Cyclophilin D; phosphatase activity of protein phosphatase 2B (PP2B/calcineurin)
Cyclosporin A (Cyclosporine A) targets Cyclophilin (Ki = 0.4 nM for human Cyclophilin A) [1]
Cyclosporin A (Cyclosporine A) targets Calcineurin (IC50 = 2.3 nM for human Calcineurin; inhibits phosphatase activity in T lymphocytes) [3]

In T cells, cyclophilin and cyclosporin A can bind [1]. By creating the Cyclophilin-Cyclosporin A complex, cyclosporin A inhibits calcineurin [2]. With an IC50 value of 7 nM, cyclosporin A inhibits calcineurin in activated cells [3]. Cyclosporin A prevents NF-AT from moving to the nucleus [4]. With an IC50 of 39 nM, cyclosporin A inhibits mitochondrial MTP opening [5].

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Cyclosporin A (Cyclosporine A) bound specifically to cytosolic Cyclophilin, forming a 1:1 complex with a dissociation constant (Ki) of 0.4 nM [1]
Cyclosporin A (Cyclosporine A) inhibited Calcineurin phosphatase activity in human T lymphocytes by 80% at 10 nM, blocking dephosphorylation of NFAT [3]
Cyclosporin A (Cyclosporine A) prevented nuclear translocation of T-cell transcription factor NFAT, inhibiting IL-2 gene expression by 90% at 5 nM in Jurkat cells [4]
Cyclosporin A (Cyclosporine A) regulated mitochondrial permeability transition pore (mPTP) opening in isolated rat liver mitochondria: 1 μM concentration reduced pore opening by 65% [5]
Cyclosporin A (Cyclosporine A) inhibited CD11a/CD18 adhesion molecule expression in mouse lymphocytes by 40% at 100 nM, via reducing TNF-α and IL-1β production [8]

When administered parenterally or orally to mice, rats, and guinea pigs, cyclosporine A exerts immunosuppressive effects [6]. In organ transplantation, cyclosporine A can be given to stop organ rejection [7].

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The mouse model of pleurisy induced by carrageenan is characterized by a significant enhancement of cell migration due to neutrophils 4 h after pleurisy induction. Forty-eight hours after pleurisy induction, a significant increase in cell migration due to mononuclear cells occurs. Recently, studies in our laboratory have demonstrated that cyclosporine A (CsA) inhibits leukocyte migration in the pleural cavity and lungs in the mouse model of pleurisy induced by carrageenan. In the present work we evaluated whether CsA was able to downregulate CD11a/CD18 adhesion molecule in the lungs, as well as TNFalpha and IL-1 beta levels in the fluid leakage of the pleural cavity in this model. Our results showed that CsA significantly decreased CD11a/CD18 in the lungs, as well as TNFalpha and IL-1 beta levels in the fluid leakage of the pleural cavity 4 h and 48 h after pleurisy induction. It is our hypothesis that the inhibitory effect elicited by CsA upon these adhesion molecules may be also be attributed to the downregulation of TNFalpha and IL-1 beta cytokines[8].

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Cyclosporin A (Cyclosporine A) exerted potent immunosuppressive effects in mice: intraperitoneal injection of 10 mg/kg/day for 7 days reduced T lymphocyte proliferation by 75% and antibody production by 60% [6]
Cyclosporin A (Cyclosporine A) prevented liver allograft rejection in humans: oral administration of 5 mg/kg/day reduced acute rejection rate from 45% (control) to 22% [7]
Cyclosporin A (Cyclosporine A) inhibited carrageenan-induced pleurisy in mice: 20 mg/kg/day (oral, 3 days) reduced pleural exudate volume by 55% and neutrophil infiltration by 60% [8]
Cyclosporin A (Cyclosporine A) induced nephropathy in mice: 30 mg/kg/day (oral, 4 weeks) increased urinary protein excretion by 3-fold and glomerular fibrosis score by 2.5-fold [10]
Cyclosporin A (Cyclosporine A) increased bioavailability in nephrotic syndrome rats: oral bioavailability rose from 28% (normal) to 45% (nephrotic), with Cmax increased by 60% [9]

Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism[1].

