Ciclosporin, also spelled cyclosporine and cyclosporin, is a

calcineurin inhibitor Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified into ...

, used as an

immunosuppressant medication Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified into ...

. It is a natural product. It is taken orally or

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

for

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

, Crohn's disease, nephrotic syndrome, and in

organ transplant Organ transplantation is a medical procedure in which an organ (anatomy), organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organ ...

s to prevent rejection. It is also used as

eye drops Eye drops or eyedrops are liquid drops applied directly to the surface of the eye usually in small amounts such as a single drop or a few drops. Eye drops usually contain saline to match the salinity of the eye. Drops containing only saline ...

for

keratoconjunctivitis sicca Dry eye syndrome (DES), also known as keratoconjunctivitis sicca (KCS), is the condition of having dry eyes. Other associated symptoms include irritation, redness, discharge, and easily fatigued eyes. Blurred vision may also occur. Symptoms range ...

(dry eyes). Common side effects include high blood pressure, headache,

kidney problems Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

, increased hair growth, and vomiting. Other severe side effects include an increased risk of infection, liver problems, and an increased risk of

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enla ...

. Blood levels of the medication should be checked to decrease the risk of side effects. Use during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

may result in

preterm birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...

; however, ciclosporin does not appear to cause

birth defects A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

. Ciclosporin is believed to work by decreasing the function of lymphocytes. It does this by forming a complex with

cyclophilin Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin (cyclosporin A), an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of l ...

to block the phosphatase activity of

calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be block ...

, which in turn decreases the production of

inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...

s by

T-lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

. Ciclosporin was isolated in 1971 from the

fungus A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from t ...

Tolypocladium inflatum ''Tolypocladium inflatum'' is an ascomycete fungus originally isolated from a Norwegian soil sample that, under certain conditions, produces the immunosuppressant drug ciclosporin. In its sexual stage ( teleomorph) it is a parasite on scarab b ...

'' and came into medical use in 1983. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In 2020, it was the 212th most commonly prescribed medication in the United States, with more than 2million prescriptions. It is available as a generic medication.

Medical uses

Ciclosporin is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

to treat and prevent graft-versus-host disease in

bone marrow transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...

and to prevent rejection of

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, and liver transplants. It is also approved in the US for treating of

and

, persistent

nummular keratitis Nummular keratitis is a feature of viral keratoconjunctivitis. It is a common feature of adenoviral keratoconjunctivitis (an ocular adenovirus infection), as well as approximately 1/3rd of cases of Herpes Zoster Ophthalmicus infections. It repr ...

following adenoviral keratoconjunctivitis, and as

for treating

dry eyes Dry eye syndrome (DES), also known as keratoconjunctivitis sicca (KCS), is the condition of having dry eyes. Other associated symptoms include irritation, redness, discharge, and easily fatigued eyes. Blurred vision may also occur. Symptoms rang ...

caused by Sjögren's syndrome and

meibomian gland Meibomian glands (also called tarsal glands, palpebral glands, and tarsoconjunctival glands) are sebaceous glands along the rims of the eyelid inside the tarsal plate. They produce meibum, an oily substance that prevents evaporation of the eye ...

dysfunction. In addition to these indications, ciclosporin is also used in severe atopic dermatitis, Kimura disease,

pyoderma gangrenosum Pyoderma gangrenosum is a rare, inflammatory skin disease where painful pustules or nodules become ulcers that progressively grow. Pyoderma gangrenosum is not infectious. Treatments may include corticosteroids, ciclosporin, infliximab, or cana ...

, chronic hives, acute

systemic mastocytosis Mastocytosis, a type of mast cell disease, is a rare disorder affecting both children and adults caused by the accumulation of functionally defective mast cells (also called ''mastocytes'') and CD34+ mast cell precursors. People affected by masto ...

, and posterior or intermediate uveitis with noninfective cause. It is also used, albeit infrequently, in severe

and related diseases. Ciclosporin has also been used in people with acute severe

ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...

and hives that do not respond to treatment with steroids.

Side effects

Side effects of ciclosporin can include gum enlargement, increased hair growth,

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...

peptic ulcer Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines ...

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"

, increased cholesterol, trouble breathing,

numbness Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli. In everyday speech this is generally referred to as num ...

and

tingling Paresthesia is an abnormal sensation of the skin (tingling, pricking, chilling, burning, numbness) with no apparent physical cause. Paresthesia may be transient or chronic, and may have any of dozens of possible underlying causes. Paresthesias ar ...

(particularly of the lips),

itchiness Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...

, high blood pressure,

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosph ...

retention (possibly leading to

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...

and

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

dysfunction, burning sensations at finger tips, and an increased vulnerability to opportunistic fungal and viral

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...

s. 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. Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and, in some cases,

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...

. This is due to the decrease in

glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pre ...

