Intron a solution for in 18 million IU/1.2 ml 1 syringe pen in Severny (Moscow)

Intron A is a drug that has antitumor, immunomodulatory and antiviral effects on the body. Its activity is determined in IU. Interferons bind specific substances located on damaged cells, after which they change their structure. As a result, the spread of the virus slows down.

Intron A

The therapeutic effect of Intron A is due to the following factors:

• Inhibition of the vital activity of the virus.
• Suppression of proliferation of functional cells.
• Activation of macrophages.
• Increased cytotoxicity of leukocytes relative to pathogens.

The drug Intron A is obtained through hybridization. Its active substance contains arginine, located at position 23. This is the main difference between interferon alpha 2b and other drugs from this group.

Indications for use

This drug is prescribed to patients from different age categories. The reasons for its appointment are the following diseases:

• Hepatitis B in chronic form. The diagnosis is confirmed by detecting HBeAg and HBV in the blood. In addition to the main pathology, there is a history of fibrosis and (or) inflammation of parenchymal tissue. Additional conditions include increased ALT activity. The patient must be over 1 year old.
• Advanced hepatitis C. The clinical picture includes symptoms of transaminase activity and liver dysfunction at the stage of decompensation. In this case, the drug is prescribed only to adult patients.
• Chronic form of hepatitis C in children over 3 years of age. The existing symptoms indicate a compensated course of the disease. Intron A will be effective if the patient has not previously been treated with this drug.

Intron A is used for relapses of hepatitis C as part of combined therapy. In addition to it, it also contains Ribavirin. The medicine is approved for use as a primary remedy for carcinoid syndrome, laryngeal papillomatosis, developing kidney cancer, leukemia (hairy cell form), multiple myeloma.

Intron A will have a positive effect after surgery, the reason for which was malignant melanoma. The drug is also prescribed for chronic myeloid leukemia, thrombocytosis, follicular lymphoma, and Kaposi's sarcoma caused by immunodeficiency syndrome. In the latter case, Intron A is prescribed if there are several important nuances, among them: the absence of opportunistic infections (regardless of the type), the CD4 cell level is not more than 250/mm³.

Intron A is used only with a confirmed diagnosis. The dosage, duration of therapy and the order of administration are determined based on the results of specific laboratory tests and instrumental studies.

Intron a 18 million IU 1.2 ml 1 pc. solution for intravenous and subcutaneous administration syringe pen

pharmachologic effect

Pharmacological action - antiviral, immunomodulatory, antitumor.
Pharmacological and immunological properties

Interferons act on cells by binding to specific receptors on their surface.

The results of several studies indicate that after binding to the cell membrane, interferon causes a complex sequence of intracellular reactions, including. induction of certain enzymes. It is believed that at least partially these processes determine the cellular effects of interferon, including suppression of viral replication in infected cells, inhibition of cell proliferation, as well as the immunomodulatory properties of interferon - increased phagocytic activity of macrophages and an increase in the specific cytotoxicity of lymphocytes towards “target cells”. These effects determine the therapeutic effect of interferon.

Recombinant interferon alpha-2β has an antiproliferative effect both against human and animal cell cultures and against xenografts of human and animal tumors. Significant immunomodulatory activity of recombinant interferon alpha-2β in vitro has been demonstrated. Recombinant interferon alpha-2β also inhibits viral replication in vitro and in vivo.

Composition and release form Intron a 18 million IU 1.2 ml 1 pc. solution for intravenous and subcutaneous administration syringe pen

Solution for injection - 1 vial:

• recombinant interferon alpha-2b - 10/18/25 million IU;
• excipients: sodium hydrogen phosphate anhydrous; sodium dihydrogen phosphate monohydrate; disodium edetate; sodium chloride; metacresol (preservative); polysorbate 80; water for injections

in bottles of 1 ml/10 million IU (1 dose), 3 ml/18 million IU (6 doses of 3 million IU), 2.5 ml/25 million IU (5 doses of 5 million IU); 1 bottle in a cardboard pack.

Solution for injection - 1 syringe pen:

• recombinant interferon alpha-2b - 18/30/60 million IU;
• excipients: sodium hydrogen phosphate anhydrous; sodium dihydrogen phosphate monohydrate; disodium edetate; sodium chloride; metacresol (preservative); polysorbate 80; water for injections

in syringe pens, 1.2 ml (6 doses of 3 million IU - 18 million IU; 6 doses of 5 million IU - 30 million IU; 6 doses of 10 million IU - 60 million IU); complete with 6 needles and 6 napkins in a plastic tray; 1 set in a cardboard pack.

Description of the dosage form

Transparent colorless solution.

Characteristic

The drug is a water-soluble globular protein with a molecular weight of about 19,300 daltons, synthesized by a strain of Escherichia coli containing a plasmid hybrid obtained by genetic engineering methods, into the genetic apparatus of which the human leukocyte interferon alpha-2β gene is integrated.

