Common side effects include high blood pressure, headache,
kidney problems, increased hair growth, and vomiting.[13] Other severe side effects include an increased risk of infection, liver problems, and an increased risk of
lymphoma.[13] Blood levels of the medication should be checked to decrease the risk of side effects.[13] Use during
pregnancy may result in
preterm birth; however, ciclosporin does not appear to cause
birth defects.[15]
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.[16] Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced
effector T-cell function;[32][33][34][35] it does not affect
cytostatic activity.[medical citation needed]
Ciclosporin also binds to the cyclophilin D protein that constitutes part of the
mitochondrial permeability transition pore (MPTP),[33][36] 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,[37][38] leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.[39]
Ciclosporin can induce a remission of proteinuria caused by such diseases as MCD and FSGS. [40] 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. [41]
Pharmacokinetics
Ciclosporin is a
cyclicpeptide of 11
amino acids; it contains a single
D-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.[42]
Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L,[43] have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity.[44] Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.[medical citation needed]
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 (Q09164) is the cyclosporin synthetase, SimB (CAA02484.1) is the alanine racemase, and SimG (similar to ATQ39432.1) is the polyketide synthase.[49] These genes are associated with an active retrotransposon.[50] 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 ~).[51] SimB has two paralogs in the same organism with different but overlapping functions thanks to their low specificity.[52]
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.[53]
The immunosuppressive effect of the natural product ciclosporin was discovered on 31 January 1972[54] in a screening test on immune suppression designed and implemented by
Hartmann F. Stähelin at Sandoz.[55][53] The chemical structure of cyclosporin was determined in 1976, also at Sandoz.[56][57] 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,[58] 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.[59] In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.[60][61][62][63]
Thomas Starzl's 1992 memoir explains through the eyes of a transplant surgeon that ciclosporin was an epoch-making drug for solid organ allotransplantation.[64] It greatly expanded the clinical applicability of such transplantation by substantially advancing the antirejection pharmacotherapy component.[64] 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. Ciclopsporin was a major advancement against the rejection part of the challenge.[64]
Society and culture
Name
The natural product was named cyclosporin by the German-speaking scientists who first isolated it[53] and cyclosporine when translated into English. Per
International Nonproprietary Name (INN) guidelines for drugs,[65] the y was replaced with i so that the INN for the medication is spelled ciclosporin.[citation needed]
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.[8] A newer
microemulsion,[67] orally-administered formulation, Neoral,[7] is available as a solution and as soft gelatin capsules. Compositions of Neoral are designed to form microemulsions in contact with water.[68][69]
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.[9] Ikervis is a similar formulation with a concentration of 0.1%.[70]Inhaled ciclosporin formulations are in clinical development, and include a solution in
propylene glycol and
liposome dispersions.[71][72]
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.[73] 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.[74]
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.[75] 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.[76] This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.[77]
Cardiac disease
Ciclosporin has been used experimentally to treat cardiac hypertrophy[33][78] (an increase in cell volume).
Inappropriate opening of the
mitochondrial permeability transition pore (MPTP) manifests in ischemia[33] (blood flow restriction to tissue) and reperfusion injury[33] (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction[34] (heart attack) and when mutations in mitochondrial DNA polymerase occur.[33] The heart attempts to compensate for disease state by increasing the intracellular Ca2+ to increase the contractility cycling rates.[36] Constitutively high levels of mitochondrial Ca2+ 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.[36][34]
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.[33][36][79] 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 Ca2+ .[36] Decreasing intramitochondrial Ca2+ allows for reversal of cardiac hypertrophy caused in the original cardiac response.[36] Decreasing the release of cytochrome C caused decreased cell death during injury and disease.[33] Cyclosporin A also inhibits the phosphatase calcineurin pathway (14).[33][34][80] Inhibition of this pathway has been shown to decrease myocardial hypertrophy.[34][78][80]
Veterinary use
The medication is approved in the United States for the treatment of
atopic dermatitis in dogs.[81] 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,
anal furunculosis (anal inflammatory disease), and
myasthenia gravis (a neuromuscular disease).[81][82]
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