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PubMed1999

Pharmacokinetics of pyrazinamide in children suffering from pulmonary tuberculosis.

SETTING: The Paediatric and Clinical Pharmacology unit of Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India. OBJECTIVE: The pharmacokinetics of the anti-tuberculosis drug pyrazinamide was evaluated in 10 children aged 6 to 12 years suffering from pulmonary tuberculosis. METHODS: Serial blood samples were collected at 0, 1, 2, 4, 6, 12 and 24 hours after administration of pyrazinamide in a dose of 35 mg/kg. Serum pyrazinamide levels were analysed by spectrophotometry. RESULTS: The serum concentrations of pyrazinamide were above the minimum inhibitory concentration of 20 microg/ml of pyrazinamide for Mycobacterium tuberculosis up to 6 hours after drug administration in all the patients, and up to 12 hours in six patients. The mean peak serum concentration of pyrazinamide was 41.2+/-11.8 microg/ml, and this was attained in (Tmax) 2.9+/-1.7 hours. The elimination half life was 10.9+/-4.5 hours, the volume of distribution 16.1+/-10.9 litres and clearance 20.2+/-16.3 ml/minute. The corresponding mean residence time was 19.9+/-14.6 hours. CONCLUSION: The serum pyrazinamide concentrations achieved with a dose of 35 mg/kg were above the minimum inhibitory concentration of pyrazinamide for M. tuberculosis for over 6 hours after drug administration. It appears that the absorption and the clearance of pyrazinamide is slower, the elimination half life longer and the volume of distribution higher in children compared with the reported values in the adult population.

Antitubercular Agents↗
PubMed1997

[Pyrazinamide-containing initial intensive short course chemotherapy of pulmonary tuberculosis].

Six-month short course regimen had been accepted all over the world since early 1980s. In Japan this short course regimen had not been accepted as a standard regimen for treatment of pulmonary tuberculosis until April 1996. The reason why this was not accepted is resumably due to hepatotoxicity of pyrazinamide. The situation around tuberculosis were changing in Japan especially in urban areas. Incidence of tuberculosis in younger generations is higher in urban areas than in rural areas. More effective and shorter course regimen were needed. Efficacy of pyrazinamide were briefly described first, then results of six-month regimen with pyrazinamide in Fukujuji Hospital since 1991 January were discussed. Pyrazinamide can kill tubercle bacilli in acidic environment. It works bacericidally during the early treatment phase. It can kill not only replicating bacilli but also semidormant ones. The results of many six-month regimens showed that only pyrazinamide containing regimens were acceptable for standard regimen in pulmonary tuberculosis with less than a few percent of relapse. Newly accepted standard chemotherapy included 2HRZ with or without S or E/4HRE, 6HRS or E/3HR, and 6HR. Among 429 tuberculosis patients treated at Fukujuji Hospital with pyrazinamide-containing regimens, the negative conversion rate after two months of chemotherapy was 95 percent and similar to those of Western, African and Asian tuberculosis trials. Six of 290 evaluable cases have relapsed. (relapse rate; 2%) Noticeably all relapsed cases were complicated with diabetes mellitus. The higher percent of patients, 8.2 had elevated serum transaminase levels 5 times of upper limit of normal level or more compared with that of patients without pyrazinamide, 6.6 percents, but this difference is not statistically significant. One patient whose pretreatment liver function was abnormal with unknown origin died from hetatoxicity of anti-tuberculous drugs. The risk factors of hepatotoxicity included HCV carrier, elderly more than 80 years old, but HB carrier, alcohol drinking and hepatic diseases were not risk factors. Less patients, 5.6% defaulted from regimen compared with that with 9-month regimen without pyrazinamide (8.6%), but this difference is not statistically significant. The efficacy of the regimen was 90.3% higher than that of 9-month regimen, 86.0% In summary, six-month regimen containing pyrazinamide is highly effective. The incidence and severity of hepatotoxicity must be further studied in Japan.

Aged↗
PubMed1999

Intrapulmonary concentrations of pyrazinamide.