Directions for use and doses

SC, IV (only for malignant melanoma).

Treatment is prescribed by a doctor who has experience in treating the relevant disease.

According to the doctor’s decision, the patient can independently administer the drug subcutaneously to continue the selected therapy regimen.

Chronic hepatitis B. The recommended dose for adults is 30 to 35 million IU per week subcutaneously at either a dose of 5 million IU daily or 10 million IU 3 times a week for 4 months (16 weeks).

For children from 1 year to 17 years inclusive, Intron A is administered subcutaneously at an initial dose of 3 million IU/m2 3 times a week (every other day) during the first week of treatment, followed by an increase in dose to 6 million IU/m2 (maximum - up to 10 million IU/m2) 3 times a week (every other day). The duration of treatment is 4–6 months (16–24 weeks).

Treatment is stopped in the absence of positive dynamics (according to a DNA study of hepatitis B virus (HBV) after 3-4 months of treatment with the drug at the maximum tolerated dose.

Recommendations for dose adjustment: the dose of the drug should be reduced by 50% if disorders of the hematopoietic system develop (leukocytes less than 1500/mm3, granulocytes - less than 1000/mm3 in children and less than 750/mm3 in adults, platelets - less than 100,000/mm3 in children and less than 50,000/mm3 in adults).

Therapy should be discontinued in case of severe leukopenia (white blood cells less than 1200/mm3), neutropenia (granulocytes less than 750/mm3 in children and less than 500/mm3 in adults) or thrombocytopenia (platelet less than 70,000/mm3 in children and less than 30,000/mm3 in adults). Treatment can be resumed at the previous dose after normalization or return to the original level of the number of leukocytes, granulocytes and platelets.

Chronic hepatitis C. SC at a dose of 3 million IU 3 times a week (every other day) as monotherapy or in combination with ribavirin.

Treatment of patients with relapse after a course of alpha-interferon monotherapy. Intron A is prescribed only in combination with ribavirin. Based on the results of clinical studies conducted over 6 months, the recommended duration of combination treatment with ribavirin is 6 months.

Treatment of patients who have not previously received therapy. The effectiveness of Intron A increases when used simultaneously with ribavirin. Monotherapy with the drug is carried out only if there are contraindications to the use or intolerance to ribavirin.

Use of Intron A in combination with ribavirin. Based on the results of clinical studies conducted over 12 months, the recommended duration of combination therapy with ribavirin is at least 6 months.

In patients with genotype 1 virus and a high content of viral RNA (according to the results of a study conducted before the start of therapy), in whom hepatitis C virus RNA (HCV RNA) is not detected in the blood serum by the end of the first 6 months of therapy, treatment is continued for another 6 months ( i.e. a total of 12 months). When deciding whether to carry out combination therapy for 12 months, other negative prognostic factors should also be taken into account: age over 40 years, male gender, progressive fibrosis. Clinical studies have shown that in patients in whom HCV RNA is still detectable after 6 months of therapy, continued treatment does not lead to the elimination of HCV RNA.

When using Intron A in combination with ribavirin, patients with impaired liver function and patients over 50 years of age should be carefully monitored due to the possible development of anemia.

Children aged 3 years and older - subcutaneous injection of 3 million IU/m2 2 times a week in combination with oral ribavirin at a dose of 15 mg/kg daily, dividing this dose into morning and evening.

Monotherapy with Intron A. It is recommended to use it for at least 3-4 months, after which HCV RNA should be determined. Then treatment is continued only if HCV RNA is not detected.

For patients who tolerate therapy well, with normalization of ALT at 16 weeks of treatment, the recommended course of treatment is from 18 to 24 months.

Laryngeal papillomatosis. The recommended dose is 3 million IU/m2 subcutaneously 3 times a week (every other day). Treatment begins after surgical (laser) removal of the tumor tissue. The dose is selected taking into account the tolerability of the drug. To achieve a positive response, therapy may be required for more than 6 months.

Hairy cell leukemia. The recommended dose of Intron A for subcutaneous administration to patients after and without splenectomy is 2 million IU/m2 3 times a week. In most cases, normalization of one or more hematological parameters occurs after 1–2 months of treatment. Normalization of peripheral blood parameters (white blood cell count, platelet count and hemoglobin level) may require up to 6 months of treatment. This dosage regimen should be followed continuously, unless rapid progression of the disease or severe intolerance to the drug occurs.

Chronic myeloid leukemia. The recommended dose is 4 to 5 million IU/m2 daily, subcutaneously.

In some cases, the combination of Intron A at a dose of 5 million IU/m2, prescribed daily subcutaneously, with cytarabine (Ara-C) at a dose of 20 mg/m2 subcutaneously for 10 days a month is effective (maximum daily dose - 40 mg). After normalization of the leukocyte count, Intron A is administered at the maximum tolerated dose (4 to 5 million IU/m2/day) to maintain hematological remission. Intron A should be discontinued after 8–12 weeks of treatment unless at least partial hematologic remission or a clinically significant decrease in the white blood cell count has been achieved by this time.

