Azidothymidine

General characteristics. Structure:

Active agent: zidovudine 0,1.

Auxiliary вещество:сахар milk, potato starch, MKTs, magnesium stearate or calcium stearate; in plastic banks on 100 or 200 pieces.

Pharmacological properties:

Pharmacodynamics. Antiviral drug with high activity against retroviruses, including human immunodeficiency virus. Drug selectively inhibits replication of virus DNA due to competitive blockade of the return transcriptase. Getting to a cell (both in infected, and in intact), a zidovudine with the participation of, respectively, cellular thymidine kinase, a timidilatkinaza and a nonspecific kinase it is phosphorylated with education mono - di - and trifosfatny connection. The zidovudine triphosphate works at the same time as inhibitor and, at the same time, as substrate for effect of reverse transcriptase of a virus. This enzyme mediates formation of DNA on a matrix of virus RNA. The zidovudine triphosphate having structural similarity to thymidine-triphosphate competes with it for communication with enzyme, is built in a pro-virus and, thereby, blocks further building of a chain of virus DNA and, thus, makes impossible synthesis of virus DNA. Reception of a zidovudine promotes increase in quantity of T4 of cells (indicators of the immune status) at the expense of what ability of an organism to resist an infection increases.

Pharmacokinetics. Pharmacokinetic parameters of a zidovudine at children are more senior than 3 months and at adults are in many respects similar. Absorption is high. Bioavailability both at adults, and at children - 60-70%. The zidovudine gets through a blood-brain barrier, concentration it in cerebrospinal fluid makes 50% of level in plasma. Communication with proteins of plasma - 34-38%. Peak level of drug is noted in 0.5 h after intake. At purpose of 200 mg of a zidovudine each 4 h equilibrium With max makes 1.5, and C min - 0.1 mkg/ml of plasma, at intravenous administration of 5 mg/kg each 4 h - respectively, 1.9 and 0.1 mkg/ml. T1/2 - 1-2 h - practically does not depend on the size of the accepted dose. The renal clearance of a zidovudine (27.1 ml/min.) exceeds clearance of creatinine that demonstrates existence of the expressed canalicular secretion. At children of T1/2 makes 1.5 h, clearance - 30.9 ml/min. In a liver children and at adults have a conjugation to glucuronic acid. The main metabolite - 5 глюкуронилазидотимидин has T1/2 about 1 h, is excreted by kidneys and has no antiviral activity. Excretion kidneys about 30% in an invariable look, 50-80% in the form of glucuronides. At long administration of drug cumulation of drug is not observed both at intravenous, and at oral use. At patients with a renal failure noticeable increase in maintenance of a zidovudine in a blood plasma is not noted. At a renal failure accumulation of metabolites is possible (conjugates with glucuronic acid) that increases risk of manifestation of toxic action. At patients with cirrhosis and a liver failure cumulation of a zidovudine owing to decrease in intensity of linkng of drug with glucuronic acid is possible.

Indications to use:

HIV infection in a stage of secondary diseases (a stage 3A, 3B, 3B on V. I. Pokrovsky's classification), in stages of an acute infection (a stage 2A) and and primary manifestations (a stage 2B, 2V) at decrease in the SD4 level of lymphocytes lower than 400-500 in mm, and also in an incubation stage (a stage 1). Prevention of professional infection of the persons who took injections and cuts during the work with the material contaminated by HIV.

Route of administration and doses:

The initial dose for patients weighing about 70-80 kg makes 200 mg x 6 times a day (1200 mg/days). The optimum dose is selected individually and can vary from 500 to 1500 mg/days. If hemoglobin level at patients decreases to 7.5-9 g/dl (or for 25% of initial level) or number of neutrophils - to 750-1000/kub.mm (or) the daily dose of a zidovudine needs to be reduced by 50% of initial level twice or even temporarily to cancel drug. Recovery of the called indicators happens more quickly at temporary drug withdrawal. At normalization (it is usually observed within 2 weeks) the dosage can be again increased to reference daily values. Treatment by a zidovudine needs to be stopped if hemoglobin is less than 7.5 g/dl, or number of neutrophils - below 750/kub.mm. The average dose of a zidovudine for children is defined at the rate of 150-180 mg / кв.м bodies each 6 h (4 times a day). Recalculation of a dose is carried out according to special tables (growth and weight) at least once in 2 months. At development of anemia or a neutropenia the dose is lowered by 30% (to 120 mg / кв.м each 6 h).

