Double-blind, placebo-controlled, 1:1 randomized Phase III clinical trial of Immunoxel honey lozenges as an adjunct immunotherapy in 269 patients with pulmonary tuberculosis.

AIM: Safer and shorter antituberculosis treatment (ATT) regimens represent the unmet medical need. PATIENTS & METHODS: The patients were randomly assigned into two arms: the first (n = 137) received once-daily sublingual honey lozenge formulated with botanical immunomodulator Immunoxel and the second (n = 132) received placebo lozenges along with conventional ATT. Immunoxel and placebo arms were demographically similar: 102 versus 106 had drug-susceptible TB; 28 versus 20 multidrug-resistant TB (MDR-TB); 7 versus 7 extensively drug-resistant TB (XDR-TB); and 22 versus 20 TB-HIV. The primary end point was sputum smear conversion. RESULTS: After 1 month 87 out 132 (65.9%) of Immunoxel recipients became sputum smear negative, whereas 32 out of 127 (25.2%) in placebo group had converted (p < 0.0001). Sputum clearance produced by Immunoxel was equally effective across all forms of TB. In the immunotherapy arm the average weight gain was 2 kg, but placebo recipients gained only 0.6 kg. Immunoxel reduced TB-associated inflammation as evidenced by defervescence and normalization of elevated leukocyte counts and erythrocyte sedimentation rate. No adverse effects were seen at any time. The liver function tests indicate that ATT-caused hepatotoxicity was counteracted by Immunoxel. These results are in agreement with prior 20 trials of Immunoxel conducted over the past 17 years. CONCLUSION: Immunoxel is affordable, safe, effective, fast-acting, commercially available immunotherapeutic intervention to supplement conventional TB chemotherapy. Clinicaltrials.gov ID: NCT01061593.

Efficacy and safety of quercetin and polyvinylpyrrolidone in treatment of patients with newly diagnosed destructive pulmonary tuberculosis in comparison with standard antimycobacterial therapy.

OBJECTIVE/BACKGROUND: The objective/background of this work was to study the efficacy and safety of quercetin and polyvinylpyrrolidone (QP) in the treatment of patients with newly diagnosed destructive pulmonary tuberculosis in comparison with standard antimycobacterial therapy. MATERIALS AND METHODS: The study involved 124 patients aged between 20years and 70years with newly diagnosed destructive pulmonary tuberculosis. Patients were allocated to two groups. The first (control) group of patients received standard antimycobacterial and pathogenetic therapy and included 31 (25.00±3.89%) patients. The second (main) group of patients received QP therapy in addition to chemotherapy and included 93 (75.00±3.89%) patients. RESULTS: Intoxication symptoms in the second group were reduced following 1.33±0.15months, whereas in the first group intoxication symptoms were reduced following 2.64±0.20months, p<.001. CONCLUSION: Administration of QP combined with chemotherapy in patients with newly diagnosed destructive pulmonary tuberculosis resulted in a comparatively quick reduction of disease manifestation.

Morphological changes in experimental tuberculosis resulting from treatment with quercetin and polyvinylpyrrolidone.

OBJECTIVE/BACKGROUND: Morphological study of a mice of tissue necrosis stages in experimental organ-preserving tuberculosis (TB) pharmacotherapy using quercetin and polyvinylpyrrolidone (QP). METHODS: A total of 32 laboratory mice of C57BL/6JLacSto strain were used in the experiment. The animals were divided into five groups (Group 1-5), with six to seven mice in each group: Group 1, Mycobacterium tuberculosis (MBT)-uninfected mice; Group 2, MBT-infected mice; Group 3, MBT infected and treated with anti-TB preparation (ATP); Group 4, MBT infected and QP treated; and Group 5, MBT infected and treated with ATP and QP. The mice were infected through caudal vein injection with the MTB H37Rv strain. The QP preparation, which belongs to the capillary-stabilizing-remedy group, was used for the research. The ATP included isoniazid and streptomycin. Thus, the drug doses for the mice contained the following drugs: isoniazid (10%, 5mL), 45mg/kg; streptomycin (1g), 90mg/kg; and QP (0.5g), 45mg/kg of the body weight of a mouse. The medicines used in the experimental studies on the mice were applied as follows: isoniazid and streptomycin, administered intramuscularly once a day; and QP, administered intraperitoneally according to a schedule (on the 5th day after the introduction of the infection every 2h, and then every 12h; on the 6th day and 7th day two times a day every 12h). RESULTS: QP produced a strict delineation of caseous necrosis from the unaffected parts of the connective tissue with fibrosis in the center and a large number of Langerhans cells, which was not observed in the control groups without QP. The combination of QP and ATP had more pronounced effects. In MBT-infected mice, where QP was not used, unlike the group where QP was used, adipose dystrophy of hepatocytes was observed. Thus, the hepatoprotective effect of QP against TB can be suggested. CONCLUSION: Under the influence of QP, the separation of caseous necrosis of granulomas from unaffected areas begins through connective tissue with fibrotization in the central part and a large number of Langerhans cells and lymphocytes that are not observed in the control groups. The interaction of QP with anti-TB drugs shows more obvious effects: fast tendency of epithelioid cellular tubercles to fibrotization and separation of TB granulomas through connective tissue. In addition, in the control groups of animals infected with TB, in contrast to the experimental groups, fatty degeneration of hepatocytes is observed. Thus, we have shown the hepatoprotective function of QP against TB.

