PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Pyrazinamide”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources

Double blind controlled comparison of aspirin, allopurinol and placebo in the management of arthralgia during pyrazinamide administration.

Chinese patients with arthralgia during treatment with an antituberculosis regimen containing pyrazinamide were allocated at random to 3 anti-arthralgia treatment series in a controlled double-blind study. One series (18 patients) received soluble aspirin 2.4 g daily, the second (23 patients) allopurinol 200 mg daily, and the third (19 patients) placebo only, for 8 weeks. The response was assessed both by independent assessors and by the patients themselves using a diary card. The serum uric acid concentration was measured before and during anti-arthralgia treatment. The joints most commonly affected were the shoulders, the knees and the fingers, and symptoms and signs were in general neither severe nor protracted. For most of the patients in all 3 series the joint symptoms and signs improved during the 8 weeks, but a higher proportion of patients in the aspirin and placebo series than in the allopurinol series experienced improvement, this being most rapid in the aspirin series. Only in the aspirin series was the mean serum uric acid concentration lower during treatment than before it, and this effect was related to the dose in mg per kg. It is concluded that the arthralgia was often self-limiting, that aspirin had a small beneficial effect, that allopurinol, in the dosage studied, may have had a slightly deleterious effect, but that it would be worth studying larger dosages of allopurinol because the dosage studied did not affect the serum uric acid concentration.

Adolescent↗

Efficacy of intermittent pyrazinamide in experimental murine tuberculosis.

CFLP mice were infected intravenously with Mycobacterium tuberculosis strain H37Rv and the progress of chemotherapy was followed by counts of viable bacilli in the lung and spleen. After spleen counts had reached log10 7.0, 12 experimental groups, each containing 10 mice, were treated for 8 weeks with pyrazinamide (PZA) given in mean daily dosages of 100, 200 or 400 mg/kg/day, with the interval between the doses within each dosage group being 1, 2, 4 or 8 days. All mice were also given 25 mg isoniazid/kg daily. An increase in the mean daily dosage from 100 mg PZA/kg to 400 mg PZA/kg resulted in a decrease of spleen viable counts at the end of treatment from log10 4.2 to log10 3.8. The organ counts, averaged over the full dosage range, were little altered by spacing out the interval between doses from 1-4 days, while increasing dose size proportionately: the counts with low mean dosages tended, however, to decrease (indicating improved efficacy) while those with high mean dosages increased (P less than 0.001). Counts increased when the interval was 8 days. Spacing out the doses while keeping the dose size constant resulted in progressive loss of efficacy. These findings suggest that, if PZA is given intermittently, the size of the dose should be increased, though not quite proportionately, to maintain full efficacy. Even with such an increase in dose, however, once weekly treatment would be less effective.

Animals↗

Comprehensive assay for pyrazinamide, rifampicin and isoniazid with its hydrazine metabolites in human plasma by column liquid chromatography.

A comprehensive assay for determination of pyrazinamide (PZA), rifampicin (RIF), isoniazid (INH) and hydrazine metabolites is described. The method involves organic solvent extraction of PZA and RIF, followed by derivatization of INH, monoacetylhydrazine (mHYD) and hydrazine (HYD) with salicylaldehyde and extraction with diethyl ether. Acetylisoniazid (acINH) and diacetylhydrazine (dHYD) were hydrolyzed to INH and mHYD, respectively, and processed as above. Using a gradient solvent programmer, PZA and RIF were analyzed on a C8 (5 microns) column at 248 nm, while INH and metabolites were analyzed on a C18 (5 microns) ODS2 column at 280 nm.

Chromatography, High Pressure Liquid↗

Rapid radiometric method for pyrazinamide susceptibility testing of Mycobacterium tuberculosis.