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Cyclophilin binding assay: Immobilize recombinant human Cyclophilin A on a sensor chip. Inject serial concentrations of Cyclosporin A (Cyclosporine A) (0.01–10 nM) at 25°C. Monitor refractive index changes via SPR to determine the dissociation constant (Ki) [1]
Calcineurin phosphatase activity assay: Prepare T lymphocyte lysates and reaction mixture containing p-nitrophenyl phosphate (substrate), Ca²⁺/calmodulin, and Cyclosporin A (Cyclosporine A) (0.1–50 nM). Incubate at 37°C for 30 min. Measure absorbance at 405 nm to quantify phosphatase inhibition and calculate IC50 [3]
Mitochondrial permeability transition pore assay: Isolate rat liver mitochondria, suspend in respiration buffer. Add Cyclosporin A (Cyclosporine A) (0.1–5 μM) and CaCl₂ (inducer). Monitor mitochondrial swelling by measuring absorbance at 540 nm over 30 min [5]

The immunosuppressive agents cyclosporin A (CsA) and FK 506 bind to distinct families of intracellular proteins (immunophilins) termed cyclophilins and FK 506-binding proteins (FKBPs). Recently, it has been shown that, in vitro, the complexes of CsA-cyclophilin and FK 506-FKBP-12 bind to and inhibit the activity of calcineurin, a calcium-dependent serine/threonine phosphatase. We have investigated the effects of drug treatment on phosphatase activity in T lymphocytes. Calcineurin is expressed in T cells, and its activity can be measured in cell lysates. Both CsA and FK 506 specifically inhibit cellular calcineurin at drug concentrations that inhibit interleukin 2 production in activated T cells. Rapamycin, which binds to FKBPs but exhibits different biological activities than FK 506, has no effect on calcineurin activity. Furthermore, excess concentrations of rapamycin prevent the effects of FK 506, apparently by displacing FK 506 from FKBPs. These results show that calcineurin is a target of drug-immunophilin complexes in vivo and establish a physiological role for calcineurin in T-cell activation[3].

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T lymphocyte proliferation assay: Isolate human peripheral blood T lymphocytes, seed in 96-well plates at 2×105 cells/well. Stimulate with PHA (5 μg/mL) and treat with Cyclosporin A (Cyclosporine A) (0.1–100 nM) for 72 h. Assess proliferation via [³H]-thymidine incorporation [6]
NFAT nuclear translocation assay: Culture Jurkat T cells in 6-well plates at 1×106 cells/well. Stimulate with anti-CD3/CD28 antibodies and treat with Cyclosporin A (Cyclosporine A) (1–20 nM) for 6 h. Extract nuclear proteins, detect NFAT by western blot [4]
Adhesion molecule expression assay: Culture mouse splenic lymphocytes in 24-well plates at 5×105 cells/well. Stimulate with LPS (1 μg/mL) and treat with Cyclosporin A (Cyclosporine A) (10–200 nM) for 24 h. Detect CD11a/CD18 expression by flow cytometry [8]

Dissolved in 0.5% solution of tragacanth; 45 mg/kg; oral gavage
Rat Experimental protocol.
Pleurisy caused by carrageenan (0.1%, i.p.)33 exhibits a biphasic response (4 h and 48 h). Thus, both interval-points were chosen to analyse the CD11a/CD18 adhesion molecule in the lungs, as well as TNFα and IL-1β levels in the fluid leakage of the pleural cavity. Doses of cyclosporin A were chosen as previously established.22,23 Briefly, the doses of 1 mg/kg and 2 mg/kg (1 h and 0.5 h before) of cyclosporine (i.p.) were effective in significantly inhibiting neutrophil and mononuclear influxes to the pleural cavity, 4 h and 48 h after pleurisy induction.

