CYCLOSPORINE Chemical Properties

form 

Solid

color 

White to light yellow

BCS Class

2,3,4

CAS DataBase Reference

79217-60-0(CAS DataBase Reference)

IARC

1 (Vol. 50, 100A) 2012

CYCLOSPORINE Usage And Synthesis

Application in Particular Diseases

In Rheumatic Arthritis:
Cyclosporine reduces production of cytokines involved in T-cell activation and has direct effects on B cells, macrophages, bone, and cartilage cells. Its onset appears to be 1 to 3 months. Important toxicities at doses of 1 to 10 mg/kg/day include hypertension, hyperglycemia, nephrotoxicity, tremor, GI intolerance, hirsutism, and gingival hyperplasia. Cyclosporine should be reserved for patients refractory to or intolerant of other DMARDs. It should be avoided in patients with current or past malignancy, uncontrolled hypertension, renal dysfunction, immunodeficiency, low white blood cell or platelet counts, or elevated liver function tests.

Description

Cyclosporine is a cyclic polypeptide with potent, partially selective immunosupressive activity. Isolated from the species Cylindrocarpon lucidium and Trichoderma polysporum, cyclosporine is useful in the prevention and treatment of graft/host disease and the prevention of rejection following organ transplantation. It appears to act by preferentially suppressing T-lymphocytes. Cyclosporine lacks myelotoxicity, although impaired renal and liver function have been observed. Initial administration is via the intravenous route, followed by oral maintenance therapy.

Chemical Properties

White crystalline solid or powder.

Originator

Sandoz (Switzerland)

Indications

Cyclosporine (Sandimmune) is a potent inhibitor of antibody- and cell-mediated immune responses and is the immunosuppressant of choice for the prevention of transplant rejection. It also has application in the treatment of autoimmune diseases.
Cyclosporine is a highly stable 11-amino acid cyclic polypeptide. The molecule is very lipophilic and essentially is not soluble in water. It can be administered intravenously, orally, or by injection.

brand name

SANDIMMUN

Mechanism of action

Cyclosporine can bind to the cytosolic protein cytophilin C. This drug–protein complex inhibits calcineurin phosphatase activity, which leads to a decreased synthesis and release of several cytokines, including interleukins IL-2, IL-3, IL-4, interferon-, and tumor necrosis factor.
Cyclosporine exhibits a high degree of specificity in its actions on T cells without significantly impairing Bcell activity. It can inhibit the T cell–dependent limb of antibody production by lymphocytes by preventing the differentiation of B cells into antibody-secreting plasma cells. Because T cells appear to require IL-2 stimulation for their continuous growth, cyclosporine impairs the proliferative response of T cells to antigens. However, once T cells have been stimulated by antigens to synthesize IL-2, cyclosporine cannot suppress the proliferation of T cells induced by this cytokine.

Pharmacology

After oral administration, cyclosporine is absorbed slowly and incompletely, with great variation among individuals. Peak plasma concentrations are reached in 3 to 4 hours, and the plasma half-life is 10 to 27 hours. The drug is extensively metabolized by hepatic mixedfunction oxidase enzymes and is excreted principally via the bile into the feces. Metabolism results in inactivation of the immunosuppressive activity.Agents that enhance or inhibit the mixed-function oxidase enzymes will alter the therapeutic response to cyclosporine.

Clinical Use

Cyclosporine has been approved for use in allogeneic kidney, liver, and heart transplant patients and is under study for use in pancreas, bone marrow, single lung, and heart–lung transplant procedures. It is recommended that corticosteroids, such as prednisone, be used concomitantly, although at half or less of their usual dose. Such combined therapy leads to fewer side effects, a decreased incidence of infectious complications, efficacy of lower doses of cyclosporine, and a better history of patient survival.
Cyclosporine appears to have promise in the treatment of autoimmune diseases. It has a beneficial effect on the course of rheumatoid arthritis, uveitis, insulindependent diabetes, systemic lupus erythematosus, and psoriatic arthropathies in some patients. Toxicity is more of a problem in these conditions than during use in transplantation, since higher doses of cyclosporine are often required to suppress autoimmune disorders.

Side effects

Compared with previously available therapy, the adverse effects associated with cyclosporine are much less severe but still worthy of concern. Nephrotoxicity, which can occur in up to 75% of patients, ranges from severe tubular necrosis to chronic interstitial nephropathy.This effect is generally reversible with dosage reduction. Vasoconstriction appears to be an important aspect of cyclosporine- induced nephrotoxicity. Hypertension occurs in 25% of the patients and more frequently in patients with some degree of renal dysfunction; the concomitant use of antihypertensive drugs may prove useful. Hyperglycemia, hyperlipidemia, transient liver dysfunction, and unwanted hair growth are also observed.

Potential Exposure

Cyclosporin A is a fungal metabolite; an amide immunosuppressant drug used in various surgeries.

Veterinary Drugs and Treatments

Cyclosporine may be useful as an immunosuppressant for immunemediated diseases (see dosage section) and as part of a protocol to reduce the rejection of allografts in transplant medicine in dogs and cats.

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).

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.

CYCLOSPORINE(79217-60-0)Related Product Information

• Cyclosporin A
• Geclosporin
• Azathioprine
• Tacrolimus
• 1,9-Pyrazoloanthrone
• Myricetin
• AG 490
• Reserpine
• Veliparib
• SB 203580
• Cyclosporin A
• Cyclosporin