Thrombocytosis in patients with chronic myeloid leukemia. The same doses are recommended as for the treatment of chronic myeloid leukemia. Dose adjustments used to control white blood cell counts may also be used to control platelet counts. Clinical data indicate that approximately 1/4 (26%) of patients with chronic myeloid leukemia have concomitant thrombocytosis (platelet count more than 500·109/l). A decrease in platelet count was achieved in all patients after 2 months of treatment. The platelet count was never less than 80·109/L when monitored monthly.

Multiple myeloma. Maintenance therapy: for patients who, as a result of induction therapy, have reached a plateau phase (a decrease in paraprotein by more than 50%), Intron A can be prescribed as monotherapy - subcutaneously at a dose of 3 million IU/m2 3 times a week.

Follicular lymphoma. In combination with chemotherapy, Intron A is prescribed subcutaneously at a dose of 5 million IU 3 times a week (every other day) for 18 months. It is recommended to use CHOP chemotherapy regimens. Clinical data are only available for the use of CHVP (a combination of cyclophosphamide, doxorubicin, teniposide and prednisolone) in 6-month cycles and subsequent 6 cycles every 2 months.

Kaposi's sarcoma associated with AIDS. The optimal dose has not been established. The effectiveness of Intron A at a dose of 30 million IU/m2 when administered 3–5 times a week subcutaneously has been demonstrated. The drug was also used in lower doses (10–12 million IU/m2/day) without a noticeable decrease in effectiveness. If the disease is stabilized or there is a clinical response to treatment, therapy is continued until tumor growth is noted or drug discontinuation is required due to the development of a severe opportunistic infection or side effect. Therapy can be carried out on an outpatient basis.

Simultaneous use with zidovudine. In clinical studies, patients with AIDS and Kaposi's sarcoma received Intron A in combination with zidovudine. In most cases, the following treatment regimen was well tolerated by patients: Intron A at a dose of 5–10 million IU/m2; zidovudine - 100 mg every 4 hours. The main toxic effect that limited the dose was neutropenia.

Treatment with Intron A can be started with a dose of 3–5 million IU/m2/day. After 2–4 weeks, the dose can be increased by 5 million IU/m2/day - up to 10 million IU/m2/day, taking into account tolerability; The dose of zidovudine can be increased to 200 mg every 4 hours. The dose should be selected individually, taking into account effectiveness and tolerability.

Kidney cancer. Monotherapy: the optimal dose and regimen have not been established. Intron A was used subcutaneously in doses from 3 to 30 million IU/m2 3 or 5 times a week or daily. The maximum effect was observed with subcutaneous application in doses of 3–10 million IU/m2 3 times a week.

In combination with other drugs such as IL-2: the optimal dose has not been established. In combination with IL-2, Intron A was used subcutaneously in doses of 3–20 million IU/m2. In clinical studies, the response rate to treatment was maximum with subcutaneous administration of Intron A at a dose of 6 million IU/m2 3 times a week; the dose was adjusted individually during treatment.

Carcinoid tumors. The standard dose is 5 million ME (3–9 million ME) subcutaneously 3 times a week (every other day). In patients with an advanced process, a dose of up to 5 million IU may be required daily. During surgical treatment, Intron A therapy is temporarily suspended for the duration of the operation and the recovery period after it. Therapy with the drug is continued until a clinical response to the treatment is observed.

Malignant melanoma. To induce postoperative remission Intron A - IV at a dose of 20 million IU/m2/day 5 days a week for 4 weeks. The dose calculated in this way is added to 100 ml of 0.9% sodium chloride solution and administered as an infusion over 20 minutes. Treatment should begin up to 56 days after surgery. For maintenance therapy, the recommended dose is 10 million IU/m2 subcutaneously 3 times a week (every other day) for 48 weeks.

If severe side effects develop during Intron A therapy (in particular, when the granulocyte count decreases to less than 500/mm3 or ALT/AST increases to values ​​exceeding the upper limit of normal by 5 times), the use of the drug is temporarily stopped until the parameters normalize. Treatment is then resumed using a dose reduced by 50%. If intolerance persists or the granulocyte count decreases to 250/mm3, or the activity of ALT and/or AST increases to values ​​exceeding the upper limit of normal by 10 times, the drug is discontinued.

Although the optimal (minimum) dose to achieve an adequate clinical effect has not been established, Intron A should be prescribed at recommended doses, taking into account their possible correction due to toxic effects, as described above.

Rules for the preparation and administration of solutions

Before administration, it is necessary to visually verify that there are no visible particles or changes in the color of the solution. The contents of the bottle or syringe pen are used to treat only one patient.

Intron A injection solution in vials can be used for intravenous or subcutaneous administration immediately after taking the required dose from the vial using a sterile injection syringe (glass or plastic).

