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PubMed1985

Hypouricemia due to renal tubular defect. A study with the probenecid-pyrazinamide test.

Hypouricemia with hyperuricosuria due to isolated renal tubular defects are rare conditions. Two patients with hypouricemia and hyperuricosuria were studied for derangements in the renal urate transport with the combined probenecid-pyrazinamide test. In the first patient a significant decrease (64.5%) in the urate clearance--creatinine clearance ratio was noted after pyrazinamide administration, suggesting a post-secretory urate reabsorption defect, whereas the significant rise (44.2%) in urate clearance after the administration of probenecid indicates that this defect may not be complete. In the second patient there was a rise of 96.9% in the urate clearance--creatinine clearance ratio after the administration of probenecid and a decline of 31.6% in that ratio after pyrazinamide. These results suggest a defect in the presecretory reabsorptive site, with a highly significant response most probably of the postsecretory reabsorptive site to probenecid.

Adult↗
PubMed1968

Concentrations of pyrazinamide attained in serum with different doses of the drug.

Serial concentrations of pyrazinamide in 3 volunteers showed that increasing the dose from 22 mg/kg of body-weight to 66 mg/kg resulted in substantially higher serum concentrations of the drug and a longer period of coverage (at a concentration of 25 mug/ml). Similarly, in a study based on 6 tuberculous patients, increasing the dose of pyrazinamide from 66 mg/kg to 88 mg/kg led to appreciably higher concentrations in the serum. In neither series of tests was any acute hepatic toxicity observed. The findings suggest that it would be interesting to study the effect of doses of about 90 mg/kg of pyrazinamide in once-weekly regimens of chemotherapy for the treatment of tuberculosis.

Aspartate Aminotransferases↗
PubMed1978

Study of urinary pyrazinamide metabolites and their action on the renal excretion of xanthine and hypoxanthine in a xanthinuric patient.

A chromatographic technique on anion exchange column was developed. It permets to determine unmetabolized pyrazinamide and three major metabolities: pyrazinoic acid, 5-hydroxypyrazinoic acid and an unidentified compound. In a xanthinuric patient only traces of 5-hydroxypyrazinoic acid were found 12 hours after 3 g pyrazinamide were given. These finding confirms that pyrazinoic acid is oxidised through the the action of xanthine oxidase. Both the clearances of hypoxanthine and of xanthine are as rapid as that of endogenous creatinine in a xanthinuric patient. But the effects of pyrazinamide are different on both purine bases. Urinary excretion of hypoxanthine is slightly but not significantly reduced while excretion of xanthine is decreased by about 75%. Evidence was demonstrated that pyrazinoic acid is likely the agent causing xanthine retention. These results suggest that the mechanisms of renal transport of xanthine and hypoxanthine are different.

Chromatography, Ion Exchange↗
PubMed1993

Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed-triple formulation) in intermittent antituberculous chemotherapy.

A study was carried out in six human volunteers, to assess the blood kinetics of isoniazid, rifampicin and pyrazinamide, administered in a fixed-triple combination intended for use in intermittent chemotherapy of tuberculosis. The formulation employed contained 125 mg of isoniazid (H), 100 mg of rifampicin (R) and 375 mg of pyrazinamide (Z) per tablet; six tablets were administered to every subject, giving a total dosage of 750 mg of isoniazid, 600 mg of rifampicin and 2,250 mg of pyrazinamide. In each subject, the same dose of each drug was administered individually in separate sessions and the results compared. The results indicated that, at the level of dose of the intermittent tablet, no negative interactions between the drugs were observed.

Adult↗
PubMed1996

A controlled trial of a 4-weekly supplement of rifampicin, pyrazinamide and streptomycin in the continuation phase of a 7-month daily chemotherapy regimen for pulmonary tuberculosis. Tanzania/British Medical Research Council Collaborative Investigation.

OBJECTIVE: To evaluate a monthly 'pulse' of rifampicin plus pyrazinamide plus streptomycin in the continuation phase of a short-course antituberculosis regimen. DESIGN: Randomised controlled trial of two 7-month chemotherapy regimens. SETTING: Inpatient chemotherapy and outpatient follow-up in Tanzania. PATIENTS: Smear-positive pulmonary tuberculosis. INTERVENTION: All patients received streptomycin plus rifampicin plus isoniazid plus pyrazinamide daily for 6 weeks followed by isoniazid daily for 24 weeks; 50%, at random, received additional doses of rifampicin, pyrazinamide and streptomycin every 4 weeks in the continuation phase. Follow-up continued for 23 months after cessation of chemotherapy. MAIN OUTCOME MEASURES: Bacteriological failure rate at the end of chemotherapy and relapse rate after stopping. RESULTS: Of the 266 patients with fully sensitive strains before treatment there was one failure in each series during chemotherapy; after stopping, 5% of the 114 who received the supplement relapsed bacteriologically compared with 10% of the 113 who did not (95% CI for the difference -0.02% to + 11.3%). The results in the 37 patients with strains resistant to isoniazid pretreatment were not as good, but similar for the two regimens. CONCLUSION: This study was not large enough to demonstrate a significant reduction in the relapse rate from 10% to 5%. If such a reduction were confirmed in a larger study it would represent an important improvement in efficacy. further, in an outpatient setting, the additional monthly doses might improve attendance.