The objective of this study was to compare the steady-state plasma and intrapulmonary concentrations of orally administered pyrazinamide in normal volunteers and subjects with AIDS. Pyrazinamide was administered at 1 g once daily for 5 days to 40 adult volunteers (10 men with AIDS, 10 normal men, 10 women with AIDS, and 10 normal women). Subjects with AIDS and with more than four stools per day were excluded. Blood was obtained prior to administration of the first dose, 2 h after the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Pyrazinamide was measured by high-performance liquid chromatography. The presence of AIDS or gender had no significant effect on the concentrations of pyrazinamide in plasma. The concentrations of pyrazinamide in ELF and AC were lower in the subjects with AIDS than in the subjects without AIDS, but the difference was not significant. The concentrations in plasma (mean +/- standard deviation) were 25.1 +/- 7.6 and 21.1 +/- 6.8 microg/ml at 2 and 4 h after the last dose, respectively, and were not significantly different from the concentration (17.4 +/- 16.9 microg/ml) in AC. The concentration of pyrazinamide in ELF was high (431 +/- 220 microg/ml) and was approximately 4 to 40 times the reported MIC for pyrazinamide-susceptible strains of Mycobacterium tuberculosis. The high concentration of pyrazinamide in ELF may contribute in part to the effectiveness of the drug in treating pulmonary tuberculosis.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Comparison of phenotypic and genotypic methods for pyrazinamide susceptibility testing with Mycobacterium tuberculosis.

Mycobacterium tuberculosis converts pyrazinamide to its active form by using the enzyme pyrazinamidase. This enzyme is coded for on the pncA gene, and mutations in the pncA gene result in absence of active enzyme, conferring resistance to the drug pyrazinamide. We investigated 27 strains of Mycobacterium tuberculosis suspected of being multidrug resistant. Each isolate was tested for susceptibility to pyrazinamide by the BACTEC 460TB method, and 19 were pyrazinamide resistant. The presence of active pyrazinamidase enzyme was sought by using the Wayne assay, which was positive in all of the sensitive isolates and four of the resistant isolates. The pncA gene was amplified by PCR, and mutations were sought by single-strand conformation polymorphism (SSCP) analysis. We identified four isolates which were phenotypically resistant to pyrazinamide, but which had active pyrazinamide enzyme on the Wayne assay and normal pncA gene SSCP. MICs measured by BACTEC 460TB and susceptibility testing at a lower pH of 5.5 confirmed genuine resistance. The pncA gene was sequenced in these four isolates and found not to have any mutations. This implies that an alternative mechanism of resistance exists in these strains. We conclude that genotypic assessment of pyrazinamide resistance is unreliable, because it depends on the identification of a single resistance mechanism. Phenotypic methods such as the BACTEC 460TB technique remain the best methods for pyrazinamide susceptibility testing.

Amidohydrolases↗
PubMed2002

Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial.

BACKGROUND: Rifampin and pyrazinamide are recommended for treatment of latent tuberculosis infection in adults without HIV infection, but reports of severe hepatotoxicity have raised concerns about its safety. Clinical trials have not compared this treatment with isoniazid in adults without HIV infection. OBJECTIVE: To compare the safety and tolerance of a 2-month regimen of rifampin and pyrazinamide with that of a 6-month regimen of isoniazid for treatment of latent tuberculosis infection. DESIGN: Multicenter, prospective, open-label trial. SETTING: Three urban public health tuberculosis clinics in the United States. PATIENTS: 589 adults with latent tuberculosis infection who met U.S. criteria for treatment. INTERVENTION: Patients were assigned in alternate weeks to receive rifampin and pyrazinamide daily for 2 months (n = 307) or isoniazid daily for 6 months (n = 282). MEASUREMENTS: Primary end points were hepatotoxicity, other adverse events, and percentage of patients who completed treatment. RESULTS: Sixteen of 207 (7.7%) patients assigned to rifampin and pyrazinamide developed grade 3 or 4 hepatotoxicity compared with 2 of 204 (1%) patients assigned to isoniazid (odds ratio, 8.46 [95% CI, 1.9 to 76.5]; P = 0.001). The rifampin plus pyrazinamide regimen was more likely than the isoniazid regimen to be discontinued because of hepatotoxicity (odds ratio, 5.19; P = 0.033). The overall percentage of nonhepatotoxic adverse events was 20% in the rifampin-pyrazinamide group and 16% in the isoniazid group. The proportion of patients who completed the study treatment was 61% and 57%, respectively. CONCLUSIONS: A 2-month regimen of rifampin and pyrazinamide was associated with an increased risk for grade 3 or 4 hepatotoxicity compared with a 6-month regimen of isoniazid. Liver enzymes should be measured routinely during treatment to screen for liver injury and prevent progression to severe toxicity.

