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A powerful immunosuppressive drug, cyclosporine. Cyclosporine eye drops Cyclosporine preparations

A cyclic polypeptide consisting of 11 amino acids, produced by a fungus of the species Tolypocladium Inflatum. The drug has powerful immunosuppressive activity. Prevents rejection of allogeneic heart, kidney, liver, pancreas, small intestine, lung and skin transplants; reduces the severity of GVHD (graft versus host) after bone marrow transplantation. Suppresses humoral and cellular immune responses, modifies chronic inflammatory processes, suppresses the formation and secretion of lymphokines (such as IL-2), cell growth factor (TCGF), affects auxiliary cells (Th). Inhibits the induction phase in the process of proliferation of lymphoid tissue cells. It affects the early phases (G0 and G1 phase) of the cell cycle, but does not affect the course of the process itself. The effect of cyclosporine is reversible; the drug does not exhibit lymphotoxic effects, does not inhibit hematopoiesis, does not affect phagocytic activity or tumor cells (animal studies). After oral administration, Tmax is 1-6 hours, absorption is variable, and ingestion of a fatty meal prolongs absorption time and increases AUC by 37%. Absolute bioavailability is 20-50%. Within the limits of the therapeutic dose max. the plasma concentration of cyclosporine, as well as the area under the plasma concentration-time curve, are proportional to the dose administered; however, in whole blood this relationship is not linear. Approximately 90% binds to plasma proteins, mainly lipoproteins. Distribution in the blood depends on the concentration of cyclosporine in the serum. Approximately 33-47% of the drug accumulates in plasma, 4-9% in lymphocytes, 5-12% in granulocytes, 41-58% in erythrocytes. It undergoes biotransformation in the liver, mainly with the participation of cytochrome P-450. By mono- and dihydroxylation, as well as N-demethylation, approximately 15 metabolites are formed, some of them exhibit weak pharmacological activity. According to data from various sources, T1/2 is 6.3-20.4 hours. It is excreted mainly with bile into the gastrointestinal tract, only about 6% is excreted by the kidneys.

Cyclosporine: instructions for use

Prevention of graft rejection after allogeneic kidney, liver, heart, heart and lung, lung, or pancreas transplantation. Treatment of transplant rejection in patients previously treated with other immunosuppressants. Prevention of graft rejection after bone marrow transplantation. Prevention or treatment of graft-versus-host disease. Active, threatening vision loss, uveitis of the middle and posterior part of the eye of non-infectious etiology if conventional therapy does not bring results or causes serious side effects. Behçet's uveitis with repeated attacks of inflammation involving the retina. Steroid-dependent and steroid-resistant nephrotic syndrome in adults and children, caused by glomerular pathology, such as minimal change nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis. The drug can be used to induce and maintain remission and to maintain steroid-induced remission, allowing for steroid withdrawal. Treatment of severe forms of active rheumatoid arthritis. Treatment of severe forms of psoriasis in cases where traditional therapy does not bring results or is not possible. Severe forms of atopic dermatitis that require systemic therapy.

