Ciclosporin

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Ciclosporin

Ciclosporin , cyclosporine (USAN

United States Adopted Name

United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists Association ....
) or cyclosporin (former BAN

British Approved Name

A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia....
), is an immunosuppressant

Immunosuppressant

An immunosuppressant is a substance that performs immunosuppression of the immune system. They may either be exogenous, as immunosuppressive drugs, or endogenous, as e....
drug

Medication

A pharmaceutical drug, also referred to as medicine or medicament, can be loosely defined as any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease....
widely used in post-allogeneic organ transplant

Organ transplant

Organ transplant is the moving of an organ from one body to another , for the purpose of replacing the recipient's damaged or failing organ with a working one from the donor site....
to reduce the activity of the patient's immune system

Immune system

An immune system is a collection of biological processes within an organism that protects against disease by identifying and killing pathogens and tumour cells....
and so the risk of organ rejection

Transplant rejection

Transplant rejection occurs when a Organ transplant organ or tissue is not accepted by the body of the transplant recipient. This is explained by the concept that the immune system of the recipient attacks the transplanted organ or tissue....
. It has been studied in transplants of skin, heart, kidney, liver, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian

Norway

Norway , officially the Kingdom of Norway, is a constitutional monarchy in Northern Europe that occupies the western portion of the Scandinavian Peninsula....
soil sample, Ciclosporin A, the main form of the drug, is a cyclic

Cyclic compound

In organic chemistry, a cyclic compound is a chemical compound in which a series of carbon atoms are connected to form a loop or ring. Benzene is a well known example....
nonribosomal peptide

Nonribosomal peptide

Nonribosomal peptides are a class of peptide secondary metabolites, usually produced by microorganisms like bacterium and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacteria commensurism these organisms....
of 11 amino acid

Amino acid

In chemistry, an amino acid is a molecule containing both amine and carboxyl functional groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H2NCHRCOOH, where R is an organic substituent....
s (an undecapeptide) produced by the fungus

Fungus

A fungus is a Eukaryote organism that is a member of the Kingdom Fungi . The fungi are a monophyletic group, also called the Eumycota , that is phylogeny distinct from the morphologically similar slime molds and water molds ....
Tolypocladium inflatum Gams, and contains D-amino acids

Chirality (chemistry)

The term chiral is used to describe an object that is non-Superposition on its mirror image.Human hands are perhaps the most universally recognized example of chirality: The left hand is a non-superposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands...
, which are rarely encountered in nature.Some sources list the fungus under an alternative species name Hypocladium inflatum gams such as Pritchard and Sneader in 2005:

However, the name, Tolypocladium inflatum Gams, also appears in several other articles including in a 2001 online publication by Harriet Upton entitled "" (retrieved June 19, 2005).

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Encyclopedia

Ciclosporin , cyclosporine (USAN

United States Adopted Name

British Approved Name

A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia....
), is an immunosuppressant

Immunosuppressant

An immunosuppressant is a substance that performs immunosuppression of the immune system. They may either be exogenous, as immunosuppressive drugs, or endogenous, as e....
drug

Medication

Organ transplant

Immune system

Transplant rejection

Norway

Cyclic compound

In organic chemistry, a cyclic compound is a chemical compound in which a series of carbon atoms are connected to form a loop or ring. Benzene is a well known example....
nonribosomal peptide

Nonribosomal peptide

Amino acid

Fungus

Chirality (chemistry)

Mycology

Mycology is the branch of biology concerned with the study of fungus, including their genetics and biochemistry properties, their taxonomy, and ethnomycology as a source for tinder, medicine , food , entheogens, as well as their dangers, such as poisoning or infection....
researcher Kathie Hodge that it is in fact a species of Cordyceps
Cordyceps

Cordyceps is a genus of ascomycete fungi that includes about 400 described species. All Cordyceps species are Parasitoid#Types_of_parasitoids, mainly on insects and other arthropods ; a few are parasitic on other fungi....
.

