Tubernak now passes registration at the Pharmacological Committee of the Ministry of Health and Social Affairs of Georgia.

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•  Tubernak  has passed preclinical and clinical trials  in the following organizations:

•  JSC “National Centre of Tuberculosis and Pulmonary diseases ”, Department of Research and the Continuous Professional Developments of the National Center of Tuberculosis and Pulmonary Diseases, Tbilisi, Georgia.

• The Center of Quantum and Genetic Medicine, Zagreb, Croatia

•  Clinical and Experimental Research Institute of Tbilisi State Medical University;

•  Medical & Biological Scientific Research Centre  – Company <<Alexis>>;

•  Laboratory  of  Cell  Signal  Mechanisms  of  the  I.Paladin  Institute  of  Biochemistry  at Ukrainian Medical Academy;

•  Medical  Research  Institute  of  Physical  Chemistry  at  the  Ministry  of  Healthcare  of the Russian Federation;

•  Pharmacological Department of the Medical University of Russian Federation;

•  Fuji  Memorial Institute of the Preclinical Research, Bivako/Japan;

• Tokushima Otsuka Immunology Research Institute, Japan;

• Tokushima Institute  of New Drug Research and Safety Evaluation, Japan;

 

Tubernak is recommended for the treatment of immunnoresistant, MDR resistant lung tuberculosis.

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Clinical trials show that the use of the drug Tubernak in the treatment of immunnoresistant, MDR resistant lung tuberculosis improves weakened immune system parameters of patients, both quantitatively and qualitatively. Multidrug-Resistant Tuberculosis (MDR TB) occurs when a Mycobacterium tuberculosis strain is resistant to isoniazid and rifampicin, two of the most powerful first-line drugs. To cure MDR TB, healthcare providers must turn to a combination of second-line drugs (cyclic Peptides, ethambutol, fluoroquinolones, pyrazinamide, PAS an aminoglycosides). Second-line drugs may have more side effects, the treatment may last much longer, and the cost may be up to 100 times more than first-line therapy. MDR TB strains can also grow resistant to second-line drugs, further complicating treatment.

 

 

What Are the Most Significant Indices of Tubernak Anti-Tubercular Action?

Positively influences the dynamics of the clinic:  significantly reduces the symptoms of intoxication, the appetite of patients gets better, the patients start increasing the body weight and the tendency of normalization of the temperature of the body is marked.

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Tubernak activates mononuclear cell (MNC - CD+3, CD+4, CD+8 T-lymphocytes and macrophages) and production effector cytokines (INF-γ TNF-α), that is the objective indicator of immunotherapeutic efficiency of this preparation.

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Tubernak significantly reduced the negative side effects of anti-tuberculosis chemotherapy and there is almost no need for suspension or termination of chemotherapy, which, in turn, increases the effectiveness of anti-tuberculosis chemotherapy.

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On a background, the action of preparation of Tubernak efficiency of basic chemotherapeutic treatment increases: achieved the complete cessation of discharge of bacilli and manifested radiographic positive dynamics.

 

 

 

 

 

 

 

 

 

 

 

 

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On the basis of immunomodulatory properties Tubernak, clinical trials, and literary data it can be assumed scheme of the molecular mechanisms of Tubernak anti-tubercular actions. Tubernak activated mononuclear cells (MNC) produce effector cytokines (INF-γ, TNF-α) and lyses infected cells and macrophages through the release of granules (perforin and granzyme) or by Fas-mediated lyses, whereas TUBERNAK directly and indirectly by activation MNC to produced TNF-α and  INF-γ activates macrophages to kill M. Tuberculosis.

