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At least 109 records · Page 6Linked to original sources
PubMed1988

Radiometric method for pyrazinamide susceptibility testing of Mycobacterium tuberculosis in egg-yolk-enriched BACTEC 12A medium.

A radiometric method for testing the susceptibility of Mycobacterium tuberculosis to pyrazinamide in egg-yolk-enriched 12A medium (pH 5.5) is described. We obtained 100% agreement between the 7H10 agar method with 25 microgram of pyrazinamide per ml and the modified radiometric method with a drug concentration of 50 microgram/ml in tests of 90 clinical isolates.

Animals↗
PubMed1999

Characterization of new mutations in pyrazinamide-resistant strains of Mycobacterium tuberculosis and identification of conserved regions important for the catalytic activity of the pyrazinamidase PncA.

A new set of mutations, including transposition of the insertion sequence IS6110, was identified in the pncA gene from 19 pyrazinamide-resistant Mycobacterium tuberculosis strains. Alignment of the PncA protein from M. tuberculosis with homologous proteins from different bacterial species revealed three highly conserved regions in PncA which may play an important role in the processing of pyrazinamide.

Amidohydrolases↗
PubMed1999

pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis isolates from northwestern Russia.

Thirty-six pyrazinamide-resistant and eight pyrazinamide-susceptible Mycobacterium tuberculosis isolates from Russia were analyzed for their pncA mutations. Thirty-one (86.1%) of the resistant isolates had a mutation either in pncA or upstream of the gene. Twenty of the 23 different mutations found in this study had not been described earlier. pncA genotype correlated well with pyrazinamidase activity and BACTEC 460 susceptibility test results.

Amidohydrolases↗
PubMed1991

Effects of pyrazinamide, probenecid, and benzbromarone on renal excretion of oxypurinol.

The effects of pyrazinamide, probenecid, and benzbromarone on renal excretion of oxypurinol were investigated. Pyrazinamide decreased the mean (SEM) fractional clearance of oxypurinol from 19.2 (2.1) to 8.8 (1.5). Probenecid increased the fractional clearance of oxypurinol from 14.1 (3.5) to 24.8 (4.1). Benzbromarone increased the fractional clearance of oxypurinol from 15.6 (2.3) to 33.8 (2.8). These results suggest that oxypurinol may be secreted by 'an organic acid system' and that oxypurinol is reabsorbed at a putative postsecretory site of the renal tubules.

Adult↗
PubMed1976

Use of pyrazinamide to assess renal uric acid transport in the rat: a micropuncture study.

Free-flow micropuncture studies were performed to evaluate renal uric acid transport in control and pyrazinamide-treated rats. In all studies [2-14C]uric acid and [methoxy-3H]inulin were administered. [2-14C]uric acid was determined after column chromatographic separation from its labeled oxidation product in tubular fluid, plasma, and urine. Tubular fluid collections were obtained from the early and late proximal tubule under hydropenic conditions and from the early proximal tubule during volume expansion induced with 0.9% sodium chloride. These studies indicate that pyrazinamide, in the dose employed, provokes a uniform reduction in fractional uric acid excretion but simultaneously inhibits both net uric acid reabsorption and secretion in the early and late proximal tubule, respectively. In addition, these experiments unmasked uric acid reabsorption within the late proximal tubule and bidirectional transport beyond this nephron site. These studies also suggest at least two mechanisms for uric acid reabsorption; one sodium dependent, the other independent of sodium and water transport.

Animals↗
PubMed1977

Familial hypouricemia due to isolated renal tubular defect. Attenuated response of uric acid clearance to probenecid and pyrazinamide.

A 37-year-old female was found to have hypouricemia (1.1-1.9 mg%) with markedly increased uric acid clearance (24.7039.5 ml/min). Uric acid excretion was only slightly affected by pyrazinamide, a drug which suppresses renal tubular uric acid secretion, and by probenecid, a drug which inhibits tubular uric acid reabsorption. The attenuated response in this subject to both drugs suggest a renal tubular defect in the proximal high capacity-high affinity uric acid reabsorption mechanism. No other renal tubular or metabolic abnormalities were detected. A survey of the family-three sisters and two brothers, revealed two similarly affected sisters. The abnormality described in this family is defined as familial renal hypouricemia due to an isolated renal tubular defect with attenuated response of uric acid clearance to probenecid and pyrazinamide.

Adult↗
PubMed1988

Renal excretion of purine bases. Effects of probenecid, benzbromarone and pyrazinamide.