, which leads to uric acid retention. Use of

azathioprine Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...

as an alternative has shown to reduce the incidence of gouty arthritis. Ciclosporin is listed as an IARC Group 1 carcinogen (i.e. there is sufficient evidence of carcinogenicity in humans), specifically leading to

squamous cell skin cancer Squamous-cell skin cancer, also known as cutaneous squamous-cell carcinoma (cSCC), is one of the main types of skin cancer along with basal cell cancer and melanoma. It usually presents as a hard lump with a scaly top but can also form an ulcer. O ...

and

non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tirednes ...

Pharmacology

Mechanism of action

Ciclosporin's main effect is to lower the activity of

T-cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

; it does so by inhibiting

in the calcineurin–phosphatase pathway and preventing the mitochondrial permeability transition pore from opening. Ciclosporin binds to the cytosolic protein

(immunophilin) of lymphocytes, especially of T cells. This cyclosporin—cyclophilin complex inhibits

, 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 (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the developme ...

(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. Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function; it does not affect

cytostatic Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Cytostasis is an important prerequisite for structured multic ...

activity. Ciclosporin also binds to the cyclophilin D protein that constitutes part of the

mitochondrial permeability transition pore The mitochondrial permeability transition pore (mPTP or MPTP; also referred to as PTP, mTP or MTP) is a protein that is formed in the inner membrane of the mitochondria under certain pathological conditions such as traumatic brain injury and stro ...

(MPTP), 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, leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.

Pharmacokinetics

Ciclosporin is a

cyclic Cycle, cycles, or cyclic may refer to: Anthropology and social sciences * Cyclic history, a theory of history * Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr. * Social cycle, various cycles in s ...

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

of 11

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

s; it contains a single D-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.
Some sources list the fungus under an alternative species name

Hypocladium inflatum gams ''Tolypocladium inflatum'' is an ascomycete fungus originally isolated from a Norwegian soil sample that, under certain conditions, produces the immunosuppressant drug ciclosporin. In its sexual stage ( teleomorph) it is a parasite on scarab b ...

such as Pritchard and Sneader in 2005:
*
*
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 19 June 2005). Mark Plotkin states in his book ''Medicine Quest'', Penguin Books 2001, pages 46-47, that in 1996

mycology Mycology is the branch of biology concerned with the study of fungi, including their genetic and biochemical properties, their taxonomy and their use to humans, including as a source for tinder, traditional medicine, food, and entheogen ...

researcher Kathie Hodg
found
that it is in fact a species of '' Cordyceps''. Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L, have less than 10% of ciclosporin's immunosuppressant activity and are associated with higher kidney toxicity. Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.

Biosynthesis

Cyclosporin is synthesized by a

nonribosomal peptide Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...

synthetase, cyclosporin synthetase. The enzyme contains an adenylation domain, a

thiolation In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

domain, a condensation domain, and an

N-methyltransferase N-methyltransferase may refer to: * (RS)-1-benzyl-1,2,3,4-tetrahydroisoquinoline N-methyltransferase * 3-hydroxy-16-methoxy-2,3-dihydrotabersonine N-methyltransferase * Amine N-methyltransferase * Anthranilate N-methyltransferase * (cytochrome c)-a ...

domain. The adenylation domain is responsible for substrate recognition and activation, whereas the thiolation domain covalently binds the adenylated amino acids to

phosphopantetheine Phosphopantetheine, also known as 4'-phosphopantetheine, is a prosthetic group of several acyl carrier proteins including the acyl carrier proteins (ACP) of fatty acid synthases, ACPs of polyketide synthases, the peptidyl carrier proteins (PCP), ...

, and the condensation domain elongates the peptide chain. Cyclosporin synthetase substrates include L-

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...

, L-

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- ...

, L-

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side ...

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...

, 2-aminobutyric acid, 4-methyl threonine, and D-alanine, which is the starting amino acid in the biosynthetic process. With the adenylation domain, cyclosporin synthetase generates the acyl-adenylated amino acids, then covalently binds the

through a

thioester In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...

linkage. Some of the amino acid substrates become N-methylated by

S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

. The cyclization step releases cyclosporin from the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

. 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 In enzymology, an alanine racemase () is an enzyme that catalyzes the chemical reaction :L-alanine \rightleftharpoons D-alanine Hence, this enzyme has one substrate, L-alanine, and one product, D-alanine. This enzyme belongs to the family o ...

pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent a ...

-dependent. The formation of butenyl-methyl-L-threonine is performed by a Bmt

polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...

that uses acetate/malonate as its starting material.

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 () is the cyclosporin synthetase, SimB () is the alanine racemase, and SimG (similar to ) is the polyketide synthase. These genes are associated with an active retrotransposon. Although these sequences are poorly-annotated on GenBank and other databases, 90% similar sequences can be found for the Cyclosporin-producing ''

Beauveria ''Beauveria'' is a genus of asexually-reproducing fungi allied with the ascomycete family Cordycipitaceae. Its several species are typically insect pathogens. The sexual states (teleomorphs) of ''Beauveria'' species, where known, are species o ...

felina'' (or ''Amphichorda ~''). SimB has two paralogs in the same organism with different but overlapping functions thanks to their low speficity.

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 Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loca ...

(now

Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...

