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PubMed1981

Liver alterations in antituberculosis regimens containing pyrazinamide.

A group of alcoholic tuberculous patients was given a pyrazinamide-containing regimen, and the liver was studied on admission and after two months of intensive treatment with IRSZ. Alterations in liver histology and in liver function tests found on admission improved or disappeared after two months' chemotherapy. A control group, give IRSE, showed similar results. A third group of nonalcoholic patients was given Z alone for 15 days, and liver tolerance was also excellent. These data support the conclusion that tuberculous alcoholic patients, in the absence of significant and persistent hepatic dysfunction, can be given Z-containing regimens. In all cases, a careful monitoring of hepatic function, with monthly SGPT and bilirubin determinations, is recommended.

Adolescent↗

PubMed1988

The role of pyrazinamide in tuberculosis chemotherapy.

Pyrazinamide is an antituberculosis drug synthesized in the 1950s and formerly used only as salvage therapy. Recent developments have elevated it to a central role in tuberculosis chemotherapy as the essential addition to isoniazid and rifampin which makes it possible to successfully complete treatment in six months. This is accomplished with no increase in hepatotoxicity. The only substantial side effect of this drug given at the dosage and for the duration used in these six-month regimens is a polyarthralgia which is only bothersome and not sufficient to warrant interruption of therapy. More rarely, acute gout is produced. The early history and pharmacology of this now first line antituberculosis drug are reviewed herein.

Humans↗

PubMed2004

Safety of rifampin and pyrazinamide for the treatment of latent tuberculosis infection.

A 2-month regimen of rifampin and pyrazinamide (2RZ) became an accepted alternative for treatment of latent tuberculosis (TB) after initial studies in HIV-seropositive patients demonstrated safety and efficacy. Once this alternative came into widespread use, however, a number of cases of severe and fatal hepatitis associated with 2RZ were reported. Although the initial experience with HIV-seropositive patients was encouraging, subsequent research demonstrated that the risk of 2RZ-associated hepatitis is considerably greater than the risk of hepatitis associated with isoniazid treatment for latent TB. Updated guidelines now recommend only restricted use of the 2RZ regimen for latent TB, with careful supervision.

Anti-Bacterial Agents↗

PubMed1999

Evaluation of the teratogenic potential of pyrazinamide in Wistar rats.

We have tested Pyrazinamide (PZA), an essential component of modern short-course tuberculosis treatment regimen, for teratogenicity using Wistar rats. The drug was given by oral intubation from 6-15 days of gestation, at doses of 0, 25, 100 and 500 mg/kg body weight per day. Reduction in body weight and food consumption were observed in the treated dams. On day 20 of gestation, all the dams were killed by cervical dislocation and signs of maternal toxicity, reproductive indices and fetal measurements were recorded. Dams given doses of 100 and 500 mg/kg had significantly higher incidence of reabsorbed fetuses, reduced litter size, and impaired neonatal growth than those given no PZA or only 25 mg/kg dose. External visceral and skeletal examination of all fetuses of PZA-treated dams showed several types of variations which were neither dose related nor having a consistent pattern. However, these variations occurred mostly in the dams treated with the dose of 500 mg/kg. In conclusion, these data show that in Wistar rats, only high doses of PZA (100 and 500 mg/kg) produced fetotoxicity. No evidence of teratogenic effect of the drug was observed.

Abnormalities, Drug-Induced↗

PubMed1989

Effects of dietary pyrazinamide, tryptophan, or nicotinic acid and gamma-ray irradiation on levels of NAD and NADP in various organs of mice.

