General Description
White prismatic needles (from acetone) or white powder.
Reactivity Profile
CYCLOSPORIN A(59865-13-3) is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).
Air & Water Reactions
Slightly water soluble .
Health Hazard
SYMPTOMS: Symptoms of exposure to this compound include hepatotoxicity, nephrotoxicity, hyperkalemia, hyperuricemia, convulsions, renal dysfunction, tremor, hirsutism, hypertension, gum hyperplasia, cramps, acne, headache, diarrhea, nausea, vomiting, abdominal discomfort, paresthesia, flushing, leukopenia, lymphoma, sinusitis and gynecomastia. In 2% or less of persons exposed, it has caused allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia and tinnitus. Rare reactions include anxiety, chest pain, constipation, depression, hair breaking hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper gastrointestinal bleeding, visual disturbance, weakness and weight loss. It has caused kidney and liver damage. An increased susceptibility to infection may occur. Other symptoms include gastrointestinal disturbance, rashes and angioedema.
Potential Exposure
Cyclosporin A is a fungal metabolite;
an amide immunosuppressant drug used in various
surgeries.
Fire Hazard
Flash point data for this chemical are not available; however, CYCLOSPORIN A is probably combustible.
First aid
Skin Contact
: Flood all areas of body that
have contacted the substance with water. Don’t wait to
remove contaminated clothing; do it under the water
stream. Use soap to help assure removal. Isolate contami-
nated clothing when removed to prevent contact by others.
Eye Contact: Remove any contact lenses at once. Flush
eyes well with copious quantities of water or normal saline
for at least 20 30 minutes. Seek medical attention.
Inhalation: Leave contaminated area immediately; breathe
fresh air. Proper respiratory protection must be supplied to
any rescuers. If coughing, difficult breathing, or any other
symptoms develop, seek medical attention at once, even if
symptoms develop many hours after exposure. Ingestion: If
convulsions are not present, give a glass or two of water or
milk to dilute the substance. Assure that the person’s air-
way is unobstructed and contact a hospital or poison center
immediately for advice on whether or not to induce
vomiting.
Shipping
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials.
Incompatibilities
Amides/imides react with azo and diazo
compounds to generate toxic gases. Flammable gases are
formed by the reaction of organic amides/imides with
strong reducing agents such as hydrideds and active metals.
Amides are very weak bases (weaker than water). Imides
are less basic yet and in fact react with strong bases to
form salts. That is, they can react as acids. Mixing amides
with dehydrating agents such as such as phosphorus pent-
oxide or thionyl chloride generates the corresponding
nitrile. The combustion of these compounds generates
mixed oxides of nitrogen (NOx).
Description
Cyclosporine A is a powerful immunosuppressive drug intended for preventing rejection
of kidney, heart, and lung transplants.
A new era in the development of immunopharmacology began with the discovery of
cyclosporines.
Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum,
Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground.
Cyclosporine A is the first drug to affect a specific line of protecting cells of the body.
Unlike usual cytotoxics, it suppresses T-cells and acts on all cell lines simultaneously.
Cyclosporine A significantly eases the ‘reception’ of transplants, and increases the possibility of treating autoimmune system diseases.
Waste Disposal
t is inappropriate and possibly
dangerous to the environment to dispose of expired or waste
drugs and pharmaceuticals by flushing them down the toilet
or discarding them to the trash. Household quantities of
expired or waste pharmaceuticals may be mixed with wet
cat litter or coffee grounds, double-bagged in plastic, discard
in trash. Larger quantities shall carefully take into consider-
ation applicable DEA, EPA, and FDA regulations. If possi-
ble return the pharmaceutical to the manufacturer for proper
disposal being careful to properly label and securely package
the material. Alternatively, the waste pharmaceutical shall be
labeled, securely packaged, and transported by a state
licensed medical waste contractor to dispose by burial in a
licensed hazardous or toxic waste landfill or incinerator.
Originator
Sandimmune,Sandoz,US,1983
Uses
An immunosuppressant that has revolutionized organ transplantation through its use in the prevention of graft rejection.
A group of nonpolar cyclic oligopeptides with immunosupppressant activity.
Uses
Cyclosporin A is a hydrophobic cyclic peptide isolated from several fungal species including Cylindrocarpon, Fusarium, Trichoderma and Tolypocladium. Cyclosporin A inhibits T-cell activation and has been marketed since 1983 as an immunosuppressant in post-allogeneic organ transplant. Cyclosporin A acts by binding to the protein, cyclophilin (immunophilin), in T-lymphocytes causing inhibition of calcineurin (protein phosphatase 2B). Cyclosporin A reduces transcription of interleukin 2, and inhibits lymphokine production, interleukin release and NO synthesis induced by interleukin 1α, lipopolysaccharides and TNFα.
Uses
prothrombogenic agent
Definition
ChEBI: A cyclic nonribosomal peptide of eleven amino acids; an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system, and therefore the risk of organ rejection. Also causes reversible inhibiti
n of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle.
