Mercaptopurinum

General characteristics. Structure:

Active ingredient: 50 mg of Mercaptopurinum in each tablet.

The drug having an antineoplastic and immunodepressive effect.

Pharmacological properties:

Pharmacodynamics. Is a competitive antagonist of purine bases, S-fazospetsifichnym drug. Activity is caused by activation of drug in fabrics and connected with inhibition of synthesis of DNA at less expressed action on RNA synthesis.

Competes with hypoxanthine and guanine for гипоксантин-гуанинфосфорибозилтрансферазу, turning drug into thioinosinic acid (territorial election commission). The territorial election commission inhibits a number of reactions with participation of the ionozinovy acid (IA), including transformation of IK into ksantinovy and adenylic acids through аденилсукцинат.

During methylation the territorial election commission is formed 6-metiltioinozinat, the territorial election commission blocking along with, глутамиí5-фосфорибозилпирофосфатамидотрансферазу — the first enzyme in synthesis of purine ribonucleotides; the mitotic cycle (S-phase), especially in proliferating cells of marrow and tumors is as a result broken, growth of malignant new growths is slowed down and the cytotoxic effect is shown.

In experiments it is shown that marked Mercaptopurinum can be recovered from DNA in the form of a dezoksitioguanozin. A quantity of Mercaptopurinum turns into nucleotide derivatives 6 thioguanines by the consecutive actions of an inozinatdegidrogenaza and ksantilataminaza converting territorial election commission into thioguanylic acid. Resistance of tumors at animals is often connected with loss of ability of cells to form territorial election commission. However resistance to Mercaptopurinum, in particular at the person at leukoses, can arise at the expense of other reasons.

In pilot studies it is established that Mercaptopurinum possesses cancerogenic action. Has also mutagen effect, causes aberation chromosomes in zooblasts and the person and it is prepotent lethal mutations at males of mice. Has embriotoxity. Causes pathological changes in embryos of rats.

Pharmacokinetics. Absorption from a GIT variable and incomplete (to 50%). Linkng with proteins of plasma — about 19%. Badly passes through GEB, in insignificant quantities it is found in medullispinal liquid. It is metabolized in a liver (activation and a catabolism); disintegration happens mainly to participation of a xanthineoxidase. It is removed by kidneys in not changed look (7–39%) and in the form of metabolites (the thiouric acid which is formed as a result of direct oxidation with participation of a xanthineoxidase, metilirovanny thiopurines). The pharmacological effect, more, is caused by metabolites. After intake of 46% of a dose it is excreted for the first 24 h with urine, metabolites in urine are found already in 2 h. Metabolites continue to be defined in urine for several weeks after the treatment termination; pharmacological are active and have bigger T1/2, than Mercaptopurinum. T1/2 — three-phase: 45 min., 2,5 h and 10 h respectively.

Because of bystry metabolism in active intracellular derivatives the hemodialysis is not effective for reduction of toxicity of Mercaptopurinum.

Indications to use:

Acute lymphoblastoid leukosis, acute myeloleukemia (including acute miyelotsitarny leukosis), myelosis (induction of remission and maintenance therapy), horionepitelioma of a uterus, reticulosis, chronic granulotsitarny leukosis.

Route of administration and doses:

Inside. Dosing mode individual. Usually to adults and children an initial dose — 2,5 mg/kg/days, adjust further a daily dose depending on clinical effect and a condition of a marrowy hemopoiesis of the patient. Increase in a dose to 5 mg/kg/days (no more) during 4 weeks is possible. Maintenance dose: 1,5–2,5 mg/kg a day.

The patient with a liver and/or renal failure the dose is reduced. At appointment along with Allopyrinolum (300–600 mg/days) apply only 1/3–1/4 usual doses of Mercaptopurinum (decrease in intensity of metabolism due to blockade of a xanthineoxidase).

The daily dose is applied usually once. Apply also in the combined chemotherapy.

Features of use:

Use at pregnancy and feeding by a breast Contraindicated at pregnancy (teratogenecity, embriotoxity). Use of Mercaptopurinum at pregnancy was followed by the increased risk of an abortion or premature births. Category of action on a fruit on FDA — D. For the period of treatment it is necessary to stop breastfeeding.

With care appoint to people of advanced age (age renal failures are more probable) and children (reduction of doses is required), to patients to whom it was carried out beam or chemotherapy, the patient with a tumor of kidneys, at a renal and liver failure earlier.

The patient has to be warned about toxicity of drug and inadmissibility of its use without consultation with the doctor. Can increase risk of secondary cancer and the nephropathy (caused by increase in formation of uric acid). In order to avoid risk of a nephropathy it is not necessary to apply uricosuric means along with Mercaptopurinum. With care apply after antineoplastic or radiation therapy.

Care at the address with tablets is recommended (their division in half) in order to avoid pollution of hands or inhalation of drug.

Dental interventions should be completed prior to therapy or to postpone until normalization of a picture of blood (possibly increase in risk of microbic infections, delay of processes of healing, bleeding of gums). During treatment to be careful when using toothbrushes, threads or toothpicks.

To be careful at a combination therapy; it is necessary to accept each drug in due time.

In the course of treatment consumption of enough liquid and the subsequent strengthening of a diuresis is important for ensuring removal of uric acid.

