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PubMedDate not supplied

Renal handling of uric acid in normal children by means of the pyrazinamide and sulfinpyrazone tests.

Thirteen normal children have been studied with the Sulfinpyrazone and Pyrazinamide tests, in order to evaluate the mechanisms of urate tubular management. A decrease in presecretory reabsorption, and an increase in tubular secretion have been identified, with regard to what has already been reported in adults. These facts could explain the higher fractional excretion of uric acid found in childhood.

Child↗

PubMed1987

[Simultaneous microdetermination of pyrazinamide and pyrazinoic acid by liquid chromatography].

The technique reported here enables to titrate concomitantly pyrazinamide as well as its main metabolite, the 2-pyrazinoic acid. The serum sample is deproteinized with acetonitrile and the portion floating on the surface is injected on an anionic column of copolymer. The detection occurs at 270 nm and the sensitivity of the method enables its use during pharmacokinetic studies. The other anti-tuberculous drugs, usually associated, produce no interference.

Acetonitriles↗

PubMed1985

[Prevention of resistance to rifampicin by pyrazinamide in experimental tuberculosis in the mouse].

The capacity of Pyrazinamide (PZA) to prevent the selection of Rifampicin (RMP) resistant mutants was tested by the intravenous innoculation of 160 mice with 2 X 10(6) c.f.u. of M. tuberculosis, and two weeks later, the treatment of the mice either with 10 mg/kg/day RMP alone or with RMP + PZA 150 mg/kg/day. After three months of treatment, lungs and spleen were culture positive in respectively 95% and 90% of the mice treated with RMP alone and in 37% and 24% of the mice treated by RMP + PZA (p less than 10(-5). The strains isolated from lungs and spleen were resistant to Rifampicin in respectively 87% and 75% of the mice treated with RMP alone and in none of those treated with RMP + PZA.

Animals↗

PubMed1983

Toxicity of morphazinamide compared with pyrazinamide.

In a toxicological study on rats two derivatives of pyrazine: morphazinamide (MZA) and pyrazinamide (PZA) were compared with the objective to verify the possibility of using MZA as a substitute for the hepatotoxic PZA. The daily recorded weight and food intake of the rats were statistically significantly changed in the experimental groups with MZA as well as those with PZA, as compared with the control group and the group fed parallelly, already after the sixth dose of MZA and PZA 2.5 g per kg body weight, and similarly changed were also the various biochemical blood and liver tissue tests. Yet, certain differences were observed between the action of MZA and PZA. Some explanation was obtained from PZA blood and tissue concentrations, determined in the course of 24 hours following the administration of the sixth dose of both drugs. A repeated administration of MZA led to a PZA cumulation in the blood and organs of the rats. The study demonstrated that both drugs are hepatotoxic and, in high doses, also nephrotoxic. Moreover, MZA decreases the concentration of plasmatic iron and causes spleen atrophy. It will not be, therefore, a suitable substitute for the hepatotoxic PZA.

Animals↗

PubMed1983

The tolerability and efficacy of a 6-month antituberculosis regimen containing rifampicin, isoniazid and pyrazinamide.

The tolerability and efficacy of a 6-month daily regimen of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) were tested in 130 hospitalized patients, mostly Black, with previously untreated pulmonary tuberculosis. PZA was discontinued at the end of the 2nd month. In 6 cases treatment was discontinued because of drug intolerance. The symptoms were severe rash, mild thrombocytopenia, deteriorating haematological and renal condition and in the remaining 3 patients hyperbilirubinaemia. Of the 125 patients who could be assessed bacteriologically, 110 were infected with organisms which were fully susceptible to INH and RMP, and 95% of their cultures and 77% of their smears had converted to negative after 2 months of treatment. Similar results were obtained for all but 2 of the 15 patients with drug-resistant bacilli. Cavitation of the lungs was reduced in 78% of the patients and the extent of other tuberculous lesions diminished in 87%.

Adolescent↗

PubMed1983

[Pyrazinamide versus ethambutol in short-term therapy of lung tuberculosis. A randomized study].

