Cycloral

Cycloral is a cyclic polypeptide consisting of 11 amino acids. It has an immunosuppressive effect.

The drug inhibits the development of cellular reactions, including immune protection against the allograft and delayed epidermal intolerance, as well as the development of GVHD pathology, allergic encephalomyelitis, arthritis associated with Freund's adjuvant, and along with this, the formation of antibodies, which depends on the activity of T-lymphocytes. [ 1 ]

Indications Cycloral

It is used in transplantology to prevent possible rejection after solid organ transplantation (including heart, lungs, kidneys, pancreas with liver or complex heart-lung transplant), and also after bone marrow transplantation. In addition, it is prescribed for the treatment of transplant rejection in individuals who have previously used other immunosuppressants.

Use in disorders not related to organ transplantation:

• endogenous uveitis (a dangerous type of active uveitis affecting the back or middle area of the eye, non-infectious in origin, when standard treatment is ineffective or causes severe side effects; Behcet's disease affecting the retina, in which relapses of inflammation are observed);
• nephrotic syndrome that occurs under the influence of GCS and is resistant to them, associated with damage to the glomerulus of blood vessels (in the following pathologies - segmental and focal glomerulosclerosis, myocardial infarction and membranous glomerulonephritis), - to induce and maintain remission, as well as to maintain remission caused by GCS, with their subsequent cancellation;
• rheumatoid arthritis in an active form and to a severe degree (in situations where standard slow-acting antirheumatic drugs have no effect or their use is impossible);
• psoriasis (in a severe degree, when standard treatment does not bring results or is impossible to perform);
• atopic dermatitis of a severe nature, when systemic treatment is required.

Release form

The release of the medicinal substance is realized in the form of capsules with a volume of 25, 50, 100 mg - 10 pieces inside a cellular pack (5 such packs inside a box). It is also produced inside polyethylene bottles - 50 or 100 pieces inside a bottle.

Pharmacodynamics

The drug blocks lymphocytes located at the Go or G1 stage of the cell cycle at the cellular level and inhibits the antigen-induced production and release of lymphokines (including IL-2, which are T-lymphocyte growth factors) that are activated by T-lymphocytes.

It is believed that the effect of Cycloral on lymphocytes is reversible. The drug does not inhibit hematopoiesis and does not affect the activity of phagocytic cells, which distinguishes it from cytostatics. [ 2 ]

Pharmacokinetics

When taken orally, the plasma Cmax value is observed after 17±0.3 hours. Stable absorption and low dependence on use with food and daily rhythm are observed. Due to these properties, the severity of interpersonal differences in pharmacokinetic parameters is reduced and a more uniform exposure relative to the drug is observed during the daily period and on different days.

Distribution occurs mainly outside the bloodstream; 33-47% of the drug is found in plasma, 4-9% in lymphocytes, 5-12% in granulocytes, and 41-58% in erythrocytes. [ 3 ]

In the blood plasma, about 90% of the drug is involved in protein synthesis (mainly with lipoproteins). It takes part in biotransformation, which includes various reactions leading to the formation of about 15 metabolic elements.

Excretion is mainly in the form of metabolic components, together with bile; 6% of the portion is excreted through the kidneys. The half-life is 7-19 hours (in individuals with severe forms of liver pathologies).

Dosing and administration

The drug is used orally, the dosage is selected and adjusted individually (laboratory and clinical indications are taken into account). The capsules are swallowed whole, without chewing.

In case of solid organ transplantation in adults, therapy begins 12 hours before the operation: at a dosage of 10-15 mg/kg, divided into 2 doses. During the period of 1-2 weeks after the operation, the drug is used daily in the specified dose, and then gradually reduced by 5% per week to a maintenance dose of 2-6 mg/kg per day in 2 doses (while it is necessary to monitor blood levels of cyclosporine).

In combination with GCS and other immunosuppressants, it can be used in lower doses (3-6 mg/kg per day at the initial therapeutic stage).

Bone marrow transplant.

On the day before transplantation, as well as during the post-transplantation period (up to 14 days), cyclosporine should be administered intravenously. After this, the patient is transferred to maintenance therapy with Cycloral in a dose of 12.5 mg / kg per day in 2 applications. The maintenance period lasts at least 3-6 months (six months are recommended), and then the dosage is gradually reduced to stop therapy 1 year after transplantation.

If GVHD develops, therapy is resumed; in mild cases of chronic disorders, low doses of the drug are used.

For children over 2 years of age, the medication is prescribed in adult portions. Doses exceeding adult doses may also be used.

During maintenance treatment, the dose is gradually reduced until the minimum effective dose is obtained (during remission it should not exceed 5 mg/kg per day).

Endogenous form of uveitis.

To induce remission, the drug is first used in a daily dose of 5 mg/kg in 2 doses - until visual acuity improves and symptoms of active inflammation disappear. In difficult-to-treat cases, the dose can be increased to 7 mg/kg per day for a short period.

Nephrotic syndrome.

To induce remission, it is necessary to use 5 mg/kg per day (for an adult) and 6 mg/kg in 2 doses (for a child). The portions are calculated for people with healthy kidney function, without taking into account proteinuria. People with renal dysfunction should use the drug in a dosage of no more than 2.5 mg/kg per day.