Adult↗
PubMed1989

Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects.

The plasma and urine pharmacokinetic parameters of pyrazinamide and of its metabolites (pyrazinoic acid, 5-hydroxy-pyrazinamide, 5-hydroxy-pyrazinoic acid and pyrazinuric acid) have been studied after a single oral dose of pyrazinamide 27 mg.kg-1 in 9 healthy subjects. Pyrazinamide was rapidly absorbed (tmax less than or equal to 1 h) and showed a short distribution phase followed by an elimination phase of t1/2 beta = 9.6 h. The close similarity of the apparent elimination rates of the metabolites led to a second trial of a single oral dose of pyrazinoic acid to evaluate the formation and elimination stages. The limiting factor was found to be the activity of a microsomal deamidase (pyrazinoic acid formation from pyrazinamide and 5-hydroxy-pyrazinoic acid formation from 5-hydroxy-pyrazinamide). In contrast, oxidation by xanthine oxidase occurred very rapidly (5-hydroxy-pyrazinamide formation and pyrazinoic acid catabolism to 5-hydroxy-pyrazinoic acid).

Chromatography, High Pressure Liquid↗
PubMed1981

The effect of pyrazines on the metabolism of tryptophan and nicotinamide adenine dinucleotide in the rat. Evidence of the formation of a potent inhibitor of aminocarboxy-muconate-semialdehyde decarboxylase from pyrazinamide.

The intraperitoneal or oral administration of pyrazinamide and pyrazinoic acid (pyrazine 2-carboxylic acid) resulted in a marked increase of the NAD content in rat liver. The injections of pyrazine and pyrazine 2,3-dicarboxylic acid exhibited no significant effect on the hepatic NAD content. The boiled extract obtained from liver and kidney of rat injected with either pyrazinamide or pyrazinoic acid exhibited a potent inhibitory effect on the aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) activity in either lier or kidney, although pyrazinamide or pyrazinoic acid per se did not inhibit the enzyme activity. The unknown inhibitor of aminocarboxymuconate-semialdehyde decarboxylase was dialysable and heat-stable, and mostly excreted in urine by 6 and 12 h after injected of pyrazinoic acid and pyrazinamide, respectively. Pyrazine 2,3-dicarboxylic acid, pyrazine, nicotinamide, nicotinic acid, tryptophan, anthranilic acid, 5-hydroxyanthranilic acid and quinolinic acid exhibited no significant effect on the aminocarboxymuconate-semialdehyde decarboxylase activity in liver and kidney at the concentration of 1 mM in the reaction mixture. The expired 14CO2 from L-[benzen ring-U-14C]tryptophan was markedly decreased by the pyrazinamide injection, while the urinary excretion of 14C-labeled metabolites from L-tryptophan, mainly quinolinic acid, was markedly increased. These results suggest that the glutarate pathway of L-tryptophan was strongly inhibited by the inhibitor produced after the administration of pyrazinoic acid and pyrazinamide. Pyrazinamide but not pyrazinoic acid also exhibited a significant inhibition of the nuclear enzyme poly(ADP-ribose) synthetase in rat liver.

Animals↗
PubMed1990

Modification of tumour radiation response in vivo by the benzamide analogue pyrazinamide.