Changes in nitric oxide synthase and nitrite and nitrate serum levels in patients with or without multidrug-resistant tuberculosis undergoing the intensive phase of antituberculosis therapy.

OBJECTIVE/BACKGROUND: There is a paucity of published data on the effect of tuberculosis (TB) chemotherapy on nitric oxide (NO) synthesis and metabolism in newly diagnosed and relapsed patients with or without multidrug-resistant TB (MDR-TB). METHODS: The pattern of NO response in 140 patients with pulmonary TB, including 74 with MDR-TB (1st group) and 66 without MDR-TB (2nd group) has been studied and compared with the NO status of 30 healthy donors (3rd group). Patients comprised those with newly diagnosed pulmonary TB (Subgroups 1B and 2B) and recurrent or relapsed TB (Subgroups 1A and 2A). The NO status was assessed by measuring inducible NO synthase (iNOS), nitrites, and nitrates levels. This was measured prior to treatment initiation and 2months after the prescribed chemotherapy. RESULTS: Increased levels of NO indices were found in patients with TB when compared with healthy controls-1st group: iNOS, 231.6±6.65pmol/min/mgB; nitrites, 5.626±0.15µmol/L; and nitrates, 62.89±1.42µmol/L (Subgroup 1A: iNOS, 208.40±8.26pmol/min/mgB; nitrites, 5.027±0.17µmol/L; and nitrates, 59.29±1.79µmol/L and Subgroup 1B: iNOS, 260.4±8.56pmol/min/mgB; nitrites, 6.371±0.19µmol/L; and nitrates, 67.36±2.03µmol/L); 2nd group: iNOS, 286.3±5.92pmol/min/mgB; nitrites, 6.747±0.17µmol/L; and nitrates, 72.02±1.43µmol/L (Subgroup 2A: iNOS, 260.9±14.12pmol/min/mgB; nitrites, 5.686±0.20µmol/L; and nitrates, 66.26±1.89µmol/L and Subgroup 2B: iNOS, 293.7±6.13pmol/min/mgB; nitrites, 7.059±0.19µmol/L; and nitrates, 73.72±1.71µmol/L) versus healthy controls (iNOS, 81.03±2.36pmol/min/mgB; nitrites, 3.83±0.093µmol/L; and nitrates, 37.98±1.30µmol/L). After 2months of chemotherapy, a significant decrease in NO indicators was observed in the patients with TB, particularly in those without MDR-TB-1st group: iNOS, 114.9±3.2pmol/min/mgB; nitrites, 4.21±0.13µmol/L; and nitrates, 46.65±1.04µmol/L (Subgroup 1A: iNOS, 125.3±4.5pmol/min/mgB; nitrites, 4.42±0.14µmol/L; and nitrates, 49.38±1.30µmol/L and Subgroup 1B: iNOS, 102±3.53pmol/min/mgB; nitrites, 3.93±0.13µmol/L; and nitrates, 43.26±1.50µmol/L) and 2nd group: iNOS, 91.4±2.53pmol/min/mgB; nitrites, 3.67±0.09µmol/L; and nitrates, 35.65±1.06µmol/L (Subgroup 2A: iNOS, 106.7±5.2pmol/min/mgB; nitrites, 4.04±0.19µmol/L; and nitrates-40.53±1.83µmol/L and Subgroup 2B, iNOS, 86.7±2.59pmol/min/mgB; nitrites, 3.56±0.1µmol/L; and nitrates, 34.22±1.19µmol/L). The decline in NO activity was less prominent in patients with recurrent TB and MDR-TB, which suggests lower level of immunologic and reparative processes in such patients. CONCLUSION: In patients with pulmonary TB, significantly higher levels of NO activity were observed as compared with the levels in healthy individuals. In patients with recurrent TB and MDR-TB, significantly lower levels of NO indicators were observed in comparison with patients with newly diagnosed pulmonary TB. After 2months on chemotherapy, a significant decrease in iNOS activity and NO metabolites was observed in patients with pulmonary TB, but the decrease in NO indicators was manifested mostly in the newly diagnosed pulmonary TB patients and patients without MDR-TB as opposed to patients with recurrent TB and MDR-TB, which suggests lower levels of immunologic and reparative processes in such patients. Therefore, the levels of nitrites and nitrates as well as iNOS activity may serve as additional diagnostic criteria to differentiate MDR-TB from nonresistant TB in patients with relapsed and newly diagnosed TB. Easily assessed NO-related markers can also serve as predictors of treatment outcome because patients with drug-susceptible strains had lower NO output approaching levels found in controls.

