Cyclosporin

Calcineurin inhibitor

 

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Other Contra-Indication

This drug is contra-indicated in patients with a known allergy to it, or to castor oil

 

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Cyclosporin

Ciclosporin (INN, pronounced /ˌsaɪklɵˈspɔərɨn/), cyclosporine (USAN), cyclosporin (former BAN) or cyclosporin A, is an immunosuppressant drug widely used in 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, liver, lung, pancreas, bone marrow, and small intestine. Initially isolated from a Norwegian soil sample, ciclosporin is a cyclic nonribosomal peptide of 11 amino acids produced by the fungus Beauveria nivea, and contains a single D-amino acid, which are rarely encountered in nature.^[1]

Indications

The immuno-suppressive effect of ciclosporin was discovered on 31 January 1972 by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune-suppression designed and implemented by Dr. Hartmann F. Stähelin, M.D. The success of ciclosporin in preventing organ rejection was shown in liver transplants performed by Dr. Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on March 9, 1980, was a 28-year-old woman.^[2] Ciclosporin was subsequently approved for use in 1983.

Apart from in transplant medicine, ciclosporin is also used in psoriasis, severe atopic dermatitis, pyoderma gangrenosum and, infrequently, in rheumatoid arthritis and related diseases, although it is only used in severe cases. It is commonly prescribed in the US as an ophthalmic ointment for the treatment of dry eyes. It has been investigated for use in many other autoimmune disorders, and is sometimes prescribed in veterinary cases, particularly in extreme cases of Immune-Mediated Hemolytic Anemia. Inhaled ciclosporin has been investigated to treat asthma and is being studied as a preventative therapy for chronic rejection of the lungs. Ciclosporin has also been used to help treat patients with ulcerative colitis that do not respond to treatment with steroids.^[3] This drug is also used as a treatment of posterior or intermediate uveitis with non-infective etiology.

Ciclosporin 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.^[4] Ciclosporin 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 cyclophilin 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 also has an effect on mitochondria. Ciclosporin prevents the Mitochondrial permeability transition pore from opening, thus inhibiting 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.

Biosynthesis

Figure 1: Ciclosporin biosynthesis. Bmt = butenyl-methyl-threonine, Abu = L-alpha-aminobutyric acid, Sar = sarcosine

Ciclosporin is synthesized by a nonribosomal peptide synthetase, ciclosporin synthetase. The enzyme contains an adenylation domain, a thiolation domain, a condensation domain, and an N-methyltransferase domain. The adenylation domain is responsible for substrate recognition and activation, whereas the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine and the condensation domain elongates the peptide chain. Ciclosporin synthetase substrates include L-Valine, L-Leucine, L-Alanine, L-Glycine, 2-aminobutyric acid, 4-methylthreonine, and D-Alanine. With the adenylation domain, ciclosporin synthetase generates the acyl-adenylated amino acids, then covalently binds the amino acid to phosphopantetheine through a thioester linkage. Some of the amino acid substrates become N-methylated by S-Adenosyl methionine. The cyclization step releases ciclosporin from the enzyme.^[5] Amino acids such as D-Ala and butenyl-methyl-L-threonine indicates that ciclosporin synthetase requires the action of other enzymes such as a D-Alanine racemase. The racemization of L-Ala to D-Ala is pyridoxal phosphate-dependent. The formation of butenyl-methyl-L-threonine is performed by a butenyl-methyl-L-threonine polyketide synthase that utilizes acetate/malonate as its starting material.^[6]

Figure 2: Butenyl-methyl-L-Threonine biosynthesis

Adverse effects and interactions

Treatment may be associated with a number of potentially serious adverse drug reactions (ADRs) and adverse drug interactions. Ciclosporin interacts with a wide variety of other drugs and other substances including grapefruit juice. There have been studies into the use of grapefruit juice to increase the blood level of ciclosporin.

