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At least 19 recordsLinked to original sources
PubMed1987

Pharmacological evaluation of urate renal handling in humans: pyrazinamide test vs combined pyrazinamide and probenecid administration.

Uricosuric and antiuricosuric drugs have been utilised widely for the study of tubular urate transport in humans. A normal suppression of urate excretion after pyrazinamide is usually taken as evidence of normal presecretory reabsorption. However, in patients with reduced presecretory reabsorption, during pyrazinamide inhibition of urate secretion unreabsorbed urate might still undergo reabsorption along postsecretory sites, allowing for a normal pyrazinamide suppression of urate excretion. To test this possibility, we have performed the pyrazinamide test both alone and after pretreatment with probenecid, which should block postsecretory urate reabsorption. The test was performed in 8 controls, in 9 patients with 'low-excretory' hyperuricaemia, and in 7 patients with tubular urate wasting. Pyrazinamide-non-suppressible urate excretion after pretreatment with probenecid did not differ from the excretion obtained after pyrazinamide alone in hyperuricaemic patients (mean difference 1.33 +/- 2.3% of filtered urate; P = NS); it was slightly higher in controls (3.4 +/- 3.4; P less than 0.05), but was much higher in patients with tubular urate wasting (19.6 +/- 12.7; P less than 0.005). The pyrazinamide test, performed alone, was normal in three patients with tubular urate wasting, but it was abnormal in all patients after pretreatment with probenecid. These results are consistent with the possibility that, during maximal pyrazinamide effect, some uric acid escaping reabsorption at presecretory sites may undergo reabsorption along postsecretory sites, leading to a quantitative overestimation of presecretory reabsorption. This phenomenon appears to have clinical relevance, especially in patients with abnormal urate reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effect of BOF-4272 on the oxidation of allopurinol and pyrazinamide in vivo. Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and pyrazinamide?

Allopurinol or pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxypyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of pyrazinamide during the period after the administration of pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidized both allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide.

Aldehyde Oxidase↗
PubMed1991

Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Results at 30 months. Hong Kong Chest Service/British Medical Research Council.

In a study in Hong Kong 1,386 Chinese patients with sputum smear-positive pulmonary tuberculosis were allocated at random to four 6-month regimens of chemotherapy, all given three times weekly from the start and all containing isoniazid (H) and rifampin (R) throughout. Three contained streptomycin (S) for the first 4 months and pyrazinamide (Z) for 2 months (Z2), 4 months (Z4), or 6 months (Z6); the fourth contained pyrazinamide for 6 months but no streptomycin (Z6noS). Every dose of all four regimens was given under the direct supervision of clinic staff on a predominantly outpatient basis. During the later part of the intake patients were allocated at random to be given their HRZ either as a combined formulation (Rifater), each tablet containing 125 mg isoniazid, 100 mg rifampin, and 375 mg pyrazinamide, or as the three drugs separately. Among 892 assessable patients with drug-susceptible strains of tubercle bacilli pretreatment, bacteriologic failure during chemotherapy occurred in 4, all Z6noS (2% of 224; p less than 0.005 for the comparison with the S-containing regimens). During 30 months of follow-up after the end of chemotherapy, bacteriologic relapse occurred in 2 (3%) of 71 Z2, 2 (3%) of 72 Z4, 4 (6%) of 66 Z6, and 6 (9%) of 64 Z6noS patients allocated to Rifater, and in 4 (3%) of 149 Z2, 8 (6%) of 133 Z4, 2 (1%) of 142 Z6, and 6 (4%) of 135 Z6noS patients allocated to separate drugs. In the relapse rates there were no significant differences between the Rifater and separate drug regimens, the different durations of pyrazinamide, or the regimens with and without streptomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

Early bactericidal activity of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide (Rifater) in patients with pulmonary tuberculosis.

The early bactericidal activity (EBA) of ethambutol, pyrazinamide and the fixed combination of isoniazid, rifampicin and pyrazinamide (Rifater: Mer National) was evaluated in patients with pulmonary tuberculosis who were sputum-positive on microscopy for acid-fast bacilli. Twenty-eight patients (mean age 33 years and weight 51 kg on average; range 40-59 kg) were studied. The fall in viable counts of Mycobacterium tuberculosis in sputum collections during the 2 days following the start of treatment was estimated from counts of colony-forming units (CFUs) of M. tuberculosis per ml of sputum cultured on selective 7H10 agar medium. The EBA for ethambutol determined in 9 patients was 0.245 +/- 0.046, log10 CFU/ml sputum/day, that for pyrazinamide was 0.003 +/- 0.014 log10 CFU/ml sputum/day and that for Rifater 0.558 +/- 0.054 log10 CFU/ml sputum/day. The results obtained are similar to those reported in a previous study of the first 2 days of treatment, but in smaller numbers of patients, and confirm the moderate EBA of ethambutol while pyrazinamide is again shown to have very little EBA. Rifater has a marked EBA which may be due mainly to the action of isoniazid. This methodology may be valuable in the rapid evaluation of the bactericidal activity of new antituberculosis agents and the comparison of different dose sizes of agents of the same class.