Conclusion

 

Clinical trials show Tubernak is a safe and effective immunotherapeutic drug for comprehensive treatment of severe, ongoing immunosuppression with severe forms of pulmonary tuberculosis. Against the background of antituberculosis chemotherapy, the application of the drug Tubernak already on the first course of treatment substantially improves the subjective feel of patients: reduces the symptoms of intoxication, the appetite of patients gets better, the patients start increasing the body weight and the tendency of normalization of the temperature of the body is marked. After completing the full course of treatment with TUBERNAK, in comparison with the control group, the reliable positive changes of immune processes are marked,  as quantitative indexes so functional parameters, such as quantitative and functional parameters, that is the objective indicator of immunotherapeutic с efficiency of this preparation. On the background of the preparation Tubernak significantly reduced the negative side effects of antitubercular chemotherapy and there is almost no need for suspension or termination of chemotherapy. On background, the action of preparation of Tubernak efficiency of basic chemotherapeutic treatment increases: achieved the complete cessation of discharge of bacilli and manifested radiographic positive dynamics.

Coming from foregoing, we deem it wise to recommend the preparation of Tubernak as an immunotherapeutic drug in the complex treatment of pulmonary tuberculosis.

Practical recommendations

 

Use of a preparation Tubernak is appropriate for complex treatment of resistant forms of pulmonary tuberculosis in immunodeficiency, that confirmed by the expressed lymphopenia. Use of a preparation Tubernak is appropriate at any stage of the treatment of drug-resistant tuberculosis if a lymphopenia comes to light and the languid dynamics of the flow of specific process take place.

Use of a preparation Tubernak is also appropriate at the considerable deficit of body (more

 

than 10%)  weight and during heavy intoxication.

 

Tubernak considerably diminishes the negative influence of antituberculosis preparations and simplifies the management of these processes, in this connection the application of preparation is recommended at the development of severe side effects.

On background, the action of preparation of  Tubernak efficiency of basic chemotherapeutic treatment increases: achieved the complete cessation of discharge of bacilli and manifested radiographic positive dynamics.

In  60%  of cases, the infection is not sensitive to anti-tuberculous medicine and disease frequently achieves a severe form. In these cases the use of the preparation Tubernak in 99% of cases a very strong healing effect.

The duration of therapy depends on the severity of the patient and the dynamics of treatment.

 

 

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    Tubernak in the Immunotherapy of the Multi Drug-Resistant Tuberculosis (MDR TB) of Lungs

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Executive Director

JSC “National Centre of Tuberculosis

and Pulmonary diseases ”

I. Kalandadze

Research Coordinator,

Head of Department of Research and

the Continuous Professional

Developments of the National Center of

Tuberculosis and Pulmonary Diseases

Prof.  L. Vashakidze

 

Presently the worldwide recognized method of treatment of resistant tuberculosis (MDRTB) is the controlled anti-tubercular chemotherapy, DOTS+) which means the long-term application of anti-tubercular preparations of the second row (reserve) – within 18-24 months by direct control of their reception. Treatment of MDRTB is a difficult and long-term process with a difficult predictable exit. Besides, preparations for the treatment of MDRTB are characterized by heavy toxic actions, management with which is quite problematic (guideline of resistant tuberculosis, 2007). One of the ways to increase the efficiency of treatment is the relief of side toxic effects of chemical preparations and the increase of immunoresistance of microorganisms. The later is reached with the use of immunomodulators, sufficient experience of application of which already exists in phthisiology practice. In this direction, our attention was drawn by the medicine of domestic production of a phytogenesis with a peptide structure of TUBERNAK which represents the standardized complex of peptides with immunotrophic properties and is received from ecologically pure plant raw materials.

The assessment of efficiency of action of an immunotherapeutic preparation of domestic production of TUBERNAK in complex treatment of resistant forms of tuberculosis of lungs and development corresponding to the recommendation was the purpose of the conducted research.

The research was conducted on 50 patients sick with resistant tuberculosis (after their written consent). The in the I group were included 30 patients to whom along with MDRTB treatment was carried out immunotherapy by the preparation TUBERNAK, according to the standard scheme. The II group of 20 patients accepted only standard treatment and control was provided. The age, gender and clinical-morphological status of patients of both groups were identical.