Pyrazinamide (PZA) is one of the most important drugs in modern chemotherapy of tuberculosis. Since PZA is active only at an acid pH, testing the susceptibility of Mycobacterium tuberculosis to PZA is difficult and timeconsuming. Therefore, we evaluated the BACTEC system for rapid testing of PZA susceptibility at pH 6. A total of 91 M. tuberculosis strains and 2 different strains of M. bovis BCG were screened for susceptibility to PZA. Each strain was tested in special 7H12 broth supplemented with polyoxyethylene stearate containing 25, 50 and 100 micrograms PZA/ml. Strains resistant to 100 micrograms/ml were retested against 25-100 micrograms/ml and at an extended range of PZA concentrations from 200-6,400 micrograms/ml. The MIC was determined with all strains within 4-20 (mean 7) days. Of the 77 susceptible strains, based on the pyrazinamidase test, MIC were less than or equal to 25 micrograms/ml for 34 strains, 50 for 38 and 100 for 2 strains. Three pyrazinamidase-positive strains had still higher MIC, 1 at 800 and 2 at 3,200 micrograms/ml. PZA-resistant strains had MIC of 800 or greater. Monoresistance to PZA has not been detected to date. The clear bimodal distribution of MIC in this method could enable the routine clinical microbiology laboratory to perform PZA susceptibility testing as easily as the 4 drugs now tested in the BACTEC system.

Evaluation Studies as Topic↗

4-, 5- and 6-month regimens containing isoniazid, rifampicin, pyrazinamide and streptomycin for treatment of pulmonary tuberculosis under program conditions in Hong Kong.

SETTING: Ten full time urban government chest clinics in Hong Kong. OBJECTIVE: To assess the effectiveness of 4-, 5- and 6-month fully supervised thrice-weekly regimens containing 4 months of isoniazid, rifampicin, pyrazinamide and streptomycin followed by nil, 1 or 2 months of isoniazid and rifampicin for the treatment of smear-negative culture-negative, smear-negative culture-positive and smear-positive pulmonary tuberculosis. DESIGN: Retrospective study of the 3 antituberculosis treatment regimens given under program conditions during a 6-month period in 1983. RESULTS: Of the 1616 patients assessed, 953 (59%) completed their treatment strictly as planned, 443 (27%) had their treatment prolonged, 107 (7%) had their treatment modified and 113 (7%) defaulted or did not complete their treatment as planned. There were 2 treatment failures at the end of chemotherapy. At 60 months of follow-up, 67 patients died, 2 from the sequelae of tuberculosis. Of 1287 patients assessable up to 60 months, a total of 47 (3.7%) patients relapsed and were eventually treated successfully. 11 (20%) relapses occurred among the 55 patients who had defaulted and did not complete treatment as planned. CONCLUSION: The effectiveness of the 3 treatment regimens depended very much on the patient's adherence to treatment. The necessity of prolongation of treatment is not known and requires further assessment.

Adolescent↗

Liquid chromatographic determination of isoniazid, pyrazinamide and rifampicin from pharmaceutical preparations and blood.

Isoniazid (IN), pyrazinamide (Pz) and rifampicin (Rf) are separated on YMC-ODS column. IN was derivatized with 2-fluorene-carboxaldehyde (FA). The separation was achieved using ethanol-chloroform-acetonitrile water by isocratic elution and detected at 337 nm. The detection limits were 0.11 ng, 0.2 ng and 13 ng/injection (5 microl) for IN, Pz and Rf, respectively. The method of analysis was applied to the pharmaceutical preparations and in the blood samples of the patients suffering from tuberculosis after undergoing chemotherapy with IN, Pz and Rf. The amounts quantitated in blood showed 0.97 to 1.58 microg/ml IN, 3.44 to 4.09 microg/ml Pz and 1.98 to 3.5 microg/ml Rf with coefficient of variations 0.8-1.8%, 0.9-1.3% and 0.8-2.1%, respectively.

Antitubercular Agents↗

Determination of pyrazinamide and its main metabolites in rat urine by high-performance liquid chromatography.