Adolescent↗
PubMed1989

Haemodialysis of pyrazinamide in uraemic patients.

The pharmacokinetics of PZA during haemodialysis were determined in 6 patients with chronic renal impairment after a single oral dose of 25.7 (1.9) mg.kg-1. The dialysis clearance of PZA and of its metabolites were: pyrazinamide 132 ml.min-1; pyrazinoic acid 121 ml.min-1; 5-hydroxy-pyrazinamide 107 ml.min-1; 5-hydroxy-pyrazinoic acid 118 ml.min-1. The average amount extracted during a dialysis session of 4.1 h was 926 mg after an oral dose of 1700 mg. The high dialysability shows that PZA can properly be administered at the end of each dialysis session in the usual dose of 25 to 30 mg.kg-1.

Adult↗
PubMed1986

Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide.

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.

Adolescent↗
PubMed1994

Genotoxicity evaluation of pyrazinamide in mice.

Pyrazinamide, an antituberculosis drug, was investigated for genotoxicity in mice, an in vivo rodent system. Three doses (125, 250 and 500 mg/kg bw corresponding to 5, 10 and 20 times the therapeutic dose respectively) were tested. The mitotic index and the frequency of chromosomal aberrations were analysed at three sample times (3, 6 and 24 h) after a single intraperitoneal treatment. The frequency of sperm shape abnormalities was also examined. The mitotic index showed a decrease in drug-treated animals compared with that recorded in the control set. The cells with chromosomal aberrations ranged from 4% to 8%. The maximum frequency of aberrations was found at the 3-h sample time. The frequency of sperm shape abnormalities showed a dose-related increase. These observations suggest pyrazinamide to be a weak genotoxicant at the doses tested.

Animals↗
PubMed1987

Liquid chromatographic assay for the simultaneous determination of pyrazinamide and rifampicin in serum samples from patients with tuberculous meningitis.

A simple high-performance liquid chromatographic assay for the simultaneous determination of pyrazinamide and rifampicin in serum from patients with tuberculous meningitis is presented. The drugs and internal standard, p-acetamidobenzoic acid, were extracted from the acidified sample containing 2% ascorbic acid at pH 4.2 into dichloromethane-diethyl ether (2:3). The solvent extract was evaporated to dryness with the aid of nitrogen and the residue redissolved in methanol (75 microliters). The concentrate was analysed by a liquid chromatograph using a reversed-phase 30-microns C8 pre-column linked to a 5-microns C8 analytical column with a gradient solvent programme, which delivered 6% to 48% (v/v) acetonitrile in phosphate buffer (10 mM potassium dihydrogenphosphate, pH 3.5) in 10 min at 1.5 ml/min. The eluate was detected at 215 nm. Twelve patients with tuberculous meningitis were given daily chemotherapy, and their serum samples were assayed for pyrazinamide and rifampicin.

Calibration↗
PubMed1995

Study of the effect of concomitant food on the bioavailability of rifampicin, isoniazid and pyrazinamide.

SETTING: Concomitant feeding and administration of antituberculosis medication has been proposed to increase compliance (by decreasing pyrazinamide associated nausea) and improve nutritional status. Food may however decrease the oral bioavailability of rifampicin and isoniazid. OBJECTIVE AND METHODS: A triple-crossover pharmacokinetic study in 27 patients with tuberculosis (15 males and 12 females) compared the bioavailability of rifampicin, isoniazid and pyrazinamide without food (control) with that when taken with a high carbohydrate (CHO) or high lipid (LIPID) diet. RESULTS: the CHO diet decreased isoniazid bioavailability. The maximum measured drug concentration (Cm) was decreased by 20% (P = 0.0002) and the area under the concentration-time curve to 8 h (AUC8) by 19% (P = 0.01). The CHO diet increased the time to maximum measured drug concentration (Tmax) for rifampicin by 21% (P = 0.03). The LIPID diet decreased the Cm of isoniazid by 9% (P = 0.03). Individual patient bioavailability on each meal was compared to the no-food control. A decrease of Cm or AUC8 of greater than 20% was considered significant. The bioavailability of isoniazid and rifampicin was decreased by food in a high percentage (33-56%) of patients. CONCLUSION: Concomitant feeding may thus have an important adverse effect on the therapy of tuberculosis and the desirability of this practice is called into question.