The efficiency of immunotherapy of TUBERNAK has estimated on a basis the dynamic clinical-radiological and especially immunological indicators, in particular, on quantitative dynamics of lymphocytes of CD3, CD8, CD4, CD19 of a phenotype of T-system and functional activity of system of T-cells.

The analysis of the obtained data showed that in the I group by the end of treatment of TUBERNAK  intoxication reduction at all patients was noted – 30 (100%), temperature was normalized in 25 cases (83,3%), addition of weight of a body was noted at 26 patients (86,7%), and positive radiological dynamics were recorded in 21 cases (70%). The allocation of bacillus stopped at 21 (70%) patients. In the II group without an immunotherapy, similar indicators were distributed as follows: 16 (80%) P<0,01; 12 (60%) P<0,01; 10 (50%) P<0,01; 11 (55%) P<0,01 и 14 (70%) P<0,5. Data confirm the positive influence of immunotherapy on clinical x-ray dynamics, however, distinctions on the frequency of the termination of allocation of bacillus did not come to light that is logical since this indicator directly reflects the result of chemotherapy.

Dynamics of immune indicators also clearly reflected result of an immunotherapy, in particular, in the I group at 23 patients (76, 6%) against TUBERNAK immunotherapy was noted growth of quantity of lymphocytes of CD3, CD4, CD8 of a phenotype as a result of which the imbalance immunoregulatory subpopulations decreased and proliferative activity of T lymphocytes, stimulated a mitogen which is followed by amplification of improvement of the immune answer. Indicators remained with 6 patients (20%) without changes or they were statistically doubtful, and parameters worsened only at 1 patient (3, 4%). In the II group without an immunotherapy certain positive dynamics, but with a ready smaller frequency also was observed: improvement was recorded at 10 patients (50%), at 8 (40%) were not changes and at 2 (10%) dynamics went down.

In summary, it is possible to tell that TUBERNAK represents an effective and safe remedy that improves clinical-immune indicators at patients, sick with tuberculosis and its application is justified in complex treatment of resistant tuberculosis together with anti-ТВ chemotherapy. 

1.  Clinical Trials TUBERNAK on Patients with MDR Tuberculosis Clinical Efficacy and Safety.

On a world scale tuberculosis is the reason of death rate noninfectious induced illness and to date remains one of the most serious public health problems. According to the WHO in 2008 was to identify 15.4 ml cases of tuberculosis, from those bacilli distinguished 6, 9 million. The tendency of the height of this disease is explained from one side by the increasing of the population(especially in developing countries) and on the other hand by the increasing of a number of co-infection (HIV) AIDS. The existence of an uncontrolled reservoir of infection creates a special high-risk group – these are children (contact). Distribution of tuberculosis causes considerable economic damage, because of that, that he looked younger and spread in the environment of capable of working population.

A basic problem is related to the treatment of tuberculosis, which especially showed up lately, there is an appearance of drug-resistant forms of tuberculosis, i.e. diseases are caused by the resistant forms of mycobacterium to medications. Multi-resistant tuberculosis does not submit to treatment of standard antitubercular chemotherapy and the necessity of his treatment by reserve preparations of the so-called  "second"  group appears, are weaker, less effective and at the same time are characterized the heavily current lateral phenomena by virtue of their toxicity.

Acute toxicity and non-regulated negative side effects of these preparations often become the reason of stopping of treatment course and therefore lead to their ineffectiveness, hat, in turn, increases the risk of the existence of an uncontrolled reservoir of dangerous infection  (headline of resistant tuberculosis). Despite the above-mentioned, the basic method of treatment of tuberculosis to date is the controlled chemotherapy and the efforts of physicians are directed. This implies, from one side, the reduction of adverse side effects and the other hand, the increase immunoresistant of the microorganism, that is the main condition for the treatment of tuberculosis, and especially of the drug-resistant forms.

