyclosporine was subsequently approved for use in 1983.

Apart from in transplant medicine, cyclosporine is also used in psoriasis and
infrequently in rheumatoid arthritis and related diseases, although it is only used in
severe cases. It has been investigated for use in many other autoimmune disorders. It
is often taken in conjunction with corticosteroids. More recently, cyclosporine has
begun to be used to help treat patients suffering from ulcerative colitis with positive
results.

Cyclosporine A has been investigated as a possible neuroprotective agent in
conditions such as traumatic brain injury, and has been shown in animal experiments
to reduce brain damage associated with injury [2]. Cyclosporine A blocks the
formation of the mitochondrial permeability transition pore, which has been found to
cause much of the damage associated with head injury and neurodegenerative
diseases.

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Mode of action
Cyclosporine is thought to bind to the cytosolic protein cyclophilin (immunophilin) of
immunocompetent lymphocytes, especially T-lymphocytes. This complex of
cyclosporin and cyclophylin inhibits calcineurin, which under normal circumstances
is responsible for activating the transcription of interleukin-2. It also inhibits
lymphokine production and interleukin release and therefore leads to a reduced
function of effector T-cells. It does not affect cytostatic activity.

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Side-effects and interactions
Treatment has a number of potentially serious side effects and has adverse
interactions with a wide variety of other drugs and other materials including
grapefruit, although there have been studies to improve the blood level of
cyclosporine with grapefruit juice. Side effects can include gum hyperplasia,
convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion,
breathing difficulties, numbness and tingling, pruritus, high blood pressure, kidney
and liver disfunction, potassium retention and possibly hyperkalemia, hepatotoxicity,
nephrotoxicity, and obviously an increased vulnerability to opportunistic fungal and
viral infections.

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External link
                                      PDF from Novartis describing Sandimmune

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Notes
                                   1. ^ Pritchard, DI. 2005. "Sourcing a chemical
                                      succession for cyclosporin from parasites and
                                      human pathogens". Drug Discovery Today 10
   [10]: 688-691 and Walter Sneader 2005.
   "Ciclosporin" in: "Drug Discovery - A History",
   John Wiley & Sons, pages: 298-299 (refs. page
   315). An alternative species name,
   Tolypocladium inflatum, appears in a 2001
   online publication by Harriet Upton entitled
   "Origin of drugs in current use: the cyclosporin
   story" (retrieved June 19, 2005).
2. ^ Sullivan PG, Thompson M, and Scheff SW.
   2000. "Continuous Infusion of Cyclosporin A
   Postinjury Significantly Ameliorates Cortical
   Damage Following Traumatic Brain Injury".
   Experimental Neurology. 161 [2]: 631-637.

				
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