Preparation of a solution for intravenous administration. The infusion should be carried out immediately after preparing the solution. To measure the required dose of the drug, you can use a bottle of any size; in this case, the final concentration of interferon alpha-2β in sodium chloride solution should be at least 0.3 million IU/ml. The appropriate dose of the drug is taken from the bottle, added to 100 ml of 0.9% sodium chloride solution in a PVC bag or glass bottle for infusion and administered intravenously over 20 minutes.

The simultaneous administration of other drugs together with Intron A is unacceptable.

The use of other solvents is unacceptable.

Intron A injection solution in syringe pens is administered subcutaneously immediately after attaching the injection needle and dialing the required dose.

The drug should be removed from the refrigerator 30 minutes before the injection so that the solution warms up to room temperature (up to 25 ° C).

After opening the package, it is recommended to use the drug within 4 weeks if stored at a temperature of 2 to 8 °C. A new needle should be used for each dose. After the injection, the needle should be thrown away and the syringe pen should be immediately placed in the refrigerator.

Pharmacodynamics

Although the exact mechanism of the antiviral action of recombinant interferon alpha-2β is not known, it has been established that it disrupts the metabolism of the cell into which the virus has entered. This leads to suppression of viral replication, and in cases where replication does occur, virions with a damaged genome are not able to leave the cell.

Chronic hepatitis B: Clinical studies of interferon alpha-2β for 4 to 6 months indicate that therapy can lead to clearance of hepatitis B virus (HBV) DNA and improvement in liver histology.

Chronic hepatitis C. The use of Intron A as monotherapy or in combination with ribavirin was studied in 4 randomized phase III clinical trials in 2552 patients with chronic hepatitis C who had not previously received interferon therapy. The studies compared the effectiveness of monotherapy or combination therapy with ribavirin. The effectiveness of therapy was determined based on the absence of viral replication 6 months after the end of treatment.

All patients had chronic hepatitis C, confirmed by a positive polymerase chain reaction (PCR reaction more than 100 copies/ml) for hepatitis C virus (HCV) RNA, liver biopsy data with histological confirmation of chronic hepatitis and the absence of any other cause for its occurrence, and increased ALT activity.

Intron A was prescribed at a dose of 3 million IU 3 times a week as monotherapy or in combination with ribavirin. The majority of patients received treatment for 1 year. All patients were observed for 6 months after the end of therapy to determine the duration of retention of results.

Combination therapy with ribavirin and Intron A significantly increased the effectiveness of therapy in all subgroups of patients. HCV genotype and the amount of viral RNA before therapy are prognostic factors. Improved results when using combination therapy are noted especially in patients who are difficult to treat (with genotype 1 virus and high levels of HCV RNA in the blood serum).

Strict adherence to the treatment regimen significantly improves treatment results. Regardless of viral genotype, patients who received 80% or more of the course of therapy (ribavirin + Intron A) had better long-term results than patients who received less than 80% of the course of therapy (sustained virological response in 56% of cases compared with 36% in data from study CI98/580).

Treatment of relapse: 345 patients received Intron A in the studies as monotherapy or in combination with ribavirin for relapse. In this group of patients, the addition of ribavirin to Intron A caused a 10-fold increase in the effectiveness of treatment compared with Intron A monotherapy (48.6 and 4.7%), which was manifested by the elimination of HCV RNA from the blood serum (less than 100 copies/ml when performing PCR -reactions), reduction of liver inflammation and normalization of ALT. Moreover, these results persisted 6 months after the end of therapy (sustained virological response).

Pharmacokinetics

The pharmacokinetics of Intron A were studied in healthy volunteers with a single dose of 5 million IU/m2 intramuscularly, subcutaneously and via intravenous infusion for 30 minutes. Mean serum interferon concentrations were comparable after subcutaneous and intramuscular administration. In this case, Cmax was achieved in 3–12 hours; T1/2 both after intramuscular and subcutaneous administration was approximately 2–3 hours: the interferon content in the blood serum was not determined after 16–24 hours. The bioavailability of the drug after subcutaneous administration was 100%.

After intravenous administration, the concentration of interferon in plasma reached maximum values ​​(135–273 IU/ml) at the end of the infusion, then decreased somewhat faster than after subcutaneous or intramuscular injections, and was not determined 4 hours after the end of the infusion; T1/2 was about 2 hours.

The concentration of interferon in urine was below the detectable value, regardless of the route of administration.

Interferon-neutralizing antibodies were determined in patients treated with Intron A during controlled clinical trials. The frequency of their detection was 2.9% in patients receiving Intron A therapy for cancer, and 6.2% in patients with chronic hepatitis. Antibody titers were low in almost all cases, and their detection was not associated with a decrease in the effectiveness of therapy or other autoimmune disorders.

Preclinical data on the safety of the drug

Although interferon is considered a species-specific substance, studies have been conducted on its toxicity in animals.