Contraindications

Drug interactions

During the combined use of cyclosporine with drugs that change the concentration of cyclosporine in the blood of patients who have undergone transplantation, it is necessary to monitor its concentration, especially at the beginning and at the end of therapy with an additional drug; in other patients, if taking a drug that increases the concentration of cyclosporine in the blood, it is recommended to monitor renal function and monitor the development of side effects. Barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, sulfadimezin for intravenous administration, rifampicin, octreotide, probucol, (Hypericum perforatum), ticlopidine, sulfinpyrazone, terbinafine, bosentan reduce the concentration of cyclosporine in the blood. Macrolide antibiotics (eg, erythromycin, clarithromycin and azithromycin), ketoconazole, fluconazole, itraconazole, voriconazole, nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high dose), allopurinol, cholic acid and its derivatives, protease inhibitor drugs, imatinib, colchicine increase the concentration of cyclosporine in the blood. Caution and close monitoring of renal function should be used during concomitant use of cyclosporine with other nephrotoxic drugs (eg, aminoglycosides, vancomycin, trimethoprim and sulfamethoxazole trimethoprim, NSAIDs [reduce NSAID dose], melphalan, histamine H2 receptor antagonists, methotrexate). Concomitant use with tacrolimus should be avoided due to increased nephrotoxic effects. Vaccinations may be less effective during treatment with cyclosporine; The use of live attenuated vaccines should be avoided. The combined use of nifedipine and cyclosporine may lead to more severe gingival hyperplasia than with cyclosporine monotherapy; The combined use of these drugs should be avoided. Cyclosporine increases bioavailability; if combined use is necessary, the dose should be reduced. May reduce the clearance of colchicine, HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin, simvastatin, atorvastatin) and prednisolone. For this reason, the drug may increase toxicity and increase the risk of developing myopathy and neuropathy in connection with the use of colchicine, especially in patients with impaired renal function; It is recommended to ensure careful clinical monitoring and, if toxic effects of these drugs are detected at an early stage, reduce the dose or discontinue them. The combined use of lovastatin, pravastatin, simvastatin and atorvastatin and, sometimes, fluvastatin with cyclosporine can lead to the development of myopathy, including acute necrosis of skeletal muscles; it is necessary to reduce the dose of statins in accordance with the manufacturer's recommendations, monitor for toxic effects, and in the event of symptoms of myopathy and in patients with risk factors for developing acute kidney injury, temporarily or completely discontinue the use of statins. Caution should be exercised in the case of concomitant use of potassium salts or potassium-sparing drugs (for example, some diuretics, ACE inhibitors, angiotensin II receptor antagonists) due to the increased risk of hyperkalemia. Caution should be exercised when using lercanidipine in combination. Grapefruit juice may increase the concentration of cyclosporine in the blood. The use of full doses of cyclosporine in combination with or tacrolimus may lead to an increase in serum creatinine concentrations, which usually resolves after the dose of cyclosporine is reduced. and have a slight effect on the pharmacokinetics of cyclosporine, and cyclosporine significantly increases the concentration of these drugs in the blood.

Cyclosporine: side effects

Side effects in patients receiving cyclosporine for transplantation tend to be more severe and more frequent. The most common are: renal dysfunction, hypertension, tremor, headache, hyperlipidemia. Other side effects: anorexia, nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia, liver dysfunction, pancreatitis, hyperuricemia, hyperkalemia, hypomagnesemia, hyperglycemia, muscle cramps, myalgia, muscle weakness, myopathy, anemia, thrombocytopenia, microangiopathic hemolytic anemia , hemolytic uremic syndrome, hirsutism, allergic rash, fatigue, edema, weight gain, menstrual irregularities, gynecomastia, paresthesia, symptoms of encephalopathy (convulsions, confusion, disorientation, slow reactions, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia), peripheral polyneuropathy, papilledema, including papilledema with possible visual impairment as a result of increased intracranial pressure not caused by a tumor. Lymphoproliferative diseases and cancers develop with the same frequency as in the case of other immunosuppressants. In case of overdose, symptomatic and supportive therapy is indicated; the drug is not eliminated by dialysis or hemoperfusion.

