PANIMUN BIORAL 25MG

Indications

• Prevention of organ transplant rejection
• Management of autoimmune diseases such as rheumatoid arthritis
• Treatment of psoriasis
• Management of atopic dermatitis

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing information based on the condition being treated, as doses may vary significantly.

Mechanism of action

Cyclosporine is a calcineurin inhibitor that binds to cyclophilin-1 inside cells to form a cyclosporine-cyclophilin complex. This complex inhibits calcineurin, preventing the dephosphorylation and activation of the nuclear factor of activated T cells (NF-AT). As a result, the production of cytokines such as IL-2, which is critical for T cell activation and proliferation, is suppressed. This mechanism underlies cyclosporine's immunosuppressive properties, making it effective against transplant rejection and certain autoimmune conditions.

Pharmacodynamics

Cyclosporine has potent immunosuppressive properties, particularly affecting T cells. It plays a critical role in prolonging survival after organ and bone marrow transplants by preventing and controlling serious immune-mediated reactions, such as allograft rejection and graft versus host disease. Common side effects include hypertrichosis, gingival hyperplasia, and hyperlipidemia, while nephrotoxicity is a potential concern associated with its use.

Pharmacokinetics

Cyclosporine is absorbed well from the gastrointestinal tract, although its bioavailability can be variable. It is extensively metabolized in the liver by cytochrome P450 enzymes, primarily CYP3A4. The drug is primarily excreted in the bile and has a half-life that can vary significantly among individuals. Therapeutic drug monitoring is often necessary to ensure effective and safe dosing.

Contra-indications

• Hypersensitivity to cyclosporine or any of its components
• Uncontrolled infections
• Malignancies
• Severe renal impairment
• Concurrent use with certain immunosuppressants

Adverse effects

• Nephrotoxicity
• Hypertension
• Hyperlipidemia
• Gingival hyperplasia
• Hypertrichosis
• Increased risk of infections
• Tremors
• Headaches
• Nausea
• Diarrhea

Interactions

• Other immunosuppressants may increase toxicity
• CYP3A4 inducers or inhibitors can alter cyclosporine levels
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase nephrotoxicity
• Antifungal agents may increase cyclosporine levels
• Anticonvulsants may decrease cyclosporine levels

Precautions

• Monitor renal function regularly during treatment
• Monitor blood pressure regularly
• Assess for signs of infection
• Consider potential interactions with other medications
• Use caution in patients with a history of malignancies

Pregnancy

Cyclosporine is classified as category C. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Cyclosporine is excreted in breast milk. Caution should be exercised when administering to a nursing mother.

Storage

Store in a cool, dry place at room temperature, protected from light. Keep out of reach of children.

Formulations

• Capsules
• Oral solution
• Injection

Mechanism of action

Cyclosporine is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development. 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 (CTL). The exact mechanism of action is unknown but seems to be related to the inhibition of production and release of interleukin-2, which is a proliferative factor necessary for the induction of cytotoxic T lymphocytes in response to alloantigenic challenge, and which plays a major role in both cellular and humoral immune responses. Cyclosporine does not affect the nonspecific defense system of the most and does not cause significant myelosuppression. The major pharmacodynamic action of cyclosporin within T cells is calcineurin inhibition. The complex cyclophilin-cyclosporin competitively binds to the Ca(2+)- & calmodulin-dependent phosphatase calcineurin which then inhibits downstream dephosphorylation & activation of NFAT(transcription factor). The greatest calcineurin inhibition is seen 1-2 hr after admin of Neoral in parallel to the highest blood concn. Treatment of patients after organ transplantation with the immunosuppressive drug cyclosporin A (CsA) is often accompanied by impaired glucose tolerance, thus promoting the development of diabetes mellitus. ... /The authors/ show that 2-5 microM CsA diminishes glucose-induced insulin secretion of isolated mouse pancreatic islets in vitro by inhibiting glucose-stimulated oscillations of the cytoplasmic free-Ca(2+) concn [Ca(2+)](c). This effect is not due to an inhibition of calcineurin, which mediates the immunosuppressive effect of CsA, because other calcineurin inhibitors, deltamethrin & tacrolimus, did not affect the oscillations in [Ca(2+)](c) of the B-cells. The CsA-induced decr in [Ca(2+)](c) to basal values was not caused by a direct inhibition of L-type Ca(2+) channels. CsA is known to be a potent inhibitor of the mitochondr

Pharmacodynamics

Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease. Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity.