Cyclosporine
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Image:Cyclosporine.png | |
| [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl- N-methyl-L-leucyl-N-methyl-L-leucyl- N-methyl-L-valyl-3-hydroxy-N,4-dimethyl- L-2-amino-6-octenoyl-L-α-amino-butyryl- N-methylglycyl-N-methyl-L-leucyl-L-valyl- N-methyl-L-leucyl) | |
| CAS number 59865-13-3 | ATC code L04AA01 |
| Chemical formula | C62H111N11O12 |
| Molecular weight | 1202.61 |
| Bioavailability | variable |
| Metabolism | hepatic |
| Elimination half-life | variable (about 24 hours) |
| Excretion | biliary |
| Pregnancy category | C (USA) C (Aus) |
| Legal status | N/A |
| Routes of administration | per os or intravenously |
Cyclosporine (IPA: Template:IPA), ciclosporin (INN), or cyclosporin (former BAN), is an immunosuppressant drug. It is widely used post-allogeneic 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.Template:Ref
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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.
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.
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 Template:Ref. 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.
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. It has also an effect on mitochondria. Cyclosporine A prevents the mitochondrial PT pore from opening and inhibits thus cytochrome c release, a potent apoptotic stimulation factor. However, this is not the primary mode of action for clinical use but rather an important effect for research on apoptosis.
Adverse effects and interactions
Treatment may be associated with a number of potentially serious adverse drug reactions (ADRs) and adverse drug interactions. Cyclosporine interacts with a wide variety of other drugs and other substances including grapefruit juice, although there have been studies into the use of grapefruit juice to increase the blood level of cyclosporine.
ADRs can include gum hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, breathing difficulties, numbness and tingling, pruritus, high blood pressure, potassium retention and possibly hyperkalemia, kidney and liver dysfunction (nephrotoxicity & hepatotoxicity), and obviously an increased vulnerability to opportunistic fungal and viral infections.
External link
Notes
- Template:Note 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).
- Template:Note 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.