During treatment performing vaccination is not recommended by virus vaccines, it is necessary to avoid contact with the people who received a vaccine against poliomyelitis with sick bacterial infections. It is not necessary to apply live virus vaccines at patients with a leukosis in a remission stage at least within 3 months after a last year of chemotherapy. Immunization by a peroral vaccine against poliomyelitis of the people who are in close contact with such patient, especially family members should be delayed.

Emergence of signs of oppression of function of marrow, unusual bleedings or hemorrhages, black tar-like chair, blood in urine or Calais or dot red spots on skin demand immediate consultation of the doctor.

To be careful in order to avoid accidental cuts sharp objects (a safety razor, scissors), to avoid occupations contact sports or other situations at which hemorrhage or injuries are possible.

At patients with the thrombocytopenia which developed as a result of use of Mercaptopurinum it is recommended to observe special precautionary measures (restriction of frequency of venipunctures, refusal of injections in oil, carrying out analyses of urine, a calla and secrets on the occult blood; prevention of locks, refusal of the use of acetylsalicylic acid, etc.).

Treatment has to be carried out under careful clinical and hematologic control. And after the end of treatment (during 2 weeks) at least 2 weekly carry out control of peripheral blood and a marrowy hemopoiesis to time. Control of functions of a liver and kidneys, level of uric acid in blood is necessary.

For prevention of a hyperuricemia plentiful drink, if necessary — Allopyrinolum and alkalifying of urine is recommended. At reduction of quantity of leukocytes and thrombocytes is lower than tolerance level, tendency to bleedings or emergence of jaundice Mercaptopurinum should be cancelled. It is necessary to watch carefully a picture of blood and, if necessary, to carry out a maintenance therapy and hemotransfusion. Patients with the developed leukopenia should be observed carefully for identification of signs of developing of an infection, if necessary appoint antibiotics. The patient with a neutropenia at fervescence antibiotics of a broad spectrum of activity are appointed empirically before obtaining results of bacteriological researches and the corresponding diagnostic tests.

During treatment of any of sexual partners it is recommended to use contraception.

Side effects:

From a nervous system and sense bodys: headache, weakness.

From cardiovascular system and blood: a leukopenia, thrombocytopenia, an agranulocytosis, anemia, a pancytopenia (during active therapy at an acute myelogenetic leukosis at patients the period of a relative aplasia of marrow is often noted, at the same time it is important to carry out the corresponding supporting treatment).

From bodies of a GIT: nausea, vomiting, diarrhea, a loss of appetite, a hepatotoxic action (a hepatotoxic has toksiko-allergic genesis and more often arises at exceeding of a dose of 2,5 mg/kg/days) or a cholestasia (yellowness of scleras or skin), an ulceration of a mucous membrane of an oral cavity; seldom — an ulceration of a mucous membrane of intestines, diarrhea, pancreatitis, гепатонекроз.

From urinogenital system: hyperuricemia, nephropathy.

Allergic reactions: medicinal fever, skin rash, itch.

Others: skin hyperpegmentation, decrease in immunity and predisposition to infections.

Interaction with other medicines:

Allopyrinolum, пробенецид, Sulfinpyrazonum, colchicine increase (mutually) activity and toxicity.

Allopyrinolum strengthens toxic action owing to metabolism delay. Against the background of uricosuric antigouty means the risk of development of a nephropathy increases.

At combined use with indirect anticoagulants Mercaptopurinum can increase anticoagulating activity and/or risk of bleedings as a result of decrease in a liver of synthesis of blood-coagulation factors and disturbances of formation of thrombocytes, or to reduce anticoagulating activity by means of increase in synthesis or activation of a prothrombin.

Miyelotoksichny drugs or radiation therapy it is additive functions of marrow oppress.

Other immunodepressants (glucocorticoids, Azathioprinum, hlorambutsit, corticotropin, cyclophosphamide, cyclosporine) increase risk of an infection and secondary tumors (strengthening of an immunodepressive effect). The concomitant use with doxorubicine considerably increases risk of a hepatotoxic.

There is a full cross resistance between Mercaptopurinum and thioguanine.

In combination with live virus vaccines can cause an intensification of process of replication of a vaccinal virus, strengthening of side effect of a vaccine and decrease in development of antibodies in response to introduction both the live, and inactivated vaccines.

Contraindications:

Hypersensitivity, pregnancy, feeding by a breast.

Restrictions to primeneniy Oppression of function of marrow (a leukopenia with number of leukocytes less than 3·10 9/l, thrombocytopenia with number of thrombocytes less than 100·10 9/l), acute virus (including chicken pox, shingles), fungus and bacterial diseases, a renal and/or liver failure, a hyperuricemia, gout or uratny нефроуролитиаз (including in the anamnesis), age up to 2 years.

Overdose:

Symptoms: immediate — anorexia, nausea, vomiting, diarrhea; delayed — a miyelosupressiya, liver dysfunction, a gastroenteritis.

The risk of overdose increases at a concomitant use of Allopyrinolum.

Treatment: symptomatic (there is no effective antagonist, the hemodialysis is almost inefficient). The first 60 min. after overdose it is possible to apply inside absorbent carbon.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 50 mg, 20 tablets in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.