Combined antituberculous drugs

FIELD: medicine.

SUBSTANCE: agent is presented in the form of a tablet, contains isoniazid and a substance which reduces its toxicity; as the substance which reduces the isoniazid toxicity, it contains thiotriazolin. The isoniazid/thiotriazolin ratio makes 4:1.

EFFECT: combined antituberculous drug ensures reducing toxicity as compared to the known ones and increasing its pharmacological activity.

2 cl, 1 ex, 1 tbl


The invention refers to pharmaceutics and medicine, namely to Phthisiology, and can be used in the pharmaceutical industry in the manufacture of drugs for the treatment of tuberculosis.

The effectiveness of providing medical care to the population depends on the availability of highly competitive medicines, and in particular, it relates to means for the treatment of tuberculosis. Today, TB is one of the most common infectious diseases. In the treatment of tuberculosis patients is chemotherapy. Clinical efficacy of anti-TB drugs depends on many factors, important among which are the sensitivity or resistance of mycobacteria to drugs used, the level of bacteriostatic concentrations in the blood, the degree of penetration of drugs in the lesion, the ability of drugs to act on the external and intracellular (phagocytosed) mycobacteria. But not less important are also the tolerability of medicines and their safety. Chemotherapy of tuberculosis requires prolonged use of anti-TB drugs, which increases the risk of side effects, pronounced violations metabolism and functions of liver, heart, and nervous system�we etc. Side effects of anti-TB drugs is one of the main reasons for the lack of effectiveness of treatment of such patients. Originating in the process of mono - or combination chemotherapy, side effects significantly limit the possibility of purposeful influence of drugs and reduce the effectiveness of treatment of TB patients by the main indicators: timing of termination of smear and frequency of complete recovery.

In this regard, the problem of preventing the side effects of TB drugs on the human body remains relevant.

Isoniazid is one of the reference drugs main group, but he, along with positive farmacoterapeutica effect, toxic to liver, Central and peripheral nervous system, cardiovascular system and hemodynamics. It is known that isoniazid adverse reactions, pathogenetic mechanisms have not been established. Correction of adverse reactions that have occurred in the process of combination chemotherapy of tuberculosis is a priority of the national Phthisiology. There remains the issue of prevention of toxic effects of isoniazid, so one of the biggest challenges of TB is the further development of new methods of prevention and treatment�ia side effects of anti-TB drugs, and pharmaceutical chemistry and technology of drugs - development of efficient and low-toxic pharmaceuticals.

The use of antioxidants in the treatment of infectious diseases, tuberculosis including, has a definite perspective. So recently in the world practice there is a tendency for the creation of drugs on the basis of fixed combinations that contain compatible on physico-chemical and pharmacological characteristics of the antioxidant and the basic drug therapy, which produce a higher, in comparison with the application as a separate component of comprehensive treatment, therapeutic efficacy and safety.

It should be noted that the indirect mechanism of action of isoniazid is hypermodule oxygen radicals, this leads to hepato-, cardio - and embryotoxicity. Therefore, it is appropriate the use of antioxidants to reduce the toxicity of isoniazid, in this regard, in recent times considerable attention attracts clinicians, in particular, thiotriazolin, which, in addition to antioxidant action, has a wide range of pharmacological activity. Studies on laboratory animals proved the protective effect of the synthetic drug metabolitic nature of the action of thiotriazolin �ri the effect of toxic doses of isoniazid.

Thus, it is important to develop means of TB action which would have had a strong anti-TB effect and low toxicity.

Known combination remedy for tuberculosis treatment (patent RF №2406518, IPC A61K 36/28 (2006.01), A61K 31/4409 (2006.01), A61P 31/06 (2006.01). TB compositional tool // the Invention. The utility model. - 20.12.2010).

Specified contains anti-tuberculosis drug isoniazid and individual glycoside plant Stevia rebaudiana - stevioside or stationbased, or a mixture of the glycosides of the specified plants, which is a sweetener with the high ratio of components, wt.%:

stevioside or stationbased, or a mixture of the glycosides of the plant Stevia rebaudiana - sweetenerelse

Common essential features of the claimed invention and the funds are as follows:

- the presence in the formulation of isoniazid,

- the presence in the medium of the substance, which reduces the toxicity of isoniazid.

But the above solution has some drawbacks.

One of the disadvantages of the aforementioned funds of the prototype is that glycosides, which are part of the Stevia ebaudiana, not only have antioxidant and hepatoprotective activity required to reduce the toxicity of isoniazid, but also enhance the hepatotoxicity of isoniazid.

In addition, methods of isolation and purification of glycosides of Stevia rebaudiana quite time consuming because of imperfections in technology and also require expensive equipment and reagents, most of which are toxic (chloroform, ethers, dioxane, n-butanol, and so forth). In addition, when using these reagents, it is assumed the existence of complex waste management systems, special equipment and devices. Not always complete extraction of glycosides from raw materials.

The tool prototype is used in powder form, the use of which is not sufficiently comfortable for the patients.

The basis of the invention tasked with improving combined anti-TB drugs by introducing in its composition other active substances which reduce the toxicity of isoniazid, which has a more broad spectrum, and has a stronger activity that will reduce the toxicity of funds in comparison with known and increasing its pharmacological activity.

The problem is solved in that in the combined anti-TB medication to�e contains isoniazid and substance reduce its toxicity, what is new is that the product is in tablet form and as a substance that reduces the toxicity of isoniazid, contains thiotriazolin. The ratio of isoniazid and thiotriazoline is 4:1.

A causal relationship between the totality of the claimed features and the technical result is the following.

Recently actively developed medicines in the form of fixed combinations, which contain compatible on physico-chemical and pharmacological characteristics of the antioxidant and the basic drug therapy. The presence of antioxidant in products such defines significantly higher in comparison with the application as a separate component of comprehensive treatment, therapeutic efficacy and safety of such funds.