Recent experience suggests that the duration of chemotherapy of tuberculosis can be shortened to 6-9 months, without an increase in the relapse rate, if the treatment if started with 3 or 4 drugs including isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA). In a controlled study of culture-positive advanced pulmonary tuberculosis we have compared treatment regimens with PZA in a dosage of less than 2 g and with ethambutol (EMB). 113 patients were given, in random order for 2-3 months, either PZA (25 mg/kg body weight) or EMB (25 mg/kg) together with RMP (450 or 600 mg) and INH (5 mg/kg). The last two drugs were given for a total of 9 months. Patients treated with PZA showed a (not significantly) earlier conversion to negative cultures after an average of 7 weeks. After 18 months follow-up there have been no relapses on these regimens. 2 patients, both treated with EMB, did not respond to therapy. Drug-induced hepatitis was seen in 5 patients with PZA and in 2 patients with EMB. The hepatitis was always observed during the first month of therapy and was fully reversible. Three of the 4 patients with clinically apparent hepatitis were over 70 years of age. Three patients with elevated uric acid levels had arthralgia which led in one of them to termination of therapy. The preliminary results of our study show that the treatment regimen with PZA does not lead to a higher rate of side effects if used with particular moderation in older patients.

Adult↗

PubMed1995

[Status quo of pyrazinamide as an antituberculosis drug].

Pyrazinamide (PZA), an antituberculosis agent, was first synthesized in 1940 by Hall and Spoerri and a clinical trial was carried out since 1949 by Yeager and others. Its usefulness as a potent antituberculosis drug was first reported by them in 1952. PZA was once believed to be a secondary choice drug for cases with refractory tuberculosis and/or relapsed cases which are resistant to all other antituberculosis drugs. There was some hesitation among doctors to use PZA for the initial treatment of tuberculosis because of rather high incidence of liver impairment after the use of regimens with PZA. It was, however, revealed later that this was not always true as PZA was ordinarily employed for clinical use in combination with ethionamide and/or cycloserin, and the latter drugs are both known to be hepatotoxic, too. PZA has a unique biological activity observed in murine experimental tuberculosis. The study showed that PZA when administered to animals, enters into the bacilli-ingested macrophages and exerts its killing effect on the bacilli under the environment of acidic pH inside the phagosome of the cells and in areas of acute inflammation both of which favors the acid-fast bacilli to stay in a dormant state and proliferate very slowly. This unique killing ability of PZA which is deficient in other drugs has recently spotlighted PZA once again as a pivotal and first line agent for the 6 months short course chemotherapy of tuberculosis. Sterile eradication of microbe is indispensable for the chemotherapy of tuberculosis, and the potency of a certain antituberculosis agent could be assessed by the availability of negative conversion of bacilli in sputum by culture within two months of administration of the drug. Another important aspect to assess the potency of a drug is to observe the relapse rate after the termination of therapy with the drug. The addition of PZA to the ordinary regimen consisting of INH, RFP and SM/EB has been reported to raise the negative conversion rate of bacilli from 60-70% by the regimen without PZA to as high as 80-90% by the regimen with PZA. In addition, there is no difference in the relapse rate of about 0-2% within 2 years after the termination of chemotherapy between the two regimens; 6 months with PZA and 9 months without PZA. Thus, the addition of PZA to the ordinary regimen enabled us to shorten the duration of antituberculosis chemotherapy than before.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

[Re-evaluation of pyrazinamide].

To re-evaluate pyrazinamide (PZA) which has been a key drug for short course anti-tuberculosis chemotherapy in the world, we started a clinical trial of short course chemotherapy containing PZA (2S (E) HRZ/EHR), and obtained information about the estimation of PZA in the tuberculosis specialists in Japan through a questionnaire. We could not evaluate precisely because of small numbers of registered cases, but the rate of negative conversion by culture was higher at the second months in the PZA group than in the control group. Although the total incidence of the adverse reactions of any kind was higher in the PZA group, the incidence of liver dysfunction was lower in the PZA group. Only about 20% of the tuberculosis specialists choose PZA in the treatment of newly diagnosed tuberculosis patients. The remainder do not choose PZA because they think that; 1) PZA has adverse reactions, 2) PZA is effectless, 3) drugs other than PZA are good enough. Almost half of the tuberculosis specialists continues antituberculosis chemotherapy for more than 9 months. The precise and strict nation-wide co-operative study for PZA should be designed to clarify the usefulness of PZA.