Experiments were conducted which revealed the renal transport mechanism(s) of oxypurines by employing uricosuric agents and pyrazinamide. All specimens being drawn from healthy, normal subjects, the data showed that probenecid increased fractional uric acid, fractional hypoxanthine and fractional xanthine clearance, 3.97-, 1.52- and 2.31-fold, respectively, while benzbromarone increased fractional uric acid clearance 2.11-fold, decreased fractional xanthine clearance 0.48-fold and had no effect on fractional hypoxanthine clearance. In addition, pyrazinamide decreased both fractional uric acid clearance 0.35-fold and fractional xanthine clearance 0.44-fold but increased fractional hypoxanthine clearance 1.49-fold. These results suggest the possibility of differing renal transport mechanisms among the purine bases, uric acid, hypoxanthine and xanthine.

Adult↗
PubMed1989

Acceptability, compliance, and adverse reactions when isoniazid, rifampin, and pyrazinamide are given as a combined formulation or separately during three-times-weekly antituberculosis chemotherapy.

In Hong Kong, 627 adult Chinese patients with newly diagnosed pulmonary tuberculosis received, for the first 2 months of chemotherapy, streptomycin together with isoniazid, rifampin, and pyrazinamide allocated at random to be given either as a combined formulation or separately. Each tablet of the combined formulation, which was designed for intermittent use, contained 125 mg of isoniazid, 100 mg of rifampin, and 375 mg of pyrazinamide. Patients weighing 42 kg or less received 5 tablets per dose, 43 to 57 kg, 6 tablets per dose, and 58 kg or more, 7 tablets per dose. The dosage of each drug was very similar whether it was given combined or separately. During the 2 months, spontaneous complaints, the commonest of which were nausea and vomiting, were made by 38% of patients receiving the combined and 39% receiving the separate formulations; 1% compared with 5%, respectively, complained that the tablets or capsules were too many, too large, difficult to swallow or that they stuck in the throat (p less than 0.05), and 32% compared with 45% regularly brought their own drink (usually milk or fruit juice) to the clinic to help them swallow their medicament (p less than 0.01). Only 14% of patients in each group missed one or more doses through default. Reported adverse reactions were mainly trivial, 4% of patients receiving the combined and 7% receiving the separate formulations having the administration of one or more drugs terminated. Thus, the differences between the combined and separate formulations showed a small advantage to the combined formulation in terms of acceptability to patients.

Drug Administration Schedule↗
PubMed1991

Assessment of a daily combined preparation of isoniazid, rifampin, and pyrazinamide in a controlled trial of three 6-month regimens for smear-positive pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council.

In a study in Singapore 310 patients with sputum smear-positive pulmonary tuberculosis were allocated at random to daily chemotherapy with streptomycin, isoniazid, rifampin, and pyrazinamide (1) for 2 months (2SHRZ), (2) for 1 month (1SHRZ), or (3) for 2 months without streptomycin (2HRZ). This was followed for all patients by three times weekly isoniazid and rifampin to a total duration of 6 months. During the initial period of daily chemotherapy the patients were also allocated at random to be given their HRZ either as a combined formulation (Rifater), each tablet containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide, or as three separate drugs. During the Rifater versus separate drugs comparison the most common spontaneous complaints were of nausea and vomiting, reported by 8% of 155 patients receiving Rifater and 7% of 155 separate drugs. Other adverse effects were also reported in similar proportions in the two series. Among 271 patients with drug-susceptible strains of tubercle bacilli pretreatment there were no bacteriologic failures during chemotherapy. During 18 months of subsequent follow-up bacteriologic relapse occurred in 3 (7%) of 46 2SHRZ, 2 (5%) of 42 1SHRZ, and 3 (8%) of 40 2HRZ patients allocated to Rifater and in 0 of 47 2SHRZ, 1 (2%) of 46 1SHRZ, and 1 (2%) of 44 2HRZ patients allocated to separate drugs. There was no evidence of therapeutic benefit from continuing SHRZ administration beyond 1 month or from adding streptomycin to HRZ. The relapse rates were slightly higher in the Rifater series (p = 0.04). Further follow-up and results from other studies are therefore needed fully to assess the combined preparation.

Adolescent↗
PubMedDate not supplied

A case of xanthinuria: a study on the metabolism of pyrazinamide and allopurinol.

A 74-year-old female was diagnosed as having xanthinuria by measurement of the uric acid level in plasma, purine bases in urine and activity of xanthine oxidase in the duodenal mucosa. The determination of the urinary excretion of purine bases in her family demonstrated a slightly increased urinary excretion of oxypurines in her younger brother, suggesting that he was a heterozygote. The pyrazinamide-loading test and allopurinol-loading test demonstrated that she could neither metabolize pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol, although there was a slight metabolizing of prazinamide into 5-hydroxypyrazinamide. This suggested that she belonged to the subgroup which can neither metabolize pyrazinamide into 5-hydroxypyrazinamide, pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol.