Manufacturing Process
10 liters of a nutrient solution (of which each liter contains 30 g of sucrose,
10 g of corn steep, 3 g of NaNO3, 1 g of K2HPO4, 0.5 g of MgSO4·7H2O, 0.5 g
of KCl and 0.01 g of FeSO4·7H2O) are inoculated with 100 cc of a conidia and mycelium suspension of the strain NRRL 5760, and incubation is effected in
700 cc penicillin flasks at 27°C for 11 days.
The mycelium, which has been separated from the culture liquid, is extracted
in a Turrax apparatus by crushing and stirring with 3.5 liters of 90%
methanol, and the crushed mycelium, which is separated from the solvent by
filtering with suction, is again treated twice in the same manner with 90%
methanol. The combined filtrates are concentrated by evaporation in a
vacuum at a bath temperature of 40°C to such an extent that the vapor
mainly consists of water alone. The resulting mixture is extracted six times
with the same volume of ethylene chloride by shaking, whereupon the
combined ethylene chloride solutions are purified by extraction with water and
are concentrated by evaporation in a vacuum at a bath temperature of 40°C.
The resulting residue is chromatographed on 250 g of silica gel (silica gel 60
Merck, grain size 0.063-0.200 mm), using chloroform containing 2% of
methanol as eluant, and is collected in 200 cc fractions. The fractions which
are antibiotically active against Aspergillus niger in the plate diffusion test are
combined, evaporated to dryness as described above, and after dissolving in
methanol are chromatographed on 110 g of Sephadex LH20 with the same
solvent, whereupon those 20 cc fractions showing an antibiotic effect against
Aspergillus niger in the test indicated above, are combined. A test in the thin
layer chromatogram, e.g., with silica gel on Polygram foils and
hexane/acetone (1:1) as eluant, indicates that the residue of the methanol
solution evaporated as described above mainly consists of the two new
antibiotics S 7481/F-1 and S 7481/F-2. These are separated and
simultaneously purified by a further chromatography of the mixture thereof,
using a 1,000-fold amount of silica gel on the above indicated quality and
chloroform contains 2% of methanol. A testing of the eluate fractions having a
volume in milliliters which is half as large as the weight of the silica gel in
grams, in the thin layer chromatogram, indicates that the antibiotic S 7481/F-
1 appears first in the eluate, followed by a mixture of the two antibiotics and
finally by homogeneous S748l/F-2.
Further amounts of the two antibiotics may be obtained from the mixture by
repeating chromatography under the same conditions.
Brand name
Gengraf (Abbott); Neoral (Novartis); Restasis (Allergan); Sandimmune (Novartis) [Names previously used: Cyclosporin A; Cyclosporin.].
Therapeutic Function
Immunosuppressive
Biochem/physiol Actions
Cyclosporin A is a non-polar cyclic oligopeptide produced by the fungus Tolypocladium inflatum. It is a potent immunosuppressive agent, affecting primarily T-lymphocytes. It has been shown to inhibit the functioning of several nuclear proteins involved in T-cell activation at the level of mRNA transcription. It forms a complex with its intracellular receptor cyclophilin, which can then bind to calcineurin, a Ca2+- and calmodulin-dependent protein phosphatase, inhibiting its enzymatic activity. CsA was found to suppress the replication of hepatitis C virus genome in cultured hepatocytes. At concentrations >10 nM, CsA protected isolated hepatocytes against the action of phalloidin. CsA can inhibit IL2 production resulting from T cell activation via Calcineurin inhibition.An extensive list of references has been reported, including a comprehensive review of analytical properties.
Pharmacology
Cyclosporine has no direct effect on keratinocytes and is not a mitotic inhibitor. Cyclosporine inhibits cytokine release, which results in a decreased recruitment of APCs into the epidermis and decreases immunoreactivity of lesions. Potential long-term side effects preclude cyclosporine’s use in all but very severe and recalcitrant psoriasis. Cyclosporine can be combined with lowdose methotrexate.
Clinical Use
Immunosuppressant:
Prophylaxis of solid organ transplant rejection
Nephrotic syndrome
Atopic dermatitis
Psoriasis
Rheumatoid arthritis
Ulcerative colitis
Synthesis
Cyclosporine A, [R-[R*
,R*
-(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-Lleucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-
octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine)
(31.2.2), is extracted from a cultural liquid of products of the vital activity of the mushroom Tolypocladium inflatum [14–17], and which is also proposed to obtain synthetically.
Carcinogenicity
Cyclosporin A is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Metabolism
Ciclosporin is widely distributed throughout the body.
Distribution in the blood is concentration-dependent,
with between 41-58% in erythrocytes and 10-20% in
leucocytes; the remainder is found in plasma, about 90%
protein-bound, mostly to lipoprotein.
Clearance from the blood is biphasic. Ciclosporin is
extensively metabolised in the liver and mainly excreted
in faeces via the bile. About 6% of a dose is reported to be
excreted in the urine, less than 0.1% unchanged.
storage
-20°C (desiccate)
References
1) Liu et al. (1993), FK506 and cyclosporin: molecular probes for studying intracellular signal transduction; Trends Pharmacol. Sci., 18 334
