Table of Contents
- What is Ciclosporin A?
- Alternative Names
- Mechanisms of Action
- Medical Uses
- Administration Methods
- Dosing
- Potential Side Effects
- Ongoing Research
What is Ciclosporin A?
Ciclosporin A (CsA) is a powerful immunosuppressive medication that has been used in various medical treatments. It was originally derived from the fungus Tolypocladium inflatum. As an immunosuppressant, Ciclosporin A works by inhibiting the activity of certain immune cells and preventing the production of substances that trigger immune responses in the body[1].
Beyond its immunosuppressive properties, Ciclosporin A can also inhibit the opening of a mitochondrial mega-channel called the permeability transition pore (mPTP). This mechanism plays a key role in preventing cell death during reperfusion following prolonged ischemic injury, which has implications for its use in cardiac conditions[2].
Alternative Names
Ciclosporin A is known by several names across different clinical contexts:
- Cyclosporine
- Cyclosporin A
- Cyclosporine A
- CsA
- Sandimmun (brand name)
- Neoral (brand name for microemulsion formulation)
Mechanisms of Action
Ciclosporin A’s primary mechanism of action is immunosuppression through targeting T-cells. It inhibits the activation of T-cells by preventing the production of interleukin-2 (IL-2), a crucial signaling molecule in the immune response[3].
In cardiac applications, Ciclosporin A inhibits the opening of the mitochondrial permeability transition pore (mPTP). Opening of this pore plays a significant role in cardiomyocyte death during reperfusion following prolonged ischemic injury. By inhibiting this process, Ciclosporin A has been shown to reduce infarct size when administered at reperfusion in experimental models[2].
As an inducer of tumor growth factor-beta1 (TGF-beta1) in experimental abdominal aortic aneurysms and in human atherosclerotic aneurysms in vitro, Ciclosporin A can cause overgrowth of inflamed tissues. Since aneurysms are caused by aortic wall atrophy, this property has been hypothesized to help stabilize small aneurysm diameter while inducing aortic wall reconstruction and healing[4].
Medical Uses
Cardiac Conditions
Acute Myocardial Infarction: Ciclosporin A has been studied for its potential to reduce infarct size when administered at reperfusion in patients with ongoing acute myocardial infarction treated by coronary angioplasty. The CYCLosporinE A in Reperfused Acute Myocardial Infarction (CYCLE) trial was conducted to determine whether a single intravenous dose of Ciclosporin A within 6 hours of symptom onset improves outcomes after successful primary percutaneous coronary intervention (PCI) by reducing reperfusion injury[2][5].
Small Abdominal Aortic Aneurysms: Research has investigated whether brief administration of Ciclosporin A can induce stabilization of the diameter of small abdominal aortic aneurysms. The ACA4 study aimed to determine if Ciclosporin A could stop the growth of small aortic aneurysms in the abdomen, potentially obviating the need for aortic surgery[4].
Dermatological Conditions
Atopic Dermatitis: Ciclosporin A is used in the treatment of moderate-to-severe atopic dermatitis. It is typically administered in varying doses depending on disease severity. For instance, high-dose treatment (4-5 mg/kg/day) may be used for initial control, followed by low-dose maintenance (2-2.5 mg/kg/day) until onset of a second flare[6].
Hand Eczema: Studies have compared the efficacy of Ciclosporin A versus other treatments like alitretinoin in patients with severe recurrent vesicular hand eczema. Typical treatment protocols include oral Ciclosporin A at a starting dose of 5 mg/kg/day (split in 2 doses), decreasing to 3-3.5 mg/kg/day after 8 weeks for a total treatment period of 24 weeks[7].
Leprosy Reactions
Ciclosporin A has been studied for the management of different types of leprosy reactions:
Type 1 Reactions (T1R): Research has compared Ciclosporin A and prednisolone in treating new Type 1 Reactions in leprosy. A randomized double-blind controlled trial was conducted to determine whether treatment with Ciclosporin A provides the same outcome as prednisolone in the treatment of new Type 1 Reactions[8].
