Pro-tube-4

General characteristics. Structure:

Active ingredients: 75,0 mg of an isoniazid, 400,0 mg of Pyrazinamidum, 150,0 mg of rifampicin, 275,0 mg of Ethambutolum of a hydrochloride.

The combined means against tuberculosis with universal impact on mycobacteria.

Pharmacological properties:

Pharmacodynamics. Pharmacological Protuba-4 properties are caused by the active ingredients which are its part. The isoniazid is the most active medicine for treatment of patients who can transfer this drug, on condition of sensitivity of mycobacteria. The isoniazid in concentration of 0,2 mkg/ml or less also has bactericidal effect on actively growing microorganisms. Concerning many active mycobacteria drug is less effective though Mycobacterium kansasii can be sensitive to it. The isoniazid reaches approximately identical concentration as inside, and out of zooblasts and therefore is capable to affect both intracellular mycobacteria, and extracellular.

The mechanism of action of an isoniazid consists in inhibition of the enzymes necessary for synthesis of mikolevy acids and a cell wall of mycobacteria. The isoniazid and a pyridoxine – structural analogs, and an isoniazid shows competitive antagonism in piridoksinkataliziruyemy reactions. However, this mechanism is not involved in antitubercular action therefore introduction of high doses of a pyridoxine to the patients receiving an isoniazid does not interfere with tuberculostatic action of an isoniazid, but prevents development of neuritis. Steady mutants meet in susceptible mikobakterialny populations frequency about 1:107. As tuberculous focuses often contain more than 108 tubercular sticks in fabrics, it is possible to assume that steady mutants can easily arise, when using an isoniazid as the only medicine.

Cross resistance to an isoniazid, rifampicin and Ethambutolum is not available therefore simultaneous use of any two from these drugs significantly detains emergence of resistance to each of them. Rifampicin is active in vitro concerning some gram-positive and gram-negative cocci, a number of bacteria of intestinal group, mycobacteria, chlamydias and poksivirus. Though many meningokokk and mycobacteria are oppressed at concentration less, than 1 mkg/ml, high-steady mutants meet in microbic populations frequency of 1:107 or bigger. Emergence of these high-steady microorganisms is promoted by rifampicin use as only medicine.

Cross resistance to other germicides and to rifampicin is absent. Resistance to rifampicin can be caused by reduction of penetration of drug or a mutation of a DNA-dependent RNA polymerase.

Pyrazinamidum – related to niacinamide connection, is stable, slightly soluble in water and inexpensive. At neutral values рН it is inactively in vitro, but at рН 5,0 in concentration of 15 mkg/ml growth of tubercular sticks and some other mycobacteria considerably oppresses. Tubercular sticks develop resistance to Pyrazinamidum very easily, but cross stability with an isoniazid or other antibacterial drugs does not arise.

Ethambutolum is synthetic water-soluble thermostable connection. Many strains of Mycobacterium tuberculosis and other mycobacteria are suppressed with in vitro with Ethambutolum in concentration of 1-5 mkg/ml. The mechanism of action is unknown. Resistance of mycobacteria to Ethambutolum appears very quickly if drug is used as the only medicine. Therefore Ethambutolum is always appointed in a combination with other antitubercular drugs.

Pharmacokinetics. The isoniazid is easily soaked up from digestive tract. Introduction of usual doses (5 mg/kg a day) leads to emergence of peak concentration in plasma 3-5 mkg/ml within 1-2 hours. The isoniazid easily gets into all fabrics and liquids of an organism.

Concentration of drug in the central nervous system and cerebrospinal liquid makes about one fifth from its concentration in plasma. Intracellular and extracellular concentration are close.

Metabolism of an isoniazid, especially acetylation, is under genetic control. In plasma of bystry inactivators average concentration of an active isoniazid makes from one third to that half at slow activators. The average elimination half-life of an isoniazid at bystry inactivators is less than 1,5 hours while at slow inactivators – 3 hours. Individual speed of acetylation significantly does not influence the drug dosing modes at daily reception, but can reduce antimikobakterialny action at discontinuous (1-2 times a week) introduction of an isoniazid.

The isoniazid is removed preferential with urine, partially in not changed, partially – in an acetylized form and in the form of other conjugates. The quantity of not changed free isoniazid in urine is higher at slow inactivators. At a renal failure usual doses of an isoniazid can be used, but at the expressed renal failure of a dose it is necessary to reduce.

Rifampicin strongly contacts a DNA-dependent RNA polymerase and thus slows down synthesis of RNA of bacteria and chlamydias. It does not affect a human RNA polymerase. At simultaneous introduction with an isoniazid rifampicin usually has bactericidal effect on mycobacteria and is capable to sterilize the infected fabrics, cavities or a phlegm.

