Cyclosporine

Cyclosporine is a neutral, lipophilic, cyclic endecapeptide, first isolated in 1970 from two strains of fungi Tolypocladium inflatum and Cylindrocarpon lucidum during the development of new antifungal drugs.

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Indications Cyclosporine

Recommended for use when other DMARDs are ineffective.

Disadvantages of the drug:

• high frequency of side effects;
• the need for frequent laboratory monitoring during treatment;
• high incidence of adverse drug interactions.

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Pharmacodynamics

Cyclosporine, due to its lipophilic properties, has the ability to diffuse into the cytoplasm through the cell membrane, where it binds to specific 17 kD proteins (peptidyl-propyl cistransisomerase), called "cyclophilins". This family of enzymes (also known as rotamases) plays an important role in the implementation of the functional activity of many cells. The presence of cyclophilins not only in lymphocytes, but also in various cells that do not have immune activity, allows us to explain some toxic effects of the drug, but not the reasons for the specific effect of cyclosporine on the synthesis of cytokines. In addition, cyclosporine affects the functional activity of several nuclear proteins (NF-AT, AP-3, NF-kB), participating in the regulation of gene transcription, cytokines. Cyclosporine binds to the catalytic subunit of serine/threonine phosphatase (calcineurin), which functions as a Ca and calmodulin-dependent complex.

The main target cells for cyclosporine are CD4 T (helper) lymphocytes, the activation of which underlies the development of the immune response. At the same time, high efficiency and low toxicity of cyclosporine are determined by its ability to selectively block the early stages of calcium-dependent T-cell activation mediated by the TCR complex, and thereby interrupt the process of activation signal transduction without affecting the later stages of cell differentiation. It has been established that cyclosporine selectively inhibits the expression of genes (c-myc, srs) involved in the early activation of T-lymphocytes, and the transcription of mRNA of some cytokines, including IL-2, IL-3, IL-4, IF-y. An important point of application of cyclosporine is partial blocking of the expression of membrane IL-2 receptors on T-lymphocytes. All this leads to a slowdown in the proliferation of CD4 T lymphocytes mediated by paracrine and autocrine effects of these cytokines. Suppression of cytokine synthesis by activated CD4 T lymphocytes, in turn, leads to suppression of cytokine-dependent proliferation of cytotoxic T lymphocytes and has an indirect effect on the functional activity of other cells of the immune system involved in the implementation of its functional activity: B lymphocytes, mononuclear phagocytic cells and other antigen-presenting cells (APC), mast cells, eosinophils. natural killer cells. Moreover, there is evidence of the ability of cyclosporine to directly suppress the activation of B lymphocytes, inhibit chemotaxis of mononuclear phagocytes, the synthesis of TNF-a, to a lesser extent IL-1, and suppress the expression of class II MHC antigens on APC membranes. The latter is probably more related to the effect of cyclosporine on the synthesis of IFN-γ, IL-4 and FIO than to the direct effect of the drug on cell membranes.

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Pharmacokinetics

Main pharmacokinetic parameters of cyclosporine in humans.

• The time required to reach maximum concentration is 2-4 hours.
• Oral bioavailability is 10-57%.
• Plasma protein binding is more than 90%.
• Binding to erythrocytes is about 80%.
• The metabolic rate is about 99%.
• Half-life is 10-27 hours.
• The main route of excretion is bile.

Due to variability in absorption, it is recommended to monitor serum (or whole blood) cyclosporine concentrations using a radioimmunoassay.

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Dosing and administration

The drug cyclosporine should not be prescribed to patients with impaired renal function, severe arterial hypertension, infectious diseases and malignant neoplasms.

Before starting treatment, conduct a detailed clinical and laboratory examination: determination of liver enzyme activity, concentration of bilirubin, potassium and magnesium, uric acid, serum lipid profile, general urine analysis.

Start treatment with a dose of the drug no more than 3 mg/kg per day, in two doses.

Increase the dose to the optimal one by 0.5-1.0 mg/kg per day depending on the effectiveness (evaluated after 6-12 weeks) and tolerability. The maximum dose should not exceed 5 mg/kg per day.

Assess blood pressure and serum creatinine (establish baseline using at least two pretreatment determinations) every 2 weeks for the first 3 months of therapy, then every 4 weeks.

If the creatinine level increases by more than 30%, reduce the dose of the drug by 0.5-1.0 mg/kg per day for 1 month.

If creatinine levels decrease by 30%, continue treatment with cyclosporine. If creatinine levels continue to increase by 30%, stop treatment. If creatinine levels decrease by 10% compared to baseline, resume treatment.

Avoid combination with drugs that affect the concentration of cyclosporine in the blood.

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Use Cyclosporine during pregnancy

Cyclosporine is not recommended for use during pregnancy and breastfeeding.

Contraindications

Cyclosporine is contraindicated in the presence of hypersensitivity, cancer, infectious diseases, dysfunction of organs such as the kidneys and liver, hypertension, elevated levels of uric acid and potassium in the blood, pregnancy and lactation.

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Side effects Cyclosporine

Compared with other immunosuppressive drugs, cyclosporine generally causes fewer immediate and late side effects, primarily in relation to the development of infectious complications and malignant neoplasms. At the same time, against the background of treatment with cyclosporine, the development of some specific complications is observed, the most severe of which is kidney damage.

• Cardiovascular: arterial hypertension.
• CNS: headaches, dizziness, insomnia, depression, migraine, anxiety, impaired concentration, etc.
• Dermatological: hirsutism, hypertrichosis, purpura, pigmentation disorders, angioedema, cellulite, dermatitis, dry skin, eczema, folliculitis, pruritus, urticaria, nail destruction.
• Endocrine/metabolic: hypertriglyceridemia, menstrual irregularities, breast pain, thyrotoxicosis, hot flashes, hyperkalemia, hyperuricemia, hypoglycemia, increased/decreased libido.
• Gastrointestinal: nausea, diarrhea, gingival hyperplasia, abdominal pain, dyspepsia; constipation, dry mouth, dysphagia, esophagitis, gastric ulcer, gastritis, gastroenteritis.
• Renal: dysfunction/nephropathy, increase in creatinine more than 50%.
• Pulmonary: upper respiratory tract infections, cough, dyspnea, sinusitis, bronchospasm, hemoptysis.
• Genitourinary: leukorrhea, nocturia, polyuria.
• Hematological: anemia, leukopenia.
• Neuromuscular: paresthesia, tremor, cramps of the lower extremities, arthralgia, bone fractures, myalgia, neuropathy, stiffness, weakness.
• Eye: visual impairment, cataract, conjunctivitis, eye pain.
• Infections.

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Overdose

Symptoms of an overdose of Cyclosporine coincide with the side effects.

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