Administration of human recombinant interferon alpha-2β for 3 months was not accompanied by signs of toxicity in mice, rats, and rabbits. Administration of the drug to cynomolgus monkeys daily for 3 months at a dose of 20·106 IU/kg/day also did not lead to the appearance of noticeable signs of toxicity. Increasing the dose in monkeys to 100·106 IU/kg/day for 3 months led to a toxic effect.

Menstrual irregularities have been observed in studies using interferon in non-human primates.

The results of studies of the effect of interferon alpha-2β on reproduction in animals indicate the absence of a teratogenic effect in rats and rabbits. The drug also does not affect the course of pregnancy, fetal development and reproductive function in the offspring of rats treated with interferon alpha-2β.

Studies in rhesus monkeys have shown that high doses (90 and 180 times the recommended dose) of interferon alpha-2β cause abortion.

Relevant studies have not established the mutagenic effect of interferon alpha-2β.

Indications for use Intron a 18 million IU 1.2 ml 1 pc. solution for intravenous and subcutaneous administration syringe pen

• treatment of adults and children (from 1 year) with chronic hepatitis B with confirmed replication of the hepatitis B virus (presence of HBV DNA or HBeAg in the blood serum) in combination with increased ALT activity in the blood plasma and histologically confirmed active inflammatory process and/or liver fibrosis;
• chronic hepatitis C:
• monotherapy or in combination with ribavirin in adult patients who have increased transaminase activity, no signs of liver decompensation and HCV RNA or antibodies to the hepatitis C virus (anti-HCV) in the blood serum;
• in children (from 3 years old) with compensated liver disease who have not previously received treatment with interferon alfa-2β, and in adult patients with relapse after therapy with interferon alfa-2β (preferably in combination with ribavirin);

• monotherapy in adult patients with CML in the presence of the Philadelphia chromosome (Ph+) or bcr/abl translocation (clinical data show that hematological remission and cytogenetic response (major/minor) is achieved in the majority of patients, while major cytogenetic response is defined as the number of Ph+ leukemia cells in the bone marrow
• combination therapy in combination with cytarabine (during the first 12 months of treatment can significantly increase the number of large cytogenetic responses and significantly increase overall patient survival compared with interferon alpha-2β monotherapy after 3 years of treatment);

Contraindications

• hypersensitivity to any component of the drug;
• severe diseases of the cardiovascular system (including heart failure in the stage of decompensation, recent myocardial infarction, severe arrhythmia);
• severe impairment of liver or kidney function, incl. caused by metastases, chronic hepatitis with liver cirrhosis in the stage of decompensation, chronic hepatitis in patients who have received or are receiving immunosuppressants (except for a short course of corticosteroid therapy), autoimmune hepatitis;
• epilepsy and other central nervous system dysfunctions, mental illnesses and disorders in children and adolescents;
• history of autoimmune disease;
• use of immunosuppressants after transplantation;
• thyroid disease if it is not controlled by appropriate therapy;
• creatinine clearance below 50 ml/min - when prescribed in combination with ribavirin;
• pregnancy;
• lactation period;
• prescription for men whose partners are pregnant.

With caution: history of mental illness.

When prescribing Intron A in combination with ribavirin, the contraindications specified in the instructions for use of ribavirin should also be taken into account.

Application Intron a 18 million IU 1.2 ml 1 pc. solution for intravenous and subcutaneous administration, syringe pen during pregnancy and breastfeeding

There are no clinical data on the use of interferon alfa-2β during pregnancy.

Experimental studies on animals revealed toxic effects on reproduction. The significance of these data for humans is unknown.

During pregnancy, Intron A is used only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is not known whether the components of Intron A are excreted in breast milk.

Due to the possible risk of adverse effects of the drug in breastfed infants, if the drug is necessary in the mother, breastfeeding should be discontinued.

Overdose

To date, no cases of overdose accompanied by any clinical symptoms have been described.

Treatment: as with an overdose of any drug - symptomatic therapy, monitoring the functions of vital organs, regular monitoring of the patient’s condition.

Side effects Intron a 18 million IU 1.2 ml 1 pc. solution for intravenous and subcutaneous administration syringe pen

In clinical studies conducted across a wide range of indications and with a wide range of doses (from 6 million IU/m2 per week in hairy cell leukemia; up to 100 million IU/m2 per week in melanoma), the most common adverse events were fever, fatigue, headache, myalgia. Fever and fatigue resolved 72 hours after discontinuation of the drug. Although fever may be a symptom of the influenza-like syndrome that often occurs with interferon treatment, evaluation should be performed to rule out other possible causes of persistent fever.

The following safety profile was obtained from 4 clinical studies in patients with chronic hepatitis C who received Intron A as monotherapy or in combination with ribavirin for 1 year. All patients received 3 million IU of Intron A 3 times a week.

Table 2 shows adverse events occurring at a frequency greater than or equal to 10% in previously untreated patients receiving Intron A (or Intron A in combination with ribavirin) for 1 year. In general, the observed adverse events were mild or moderate.