Rifampicin well gets into phagocytes and can cause death of intracellular mycobacteria and other microorganisms. After oral administration rifampicin is well soaked up, the maximum concentration of rifampicin in plasma is reached in 2 hours. The elimination half-life of rifampicin makes 3-4 hours. It is excreted, mainly, through a liver with bile. After that is exposed to enteropechyonochny recirculation and it is removed preferential with a stake and it is only insignificant – with urine. Usual doses create concentration in serum of 5-7 mkg/ml, level in cerebrospinal liquid makes from 10 to 40% of concentration in serum.

Rifampicin is widely distributed in liquids and body tissues. Ethambutolum is well soaked up in intestines. After reception of 25 mg/kg peak concentration in blood of 2-5 mkg/ml is reached in 2-4 hours. About 10-40% of drug contact proteins of plasma. About 20% of drug are removed with a stake and 50% with urine in not changed form. Removal is slowed down at a renal failure. After drug intake peak concentration of Pyrazinamidum reaches in plasma 24,1 mkg/ml in 3 hours. Drug is widely distributed in an organism. Its concentration in spino-brain liquid is almost identical to concentration in blood. The elimination half-life makes 10-24 hours.

Pyrazinamidum in a liver is metabolized. About 30-40% of the accepted dose are excreted with urine in the form of the main metabolite – pirazinovy acid and about 4% of Pyrazinamidum is brought out of an organism in not changed look.

Indications to use:

The isoniazid, rifampicin, Pyrazinamidum and Ethambutolum are drugs of the first row for treatment of tuberculosis. Microbacteria are, as a rule, localized intracellularly, have the long periods of metabolic inertness and are characterized by high probability of development of resistance to any of the medicines used usually. It causes difficulties of antitubercular therapy. For prevention of bystry emergence of steady forms of the activator in big mikobakterialny populations that meets at an active clinical form of tuberculosis, use combinations of drugs of the first row. If activators are susceptible to these drugs, elimination of bacilli usually stops within 2-3 weeks. While treatment at tubercular meningitis or miliary tuberculosis usually continues within 18-24 weeks, at the uncomplicated tuberculosis which is the most frequent clinical option in such long therapy there is no need. At the most effective combinations of drugs, "the short course" of treatment lasting 6-9 months yields satisfactory results. The prevailing most of patients needs short hospitalization.

Route of administration and doses:

The isoniazid is the most widely used medicine at tuberculosis. At active process with the expressed clinical manifestations it is appointed in combination with other antitubercular drugs.

Usually the dose makes 5 mg/kg a day (at most for adults – 300 mg a day). At severe forms the dose is doubled sometimes.

Children have to receive 10 mg/kg a day, and for a maintenance therapy, after the beginning of improvement they are given sometimes drug on 15 mg/kg two times a week. Apply a pyridoxine in a dose of 10 mg on 100 mg of the entered isoniazid to prevention of development of neuritis.

Patients at whom negative tuberkulinovy skin tests changed on positive can give an isoniazid in a dose of 5-10 mg/kg (at most 300 mg/day) for the purpose of prevention of meningitis or miliary tuberculosis which risk of emergence makes 5-15%.

For prevention the isoniazid is used as the only medicine. Preventive use of an isoniazid is offered for the persons having close contacts with fresh cases of active tuberculosis, for persons with positive skin reactions and the infected HIV, and also for the patients receiving an immunosuppressive or antineoplastic chemotherapy if they did not receive adequate antitubercular treatment in the past.

The isoniazid is usually appointed orally. For treatment of tuberculosis rifampicin preparatm for prevention of emergence of rifampitsinustoychivy mycobacteria use in a dose 600 mg/day (10-20 mg/kg) orally, usually in a combination with an isoniazid, Ethambutolum or others antitubercular. The similar mode of dosing can be also used concerning the infections caused by atypical mycobacteria. In some schemes of treatment with a short course rifampicin in a dose of 600 mg is appointed by 2 times a week.

Rifampicin is effective also at a leprosy where it is used with sulphone. The peroral dose of 600 mg twice a day within 2 days can eliminate the majority of meningokokk at carriers. Pyrazinamidum is used orally, by daily doses of 1,5 - 2,0 g (20-30 mg/kg). In this dose drug is appointed once a day, and in a dose of 0,75 g – twice a day. In certain cases drug is appointed by 3 times a week in a dose of 50-70 mg/kg. Ethambutolum the hydrochloride in a dose of 15 mg/kg is usually applied in a combination with an isoniazid or rifampicin once a day. The maximum daily dose makes 25 mg/kg/day. The combined antitubercular drug Protub-4 includes in the structure an isoniazid (75 mg), rifampicin (150 mg), Pyrazinamidum (400 mg) and Ethambutolum a hydrochloride (275 mg). Is accepted inside in 1-2 hours prior to food on 4 tablets a day once for 2 months.