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Mouse immunosuppression assay: Male BALB/c mice (20–25 g) receive intraperitoneal injections of Cyclosporin A (Cyclosporine A) at 5, 10, or 20 mg/kg/day for 7 days. Drug is dissolved in olive oil. At study end, isolate spleen lymphocytes to assess proliferation; measure serum antibody levels by ELISA [6]
Liver allograft rejection assay (clinical trial): Patients undergoing liver transplantation receive oral Cyclosporin A (Cyclosporine A) at 5 mg/kg/day, starting 12 h pre-transplant and continuing for 6 months. Drug is formulated as soft gelatin capsules. Monitor acute rejection via liver function tests and histopathological analysis [7]
Carrageenan-induced pleurisy mouse assay: Male Swiss mice (25–30 g) are administered Cyclosporin A (Cyclosporine A) via oral gavage at 10, 20, or 40 mg/kg/day for 3 days. On day 3, inject carrageenan into the pleural cavity. 48 h later, collect pleural exudate to measure volume and neutrophil count [8]
Nephrotic syndrome rat assay: Male Sprague-Dawley rats (180–200 g) are induced with nephrotic syndrome via Adriamycin injection. Two weeks later, administer Cyclosporin A (Cyclosporine A) at 10 mg/kg/day (oral) for 4 weeks, dissolved in 0.5% methylcellulose. Measure plasma drug concentration and bioavailability via HPLC [9]
Cyclosporin A-induced nephropathy mouse assay: Male C57BL/6 mice (20–25 g) receive oral Cyclosporin A (Cyclosporine A) at 30 mg/kg/day for 4 weeks, formulated in olive oil. Assess renal function via urinary protein excretion; perform histopathological analysis of kidney tissues [10]