Clinical Trials as Topic↗

PubMed1993

[Results of short-term tuberculosis therapy with isoniazid, rifampicin and pyrazinamide].

Short-course chemotherapy of six-month duration with an initial combination of three drugs (isoniazid [H], rifampin [R] and pyrazinamide [Z]) is recommended as the treatment of choice in tuberculosis today. Use of fixed-combination tablet (Rifater) prevents prescription errors by physicians and selective intake by noncompliant patients. It should therefore assist in the prevention of emergence of drug resistance. In a controlled study at a chest hospital in Switzerland involving 261 patients with culture proven tuberculosis, the following two regimens were compared: 1) Six-month therapy (n = 128) with daily Rifater for two months, followed by H and R for four months. 2) Nine-month therapy (n = 133) with H and R daily for nine months, supplemented by ethambutol for the first two months. The two patient groups were comparable except for initial drug resistance (16% vs 8%, p < 0.05). Overall resistance to H was 10%. Five patients had initial resistance to two or more drugs. 227 patients were re-examined 1-8, and on average 4 years after therapy: four patients relapsed after 12, 20, 36 and 90 months. Two patients with initial drug resistance to H later developed resistance to R; both of these, as well as a third relapse patient, were cured with subsequent multi-drug therapy. Despite two and a half years of chemotherapy and repeated surgery, the fourth patient with initial resistance to H and R could not be cured. All relapse patients with initial drug resistance were randomized into the six-month therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Bactericidal action of pulsed exposure to rifampicin, ethambutol, isoniazid & pyrazinamide on Mycobacterium tuberculosis in vitro.

The bactericidal action of pulsed exposure to rifampicin (R), ethambutol (Emb), isoniazid (I) and pyrazinamide (Z) together on alternate days (REmbIZ) and as REmb and IZ separately on alternate days (REmb/IZ) on M.tuberculosis H37Rv, two isolates of M.tuberculosis sensitive to these drugs, as well as four isolates resistant to one or more drugs, was studied using an in vitro method. The experimental duration was 6 days. REmbIZ and REmb/IZ appeared to have equally good bactericidal action on M.tuberculosis strains in the in vitro system. The results suggest that splitting REmbIZ into REmb and IZ on alternate days in short course chemotherapy regimens for tuberculosis may not affect the bactericidal action of the regimens.

Antitubercular Agents↗

PubMed1995

Effect of antituberculous drugs, isoniazid, pyrazinamide and rifampicin, on chemiluminescence of the human polymorphonuclear leukocytes.

Luminol-dependent chemiluminescence (CL) was used to assay the effect of three antituberculous drugs [isoniazid (INH), pyrazinamide (PZA), rifampicin (RM)] on the production of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMN) isolated from blood of 5 healthy donors. Drugs were added directly to the medium in concentrations; INH 5 micrograms/ml, PZA 40 micrograms/ml, RM 7 micrograms/ml. These concentrations correspond to peak serum concentrations after usual doses. RM was found to inhibit FMLP (N-formyl-methionyl-leucyl -phenylalanine)-induced CL response of PMN, PZA did not influence the metabolic activity of neutrophils, and INH stimulated PMN CL.

Antitubercular Agents↗

PubMed1998

[Determination of pyrazinamide susceptibility for Mycobacterium tuberculosis by use of Middlebrook culture media and comparison with results of pyrazinamidase test].