Pyrazinamide, the pyrazine analogue of nicotinamide, has been evaluated for its ability to modify the radiation response of hypoxic cells both in vivo and in vitro. Results obtained with three different murine tumour systems EMT6, LLC and SCCVII showed that pyrazinamide at a dose of 0.5 mg g-1 i.p. resulted in enhanced radiation response. Dose modification factors of between 1.3 and 1.6 were observed using in vivo/in vitro clonogenic assays. This enhancement was greater than that obtained in mouse intestine using crypt cell survival as an endpoint (DMF 1.1). In contrast to the tumour data in vivo, the in vitro results indicate that pyrazinamide displays little radiosensitising or toxic properties towards hypoxic CHO cells in culture. These results suggest that pyrazinamide exerts its effects in vivo either by directly perturbing tumour physiology or by being converted to an active metabolite. Blood flow studies performed using laser Doppler flowmetry indicate that pyrazinamide produces a small (32%) increase in overall tumour blood flow in the SCCVII tumour. Based on this finding, additional studies on tumour perfusion at the microregional level were performed in the SCCVII tumour using a histological technique involving injection of fluorescent stains which demarcate functional vasculature. The data show that when compared to saline injected controls, pyrazinamide reduced the number of vessels opening and closing over a 20 min period from 10.2% to 3.8%. This finding suggests that pyrazinamide may exert its effects at least in part by reducing the occurrence of acute hypoxia resulting from dynamic changes in microregional perfusion.

Animals↗
PubMed1994

[Six-month short course chemotherapy containing pyrazinamide for initial treatment of pulmonary tuberculosis].

From January 1991 to December 1992, 419 patients with pulmonary tuberculosis were initially treated at Fukujuji Hospital. Among them, 190 patients, who were younger than 80 years old and had pulmonary tuberculosis with cavities or infiltration of extension 2 or 3, and/or were sputum-smear positive, had been treated by 6-month short course regimen containing pyrazinamide, 2HRS(E)Z/4HRE. And were eligible for the evaluation of the clinical usefulness of pyrazinamide-containing regimen for the initial treatment of pulmonary tuberculosis. The dose of pyrazinamide was 1.2 g per day irrespective of body weight. The patients of this treatment group consisted of 151 males and 39 females, and mean age of the males was 45.3 and that of the females was 43.8 years old. At the start of the treatment, 74% of the cases were smear positive, 70% were cavitary, and 6 cases each showed primary resistance to isoniazid and to streptomycin, respectively, and only one case showed resistance to both of isoniazid and streptomycin. There was no primary resistant case to either rifampicin or ethambutol. Bacteriologic negative conversion rates were 95% and 90% after 2 months of treatment by PZA-containing regimen and by the standard regimen, respectively, and treatment durations required to achieve the negative conversion of all cases were 3 and 6 months for respective regimens. Of 90 patients who completed 6-month PZA-containing regimen and could be followed-up, only one bacteriologic relapse (1.1%) was noticed. Elevation of serum GPT level higher than 150 IU/ml during the treatment was noticed in 6.3% of 175 cases under PZA-containing regimen in comparison with 4.0% of 174 cases under the standard regimen (not significant). The interval between the onset of the treatment and the detection of abnormal liver function was much shorter (mean 31.3 days) in the PZA-containing regimen than in the standard regimens (mean 63.4 days). Hyperuricaemia (> 10 mg/ml) was noticed in 46.7% of 57 males and 59.4% of 19 females tested, but pyrazinamide was not discontinued in any case due to arthralgia. These results clearly show that pyrazinamide can be used rather safely for Japanese tuberculosis patients. If the pyrazinamide-containing regimen [2HRS(E)Z/4HRE] is adopted as the new standard regimen in place of on-going standard regimen in Japan, 6HRS(E)/3HR, the duration of chemotherapy could be shortened by three months with the same level of both efficacy and safety. We recommended pyrazinamide-containing 6-month regimen, 2HRS(E)Z/4HRE, as the new standard regimen for the initial treatment of pulmonary tuberculosis.

Adolescent↗
PubMed1996

[In vitro antimycobacterial activities of pyrazinamide analogs: results of screening tests].