Features of use:

Unreasonable use of rifampicin for treatment of "small infections" can promote broad selection of rifampitsinustoychivy mycobacteria and thus limit use of this medicine.

Side effects:

Side effects at treatment by the drug Protub-4 are defined by the active ingredients which are its part. Frequency and weight of adverse reactions to an isoniazid are closely connected with a dose and duration of use.

Allergic reactions. Sometimes there are fever, an enanthesis and hepatitis develops.

Direct toxic effects: the most often toxic effects (10-20%) are shown concerning peripheral and the central nervous system. They are explained by relative deficit of a pyridoxine which arises in connection with the competition of an isoniazid to pyridoxal phosphate for enzyme to an apotriptofanaz.

These toxic reactions include peripheral neuritis, sleeplessness, concern. There is a feeling of a pricking and numbness in fingers of hands and legs, at some patients muscular weakness, a headache, dizziness is shown. The majority of complications can be prevented introduction of a pyridoxine. Accidental overdose of an izoniaziad it is also possible to treat a pyridoxine in the doses equivalent to quantity of the accepted isoniazid.

The isoniazid possesses a hepatotoxic. Cases of development of clinical jaundice and a lobular necrosis of a liver were observed. Approximately at 1% of people clinical hepatitis develops, and the number of patients with subclinical frustration reaches 10%.

Developing of hepatitis is connected with the progressing damages of a liver of the patient with age. The disease seldom meets aged up to 20 years, aged between 30 and 50 years is observed in 1,5% of cases, and in more senior age group – 2,5% of cases. At alcoholics the risk of developing of hepatitis is higher. At deficit glyukozo-6-fosfatdegidrogenazy isoniazid can cause hemolysis. Rifampicin can cause side effects from digestive tract, such as heartburn, unpleasant feelings in epigastriums, anorexia, vomiting, intestinal gripes and diarrhea. At some patients the headache, drowsiness, weakness, dizziness, visual frustration, muscular weakness, fever, extremity pains is observed.

Rare side effects are skin rashes, thrombocytopenia, nephrite and abnormal liver functions. Rifampicin usually causes Bens-Jones's proteinuria and can break reaction of antibody formation. If drug is used less often 2 weekly, then emergence of "a grippopodobny syndrome" of the unknown nature and anemia is possible.

Rifampicin causes emergence of harmless orange coloring of urine, sweat, tears and contact lenses. The main thing side effects of Pyrazinamidum are a hepatotoxic (at 1-5% of patients), nausea, vomiting, fever of a medicinal origin and a hyperuricemia.

The most frequent side effects of Ethambutolum are vision disorders: decrease in visual acuity, optic neuritis and damages of a retina. Such phenomena can be noted at some patients receiving drug in a dose of 25 mg/kg/day within several months. Most of them is reversible after cancellation of Ethambutolum, however, during treatment periodic checks of visual acuity are necessary. When using doses of 15 mg/kg/day or less vision disorders are noted very seldom.

Other side effects include confusion of consciousness, a disorientation, hallucinations, a headache, a febricula, a tranzitorny abnormal liver function, peripheral neuropathy. Disturbances from outside zheludochno – an intestinal path, such as nausea, vomiting, anorexia, metal smack in a mouth are possible. Allergic reactions to Ethambutolum are noted seldom.

Interaction with other medicines:

The isoniazid reduces metabolism of Phenytoinum, increasing its level in blood and toxicity. Rifampicin causes induction of microsomal enzymes (for example, R-450 cytochrome) therefore it increases elimination of anticoagulants and contraceptive means. In the same way administration of rifampicin with ketokonazoly, cyclosporine or chloramphenicol considerably reduces levels of these drugs in serum. Rifampicin increases removal with methadone urine, reduces its plasma concentration and can lead to emergence of symptoms of a methadone withdrawal. Absorption of Ethambutolum is broken by aluminum hydroxide therefore when using Ethambutolum alternative antacids are necessary. Pyrazinamidum reduces concentration of an isoniazid in blood serum, especially at slow acetylizers a little.

Contraindications:

The pro-tube-4 is contraindicated: at hypersensitivity to any ingredient of this drug; to patients with vision disorders (a diabetic retinopathy, damage of an optic nerve, inflammatory diseases of eyes); epilepsies and tendencies to convulsive attacks in case of earlier postponed poliomyelitis; at an abnormal liver function and kidneys; thrombophlebitis and the expressed atherosclerosis; at pregnancy and a lactation; to children up to 13 years.

Overdose:

Accidental overdose of an izoniaziad it is possible to treat a pyridoxine in the doses equivalent to quantity of the accepted isoniazid.

Storage conditions:

List B. In the dry place protected from light at a temperature not over 25 ºС.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated, on 100 or 500 tablets in a polymeric can.