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Ciclosporin
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| Systematic (IUPAC) name | |
| (E)-14,17,26,32-tetrabutyl-5-ethyl-8-(1-hydroxy-2-methylhex-4-enyl) -1,3,9,12,15,18,20,23,27-nonamethyl-11,29-dipropyl-1,3,6,9,12,15,18,21,24,27,30- undecaazacyclodotriacontan-2,4,7,10,13,16,19,22,25,28,31-undecaone | |
| Identifiers | |
| CAS number | |
| ATC code | L04 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C62H111N11O12 |
| Mol. mass | 1202. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 61 |
| Pharmacokinetic data | |
| Bioavailability | variable |
| Metabolism | hepatic |
| Half life | variable (about 24 hours) |
| Excretion | biliary |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | oral, IV, ophthalmic |
Ciclosporin (pronounced /ˌsaɪkləˈspɔrən/), cyclosporine (USAN) or cyclosporin (former BAN), is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems The liver is a vital organ in the human body and is present in Vertebrates and some other animals The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction The Standard for the Uniform Scheduling of Drugs and Poisons, abbreviated SUSDP, is a document used in the regulation of drugs and poisons in Australia. For a topic outline on this subject see List of basic Australia topics. A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United States of America —commonly referred to as the In Pharmacology and Toxicology, a route Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. United States Adopted Names are unique nonproprietary names assigned to Pharmaceuticals marketed in the United States. A British Approved Name ( BAN) is the official non-proprietary or generic name given to a Pharmaceutical Substance, as defined in the British Pharmacopoeia An immunosuppressant is a substance that performs Immunosuppression of the Immune system. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease An allograft or allogeneic transplant or homograft is a transplant in which transplanted cells, tissues, or organs are sourced from An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Transplant rejection occurs when a transplanted organ or tissue fails to be accepted by the body of the transplant recipient It has been studied in transplants of skin, heart, kidney, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian soil sample, Ciclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids (an undecapeptide) produced by the fungus Tolypocladium inflatum Gams, and contains D-amino acids, which are rarely encountered in nature. Norway ( Norwegian: Norge ( Bokmål) or Noreg ( Nynorsk) officially the Kingdom of Norway, is a Constitutional In Organic chemistry, a cyclic compound is a compound in which a series of carbon atoms are connected to form a loop or ring Nonribosomal peptide s (NRP are a class of Peptide Secondary metabolites, usually produced by Microorganisms like bacteria and Fungi In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this A fungus (ˈfʌŋgəs is a eukaryotic Organism that is a member of the kingdom Fungi (ˈfʌndʒaɪ Tolypocladium inflatum is a Fungus isolated from Norwegian Soil that in certain conditions produces Ciclosporin (Cyclosporine The term chiral (pronounced /ˈkaɪɹ(əl̩/ is used to describe an object that is non- superimposable on its mirror image [1]
Contents |
Indications
The immuno-suppressive effect of cyclosporin was discovered on January 31, 1972, by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune-suppression designed and implemented by Dr. Events 1504 - France cedes Naples to Aragon. 1606 - Gunpowder Plot: Guy Fawkes Year 1972 ( MCMLXXII) was a Leap year starting on Saturday (link will display full calendar of the Gregorian calendar. Sandoz is the generics subsidiary of Novartis, a multinational Pharmaceutical company. Novartis International AG is a multinational Pharmaceutical company based in Basel Switzerland that manufactures drugs such as Clozapine "Basilia" redirects here For the Fly Genus, see Basilia (fly. Switzerland (English pronunciation; Schweiz Swiss German: Schwyz or Schwiiz Suisse Svizzera Svizra officially the Swiss Confederation Hartmann F. Stähelin, M. Hartmann F Stähelin, MD (born October 20, 1925) is a Swiss Pharmacologist with an outstanding record in basic and applied Cancer D. The success of Ciclosporin A in preventing organ rejection was shown in liver transplants performed by Dr. Thomas Starzl at the University of Pittsburgh hospital. Thomas E Starzl (born March 11, 1926) is an American physician, researcher, and is an expert on Organ transplants He performed the The first patient, on March 9, 1980, was a 28-year-old woman. [2] Ciclosporin was subsequently approved for use in 1983.