Steroid-Resistant Type 1 Reactions: Ciclosporin A has been investigated as a second-line drug for patients with Type 1 Reactions who have not responded to a 12-week course of prednisolone[9].
Erythema Nodosum Leprosum (ENL): Studies have assessed the safety, tolerability, and efficacy of Ciclosporin A in the treatment of patients with new acute Type 2 reactions (ENL) as well as chronic or recurrent ENL that is not controlled with standard prednisolone treatment[10][11].
In these leprosy-related applications, Ciclosporin A is typically administered at a dose of 7.5 mg/kg in a reducing regimen over 16-24 weeks, often with additional prednisolone given for the first four weeks[8][9][10][11].
Hematological Disorders
Immune Thrombocytopenia (ITP): Ciclosporin A has been studied in the management of steroid-resistant or relapsed immune thrombocytopenia, both as monotherapy and in combination with other treatments such as recombinant human thrombopoietin (rhTPO). Treatment protocols typically involve oral administration at a dose of 1.5-2.0 mg/kg twice daily for 3 consecutive months, adjusted to maintain serum levels between 200-400 ng/ml[12].
Paroxysmal Nocturnal Hemoglobinuria (PNH): Ciclosporin A, often in combination with other drugs like levamisole and glucocorticoids, has been investigated for treating different forms of PNH, including classic PNH and subclinical PNH in the setting of bone marrow failure syndromes. Dosing regimens vary, with studies using 1.5-2.5 mg/kg every other day or 3-5 mg/kg every day[13][14].
Aplastic Anemia: Research has explored the efficacy and safety of rhTPO in combination with Ciclosporin A versus Ciclosporin A alone for the treatment of transfusion-dependent non-severe aplastic anemia[15].
Transplantation
Kidney Transplantation: Ciclosporin A is widely used in immunosuppressive regimens for kidney transplant recipients. Research has explored strategies to optimize dosing, such as reducing Ciclosporin A exposure to prevent degradation of renal function. In one study, the usual-exposure target for Ciclosporin A AUC0-12h was 4.3 mg•h/L, while the low-exposure target was 50% of this or 2.2 mg•h/L[16].
Heart Transplantation: Ciclosporin A is a component of immunosuppressive regimens after heart transplantation. Studies have examined strategies to optimize these regimens, such as Ciclosporin A dose reduction combined with other immunosuppressants to improve renal function and decrease cardiac risk factors[17][18].
Lung Transplantation: Liposomal Ciclosporin A (L-CsA) has been studied for patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation. This formulation is designed for inhalation use, allowing targeted delivery to the lungs[19].
Other Applications
Sjögren’s Syndrome: Low-dose Ciclosporin A (approximately 2 mg/kg/day) has been studied for treating musculoskeletal manifestations of primary Sjögren’s Syndrome[20].
Autoimmune Hepatitis: Ciclosporin A has been compared with prednisolone for induction of remission in treatment-naive autoimmune hepatitis patients, particularly for cases where corticosteroid side effects hamper effective therapy[3].
Behçet’s Disease: Ciclosporin A has been used as a standard treatment for severe ocular manifestations of Behçet’s disease, typically at a dose of 3 mg/kg body weight, augmented to 5 mg if necessary and combined with prednisolone[21].
Recurrent Miscarriage: Research has investigated whether Ciclosporin A in early pregnancy reduces the risk of miscarriage in women with unexplained recurrent miscarriages compared to treatment with dydrogesterone. The hypothesis is that Ciclosporin A can induce maternal-fetal tolerance, potentially reducing miscarriage risk[22].
COVID-19 Pneumonia: A pilot study examined the utility of low doses of corticosteroids and Ciclosporin A combined with enoxaparin in patients with COVID-19 pneumonia, with Ciclosporin A administered orally at a dose of 1-2 mg/kg/day divided into two doses for 7 days from hospitalization[23].