A new high-performance liquid chromatograhic procedure for simultaneous determination of pyrazinamide (PZA) and its three metabolites 5-hydroxypyrazinamide (5-OH-PZA), pyrazinoic acid (PA), and 5-hydroxypyrazinoic acid (5-OH-PA), in rat urine was developed. 5-OH-PZA and 5-OH-PA standards were obtained by enzymatic synthesis (xanthine oxidase) and checked by HPLC and GC-MS. Chromatographic separation was achieved in 0.01 M KH2PO4 (pH 5.2), circulating at 0.9 ml/min, on a C18 silica column, at 22 degrees C. The limits of detection were 300 microg/l for PZA, 125 microg/l for PA, 90 microg/l for 5-OH-PZA and 70 microg/l for 5-OH-PA. Good linearity (r2>0.99) was observed within the calibration ranges studied: 0.375-7.50 mg/l for PZA, 0.416-3.33 mg/l for PA, 0.830-6.64 mg/l for 5-OH-PZA and 2.83-22.6 mg/l for 5-OHPA. Accuracy was always lower than +/- 10.8%. Precision was in the range 0.33-5.7%. The method will constitute a useful tool for studies on the influence of drug interactions in tuberculosis treatment.

Animals↗

Quantification of pyrazinamide and its metabolites in plasma by ionic-pair high-performance liquid chromatography. Implications for the separation mechanism.

Pyrazinamide, the amide of pyrazinoic acid, is one of the basic therapeutic agents currently used in combination for chemotherapy of tuberculosis. A reversed-phase high-performance liquid chromatography method based on ionic pair chromatography, was developed after solid-phase extraction of the analytes from plasma with prior addition of internal standard. The main metabolites, pyrazinoic acid, 5-hydroxypyrazinoic acid and 5-hydroxypyrazinamide, were included as well as uric acid and other purine derivatives to allow detailed study of the pharmacokinetics of the drug, especially in patients with impaired kidney function. Some interesting features of the chromatographic system giving some insight in the retention mechanism and of the solid-phase extraction are discussed in detail.

Administration, Oral↗

Assessment of bioequivalence of rifampicin, isoniazid and pyrazinamide in a four drug fixed dose combination with separate formulations at the same dose levels.

Tuberculosis (TB) needs treatment with three to five different drugs simultaneously, depending on the patient category. These drugs can be given as single drug preparations or fixed dose combinations (FDCs) of two more drugs in a single formulation. World Health Organization and International Union against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. The relative bioavailability of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PYZ) was assessed on a group of 13 healthy male subjects from a four drug FDC versus separate formulations at the same dose levels. The study was designed to be an open, crossover experiment. A total of nine blood samples each of 3 ml volume were collected over a period of 24-h. The concentrations of RIF, its main metabolite desacetyl RIF (DRIF), INH and PYZ in plasma were assessed by HPLC analysis. Pharmacokinetic parameters namely AUC(0-24), AUC(0-inf), C(max), T(max), were calculated and subjected to different statistical tests (Hauschke analysis, two way ANOVA, normal and log transformed confidence interval) at 90% confidence interval. In addition, elimination rate constant (K(el)) and absorption efficiencies for each drug were also calculated. It was concluded that four drugs FDC tablet is bioequivalent for RIF, INH and PYZ to separate formulation at the same dose levels.

Analysis of Variance↗

Validation of a RP-LC method for the simultaneous determination of isoniazid, pyrazinamide and rifampicin in a pharmaceutical formulation.

A simple and accurate liquid chromatographic method was developed and validated for estimation of isoniazid (ISN), pyrazinamide (PYR) and rifampicin (RIF) in combined dosage forms. Drugs were chromatographed on a reverse phase C18 column using a mobile phase gradient and monitored at the corresponding maximum of each compounds. Peaks were identified with retention time as compared with standards and confirmed with characteristic spectra using diode-array detector. Solution concentrations were measured on a weight basis to avoid the use of an internal standard. The method does not require any specific sample preparation except the use of a guard column. The method is linear (r(2)>0.999), precise (RSD%: 0.50% for ISN, 0.12% for PYR and 0.98% for RIF), accurate (overall average recovery yields: 98.55% for ISN, 98.51 for PYR and 98.56% for RIF) and selective. Due to its simplicity and accuracy the method is suitable for routine quality control analysis of antitubercolosis combination dosage form.