Aged↗
PubMedDate not supplied

Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis.

OBJECTIVE: We administered pyrazinamide (PZA) and probenecid (PB) --two well-known modulators of urate transport via the proximal tubules - to evaluate their impact on urate transport through the peritoneal membrane and to clarify mechanisms affecting peritoneal transport. SETTING: A continuous ambulatory peritoneal dialysis (CAPD) unit in 2nd Hospital of IKA (Social Services Institute), Greece. PATIENTS: In 20 stable CAPD patients, on the study day, a 4-hour, 2-L, 1.36% glucose exchange was performed (control exchange). Pyrazinamide 3 g was given orally and another identical exchange was performed (study exchange). The same protocol was repeated with 2 g PB. KtN, peritoneal clearances of urea, creatinine, and urate for each exchange, and mass transfer area coefficients (MTAC) for the three solutes and their dialysate-to-plasma concentration (D/P) ratios were used to estimate peritoneal transport. RESULTS: Administration of PZA resulted in decreased clearances and MTAC values for the three solutes. The D/P ratio decreased significantly only for urate, indicating a more intense influence of PZA on urate. After PB administration, clearances of urea, creatinine, and urate were increased. MTAC and DIP ratio increased significantly only for urate (p < 0.05), demonstrating an action similar to that exerted on renal tubules. CONCLUSIONS: These findings provide evidence that unrestricted diffusion is not the only transport mechanism in the case of urate, and demonstrate the existence of an active mechanism in peritoneal urate transport with a reabsorptive and, probably, a secretive component that resembles that of renal tubule urate transport. Attention should be given in the case of CAPD patients undergoing antituberculous (PZA) treatment: it might have a negative impact on urea, creatinine, and urate peritoneal transport rates.

Female↗
PubMed2000

Pyrazinamide is not active against Mycobacterium tuberculosis residing in cultured human monocyte-derived macrophages.

SETTING: Mycobacteriology Laboratory, National Jewish Medical and Research Center, Denver, Colorado. OBJECTIVE: To evaluate the antimicrobial activity of pyrazinamide against Mycobacterium tuberculosis in cultured human monocyte-derived normal and activated macrophages. DESIGN: Monocytes separated from human blood were incubated in plastic plates for seven days to mature into macrophage monolayers. After activation with TNF-alpha or IFN-gamma or without prior treatment, the macrophages were infected with M. tuberculosis. Various concentrations of pyrazinamide (PZA), morphazinamide (MZA) or isoniazid (INH) were added the next day, and the viable counts of the intracellular bacteria were determined at days 0, 4, and 8. RESULTS: No inhibitory activity of PZA at any concentration was detected, while clear dose-dependent bacteriostatic and bactericidal activities were demonstrated by MZA and INH in the same experimental model. CONCLUSIONS: PZA has neither bacteriostatic nor bactericidal activity against M. tuberculosis persisting or multiplying in cultured monocyte-derived human macrophages, and it might be that the well-known effectiveness of this drug in tuberculosis patients is not related to its supposed activity against intracellular bacterial subpopulations.

Antitubercular Agents↗
PubMed1990

Short-course chemotherapy for pulmonary tuberculosis with a rifampicin-isoniazid-pyrazinamide combination tablet.

The effectiveness of a tablet containing a combination of rifampicin, isoniazid and pyrazinamide (Rifater; Mer-National) in the treatment of pulmonary tuberculosis was examined by comparing it with a previously evaluated four-drug regimen. Of 150 black goldminers with a first case of pulmonary tuberculosis, 69 were randomly allocated to receive the combination tablet (RHZ), 5 tablets per day on weekdays for 100 treatment-days, and 81 the four-drug regimen (streptomycin, rifampicin, isoniazid and pyrazinamide) (RHZS). Non-compliance was detected in 42% of the RHZ group and in 16% of the RHZS group. Two patients in the RHZ group and 4 in the RHZS group had to have their treatment altered because routine investigations revealed drug-resistant mycobacteria. Treatment was unsuccessful in 10 patients in the RHZ group, with 4 men failing to complete the regimen and being lost to follow-up, 3 cases of failure of conversion of sputum on the regimen, and 3 relapses. The results for the RHZS group were similar, with 4 failures to complete the regimen, 2 treatment failures and 4 relapses. Evaluation of RHZ showed it to be comparable with a previously evaluated, successful short-course regimen (RHZS). The high incidence of non-compliance probably reflects reduced supervision of this wholly oral regimen.

