Method of treating patients with drug-resistant tuberculosis or hiv-infection

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to phthisiology and infectious diseases, and may be used for treating the patients with drug-resistant tuberculosis and HIV infection. For this purpose, with underlying high-active antiretroviral therapy (HA ART), the patient's state is clinically assessed, and observing the deterioration, temperature rise, developing inflammatory process in the involved organs, prednisolone 0.5 mg/kg is administered once daily orally for 10-12 days. After termination of the therapeutic course, the clinical parameters are assessed; observing the normalisation thereof enables stating the presence of the inflammatory immune reconstitution syndrome in the patients with drug-resistant tuberculosis and HIV infection with underlying the HAART. The prednisolone therapy is continued up to 3 weeks. In the absence of a positive effect of the use of prednisolone, the developing disease is associated by the progression of drug-resistance of tuberculosis mycobacteria, and the prednisolone therapy is withdrawn herewith correcting the anti-tuberculosis therapeutic regimen by prescribing the second-line anti-tuberculosis preparations.

EFFECT: method ensured providing higher clinical effectiveness in the patients with drug-resistant tuberculosis and HIV infection by eliminating the inadequate intensive therapy receiving the second-line anti-tuberculosis preparations causing a risk of developing side effects.

2 ex

 

The invention relates to medicine, namely tuberculosis and infectious diseases, and can be used for the treatment of patients with drug-resistant TB and HIV-infection.

For the treatment of patients with drug-resistant TB and HIV are on antiretroviral and anti-TB drugs. In patients with severe immune deficiency at the background of starting HAART progression of disease or activation of previously subclinical flowed infections. This condition was called inflammatory syndrome immune reconstitution (IRIS). The frequency of inflammatory syndrome immune reconstitution corallium with CD4-lymphocytes and viral load of HIV in the early antiviral therapy. The frequency of the syndrome of immune reactivation increases in patients starting HAART with a small interval from the start of TB treatment.

Clinical development of IRIS in patients with HIV-infection and tuberculosis is characterized by General deterioration, increased body temperature, rapid increase in both hilar and peripheral lymph nodes, zones of inflammatory infiltration in the lung tissue or the appearance of miliary dissemination, development of polyserositis with the accumulation of fluid in the serous cavities. The timing of the development of a syndrome of immune Rea the activation, according to different authors, ranging from 3-5 days to six months.

In 2006, a consensus on the formulation of a case of syndrome of immune restoration with the manifestation of tuberculosis. In accordance with the consensus diagnosis of tuberculosis-associated inflammatory syndrome immune reconstitution is based on (A) data history and (B) clinical manifestations, which in turn can be divided into major and minor manifestations.

A. Previous state:

- The presence of a diagnosis of tuberculosis infection prior to initiating HAART;

- Improvement on the background of anti-TB therapy at start of HAART.

B. Clinical criteria:

- Start the immune reactivation during the first 3 months. from starting or restarting or changing HAART regimens;

The availability of one or two minor criteria:

1. Large criteria:

- The onset or progression of local tuberculous lesions of tissues (instrumental confirmation);

- The onset or progression of local changes in the lung tissue according to x-ray examinations.

2. Minor criteria:

- The onset or progression of clinical deterioration;

- The onset or progression of respiratory and/or abdominal symptoms;

For diagnosis of inflammatory syndrome restore the means of immunity should be excluded:

- The development or progression of other opportunistic infections;

- Drug resistance of Mycobacterium tuberculosis (MBT);

Low adherence to anti-TB therapy;

Toxic side effects or unwanted drug interactions.

Thus, in accordance with the criteria for the diagnosis of IRIS, the presence of drug resistance is an exclusion criterion for this condition and requires correction scheme of TB treatment, as the worsening condition of the patient is viewed as a progression of TB and drug-resistant office(1, 2, 3, 4, 5).

On the closest in technical essence as a prototype we have chosen a method of treating patients with drug-resistant TB and HIV infection, which in medical exposure, including the introduction of antiretroviral (arit) and TB (PTP) drugs. When the deterioration of the patients, which is assessed according to the clinical picture, characterized by fever, a change in the inflammatory process in the affected organs, the deterioration of the General condition of the patient, the patient's condition is considered as the progression of TB and drug-resistant M. tuberculosis. The presence of drug-resistant TB is a criterion lawsuit is Uchenie diagnosis of inflammatory syndrome immune reconstitution (6). This produces a change in the scheme of anti-TB therapy adherence PTP second row.