Antitubercular Agents↗

Simultaneous determination of rifampicin, isoniazid and pyrazinamide in tablet preparations by multivariate spectrophotometric calibration.

The use of multivariate spectrophotometric calibration is presented for the simultaneous determination of the active components of tablets used in the treatment of pulmonary tuberculosis. The resolution of ternary mixtures of rifampicin, isoniazid and pyrazinamide has been accomplished by using partial least squares (PLS-1) regression analysis. Although the components show an important degree of spectral overlap, they have been simultaneously determined with high accuracy and precision, rapidly and with no need of nonaqueous solvents for dissolving the samples. No interference has been observed from the tablet excipients. A comparison is presented with the related multivariate method of classical least squares (CLS) analysis, which is shown to yield less reliable results due to the severe spectral overlap among the studied compounds. This is highlighted in the case of isoniazid, due to the small absorbances measured for this component.

Antitubercular Agents↗

Evaluation of BACTEC MGIT 960 PZA medium for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide (PZA): compared with the results of pyrazinamidase assay and Kyokuto PZA test.

The fully automated BACTEC MGIT 960 PZA medium for susceptibility testing of Mycobacterium tuberculosis to pyrazinamide (PZA) was evaluated using 101 Mycobacterium tuberculosis clinical isolates. The results obtained with the system were compared with those of the pyrazinamidase (PZase) assay and the Kyokuto PZA test based on a broth culture, which is commercially available in Japan. The overall concordance rate was 90.1% (91/101) among the three methods in the initial test. The concordance rates between the BACTEC MGIT 960 PZA medium vs the PZase assay, the BACTEC MGIT 960 PZA medium vs the Kyokuto PZA test, and the PZase assay vs the Kyokuto PZA test were 93.1, 91.1, and 96.0%, respectively. On the repeat test of the 10 strains with discrepant results among the three methods, the concordance rates reached over 97% between each of the two systems. The results of the repeat test were confirmed by MIC testing and sequencing analysis of the pncA gene encoding PZase of M. tuberculosis. The mean turnaround times from incubation for PZA susceptibility testing were almost similar for the two methods based on liquid media, the BACTEC MGIT 960 PZA medium and the Kyokuto PZA test (7.7 and 7.4 days, respectively). These results indicate that both methods based on liquid media, the fully automated BACTEC MGIT 960 PZA medium and the Kyokuto PZA test for susceptibility testing to PZA, are useful for rapid diagnosis of PZA resistant tuberculosis.

Amidohydrolases↗

Selection of in vitro mutants of pyrazinamide-resistant Mycobacterium tuberculosis.

Mutations within the pncA gene coding for pyrazinamidase of Mycobacterium tuberculosis can cause pyrazinamide (PZA) resistance. The effect of drug concentrations on PZA resistance in a clinical isolate of M. tuberculosis was studied in vitro. Serial passage at gradually increased concentrations of PZA from 200 to 500 microg/ml was performed using BACTEC radiometric method. Thirteen in vitro-selected variant strains were assembled and sequence analysis showed that 12 of the 13 variants had a novel single point mutation within the pncA gene by deletion at nucleotide 381 (G), codon 127. This lead to a frameshift that affected the function of the pyrazinamidase resulting in PZA resistance regardless of different PZA concentrations used. One variant had a silent mutation at nucleotide 6 (G-->A) and remains PZA sensitive. We conclude that the mutation location found is an important position for full resistance, at least in this strain. The lack of further mutations even after exposure to higher PZA concentrations implies a critical value for development of resistance-a level exceeded in tissues in clinical treatment regimes.

