Cyclosporin

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

[1], [2], [3], [4]

Indications Cyclosporin

Recommended for use with ineffectiveness of other BPA.

Disadvantages of the drug:

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

[5]

Pharmacodynamics

Cyclosporine, due to its lipophilic properties, has the ability to diffuse into the cytoplasm through the cell membrane, where it binds to specific 17kD proteins (peptidyl-propyl cisransisomerase), called "cyclophilins". This family of enzymes (which are also known as rotamases) plays an important role in the realization of the functional activity of many cells. The presence of cyclophilins not only in lymphocytes, but also in various cells lacking immune activity, makes it possible to explain some of the toxic effects of the drug, but not the causes of the specific effect of cyclosporin on the synthesis of cytokines. In addition, cyclosporine affects the functional activity of several nuclear proteins (NF-AT, AP-3, NF-KV), involved in the regulation of transcription of genes, cytokines. Cyclosporine binds to the catalytic subunit of serine / threonine phosphatase (calcineurin), which functions as Ca and the calmodulline dependent complex.

The main target cells for cyclosporin are CD4 T (helper) lymphocytes, the activation of which underlies the development of the immune response. In this case, high efficiency and low toxicity of cyclosporin determines its ability to selectively block the early stages of calcium-dependent T-cell activation mediated by the TCR complex and thereby interrupt the transduction of the activation signal without affecting the later stages of cell differentiation. It was found that cyclosporin selectively inhibits the expression of genes (c-mu, srs) involved in early activation of T lymphocytes and transcription of the mRNA of some cytokines, including IL-2. IL-3, IL-4, IF-y. An important point of application of cyclosporine is partial blocking of expression of membrane IL-2 receptors on T-lymphocytes. All this leads to a slowdown in the proliferation of CD4 T-lymphocytes, mediated by the paracrine and autocrine effects of these cytokines. Suppression of the synthesis of cytokines by activated C04 T lymphocytes, in turn, leads to suppression of the cytokine-dependent proliferation of cytotoxic T-lymphocytes and has an indirect effect on the functional activity of other cells of the immune system that take in the realization of its functional activity: B-lymphocytes, mononuclear phagocytic cells and others antigen-presenting cells (APC), mast cells, eosinophils. Natural killer cells. Moreover, there is evidence of the ability of cyclosporine to directly inhibit the activation of B-lymphocytes, inhibit the chemotaxis of mononuclear phagocytes, synthesize TNF-a, to a lesser extent IL-1, and inhibit the expression of Class II MHC antigens on AIC membranes. The latter is probably more related to the effect of cyclosporine on the synthesis of IFN-y, IL-4 and FIO than with the direct action of the drug on cell membranes.

[6], [7], [8], [9], [10], [11]

Pharmacokinetics

The main pharmacokinetic parameters of cyclosporine in humans.

• The time required to reach the maximum concentration is 2-4 hours.
• Oral bioavailability - 10-57%.
• Binding to plasma proteins - more than 90%.
• Binding to erythrocytes - about 80%.
• The degree of metabolism is about 99%.
• The elimination half-life is 10-27 hours.
• The main way of excretion is bile.

In connection with the variability of absorption, it is recommended to monitor the concentration of cyclosporin in serum (or whole blood) using the radioimmunoassay method.

[12], [13], [14], [15], [16], [17]

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 the beginning of treatment, conduct a detailed clinical and laboratory examination: the determination of the activity of liver enzymes, the concentration of bilirubin, potassium and magnesium, uric acid, lipid profile in the serum, general urine analysis.

Start treatment with a dose of the drug not more than 3 mg / kg per day, in two steps.

Increase the dose to the optimal 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.

Evaluate blood pressure and serum creatinine level (establish a baseline by at least two determinations before treatment) every 2 weeks in the first 3 months of therapy, then every 4 weeks.

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

With a decrease in creatine levels by 30% continue treatment with cyclosporine. If a 30% increase in creatinine concentration is maintained, discontinue treatment. If the creatinine content is reduced by 10% compared to the basal level, resume treatment.

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

[25], [26], [27], [28], [29]

Use Cyclosporin during pregnancy

Cyclosporine is not recommended for use during pregnancy and during lactation.

Contraindications

Cyclosporine is contraindicated in the presence of hypersensitivity, cancerous tumors, infectious diseases, impaired functioning of organs such as kidney and liver, hypertension, elevated levels of uric acid and potassium in the blood, pregnancy and lactation.

[18], [19], [20], [21], [22]

Side effects Cyclosporin

Compared with other immunosuppressive drugs, cyclosporine generally causes fewer immediate and distant 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 serious of which is renal damage.

• Cardiovascular: arterial hypertension.
• CNS: headaches, dizziness, insomnia, depression, migraine, anxiety, impaired ability to concentrate, etc.
• Dermatological: hirsutism, hypertrichosis, purpura, pigmentation disorder, angioedema, cellulitis, dermatitis, dry skin, eczema, folliculitis, skin itching, urticaria, nail destruction.
• Endocrine / metabolic: hypertriglyceridemia, menstrual disorders, mammary glands, hyperthyroidism, hot flushes, hyperkalemia, hyperuricemia hypoglycemia, increased / decreased libido.
• Gastrointestinal tract: nausea, diarrhea, gingival hyperplasia, abdominal pain, indigestion; constipation, dry mouth, dysphagia, esophagitis, gastric ulcer, gastritis, gastroenteritis.
• Renal: dysfunction / nephropathy, increase in creatinine more than 50%.
• Pulmonary: infections of the upper respiratory tract, cough, shortness of breath, sinusitis, bronchospasm, hemoptysis.
• Genitourinary: leukorrhea, nocturia, polyuria.
• Hematologic: anemia, leukopenia.
• Neuromuscular: paresthesia, tremor, convulsions of the lower extremities, arthralgia, bone fractures, myalgia, neuropathy, stiffness, weakness.
• Ophthalmic: visual impairment, cataract, conjunctivitis, pain in the eyes.
• Infections.

[23], [24],

Overdose

Symptoms of an overdose of Cyclosporin coincide with side effects.

[30], [31], [32], [33]