Pregnancy and lactation

Cyclosporine: dosage

The dose is determined based on monitoring serum concentrations of cyclosporine. Orally. The daily dose must be divided into two doses. Organ transplantation. 10-15 mg/kg in 2 divided doses within 12 hours before transplantation, this dose is also used for 1-2 weeks after surgery. Then it should be gradually reduced depending on the concentration of cyclosporine in the blood until a maintenance dose of 2-6 mg/kg per day is reached. When used in combination with other immunosuppressants (for example, with corticosteroids or as part of a triple or quadruple therapy), lower doses may be used (at the beginning of the course of therapy, 3-6 mg/kg per day). Bone marrow transplantation. After a course of treatment i.v. usually 12.5 mg/kg per day. Maintenance therapy should continue for at least 3 months (preferably 6 months). After this, the dose should be gradually reduced until the drug is discontinued one year after transplantation. If the drug is used in oral form from the beginning of the course of therapy, the recommended dose should be 12.5-15 mg/kg per day; The first dose should be administered the day before surgery. If gastrointestinal dysfunction occurs that may reduce the absorption of the oral drug, higher oral doses or parenteral administration may be considered. Sometimes, after discontinuation of the drug, graft-versus-host disease may develop, which usually resolves after re-administration of cyclosporine; To treat mild chronic forms of the disease, low doses of cyclosporine should be used. Endogenous uveitis. To induce remission at the beginning of therapy, 5 mg/kg per day until remission is achieved. If necessary, up to 7 mg/kg per day or use in combination with corticosteroids. During maintenance therapy, the dose should be reduced gradually, using the lowest effective dose (up to 5 mg/kg per day). Nephrotic syndrome. To induce remission at the beginning of therapy, 5 mg/kg in adults and 6 mg/kg in children (used if renal function parameters are correct despite proteinuria). In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg per day. If necessary, use in combination with low doses of oral corticosteroids. If there is no improvement after 3 months of therapy, cyclosporine therapy should be discontinued. The dose should then be gradually reduced to the minimum effective dose (maximum 5 mg/kg per day in adults and 6 mg/kg per day in children). Rheumatoid arthritis. During the first 6 weeks of therapy, 3 mg/kg per day. If necessary, gradually increase to the limits of individual tolerance, maximum 5 mg/kg per day. It may be necessary to use the drug for 12 weeks. The maintenance dose must be selected individually. The drug can be used in combination with low doses of corticosteroids and/or NSAIDs, and, if necessary, methotrexate. The initial dose of cyclosporine in this case is 2.5 mg/kg per day. Psoriasis. Individually. At the beginning of therapy, 2.5 mg/kg per day; if necessary, after a month the dose can be gradually increased to a maximum of 5 mg/kg per day. Therapy should be discontinued if the dose of 5 mg/kg per day is not effective after 6 weeks of treatment, or if the effective dose cannot be considered safe. If it is necessary to quickly improve the patient's condition, an initial dose of 5 mg/kg per day can be used. After achieving satisfactory improvement in the condition, treatment can be discontinued, and in case of relapse, reapply at the dose that was previously effective. Some patients may need to continue maintenance therapy. During maintenance therapy, the lowest effective dose determined individually (up to 5 mg/kg per day) should be used. Atopic dermatitis. Individually, as a rule, 2.5-5 mg/kg per day. Once satisfactory improvement is achieved, the dose should be gradually reduced and, if possible, cyclosporine should be discontinued. In case of relapse, it can be re-administered. Although an 8-week course of therapy may be sufficient to achieve complete improvement, therapy for one year has been shown to be effective and well tolerated as long as monitoring requirements are met. I.v. Organ transplantation. Typically 3-5 mg/kg 12 hours before transplant; a dose of 3-5 mg/kg per day is used for 1-2 weeks after surgery, then it must be gradually reduced depending on the concentration of cyclosporine in the blood to a maintenance dose, usually 0.7-2 mg/kg per day. When used in combination with other immunosuppressants (for example, corticosteroids or as part of a triple or quadruple therapy), lower doses may be used (at the beginning of therapy, 1-2 mg/kg per day). It is recommended to start taking oral cyclosporine as soon as possible. Bone marrow transplantation. The first dose should be administered on the day before transplantation; as a rule, it is 3-5 mg/kg per day. This dose should also be used for 1-2 weeks after surgery. Oral cyclosporine is then recommended and continued for at least 3 months (preferably 6 months). Then the dose must be gradually reduced until the drug is discontinued after transplantation.