We developed a new test method to determine pyrazinamide (PZA) susceptibility for Mycobacterium tuberculosis in an acidified Middlebrook 7H9 broth (pH6.0), and evaluated in comparison with the agar proportion method of the National Committee for Clinical Laboratory Standards (NCCLS) M24-T and with pyrazinamidase assay. The test method is based on a culture in 4 ml of the modified Middlebrook 7H9 broth containing 100, 200 and 400 micrograms PZA/ml, respectively. First, the cell suspension was adjusted to a McFarland #1 turbidity, and then diluted 1:10. After mixing, 0.1 ml of the diluted cell suspension was inoculated and incubated at 36 +/- 1 degrees C in an ambient air. After 7 day-incubation, the test broth was read in comparison with the growth control. When a significant growth at 100 micrograms PZA/ml or an attenuated growth at 100 micrograms PZA/ml but a significant growth at 400 micrograms PZA/ml were observed, the test isolate was interpreted as being PZA-resistant. When PZA-susceptible and PZA-resistant ATCC reference strains were repeatedly tested, the results obtained were highly precise and accurate. A total of 65 clinical isolates were tested, the results indicating 95.4% of agreements with the agar proportion method and 90.8% with pyrazinamidase assay. There found six discrepant results of 13 resistant isolates; three were susceptible by the agar proportion and all the six were positive by pyrazinamidase assay. Accordingly, we can conclude that, in place of radiometric Bactec System, our newly developed test method is an accurate, practical, rapid and nonradiometric alternative to determine PZA susceptibility for M. tuberculosis in clinical mycobacteriology laboratories.

Amidohydrolases↗

PubMed1998

Is pyrazinamide really the third drug of choice in the treatment of tuberculosis?

SETTING: University Hospital in a rural area of Greece. OBJECTIVE: Pyrazinamide (PZA) is recommended as the third drug in the 6-month regimens for tuberculosis. This has replaced previously satisfactory 9-month regimens with ethambutol (EMB). Several cases of severe hyperuricemia and at least one episode of acute arthritis in patients receiving PZA prompted us to study PZA prospectively with regard to these side effects. DESIGN AND SUBJECTS: Prospective study of 20 patients receiving PZA for tuberculosis compared to control patients with tuberculosis not receiving PZA. RESULTS: The study was discontinued with the twentieth patient when it became obvious that uric acid was elevated in all patients while on PZA and the last patient developed acute arthritis. This occurred in none of the control patients. CONCLUSION: Hyperuricemia should either be considered a significant side effect and make us reconsider PZA as the third drug of choice in tuberculosis, or it should be officially declared trivial by a major health organization. If so, it should be suggested to all health providers involved that there is no need to monitor uric acid in tuberculosis patients receiving PZA.

Adult↗

PubMedDate not supplied

Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA). DESIGN: Randomized, four-period, crossover phase I study. SUBJECTS: Fourteen healthy men and women volunteers. INTERVENTIONS: Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminum-magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. MEASUREMENTS AND MAIN RESULTS: Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4+/-10.4 microg/ml, Tmax 1.43+/-1.06 hours, and AUC(0-infinity) 673+/-79.7 microg x hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6+/-9.0 microg/ml, Tmax of 1.43+/-1.23 hours, and AUC(0-infinity) of 628+/-88.4 microg x hr/ml. In the presence of the high-fat meal, mean Cmax was 45.6+/-9.44 pg/ml, Tmax 3.09+/-1.74 hours, and AUC(0-infinity) 687+/-116 microg x hr/ml. CONCLUSIONS: These small changes in Cmax, Tmax, and AUC(0-infinity) can be avoided by giving PZA on an empty stomach whenever possible.

Adult↗

PubMed1998

[Short-course chemotherapy of tuberculosis with pyrazinamide].

A 6-month regimen consisting of isoniazid (INH. 0.3-0.5 g).rifampicin (RFP. 0.3-0.45 g).pyrazinamide (PZA. 1.2-2.0 g) and streptomycin (SM. 0.75 g) or ethambutol (EB. 0.75-1.0 g) given for 2 month followed by isoniazid and rifampicin for 4 month is the preferred treatment for patients with fully susceptible organism, who adhere to treatment. Consideration should be given to treating all patients with directly observed treatment.

Antibiotics, Antitubercular↗

PubMed1996

Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus.