Attempting to find new drugs, which are more effective than pyrazinamide against Mycobacterium tuberculosis and also active against M. avium complex (MAC), we synthesized various pyrazinamide analogs and pyrazine derivatives and assayed their antimycobacterial activities in vitro against M. tuberculosis, M. avium and M. intracellulare. As is well known, pyrazinamide is more active in acidic medium than in neutral medium, but the growth of mycobacteria in acidic media is poor and inconsistent. Our preliminary experiments revealed that the relative antimycobacterial activities of test-drugs compared with pyrazinamide were essentially the same in pH5.5 medium as in pH6.0 medium. Therefore, Middlebrook 7H9 broth adjusted to pH6.0 was used throughout the present studies. Among 39 compounds synthesized, four drugs were insoluble in any of the solvent suitable for culture experiments and could not be tested, and remaining 35 compounds were screened. The growth of mycobacteria was followed by measuring the optical density at 530 nm (OD), and the OD of the culture in the presence of 200 micrograms/ml of the test-drug (OD-TD) was compared with that in the presence of pyrazinamide (OD-PZA). Each test-drug was ranked as A, B, C, D or E according to the ratio (OD-TD/OD-PZA) x 100%, if the ratio was equal to or less than 10%, 11-20%, 21-40%, 41-60% or 61-80%, respectively. Any drugs showing the ratio above 80% were excluded from further examinations. For M. tuberculosis, 11 drugs were ranked as A and 4 more as B. For M. avium, 2 drugs were ranked as A and 2 more as B. For M. intracellulare, 5 drugs were ranked as A and 2 more as B. Among highly ranked ones, 4 compounds, namely, pyrazinoic acid noctyl ester, pyrazinoic acid pivaloyloxymethyl ester, pyrazine thiocarboxamide and N-hydroxymethyl pyrazine thiocarboxamide were ranked as A against M. tuberculosis and M. intracellulare, and ranked as A, B or C against M. avium, and considered as hopeful candidates of new antimycobacterial drugs. Their bacteriostatic and bacteriocidal activities against M. tuberculosis as well as M. avium and M. intracellulare have been studied in details and reported in a separate paper. In vivo activities against murine experimental tuberculosis of these 4 drugs is now under investigation. Further, two drugs, N-hydroxy pyrazinamide and N-hydroxy pyrazinamide-4-oxide were ranked as A against M. tuberculosis and ranked A or B against M. intracellulare, and their more precise in vitro antimycobacterial activities are now under examination.

Antitubercular Agents↗
PubMed2000

Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS Clinical Trials Group, the Pan American Health Organization, and the Centers for Disease Control and Prevention Study Group.

CONTEXT: Because of problems with adherence, toxicity, and increasing resistance associated with 6- to 12-month isoniazid regimens, an alternative short-course tuberculosis preventive regimen is needed. OBJECTIVE: To compare a 2-month regimen of daily rifampin and pyrazinamide with a 12-month regimen of daily isoniazid in preventing tuberculosis in persons with human immunodeficiency virus (HIV) infection. DESIGN: Randomized, open-label controlled trial conducted from September 1991 to May 1996, with follow-up through October 1997. SETTING: Outpatient clinics in the United States, Mexico, Haiti, and Brazil. PARTICIPANTS: A total of 1583 HIV-positive persons aged 13 years or older with a positive tuberculin skin test result. INTERVENTIONS: Patients were randomized to isoniazid, 300 mg/d, with pyridoxine hydrochloride for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazinamide, 20 mg/kg per day, for 2 months (n = 791). MAIN OUTCOME MEASURES: The primary end point was culture-confirmed tuberculosis; secondary end points were proven or probable tuberculosis, adverse events, and death, compared by treatment group. RESULTS: Of patients assigned to rifampin and pyrazinamide, 80% completed the regimen compared with 69% assigned to isoniazid (P<.001). After a mean follow-up of 37 months, 19 patients (2.4%) assigned to rifampin and pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed tuberculosis at rates of 0.8 and 1.1 per 100 person-years, respectively (risk ratio, 0.72 [95% confidence interval, 0.40-1.31]; P = .28). In multivariate analysis, there were no significant differences in rates for confirmed or probable tuberculosis (P = .83), HIV progression and/or death (P = .09), or overall adverse events (P = .27), although drug discontinuation was slightly higher in the rifampin and pyrazinamide group (P = .01). Neither regimen appeared to lead to the development of drug-resistant tuberculosis. CONCLUSIONS: Our data suggest that for preventing tuberculosis in HIV-infected patients, a daily 2-month regimen of rifampin and pyrazinamide is similar in safety and efficacy to a daily 12-month regimen of isoniazid. This shorter regimen offers practical advantages to both patients and tuberculosis control programs.

AIDS-Related Opportunistic Infections↗
PubMed1976

Observations on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide.