Adverse events observed in patients with viral hepatitis C correspond to those observed when using Intron A for other indications, with some dose-dependent increase in incidence.

When using Intron A for other indications (in clinical and non-clinical studies) rarely (>|1/10000,

From the body as a whole: very rarely - swelling of the face.

Asthenic conditions (asthenia, malaise and fatigue), dehydration, palpitations, psoriasis, fungal infection and bacterial infection (including sepsis) have been reported.

From the immune system: very rarely - sarcoidosis or its exacerbation.

Various autoimmune and immune system-mediated disorders have been reported with the use of alpha interferons, including idiopathic or thrombotic thrombocytopenic purpura, rheumatoid arthritis, systemic lupus erythematosus, vasculitis and Vogt-Koyanagi-Harada syndrome.

Cases of acute hypersensitivity reactions, including urticaria, angioedema and anaphylaxis, have been reported.

From the cardiovascular system: rarely - arrhythmia (usually occurred in patients with a history of previous diseases of the cardiovascular system or with previous cardiotoxic therapy), transient reversible cardiomyopathy (noted in patients without a complicated history of the cardiovascular system); very rarely - arterial hypotension, myocardial ischemia and myocardial infarction.

From the central nervous system and peripheral nervous system: rarely - suicidal tendencies; very rarely - aggressive behavior, incl. directed at other people, suicide attempts, suicide, psychosis (including hallucinations), impaired consciousness, neuropathy, polyneuropathy, encephalopathy, cerebrovascular ischemia, cerebrovascular hemorrhage, peripheral neuropathy, convulsions.

On the part of the hearing organ: very rarely - hearing loss.

From the endocrine system: very rarely - diabetes mellitus, worsening of existing diabetes mellitus.

From the gastrointestinal tract: very rarely - pancreatitis, increased appetite, bleeding gums, colitis.

From the liver and biliary tract: very rarely - hepatotoxicity (including death).

Changes in teeth and periodontium. In patients receiving combination therapy with Nitron A and ribavirin, pathological changes in the teeth and periodontium were observed. Dry mouth during long-term combination therapy with ribavirin and Intron A may contribute to damage to the teeth and oral mucosa. Patients should brush their teeth twice a day and have regular dental checkups. In addition, some patients may experience vomiting.

Metabolism: rarely - hyperglycemia, hypertriglyceridemia.

From the musculoskeletal system: rarely - rhabdomyolysis (sometimes severe), leg cramps, back pain, myositis.

Skin: very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, necrosis at the injection site.

From the respiratory system: rarely - pneumonia; very rarely - pulmonary infiltrates, pneumonitis.

From the urinary system: very rarely - nephrotic syndrome, impaired renal function, renal failure.

From the hematopoietic system: very rarely, when using Intron A as monotherapy or in combination with ribavirin, aplastic anemia and complete aplasia of the red bone marrow were observed.

From the organ of vision: rarely - hemorrhage in the retina, focal changes in the fundus, thrombosis of the arteries and veins of the retina, decreased visual acuity, decreased visual fields, optic neuritis, papilledema.

Clinically significant changes in laboratory parameters: (more often noted when the drug was prescribed in doses of more than 10 million IU / day) - a decrease in the number of granulocytes and leukocytes, a decrease in hemoglobin levels and the number of platelets, an increase in the activity of alkaline phosphatase, LDH, the level of creatinine and serum urea nitrogen. An increase in the activity of ALT and AST in the blood plasma is noted as pathological when used for all indications except hepatitis, as well as in some patients with chronic hepatitis B in the absence of HBV DNA.

If adverse events develop during use of Intron A for any indication, the dose should be reduced or treatment should be temporarily interrupted until the adverse events are eliminated. If persistent or recurrent intolerance to an adequate dosage regimen develops or the disease progresses, Intron A therapy should be discontinued.

Drug interactions

Intron A should be used with caution simultaneously with opioid analgesics, hypnotics and sedatives, and drugs that potentially have a myelosuppressive effect, such as zidovudine.

Interferons can influence oxidative metabolic processes. This should be taken into account when used simultaneously with drugs that are metabolized by oxidation (including xanthine derivatives - aminophylline and theophylline). When using Intron A simultaneously with theophylline, it is necessary to monitor the concentration of the latter in the blood serum and, if necessary, adjust the dosage regimen.

When using Intron A in combination with chemotherapeutic drugs (cytarabine, cyclophosphamide, doxorubicin, teniposide), the risk of developing toxic effects (their severity and duration) increases, which can be life-threatening or lead to death (due to increased toxicity when using drugs together) .

When Intron A and hydroxyurea are used together, the incidence of cutaneous vasculitis may increase.

Pharmaceutical interaction. Intron A cannot be mixed with other medicinal substances except 0.9% sodium chloride solution.