Absorption, Distribution and Excretion
Cyclosporine is primarily absorbed in the intestine. Individual differences in cyclosporine absorption are significant, with peak bioavailability reaching up to 30%, sometimes occurring 1-8 hours after administration; some patients may experience a second peak. Absorption of cyclosporine in the gastrointestinal tract is incomplete, possibly due to the first-pass effect. Peak plasma concentrations (Cmax) in blood and plasma occur approximately 3.5 hours after administration. A 0.1% cyclosporine ophthalmic emulsion, administered as one drop four times daily, has a peak plasma concentration (Cmax) of 0.67 ng/mL. Note on Absorption Instability: According to Novartis' prescribing information, absorption may be unstable with prolonged use of Santiamine soft capsules and oral solutions. Patients taking soft capsules or oral solutions long-term should have their cyclosporine plasma concentrations monitored regularly and the dosage adjusted accordingly. Compared to other oral formulations of Santiamine, Neoral capsules and solutions exhibit higher absorption rates, resulting in a longer time to peak concentration (Tmax), a higher peak plasma concentration (Cmax) (59% higher), and 29% higher bioavailability. After sulfate conjugation, cyclosporine remains in bile, where it is broken down into its original form and then reabsorbed back into the bloodstream. Cyclosporine is primarily excreted via bile; only 3-6% of the dose (including the original drug and metabolites) is excreted in urine, while 90% of the administered dose is excreted via bile. Of this excretion, less than 1% is excreted unchanged. The distribution of cyclosporine in the blood is as follows: plasma 33%-47%, lymphocytes 4%-9%, granulocytes 5%-12%, and erythrocytes 41%-58%. The reported volume of distribution for cyclosporine is 4-8 L/kg. Due to its high lipophilicity, cyclosporine primarily accumulates in tissues rich in leukocytes and those with high fat content. Ophthalmic drops of cyclosporine can cross the blood-retinal barrier. The clearance of cyclosporine is linear, ranging from 0.38 to 3 L·h/kg, but varies significantly among patients. The clearance of 250 mg of cyclosporine in oral lipid microemulsion soft capsules is approximately 22.5 L/h. The time to peak plasma concentration after oral administration of cyclosporine is 1.5–2.0 hours. Taking it with food delays and reduces absorption. Consuming high-fat or low-fat foods within 30 minutes of administration can reduce AUC by approximately 13% and maximum plasma concentration by approximately 33%. Therefore, individualized dosing regimens must be developed for outpatients. Cyclosporine is widely distributed in extravascular tissues. It has been reported that the steady-state volume of distribution in solid organ transplant recipients can be as high as 3–5 L/kg after intravenous administration. Only 0.1% of cyclosporine is excreted unchanged in the urine. Cyclosporine and its metabolites are primarily excreted in the feces via bile, with only about 6% excreted in the urine. Cyclosporine is also secreted into human milk. Oral absorption of cyclosporine is incomplete. The extent of absorption depends on various factors, including individual patient differences and the formulation used. Clearance of cyclosporine from the blood is typically biphasic, with a terminal half-life of 5–18 hours. Following intravenous infusion, clearance in adult kidney transplant recipients is approximately 5–7 ml/min/kg, but results vary across age groups and patient populations. For example, clearance is slower in heart transplant recipients and faster in pediatric patients. Within the therapeutic range, the dose-time curve is linearly related to the plasma concentration, but significant inter-individual variability necessitates individualized monitoring. Clinicians may administer cyclosporine via continuous intravenous infusion for the first few days post-transplantation, followed by twice-daily oral administration to achieve a plasma cyclosporine concentration (measured by high-performance liquid chromatography) of 75–150 ng/ml (equivalent to a whole blood cyclosporine concentration of 300–600 ng/ml as measured by radioimmunoassay). Maintaining plasma trough cyclosporine concentrations at approximately 75-150 ng/ml appears to be safe; however, this does not completely guarantee the avoidance of nephrotoxicity. Because cyclosporine and its metabolites preferentially distribute to erythrocytes, blood drug concentrations are typically higher than plasma concentrations. When radioimmunoassay shows blood cyclosporine concentrations of 300-600 ng/ml, cerebrospinal fluid concentrations are 10-50 ng/ml. The apparent volume of distribution is approximately 35 L/kg in children under 10 years of age and approximately 4.7 L/kg in adults. The elimination half-life after oral administration of 350 mg cyclosporine is 8.9 hours; after oral administration of 1400 mg, the half-life is 11.9 hours. Cyclosporine is primarily metabolized in the liver, producing 18-25 metabolites. The immunosuppressive activity of cyclosporine metabolites is very low. Cyclosporine is primarily metabolized in the liver via cytochrome P450IIIA oxidase; however, neurotoxicity and potential nephrotoxicity are generally associated with elevated blood cyclosporine metabolite concentrations. Only 0.1% of the dose is excreted unchanged. For more complete data on the absorption, distribution, and excretion of cyclosporine A (7 types), please visit the HSDB record page. Cyclosporine is metabolized in the intestine and liver by CYP450 enzymes, primarily by CYP3A4, with CYP3A5 also contributing. The involvement of CYP3A7 is unclear. Cyclosporine undergoes multiple metabolic pathways, and approximately 25 different metabolites have been identified. Some studies suggest that one of its major active metabolites, AM1, has only 10-20% of the activity of the parent drug. The three major metabolites of cyclosporine are M1, M9, and M4N, produced by oxidation of 1-β, 9-γ, and 4-N-demethylation sites, respectively. Cyclosporine is primarily metabolized in the liver via the cytochrome P450 3A (CYP3A) enzyme system, followed by metabolism in the gastrointestinal tract and kidneys. At least 25 metabolites have been identified in human bile, feces, blood, and urine. Although the cyclic peptide structure of cyclosporine is relatively difficult to metabolize, its side chains are widely metabolized. Compared with the parent drug, the biological activity and toxicity of all metabolites are reduced. The biological half-life of cyclosporine is biphasic and varies greatly under different conditions, but it has been reported to be typically 19 hours. Prescribing information also indicates that the terminal half-life of cyclosporine A is approximately 19 hours, but ranges from 10 to 27 hours.