Indications

The immuno-suppressive effect of cyclosporin was discovered on January 31, 1972, by employees of Sandoz

Sandoz

Sandoz is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets off-patent medicines as well as pharmaceutical and biotechnological active ingredients....
(now Novartis

Novartis

Basel

Basel is Switzerland's third most populous city . With 731,000 inhabitants in the tri-national metropolitan area , Basel is Switzerland's third-largest urban area....
, Switzerland

Switzerland

Switzerland is a landlocked Swiss Alps country of roughly 7.7 million people in Western Europe with an area of 41,285 km?. Switzerland is a federal republic consisting of 26 states called Cantons of Switzerland....
, in a screening test on immune-suppression designed and implemented by Dr.Hartmann F. Stähelin

Hartmann F. Stähelin

Hartmann F. St?helin, M.D. is a Swiss pharmacologist with an outstanding record in basic and applied cancer and immunology research. He discovered two important drugs: etoposide and cyclosporine A....
, M.D. The success of Cyclosporin A in preventing organ rejection was shown in liver

Liver

The liver is a vital organ present in vertebrates and some other animals; it has a wide range of functions, a few of which are detoxification, protein synthesis, and production of biochemicals necessary for digestion....
transplants performed by Dr. Thomas Starzl

Thomas Starzl

Thomas E. Starzl is an Health care in the United States, Medical research, and is an expert on organ transplants. He performed the first human liver transplants, and has often been referred to as "the father of modern transplantation."...
at the University of Pittsburgh Hospital. The first patient, on March 9, 1980, was a 28-year-old woman. Cyclosporin was subsequently approved for use in 1983.

Apart from in transplant medicine, cyclosporin is also used in psoriasis

Psoriasis

Psoriasis is a chronic, non-contagious autoimmune disease which affects the skin and joints. It commonly causes red scaly patches to appear on the skin....
, severe atopic dermatitis

Atopic dermatitis

Atopic dermatitis is an inflammation, chronically relapsing, non-contagious and pruritis skin disease. It has been given names like "prurigo Besnier," "neurodermitis," "endogenous eczema," "flexural eczema," "infantile eczema," and "prurigo diathsique"....
and infrequently in rheumatoid arthritis

Rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic disease inflammation that may affect many tissues and organs, but principally attacks the joints producing a inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints....
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. Inhaled cyclosporine

Inhaled cyclosporine

Cyclosporine A is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant. It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis, rheumatoid arthritis, dry eye and other auto-immune related conditions....
has been investigated to treat asthma is being studied as a preventative therapy for chronic rejection of the lungs. Cyclosporin has also been used to help treat patients with ulcerative colitis

Ulcerative colitis

Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon , that includes characteristic Peptic ulcer, or open sores, in the colon....
who do not respond to treatment with steroids. This drug is also used as a treatment of posterior or intermediate uveitis

Uveitis

Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye, with inflammation specifically of the uvea termed iridocyclitis....
with non-infective etiology

Etiology

Etiology is the study of Causality. The word is derived from the Ancient Greek , aitiologia, "giving a reason for" .The word is most commonly used in medical and philosophical theories, where it is used to refer to the study of why things occur, or even the reasons behind the way that things act, and is used in philosophy, physics, psy...
.

Cyclosporin A has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury

Traumatic brain injury

Traumatic brain injury occurs when an outside force physical trauma the brain. TBI can be classified based on severity, mechanism , or other features ....
, and has been shown in animal experiments to reduce brain damage

Brain damage

Brain damage, or acquired brain injury, is the destruction or degeneration of brain cells....
associated with injury. Cyclosporin A blocks the formation of the mitochondrial permeability transition pore

Mitochondrial permeability transition pore

Mitochondrial permeability transition, or MPT, is an increase in the permeability of the mitochondrial membranes to molecules of less than 1500 Atomic mass units in molecular weight....
, which has been found to cause much of the damage associated with head injury

Head injury

Head injury refers to Physical trauma to the head . This may or may not include injury to the human brain . However, the terms traumatic brain injury and head injury are often used interchangeably in the medical literature....
and neurodegenerative disease

Neurodegenerative disease

Neurodegenerative disease is a condition in which cells of the brain and spinal cord are lost. The brain and spinal cord are composed of neurons that do different functions such as controlling movements, processing sensory information, and making decisions....
s.

