The Role of Pyrazinamide in Tuberculosis Chemotherapy

Steele, Malcolm A.; Prez, Roger M. Des

doi:10.1378/chest.94.4.845

Cited by 98 publications

(72 citation statements)

References 35 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: 79%

“…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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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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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: 79%

mentioning

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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“…61,64 Cirrhosis Most authorities suggest that PZA is contraindicated in the presence of liver disease although some authors believe that PZA is well tolerated in these patients. [65][66][67][68][69] Current recommended dose of 15-30 mg/kg has significantly less risk of hepatotoxicity. The frequency of hepatotoxicity in patients who received PZA in doses of 25-35 mg/kg along with RIF and INH was found to be similar to those who received only RIF and INH.…”

Section: Chronic Hepatitis C Virus Infectionmentioning

confidence: 99%

“…The frequency of hepatotoxicity in patients who received PZA in doses of 25-35 mg/kg along with RIF and INH was found to be similar to those who received only RIF and INH. 66,67 Dhingra et al 69 recommended that, in patients with cirrhosis of liver, treatment may be started with an aminoglycoside, a quinolone and EMB. If further addition of drugs is considered necessary RIF may be added.…”

Section: Chronic Hepatitis C Virus Infectionmentioning

confidence: 99%

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

Dhiman

Saraswat

Rajekar

et al. 2012

Journal of Clinical and Experimental Hepatology

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Tuberculosis remains one of the 'Captains of the Men of Death' even today, particularly in the developing world. Its frequency is increased 14-fold in patients with chronic liver diseases (CLD) and liver cirrhosis, more so in those with decompensated disease, probably due to the cirrhosis-associated immune dysfunction syndrome, and case-fatality rates are high. The diagnosis of tuberculosis, particularly the interpretation of the Mantoux test, is also fraught with difficulties in CLD, especially after previous BCG vaccination. However, the greatest challenge in the patient with CLD or liver cirrhosis and tuberculosis is managing their therapy since the best first-line anti-tuberculosis drugs are hepatotoxic and baseline liver function is often deranged. Frequency of hepatotoxicity is increased in those with liver cirrhosis, chronic hepatitis B and chronic hepatitis C, possibly related to increased viral loads and may be decreased following antiviral therapy. If hepatotoxicity develops in those with liver cirrhosis, particularly decompensated cirrhosis, the risk of severe liver failure is markedly increased. Currently, there are no established guidelines for anti-tuberculosis therapy (ATT) in CLD and liver cirrhosis although the need for such guidelines is self-evident. It is proposed that ATT should include no more than 2 hepatotoxic drugs (RIF and INH) in patients with CLD or liver cirrhosis and stable liver function [ChildTurcotte-Pugh (CTP) #7], only a single hepatotoxic drug (RIF or INH) in those with advanced liver dysfunction and no hepatotoxic drugs with very advanced liver dysfunction (CTP $11). A standard protocol should be followed for monitoring ATT-related hepatotoxicity and for stop rules and reintroduction rules in all these patients, on the lines proposed here. It is hoped that these proposals will introduce uniformity and result in streamlining the management of these difficult patients. ( J CLIN EXP HEPATOL 2012;2:260-270)

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Management of Tuberculosis

Leitch¹

2000

Crofton and Douglas's Respiratory Diseases

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The Role of Pyrazinamide in Tuberculosis Chemotherapy

Cited by 98 publications

References 35 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

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

Management of Tuberculosis

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