Article: Ciclosporin

Ciclosporin
Systematic (IUPAC) name
[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)
Identifiers
CAS number	59865-13-3
ATC code	L04AA01
PubChem	2909
DrugBank	BTD00003
Chemical data
Formula	C62H111N11O12
Mol. weight	1202.61
Pharmacokinetic data
Bioavailability	variable
Metabolism	hepatic
Half life	variable (about 24 hours)
Excretion	biliary
Therapeutic considerations
Pregnancy cat.	C (U.S.), C (Au)
Legal status	S4 (Au), POM (UK)
Routes	oral, IV

Ciclosporin (INN) (IPA: [ˈsaɪkləˌspɔrən]) , cyclosporine (USAN) or cyclosporin (former BAN), is an immunosuppressant drug 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. Ciclosporin is a cyclic nonribosomal peptide of 11 amino acids (an undecapeptide) produced by the fungus Tolypocladium inflatum Gams, initially isolated from a Norwegian soil sample.^[1]

Indications

The immuno-suppressive effect of ciclosporin 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. Ciclosporin was subsequently approved for use in 1983.

Apart from in transplant medicine, ciclosporin 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, ciclosporin has begun to be used to help treat patients suffering from ulcerative colitis with positive results.

Ciclopsorin 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] Ciclopsorin 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

Ciclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin 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. Ciclosporin 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. Ciclopsorin 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 ciclopsorin.

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.

Formulations

The drug is marketed by Novartis under the brand names Sandimmune, the original formulation, and Neoral for the newer microemulsion formulation. Generic ciclosporin preparations have been marketed under various trade names including Cicloral (Sandoz/Hexal) and Gengraf (Abbott). Since 2002 a topical emulsion of ciclosporin for treating keratoconjunctivitis sicca has been marketed under the trade name Restasis. Annual sales of ciclosporin are around $1 billion.