The urinary excretion of pyrazinamide, pyrazinoic acid, 5-hydroxypyrazinoic acid and uric acid were determined in a healthy subject after giving single or multiple doses of pyrazinamide or its metabolite pyrazinoic acid. The results obtained demonstrated that 5-hydroxypyrazinoic acid is a major metabolite of pyrazinoic acid in man and supported previous evidence indicating that the retention of uric acid caused by the administration of pyrazinamide is mediated by pyrazinoic acid. After giving 3 g pyrazinamide the urinary excretion of uric acid was maximally suppressed for 24 hours and partially reduced for a further 24 hours. Prolonged exposure to pyrazinoic acid resulted in a net reduction in the urinary excretion of uric acid. The findings suggested that the degree of uric acid retention in patients treated with pyrazinamide-containing regimens could be reduced by giving pyrazinamide intermittently.

Humans↗
PubMed1998

Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection.

BACKGROUND: Tuberculosis is a common complication of HIV-1 infection, especially in developing countries. Practical and effective chemoprophylaxis regimens for HIV-1-related tuberculosis are needed. Our aim was to test the efficacy of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1-positive individuals. METHODS: We compared the efficacy of 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1-seropositive individuals. Eligible participants were aged 16-77 years, HIV-1 seropositive, had a positive purified-protein derivative (PPD) skin test reaction of at least 5 mm, and had a normal chest radiograph. Participants were randomly assigned partially supervised twice weekly isoniazid for 24 weeks or twice weekly rifampicin and pyrazinamide for 8 weeks. Participants were followed up for up to 4 years for the development of tuberculosis and survival. FINDINGS: Tuberculosis developed in 14 (3.8%) of 370 participants assigned isoniazid and 19 (5.0%) of 380 participants assigned rifampicin and pyrazinamide (Cox model rate ratio 1.3 [95% CI 0.7-2.7]). The Kaplan-Meier estimate of the risk of tuberculosis during the first 10 months after entry was 3.7% among participants who received rifampicin and pyrazinamide compared with 1.0% (p=0.03) among participants who received isoniazid, and 5.4% versus 5.1%, respectively (p=0.9) at 36 months after entry. Higher rates of tuberculosis were observed in people with baseline CD4 percentages (of total lymphocytes) of less than 20 (rate ratio 4.0 [95% CI 1.8-9.0]). There were no significant differences in total mortality at any time. INTERPRETATION: Twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar overall protection against tuberculosis in HIV-1-infected, PPD-positive adults. The better protection among recipients of isoniazid during the first 10 months was most likely secondary to the longer duration of chemoprophylaxis. Preventive therapy for HIV-1-seropositive, PPD-positive individuals could be practical in developing countries with a once weekly clinic visit, but optimum duration of chemoprophylaxis has not been determined.

AIDS-Related Opportunistic Infections↗
PubMed2003

Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid.

Pyrazinamide is an important sterilizing drug that shortens tuberculosis (TB) therapy. However, the mechanism of action of pyrazinamide is poorly understood because of its unusual properties. Here we show that pyrazinoic acid, the active moiety of pyrazinamide, disrupted membrane energetics and inhibited membrane transport function in Mycobacterium tuberculosis. The preferential activity of pyrazinamide against old non-replicating bacilli correlated with their low membrane potential and the disruption of membrane potential by pyrazinoic acid and acid pH. Inhibitors of membrane energetics increased the antituberculous activity of pyrazinamide. These findings shed new light on the mode of action of pyrazinamide and may help in the design of new drugs that shorten therapy.

Antitubercular Agents↗
PubMed2002

Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis.