The hematologic changes demanding a zidovudine dose decline from children: decrease in level of hemoglobin by 2 g/dl from initial or to 8 g/dl or decrease in quantity of neutrophils to 750 in cubic mm in two analyses at an interval of 24 h or reduction of quantity of thrombocytes to 50 000 in cubic mm. The termination of reception of a zidovudine is required from children at: decrease in level of hemoglobin it is lower than 8 g/dl or decrease in quantity of neutrophils to 500 in cubic mm in two sequential analyses at an interval of 24 h or - reduction of quantity of thrombocytes to 25 000 in cubic mm or at the progressing renal failure - creatinine level on in serum - more than 200 microns/l or at the expressed allergic reaction (exfoliative dermatitis, an anaphylaxis). After stabilization of hematologic parameters it is possible to resume treatment by a zidovudine in smaller doses. If after resuming of therapy undesirable dynamics of hematologic parameters against the background of a reduced dose is not noted, then it can be increased till recommended.

Features of use:

It is necessary to conduct researches of peripheral blood systematically (in the first 3 months of treatment - each 2 weeks; then at least 1 time a month). With extra care it is necessary to appoint drug sick with a renal and liver failure, and also the elderly patient; in these cases correction of the mode of dosing depending on dynamics of concentration of drug in blood is recommended. It is necessary to be careful at the co-administration of a zidovudine and drugs capable to change metabolism in a liver. Not studied up to the end there is a question of influence of a zidovudine on a fruit of the pregnant woman and the clinical importance of excretion of drug with milk. As there are experimental data about existence of excretion of a zidovudine with milk in the doses sufficient for rendering side effects for the baby, it is not recommended to feed children with milk of mother receiving therapy by a zidovudine.

Side effects:

The anemia (demanding cancellation/decrease in a dosage of a zidovudine sometimes arises need for hemotransfusions), a neutropenia and a leukopenia. These side effects arise, as a rule, at use of high doses (1500 mg/days), and also at patients with far come AIDS stages (especially in cases of initial decrease in hemopoietic function of marrow) and at patients with decrease is contents T-helperov (T4) lower than 100 000 in 1 ml.

Other side effects: dispepsichesky frustration (nausea, vomiting, lack of appetite, abdominal pain, diarrhea, meteorism), headache, rash, temperature increase, muscle pain, paresthesias, sleeplessness, sensation of discomfort, adynamy, drowsiness, food faddism, cardialgias, depression, increase of an urination, fever, cough.

Interaction with other medicines:

Combined use of paracetamol with a zidovudine increases the frequency of emergence of neutropenias, apparently, owing to oppression of metabolism of a zidovudine (both drugs glyukuronirutsya). Other drugs (aspirin, morphine, codeine, indometacin, oxazepam, Cimetidinum, Clofibratum) also change metabolism of a zidovudine, by inhibition of activity of glucuronidase or direct inhibition of microsomal metabolism in a liver. Simultaneous treatment by the drugs possessing nephrotoxic action or suppressing function of marrow (pentamidine, Amphotericinum, ганцикловир, Vincristinum, vinblastine, etc.), increase risk of toxic action of a zidovudine. In need of performing antimicrobic therapy it is possible to apply co-trimoxazole; anti-virus antiherpetic therapy - an acyclovir. Inhibitor of canalicular secretion пробенецид extends a zidovudine elimination half-life.

Contraindications:

It is impossible to appoint a zidovudine the patient with low number of neutrophils (less 750/kub.mm) or a low hemoglobin content (less than 7.5 g/dl). Relative contraindications to purpose of drug are vomiting, the expressed nausea, decrease in level of hemoglobin is lower than 50 g/l, increase in aminotransferases and creatinine more, than by 3 times of rather upper bound of norm, decrease in quantity of neutrophils to 500 in мкл, decrease in quantity of thrombocytes less than 25 thousand in мкл.

Overdose:

There are no data.

Storage conditions:

In the dry, protected from light place, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

In plastic banks on 100 or 200 pieces.