The effects of large amounts of tryptophan, pyrazinamide, or nicotinic acid in diets on the contents of total NAD (NAD + NADH) and NADP (NADP + NADPH) of various organs were investigated in mice with or without gamma-irradiation. Female C3H/HeN mice were fed one of the following 4 kinds of experimental diets for one week: 1) control diet (20% casein diet containing 3 mg niacin per 100g diet); 2) diet supplemented by 0.5% L-tryptophan (T-diet); 3) diet supplemented by 0.5% L-tryptophan (T-diet); 4) diet supplemented by 0.1% nicotinic acid (NA-diet). Half of the mice in each group were subsequently irradiated with 8 Gy of gamma-ray (60 Co) after 4 h of fasting. Then, the contents of total NAD and NADP in thymus, spleen, kidney, liver, and blood were determined in all animals. The results indicated that NAD content of spleen was higher in PT-group (21.5%) and NA-group (23.2%) than in that of control group. In thymus, however, NAD content of only the PT-group was significantly greater (13.1%) than control. NAD level of kidney was also significantly higher (32.6%) in PT-group. By gamma-irradiation, NAD contents of thymus and spleen of all groups tended to be decreased, but those of kidney and liver were not always reduced. In the latter two organs, significant NAD reduction was shown only in kidney of PT-group and in liver of PT- and NA-groups. Even after irradiation, NAD levels of spleen and thymus in PT- and NA-groups tended to be kept higher than those in irradiated control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2001

Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Korea.

Pyrazinamide (PZA) is one of the most important drugs for the treatment of Mycobacterium tuberculosis infection. However, the increasing frequency of PZA-resistant strains limits its effectiveness. In Korea, most PZA-resistant strains also exhibit both isoniazid and rifampin resistance making it essential to identify these resistant strains accurately and rapidly for effective treatment of mycobacterial infection. In this study, the characteristics and frequency of mutations of the pncA gene encoding pyrazinamidase were investigated in PZA-resistant clinical isolates from Korea. Automated DNA sequencing was used to evaluate the usefulness of DNA-based detection of PZA resistance. Among 95 PZA-resistant clinical isolates, 92 (97%) exhibited mutations potentially affecting either the production or the activity of the enzyme. Mutations were found throughout the pncA gene including the upstream region. Single nucleotide replacement appeared to be the major mutational event (69/92), although multiple substitutions as well as insertion and deletion of nucleotides were also identified. The high frequency of pncA mutations observed in this study supports the usefulness of DNA-based detection of PZA-resistant M. tuberculosis. Having verified the scattered and diverse mutational characteristics of the pncA gene, automated DNA sequencing seems to be the best strategy for rapid detection of PZA-resistant M. tuberculosis.

Amidohydrolases↗

PubMed1999

Assessment of a combined preparation of isoniazid, rifampicin and pyrazinamide (Rifater) in the initial phase of chemotherapy in three 6-month regimens for smear-positive pulmonary tuberculosis: a five-year follow-up report.

SETTING: Singapore Tuberculosis Service. OBJECTIVE: To assess the acceptability, efficacy and relapse rate of a combined formulation of three drugs--isoniazid, rifampicin and pyrazinamide (Rifater)--given in the initial phase of chemotherapy in three 6-month regimens (2SHRZ/4H3R3, 1SHRZ/5H3R3 and 2HRZ/4H3R3) under direct observation for all patients. DESIGN: A randomised, controlled, unblinded study comparing a group of patients treated with Rifater and another given the three component drugs as separate formulations. RESULTS: The 310 patients admitted to the study were divided into two groups of 155 patients. The frequency of side effects was similar in both groups. Of 271 patients with drug-sensitive strains who had completed treatment without interruption, sputum cultures converted in all patients. At the end of 5 years, there were 15 relapses: three (2.2%) in the separate drugs group and 12 (9.3%) in the Rifater group. Exclusion of two cases in the Rifater group, one with silicotuberculosis and another with no bacteriological confirmation of diagnosis, gave a relapse rate of 7.9% (P = 0.03 for the comparison of relapse rates in the two groups). CONCLUSION: A combined formulation of three drugs given daily in the initial phase of 6-month short-course therapy, followed by intermittent treatment with isoniazid and rifampicin given three times a week under direct observation for all patients, appears to be less effective than treatment with the component drugs given as separate formulations.