Apart from in transplant medicine, cyclosporin is also used in psoriasis, severe atopic dermatitis and infrequently in rheumatoid arthritis and related diseases, although it is only used in severe cases. Psoriasis (səˈraɪəsɪs ( suh-RI-uh-sus) is a non-contagious disorder which affects the Skin and Joints It commonly causes red scaly Atopic dermatitis, also known as atopic eczema, is a disease characterized by Chronic inflammation of the skin which is atopic, hereditary and non-contagious Rheumatoid arthritis ( RA) is a chronic systemic autoimmune disorder that causes the Immune system to attack the Joints, where It has been investigated for use in many other autoimmune disorders. Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues Cyclosporin has also been used to help treat patients with ulcerative colitis who do not respond to treatment with steroids. Ulcerative colitis ( Colitis ulcerosa, UC) is a form of Inflammatory bowel disease (IBD [3] This drug is also used as a treatment of posterior or intermediate uveitis with non-infective etiology. Uveitis specifically refers to Inflammation of the middle layer of the Eye, termed the " Uvea " but in common usage may refer to any inflammatory
Cyclosporin A 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. The term neuroprotection refers to mechanisms within the Nervous system which protect Neurons from Apoptosis or Degeneration, for example following Traumatic brain injury (TBI also called intracranial injury, occurs when Physical trauma injures the Brain. Animal testing or animal research is the use of non-human Animals in scientific experimentation. Brain damage, or Acquired brain injury, is the destruction or degeneration of Brain cells. [4] Cyclosporin A 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. Mitochondrial permeability transition, or MPT, is an increase in the permeability of the Mitochondrial membranes to Molecules of less than 1500 Daltons Traumatic brain injury. THIS PAGE IS FOR INFORMATION ON HEAD INJURY (NOT SPECIFICALLY THE BRAIN--> Head injury is Neurodegenerative Disease ( Greek νέυρο- néuro-, "nerval" and Latin dēgenerāre, "to decline" or "to
Mode of action
Ciclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. Cyclophilins, abbreviated Cyp (not to be confused with CYP, which is the approved abbreviation for Cytochrome P450) are Proteins that bind to T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. This complex of ciclosporin and cyclophylin inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. Protein phosphatase 3 (formerly 2B catalytic subunit alpha isoform, also known as PPP3CA, is a human Gene. Interleukin-2 ( IL-2) is an Interleukin, a type of Cytokine Immune system signaling molecule that is instrumental in the body's natural response It also inhibits lymphokine production and interleukin release and therefore leads to a reduced function of effector T-cells. Lymphokines are a subset of Cytokines that are produced by a type of Immune cell known as a Lymphocyte. Interleukins are a group of Cytokines (secreted Signaling molecules) that were first seen to be expressed by White blood cells ( Leukocytes hence It does not affect cytostatic activity.
It also has an effect on mitochondria. In Cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed Organelle found in most eukaryotic cells. Ciclosporin A prevents the mitochondrial PT pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. Cytochrome c, or cyt c (horse heart PDB 1HRC is a small Heme Protein found loosely associated with the inner membrane However, this is not the primary mode of action for clinical use but rather an important effect for research on apoptosis.
Adverse effects and interactions
Treatment may be associated with a number of potentially serious adverse drug reactions (ADRs) and adverse drug interactions. An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted negative consequences Ciclosporin interacts with a wide variety of other drugs and other substances including grapefruit juice. The grapefruit is a subtropical Citrus Tree grown for its Fruit which was originally named the "forbidden fruit " of Barbados There have been studies into the use of grapefruit juice to increase the blood level of cyclosporin.
ADRs can include gum hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, breathing difficulties, numbness and tingling, pruritus, high blood pressure, potassium retention and possibly hyperkalemia, kidney and liver dysfunction (nephrotoxicity & hepatotoxicity), and obviously an increased vulnerability to opportunistic fungal and viral infections. Hyperplasia (or "hypergenesis" is a general term referring to the proliferation of cells within an organ or tissue beyond that which is ordinarily seen in e An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting A peptic ulcer, also known as PUD or peptic ulcer disease, is an Ulcer (defined as mucosal erosions equal to or greater than 0 Pancreatitis is the Inflammation of the Pancreas. See also Acute pancreatitis and Chronic pancreatitis for more details Fever (also known as pyrexia, from the Greek pyretos meaning fire or a febrile response, from the Latin word Febris Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the In Medicine, diarrhea, also spelled diarrhoea (see spelling differences) is frequent loose or liquid Bowel movements Acute diarrhea Confusion, of a Pathological degree usually refers to loss of orientation (ability to place oneself correctly in the world by time location and personal identity and Paresthesia (pron /ˌpɛɹɪsˈθiʒə/ paraesthesia in British English, pron Tingling or Tili was a tribe union west of China before 300 BC. Itch ( Latin: pruritus) is an unpleasant Sensation that evokes the desire or Reflex to scratch Blood pressure is also the title of a short story by Damon Runyan in Guys and Dolls and Other Stories Hyperkalemia ( AE) or Hyperkalaemia ( BE) is an elevated blood level of the Electrolyte Potassium. Nephrotoxicity (from Greek nephros "kidney" is a Poisonous effect of some substances both Toxic chemicals and Medication, on the Kidney Drug metabolism in liver The human body identifies almost all drugs as foreign substances (i An infection is the detrimental Colonization of a host Organism by a foreign Species.