Adult↗
PubMed1990

Pharmacokinetics of pyrazinamide and its metabolites in patients with hepatic cirrhotic insufficiency.

The pharmacokinetics of pyrazinamide (Pirilène) and its metabolites are evaluated in ten subjects with hepatic insufficiency, after an oral dose of 19.3 +/- 0.6 mg.kg-1 and the results are compared to those of a group of nine healthy subjects (control group). The results exhibit a marked reduction of the pyrazinamide total clearance (0.48 vs 0.84 ml.min-1.kg-1) and an increase in half-life from 9.19 h to 15.07 h in the patients group. The area under the curve of pyrazinoic acid (the main metabolite) is increased from 97 to 280 mg.h.l-1 with a half-life twice as much as that of the control group. The hepatic insufficiency entails a marked reduction of the common posology as well as a closer survey of the biologic hepatic parameters and of uric acid the renal elimination of which is inhibited by pyrazinoic acid.

Adult↗
PubMed1989

[Therapeutic trial of a combination of isoniazid, rifampicin and pyrazinamide in the first 2 months of treatment of pulmonary tuberculosis].

250 patients suffering from smear positive pulmonary tuberculosis who had never been treated before, received a six-month regimen combining isoniazid and rifampicin every day with a supplement of pyrazinamide for the first eight weeks of treatment. The three drugs given during the initial phase of therapy were administered in two different forms: either as separate tablets or in a form combining all three drugs in fixed proportions (each tablet contained 50 mg of isoniazid, 120 mg of rifampicin and 300 mg of pyrazinamide). The patients were randomised into two groups of 125 receiving one or other combination of medications with the dose adapted for their weight. An analysis of the results at the end of the second month of treatment was carried out on 240 cases who could be analysed for tolerance and acceptability and in 193 cases who were analysed for the efficacy of therapy as judged by negative cultures. The treatment results were excellent in both groups, as was patient acceptability. The level of side effects was significantly lower in the group receiving combined medication (p less than 0.02). Both groups gave a similar proportion of negative cultures at the end of two months. The combined medicaments studied are thus well tolerated and at least as effective as individual drugs. They may thus replace them.

Adolescent↗
PubMed1989

[Short-term therapy of lung tuberculosis using a fixed combination of isoniazid, rifampicin and pyrazinamide. Results after 2 years].

Treatment of tuberculosis should be as short and as simple as possible in order to improve patient compliance; and combinations of at least three drugs should be used in order to kill the different populations of mycobacteria and to avoid development of drug resistance.--In a controlled multicentre study two regimens were compared in 93 patients with newly-diagnosed pulmonary tuberculosis: 1) Six-month therapy (47 cases): Daily rifampicin and isoniazid, supplemented with pyrazinamide for the first 2 months. A tablet with a fixed combination of 120 mg rifampicin, 50 mg isoniazid and 300 mg pyrazinamide (Rifater) was used. 2) Present Swiss standard therapy (46 cases): Daily rifampicin, isoniazid and ethambutol for 2 months followed by rifampicin and isoniazid for 7 months.--The time-course of culture negativation and the frequency of adverse events were similar in the two groups. During a follow-up period of at least two years only one relapse was observed in the six-month regimen, 3 months after completion of treatment. This was one of three patients with pretreatment resistance to isoniazid. Nevertheless, two of them were cured with the six-month regimen containing Rifater.--Patient compliance, assessed during outpatient treatment by detecting isoniazid metabolites in the urine, was very good (93% of tests were positive in each group).--These results with a follow-up of more than 2 years, indicate that short-course therapy of 6 months duration with the fixed combination tablet may be recommended as treatment of choice in pulmonary tuberculosis except in cases of isoniazid resistance and other special situations (i.e. large cavitations, large number of viable bacilli).

Adult↗
PubMedDate not supplied

[Pharmacokinetic study of pyrazinamide and pyrazinoic acid in subjects with normal renal function and patients with renal failure].

The main pharmacokinetic parameters of pyrazinamide and pyrazinoïc acid (its major metabolite) were determined after oral administration of 1,500 mg/d in 10 patients with normal renal function and of 1,000 mg/d in 10 patients with impaired renal function (renal insufficiency). This study shows that, with these dosage regimens, almost all the pharmacokinetic parameters are identical for pyrazinamide and pyrazinoic acid in patients with normal renal function and patients with impaired renal function. Comparison of results between patients allows us to propose a dosage regimen of 1,000 mg/d as maintenance in patients with renal insufficiency.

Humans↗