The disadvantage of this method, we have chosen as a prototype, is inadequate intensive care PTP second row, because the deterioration of the patients, according to the prototype, in all cases indicates the presence of drug resistance and the absence of inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on a background of application of HAART. Make a schema change anti-TB therapy adherence PTP second row (6).

According to the authors of the proposed method, it is not always the deterioration of patients indicates the presence of drug resistance and the absence of inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on a background of application of HAART. Therefore, long-term administration of anti-TB second-line drugs in some cases is excessive and inadequate intensive therapy, which is the risk of hepatotoxic, neurotoxic and nephrotoxic side effects caused by anti-TB drugs 2 rows(7, 8, 9).

The technical result of the invention is to increase effective the particular treatment of patients with drug-resistant TB and HIV infection by eliminating inadequate intensive care, calling the risk of side effects caused by anti-TB drugs 2 rows.

The technical result of the invention is achieved by the fact that despite the use of HAART conduct a clinical assessment of the patient and when the deterioration of the General condition, fever, progression of the inflammatory process in the affected organs enter patient prednisolone at a dose of 0.5 mg/kg once a day orally for 10 to 12 days. After completing the course, evaluate clinical parameters, such as temperature, changes of inflammation in the affected organs, the General condition of the patient. When the normalization of temperature, regression of the inflammatory process in the affected organs, improve the General condition of the patient determine the presence of inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on a background of application of HAART. At the same time continue prednisonetherapyeo to 3 weeks. In the absence of positive effect of prednisolone and maintaining the elevated temperature, lack of regression of inflammatory changes in the affected organs progression of the disease is considered in connection with the progression of drug resistance of Mycobacterium tuberculosis. Prednisonetherapyeo overturned. When this interviewer is ktrout scheme of TB treatment including the introduction of anti-TB drugs of the second row.

The method is as follows:

Against the backdrop of HAART, including nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, inhibitors of fusion, daily in the morning after eating take 0.5 mg/kg prednisolone once a day for 10-12 days. After completing the course, evaluate clinical parameters, such as temperature, changes of inflammation in the affected organs, the General condition of the patient. Twice a day (morning and evening) conduct thermometry body with a mark in the medical records. Changes of inflammation in the affected organs assessed by radiography of the chest. If you have a local pathology produce daily inspection and estimate local changes occurred. When determining the General condition of the patient produce a survey of systems and organs. When the normalization of temperature, regression of the inflammatory process in the affected organs, improve the General condition of the patient determine the presence of inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on a background of application of HAART. Prednisonetherapyeo continue to 3 weeks. In the absence of a positive effect of the application of the Oia prednisolone and maintaining the elevated temperature, the lack of regression of inflammatory changes in the affected organs progression of the disease is considered in connection with the progression of drug resistance of Mycobacterium tuberculosis. Prednisonetherapyeo overturned. If this corrects the scheme of anti-TB treatment, including the introduction of anti-TB drugs of the second row.

Distinguishing the essential features of the proposed method are:

against the background of the introduction of antiretroviral (arit) and anti-tuberculosis (anti-TB drugs) drugs when deterioration of the patients, assessed by clinical picture, characterized by fever, a change in the inflammatory process in the affected organs, the deterioration of the General condition of the patient him enter prednisolone at a dose of 0.5 mg/kg once a day for 10-12 days;

after completion of the course prednisonetherapyhy assess clinical performance, and the normalization of temperature, regression of the inflammatory process in the affected organs, while improving the General condition of the patient determine the presence of inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on a background of application of HAART and still retain the regimen ARUP and PTP, prednisonetherapyeo continue to 3 weeks;

- in the absence of positive the playing technique from the use of prednisolone and maintaining the elevated temperature, the absence of regression of inflammatory changes in the affected organs progression of the disease is considered in connection with the progression of drug resistance of Mycobacterium tuberculosis and prednisonetherapyeo overturned. If this corrects the scheme of anti-TB treatment, including the introduction of anti-TB drugs of the second row.

