The action of antituberculosis drugs in short-course chemotherapy

Mitchison, D.A.

doi:10.1016/0041-3879(85)90040-6

Cited by 467 publications

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“…If CQ enhanced the anti-TB effectiveness of SM solely by raising phagolysosomal pH (16,19,24) as was originally postulated for these experiments, then it should have proportionally decreased the effectiveness of PZA, because PZA requires a low pH to inhibit TB (21,22,27 direct role in the cooperation between CQ and the various drugs tested against the intracellular TB. The natively low pH of lysosomes could, however, be important indirectly in the anti-TB activity of CQ in MPs by promoting the intravacuolar accumulation of CQ (12,19,28 (15) mentioned briefly some experiments on lysosome-phagosome fusion in which they found that 0.02 mM (10 ,ug/ml) CQ was able to inhibit TB in cultured mouse MPs.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

“…The presumed vacuolar acidity is thought to affect the activities of certain anti-TB drugs. It is supposed to decrease that of streptomycin (SM) (7) and increase that of pyrazinamide (PZA) (21,22,27).Chloroquine (CQ) is a drug which is widely used against malaria and certain kinds of chronic inflammatory diseases (3, 28). It is also used experimentally to study the acidic vacuoles of animal cells (16,24), because it is a lysosomotropic base (13, 28) which can increase the pH of these vacuoles and inhibit their acid-dependent activities (16,24).…”

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Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Crowle

May

1990

Antimicrob Agents Chemother

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Intracellular tubercle bacilli (TB) reside in vacuoles in infected human macrophages (MPs). The Tubercle bacilli (TB) in infected human macrophages (MPs) reside in vacuoles (4). These vacuoles might be phagolysosomes, which would be acidic and have several acid-dependent enzymes and activities (18). The presumed vacuolar acidity is thought to affect the activities of certain anti-TB drugs. It is supposed to decrease that of streptomycin (SM) (7) and increase that of pyrazinamide (PZA) (21,22,27).Chloroquine (CQ) is a drug which is widely used against malaria and certain kinds of chronic inflammatory diseases (3, 28). It is also used experimentally to study the acidic vacuoles of animal cells (16,24), because it is a lysosomotropic base (13, 28) which can increase the pH of these vacuoles and inhibit their acid-dependent activities (16,24). Thus, it inhibits malaria parasites by concentrating in the parasite's food vacuoles (lysosomes), raising their pH, and interfering with their digestive functions. This deprives the parasites of critical nutrients (13). Similarly, CQ can raise the pH of phagolysosomes in mammalian cells and affect their digestive functions (16,18,24). If TB do live in acid phagolysosomes in MPs and CQ can raise the pH of these vacuoles, then this drug should increase the anti-TB effectiveness of SM and lower that of PZA. This was tested in the experiments described here. While CQ enhanced the effectiveness of SM, as expected, it did not suppress that of PZA. Also, unexpectedly, it was itself able to inhibit TB in MPs, and it enhanced the anti-TB activity of another drug, isoniazid (INH), whose activity is not pH sensitive.(

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Crowle

May

1990

Antimicrob Agents Chemother

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“…Moreover, current DOTS requires 6-9 months for an effective cure, since it is difficult to kill dormant bacteria with chemotherapeutic drugs. 6 BCG has been used worldwide and appears to be effective in protecting young children from disseminated TB, but not adults. 7 BCG is also ineffective against the endogenous reactivation of M. tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis

Jeon

Kim

et al. 2003

Gene Ther

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“…However, active disease may also develop decades later either as a relapse of the initial infection or because of a secondary infection. Although most cases of tuberculosis were once believed to result from a endogenous reactivation acquired in the past, 4 recent studies indicate that onethird of tuberculosis cases are due to recent transmission by exogenous reinfection of multiple M. tuberculosis strains, [5][6][7][8][9] implicating that the exogenous reinfection significantly contributes to disease transmission. Therefore, novel immunotherapeutic approaches will be required to prevent reinfection as well as reactivation of M. tuberculosis in individuals with latent tuberculosis.…”

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Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

Jeon

Youn

et al. 2005

Gene Ther

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Active disease of tuberculosis (TB) can be developed decades later by either a relapse of the initial infection (endogenous reactivation) or by an entrance of the secondary infection (exogenous reinfection), since the current chemotherapy cannot lead to complete elimination of tuberculosis. Although the immunotherapeutic approaches in conjunction with conventional chemotherapy were tried to prevent TB growth via boosting the immune system, their therapeutic effects are still controversial. Here, we found that TB DNA vaccination completely blocked tuberculosis reactivation and significantly prevented from the secondary infection when chemotherapy was combined simultaneously.In particular, double-gene DNA vaccine composed of Ag85A and PstS-3 genes could reduce bacteria growth better than single-gene DNA vaccine after a secondary reinfection, indicating a correlation between the breadth of Th1 IFN-g response and the efficacy of the protection from reinfection. Thus, we propose that multigene TB DNA immunotherapy including Ag85A and PstS-3 genes during the period of chemotherapy could benefit patients undergoing TB chemotherapy in prevention from exogenous reinfection as well as endogenous reactivation. Gene Therapy (2005) Tuberculosis (TB) holds the dubious honor of being the leading single-agent infectious disease killer in the world 1,2 and the situation is worsened by the increasing incidence of both multidrug resistant (MDR) stains and combination with AIDS. 1,3 After Mycobacterium tuberculosis infection, active disease arises in about 5% of exposed individuals and most of the others will develop a latent infection in which the tubercle bacilli can persist in vivo without causing any clinical symptoms. However, active disease may also develop decades later either as a relapse of the initial infection or because of a secondary infection. Although most cases of tuberculosis were once believed to result from a endogenous reactivation acquired in the past, 4 recent studies indicate that onethird of tuberculosis cases are due to recent transmission by exogenous reinfection of multiple M. tuberculosis strains, [5][6][7][8][9] implicating that the exogenous reinfection significantly contributes to disease transmission. Therefore, novel immunotherapeutic approaches will be required to prevent reinfection as well as reactivation of M. tuberculosis in individuals with latent tuberculosis.DNA vaccination has become a promising strategy for developing an effective vaccine against TB, since it efficiently induces Th1 immunity, an essential arm of immune system to clear the bacteria. In prophylactic settings, there are several reports that DNA vaccines expressing M. tuberculosis antigens are effective for limiting the bacterial growth in mice. 10-13 However, it is still controversial whether DNA vaccines work against TB reactivation in postexposure models. 14-16 For example, the vaccination of plasmid DNA expressing hsp65 after completion of chemotherapy was shown to be effective in preventing the reactivation of intravenou...

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The action of antituberculosis drugs in short-course chemotherapy

Cited by 467 publications

References 4 publications

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis

Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

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