Triple Negative Breast Cancer: A pre-surgical window of opportunity trial has investigated the effect of Ciclosporin A on triple negative breast cancer with defective DNA repair. Patients in this study began treatment at 5 mg/kg/day in 2 divided doses until the day before surgery[24].
Dry Eye Syndrome: Topical Ciclosporin A has been studied for treating keratoconjunctivitis sicca (dry eye syndrome), with research suggesting it may increase tear production or decrease inflammation on the eye surface, or both[25].
Administration Methods
Ciclosporin A can be administered through various routes depending on the medical condition being treated:
- Oral administration: This is the most common route for chronic conditions, using tablets, capsules, or oral solutions[8][12].
- Intravenous (IV) infusion: Used in acute settings such as during or immediately before procedures like percutaneous coronary intervention for myocardial infarction, or when oral administration is not possible[2][5].
- Topical application: Used for conditions affecting the skin or eyes, such as atopic dermatitis or dry eye syndrome[25].
- Inhalation: Liposomal formulations of Ciclosporin A have been developed for inhalation use in conditions like bronchiolitis obliterans syndrome after lung transplantation[19].
Dosing
Dosing of Ciclosporin A varies widely depending on the condition being treated, the patient’s characteristics, and the formulation used. Some common dosing regimens include:
- Cardiac conditions: For myocardial infarction, a single intravenous bolus injection of 2.5 mg/kg has been studied[5].
- Dermatological conditions: For atopic dermatitis, high-dose treatment may be 4-5 mg/kg/day, with maintenance doses of 2-2.5 mg/kg/day[6]. For hand eczema, starting doses of 5 mg/kg/day, decreasing to 3-3.5 mg/kg/day have been used[7].
- Leprosy reactions: Typically 7.5 mg/kg in a reducing regimen over 16-24 weeks, often with additional prednisolone for the first four weeks[8][9].
- Immune thrombocytopenia: Oral administration at 1.5-2.0 mg/kg twice daily for 3 months, adjusted to maintain serum levels between 200-400 ng/ml[12].
- Paroxysmal nocturnal hemoglobinuria: Regimens vary from 1.5-2.5 mg/kg every other day to 3-5 mg/kg every day[13][14].
- Transplantation: Dosing is carefully tailored based on plasma drug concentrations, with therapeutic targets often expressed in terms of the area under the concentration-time curve (AUC)[16].
Potential Side Effects
Ciclosporin A may cause various side effects, which are closely monitored during clinical use:
- Renal function impairment: Long-term administration of calcineurin inhibitors like Ciclosporin A is associated with chronic nephrotoxicity[17][18].
- Hypertension: Ciclosporin A can cause or exacerbate high blood pressure[4].
- Increased infection risk: Due to its immunosuppressive effects, Ciclosporin A may increase susceptibility to infections[12].
- Neurological effects: These can include tremors, headaches, and in rare cases, more severe neurological complications[16].
- Gastrointestinal disturbances: These might include nausea, vomiting, or diarrhea[17].
- Hyperlipidemia: Ciclosporin A can cause elevated blood lipid levels[18].
- Allergic reactions: In rare cases, patients may experience allergic reactions to the drug[16].
The risk and severity of side effects often depend on the dose, duration of treatment, and individual patient factors[16].
Ongoing Research
Ongoing research is exploring new applications and formulations of Ciclosporin A:
- Novel delivery systems: Liposomal formulations for targeted delivery to specific organs or tissues, such as L-CsA for inhalation in lung transplant patients with bronchiolitis obliterans syndrome[19].
- Combination therapies: Studies are investigating synergistic effects of Ciclosporin A with other drugs, such as recombinant human thrombopoietin for immune thrombocytopenia or levamisole for paroxysmal nocturnal hemoglobinuria[12][13][14].
- Dose optimization: Research aims to find the optimal balance between efficacy and minimizing side effects, such as Ciclosporin A dose reduction strategies in transplant recipients[16][17][18].
- New indications: Investigations continue into potential new applications, such as for triple negative breast cancer, COVID-19 pneumonia, and recurrent miscarriage[22][23][24].