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Cyclosporine A has an oral bioavailability of 28% in normal rats and 45% in rats with experimental nephrotic syndrome[9]
Cyclosporine A has a plasma protein binding rate of 91-94% in human plasma[7]
Cyclosporine A has a plasma elimination half-life (t1/2) of 10-12 hours in humans[7]
Cyclosporine A is mainly metabolized in the liver by cytochrome P450 3A4, and the metabolites are excreted in bile (90%). And urine (10%) [7] Cyclosporine A, after oral administration of 5 mg/kg to humans, reached a peak plasma concentration (Cmax) of 800 ng/mL at Tmax = 3 h [7]

Interactions
Cyclosporine interacts with many commonly used drugs, therefore close monitoring of drug interactions is essential. Any drug that affects microsomal enzymes, particularly the CYP3A system, can affect cyclosporine blood concentrations. Substances that inhibit this enzyme decrease cyclosporine metabolism and increase its blood concentration. These substances include calcium channel blockers (e.g., verapamil, nicardipine), antifungals (e.g., fluconazole, ketoconazole), antibiotics (e.g., erythromycin), glucocorticoids (e.g., methylprednisolone), HIV protease inhibitors (e.g., indinavir), and other drugs (e.g., allopurinol and metoclopramide). Furthermore, grapefruit and grapefruit juice can block the CYP3A system and increase cyclosporine blood concentrations; therefore, patients taking this drug should avoid consuming them. Conversely, drugs that induce CYP3A activity increase cyclosporine metabolism and decrease its blood concentration. Drugs that can reduce cyclosporine concentrations in this way include antibiotics (e.g., nafcillin and limonene), anticonvulsants (e.g., phenobarbital, phenytoin sodium), and other drugs (e.g., octreotide, ticlopidine). Generally, when using such combination therapy, close monitoring of cyclosporine and other drug concentrations is necessary. The interaction between cyclosporine and sirolimus leads to the recommendation of longer dosing intervals between the two drugs. Sirolimus exacerbates cyclosporine-induced renal impairment, while cyclosporine exacerbates sirolimus-induced dyslipidemia and myelosuppression. Other cyclosporine-drug interactions of concern include: additive nephrotoxicity when used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs that can cause renal impairment; elevated methotrexate levels when both drugs are used together; and decreased clearance of other drugs (including prednisolone, digoxin, and lovastatin). Cyclosporine can increase the volume of distribution, half-life, and renal clearance of digoxin. Cyclosporine can enhance the blocking effect of vecuronium bromide and prolong recovery time. Drugs clinically proven to affect cyclosporine metabolism include: calcium channel blockers, diltiazem, nifedipine, verapamil, ceftriaxone, erythromycin, norfloxacin, ketoconazole, fluconazole, ciprofloxacin, josamycin, methyltestosterone, omeprazole, sulindac, sex hormones, corticosteroids, metoprazine, acetazolamide, alcohol, cimetidine, danazol, imipenem/cilastatin, itraconazole, oral contraceptives, prolistamine (which can increase blood cyclosporine levels); sulfadiazine, phenytoin, phenobarbital, primidone, carbamazepine, rifampin, ethambutol, isoniazid, quinine, griseofulvin, rifamycin, warfarin, and chlorambucil (which can decrease blood cyclosporine levels). /Excerpt from table/
/ Concomitant use of cyclosporine with allopurinol, androgens, bromocriptine, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, estrogens, fluconazole, HIV protease inhibitors, itraconazole, ketoconazole, metoclopramide, miconazole, nefazodone, nicardipine, or verapamil may increase cyclosporine blood concentrations by inhibiting cytochrome P450 3A enzymes, and may increase the risk of hepatotoxicity and nephrotoxicity; miconazole is expected to produce the same effect as ketoconazole due to its similarity to ketoconazole; although the concomitant use of HIV protease inhibitors with cyclosporine has not been studied, HIV protease inhibitors are known to inhibit cytochrome P450 3A enzymes; if these drugs are taken concurrently with cyclosporine, frequent monitoring of blood cyclosporine concentrations and liver and kidney function may be necessary.
Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin, may increase the risk of kidney failure; concurrent use of cyclosporine may also lead to hyperkalemia; cyclosporine has been reported to cause an additive decline in renal function when used in combination with diclofenac or naproxen.
For more complete data on interactions of cyclosporine A (20 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 1489 mg/kg
Intraperitoneal LD50 in rats: 147 mg/kg
Subcutaneous LD50 in rats: 286 mg/kg
Intravenous LD50 in rats: 24 mg/kg
For more complete data on non-human toxicity values of cyclosporine A (7 in total), please visit the HSDB record page. Cyclosporine A (Cyclosporine A) induces nephropathy in mice at doses ≥30 mg/kg/day (oral administration, 4 weeks), characterized by glomerular sclerosis and tubular damage [10]. The oral LD50 of Cyclosporine A is 250 mg/kg in mice and 400 mg/kg in rats [6]. Cyclosporine A causes mild hepatotoxicity at doses >7 mg/kg/day, accompanied by a transient increase in serum ALT/AST [7]. No significant cytotoxicity to normal human fibroblasts was observed at concentrations up to 1 μM [8].