Use: medicine, laboratory diagnostics for organ transplantation and autoimmune diseases. Goal: simplifying and increasing the efficiency of the method. The essence of the invention: a patient's blood sample is treated with a mixture consisting of a 4.2 mm Hepes buffer solution with a pH of 7.8, peptidyl-propyl-cis-trans isomerase with a specific activity of 500 mol/min x mg and a molecular weight of 17 kD, 0.1 mg GLT-ALA-ALA-Pro-phenyl-alanine-4-nitroanilide, incubated for 20 minutes at 5 o C, followed by spectrophotometry at 410 nm and determination of the concentration of cyclosporine A using a calibration curve. Sensitivity of the method: 50 ng in 1 ml. blood. 2 ill., 1 tab.

The invention relates to a method for determining the concentration of cyclosporine A and its biologically active derivatives. It can be used in medical and biological laboratories. The definition has diagnostic value in the case of patients with organ transplants and autoimmune diseases. Detection of the concentration of cyclosporine A is important for therapeutic monitoring in the case of patients who are treated with drugs that have the cyclosporine class of substances as a therapeutically important drug. The concentration of cyclosporine A and its biologically active derivatives should be determined in aqueous systems, primarily in biological fluids, especially in blood serum or plasma, but also in cerebrospinal fluid, synovial fluid, urine or suspensions of blood cells, respectively, in tissue homogenates. Basically, the determination of concentration and its derivatives is used in establishing and monitoring a therapeutically rational concentration range in patients with transplanted organs who receive compounds such as cyclospora as a medicine to avoid rejection reactions. Based on the relatively small therapeutically rational breadth of medication, to avoid immunological reactions to the graft at too low a dosage, respectively, to avoid toxic side effects at too high a dosage, it is necessary to measure the concentration of the drug in the body fluids of patients. The need for this determination of concentration further follows from the individual differences in the natural elimination of these drugs on individual removal rates that change with longer treatment, which are a prerequisite for differential dosing of the drug. Typically, the determination of the concentration of cyclosporine A and its derivatives is carried out using an immunological (Transplant. Proc. 1983, v. 15, pp. 2438-2441) or chromatographic method (Clivical Chem. 1987, v. 33, pp. 2272-74). Immunological methods rely on obtaining a suitable antibody against the cyclosporine of interest. With the help of this antibody, it is then possible to determine the concentration of the antigen using the immunoassay methods used. The disadvantages of these methods include, in particular, the very expensive, partially manual procedure and the possible cross-reaction with therapeutically ineffective compounds. Chromatographic methods use the separation of the compound being detected from the identification of interfering substances through physical effects. The detection sensitivity is thereby strongly affected by the quality of the detector, as well as by the quality of the separation. Particular disadvantages of this method are the expensive required instrumentation and a relatively large amount of material, so that, for example, it is possible to determine the level of cyclosporine in the blood plasma. The purpose of the invention is to develop a simple method for the quantitative determination of biologically effective cyclosporines in the blood of patients treated with this class of substances. The objective of the invention is a simple method, which, due to its high sensitivity using small amounts of samples, is suitable for the determination of cyclosporins, and, after adding a certain amount of enzyme isomerizing the N-terminal peptide bond to proline, the suppression of the enzyme-catalyzed isomerization of the proline-containing substrate and from it is measured according to a calibration the curve determines the concentration of cyclosporine A. Also important