Morphological changes in experimental tuberculosis resulting from treatment with quercetin and polyvinylpyrrolidone.

RESEARCH OBJECTIVE: Morphological study of tissue necrosis stages in experimental organ-preserving tuberculosis pharmacotherapy using Quercetin and Polyvinylpyrrolidone (QP). BACKGROUND AND METHODS: 32 laboratory mice of C57BL/6JLacSto strain were used in the experiment. The animals were divided into five groups, six to seven mice in each: group 1- Mycobacterium tuberculosis (MBT) uninfected mice; group 2- MBT infected mice; group 3- MBT infected and treated with antituberculosis preparation (ATP); group 4- MBT infected and QP treated; group 5- MBT infected and treated with ATP and QP. The mice were infected through caudal vein injection with MTB H37Rv strain. The preparation QP, which belongs to the capillary-stabilizing-remedy group, was used for the research. The ATP were izoniazid and streptomycin. RESULTS: QP produced a strict delineation of caseous necrosis from the unaffected parts of the connective tissue with fibrosis in the center and a large number of Langerhans cells, which was not observed in the control groups without QP. The combination of QP and ATP had more pronounced effects. In MBT-infected mice, where QP was not used, unlike the group where QP was used, adipose dystrophy of hepatocytes was observed. Thus, the hepatoprotective effect of QP against TB can be suggested. CONCLUSION: QP produces a clear delineation of caseous necrosis from an uninfected tissue by connective-tissue formation, and by forming fibrotic tissue in the center of epithelioid cells that prevents further TB dissemination by enhancing TB pharmacotherapy.

Changes in nitric oxide synthase and nitrite and nitrate serum levels in patients with or without MDR-TB undergoing the intensive phase of anti-tuberculosis therapy.

BACKGROUND: There is a paucity of published data on the effect of TB chemotherapy on nitric oxide (NO) synthesis and metabolism in newly diagnosed and relapsed patients with or without multi-drug resistant tuberculosis (MDRTB). METHODS: The pattern of NO response in 140 patients with pulmonary TB, including 74 with MDR-TB and 66 without MDR-TB has been studied and compared to the NO status of 30 healthy donors. Patients comprised those with newly diagnosed TB and recurrent or relapsed TB. The NO status was assessed by measuring inducible NO synthase (iNOS) and nitrites and nitrates levels. This was measured prior to treatment initiation and two months after the prescribed chemotherapy. RESULTS: Increased levels of NO indices were found in patients with tuberculosis when compared to healthy controls. After two months of chemotherapy a significant decrease in NO indicators was observed in the patients with TB, particularly in those without MDR-TB and newly diagnosed TB. The decline in NO activity was less prominent in patients with recurrent TB and MDR-TB, which suggests lower level of immunologic and reparative processes in such patients. CONCLUSION: Changes in serum levels of nitrites and nitrates as well as iNOS activity in neutrophils may serve as diagnostic criteria to differentiate various clinical forms of TB and help as prognostic tool to predict treatment outcome.