Mode of action

Cyclosporin is thought to bind to the cytosolic protein cyclophilin

Cyclophilin

Cyclophilins, abbreviated Cyp , are proteins that bind to cyclosporine , an immunosuppressant which is usually used to suppress Transplant rejection after internal organ transplants....
(immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin

Cyclophilin

Calcineurin

Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and formerly known as protein phosphatase 2B . Calcineurin activates NFATC1 , a transcription factor by dephosphorylation it....
, which under normal circumstances is responsible for activating the transcription of interleukin 2

Interleukin 2

Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self....
. It also inhibits lymphokine

Lymphokine

Lymphokines are a subset of cytokines that are produced by a type of immune cell known as a lymphocyte. They are typically produced by T cells to direct the immune system response by signaling between its cells....
production and interleukin

Interleukin

Interleukins are a group of cytokines that were first seen to be expressed by white blood cells as a means of communication . The name is something of a relic though ; it has since been found that interleukins are produced by a wide variety of body cells....
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. Cyclosporin A prevents the Mitochondrial permeability transition pore from opening, thus inhibiting cytochrome c

Cytochrome c

Cytochrome c, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins....
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

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed Cell death involves a series of biochemical events leading to a characteristic cell Morphology and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including Bleb , changes...
.

Biosynthesis

Cyclosporine A is synthesized by a nonribosomal peptide

Nonribosomal peptide

Adenylation

Adenylation is a posttranslational modification that can occur to e.g. tyrosine residues. Adenylation involves a phosphodiester bond between the hydroxyl group of the tyrosine residue and the phosphate group of the adenosine monophosphate nucleotide....
domain, thiolation domain, condensation

Condensation

Condensation is the change of the physical state of aggregation of matter from gaseous phase into liquid phase. When the transition happens from the gaseous phase into the solid phase directly, bypassing the liquid phase the change is called Deposition , which is the opposite of sublimation....
domain, and an N-methyltransferase] domain. The [[adenylation]] domain is responsible for substrate recognition and activation. While the thiolation domain covalently binds the [[adenylated]] [[amino acids]] to [[phosphopantetheine]] and the [[condensation]] domain elongates the [[peptide chain]]. Cyclosporine synthetase substrates includes: L-[[Valine]], L-[[Leucine]], L-[[Alanine]], L-[[Glycine]], [[2-aminobutyric acid]], [[4-methylthreonine]], and [[D-Alanine]]. With the [[adenylation]] domain, cyclosporine 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 cyclosporine A from the [[enzyme]]. Amino acids such as [[D-Ala]] and [[butenyl-methyl-L-threonine]] indicates that cyclosporine 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.

Adverse Effects and Interactions

Treatment may be associated with a number of potentially serious adverse drug reaction

Adverse drug reaction

An adverse drug reaction or adverse drug event is an expression that describes the unwanted, negative consequences associated with the use of given medications....
s (ADRs) and adverse drug interactions. Ciclosporin interacts with a wide variety of other drugs and other substances including grapefruit juice

Grapefruit

The grapefruit is a subtropics citrus tree grown for its bitter fruit which was originally named the "forbidden fruit" of Barbados.These evergreen trees are usually found at around 5-6 m tall, although they can reach 13-15 m ....
. There have been studies into the use of grapefruit juice to increase the blood level of cyclosporin.

ADRs can include gum hyperplasia

Hyperplasia

Hyperplasia is a general term referring to the proliferation of cells within an organ or tissue beyond that which is ordinarily seen . Hyperplasia may result in the gross enlargement of an organ, the formation of a benign tumor, or may be visible only histology....
, convulsion

Seizure

An epileptic seizure is a transient symptom of abnormal, excessive or synchronous neuronal activity in the brain. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms ....
s, peptic ulcer

Peptic ulcer

A peptic ulcer, also known as ulcus pepticum, PUD or peptic ulcer disease, is an ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful....
s, pancreatitis

Pancreatitis

Pancreatitis is the inflammation of the pancreas. See also acute pancreatitis and chronic pancreatitis for more details....
, fever

Fever

Fever is a frequent medical sign that describes an increase in internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, usually by about 1?2 ?C ....
, vomiting, diarrhea

Diarrhea

In medicine, diarrhea, also spelled diarrhoea , is characterized by frequent loose or liquid bowel movements. The spelling of "diarrhea" is an appropriation of the Greek "diarrhoia" meaning "a flowing through." ....
, confusion

ConFusion

ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association....
, breathing difficulties, numbness and tingling

