Ciclosporin

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.<ref name=WHO2008>Template:Cite book</ref><ref name=AHFS2016>Template:Cite web</ref> It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).<ref name=AHFS2016B>Template:Cite web</ref>

Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting.<ref name=AHFS2016/> Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma.<ref name=AHFS2016/> Blood levels of the medication should be checked to decrease the risk of side effects.<ref name=AHFS2016/> Use during pregnancy may result in preterm birth; however, ciclosporin does not appear to cause birth defects.<ref>Template:Cite web</ref>

Ciclosporin is believed to work by decreasing the function of lymphocytes.<ref name=AHFS2016/> 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.<ref name="Matsuda_2000" />

Ciclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref><ref name="WHO22nd">Template:Cite book</ref> In 2023, it was the 179th most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref name="Top 300">Template:Cite web</ref><ref>Template:Cite web</ref> It is available as a generic medication.<ref>Template:Cite press release</ref>

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.<ref name="Sandimmune FDA label">Template:Cite web</ref><ref name="Neoral FDA label">Template:Cite web</ref> It is also approved in the US for treating of rheumatoid arthritis and psoriasis, persistent nummular keratitis following adenoviral keratoconjunctivitis,<ref>Template:Cite journal</ref><ref name="Neoral FDA label" /> and as eye drops for treating dry eyes caused by Sjögren's syndrome and meibomian gland dysfunction.<ref name="Restasis FDA label">Template:Cite web</ref>

In addition to these indications, ciclosporin is also used in severe atopic dermatitis,<ref>Template:Cite journal</ref> It has been used in severe rheumatoid arthritis and related diseases.<ref>Template:Cite journal</ref>

Ciclosporin has also been used in people with acute severe ulcerative colitis and hives that do not respond to treatment with steroids.<ref name="pmid8196726">Template:Cite journal</ref>

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,<ref name="pmid19218475">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and, in some cases, gout.<ref>Template:Cite journal</ref>

Ciclosporin is listed as an IARC Group 1 carcinogen (i.e. there is sufficient evidence of carcinogenicity in humans),<ref>Agents Classified by the IARC Monographs, Volumes 1–110 Template:Webarchive</ref> specifically leading to squamous cell skin cancer and non-Hodgkin lymphoma.<ref>Template:Cite book</ref>

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.<ref name="Matsuda_2000">Template:Cite journal</ref> Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function;<ref>Template:Cite book</ref><ref name=Mott04/><ref name=Youn02>Template:Cite journal</ref><ref name=Handschumacher84>Template:Cite journal</ref> it does not affect cytostatic activity.Template:Medical citation needed

Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore (MPTP),<ref name=Mott04>Template:Cite journal</ref><ref name=Elrod10>Template:Cite journal</ref> thus preventing MPTP opening. The MPTP is found in the mitochondrial membrane of cardiac muscle cells. MPTP opening signifies a sudden change in the inner mitochondrial membrane permeability, allowing protons and other ions and solutes of a size up to ~1.5 kDa to go through the inner membrane. This change of permeability is considered a cellular catastrophe,<ref name="pmid30527591">Template:Cite journal</ref><ref name="pmid25172387">Template:Cite journal</ref> leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.<ref name="pmid24987008">Template:Cite journal</ref>

Ciclosporin can induce a remission of proteinuria caused by such diseases as MCD and FSGS.<ref>Template:Cite journal</ref> Ciclosporin blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. Altogether, the antiproteinuric effect of Ciclosporin results, at least in part, from the maintenance of synaptopodin protein abundance in podocytes, which, in turn, is sufficient to maintain the integrity of the glomerular filtration barrier and to safeguard against proteinuria.<ref>Template:Cite journal</ref>

Pharmacokinetics

Ciclosporin is a cyclic peptide of 11 amino acids with notable molecular weight (1,202 Da)—achieves oral bioavailability up to ~30% due to its N-methylated cyclic structure, which confers both metabolic stability and a pronounced chameleonic properties.<ref name="Asano_2023">Template:Cite journal</ref> It contains a single D-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.<ref name="pmid12422576">Template:Cite journal
Some sources list the fungus under an alternative species name Hypocladium inflatum gams such as Pritchard and Sneader in 2005:
* Template:Cite journal
* Template:Cite book
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 Template:Webarchive" (retrieved 19 June 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.</ref>