A causal relationship between significant distinctive features and achieve the result:

We first proved that in patients with drug-resistant TB and HIV infection on the background of the application HAART deterioration is not always indicative of the progression of TB associated with the presence of drug resistance MW and no inflammatory syndrome immune reconstitution.

According to the method prototype in the presence of drug resistance MW when determining inflammatory syndrome immune reconstitution is the exclusion criterion. However, in patients (with the presence of drug resistance and drug sensitivity MW) to the time of starting HAART can be obtained improvement with regression of symptoms of intoxication on the background of anti-TB therapy. On the background of prednisolone is the regression of clinical symptoms exacerbation of the tuberculous process without carrying out the correction of TB treatment, it would be impossible for the progression of TB caused by drug-resistant M. tuberculosis. The mechanism of action of glucocorticoids is that after passing through the cell membrane glucocorticoids in the cytoplasm associated with specific steroid receptor. The activated complex "glucocorticoid receptor" enters the nucleus of cells, connected with DNA and stimulates the formation of the RNA. In the broadcast RNA are synthesized on ribosomes of different regulatory proteins. One of the most important is lipokortin, which inhibits the enzyme phospholipase-A2and thus inhibits the synthesis of prostaglandins and leukotrienes, which play a key role in the development of inflammatory reactions (7). Inflammatory syndrome immune reconstitution is characterized by rapid increase of CD4-lymphocytes and hyperimmune reactions with massive release of proinflammatory cytokines, which blocks the use of prednisolone.

Subsequent monitoring of patients in case of a positive response to prednisonetherapyeo not observed further progression of tuberculous process. Thus, the presence of drug resistance should not be an exclusion criterion inflammatory syndrome immune reconstitution.

Use the prednisolone at a dose of 0.5 mg/kg once a day for 10-12 days in the claimed method is sufficient to determine the presence or absence of inflammatory syndrome immune reconstitution.

When determining the presence of inflammatory syndrome immune reconstitution must continue prednisonetherapyhy up to 3 weeks to improve the effectiveness of treatment.

In the absence of positive effect of prednisone after a 10-12-day course and maintaining the elevated temperature, the absence of regression of inflammatory changes in the affected organs progression of the disease is considered in connection with the progression of drug resistance of Mycobacterium tuberculosis, and therefore need adjusting circuit TB treatment, including the abolition of prednisonetherapyhy and the introduction of anti-TB drugs of the second row.

The distinctive set of essential features is new and allows to increase the efficiency of treatment of patients with drug-resistant TB and HIV infection by eliminating inadequate intensive care, which causes the risk of side effects caused by anti-TB drugs 2 rows.

Clinical examples:

Example 1

And/b No. 1279. Patient K., 32 years.

Did 30.08.2010 in the City tuberculosis hospital №2

In St. Petersburg.

Complaints: fever up to 39.5, enlarged lymph nodes in the neck from both sides, weakness, shortness of breath.

Objective: State Edna of gravity, low power, skin pale. On the neck with two sides palpable increased to 3-4 cm lymph nodes, welded in packages. In the lungs breathing hard, wheezing is not heard, the NPV of 20 per minute. Heart sounds are clear, rhythmic, pulse rate 96 / min. The abdomen is not swollen, soft, pain in the right hypochondrium and paraumbilical area, the liver performs at 3 cm from under the costal arch.

Diagnosis: HIV infection in stage 4B, the progression without HAART:

Tuberculosis of intrathoracic lymph nodes in F. infiltration and contamination of the CUBE(+). Tuberculosis of peripheral lymph nodes in F. infiltration CUBE(+), tuberculosis of the mesenteric lymph nodes in F. infiltration CUBE(-). In sputum growth of the office with multidrug resistance.