) in

Basel , french: link=no, Bâlois(e), it, Basilese , neighboring_municipalities= Allschwil (BL), Hégenheim (FR-68), Binningen (BL), Birsfelden (BL), Bottmingen (BL), Huningue (FR-68), Münchenstein (BL), Muttenz (BL), Reinach (BL), Riehen (BS ...

, 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 January 31, 1972 in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz. The chemical structure of cyclosporin was determined in 1976, also at Sandoz. The success of the drug candidate ciclosporin in preventing

organ rejection Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient a ...

was shown in kidney transplants by R.Y. Calne and colleagues at the University of Cambridge, and in

transplants performed by Thomas Starzl at the

University of Pittsburgh The University of Pittsburgh (Pitt) is a public state-related research university in Pittsburgh, Pennsylvania. The university is composed of 17 undergraduate and graduate schools and colleges at its urban Pittsburgh campus, home to the univers ...

Hospital. The first patient, on 9 March 1980, was a 28-year-old woman. In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.

Society and culture

Name

The natural product was named cyclosporin by the German-speaking scientists who first isolated it and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs, the ''y'' was replaced with ''i'' so that the INN for the medication is spelled ciclosporin. Ciclosporin is the INN and the British Approved Name (BAN), while cyclosporine is the

United States Adopted Name A United States Adopted Name (USAN) is a unique nonproprietary name assigned to a medication marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United Sta ...

(USAN) and cyclosporin is a former BAN.

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

), 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. A newer

microemulsion Microemulsions are clear, thermodynamically stable isotropic liquid mixtures of oil, water and surfactant, frequently in combination with a cosurfactant. The aqueous phase may contain salt(s) and/or other ingredients, and the "oil" may actually be ...

, orally-administered formulation, Neoral, is available as a solution and as soft gelatin capsules. Compositions of Neoral are designed to form microemulsions in contact with water. Generic ciclosporin preparations have been marketed under various trade names, including Cicloral (by Sandoz/Hexal), Gengraf (by Abbott) and Deximune (by Dexcel Pharma). Since 2002, a topical

emulsion An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or unblendable) owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Altho ...

of ciclosporin for treating inflammation caused by

(dry eye syndrome) has been marketed under the trade name Restasis. Ikervis is a similar formulation with a concentration of 0.1%. Inhaled ciclosporin formulations are in clinical development, and include a solution in

propylene glycol Propylene glycol (IUPAC name: propane-1,2-diol) is a viscous, colorless liquid, which is nearly odorless but possesses a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. Containing two alcohol groups, it is classed as a diol. It i ...

and

liposome A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...

dispersions.

Research

Neuroprotection

Ciclosporin is currently 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 trade name of ''CicloMulsion''). This formulation uses a lipid emulsion base instead of cremophor and ethanol. 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. Ciclosporin has been investigated as a possible

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...

agent in conditions such as

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic br ...

, and has been shown in animal experiments to reduce brain damage associated with injury. Ciclosporin blocks the formation of the

, which has been found to cause much of the damage associated with

head injury A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of inju ...

and

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

s. 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. This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.

Cardiac disease

Ciclosporin has been used experimentally to treat cardiac hypertrophy (an increase in cell volume). Inappropriate opening of the

(MPTP) manifests in ischemia (blood flow restriction to tissue) and reperfusion injury (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction (heart attack) and when mutations in mitochondrial DNA polymerase occur. The heart attempts to compensate for disease state by increasing the intracellular to increase the contractility cycling rates. Constitutively high levels of mitochondrial 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. Cyclosporin A has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. Cyclosporin A binds to

cyclophilin D Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an enzyme which in humans is encoded by the ''PPID'' gene on chromosome 4. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-t ...

to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death. 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 . Decreasing intramitochondrial allows for reversal of cardiac hypertrophy caused in the original cardiac response. Decreasing the release of cytochrome C caused decreased cell death during injury and disease. Cyclosporin A also inhibits the phosphatase calcineurin pathway (14). Inhibition of this pathway has been shown to decrease myocardial hypertrophy.

Veterinary use

The medication is approved in the United States for the treatment of atopic dermatitis in dogs. 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 Merck & Co., Inc. is an American Multinational corporation, multinational pharmaceutical company headquartered in Rahway, New Jersey, and is named for Merck Group, founded in Germany in 1668, of whom it was once the American arm. The company doe ...

, which is part of Merck. It is also used to treat

sebaceous adenitis Sebaceous adenitis in an uncommon skin disease found in some breeds of dog, and more rarely in cats, rabbits and horses. characterised by an inflammatory response against the dog's sebaceous glands (glands found in the hair follicles in the skin ...

(immune response against the

sebaceous glands A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest num ...

pemphigus foliaceus Pemphigus foliaceus is an autoimmune blistering disease ( bullous disorder) of the skin. Pemphigus foliaceus causes a characteristic inflammatory attack at the subcorneal layer of epidermis, which results in skin lesions that are scaly or cruste ...

(autoimmune blistering skin disease), Inflammatory bowel disease, anal furunculosis (anal inflammatory disease), and myasthenia gravis (a neuromuscular disease).

References

External links

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ChemSub Online: Cyclosporin A
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