Adolescent↗
PubMed2002

Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations.

Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.

Analysis of Variance↗
PubMed1997

The pncA gene from naturally pyrazinamide-resistant Mycobacterium avium encodes pyrazinamidase and confers pyrazinamide susceptibility to resistant M. tuberculosis complex organisms.

The antituberculosis drug pyrazinamide (PZA) needs to be converted into pyrazinoic acid (POA) by the bacterial pyrazinamidase (PZase) in order to show bactericidal activity against Mycobacterium tuberculosis. M. avium is naturally resistant to PZA. To investigate whether this natural resistance to PZA is due to inability of the M. avium PZase to convert PZA to bactericidal POA, the M. avium PZase gene (pncA) was cloned by using the M. tuberculosis pncA gene as a probe. Sequence analysis showed that the M. avium pncA gene is 561 bp long, encoding a protein with a predicted size of about 19.8 kDa; but Western blotting showed that the M. avium PZase migrated as a 24 kDa band when expressed in M. bovis BCG and Escherichia coli. Sequence comparison revealed that M. avium PZase has 67.7% and 32.8% amino acid identity with the corresponding enzymes from M. tuberculosis and E. coli, respectively. Southern blot analysis with the M. avium pncA gene as a probe showed that M. terrae, M. gastri, M. marinum, M. fortuitum, M. xenopi, M. gordonae, M. szulgai, M. celatum and M. kansasii have close pncA homologues, whereas M. chelonae and M. smegmatis did not give significant hybridization signals. Transformation with the M. avium pncA gene conferred PZA susceptibility to PZA-resistant M. tuberculosis complex organisms, indicating that the nonsusceptibility of M. avium to PZA is not due to an ineffective PZase enzyme, but appears to be related to other factors such as transport of POA.

Amidohydrolases↗
PubMed1995

Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide.

The mechanism of action of pyrazinamide (PZA) is not known. One hypothesis is that PZA functions as a prodrug of pyrazinoic acid. Susceptibility to PZA correlates with amidase activity of the Mycobacterium tuberculosis isolate in question. PZA-resistant isolates retain susceptibility in vitro to pyrazinoic acid and n-propyl pyrazinoate. Esters of pyrazinoic acid appear to circumvent the requirement for activation by mycobacterial amidase. The MICs of n-propyl pyrazinoate for M. tuberculosis isolates are lower than those of pyrazinoic acid. Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way. This may lead to a candidate compound with enhanced activity against both PZA-susceptible and PZA-resistant M. tuberculosis isolates suitable for clinical development.

Amidohydrolases↗
PubMed2004

Iron enhances the antituberculous activity of pyrazinamide.

BACKGROUND: Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high in vivo sterilizing activity but poor in vitro activity. This separation in pyrazinamide activity reflects differences between the in vivo tissue environment and in vitro culture conditions. The well-known acid pH requirement for pyrazinamide activity was discovered previously based on such reasoning but does not completely explain the discrepancy between in vivo and in vitro activity of pyrazinamide. This study examined the effect of iron, which could potentially be elevated in local inflammatory lesions, on pyrazinamide activity in vitro. MATERIALS AND METHODS: The effect of iron on the activity of pyrazinamide or its active derivative pyrazinoic acid against Mycobacterium tuberculosis was assessed in liquid medium in a drug exposure assay or in solid medium with pyrazinamide plus iron or pyrazinamide alone. The effect of iron on pyrazinamide or pyrazinoic acid was expressed as percentage of growth inhibition. RESULTS: We have shown that iron enhances the activity of pyrazinamide and pyrazinoic acid against M. tuberculosis in both liquid and solid media at acid pH 5.6. Iron enhanced the activity of pyrazinoic acid but not pyrazinamide against the naturally pyrazinamide-resistant Mycobacterium bovis BCG. Other metal ions such as magnesium, calcium and zinc did not enhance the activity of pyrazinamide or pyrazinoic acid. CONCLUSIONS: Iron increased the activity of pyrazinamide or pyrazinoic acid against M. tuberculosis in vitro. These findings may have implications for the study of mechanism of action of pyrazinamide and possible iron supplement for improving the activity of pyrazinamide.