Adolescent↗
PubMed1978

Mass fragmentographic determination of pyrazinamide and its metabolites in serum and urine.

A combined gas chromatographic-mass spectrometric technique is described for the simultaneous determination of pyrazinamide and its two main metabolites, pyrazinoic acid and 5-hydroxypyrazinoic acid. Serum (200 microliter) is deproteinized and evaporated to dryness; urine (20 microliter) is evaporated. The crude residues are silylated and selected ions are monitored in the chemical-ionization mode with isobutane as both chromatographic carrier and reagent gas. The sensitivity is 10 ng/ml for pyrazinamide and pyrazinoic acid and 20 ng/ml for the 5-hydroxy metabolite in a single analysis. Nicotinic acid and nicotinamide are internal standards. Both unchanged drug and metabolites were identified and quantified in the serum and urine of human subjects.

Gas Chromatography-Mass Spectrometry↗
PubMed1986

High-performance liquid chromatographic determination of pyrazinamide in cerebrospinal fluid and plasma in the rabbit.

A simple procedure for the determination of pyrazinamide in plasma and cerebrospinal fluid in the rabbit is described. The assay involves a preliminary extraction of the drug and an internal standard, paracetamol, from the acidified sample (pH 4.2). The extract is evaporated to dryness at 45 degrees C and the residue is redissolved in methanol (50 microliters). A 25-microliters aliquot is injected into the liquid chromatograph and eluted with acetonitrile-10 mM phosphate buffer of pH 3.5 (10:90, v/v) on a 30-microns C8 pre-column linked to a 5-microns C8 reversed-phase column at ambient temperature (25 +/- 1 degree C). The eluate is detected at 215 nm. The method has been used to investigate the disposition of pyrazinamide in plasma and cerebrospinal fluid in six rabbits.

Animals↗
PubMed1999

Determination of rifampicin and its main metabolite in plasma and urine in presence of pyrazinamide and isoniazid by HPLC method.

A reversed phase HPLC method is described for the simultaneous estimation of rifampicin and its major metabolite desacetyl rifampicin, in the presence of isoniazid and pyrazinamide, in human plasma and urine. The assay involves simple liquid extraction of drug, metabolite and internal standard (rifapentine) from biological specimens and their subsequent separation on a C18 reversed phase column and single wavelength UV detection. In plasma as well as in urine samples, all the three compounds of interest eluted within 17 min. Using methanol-sodium phosphate buffer (pH 5.2; 0.01 M) (65:35, v/v) as mobile phase under isocratic conditions, it was established that isoniazid, pyrazinamide and ascorbic acid (added to prevent oxidative degradation of analytes) did not interfere with the analyte peaks. Recoveries (extraction efficiency) for drug were greater than 90% in both plasma and urine, whereas for metabolite the values were found to be 79 and 86% in plasma and urine, respectively. The plasma and urine methods were precise (total coefficient of variation ranged from 5 to 23%) and accurate (-7 to 5% of the nominal values) for both the analytes. Individual variance components, their estimates and their contribution to the total variance were also determined. Using the same method, unknown samples supplied by WHO were assayed and good correlations were obtained between the found and intended values. The method developed proved to be suitable for simultaneous estimation of rifampicin and desacetyl rifampicin in plasma and urine samples.

Antibiotics, Antitubercular↗
PubMed1996

Short course chemoprophylaxis with rifampicin, isoniazid and pyrazinamide for tuberculosis evaluated in gold miners with chronic silicosis: a double-blind placebo controlled trial.

SETTING: A medical facility for approximately 90,000 gold miners employed on 24 South African gold mines. OBJECTIVE: To evaluate the effectiveness of rifampicin, isoniazid and pyrazinamide given for 3 months for the prevention of tuberculosis in men with silicosis. DESIGN: A randomised double-blind placebo controlled trial with active 4-year follow up of subjects by routine radiographic screening. RESULTS: A total of 382 gold miners with silicosis were randomised to receive rifampicin 600 mg, isoniazid 400 mg and pyrazinamide 1.25 g daily as Rifater or a placebo. These men have been followed for 4 years since the end of the treatment period. Eleven men who received the combination tablet and 15 men who received the placebo tablet have developed tuberculosis (chi 2 df1 = 0.66, P = 0.4). CONCLUSION: This multi-drug short course chemoprophylaxis regimen has failed to prevent tuberculosis in miners with silicosis. Even if a larger study had demonstrated a statistically significant effect of the regimen as compared with placebo, the rate of tuberculosis in the men who received the three-drug regimen was unacceptably high.