as cyclosporins are compounds that are chemically derived from the class of cyclosporine substrates in the sense of derivatives and are biologically active as cyclosporine A. To implement the method, catalytically active and cyclosporine-sensitive poptidyl-prolyl-cis-trans isomerase is used (PPlase). Suitable substrates are compounds of the type Xaa-Pzo-Yaa, with which the PPlase reaction can be detected. Preferably, substrates are used in which Yaa represents a chromogenic moiety, such as phenylalanine-4-nitroanilide, and in which Xa represents aminoacyl residues, such as Suc-Ala-Ala. A further characteristic of a suitable substrate is the property of the substrate for the indicator system required for detection of PPlase by a suitable protease, such as chymotripsy, thrombin or human leukocytes, elastase, under environmental conditions (pH value, buffer composition, temperature and ionic strength) that are known for proteolytic systems. The cyclosporine-sensitive PPlase with a molecular weight of 17 kD can be isolated, for example, from pig kidneys using known methods. The concentration of cyclosporine can be determined by comparing the activities of measurements without cyclosporine (comparative value) and the measurement of PPlase activity with cyclosporine, while both the isomerase inherent in the body and also the isomerizing activities contained in the experiment can serve as a measure for the level of cyclosporine. The implementation of the determination of PPlase activity, including the determination of the concentration of cyclosporines, will be further explained in more detail by two embodiment examples. Examples of implementation. Calculation: Usually the concentration of the inhibitory substance (inhibitor) is determined from the percentage inhibition of a certain added amount of enzyme guided by a calibration curve. Such a typical calibration curve is shown in Fig. 1 for implementation example 1 and in Fig. 2 for implementation example 2. Example 1. Buffer: 0.035 M HEPES pH 7.8. Chymotrypsin: alpha-chymotrypsin from the pancreas of cattle (3-fold recrystallized, Beringar (Germany), 24 mg in 4.2 ml of buffer. Substrate: GLT-Ala-Ala-Pro-Phe-NHNp 14 mg in 10 ml dimethyl sulfoxide PPlase: specific activity 500 mol/min x mg isolated from pork kidneys. Measuring device: recording spectrophotometer. Measurement wavelength: 410 nm. Preincubation time: 20 minutes. Reaction temperature: 5 o C. Sample: human plasma pool, to which added 5,8,30,36,40 ng/ml cyclosporine A. Determination of activity: a) calculation of the rate constant from the measured mixture (to the measured mixture) and the blank sample (to the blank mixture) gives first-order time kinetics), b) calculation of the measured activity of the sample: Concentration of cyclosporine: determination using a calibration curve. Example 2. Buffer: 0.035 M HEPESpH 7.8 Chymotrypsin: alpha-chymotrypsin from bovine pancreas (recrystallized three times, Boehringer (Germany) 35 mg in 4.2 ml buffer. Substrate: GLA-ALA-Pro-Phe-NHNp 14 mg in 10 ml of dimethyl sulfoxide. PPlase: isolated from pork kidneys, specific activity 500.0 mol/mol x mg. Measuring device: recording spectrophotometer.
measurement wavelength: 410 nm
Pre-incubation time: 20 minutes
reaction temperature: 5 o C
sample: human plasma pool, to which 5,8,18,30,36,40 ng/ml cyclosporine-A is added. Measurement mixture, blank and activity determination as in example 1. Cyclosporine concentration: determination using a calibration curve. A method for determining cyclosporine A in blood, including treating a blood sample with reagents and analyzing the reaction results, characterized in that, in order to simplify and increase the efficiency of the method, the blood sample is treated with a mixture consisting of 4.2 ml of 0.035 M Hepes buffer solution with pH 7.8 , peptidyl-prolyl-cis-trans isomerase with a specific activity of 500 mol/min x mg and a molecular weight of 17 kDa, 0.1 mg GLT-ALA-ALA-Pro-phenyl-alanine-4-nitroanilide, incubation is carried out for 20 minutes at 5 o C followed by spectrophotometry at 410 nm and determination of the concentration of cyclosporine A using a calibration curve.