In the available literature, we did not find descriptions of complex solid dosage forms with isoniazid, which would contain an antioxidant.

It is known that isoniazid is a rather toxic drug and has a number of serious side effects, such as those focused on breaking the delicate parts of metabolism of neurocytes, cardionet and hepatocytes; isoniazid exhibits neuron-, cardio-, hemato - and hepatotoxicity. So, isoniazid affects the cardiovascular, n�rvnoy and hepato-biliary system and the hematopoietic system. The introduction of thiotriazolin in the product with isoniazid significantly reduces the negative toxic effects of the Central nervous system, cardiovascular, under own trade mark system and on the blood and thereby increases the safety of the treatment of tuberculosis. A similar effect takes place because thiotriazolin has strong oxidative properties, reduces the overproduction of superexcitation and peroxynitrite, prevents oxidative modification of protein structures of receptors, ion channels, enzymes, transcription factors, activates antioxidant system enzymes. Thiotriazolin has also metabolitic action aimed at the preservation of oxidative energy production, reducing the severity of mitochondrial dysfunction and apoptosis. Thiotriazolin is a powerful hepatoprotector. Metabolitic and hepatoprotective properties of thiotriazolin provide a significant reduction of negative influence of isoniazid on the human body. The proposed fixed dose combination of isoniazid and thiotriazoline provides significant security improvements in the treatment of tuberculosis.

In our experiments, it was found that the optimal ratio of isoniazid and thiotriazoline in the proposed measure is the ratio of 4:1.


R�the results of our research, presented in the table below, indicate that the introduction of thiotriazolin in the composition of tablets with isoniazid leads to a significant reduction of acute toxicity of isoniazid.

So, the value of LD50isoniazid the determination method of Kerber is 1500±347 mg/kg after intragastric administration white outbred rats weighing 140-160 grams. The introduction of thiotriazolin in the composition of tablets with isoniazid leads to lower acute toxicity of isoniazid in 2.67 times (LD50of isoniazid in tablets with thiotriazolin is 4014,6±165 mg/kg after intragastric administration).

Rates of acute toxicity of isoniazid and fixed combination of isoniazid with thiotriazolin after a single injection (M±M)
Groups of animalsThe ratio of the mass of the heartThe ratio of the mass of the liverThe ratio of the mass of the brainLD50mg/kg
Intact animals (n=6)18,1±0,611,95±0,0922,1±1,38-
Animals that received isoniazid (n=6)22,7±0,533,77±0,45*28,9±3,41*1500±347
Animals that received isoniazid + titerator (n=6)17,9±1,2512,17±0,65121,8±3,7516691±275 (in terms of pure isoniazid - 4014,6±165)
* - p≤0,05 relative to the group of intact animals;
1-p≤0.05 relative to the group of animals which received only isoniazid

LD50a combined preparation of isoniazid with thiotriazolin in the form of tablets is 6691±275 mg/kg.

When studying the toxicity of isoniazid was found that the drug exhibits expressed hepato-, neuro - and cardiotoxicity, increasing the ratio of the mass (Km) liver 93%, of the brain is at 31% and 25%. Drug fixed dose combination of isoniazid with thiotriazolin is not hepato-, neuro - and ka�detoxacai after a single dose. The coefficients of the mass of the liver, brain and heart of animals which received the tablets of isoniazid with thiotriazolin, are within the physiological norm, and they are lower than in the group of animals which received only isoniazid, 42%, 24% and 21%, respectively.

Thus, the introduction of thiotriazolin in the composition of anti-tuberculosis drugs containing isoniazid, decreasing the overall and neuro-, cardio - and hepatotoxicity latter, unlike the prototype, where only decreases cardiotoxicity funds.

Pills, depending on the clinical purpose (prevention of relapses of tuberculosis, treatment of active forms, for children and the like) can be manufactured with different content of active substances, while maintaining the claimed ratio of isoniazid with thiotriazolin 4:1.

For example, it can be tablets containing isoniazid 100 mg and thiotriazolin 25 mg, or 200 mg and 50 mg, or 400 mg and 100 mg, or 600 mg and 150 mg, respectively.

Pills that contain isoniazid and thiotriazolin, is made by obtaining a powdery mixture of active ingredients isoniazid and thiotriazoline with the addition of a sufficient amount of excipients and subsequent pressing. The composition of the tablets include various excipients, for example polyfunctional auxiliary prophetic�TWA, fillers, disintegrants, anti-friction substance.

Preformed tool, which States, fully meet pharmacopoeial requirements. Thanks to its antioxidant thiotriazolin obtained preformed tool provides a significant reduction of the toxicity of isoniazid and better pharmacological properties of the integrated product compared to the vehicle-prototype and can be proposed for the industrial production of anti-TB drugs.

1. Combined anti-tuberculosis drug containing isoniazid and substance to reduce its toxicity, characterized in that the product is in tablet form and as a substance that reduces the toxicity of isoniazid, contains thiotriazolin.

2. Combined anti-TB drug according to claim 1, characterized in that the ratio of isoniazid and thiotriazoline is 4:1.


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SUBSTANCE: invention refers to a chemical compound of formula wherein R=benzyl and to an antituberculous therapeutic agent representing a composition of imidazo[1,2-b][1,2,4,5]tetrazine derivative of formula I, wherein R=benzyl, isopropyl or phenyl and the known antituberculous preparation pyrazinamide with the ingredients in mole ratio 1:1.

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2 cl, 2 tbl, 6 ex

FIELD: chemistry.

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4 cl, 2 tbl, 3 ex

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1 tbl, 2 ex

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3 cl, 2 ex

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