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Glutoxim in complex therapy of tuberculosis.

 

G.B.Sokolova, M.V.Sinistyn, L.A.Kozhemyakin, M.I.Perelman I.M.Sechenov.
Moscow Medical Academy Phthysiopulmonology Research Institute,
Moscow ZAO “VAM — Research Laboratories”, St.-Petersburg.

 

In the context of tuberculosis epidemic affecting Russia in the recent years the course of tuberculosis and the structure of its clinical forms have drastically changed (M.V.Shilova, 2000). There has been an increase in the prevalence of disseminated processes, infiltration-caseous and caseous pneumonia. The share of progressing tuberculosis characterized by acute onset and massive bacteria production has increased to 72.3%. A great (from 18 to 50%) increase in the number of patients with primary drug resistance of tuberculosis mycobacteria has posed a clinical problem (G.B.Sokolova, 2000; Ye.I.Shmelev, V.I.Chukanov, 2000).

In this situation the role of pathogenetic drugs acting to restore patient’s reactivity becomes of increasing importance. Glutoxim, a new metabolic immunorehabilitator, is one of such drugs.

 

Study objective: to evaluate the possibility and advisability of using Glutoxim in tuberculosis patients.

 

Tasks:

-          to evaluate the effect of Glutoxim on the course of disseminated and severe forms of tuberculosis;

-          to evaluate the effect of Glutoxim on the course of tuberculosis in patients with multiple drug resistance;

-          to evaluate the effect of the drug on the course of the postoperative period in tuberculosis patients;

-          to evaluate hepatoprotective effect of Glutoxim in drug-induced and viral hepatitis in tuberculosis patients.

 

Study design: open randomized (envelope method) trials. Duration of therapy — 2 months; follow-up period — 3 months.

 

Study methods:

Inclusion criteria:

-          either sex, 18 to 70 years old;

-          primary or chronic pulmonary tuberculosis;

-          sputum positive for the drug-susceptible (DS) or drug-resistant (DR) pathogen;

-          chronic viral hepatitis (B and C)

-          drug-induced hepatitis due to anti-tuberculosis therapy.

 

Exclusion criteria:

-          myocardial infarction within 12 months before therapy;

-          severe angina pectoris and heart failure;

-          uncontrolled arterial hypertension;

-          psychic disorders;

-          participation in clinical trials of other drugs within 60 days before the study;

-          pregnancy and lactation.

 

Study protocol:

-          physical examination (daily);

-          X-ray examination (before therapy, 2 and 4 months after the beginning of therapy);

-          luminescent microscopy and culture test for tuberculosis mycobacteria (prior to therapy and monthly thereafter).

-          determination of tuberculosis mycobacteria susceptibility to drugs;

-          laboratory tests: blood test; urinalysis; pigmentary, enzymatic and protein-synthetic liver function; blood coagulation system; blood serum urea, creatinine and glucose tests       (prior to therapy and monthly thereafter);

-          electrocardiography;

-          pronchoscopy, when indicated.

 

Therapy methods:

Glutoxim therapy course duration was 52 days (104 doses). The drug was administered intravenously and intramuscularly, 1 ml of 3% solution twice a day. The drug was administered postprandially, at 10.00 a.m. and 6.30 p.m. Concurrent therapy included isoniazide, maxaquine (or rifabutin), protionamide, and canamycin. Additionally vitamin B6, allochol and folic acid were prescribed.

Anti-tuberculosis therapy was identical in the study and the control group. In most patients Glutoxim was introduced 2 weeks after verification of the diagnosis of tuberculosis, following exacerbation of viral hepatitis or at symptoms of drug-induced liver impairment. In the control group, in case of exacerbation of viral hepatitis or at symptoms of drug-induced liver impairment hepatotoxic anti-tuberculosis drugs were cancelled.

 

Glutoxim efficacy evaluation criteria (clinical, bacteriological, roentgenological):

-          tuberculosis intoxication dynamics;

-          time of sutum conversion to negative;

-          resolution of infiltrational changes and dissemination foci, lung degradation cavern reduction or healing;

-          uncomplicated postoperative period.

 

Adverse events:

Adverse events due to Glutoxim and those due to concomitantly administered anti-tuberculosis drugs (ATD) were registered.

 

Clinical trials:

The study started in November, 2000. The results of treating 72 pulmonary tuberculosis patients were analyzed.

Glutoxim was administered concomitantly with ATD to 42 patients (the study group). Of the 42 patients 12 were prepared for and underwent successful surgery. Postoperatively they continued receiving Glutoxim for 12 more days. The control group included 30 patients on ATD. Comparative clinical characteristics of the two groups are presented in tables 1 through 4.

 

Table 1.

 

Clinical characteristics of tuberculosis patients in the observation groups:

 

Group

Number of patients

Sex

Age

Nature of disease

Tuberculosis mycobacteria in sputum

Caverns

M

F

Primary

Chronic

Study

42

32

10

18-50

29

13

37

32

Control

30

18

12

19-50

22

8

28

27

 

Table 2.

 

Tuberculosis intoxication rate in the observation groups:

 

Group

Number of patients

Degree of tuberculosis intoxication

Severe

Moderate

Absent

Study

42

29

10

3

Control

30

18

8

4

 

Table 3.