It is established, with tuberculosis disease, the changes of the immune system are mainly related to the immune deficit of Т-system, this process develops before or during the disease and occurs in 80-90% of patients. The changes are characterized by structural and morphological changes in immunocompetency cells and their apoptosis that, in turn, causes the deficit of Т-lymphocytes and regulative subpopulations. In physiological practice, in the flow of many years, the experience of immunotherapeutic treatment accumulated with the use of immunomodulators (levomizil, nukleinat natrium, etc.) and positive results are described. In this connection, our interest caused new, home peptide preparation  TUBERNAK, prepared from the plants of the Georgian flora. TUBERNAK is a standardized complex of peptides with immunotropic properties, that is got from environmentally clean plants.

TUBERNAK  is created on the basis of preparation TUBERNAK, having immunotropic and anticarcenogenic properties. In particular, with the use of methods of affine and ion-exchange chromatography from peptides, constituents of TUBERNAK, removed peptides with cytotoxic activity, as a result, was got  TUBERNAK  with a combination of peptides, which has increased immunotropic effect on living organisms as compared to TUBERNAK.

A study of the primary biochemical structure of the drug TUBERNAK found, that he consists of  7 peptides and the molecular weight of them is not more than 10-50 kDa. 

Tandem analysis of the primary structure of the non-drug TUBERNAK seven peptides using LTQ FT ICR mass spectroscopy and subsequent patent searches revealed, that the TUBERNAK does not have today well-known analogs. It is necessary to mark that the molecular weight of most endogenous peptides having biological activity and entering in the complement of the human organism (cytokines, hormones, antibodies, defensins, alarmins), varies from 10 to 50 kDa.

It is known that peptides are small molecules, can be easily transported between tissues in the organism and at the same time have a ligand tropism, i.e. specific interference with membrane receptors. It is necessary to mark that these peptides operate in very little  -  nano-  and pico-  concentrations.

As a result, in preclinical studies was established that the immunotherapeutic preparation TUBERNAK causes renewal of quantitative and functional indexes of B and  T cellular immune systems in blood, in particular, T-helper cells, cytotoxic T-cells, T-killer cells (NK-cells), macrophages, neutrophils, the activation of phagocytosis of granulocytes; causes the normalization of the ratio of T-helper and T-suppressor cells, the induction of cytokine production, including tumor necrotic factor (TNF-α), γ-interferon, etc.; Restores the functional activity of hematopoietic stem cells; in the blood causes a normalization of white blood cells, red blood cells, neutrophils, platelets, lymphocytes, formed elements, ESR, and temperature of the body; the preparation TUBERNAK also has a positive effect on the composition of potassium, sodium, calcium and other mineral salts in the blood; the drug has a pronounced effect of detoxification, antioxidant effect and the property of elimination of heavy metals from the body.

Preclinical studies of estimation of the safety of action of preparation, conducted under the standard program, educed his absolute safety on living organisms. In particular, the toxicological, macromorphological, micromorphological, pathological, physiological, biochemical, histological, pathophysiological, immunological and other methods of research shows, that preparation of TUBERNAK does not cause local inflammation and allergic reactions, pathological changes in biochemical, immunological and other parameters of the peripheral blood, does not influence on lipid and carbohydrate metabolism, does not cause morphological and histomorphological changes in the external and the internal organs of the body: heart, liver, spleen, gastrointestinal tract, pancreas, central nervous system (behavioral reactions), and also on other fabrics of organism. Preparation of TUBERNAK also does not cause the changes of temperature and blood pressure, which together indicate that the drug is nontoxic in investigated doses.

In 2005, the National Center for Tuberculosis and Lung Diseases of Georgia was held preliminary preclinical studies in human volunteers, patients with tuberculosis and positive results were obtained, but the relatively small number of studied patients, scarce financial resources and not having the possibility of the realization of researches with the use of modern experimental methods, did not give an opportunity of realization of deeper researches and respectively for statistically confirmed results.