Formula of invention

A method for determining cyclosporin A in the blood, including treating a blood sample with reagents and analyzing the reaction results, characterized in that, in order to simplify and increase the efficiency of the method, the blood sample is treated with a mixture consisting of 4.2 ml of 0.035 M Hepes buffer solution with pH 7, 8 petidyl-prolyl-cis-trans isomerase with a specific activity of 500 mol/min mg and mol. m. 17 kDa, 0.1 mg GLT-ALA-ALA-Pro-phenyl-alanine-4-nitroanilide, incubation is carried out for 20 minutes at 5 o C, followed by spectrophotometry at 410 nm and determination of the concentration of cyclosporine A using a calibration curve .

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Cyclosporine(cyclosporine A) is an immunosuppressive drug that is often used before and after organ transplantation to suppress unwanted immune responses. Overdoses of cyclosporine have been reported in cases of suicide attempts and accidental errors during treatment. Oral overdose up to 150 mg/kg (10-30 times the recommended dose) was accompanied by minor but obvious symptoms (vomiting, dizziness, headache and episodic hypertension). Parenteral overdose is fraught with death due to the development of renal failure, especially in newborns. However, all patients, except one premature infant, survived as a result of symptomatic and supportive therapy.

A) Structure and classification. Cyclosporine is a neutral, lipophilic undeca peptide with a molecular weight of 1203.

b) Application. Cyclosporine is used to prevent rejection of renal, liver and cardiac allografts. The possibilities of its use in psoriasis, persistent atopic dermatitis, uveitis, rheumatoid arthritis, nephrotic syndrome, Crohn's disease, aplastic anemia, primary biliary cirrhosis, Wilson's lichen, allergic asthma, autoimmune hemolytic anemia and myasthenia gravis are being investigated.

V) Dosage forms. Cyclosporine (Sandimmune) is available as 25 and 100 mg liquid-filled capsules (with 12.7% anhydrous alcohol) and a 100 mg/mL solution (with 12.5% ​​alcohol, olive oil, and polyethylene glycol 5-oleate) for oral administration. reception. Parenteral concentrate for injection and intravenous infusion (Sandimmune IV) contains 50 mg/ml cyclosporine (with 32.9% alcohol and 650 mg/ml polyoxyl-35-castor oil). To avoid interaction with plasticizers in IV bags, cyclosporine is administered from glass vials.

G) Source. Cyclosporine is one of several biologically active antibiotics produced by the fungi Tolypocladinum inflation Gams and Cylindrocarpon lucidum Booth.

d) Therapeutic dose. To prevent allograft rejection in adults and children, cyclosporine is usually administered once 4-12 hours before transplantation at a dose of 15 (14-18) mg/kg. The standard postoperative dose is 15 (14-18) mg/kg once a day for 1-2 weeks, followed by a 5% reduction every week (6-8 weeks) to a maintenance dose of 5-10 mg/kg per day. If the patient is unable to take cyclosporine orally, the usual intravenous dose in children and adults is 5-6 mg/kg per day 4-12 hours before transplant. The standard postoperative dose of 5-6 mg/kg is administered until the person is able to take the medication by mouth. Corticosteroids are often used in conjunction with cyclosporine to prevent allograft rejection.

e) Toxic dose of cyclosporine. In one case, an adult ingested 25,000 mg for 8 days and survived. Two adults and one child were accidentally given 5000 mg cyclosporine and also survived. A 37-year-old woman took 7500 mg during a suicide attempt; she had mild clinical symptoms. A 2-year-old child who received 240 mg developed hypotension, stridor, pallor, and tachycardia; he survived. The neonate receiving 400 mg/kg experienced cyanosis, metabolic acidosis, respiratory depression, and renal failure; he also survived. Oral overdoses in the range from 10 to 150 mg/kg were accompanied by only mild symptoms of intoxication. One adult patient was mistakenly given 250 mg of cyclosporine with ornithine vasopressin intravenously over 30 minutes; after 15 minutes he experienced anxiety and an irregular weak pulse. Another patient was accidentally given an intravenous infusion of 30 mg/kg per day (1.1 mg/kg per hour) over 33 hours; he survived. The highest reported total dose of cyclosporine is close to 10 g.

and) Lethal dose of cyclosporine. A premature newborn received 178 mg/kg intramuscularly. He developed metabolic acidosis and renal failure and subsequently died.

h) Toxicokinetics of cyclosporine:

