Cyclosporine is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after solid organ transplantation. Cyclosporine therapy can be associated with mild elevations in serum bilirubin and transient serum enzyme elevations, and to rare instances of clinically apparent cholestatic liver injury.
Cyclosporine is a natural cyclic polypeptide immunosuppressant isolated from the fungus Beauveria nivea. The exact mechanism of action of cyclosporine is not known but may involve binding to the cellular protein cyclophilin, resulting in inhibition of the enzyme calcineurin. This agent appears to specifically and reversibly inhibit immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited with T-helper cells as the primary target. Cyclosporine also inhibits lymphokine production and release
It is used by mouth and injection into a vein for rheumatoid arthritis, psoriasis, Crohn’s disease, nephrotic syndrome, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).
Mechanism of action of Cyclosporine
Cyclosporine suppresses some humoral immunity but is more effective against T cell-dependent immune mechanisms such as those underlying transplant rejection & some forms of autoimmunity. It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines, including /(interleukin-2)/ IL-2, as well as expression of antiapoptotic proteins. Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin, inhibiting Ca2+ stimulated dephosphorylation of the cytosolic component of NFAT. When the cytoplasmic component of NFAT is dephosphorylated, it translocates to the nucleus, where it complexes with nuclear components required for complete T-cell activation, including transactivation of IL-2 & other lymphokine genes. Calcineurin enzymatic activity is inhibited following physical interaction with the cyclosporine/cyclophilin complex. This results in the blockade of NFAT dephosphorylation; thus, the cytoplasmic component of NFAT does not enter the nucleus, gene transcription is not activated, & the T lymphocyte fails to respond to specific antigenic stimulation Cyclosporine also increases expression of transforming growth fact /beta/ (TGF-B), a potent inhibitor of IL-2-stimulated T-cell proliferation & generation of cytotoxic T lymphocytes
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Cyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Used in immunosuppression for prophylactic treatment of organ transplants, cyclosporine exerts specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T1-helper cell is the main target, although the T1-suppressor cell may also be suppressed. Sandimmune (cyclosporine) also inhibits lymphokine production and release including interleukin-2.
Indications of Cyclosporine
- Psoriatic arthritis
- Ankylosing Spondylities
- Steroid induce arthritis
- Multiple joints pain
- Rheumatoid Arthritis
- Juvenile idiopathic arthritis
- Ulcerative colitis
- Crohn’s disease
- Idiopathic thrombocytopenic purpura
- Inflammatory bowel disease
- Organ transplant, rejection prophylaxis
- Organ transplant, rejection reversal
- Bone marrow transplant rejection
- Glomerulonephritis minimal lesion
- Glomerulosclerosis, focal segmental
- Graft versus host disease
- Heart transplant rejection
- Idiopathic thrombocytopenic purpura
- Interstitial cystitis
- Kidney transplant rejection
- Liver transplant rejection
- Nephritis, lupus
- Psoriasis
- Severe ulcerative colitis
- Uveitis
- Refractory ulcerative colitis
- Severe, active rheumatoid arthritis
- Severe, recalcitrant plaque psoriasis
- Suppressed tear production
Therapeutic Uses
- Clinical indications for cyclosporine are kidney, liver, heart, & other organ transplantation; rheumatoid arthritis; & psoriasis.
- Cyclosporine usually is used in combination with other agents, especially glucocorticoids & either azathioprine or mycophenolate mofetil &, most recently, sirolimus.
- In rheumatoid arthritis, cyclosporine is used in cases of severe disease that have not responded to methotrexate. Cyclosporine can be used in combination with methotrexate, but the levels of both drugs must be monitored closely.
- In psoriasis, cyclosporine is indicated for the treatment of adult nonimmunocompromised patients with the severe & disabling disease who have failed other systemic therapies. Because of its mechanism of action, there is a theoretical base for the use of cyclosporine in a variety of other T-cell-mediated diseases. Cyclosporine has been reported to be effective in Behcet’s acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel disease, & nephrotic syndrome when standard therapies have failed.
- For the prevention of allograft rejection in adults and children
- Cyclosporine is indicated, usually in combination with corticosteroids, for prevention of rejection of renal, hepatic, and cardiac transplants (allografts).
- Cyclosporine is also indicated for the prevention of rejection of heart-lung and pancreatic transplants.
- Cyclosporine is indicated for the treatment of chronic rejection in patients previously treated with other immunosuppressants.
- Cyclosporine is indicated for severe, active, rheumatoid arthritis failing to respond adequately to therapy with methotrexate alone.
- Cyclosporine is indicated for severe, recalcitrant, plaque-type psoriasis failing to respond to at least one systemic therapy or in patients unable to tolerate other systemic therapy.
- Cyclosporine is indicated for prophylaxis and treatment of graft-versus-host disease after bone marrow transplantation.
- Cyclosporine is indicated to induce and maintain remissions for steroid-dependent and steroid-resistant nephrotic syndrome due to glomerular diseases.