Naturally pyrazinamide (PZA)-resistant Mycobacterium bovis and acquired PZA-resistant M. tuberculosis strains lose pyrazinamidase (PZase). To investigate the molecular mechanism of PZA resistance, we have cloned the gene (pncA) encoding M. tuberculosis PZase. Mutations in pncA were identified in both types of PZA-resistant strains, and transformation of these strains with a functional pncA gene restored PZase activity and PZA susceptibility. These findings, besides providing the basis for understanding how PZA works, should have implications for rapid detection of PZA-resistant clinical isolates of M. tuberculosis and also for rapid differentiation of M. bovis from M. tuberculosis strains.

Amidohydrolases↗

PubMed1997

A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B.

In order to evaluate the incidence, predisposing factors and clinical course of antituberculous drug-induced liver injury in hepatitis B surface antigen (HBsAg)-positive carriers and non-carriers, in an area endemic for hepatitis B, we prospectively followed 240 patients (154 male, 86 female; mean age 40 years) who had received daily isoniazid, rifampicin, ethambutol and pyrazinamide for the treatment of pulmonary tuberculosis. Patients with heavy alcohol consumption, with pretreatment serum alanine aminotransferase (ALT) elevation and who had less than 3 months post-treatment follow-up were excluded from the study. Thirty-one (13%) patients were positive for serum HBsAg before treatment. Sixty-three (26%; 95% CI: 21-32%) patients developed antituberculous drug-induced liver injury. The incidence of drug-induced liver injury was significantly more frequent in patients > 35 years of age than in patients < or = 35 years of age (33 vs 17%; P < 0.05), but was not different between HBsAg carriers and non-carriers (29 vs 26%; P > 0.05). Using step-wise logistic regression analysis, patient age > 35 years was the only independent variable for predicting antituberculous drug-induced liver injury, while sex, acetylator phenotype, HBsAg carrier status and severity of tuberculosis were not. The peak serum ALT levels in antituberculous drug-induced liver injury were not significantly different between HBsAg carriers and non-carriers. Only one 61-year-old HBsAg carrier developed severe jaundice after 6 months antituberculous therapy; he subsequently died of hepatic failure. In conclusion, the incidence of antituberculous drug-induced liver injury was significantly higher in patients > 35 years of age than in patients < or = 35 years of age, but was not different between HBsAg carriers and non-carriers. Mortality occurred in an aged HBsAg carrier superimposed with antituberculous drug-induced liver injury.

Adult↗

PubMed2004

Evaluation of the fully automated BACTEC MGIT 960 system for testing susceptibility of Mycobacterium tuberculosis to pyrazinamide, streptomycin, isoniazid, rifampin, and ethambutol and comparison with the radiometric BACTEC 460TB method.

The performance of the fully automated BACTEC MGIT 960 (M960) system for the testing of Mycobacterium tuberculosis susceptibility to streptomycin (SM), isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) was evaluated with 100 clinical isolates and compared to that of the radiometric BACTEC 460TB (B460) system. The agar proportion method and the B460 system were used as reference methods to resolve the discordant results for SM, INH, RMP, and EMB (a combination known as SIRE) and PZA, respectively. The overall agreements were 96.3% for SIRE and 92% for PZA. For SIRE, a total of 26 discrepancies were found and were resolved in favor of the M960 system in 8 cases and in favor of the B460 system in 18 cases. The M960 system produced 8 very major errors (VME) and 10 major errors (ME), while the B460 system showed 4 VME and 4 ME. No statistically significant differences were found. Both systems exhibited excellent performance, but a higher number of VME was observed with the M960 system at the critical concentrations of EMB and SM. For PZA, a total of eight discrepancies were observed and were resolved in favor of the M960 system in one case and in favor of the B460 system in seven cases; no statistically significant differences were found. The M960 system showed four VME and three ME. The mean times to report overall PZA results and resistant results were 8.2 and 9.8 days, respectively, for the M960 system and 7.4 and 8.1 days, respectively, for the B460 system. Statistically significant differences were found. The mean times to report SIRE results were 8.3 days for the M960 system and 8.2 days for the B460 system. No statistically significant differences were found. Twelve strains tested for SIRE susceptibility and seven strains tested for PZA susceptibility had been reprocessed because of contamination. In conclusion, the M960 system can represent a valid alternative to the B460 for M. tuberculosis susceptibility testing; however, the frequent contamination of the tests needs to be improved.

Antitubercular Agents↗