Portions are selected individually, taking into account the values of effectiveness (proteinuria) and safety (serum creatinine), but it is prohibited to exceed the daily dosage of 5 mg/kg (adult) and 6 mg/kg (child).

During maintenance treatment, the dosage is gradually reduced to the lowest effective dose.

Rheumatoid arthritis.

During the first 1.5 months of therapy, it is necessary to use 3 mg/kg per day in 2 doses. If the effect of the drug is insufficient (subject to good tolerability), the dose can be gradually increased to a maximum of 5 mg/kg.

The treatment lasts up to 3 months. During maintenance treatment, the dose is selected individually, taking into account the tolerance of the drug.

Psoriasis.

The portion size is determined individually. Remission induction usually requires the use of 2.5 mg/kg per day in 2 doses. If no improvement is observed after 1 month of treatment, the daily dose is gradually increased (but not higher than 5 mg/kg). If there are no positive changes after 1.5 months of therapy using a daily dose of 5 mg/kg (or if the appropriate dosage does not meet the established safety restrictions), it is discontinued.

Maintenance doses are selected individually (the lowest effective dose) and should not exceed 5 mg/kg per day.

Atopic form of dermatitis.

The dosage is selected individually. At first, it is recommended to use 2.5-5 mg/kg per day (in 2 doses). If there are no positive changes when using the initial dosage of 2.5 mg/kg, it can be increased to the maximum level (5 mg/kg) over a period of 2 weeks. If the patient's case is extremely severe, adequate and rapid control of the pathology can be achieved by using a dose of 5 mg/kg per day at once. After obtaining the desired effect, the dose is gradually reduced, after which, if possible, Cycloral should be discontinued. If a relapse occurs, a repeat cycle can be prescribed.

Although a 2-month course of treatment is sufficient to cleanse the epidermis, it has been established that treatment lasting up to 1 year is tolerated without complications and shows good efficiency (under conditions of constant monitoring of important vital signs).

Use Cycloral during pregnancy

It is prohibited to prescribe Cycloral during pregnancy (due to lack of clinical data). It is necessary to stop breastfeeding during the period of therapy.

Contraindications

Contraindicated for use in case of severe sensitivity to the medication.

Side effects Cycloral

Main side effects:

• urogenital disorders: renal dysfunction sometimes occurs, with an increase in serum urea and creatinine levels (depending on the dosage and observed during the first weeks of therapy). Long-term use may cause interstitial fibrosis (must be distinguished from changes associated with chronic rejection);
• liver and gastrointestinal tract damage: nausea, abdominal pain, anorexia, diarrhea, pancreatitis and vomiting; treatable liver dysfunctions may be observed - an increase in bilirubin and transaminase levels (depending on the dosage);
• problems with the functioning of the cardiovascular system and the blood system (hemostasis and hematopoiesis): blood pressure often increases (especially in people after a heart transplant). Rarely, anemia and thrombocytopenia are observed, which occurs due to kidney failure and hemolytic anemia of the microangiopathic type (HUS);
• disorders of the sensory organs and the nervous system: paresthesia, headaches and convulsions may occur. Muscle spasms and weakness, tremor and myopathy occasionally develop. In people after liver transplantation, symptoms of visual impairment, impaired motor activity and consciousness, as well as encephalopathy occur;
• metabolic disorders: amenorrhea and treatable dysmenorrhea; hyperuricemia and -kalemia, as well as hypomagnesemia. Rarely, a weak reversible increase in serum lipid values is observed;
• signs of allergy: epidermal rashes;
• others: fatigue, swelling, hypertrichosis, gingival hypertrophy and weight gain. Lymphatic proliferative and malignant pathologies may occur (also in people with nephrotic syndrome). Malignant neoplasms (e.g. epidermal) may occur with psoriasis.

Overdose

Signs of overdose include: renal dysfunction.

Symptomatic and non-specific actions are performed (starting with gastric lavage). Hemoperfusion and hemodialysis procedures do not have the desired effect.

Interactions with other drugs

The drug reduces the clearance rates of prednisolone.

When using Cycloral together with potassium-containing substances and potassium-sparing diuretics, the likelihood of hyperkalemia increases.

Combination with aminoglycosides, trimethoprim, NSAIDs, as well as ciprofloxacin, amphotericin B and colchicine increases the risk of developing nephrotoxicity.

Combination with lovastatin (or colchicine) increases the likelihood of developing weakness and myalgia.

Plasma levels of the drug are increased by doxycycline, certain macrolides (including josamycin and erythromycin), ketoconazole, propafenone, oral contraception, certain calcium channel blockers (including diltiazem and verapamil and nicardipine), and high doses of methylprednisolone.

Plasma values of the drug are reduced when combined with phenytoin, barbiturates, metamizole Na, rifampicin and carbamazepine. Trimethoprim with sulfadimezine (in case of their intravenous administration) have a similar effect.

Storage conditions

Cycloral should be stored in a dark place, out of reach of children. The medicine should not be kept in the refrigerator. Temperature indicators – no more than 25 °C.

Shelf life

Cycloral can be used for a period of 24 months from the date of sale of the therapeutic substance.

Analogues

The analogs of the drug are Imusporin, Cellcept, Arava and Ekvoral with Panimun, as well as Myfortic and Lifemun.