STUDY OBJECTIVE: To determine population pharmacokinetic parameters of pyrazinamide after multiple oral doses given to children and adults with tuberculosis. DESIGN: Prospective, multiple-dose population pharmacokinetic study. SETTING: Five hospitals in the United States. PATIENTS: Sixty-seven adults and 23 children with active tuberculosis. INTERVENTION: The 90 patients received multiple oral doses of pyrazinamide as part of their treatment, based on the best clinical judgment of the attending physicians and in keeping with standard clinical practices at each institution. The patients also received other antituberculosis drugs empirically or based on in vitro susceptibility data. MEASUREMENTS AND MAIN RESULTS: Serum samples were collected over 12 hours after dosing and were assayed with a validated gas chromatography assay with mass selective detection. Concentration-time data were analyzed by using population methods. Pyrazinamide concentrations increased linearly with increasing oral doses (185-3550 mg). Median maximum serum concentration values were 41.0 microg/ml with daily dosing and 66.1 microg/ml with larger, twice-weekly dosing. Incomplete (18%) or delayed (30%) absorption was more common in children than in adults (1% for each). Pharmacokinetic parameters of pyrazinamide were independent of human immunodeficiency virus status and patient demographics, except for body weight. Population elimination half-life values in pediatric and adult patients were 3.5 and 6.0 hours, respectively. Median volume of distribution (L/kg) was 32% larger in children, and median clearance (L/hr/kg) was 106% larger in children, with a resultant median half-life 43% shorter in children. CONCLUSION: Pyrazinamide concentrations and most pharmacokinetic parameters were comparable to those previously published. Apparent half-life was somewhat shorter than that in previous reports. Compared with adults, absorption of pyrazinamide in children appeared more likely to be incomplete or delayed.

Adult↗
PubMed1990

Alteration in the levels of pyrazinamide in pleural fluid following simultaneous administration of prednisoline in patients of tubercular pleural effusion.

20 Patients of tuberculous pleural effusion were administered a combination of pyrazinamide (30 mg/kg) + isoniazid (300 mg) orally for 7 consecutive days and pyrazinamide was estimated by spectrophotometric method in serum and pleural fluid. Prednisolone was added to the above regimen for next 7 consecutive days and pyrazinamide was again estimated. The level of pyrazinamide in pleural fluid was 23.4 +/- 1.2 (micrograms/ml). Following addition of prednisolone the level increased (27.6 +/- 1.3) significantly (P less than 0.001). The serum pyrazinamide level was not influenced by simultaneous administration of prednisolone. The pleural fluid/serum pyrazinamide ratio was increased from 0.465 to 0.542 by the addition of prednisolone to therapeutic regimen.

Adolescent↗
PubMed1995

Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculous treatment including isoniazid.

Isoniazid and pyrazinamide are well-known hepatotoxic drugs, often used in combination. The aim of this study was to assess the prognostic influence of pyrazinamide on the outcome of fulminant or subfulminant liver failure caused by antituberculous therapy. Eighteen patients with fulminant or subfulminant liver failure due to antituberculous therapy were studied. Nine patients received isoniazid and rifampicin without pyrazinamide (group 1), and nine patients received isoniazid and rifampicin together with pyrazinamide (group 2). The severity of fulminant and subfulminant liver failure, as judged by the prevalence of coma and the lowest level of factor V, was similar in the two groups. Spontaneous survival was greater in group 1 (eight of nine) than in group 2 (two of nine) (P < .02). The authors conclude that pyrazinamide co-administration was associated with an increased mortality in patients with fulminant or subfulminant hepatitis occurring during antituberculous therapy. In these patients, pyrazinamide administration and an interval of more than 15 days between the onset of antituberculous treatment and jaundice, combined with grade III encephalopathy and factor V below 20%, predicted death without liver transplantation.

Adolescent↗
PubMed1998

[Eruption after the 1st dose of standard antitubercular chemotherapy. Thoughts on pyrazinamide].

UNLABELLED: We report 3 cases of rash after the first dose of antituberculosis polytherapy, thus raising questions concerning the procedures to be followed. CASE REPORT: Three patients developed a pruritic rash 1 hour after the first dose of isoniazide, rifampicine, pyrazinamide and ethambutol given simultaneously. The eruption did not recur after readministration of isoniazide and rifampicine successively. Pyrazinamide, which was readministered last (at the full dose in one case and at progressive doses in the two others), induced a recurrence in two of them. Pyrazinamide was definitively withdrawn in one patient with recurrence and slower pyrazinamide readministration allowed continuation of treatment in the other two patients. CONCLUSION: Since pyrazinamide appeared to be responsible for rash following the first administration of antituberculosis polytherapy, a protocol for readministration of the 4 drugs is suggested. If the responsibility of pyrazinamide is confirmed it should be readministered very slowly.

Aged↗