Contraindications

Intron A is strictly prohibited for use by patients whose medical history includes:

Myocardial infarction

• changes in the cardiovascular system (severe arrhythmia, myocardial infarction);
• autoimmune pathologies;
• neurological disorders and mental disorders;
• diseases of the endocrine system (if there is no effective treatment).

When selecting a therapeutic regimen, the doctor must take into account the likelihood of an allergic reaction. Intron A, like other medications, can provoke the appearance of unpleasant symptoms due to individual intolerance to its components.

Also, people who are planning to conceive or are already expecting a child will have to refuse it (applies to both women and men). This is due to the fact that interferon alpha 2b has a negative effect on the reproductive system. A significant reason for revising the treatment regimen is:

• Functioning of the liver in decompensation mode (with chronic hepatitis complicated by cirrhosis).
• Taking immunosuppressants (exception: glucocorticosteroids for a short course).
• Creatinine clearance, which is less than 50 ml/min.
• Elderly age. Elderly age
• Immunodeficiency virus (if the therapeutic regimen includes antiretroviral drugs).
• Severe forms of chronic pathologies (arterial hypertension, obstructive pulmonary pathologies, severe myelosuppression, diabetes mellitus).
• Blood clotting disorders.
• Psoriasis, sarcoidosis (interferons can cause exacerbation).
• Undergoing chemotherapy.

Intron A is not recommended to be combined with medications from the group of narcotic painkillers, myelosuppressors, hypnotics and sedatives. It affects the metabolism of medications in the body and changes their pharmacological action. Therefore, self-medication is strictly prohibited. When taking Intron A, you should regularly undergo clinical studies to evaluate the effectiveness of the therapeutic regimen. This will help to correct it in a timely manner and prevent overdose.

Notes[ | ]

1. Brown T.A.
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2. Nucleic acids: from A to Z / B. Appel [et al.]. - M.: Binom: Laboratory of Knowledge, 2013. - 413 p. — 700 copies. — ISBN 978-5-9963-0376-2.
3. Gilbert W.
   Why genes in pieces? (English) // Nature. - 1978. - Vol. 271, no. 5645. - P. 501-501. - doi:10.1038/271501a0.
4. Poverennaya I.V., Roitberg M.A.
   Spliceosomal introns: properties, functions and evolution (Russian) // Biochemistry. - 2021. - T. 85, No. 7. - P. 851-862. - doi:10.31857/S0320972520070015.
5. Zhou Y. et al.
   GISSD: group I intron sequence and structure database (English) // Nucleic acids research. - 2008. - Vol. 36, no. suppl_1. — P. D31-D3. - doi:10.1093/nar/gkm766.
6. David Rearick, Ashwin Prakash, Andrew McSweeny, Samuel S. Shepard, Larisa Fedorova.
   Critical association of ncRNA with introns // Nucleic Acids Research. — 2011-3. - T. 39, issue. 6. - pp. 2357–2366. — ISSN 0305-1048. - doi:10.1093/nar/gkq1080.

Medicinal composition

Intron A is based on highly purified interferon alpha 2b, which is obtained from recombinant DNA. The active substance is a protein characterized by good water solubility. Intron A is sold in the form of a parenteral solution, which is bottled in glass bottles. The dosage varies depending on the pharmacological activity of the drug. One package can contain 10, 18 and 25 million IU/1 ml. The bottle is placed in a cardboard box.

Syringe pen

Intron A is also available in syringe pens. Each device contains 6 doses, the concentration of the active substance is different (18 million IU, 30 million IU, 60 million IU). In addition to the syringe pen, the kit includes 6 disinfectant wipes and 6 needles.

Evolution[ | ]

There are two alternative theories that explain the origin and evolution of spliceosomal introns: the so-called early intron (EI) and late intron (LI) theories. The RI theory states that numerous introns were present in the common ancestors of eu- and prokaryotes and, accordingly, introns are very old structures. According to this model, introns have been lost from the prokaryotic genome. It also suggests that early introns facilitated the recombination of exons representing protein domains. PI argues that introns appeared in genes relatively recently, and the insertion of introns into the genome occurred after the division of organisms into pro- and eukaryotes. This model is based on the observation that spliceosomal introns are present only in eukaryotes.

Principle of action on the body

There are three groups of interferons. They were classified based on differences in the structure of the molecule. Intron A is recombinant interferon alpha-2b. It binds to the cell membrane, thereby causing a chain reaction. Its last stage is a disruption of the synthesis of protein compounds and viral RNA in the infected cell. Thus Intron A:

• Changes the properties of specific receptors.
• Prevents virus adhesion.
• Reduces the risk of infection.
• Strengthens the body's protective function.
• Slows down the growth of tumors.
• Normalizes the process of neoplastic cell transformation.

Ribavirin
In chronic hepatitis B, with the help of Intron A, elimination (death) of the pathogen's DNA is achieved and the results of histology are improved. In patients suffering from advanced hepatitis C, after complex therapy (interferon alfa-2b and Ribavirin), a persistent virological response is noted.