By the time of starting HAART temperature was normalized, marked decrease in the size of lymph nodes in the neck. Antiretroviral therapy is started 20.10.10 (Epivir videx, Kaletra). On the 32nd day of HAART has deteriorated General condition, consisting in the appearance of weakness, sweating, loss of appetite. Appeared fever, recurrent lymph node enlargement in the neck. Due to the ongoing reception of protionamide, amikacin, cycloserine, and pyrazinamide administered a course of prednisonetherapyhy - 20 mg once a day for 10 days 8.11.2010 on 18.11.2010. Temperature normalized on the 4th day of prednisolone, mark the expected reduction in the size of lymph nodes in the neck. After a 10-day course of prednisonetherapyhy treatment with prednisolone was continued for up to 3 weeks, that is, after a 10-day course of prednisonetherapyhy patient K. continued to receive prednisone for 11 days.

The deterioration of the patient prior to the course of prednisonetherapyhy was regarded as the development of the IRIS.

Example 2

And/b No. 496, Patient R., 37 years.

Did 31.03.09 City tuberculosis hospital №2

In St. Petersburg.

Complaints: weakness, sweating.

Objectively: the patient is in satisfactory Condition, normal nutrition, the skin is clean, normal color. On the neck with two sides palpable increased to 3-4 cm lymph nodes, welded in packages. In the lungs breathing hard, wheezing is not heard, the NPV 18 in minutes heart sounds clear, rhythmic. HR 18 min, BP 110/70 mm of water. Art. the Abdomen is not swollen, soft, painless, liver acts 2 cm under the costal arch.

The diagnosis of Infiltrative tuberculosis of the lower lobe of the right lung in F. decay and contamination of the CUBE(+). In sputum growth of the office of drug resistance.

4.05.09 started HAART, 7 days a deterioration of the appearance of high temperature, weakness. The radiological examination revealed the progression of tuberculosis in the lung tissue. While taking isoniazid, pyrazinamide, ethambutol, streptomycin holding to the PCA of prednisonetherapyhy for 12 days at a dose of 20 mg did not improve the condition of the patient. Prednisonetherapyra cancelled. Follow-up showed further progression of tuberculosis associated with drug-resistant M. tuberculosis. This incident was regarded as the progression of drug-resistant tuberculosis is not associated with the IRIS. The patient was prescribed protionamide, pyrazinamide, ofloxacin, and cycloserine.

15 we see patients with HIV infection and bacteriologically confirmed tuberculosis drug resistance of MBT on the background of starting antiretroviral therapy at the time of 41.7±8.7 days developed deterioration with increased body temperature, accumulation of inflammatory changes in peripheral lymph nodes, radiographic evidence of progression of tuberculosis in the lung tissue. Prescribed course of prednisonetherapyhy by the present method, the application of which in the course of 7.5±0.4 days in 13 patients (87%) were able to obtain a regression of the clinical manifestations of acute tuberculosis. Further monitoring of these patients showed no deterioration or progression of tuberculosis after prednisone, which helped to define the inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on the background of the application of highly active antiretroviral therapy (HAART) and save the th previous regimen ARUP and PTP, while prednisonetherapyeo up to 3 weeks.

In 2 patients after completion of the course prednisonetherapyhy condition has not improved, it was revealed progression of tuberculosis associated with drug-resistant M. tuberculosis. Prednisonetherapyra terminated. Adjusted scheme of TB treatment, including the introduction of anti-TB drugs of the second row.

Using the prototype in all 15 cases, the deterioration in patients with drug-resistant TB was defined as progression of TB drug resistance the office, there was observed the absence of an inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection on the background of the application of highly active antiretroviral therapy (HAART), and this caused a subsequent change in the scheme of anti-TB therapy adherence PTP second row (6).

Thus, the claimed method of treatment of patients with drug-resistant TB and HIV infection compared with the prototype 87% increases the efficiency of treatment of patients with drug-resistant TB and HIV infection by eliminating inadequate intensive care, which causes the risk of side effects caused by taking the however, ercolessi drugs 2 rows.

Literature

1. Bourgarit A., Carcelain G., Martinez V. et al. Reconstitution of immune responses to tuberculosis in patients with HIV infection who receive antiretroviral therapy // Chest. - 2002. - Vol.122. - P.597-602.

2. Lawn S.D., R.J. Wilkinson, Lipman M.C. Immune reconstitution and "unmasking" of tuberculosis during antiretroviral therapy // Am. J. Respir. Crit. Care Med. - 2008 - Vol.177. - P.680-685.