Antitubercular Agents↗

Combined effect of pyrazinamide and ofloxacin within the human macrophage.

SETTING: Recent reports of outbreaks of multidrug resistant tuberculosis have raised questions as to the most appropriate therapeutic response for those exposed to such organisms. A recent Centers for Disease Control National Action Plan suggests the combination of pyrazinamide (PZA) and a quinolone as a potential preventive therapy regimen. OBJECTIVE: Prior studies in the ex-vivo human macrophage model have shown PZA to have only a bacteriostatic effect and, in addition, to diminish the bactericidal effect of rifampin. This study was designed to quantify the intramacrophage antimycobacterial effect of PZA when combined with a quinolone (ofloxacin). DESIGN: Forty micrograms/ml of PZA was combined with varying concentrations of ofloxacin and administered to human macrophages infected with virulent tubercle bacilli; drug sequencing was also studied. RESULTS: A clinically achievable level of PZA enhances the antimycobacterial effect of low, non-bactericidal levels of ofloxacin and does not impede the bactericidal effect of a higher clinically effective level of ofloxacin. Unlike the combination of PZA and rifampin, these interactive effects are not affected by the sequence of drug administration. CONCLUSIONS: Findings support the use of these agents as a potentially effective preventive therapy combination for individuals exposed to multidrug resistant tuberculous organisms.

Animals↗

Mutation in pncA is a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis.

OBJECTIVE: To characterize the correlation of the mutations in the pncA gene encoding pyrazinamidase (PZase) of Mycobacterium tuberculosis to a loss of PZase activity and development of pyrazinamide (PZA) resistance. DESIGN: The association of PZase activity, minimum inhibitory concentrations (MICs), and mutations in the pncA gene of M. tuberculosis isolated in mostly Asian countries was investigated. RESULTS: One hundred thirty-five out of 168 isolates were PZase positive, and 33 were negative. The MICs of PZA at pH 6.0 were over 400 micrograms/ml for all 33 PZase-negative isolates, while those of PZase-positive isolates were equal to or less than 200 micrograms/ml. Among 33 PZase-negative isolates sequenced, 32 (97%) had mutations within the pncA gene. A mutation was seen in various regions throughout the pncA gene. It was surprising that all three strains of in vitro selected PZA resistant mutants were PZase-positive and showed no change in the pncA gene. These results indicate that additional mechanisms may be involved in PZA resistance. No mutations were observed in all of 135 PZase-positive M. tuberculosis isolates tested, indicating that mutations in the pncA gene could be involved in the loss of PZase activity. CONCLUSIONS: Sequencing analysis of the pncA gene should provide rapid diagnosis of PZA resistant clinical isolates of M. tuberculosis.

Amidohydrolases↗

Pyrazinamide resistance associated with pncA gene mutation in Mycobacterium tuberculosis in Japan.

Thirty Japanese clinical isolates of Mycobacterium tuberculosis were analysed by pyrazinamide susceptibility testing and pyrazinamidase assay, as well as polymerase chain reaction for single-strand conformational polymorphism and direct sequencing of the gene encoding pyrazinamidase (pncA). All sensitive isolates showed pyrazinamidase activity and a wild-type pncA gene, but three resistant isolates had pncA gene mutations and lacked pyrazinamidase activity. The latter isolates showed a minimum inhibitory concentration of at least 100 mg/l by the 7H10 agar proportion method and 400 mg/l by the 7H9 liquid medium method. Isolate 28 showed T-to-C change at position 11, leading to Leu4 --> Ser substitution; isolate 29 had an 8-bp deletion from position 382; and isolate 30 had A-to-C change at position 29, leading to Gln10 --> Pro substitution. The deletion has not been described previously. This is the first demonstration of pncA gene mutations in PZA-resistant M. tuberculosis strains isolated from Japanese patients.

Amidohydrolases↗