Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczema, and in organ transplants to prevent rejection.[9][10] It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).[11]
Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting.[10] Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma.[10] Blood levels of the medication should be checked to decrease the risk of side effects.[10] Use during pregnancy may result in preterm birth; however, ciclosporin does not appear to cause birth defects.[12]
Ciclosporin is believed to work by decreasing the function of lymphocytes.[10] It does this by forming a complex with cyclophilin to block the phosphatase activity of calcineurin, which in turn decreases the production of inflammatory cytokines by T-lymphocytes.
Ciclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983.[13] It is on the World Health Organization's List of Essential Medicines.[14][15] In 2023, it was the 179th most commonly prescribed medication in the United States, with more than 2million prescriptions.[16][17] It is available as a generic medication.[18]
Medical uses
Ciclosporin is indicated to treat and prevent graft-versus-host disease in bone marrow transplantation and to prevent rejection of kidney, heart, and liver transplants.[19][20] It is also approved in the US for treating of rheumatoid arthritis and psoriasis, persistent nummular keratitis following adenoviral keratoconjunctivitis,[21][20] and as eye drops for treating dry eyes caused by Sjögren's disease and meibomian gland dysfunction.[22]
In addition to these indications, ciclosporin is also used in severe
Side effects
Side effects of ciclosporin can include gum enlargement, increased hair growth, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, increased cholesterol, trouble breathing, numbness and tingling (particularly of the lips), itchiness, high blood pressure, potassium retention (possibly leading to hyperkalemia), kidney and liver dysfunction,[26] burning sensations at finger tips, and an increased vulnerability to opportunistic fungal and viral infections. Ciclosporin causes hypertension by inducing vasoconstriction in the kidneys and increasing sodium reabsorption. The increase in blood pressure can cause cardiovascular events; it is thus recommended that the lowest effective dose for people requiring long-term treatment be used.[27]
Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and, in some cases, gout.[28]
Pharmacology
Mechanism of action
Ciclosporin's main effect is to lower the activity of T-cells; it does so by inhibiting calcineurin in the calcineurin–phosphatase pathway and preventing the mitochondrial permeability transition pore from opening. Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially of T cells. This cyclosporin—cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of interleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the T-cell nucleus and increases the transcription of genes for IL-2 and related cytokines.[31] Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function;[32][33]
Biosynthesis
Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase.[47] 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. Cyclosporin synthetase substrates include L-valine, L-leucine, L-alanine, glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine, which is the starting amino acid in the biosynthetic process.[48] With the adenylation domain, cyclosporin 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 cyclosporin from the enzyme.[49]
History
In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees of Sandoz (now Novartis) in Basel, Switzerland. Both strains produced a family of natural products called cyclosporins. Two related components that had antifungal activity were isolated from extracts from these fungi. The Norwegian strain, Tolypocladium inflatum Gams, was later used for the large scale fermentation of ciclosporin.
The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972[55] in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz.[56][57] The chemical structure of cyclosporin was determined in 1976, also at Sandoz.[58][59]
Society and culture
Legal status
In July 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vevizye, intended for the treatment of dry eye disease. The applicant for this medicinal product is Novaliq GmbH.[67] Vevizye was authorized for medical use in the European Union in September 2024.[67]
Names
The natural product was named cyclosporin by the German-speaking scientists who first isolated it[57] and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs,[68]
Research
Neuroprotection
Ciclosporin is in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage and reperfusion injury (phase III) in traumatic brain injury. This multi-center study is being organized by NeuroVive Pharma and the European Brain Injury Consortium using NeuroVive's formulation of ciclosporin called Neurostat (also known by its cardioprotection brand name of Ciclomulsion). This formulation uses a lipid emulsion base instead of cremophor and ethanol.[76] NeuroSTAT was compared to Sandimmune in a phase I study and found to be bioequivalent. In this study, NeuroSTAT did not exhibit the anaphylactic and hypersensitivity reactions found in cremophor- and ethanol-based products.[77]
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.[78] Ciclosporin blocks the formation of the
Veterinary use
The medication is approved in the United States for the treatment of atopic dermatitis in dogs and cats.[84] Unlike the human form of the medication, the lower doses used in pets mean the drug acts as an immunomodulator and has fewer side effects than in humans. The benefits of using this product include the reduced need for concurrent therapies to bring the condition under control. It is available as an ophthalmic ointment for dogs called Optimmune, manufactured by Intervet, which is part of Merck. It is also available for dogs and cats via an oral solution called Atopica, manufactured by Elanco. It is also used to treat sebaceous adenitis (immune response against the sebaceous glands), pemphigus foliaceus (autoimmune blistering skin disease), Inflammatory bowel disease, perianal fistulas (anal inflammatory disease), and myasthenia gravis (a neuromuscular disease).[84][85]
External links
References
- cyclosporin Dictionary.com Unabridged, Random House, n.d., retrieved 13 July 2011^
- Regulatory Decision Summary for Restasis Multidose Drug and Health Product Register, 23 October 2014, retrieved 7 June 2022^
- Regulatory Decision Summary for Verkazia