Antitubercular Agents↗

PubMed1999

[Hyperuricemia and arthralgia during pyrazinamide treatment].

We studied 51 pulmonary tuberculosis patients who were initially treated with pyrazinamide (PZA) at our hospital between April 1996 and December 1997. PZA dosage was less than 1.5 g per day, and the chemotherapy course lasted 2 months. Uric acid levels of higher than 8 mg/dl were observed in 44 patients (86%). Arthralgia was observed in 9 patients. Acute gout was observed in only 1 patient who had hyperuricemia prior to PZA treatment and a predisposition for gout. The other 8 patients with arthralgia had symptoms in the shoulders and knees, but no gouty pain. Arthralgia was not related to serum uric acid level and disappeared after PZA treatment was stopped. We concluded that PZA can be used for up to 2 months without the combined administration of allopurinol or benzbromarone even if hyperuricemia or arthralgia develops.

Antitubercular Agents↗

PubMed1999

[pncA gene mutations in clinical isolates of tubercle bacillus by polymerase chain reaction-direct sequencing method: in relationship to pyrazinamide resistance].

We screened clinical isolates of tubercle bacillus for mutations in the pncA gene, which encodes pyrazinamidase (PZase), by polymerase chain reaction (PCR)-direct sequencing method. Sixty-eight strains of tubercle bacillus were isolated from 32 patients with pulmonary tuberculosis. The patients were treated with antituberculous agents including pyrazinamide (PZA) for 2 months. Thirty-two of the 68 strains were isolated from sputum samples collected from the patients before treatment; 29 strains and 7 strains were collected after 1 month and 2 months of treatment, respectively. The pncA genes in these strains, were assessed for mutations by direct sequencing of PCR products using an automated sequencer. Similarly, we examined two clinical isolates (ka567 and minami22) of tubercle bacillus, determined to be deficient in PZase activity by the Wayne method. A PZA-sensitive strain (H37Rv, ATCC27294), and a PZA-resistant strain (H37Rv-PZA-R, ATCC35828) were used as negative and positive controls for mutations in the pncA gene, respectively. None of the 68 strains demonstrated any mutations in the pncA gene; however, the 2 PZase-deficient strains had missense mutations in the pncA gene resulting in an amino acid substitution from His82 to Arg in clone ka567, and from Ala171 to Val in clone minami22.

Adult↗

PubMed1999

Determination of rifampicin, isoniazid and pyrazinamide by high performance liquid chromatography after their simultaneous extraction from plasma.

SETTING: Isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) are first-line antituberculosis drugs. Due to difficulties in producing effective combined formulations of these three drugs, the bioavailability of new combination formulations needs to be assessed prior to registration. OBJECTIVE: To develop a rapid, simple and sensitive high performance liquid chromatography (HPLC) assay method suitable for assaying RIF, INH and PZA in large numbers of plasma samples generated in bioavailability studies. METHOD: RIF, desacetyl-rifampicin (DRIF), INH and PZA were extracted simultaneously from plasma using a solid phase extraction column. RIF and DRIF were quantitated by HPLC using an 80% acetonitrile/0.1% trifluoroacetic acid (TFA) mobile phase and a C8 reversed phase column. INH and PZA were also quantitated on a C8 reversed phase column, but a 3% acetonitrile/0.6% TFA mobile phase was used. RESULTS: Mean recovery of RIF, DRIF and PZA from plasma was well over 90%, and over 70% for INH. Calibration graphs were linear for all the drugs in their therapeutic range. Correlation coefficients were all above 0.9995, and between- and within-run coefficients of variation below 10%. CONCLUSION: A simple, accurate, sensitive and cost effective assay for first-line antituberculosis drugs has been developed.

Antitubercular Agents↗

PubMedDate not supplied

[Evaluation of the pyrazinamidase test for the detection of susceptibility of Mycobacterium tuberculosis to pyrazinamide].