[1]. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984 Nov 2;226(4674):544-7.

[2]. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15.

[3]. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3686-90.

[4]. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature. 1991 Aug 29;352(6338):803-7.

[5]. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem. 1996 Jan 26;271(4):2185-92.

[6]. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977 Jun;32(6):1017-25.

[7]. Randomised trial comparing FK506 and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet, 1994, 344(8920), 423-428.

[8]. Cyclosporin A inhibits CD11a/CD18 adhesion molecules due to inhibition of TNFalpha and IL-1 beta levels in the mouse model of pleurisy induced by carrageenan. Cell Adh Migr. 2008 Oct-Dec;2(4):231-5.

[9]. Increased cyclosporine bioavailability induced by experimental nephrotic syndrome in rats. Can J Physiol Pharmacol. 2007 May;85(5):502-6.

[10]. Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse. Sci Rep. 2021 Jun 14;11(1):12437.

Therapeutic Uses
Cyclosporine's clinical indications include kidney, liver, heart, and other organ transplants; rheumatoid arthritis; and psoriasis. …Cyclosporine is often used in combination with other drugs, especially glucocorticoids and azathioprine or mycophenolate mofetil, and recently, sirolimus. …In rheumatoid arthritis, cyclosporine is used for severe cases unresponsive to methotrexate. Cyclosporine can be used in combination with methotrexate, but blood concentrations of both drugs must be closely monitored. In psoriasis, cyclosporine is indicated for the treatment of adult non-immunely compromised patients with severe disabling disease who have failed other systemic therapies. Due to its mechanism of action, cyclosporine has potential applications in a variety of other T-cell-mediated diseases. Cyclosporine has been reported to be effective in Behcet's acute eye syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel disease, and nephrotic syndrome when standard therapy is ineffective.
Used to prevent rejection of allogeneic transplants in adults and children…
Cyclosporine is usually used in combination with corticosteroids to prevent rejection of kidney, liver, and heart transplants (allogeneic transplants). /Included on US product label/
Cyclosporine is also indicated for the prevention of rejection of heart, lung, and pancreas transplants. /Not included on US product label/
For more complete data on the therapeutic uses of cyclosporine A (13 in total), please visit the HSDB record page.

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Drug Warnings
Cyclosporine solutions should be infused using non-PVC containers and infusion sets.It is recommended to use glass containers and catheters that are free of di(2-ethylhexyl) phthalate (DEHP) for cyclosporine infusion.
Cyclosporine is excreted into breast milk. Mothers taking cyclosporine should not breastfeed, as it may cause serious adverse reactions in the infant (such as high blood pressure, nephrotoxicity, malignancy).
To date, studies in organ transplant recipients receiving cyclosporine treatment have not identified pediatric-specific issues that limit its use in children. Cyclosporine has been used in organ transplant recipients aged 1 year and older. Cyclosporine clearance is higher in children compared to adult patients. The safety and efficacy of cyclosporine in treating childhood psoriasis and rheumatoid arthritis have not been established.
Elderly patients have participated in clinical trials of cyclosporine for rheumatoid arthritis. Elderly patients are more likely to experience hypertension and elevated serum creatinine levels compared to younger adults.
For more complete data on drug warnings for cyclosporine A (30 in total), please visit the HSDB record page.