Antitubercular Agents↗
PubMed2006

Effects of weak acids, UV and proton motive force inhibitors on pyrazinamide activity against Mycobacterium tuberculosis in vitro.

BACKGROUND: Pyrazinamide is a paradoxical frontline tuberculosis drug characterized by high sterilizing in vivo activity but poor in vitro activity. Pyrazinamide is thought to act by the entrapment of pyrazinoic acid in the bacterial cell, leading to acidification and membrane damage. Consequently, the effects of weak acids and molecules affecting membranes added to pyrazinamide were studied. OBJECTIVES: To examine the effects of weak acids, UV, oxidative stress and additional energy inhibitors on pyrazinamide activity in vitro against Mycobacterium tuberculosis as well as the effect of pyrazinamide on Escherichia coli ampicillin persisters. METHODS: Drug exposure experiments followed by cfu counts were performed to determine the effects of the above various factors on pyrazinamide activity in vitro against M. tuberculosis. RESULTS: Some weak acids such as benzoic acid, sorbic acid and propyl hydroxybenzoic acid could enhance the activity of pyrazinamide in vitro against old tubercle bacilli but not young bacilli whereas other weak acids such as salicylic acid and lactic acid did not appear to enhance pyrazinamide activity. While energy inhibitors carbonylcyanide m-chlorophenylhydrazone and dinitrophenol enhanced pyrazinamide activity for old tubercle bacilli but not young bacilli, valinomycin and KCN increased pyrazinamide activity for both young and old bacilli. Oxidative stresses due to H2O2 and menadione did not have a significant effect on pyrazinamide activity. UV, which presumably damages the membrane, enhanced the activity of pyrazinamide. Pyrazinamide, which otherwise has no activity against actively growing E. coli bacteria, could kill non-growing starved E. coli and also ampicillin-tolerant persisters. CONCLUSIONS: Some weak acids, UV and various energy inhibitors were found to enhance the activity of pyrazinamide in vitro against M. tuberculosis. Pyrazinamide shows preferential activity against both M. tuberculosis and E. coli persisters over the growing forms.

Ampicillin↗
PubMed2005

National survey to measure rates of liver injury, hospitalization, and death associated with rifampin and pyrazinamide for latent tuberculosis infection.

BACKGROUND: Cases of severe and fatal liver injury were reported after a 2-month course of rifampin-pyrazinamide therapy was recommended in 2000 as an alternative to isoniazid for treatment of latent tuberculosis infection. We estimated rates of rifampin-pyrazinamide-associated liver injury and compared these with historical rates for isoniazid. METHODS: We conducted a survey of state and city tuberculosis programs and other health care settings in the United States where rifampin-pyrazinamide was prescribed. The number of rifampin-pyrazinamide therapy initiations was collected, as well as the number of occurrences of (1) asymptomatic aspartate aminotransferase serum concentration >5 times the upper limit of normal, (2) symptomatic hepatitis (in which the patient was not hospitalized), (3) hospitalization for liver injury, (4) death with liver injury, and (5) treatment completion. We also searched a national pharmacy claims database (Verispan). Rates of these events were calculated. RESULTS: Among 139 programs, 110 (79%) responded; 87 (79%) had initiated rifampin-pyrazinamide therapy for a total of 8087 patients between January 2000 and June 2002. Rates per 1000 rifampin-pyrazinamide therapy initiations during this period were 25.6 (95% confidence interval [CI], 22.3-29.3) for asymptomatic aspartate aminotransferase level >5 times the upper limit of normal and 18.7 (95% CI, 15.9-21.9) for hepatitis. Seven fatalities and 23 hospitalizations occurred, with rates of 0.9 (95% CI, 0.4-1.9) and 2.8 (95% CI, 1.8-4.3) per 1000 rifampin-pyrazinamide therapy initiations, respectively. Of 8087 patients, 64% completed rifampin-pyrazinamide therapy. The Verispan search revealed 1 rifampin-pyrazinamide-associated hospitalization (2.9 hospitalizations per 1000 rifampin-pyrazinamide therapy initiations; 95% CI, 0.1-18.4) and no deaths. Articles on the use of isoniazid therapy for latent tuberculosis infection that were published after 1990 reported fatality rates of 0.0-0.3 deaths per 1000 persons. CONCLUSIONS: Rates of liver injury, hospitalization, and death associated with rifampin-pyrazinamide therapy exceed rates reported for isoniazid therapy. Because earlier randomized trials of rifampin-pyrazinamide lacked adequate statistical power to detect fatal events, the Centers for Disease Control and Prevention recommends that rifampin-pyrazinamide generally should not be used for treatment of latent tuberculosis infection.

Antitubercular Agents↗