Adult↗
PubMed2002

Characterization of pyrazinamide and ofloxacin resistance among drug resistant Mycobacterium tuberculosis isolates from Singapore.

OBJECTIVES: To evaluate rapid molecular approaches for the detection of pyrazinamide (PZA) and ofloxacin resistance, by screening 100 known drug-resistant Mycobacterium tuberculosis isolates. METHODS: Mycobacterium tuberculosis isolates were tested for phenotypic resistance to pyrazinamide and ofloxacin using the BACTEC 460 radiometric method and the E-test, respectively. Mutation screening was done by amplifying the pncA, gyrA, and gyrB genes by the polymerase chain reaction (PCR) and direct automated sequencing. RESULTS: Twelve isolates were PZA-resistant and 8 of 12 (66.7%) isolates had missense mutations or deletions at the pncA gene, suggesting that mutation or deletion at the pncA gene is the major molecular mechanism of PZA resistance among the Singaporean isolates. Using the E-test, 48 isolates were resistant to ofloxacin, with minimum inhibitory concentrations of 4 microg/mL or higher. No mutations were observed at the quinolone resistance-determining region (QRDR) of gyrA in all isolates. At the QRDR of gyrB, mutations were present in 1 of 48 ofloxacin-resistant isolates and 0 of 19 ofloxacin-susceptible isolates. CONCLUSIONS: In Singapore, genotypic analysis of resistance to PZA and ofloxacin is inadequate and should be complemented by conventional methods.

Amidohydrolases↗
PubMed2000

Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis.

Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.

Animals↗
PubMed1983

Tryptophan and glucose metabolism in rat liver cells. The effects of DL-6-chlorotryptophan, 4-chloro-3-hydroxyanthranilate and pyrazinamide.

Liver cells pre-incubated with 1 mM-DL-6-chlorotryptophan are less sensitive to tryptophan-mediated inhibition of gluconeogenesis; this effect is apparent both at physiological (0.1 mM) and higher (0.5 mM) concentrations of tryptophan. 4-Chloro-3-hydroxyanthranilate (1-100 microM) has effects similar to those of DL-6-chlorotryptophan. The effects of both compounds are consistent with a decrease in quinolinate formation, a consequence of inhibition of 3-hydroxyanthranilate oxidase. Pyrazinamide (0.25-5.0 mM) significantly decreased flux through the glutarate pathway and potentiated tryptophan-mediated inhibition of gluconeogenesis; these changes were apparent at physiological concentrations of tryptophan. The effects of pyrazinamide are consistent with an increase in quinolinate formation resulting from inhibition of picolinate carboxylase.

3-Hydroxyanthranilic Acid↗
PubMed2005

Severe or fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent tuberculosis infection.

BACKGROUND: Severe liver injuries were attributed to the rifampin and pyrazinamide (RZ) regimen after it was recommended for treating latent tuberculosis infection. Implicating RZ as the likeliest cause required excluding alternative causes. METHODS: US health departments reported data on patients who died or were hospitalized for liver disease within 1 month after taking RZ for latent tuberculosis infection from October 1998 through March 2004. The circumstances were investigated on site for each case. Illness characteristics, reasons for RZ treatment, doses and frequency of administration of pyrazinamide, monitoring during treatment, and causes of liver injury were determined. RESULTS: Liver injury was attributable to RZ use for all 50 patients reported, 12 of whom died. For 47 patients, RZ was the likeliest cause of liver injury. The median patient age was 44 years (range, 17-73 years). Thirty-two patients (64%) were male. Seven (16%) of 43 patients tested had hepatitis C virus antibodies, 1 (2%) of 45 had chronic hepatitis B, 3 (14%) of 22 had positive results of HIV serologic tests, 34 (71%) of 48 had alcohol use noted, and 33 (66%) of 50 were taking additional hepatotoxic medications. Six patients, 2 of whom died, had no predictors for liver disease. Patients who died were older (median age, 52 vs. 42 years; P=.08) and took a greater number of other medications (median number of medications, 4 vs. 2; P=.05) than did those who recovered, but these 2 factors were correlated (P<.01). Thirty-one patients (62%) were monitored according to guidelines, 9 of whom died. CONCLUSIONS: RZ was the likeliest cause of most of these liver injuries, some of which were fatal in spite of monitoring. Fatality was predicted by age or use of other medications, but none of the cofactors showed promise as a reliable clinical predictor of severe liver injury.

Adolescent↗