An alternate form of the drug, ciclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin A. [5] Ciclosporin G (Mol. mass 1217) differs from ciclosporin A in the amino acid 2 position, where an L-nor-valine replaces the α-aminobutyric acid. The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one [6]
Formulations
The drug is marketed by Novartis under the brand names Sandimmune, the original formulation, and Neoral for the newer microemulsion formulation. Novartis International AG is a multinational Pharmaceutical company based in Basel Switzerland that manufactures drugs such as Clozapine Microemulsions are clear stable Isotropic liquid mixtures of oil water and Surfactant, frequently in combination with a cosurfactant Generic ciclosporin preparations have been marketed under various trade names including Cicloral (Sandoz/Hexal) and Gengraf (Abbott). Sandoz is the generics subsidiary of Novartis, a multinational Pharmaceutical company. Abbott Laboratories ( is a diversified pharmaceuticals Health care company Since 2002 a topical emulsion of ciclosporin for treating keratoconjunctivitis sicca has been marketed under the trade name Restasis. See also 2002 (disambiguation Year 2002 ( MMII) was a Common year starting on Tuesday of the Gregorian calendar. An emulsion ( IPA: /ɪˈmʌlʃən/ is a mixture of two Immiscible (unblendable liquids Keratoconjunctivitis sicca (KCS, also called Keratitis sicca, sicca syndrome, Annual sales of ciclosporin are around $1 billion.
The drug is also available in a dog preparation manufactured by Novartis called Atopica. Atopica is indicated for the treatment of atopic dermatitis in dogs. Atopy (/ˈætəpi/ Greek ἀτοπία - placelessness or atopic syndrome is an allergic Hypersensitivity affecting parts of the body 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.
References
- ^ Borel JF (2002). "History of the discovery of cyclosporin and of its early pharmacological development". Wien. Klin. Wochenschr. 114 (12): 433-7. PMID 12422576.
Some sources list the fungus under an alternative species name Hypocladium inflatum gams such as Pritchard and Sneader in 2005:
* Pritchard DI (2005). Tolypocladium inflatum is a Fungus isolated from Norwegian Soil that in certain conditions produces Ciclosporin (Cyclosporine "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discov. Today 10 (10): 688-91. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15896681.
* "Ciclosporin", Drug Discovery - A History. John Wiley & Sons, pp 298-299 (refs. page 315).
However, the name, Tolypocladium inflatum Gams, 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 June 19, 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. Mycology (from the Greek μύκης meaning "fungus" is the branch of Biology concerned with the study of fungi, including their genetic Cordyceps is a Genus of Ascomycete Fungi that includes about 400 described species - ^ Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP (1981). "Liver transplantation with use of cyclosporin a and prednisone". N. Engl. J. Med. 305 (5): 266-9. PMID 7017414.
- ^ Lichtiger S, Present DH, Kornbluth A, et al (1994). "Cyclosporine in severe ulcerative colitis refractory to steroid therapy". N. Engl. J. Med. 330 (26): 1841-5. PMID 8196726.
- ^ Sullivan PG, Thompson M, Scheff SW (2000). "Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury". Exp. Neurol. 161 (2): 631-7. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10686082.
- ^ Henry ML, Elkhammas EA, Davies EA, Ferguson RM (1995). "A clinical trial of cyclosporine G in cadaveric renal transplantation". Pediatr. Nephrol. 9 Suppl: S49-51. PMID 7492487.
- ^ Calne RY, White DJ, Thiru S, Rolles K, Drakopoulos S, Jamieson NV (1985). "Cyclosporin G: immunosuppressive effect in dogs with renal allografts". Lancet 1 (8441): 1342. PMID 2860538.
See also
- Cremophor EL ( Additive in Sandimmune )
- Castor oil ( Additive in Sandimmune )
External links
- Neoral U.S. Prescribing Information
- Sandimmune U.S. Prescribing Information
- Atopica brand (for atopic dermatitis in dogs)
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