Ciclosporin is highly metabolized by the CYP3A4 enzyme in humans and animals after ingestion.<ref name="Vander Schaaf 2024">Template:Cite journal</ref> The metabolites, which include cyclosporin B, C, D, E, H, and L,<ref>Template:Cite journal</ref> have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity.<ref>Template:Cite journal</ref>

Biosynthesis

Cyclosporin biosynthesis. Bmt = butenyl-methyl-threonine, Abu = L-alpha-aminobutyric acid, Sar = sarcosine

Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase.<ref name="pmid25497210">Template:Cite journal</ref> 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.<ref name="pmid8300618">Template:Cite journal</ref> 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.<ref>Template:Cite journalTemplate:Dead link</ref> Amino acids such as D-Ala and butenyl-methyl-L-threonine (Bmt) indicate cyclosporin synthetase requires the action of other enzymes. The racemization of L-Ala to D-Ala by alanine racemase is pyridoxal phosphate-dependent. The formation of butenyl-methyl-L-threonine is performed by a Bmt polyketide synthase that uses acetate/malonate as its starting material.<ref>Dewick, P. (2001) Medicinal Natural Products. John Wiley & Sons, Ltd. 2nd ed.</ref>

Gene cluster

Tolypocladium inflatum, the species currently used for mass production of Cyclosporin, has the biosynthetic genes arranged into a 12-gene cluster. Of these 12 genes, SimA (Template:UniProt) is the cyclosporin synthetase, SimB (Template:Plainlink) is the alanine racemase, and SimG (similar to Template:Plainlink) is the polyketide synthase.<ref name="CLUST12">Template:Cite journal</ref> These genes are associated with an active retrotransposon.<ref>Template:Cite journal</ref> Although these sequences are poorly-annotated on GenBank and other databases, 90% similar sequences can be found for the Cyclosporin-producing Beauveria felina (or Amphichorda ~).<ref>Template:Cite journal</ref> SimB has two paralogs in the same organism with different but overlapping functions thanks to their low specificity.<ref>Template:Cite journal</ref>

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.<ref name = "Borel_1995" />

The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972<ref>Template:Cite journal</ref> in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz.<ref name="pmid8969">Template:Cite journal</ref><ref name="Borel_1995">Template:Cite book</ref> The chemical structure of cyclosporin was determined in 1976, also at Sandoz.<ref name="Rüegger_1976">Template:Cite journal</ref><ref name="Heusler_2001">Template:Cite journal</ref> The success of the drug candidate ciclosporin in preventing organ rejection was shown in kidney transplants by R.Y. Calne and colleagues at the University of Cambridge,<ref name="pmid82836">Template:Cite journal</ref> and in liver transplants performed by Thomas Starzl at the Children's Hospital of Pittsburgh. The first patient, on 9 March 1980, was a 28-year-old woman.<ref name="pmid7017414">Template:Cite journal</ref> In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.<ref name="Kolata_1983">Template:Cite journal</ref><ref name="Gottesman_1988">Template:Cite news</ref><ref name="Columbia_1984Columbia-University-Medical-Center-(in-house_publication)">Template:Cite web</ref><ref name="FDA_approval">Template:Cite web</ref>

Thomas Starzl's 1992 memoir explains through the eyes of a transplant surgeon that ciclosporin was an epoch-making drug for solid organ allotransplantation.<ref name="Starzl-1992">Template:Cite book</ref> It greatly expanded the clinical applicability of such transplantation by substantially advancing the antirejection pharmacotherapy component.<ref name="Starzl-1992"/> Put simply, the biggest limits of applying such transplantation more widely were not cost or surgical skill (as formidable as those are) but rather the problem of allograft rejection and the scarcity of donor organs. Ciclosporin was a major advancement against the rejection part of the challenge.<ref name="Starzl-1992"/>

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.<ref name="Vevizye EPAR" /> The applicant for this medicinal product is Novaliq GmbH.<ref name="Vevizye EPAR">Template:Cite web Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Vevizye was authorized for medical use in the European Union in September 2024.<ref name="Vevizye EPAR" />

Names

The natural product was named cyclosporin by the German-speaking scientists who first isolated it<ref name = "Borel_1995" /> and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs,<ref>Template:Cite webTemplate:Dead linkTemplate:Cbignore</ref> the y was replaced with i so that the INN for the medication is spelled ciclosporin.Template:Citation needed