3. Meintjes g, Lawn S.D., F. Scano, at al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings // Lancet Infect. Dis. - 2008. - Vol.8(8). - P.516-523.

4. Valin N, Pacanowski J, Denoeud L, Lacombe K, Lalande V, Fonquernie L, Girard PM, Meynard JL. Risk factors for 'unmasking immune reconstitution inflammatory syndrome' presentation of tuberculosis following combination antiretroviral therapy initiation in HIV-infected patients. // AIDS. - 2010. - Vol.24 (10). - P.1519-1525.

5. Sharma SK, Dhooria S, Barwad P, Kadhiravan T, Ranjan S, Miglani S, Gupta D. A study of TB-associated immune reconstitution inflammatory syndrome using the consensus case definition. - Indian J. Med. Res. - 2010. - Vol.131. - P.804-808.

6. (Meintjes g, Lawn S.D., F. Scano, at al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings // Lancet Infect. Dis. - 2008. - Vol.8(8). - P.516-523.)

7. Mishin V.Y., Chukanov, V., Grigoriev YG Side effects of anti-TB drugs in the standard and individualized modes of chemotherapy / Moscow. - Publishing house "Computerbank", 2004. - 208 S.

8. Sokolova G.B. Side effects of tuberculostatic drugs. - M., 1983. 154 C.

9. Nasmail, Essepian. Side effects of anti-TB drugs), 1977. - 280 S.

A method of treating patients with drug-resistant TB and HIV infection, which in medicamen snom impact including the introduction of antiretroviral (arit) and TB (PTP) preparations, characterized in that when the deterioration of the patients, assessed by clinical picture, characterized by fever, a change in the inflammatory process in the affected organs, the deterioration of the General condition of the patient him enter prednisolone at a dose of 0.5 mg/kg once a day for 10-12 days, and after completion of the course prednisonetherapyhy assess clinical performance, and the normalization of temperature, regression of the inflammatory process in the affected organs, improving the overall determine the presence of inflammatory syndrome immune reconstitution in patients with drug-resistant TB and HIV infection against the backdrop of highly active antiretroviral therapy (HAART) and still retain the regimen ARUP and PTP, while prednisonetherapyeo to 3 weeks, and if no effect or deterioration of the patient after a 10-12-day course of prednisonetherapyhy her stop and adjust the scheme of anti-TB treatment, including the introduction of anti-TB second-line drugs.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to dimephosphone nicotinoylhydrazone of formula (I) which may be used in medicine and veterinary science: I.

EFFECT: what is presented is a new compound showing high anti-tuberculosis activity and low toxicity.

2 cl, 1 ex, 3 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: for the purpose of producing a probiotic preparation, a biomass of the symbiontic strain Corynebacterium diphtheriae tox No. 2 of Federal State Institution L.A. Tarasevich State Institution of Standardization and Control is cultured in a liquid nutrient medium; microbial cells are deposited by centrifugation, washed to precipitate whole cells by centrifugation; the cells are suspended in a sodium chloride solution. Then, the cells are disintegrated at temperature 25-30°C for 15 min at frequency 20 kHz and amplitude 14 mcm; the desintegrant is centrifugated at 5000 g; and the remained whole cells are removed. The prepared precipitation is centrifugated at 14000 g for 20 min. to produce precipitated corpuscular antigens of cell walls of lipopeptidopolysaccharide corynebacteria which is resuspended and disintegrated at temperature 25-30°C for 5 min. at frequency 20 kHz and amplitude 14 mcm. Then the preparation is diluted to the concentration of 225-275 mcg/ml, sterilised and lyophilised.

EFFECT: use of the invention enables producing the safe and effective preparation of corpuscular antigens providing creating specific and non-specific immunity to tuberculosis.

2 cl, 2 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry. A pharmaceutical composition as active therapeutic agents contains cytidine, uridine, pyridoxine hydrochloride or folic acid, lidocaine hydrochloride and excipients. sodium polyphosphate, potassium (III) ferricyanide, sodium hydroxide, benzole alcohol and water for injections. The pharmaceutical composition is presented in the form of ampoules for injections.

EFFECT: preparing the pharmaceutical compositions used for preventing and treating neuropathies.

2 cl, 1 tbl

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