Contra-Indications of Cyclosporine
- Malignant tumor or cancer
- Tumor
- high cholesterol
- high amount of triglyceride in the blood
- low amount of magnesium in the blood
- the high amount of potassium in the blood
- pseudotumor cerebri
- Disorder of the brain
- high blood pressure
- Severe uncontrolled high blood pressure
- Thrombotic thrombocytopenic purpura
- Liver problems
- Kidney damage
- kidney disease with the reduction in kidney function
- seizures
- High amount of bilirubin in the blood
- High amount of uric acid in the blood
- Abnormal liver function tests
- Malignant Lymphoma
- Poisoning by immune suppression drug cyclosporine
- Progressive disease in the white matter of the brain
- Hyperchloremic Acidosis
- BK virus reactivation causing kidney problems
- A compromised immune system
- Abnormal kidney function
- High blood pressure
- Cancer, or a history of cancer (other than basal or squamous cell skin cancers)
- Severe gout
- Pregnant or breastfeeding
- Undergoing radiation treatments
Dosages of Cyclosporine
- Strengths: 25 mg; 50 mg; 100 mg; 100 mg/mL; 50 mg/mL; 100 mg/mL.
Rheumatoid Arthritis
- Initial dose: 1.25 mg/kg orally 2 times a day; onset of action usually occurs between 4 and 8 weeks
- Titration: If the insufficient benefit is seen and tolerability is good at the initial dose (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks
- Maximum dose: 4 mg/kg/day orally in 2 divided doses; if no benefit is seen by 16 weeks, therapy should be discontinued
Organ Transplant – Rejection Prophylaxis
- Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.
Newly transplants patients
- Renal: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
- Liver: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
- Heart: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
Psoriasis
- Initial dose: 1.25 mg/kg orally 2 times a day for at least 4 weeks
- Titration: If insufficient benefit is seen at 4 weeks and tolerability is good at the initial dose, the dose may be increased by 0.5 mg/kg/day at 2-week intervals based on patient response.
- Maximum dose: 4 mg/kg/day in 2 divided doses
Note: Doses below 2.5 mg/kg/day may also be effective.
Pediatric Organ Transplant – Rejection
ORAL FORMULATION (MODIFIED)
1 year and older
- Initial dose: Give 4 to 12 hours prior to transplantation or postoperatively; the initial dose varies depending on the organ and concomitant immunosuppressives.
Newly transplant patients
- Renal: 9 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
- Liver: 8 mg/kg/day (plus or minus 4 mg/kg/day) orally in 2 divided doses
- Heart: 7 mg/kg/day (plus or minus 3 mg/kg/day) orally in 2 divided doses
Side Effects of Cyclosporine
The most common
- stomach pain
- nausea, vomiting
- diarrhoea
- agitation, including aggressive behaviour and/or hostility
- headache
- muscle, bone or joint pain
- high blood pressure
- skin sensitivity
- high cholesterol
- excessive hair growth
- irritability, restlessness, feeling anxious
- depression
- tingling or burning sensation in the arms or legs
More common
- Abdominal or stomach pain or tenderness
- back pain
- black, tarry stools
- blurred vision
- chest pain
- Sweating
- Blurred vision
- Dizziness.
- slower heart rate
- diarrhea
- dry eyes
- hair loss
- nausea
- weakness or tiredness
Common
- Cough producing mucus
- difficulty with breathing
- tightness in the chest
- Abdominal or stomach pain and tenderness
- blistering, peeling, or loosening of the skin
- Anxiety
- dry mouth
- irritability
- shaking
- sleepiness or unusual drowsiness
- trouble sleeping
- unusual dream blood in the urine
- Decreased appetite
Drug Interactions of Cyclosporine
Cyclosporine may interact with following drugs,supplement & may change the efficacy of drugs
- antihistamines (e.g,. cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
- H2 antagonists (e.g., famotidine, ranitidine)
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- antiseizure medications (e.g., clobazam, phenobarbital, phenytoin, valproic acid, )
- angiotensin-converting enzyme inhibitors (ACEIs; e.g., ramipril, lisinopril)
- angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
- aripiprazole
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- baclofen
- fusidic acid
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- domperidone
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- famotidine
- gabapentin
- ipratropium
- ketotifen
- levodopa
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- magnesium sulfate
- methylphenidate
- mirtazapine
- monoamine oxidase inhibitors (MAOIs; e.g. rasagiline, selegiline, tranylcypromine)
- muscle relaxants (e.g., cyclobenzaprine, methocarbamol, orphenadrine)
- non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
- orphenadrine
- quinolone antibiotics (e.g., levofloxacin, norfloxacin, moxifloxacin)
- selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, fluoxetine, citalopram)
- serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
- sotalol
- tapentadol
- thiazide diuretics (water pills; e.g., hydrochlorothiazide, indapamide, )
- thioridazine
- multivitamins/minerals
- mycophenolate
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- tolterodine
- tramadol
- trimethoprim
- “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
- “triptan” migraine medications (e.g., eletriptan, sumatriptan)
- tryptophan
- tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
- vardenafil
Pregnancy & Lactation of Cyclosporine
FDA Pregnancy Category C
Pregnancy
This medication should be used during pregnancy only if the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. Do not stop taking this medication without guidance from your doctor.
Lactation
This medication passes into breast milk. If you are a breastfeeding mother and are taking cyclosporine, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.
References
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