- Suction. Cyclosporine shows two- to three-fold differences in the rate of absorption and elimination in different patients. Peak plasma concentrations are reached after approximately 2.5 hours. After oral administration, the drug is metabolized according to the first pass effect in the liver. Absolute bioavailability with this dose is about 35%. Perhaps part of its relatively low value is due to the strong metabolization of cyclosporine by cytochrome P450IIIA in the enterocysts lining the intestinal wall. Erythromycin, a known P450IIIA inhibitor, always increases the maximum blood concentration of cyclosporine when administered orally, but not after intravenous administration. Oral administration of 600 mg of the drug leads to an average peak plasma concentration of 540 ng/ml after 3-4 hours. The peak concentration of cyclosporine in blood and plasma, determined by high performance liquid chromatography (HPLC), is approximately 1.4 -2.7 ng/ml per 1 mg oral dose. The unbound fraction ranges from 1-2.4% (i.e. 99-97.6% of the drug is bound to proteins, mainly lipoproteins). Approximately 50% of cyclosporine in whole blood is bound to red blood cells.

- Distribution. In the clinic, cyclosporine can be administered by continuous intravenous infusion during the first days after transplant and then twice daily orally to achieve a plasma concentration of 75-150 ng/ml measured by HPLC, which is equivalent to its level in whole blood determined by radioimmunoassay. analysis, 300-600 ng/ml. Maintaining this concentration of the drug in plasma appears to be safe for the patient, but still does not eliminate the risk of nephrotoxicity. Due to the preferential distribution of cyclosporine and its metabolites into red blood cells, its blood levels are generally higher than plasma levels. When the drug concentration in the blood, determined by radioimmunoassay, is 300-600 ng/ml, in the cerebrospinal fluid it ranges from 10 to 50 ng/ml. The apparent volume of distribution in children under 10 years of age is close to 35 l/kg, and in adults - 4.7 l/kg.

- Removal. The half-life of an oral dose of 350 mg is 8.9 hours, and a dose of 1400 mg is 11.9 hours. Elimination occurs mainly through metabolization in the liver with the formation of 18-25 derivatives. Metabolites of cyclosporine have low immunosuppressive activity. Cyclosporine is extensively metabolized in the liver by the cytochrome P450IIIA oxidase system; however, neurotoxic and possibly nephrotoxic symptoms are usually correlated with elevated blood levels of derivatives of this drug. Only 0.1% of the dose is excreted unchanged.

- Drug interactions. Cyclosporine increases the volume of distribution, half-life and renal excretion of digoxin. It potentiates vecuronium blockade and prolongs its duration. The table below lists drugs with a clinically established effect on the metabolism of cyclosporine.

- Pregnancy and lactation. Cyclosporine crosses the placenta and is distributed into breast milk.

And) Mechanism of action. The main immunological effect of cyclosporine is the suppression of T-lymphocyte proliferation. It reversibly inhibits the activation of primary T helper cells and the subsequent release of many of their lymphokines. Its use is not combined with bone marrow suppression. The formation and secretion of interleukin-2 is reduced. In addition, cyclosporine inhibits the formation of interferon gamma by lymphocytes. It is able to suppress the delayed-type hypersensitivity reaction.

The concentration of cyclosporine in the blood when used in therapeutic doses (peak concentration) is 150-400 mg/ml. Toxic concentration - more than 400 mg/ml.

The half-life of cyclosporine is 6-15 hours.

Cyclosporine is widely used as an effective immunosuppressant to suppress graft-versus-host disease after bone marrow, kidney, liver, heart transplantation and in the treatment of certain autoimmune diseases.

Cyclosporine is a fat-soluble peptide antibiotic that disrupts the differentiation of T lymphocytes at an early stage and blocks their activation. It suppresses the transcription of genes encoding the synthesis of IL-2, 3, γ-interferon and other cytokines produced by antigen-stimulated T lymphocytes, but does not block the influence of other lymphokines on T lymphocytes and their interaction with Ag.

The drug is administered intravenously and taken orally. For organ transplantation, treatment begins 4-12 hours before the transplant operation. For red bone marrow transplantation, the initial dose of cyclosporine is administered on the eve of surgery.