Ciclosporin is the INN and the British Approved Name (BAN), while cyclosporine is the United States Adopted Name (USAN) and cyclosporin is a former BAN.<ref>Template:Cite web</ref>

Available forms

Ciclosporin exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the medication have been developed for oral administration and for injection. Ciclosporin was originally brought to market by Sandoz (now Novartis), under the brand name Sandimmune, which is available as soft gelatin capsules, an oral solution, and a formulation for intravenous administration. These are all nonaqueous compositions.<ref name="Sandimmune FDA label" /> A newer microemulsion,<ref>Template:Cite journal</ref> orally-administered formulation, Neoral,<ref name="Neoral FDA label" /> is available as a solution and as soft gelatin capsules. Compositions of Neoral are designed to form microemulsions in contact with water.<ref name="pmid9157923">Template:Cite journal</ref><ref>Template:Cite web</ref>

Generic ciclosporin preparations have been marketed under various brand names, including Cicloral (by Sandoz/Hexal), Gengraf (by Abbott) and Deximune (by Dexcel Pharma). Since 2002, a topical emulsion of ciclosporin for treating inflammation caused by keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the brand name Restasis.<ref name="Restasis FDA label" /> Ikervis is a similar formulation with a concentration of 0.1%.<ref>Template:Cite web</ref> Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.<ref>Template:ClinicalTrialsGov.</ref><ref>Template:Cite journal</ref>

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.<ref name="Wwwneurovivecom">Template:Cite web</ref> 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.<ref name="Ehinger">Template:Cite journal</ref>

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.<ref name="pmid10686082">Template:Cite journal</ref> 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. Ciclosporin's neuroprotective properties were first discovered in the early 1990s when two researchers (Eskil Elmér and Hiroyuki Uchino) were conducting experiments in cell transplantation. An unintended finding was that cyclosporin A was strongly neuroprotective when it crossed the blood–brain barrier.<ref name="pmid8719269">Template:Cite journal</ref> This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.<ref name="pmid21142667">Template:Cite journal</ref>

Cardiac disease

Ciclosporin has been used experimentally to treat cardiac hypertrophy<ref name=Mott04/><ref name=Mende98>Template:Cite journal</ref> (an increase in cell volume).

Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia<ref name=Mott04/> (blood flow restriction to tissue) and reperfusion injury<ref name=Mott04/> (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction<ref name=Youn02/> (heart attack) and when mutations in mitochondrial DNA polymerase occur.<ref name=Mott04/> The heart attempts to compensate for disease state by increasing the intracellular Template:Chem to increase the contractility cycling rates.<ref name=Elrod10/> Constitutively high levels of mitochondrial Template:Chem cause inappropriate MPTP opening leading to a decrease in the cardiac range of function, leading to cardiac hypertrophy as an attempt to compensate for the problem.<ref name=Elrod10/><ref name=Youn02/>

Cyclosporin A has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. Cyclosporin A binds to cyclophilin D to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death.<ref name=Mott04/><ref name=Elrod10/><ref>Template:Cite journal</ref> CypD is a protein within the MPTP that acts as a gate; binding by cyclosporin A decreases the amount of inappropriate opening of MPTP, which decreases the intramitochondrial Template:Chem.<ref name=Elrod10/> Decreasing intramitochondrial Template:Chem allows for reversal of cardiac hypertrophy caused in the original cardiac response.<ref name=Elrod10/> Decreasing the release of cytochrome C caused decreased cell death during injury and disease.<ref name=Mott04/> Cyclosporin A also inhibits the phosphatase calcineurin pathway (14).<ref name=Mott04/><ref name=Youn02/><ref name=Lim00>Template:Cite journal</ref> Inhibition of this pathway has been shown to decrease myocardial hypertrophy.<ref name=Youn02/><ref name=Mende98/><ref name=Lim00/>

Veterinary use

The medication is approved in the United States for the treatment of atopic dermatitis in dogs.<ref name="Archer_2014">Template:Cite journal</ref> Unlike the human form of the medication, the lower doses used in dogs 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 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).<ref name="Archer_2014"/><ref name="Palmeiro_2013">Template:Cite journal</ref>

External links

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