Intron A is administered subcutaneously, intramuscularly or intravenously (using a dropper). In the first case, the bioavailability of the drug will be 100%. The maximum concentration of the active substance in the blood is recorded 6–12 hours after the administration of Intron A. In the second case, the drug penetrates the blood much faster, which affects the duration of the beneficial effect. Already 4 hours after Intron A enters the body, it is not in the plasma.

quiz

1. What organisms do not have introns? A. bacteria B. fungi C. protozoan unicellular organisms D. plants

Answer to question #1

right. Introns are found only in eukaryotic organisms. While the prevalence of introns varies between taxa, they can be found in all eukaryotic phyla.

2. Where does fusion occur? A. cytosol B. ribosomes C. nucleus D. chloroplasts

Answer to question No. 2

C is correct. Splicing, or removal of introns from pre-mRNA, occurs in the nucleus. Splicing is a component of mRNA processing along with the addition of a 5′ cap and a 3′ poly-A tail. After processing, the mature mRNA is transported out of the nucleus for translation.

3. What molecules contain introns? A. pre-mRNA B. pre-rRNA C. pre-tRNA D. all of the above

Answer to question number 3

D is correct. Although introns are rare in pre-rRNA and rare in tRNA, they can be found in both these and pre-mRNA molecules. In many organisms, introns are common in pre-mRNA and are found in more than 90% of human genes and in similar proportions of other vertebrate genomes.

Instructions for use

The treatment regimen with Intron A directly depends on the identified diagnosis and the general condition of the patient. Only the attending physician can prescribe the drug. To achieve a positive effect, you must follow all of his recommendations. The dosage, order of administration and duration of therapy for each patient are determined individually.

The drug is prescribed by a specialist

Injections are given according to the rules of asepsis. Before administering the drug, it is necessary to check it for signs indicating poor quality. These include changes in color and the presence of visible particles. The dose is drawn into the syringe immediately before the procedure. In addition to Intron A, the infusion composition includes saline solution. The use of other medications during intravenous administration of interferon alfa 2b is strictly prohibited. Otherwise, negative consequences cannot be avoided.

When using a syringe pen, everything is much simpler. To inject Intron A, a needle is attached to the device and the required dose is drawn. At the last stage, all that remains is to administer the drug. The syringe pen is good for 28 days after opening. Then it should be disposed of immediately. Until this point, the medicine should be stored in the refrigerator.

If side effects occur, you should consult a doctor, he will review the treatment regimen. To eliminate unpleasant symptoms, reduce the dose or take a break from treatment. Intron A is not administered chilled; the solution must be at room temperature. It is recommended to take the medicine 30 minutes before the procedure.

Intron A must be kept out of the reach of children and pets. The shelf life depends on the form of release. The drug, sold in bottles, remains effective for 2 years. Syringe pens remain usable for 15 months. Storage temperature varies from 2 to 8 degrees Celsius. The medicinal composition must not be frozen.

Literature[ | ]

• Gilbert W. Why genes in pieces? //Nature. – 1978. – T. 271. – No. 5645. – pp. 501-501.
• Roy SW, Gilbert W. The evolution of spliceosomal introns: patterns, puzzles and progress //Nature Reviews Genetics. – 2006. – T. 7. – No. 3. – pp. 211-221.
• Gogarten JP, Hilario E. Inteins, introns, and homing endonucleases: recent revelations about the life cycle of parasitic genetic elements //BMC evolutionary biology. – 2006. – T. 6. – No. 1. – pp. 1-5.
• Yandell M. et al. Large-scale trends in the evolution of gene structures within 11 animal genomes //PLoS Comput Biol. – 2006. – T. 2. – No. 3. – P. e15.

Analogs

If there are contraindications to taking Intron A, replace it with analogues. These include the following medications:

Altevir

• Altevir;
• Insivo;
• Alfarona;
• Baraclude;
• Herpferon;
• Gepadif;
• Grippferon;
• Havrix;
• Laifferon;
• Alfit-3;
• Realdiron.

Allohol, Engerix B, Gepamerz, Eslidin, Enerliv, Copegus, Atoxil are added to this list. Most Intron A analogues are functional substitutes. Each of them has its own side effects and contraindications, so the selection of an analogue should be done by the attending physician.

Intron Structure

In general, introns are much longer than exons; they can make up up to 90% of the gene and be more than 10,000 nucleotides long. Introns predominate in genes; over 90% of human genes contain introns, with an average of nine introns per gene.

An intron is a section of DNA that begins and ends with a specific series of nucleotides. These sequences act as the boundary between introns and exons and are known as splice sites. Recognizing the boundary between coding and non-coding DNA is critical to the creation of functioning genes. In humans and most other vertebrates, introns begin at 5' GUA and end at CAG 3'. There are other conserved sequences found in both vertebrate and invertebrate introns, including a branch point involved in the formation of the lariat (loop).