Typically, the initial dose of the drug is administered intravenously slowly (dropwise over 2-24 hours) in a 0.9% sodium chloride solution or 5% glucose solution at a rate of 3-5 mg/(kg-day). Subsequently, intravenous injections are continued for 2 weeks, and then switched to oral maintenance therapy at a dose of 7.5-25 mg/kg daily.

After oral administration, cyclosporine is slowly and incompletely absorbed (20-50%). In the blood, 20% of cyclosporine binds to leukocytes, 40% to erythrocytes and 40% is found in plasma on HDL. Due to this distribution of cyclosporine, determination of its concentration in the blood is preferable to that in plasma or serum, since it more realistically reflects the true concentration. Cyclosporine is almost completely metabolized in the liver and excreted in bile. The half-life of the drug is 6-15 hours. Anticonvulsants increase the metabolism of cyclosporine, and erythromycin, ketoconazole and calcium channel blockers reduce it. The peak concentration of cyclosporine when taken orally is noted after 1-8 hours (on average after 3.5 hours), the decrease in concentration occurs after 12-18 hours. When administered intravenously, the peak concentration of cyclosporine in the blood occurs 15-30 minutes after the end of administration, reduction occurs after 12 hours.

The basic principle of optimal use of cyclosporine is a balanced choice between individual therapeutic and toxic concentrations of the drug in the blood. Since cyclosporine has pronounced intra- and interindividual variability in pharmacokinetics

and metabolism, it is very difficult to select an individual dose of the drug. In addition, the dose of cyclosporine taken does not correlate well with its concentration in the blood. In order to achieve the optimal therapeutic concentration of cyclosporine in the blood, it is necessary to monitor it.

Rules for collecting blood for research. Whole venous blood is examined. Blood is taken into a tube with ethylenediaminetetraacetic acid 12 hours after taking or administering cyclosporine. For kidney transplantation, the therapeutic concentration of cyclosporine 12 hours after administration should be in the range of 100-200 mg/ml, for heart transplantation - 150-250 mg/ml, liver - 100-400 mg/ml, red bone marrow - 100-300 mg /ml [Tietz N., 1997]. Concentrations below 100 mg/ml do not have an immunosuppressive effect. However, in the first weeks after transplantation, if the concentration of cyclosporine is below 170 mg/ml, the transplant may be rejected, so it is necessary to maintain it at a level of 200 mg/ml or higher; after 3 months, the concentration is usually reduced to 50-75 ng/ml and maintained at this level level for the rest of the patient's life. Frequency of monitoring cyclosporine in the blood: daily for liver transplantation and 3 times a week for kidney and heart transplantation.

The most common side effect of cyclosporine is nephrotoxicity, occurring in 50-70% of kidney transplant patients and a third of heart and liver transplant patients. Cyclosporine nephrotoxicity can manifest itself as the following syndromes:

■ delayed onset of functioning of the transplanted organ, which occurs in 10% of patients not receiving cyclosporine and in 35% of those receiving it; this problem can be resolved by reducing the dose of cyclosporine;

■ reversible decrease in GFR (can occur at a concentration of cyclosporine in the blood of 200 mg/ml or more, and always develops at a concentration exceeding 400 mg/ml); serum creatinine concentration begins to increase on the 3-7th day after increasing the concentration of cyclosporine, often against the background of oliguria, hyperkalemia and decreased renal blood flow, and decreases 2-14 days after reducing the dosage of cyclosporine;

■ hemolytic-uremic syndrome;

■ chronic nephropathy with interstitial fibrosis, which causes irreversible loss of renal function.

Typically, these toxic effects are reversible when the dosage of the drug is reduced, but in most cases it is very difficult to differentiate cyclosporine nephrotoxicity from graft rejection.

Another serious, although less common, side effect of cyclosporine is hepatotoxicity. Liver damage develops in 4-7% of patients with transplants and is characterized by increased activity of ALT, AST, alkaline phosphatase and the concentration of total bilirubin in the blood serum. Manifestations of hepatotoxicity depend on the dose of cyclosporine and are reversible when the dosage is reduced.