Based on the foregoing, in the National center of tuberculosis and disease of lungs of Georgia, with the purpose of estimation of clinical efficiency and safety of the preparation TUBERNAK, clinical studies are undertaken on the wide program.

Head of Research - Professor, Doctor of Medicine L.Vashakidze, in the study involved physicians E.Barbakadze, M.Gachechiladze, immunologist, immunologist, M. D V.Torondzhadze, as well as the technical staff.

The .cClinical researches began at the beginning of October 2009 and came to an end at the beginning of March 2010. The aim of this work was to evaluate the effectiveness of the drug TUBERNAK at the complex pathogenic treatment of patients with pulmonary tuberculosis (an antitubercular chemotherapy +  immunotherapy of TUBERNAK) for the exposure of action of the investigated preparation and making of methods of his application in case of a positive result.

In the tasks of researches included:

• Estimation  of action of the drug TUBERNAK  on the dynamics of clinical-laboratory and especially immunological indexes in patients, being  on antitubercular treatment;

• Evaluation of the drug TUBERNAK on the negative side effects and their management processes caused by anti-tuberculosis chemotherapy;

• Making of practical recommendations to application of the drug TUBERNAK.

• Investigated object  -  Researches were conducted on 50 patients, patients with the resistant form of tuberculosis, from that 30 patients were in a basic group and 20 patients in a control group.

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Clinical research shows that use of the drug TUBERNAK in the complex treatment of immunnoresistant tuberculosis improves immune parameters of patients, both quantitatively and qualitatively, positively influences on the dynamics of clinic, significantly reduces the toxicity of chemotherapy expressed in by-effects and allows their management, which, in turn, increases the effectiveness of anti-tuberculosis chemotherapy.

All foregoing gives an opportunity to recommend the preparation  TUBERNAK in the complex treatment of drug-resistant tuberculosis.

Conclusion

Domestic preparation TUBERNAK is a safe and effective immunotherapeutic drug for comprehensive treatment of severe, ongoing immunosuppression with severe forms of pulmonary tuberculosis. Against the background of antituberculosis chemotherapy, the application of the drug TUBERNAK already on the first course of treatment substantially improves the subjective feel of patients: reduces the symptoms of intoxication, the appetite of patients gets better, the patients start increasing the body weight and the tendency of normalization of the temperature of body is marked. After completing the full course of treatment with TUBERNAK, in comparison with the control group, the reliable positive changes of immune processes are marked, as quantitative indexes so functional parameters, such as quantitative and functional parameters, that is the objective indicator of immunotherapeutic с efficiency of this preparation.

On the background of the preparation TUBERNAK significantly reduced the negative side effects of antitubercular chemotherapy and there is almost no need for suspension or termination of chemotherapy.

On background, the action of preparation of TUBERNAK efficiency of basic chemotherapeutic treatment increases: achieved the complete cessation of discharge of bacilli and manifested radiographic positive dynamics.

Coming from foregoing, we deem it wise to recommend the preparation of TUBERNAK  as a immunotherapeutic drug in the complex treatment of pulmonary tuberculosis.

Practical   recommendations

• The use of a preparation TUBERNAK is appropriate for complex treatment of resistant forms of pulmonary tuberculosis in immunodeficiency, that confirmed by the expressed lymphopenia.

• Use of a preparation TUBERNAK is appropriate at any stage of the treatment of drug-resistant tuberculosis if a lymphopenia comes to light and the languid dynamics of the flow of specific process take place.

• Use of a preparation TUBERNAK is also appropriate at the considerable deficit of body (more than 10%)   weight and during heavy intoxication.

• TUBERNAK considerably diminishes the negative influence of antituberculosis preparations and simplifies the management of these processes, in this connection the application of preparation is recommended at the development of severe side effects.

• On background, the action of preparation  of TUBERNAK efficiency of basic chemotherapeutic treatment increases: achieved the complete cessation of discharge of bacilli and manifested radiographic positive dynamics

• Application of the preparation TUBERNAK is recommended on a standard methodology that is added to the preparation.