 

Forms of pulmonary tuberculosis in the study and the control group:

 

Form of tuberculosis

Number of patients

Group

Study

Control

Infiltrational

17

10

7

Caseous pneumonia

21

12

9

Disseminated

10

6

4

Multiple tuberculomas

11

6

5

Fibrous-cavernous

13

8

5

Total

72

42

30

 

Table 4.

 

Lung involvement by tuberculosis process in the observation groups:

 

Patient category

Lung involvement (study group / control group)

 

2 lungs

1 lung

1 lobe

2 segments

Primary tuberculosis

3/1

7/4

16/14

3/3

Chronic tuberculosis

3/1

6/2

3/4

1/1

Total

6/2

13/6

19/18

4/4

 

The above tables demonstrate that patients in the study and the control group were comparable in terms of sex, age and nature of tuberculosis process. Tuberculosis intoxication (fever, cough, lung rales, changes in the blood picture, weigh deficiency, menstrual disorders, depression) was observed in 39 of 42 patients in the study group and in 26 of 30 patients in the control group (table 2).

Dynamics of intoxication symptoms disappearance are presented in table 5.

 

 

Table 5.

 

Intoxication symptoms disappearance dynamics:

 

Group

Number of patients

Of them with intoxication, n/%

Intoxication disappearance, %

Month 1

Month 2

Month 3

Total

Study group

42

39/92.9

46.2

35.9

17.9

100

Control group

30

26/86.7

26.9

30.8

34.6

92.3

 

As seen from table 5, in the study group in the first two months intoxication disappeared in 82.1% of cases. The respective figure in the control group was 57.7%. Compared to the control group, patients receiving Glutoxim demonstrated faster body temperature normalization, cough and lung rales disappearance, normalization of peripheral blood parameters, hormonal status normalization, potency restoration and mood improvement. During the first two months patients in the study group had considerable gain of weight (average 8.9 kg) compared to 4.7 kg in the control group.

Table 6 illustrates the rate and time of bacterioexcretion termination in the observation groups.

 

Table 6.

 

Bacterioexcretion termination rate and time:

 

Group

Number of MBT+ patients

MBT drug susceptibility

Bacterioexcretion termination, %

Month 1

Month 2

Month 3

Total

Study group

37

DS – 20

35.0

55.0

5.0

95.0

DR – 17

41.2

41.2

5.9

88.3

Control group

28

DS – 18

16.7

44.4

27.8

88.9

DR – 10

-

40.0

30.0

70.0

 

The study group patients excreting ATD-sensitive, and especially ATD-resistant, tuberculosis mycobacteria, demonstrated rapid termination of bacterioexcretion.

According to the data of X-ray examination after 2 months, patients receiving Glutoxim demonstrated better resolution of infiltrational changes in the lungs, perifocal and pericavital infiltration, greater reduction in the size of the foci and partial regression of caseous pneumonic foci compared to the control group.

 

Adverse events:

3 patients receiving Glutoxim had body temperature elevation to 37.2-37.9°C. After discontinuation of the drug for 1-2 days body temperature came back to normal. For 3 days thereafter Glutoxim was administered at half the daily dose, once a day. Fever did don recur and Glutoxim therapy was continued.

None of the 9 study patients with chronic hepatitis had exacerbations of this disease, while in the control group liver disease symptoms developed in 3 of the 5 patients with chronic hepatitis. In these patients hepatotoxic drugs were cancelled and desintoxication and symptomatic therapy given.

In five cases Glutoxim was prescribed due to the development of drug-induced hepatitis and due to drug-induced leucosis in six more cases. After 14-21 days of Glutoxim therapy symptoms of liver impairment disappeared and leukocyte count returned to normal values despite continuation of ATD therapy. In the control group hepatotoxic drugs were cancelled in 2 patients due to drug-induced liver impairment and in 3 patients due to leucopenia. Attempts to resume these drugs resulted in recurrence of hepatotoxic reactions and a decrease in leukocyte count. Glutoxim therapy was effective in menstrual cycle disorders (6 cases) and in decreased potency (5 cases). Similar hormonal disorders in the control group persisted throughout the entire period if intensive anti-tuberculosis therapy.

 

Conclusion:

The open randomized study of Glutoxim in patients with severe disseminated drug-susceptible and drug-resistant pulmonary tuberculosis has demonstrated high efficacy and good tolerance of the drug.

Glutoxim therapy contributes to faster resolution of tuberculosis intoxication symptoms, sputum conversion to negative and reversion of pulmonary inflammatory processes.

Glutoxim administration prevents exacerbations of chronic hepatitis in tuberculosis patients, eliminated symptoms of drug-induced hepatitis and leucopenia, normalized the menstrual cycle and increases potency without the need to cancel ATD therapy.

Clinical use of Glutoxim has good prospects in treating tuberculosis, especially severe drug-resistant tuberculosis accompanied by viral or drug-induced hepatitis.

 

For more references:

Dr. Giorgio Castello

Via A. Cecchi, 19/9

16129 – Genova (Italy)

Tel: +39.010.58.94.95

Mobil phone: +39.335.628.34.24

e-mail: castello@tiopoietine.info

 

 

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