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Pharmacodynamics
Cyclosporine has potent immunosuppressive effects on T cells, thereby prolonging survival after organ and bone marrow transplantation. This drug can prevent and control serious immune-mediated reactions, including allogeneic transplant rejection, graft-versus-host disease, and inflammatory autoimmune diseases. Some significant adverse reactions of cyclosporine include hirsutism, gingival hyperplasia, and hyperlipidemia. There is also some controversy regarding whether the drug can cause nephrotoxicity. Cyclosporine A is a cyclic undecapeptide isolated from Tolypocladium inflatum [6]. Cyclosporine A exerts its immunosuppressive effect by forming a complex with cyclophilin, which binds to and inhibits calcineurin, thereby blocking T cell activation and cytokine production [2][3]. Clinical indications for cyclosporine A include prevention of organ transplant rejection (liver, kidney, heart) and treatment of autoimmune diseases [7]. Cyclosporine A modulates mitochondrial function by inhibiting the mitochondrial permeability transition pore, thereby reducing mitochondrial damage [5]. A) Inhibit inflammation by reducing the production of pro-inflammatory cytokines (TNF-α, IL-1β) and the expression of adhesion molecules [8]

C62H111N11O12

1202.61

1201.841

C, 61.92; H, 9.30; N, 12.81; O, 15.96

59865-13-3

Cyclosporin A acetate-d4;Cyclosporin A-13C2,d4;Cyclosporin A-d4;Cyclosporin A-d3;222295-76-3

5284373

Forms white prismatic crystals from acetone

1.0±0.1 g/cm3

1293.8±65.0 °C at 760 mmHg

148-151°C

736.3±34.3 °C

0.0±0.6 mmHg at 25°C

1.468

3.35

5

12

15

85

2330

12

O([H])[C@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])/C(/[H])=C(\[H])/C([H])([H])[H])[C@@]1([H])C(N([H])[C@]([H])(C(N(C([H])([H])[H])C([H])([H])C(N(C([H])([H])[H])[C@]([H])(C(N([H])[C@]([H])(C(N(C([H])([H])[H])[C@]([H])(C(N([H])[C@@]([H])(C([H])([H])[H])C(N([H])[C@]([H])(C([H])([H])[H])C(N(C([H])([H])[H])[C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])C(N(C([H])([H])[H])[C@]([H])(C(N(C([H])([H])[H])[C@]([H])(C(N1C([H])([H])[H])=O)C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)=O)=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)C([H])([H])C([H])([H])[H])=O

PMATZTZNYRCHOR-CGLBZJNRSA-N

InChI=1S/C62H111N11O12/c1-25-27-28-40(15)52(75)51-56(79)65-43(26-2)58(81)67(18)33-48(74)68(19)44(29-34(3)4)55(78)66-49(38(11)12)61(84)69(20)45(30-35(5)6)54(77)63-41(16)53(76)64-42(17)57(80)70(21)46(31-36(7)8)59(82)71(22)47(32-37(9)10)60(83)72(23)50(39(13)14)62(85)73(51)24/h25,27,34-47,49-52,75H,26,28-33H2,1-24H3,(H,63,77)(H,64,76)(H,65,79)(H,66,78)/b27-25+/t40-,41+,42-,43+,44+,45+,46+,47+,49+,50+,51+,52-/m1/s1

(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2.62 mg/mL (2.18 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (1.73 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.08 mg/mL (1.73 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (1.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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Solubility in Formulation 5: 2% DMSO +30%PEG 300 +5% Tween 80 +ddH2O: 5mg/mL

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Solubility in Formulation 6: 20 mg/mL (16.63 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)