The pyrazinamidase test was used to determine susceptibility to pyrazinamide in 55 strains of Mycobacterium tuberculosis received at the National Laboratory of Reference and Research of Tuberculosis and Mycobacteria of the "Pedro Kourí" Institute of Tropical Medicine during the first semester of 1997. On comparing the results obtained with the method of proportions, it was attained a correlation of 83.6% of sensitivity with 16.4% of false positives. It was proved that the pyrazinamidase test should not replace the method of proportions.

Amidohydrolases↗

PubMed2001

Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection--New York and Georgia, 2000.

One of the recommended treatments for latent tuberculosis infection (LTBI) is a 9-month regimen of isoniazid (INH); a 2-month regimen of rifampin (RIF) and pyrazinamide (PZA) is an alternative in some instances. In September 2000, a man in New York died of hepatitis after 5 weeks of RIF-PZA, and in December, a woman in Georgia was admitted to a hospital because of hepatitis after 7 weeks of this regimen. This report summarizes the findings of the investigations of these incidents, which underscore the need for clinical monitoring for adverse effects in all patients receiving treatment for LTBI.

Antitubercular Agents↗

PubMed2001

Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations--United States, 2001.

During February 12-August 24, 2001, a total of 21 cases of liver injury associated with a 2-month rifampin-pyrazinamide (RIF-PZA) regimen for the treatment of latent tuberculosis infection (LTBI) was reported to CDC. These 21 cases are in addition to two previously reported RIF-PZA-associated cases. Cases of liver injury have occurred each year since 1999. CDC also received reports of 10 cases associated with other LTBI treatment regimens; however, risk for liver injury cannot be compared among treatment regimens in part because the number of patients treated for LTBI with each treatment regimen is unknown. This report provides preliminary information about the 21 cases associated with RIF-PZA and the revised recommendations on selecting appropriate LTBI therapy for patients and monitoring the use of RIF-PZA to treat LTBI. In most instances, the 9-month isoniazid (INH) regimen is preferred for the treatment of patients with LTBI. RIF-PZA may be used in selected cases and requires more intensive clinical and laboratory monitoring than previously recommended.

Adult↗

PubMed2002

[The study on the duration of treatment in the standard short course chemotherapy containing pyrazinamide].

Based on the results of a questionnaire for the tuberculosis specialists in the whole country, we investigated whether the standard short course chemotherapy containing pyrazinamide (four drugs regimen: HRZE/S) were given for adequate duration. The results of a questionnaire revealed that the duration of treatment was prolonged in 60% of 848 cases due to several reasons. The reasons for the longer duration of treatment were (1) complication of other disease, (2) delay in the improvement on chest X-ray, (3) delay in negative conversion of bacilli, (4) drug resistance, (5) patient's request, and (6) others. According to our own experience in the National Dohoku Hospital for the past four years, the duration of therapy was prolonged in 86% of cases treated with the four drugs regimen, and in 64% of cases with the three drugs regimen (HRE/S). Four drugs regimen was preferred for severer cases and the three drugs regimen for older patients. The reasons for the prolonged duration of treatment in our hospital were similar to those in the results of a questionnaire in the whole country. We recognized that the treatment was prolonged due to several meaningless reasons such as "no particular reason", "anxiety on relapse" and "patient's request". In order to decide the adequate duration of treatment, it is needed to know the relapse rate in cases with the short course chemotherapy and its relationship with complications. It is hoped to establish the guideline for tuberculosis treatment including the duration of treatment based on the results of detailed clinical studies.

Antitubercular Agents↗

PubMed2002

Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection.

Reports of fatal and severe liver injury associated with treatment of latent tuberculosis infection (LTBI) with the drug combination rifampin and pyrazinamide (RZ) prompted CDC to issue revised guidelines for the use of this regimen on August 31, 2001. To determine if these revised guidelines were effective in reducing morbidity and mortality, CDC has continued to collect reports on adverse effects associated with this regimen. This update summarizes the results of this ongoing investigation.