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 an increased vulnerability to opportunistic fungal and viral infections.

An alternate form of the drug, cyclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin (cyclosporin A).^[7] Cyclosporin G (molecular mass 1217) differs from cyclosporin A in the amino acid 2 position, where an L-nor-valine replaces the α-aminobutyric acid.^[8]

Formulations

The drug exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the drug have been developed for oral administration and for injection. Ciclosporin was originally brought to market by Sandoz, now Novartis, under the brand name of Sandimmune, which is available as soft-gelatin capsules, as an oral solution, and as a formulation for intravenous administration. These are all non-aqueous compositions Sandimmune-Novartis. A newer microemulsion orally-administered formulation Neoral Neoral-Novartis is available as a solution and as soft gelatin capsules. The Neoral compositions are designed to form microemulsions in contact with water. 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. Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.

The drug is also available in a dog preparation manufactured by Novartis called Atopica. Atopica is indicated for the treatment of atopic dermatitis in dogs. Unlike the human form of the drug, the lower doses used in dogs mean the drug acts as an immuno-modulator and has fewer side-effects than in man. The benefits of using this product include the reduced need for concurrent therapies to bring the condition under control.

See also

• Cremophor EL ( Additive in Sandimmune )
• Castor oil ( Additive in Sandimmune )
• Alcohol (Additive in Sandimmune and Neoral)
• Medicinal mushrooms

References

1. ^ Borel JF (2002). "History of the discovery of cyclosporin and of its early pharmacological development". Wien. Klin. Wochenschr. 114 (12): 433–7. PMID 12422576. 
   Some sources list the fungus under an alternative species name Hypocladium inflatum gams such as Pritchard and Sneader in 2005:
   * Pritchard DI (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discov. Today 10 (10): 688–91. doi:10.1016/S1359-6446(05)03395-7. PMID 15896681. 
   * "Ciclosporin". Drug Discovery - A History. John Wiley & Sons. pp. 298–299 (refs. page 315). 
   However, the name, "Beauveria nivea", also appears in several other articles including in a 2001 online publication by Harriet Upton entitled "Origin of drugs in current use: the cyclosporin story" (retrieved June 19, 2005). Mark Plotkin states in his book Medicine Quest, Penguin Books 2001, pages 46-47, that in 1996 mycology researcher Kathie Hodge found that it is in fact a species of Cordyceps.
2. ^ Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP (1981). "Liver transplantation with use of cyclosporin a and prednisone". N. Engl. J. Med. 305 (5): 266–9. PMID 7017414. 
3. ^ Lichtiger S, Present DH, Kornbluth A, et al. (1994). "Cyclosporine in severe ulcerative colitis refractory to steroid therapy". N. Engl. J. Med. 330 (26): 1841–5. doi:10.1056/NEJM199406303302601. PMID 8196726. 
4. ^ Sullivan PG, Thompson M, Scheff SW (2000). "Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury". Exp. Neurol. 161 (2): 631–7. doi:10.1006/exnr.1999.7282. PMID 10686082. 
5. ^ Hoppert, M.; Gentzsch, C.; Schӧrgendorfer, K. Arch. Microbiol. 2001, 176, 285-293.
6. ^ Dewick, P. (2001) Medicinal Natural Products. John Wiley & Sons, Ltd. 2nd ed.
7. ^ Henry ML, Elkhammas EA, Davies EA, Ferguson RM (1995). "A clinical trial of cyclosporine G in cadaveric renal transplantation". Pediatr. Nephrol. 9 Suppl: S49–51. doi:10.1007/BF00867684. PMID 7492487. 
8. ^ Calne RY, White DJ, Thiru S, Rolles K, Drakopoulos S, Jamieson NV (1985). "Cyclosporin G: immunosuppressive effect in dogs with renal allografts". Lancet 1 (8441): 1342. doi:10.1016/S0140-6736(85)92844-2. PMID 2860538.

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