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.