Antitubercular Agents↗

PubMed2003

The curious characteristics of pyrazinamide: a review.

Pyrazinamide (PZA) is an important sterilising tuberculosis drug that helps to shorten the duration of current chemotherapy regimens for tuberculosis. When first discovered, it had activity in murine tuberculosis but no apparent in vitro activity, and its subsequent use in treatment depended largely on classic experiments at Cornell University, which showed its requirement for an acid pH for activity and its sterilising activity in the mouse. Recent studies have shown that PZA enters Mycobacterium tuberculosis by passive diffusion, is converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase) and is then excreted by a weak efflux pump. Protonated POA (HPOA) is reabsorbed into the bacilli under acid conditions and accumulates because the efflux pump is inefficient, causing cellular damage. Unlike other antibacterials, PZA has no defined target of action. PZA is more active against old than against actively growing cultures, probably because the energy production and efflux pump would be slowed down by low bacterial metabolism. This review deals with the activity of PZA in vitro, in macrophages and in animal models. It describes the evidence from clinical trials that it is an effective sterilising drug that acts synergistically with rifampicin. The highly diverse mutations in the PZase gene (pncA) that lead to loss of PZase activity cause PZA resistance. Methods for susceptibility determination either as tests against PZA or nicotinamide in liquid and solid media, as tests for PZase activity or for mutations in pncA, are reviewed.

Amidohydrolases↗

PubMed2003

Bioavailability of rifampicin following concomitant administration of ethambutol or isoniazid or pyrazinamide or a combination of the three drugs.

BACKGROUND & OBJECTIVES: Poor bioavailability of rifampicin (R) in combination with other anti-tuberculosis drugs such as isoniazid (H), pyrazinamide (Z), and ethambutol (E) is a subject of much concern for the last few decades. This could be due to an interaction between R and other drugs. An investigation was therefore undertaken to examine the bioavailability of R in the presence of H, Z and E or a combination of the three drugs. METHODS: The study included eight healthy volunteers, each being investigated on four occasions at weekly intervals once with R alone and with three of the four combinations on the three remaining occasions. A partially balanced incomplete block design was employed and the allocation of R or the drug combinations was random. Plasma concentrations of R at intervals up to 12 h were determined by microbiological assay using Staphylococcus aureus as the test organism. The proportion (%) dose of R as R plus desacetyl R (DR) in urine excreted over the periods 0-8 and 8-12 h was also determined. Bioavailability was expressed as an index (BI) of area under time concentration curve (AUC) calculated from the plasma concentrations or proportion of dose of R excreted as R plus DR in urine with the combinations to that with R alone. RESULTS: The bioavailability indices based on AUC were 0.96 with RE, 0.76 with RH, 1.08 with RZ and 0.65 with REHZ. The indices based on urine estimations (0-8 h) were similar, the values being 0.94, 0.84, 0.94 and 0.75, respectively. A second investigation revealed that the decrease of bioavailability of R with H was not due to the excipients present in H tablets. INTERPRETATION & CONCLUSION: Isoniazid alone or in combination with E and Z reduces the bioavailability of R. Urinary excretion data offer a simple and non invasive method for the assessment of bioavailability of R.

Adolescent↗

PubMed1978

[Determination of the sensitivity of mycobacteria to pyrazinamide and nicotinamide (author's transl)].

Since pyrazinamide (PZA) has had a come-back in therapy of tuberculosis a simple and reliable method for sensitivity tests has been necessary. A comparison of resistance tests to PZA in acid Löwenstein-Jensen-medium and in fluid medium with those to nicotinamide (NSA) showed a clear superiority of the NSA method, recommended by BRANDER. Also in routine sensitivity tests the use of NSA instead of PZA has stood the test. Another advantage of the method is the possibility to integrate it in the simplified proportion method without any additional work.

Drug Resistance, Microbial↗