Tingling

Tingling or Tili was a tribe union west of China before 300 BC. After c.300BC they were called tieloe or kauko. The avars was the tieloe tribe union most west members....
, pruritus, high blood pressure

Blood pressure

Blood pressure is the pressure exerted by circulating blood on the walls of blood vessels, and constitutes one of the principal vital signs. The pressure of the circulating blood decreases as it moves away from the heart through artery and capillary, and toward the heart through veins....
, potassium

Potassium

Potassium is a chemical element. It has the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash, hence the name....
retention and possibly hyperkalemia

Hyperkalemia

Hyperkalemia Hyperkalaemia is an elevated blood level of the electrolyte potassium. The prefix hyper- means high . The middle kal refers to kalium, which is neo-Latin for potassium....
, kidney

Kidney

The kidneys are Organ that have numerous biological roles. Their primary role is to maintain the homeostasis balance of bodily fluids by filtering and secreting Metabolomics#Metabolitess and minerals from the blood and excreting them, along with water , as urine....
and liver

Liver

Nephrotoxicity

Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidney. There are various forms of toxicity....
& hepatotoxicity

Hepatotoxicity

Hepatotoxicity implies chemical-driven liver damage. The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents....
), and obviously an increased vulnerability to opportunistic fungal and viral infection

Infection

An infection is the detrimental colonization of a host organism by a foreign species. In an infection, the infecting organism seeks to utilize the host resources to multiply ....
s.

An alternate form of the drug, ciclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin A. Ciclosporin G (Mol. mass

Molecular mass

The molecular mass of a chemical compound, frequently referred by the older term molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u ....
1217) differs from ciclosporin A in the amino acid

Amino acid

Formulations

The drug exhibits very poor solubility in water and consequently suspension and emulsion forms of the drug have been developed for oral administration and for injection. Cyclosporine was originally brought to market by Sandoz

Sandoz

Novartis

Novartis International AG is a multinational corporation pharmaceutical company based in Basel, Switzerland that manufactures drugs such as clozapine , diclofenac , carbamazepine , valsartan , imatinib mesylate , ciclosporin , letrozole , methylphenidate , terbinafine , and others....
, 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 . A newer microemulsion

Microemulsion

Microemulsions are clear, stable, isotropic liquid mixtures of oil, water and surfactant, frequently in combination with a cosurfactant. The aqueous Phase may contain salt and/or other ingredients, and the "oil" may actually be a complex mixture of different hydrocarbons and olefins....
orally-administered formulation Neoral 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

Sandoz

Abbott Laboratories

Abbott Laboratories is a diversified Pharmacology health care company. It has 68,000 employees and operates in 130 countries. The corporate headquarters are in Abbott Park, Illinois, located near North Chicago, Illinois....
). Since 2002 a topical emulsion

Emulsion

An emulsion is a mixture of two immiscible liquids. One liquid is dispersion in the other . Many emulsions are oil/water emulsions, with dietary fats being one common type of oil encountered in everyday life....
of ciclosporin for treating keratoconjunctivitis sicca

Keratoconjunctivitis sicca

Keratoconjunctivitis sicca , also called keratitis sicca, sicca syndrome, xerophthalmia, dry eye syndrome , or simply dry eyes, is an eye disease caused by decreased Tears production or increased tear film evaporation commonly found in humans and some animals....
has been marketed under the trade name Restasis. Inhaled cyclosporine

Inhaled cyclosporine

Cyclosporine A is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant. It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis, rheumatoid arthritis, dry eye and other auto-immune related conditions....
formulations are in clinical development and include a solution in propylene glycol

Propylene glycol

Propylene glycol, known also by the systematic name propane-1,2-diol, is an organic compound , usually a faintly sweet, and colorless clear viscous liquid that is hygroscopic and miscible with water, acetone, and chloroform....
and liposome

Liposome

A liposome is a tiny bubble , made out of the same material as a biological membrane. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases....
dispersions.

The drug is also available in a dog preparation manufactured by Novartis called Atopica. Atopica is indicated for the treatment of atopic dermatitis

Atopy

Atopy or atopic syndrome is an allergic hypersensitivity affecting parts of the body not in direct contact with the allergen....
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.

Ciclosporin

Indications

Mode of action

Biosynthesis

Adverse Effects and Interactions

Formulations

See also

External links