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Journal of the American Academy of... May 2004
Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Liver; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 15097974
DOI: 10.1016/j.jaad.2003.10.673 -
Antimicrobial Agents and Chemotherapy Feb 1988
Topics: Animals; Cell Line; Macrophages; Mycobacterium tuberculosis; Pyrazinamide
PubMed: 3129990
DOI: 10.1128/AAC.32.2.287 -
Pharmaceutical Development and... 2016The aim of this study was to investigate the effect of adding L-leucine and using an ethanolic solvent on the physicochemical properties and aerodynamic behavior of nano...
OBJECTIVE
The aim of this study was to investigate the effect of adding L-leucine and using an ethanolic solvent on the physicochemical properties and aerodynamic behavior of nano spray-dried pyrazinamide (PZA)-L-leucine powders.
MATERIALS AND METHODS
A nano spray dryer was employed to prepare PZA-L-leucine powders. The physicochemical properties were evaluated using a scanning electron microscope (SEM), differential scanning calorimetry and X-ray diffraction. The Andersen cascade impactor was used to evaluate the in vitro aerosolization performance of the sprayed powders.
RESULTS AND DISCUSSION
The incorporation of L-leucine at 10% improved the percentage fine particle fraction (%FPF) in all ethanolic solvent formulations by up to nearly twofold (20.0-23.4%) compared to the normal spray-dried PZA of (8.8-13.0%). Changes in the particle density and morphology were also observed. The dense solid particles of PZA were completely converted to bulk hollow particles with a thin shell by increasing the L-leucine content up to 50%. Higher ethanol concentration resulted in larger dimensions of the hollow particle but did not directly affect the aerosolization performance. The co-spray dried PZA with 20% L-leucine in a 10% ethanol feed solvent gave the best aerosolization performance (FPF = 33.0%).
CONCLUSIONS
The co-spray dried PZA with a suitable L-leucine content using a nano spray drying technique could be applied to formulate the PZA DPI.
Topics: Aerosols; Chemistry, Pharmaceutical; Dry Powder Inhalers; Feasibility Studies; Leucine; Nanoparticles; Particle Size; Powders; Pyrazinamide; X-Ray Diffraction
PubMed: 25331092
DOI: 10.3109/10837450.2014.971373 -
European Journal of Clinical... 1989The pharmacokinetics of PZA during haemodialysis were determined in 6 patients with chronic renal impairment after a single oral dose of 25.7 (1.9) mg.kg-1. The dialysis...
The pharmacokinetics of PZA during haemodialysis were determined in 6 patients with chronic renal impairment after a single oral dose of 25.7 (1.9) mg.kg-1. The dialysis clearance of PZA and of its metabolites were: pyrazinamide 132 ml.min-1; pyrazinoic acid 121 ml.min-1; 5-hydroxy-pyrazinamide 107 ml.min-1; 5-hydroxy-pyrazinoic acid 118 ml.min-1. The average amount extracted during a dialysis session of 4.1 h was 926 mg after an oral dose of 1700 mg. The high dialysability shows that PZA can properly be administered at the end of each dialysis session in the usual dose of 25 to 30 mg.kg-1.
Topics: Adult; Biotransformation; Chromatography, High Pressure Liquid; Female; Humans; Male; Pyrazinamide; Renal Dialysis; Uremia
PubMed: 2612545
DOI: 10.1007/BF00679791 -
Antimicrobial Agents and Chemotherapy Dec 2014Pyrazinamide (PZA) is a first-line tuberculosis drug that inhibits the growth of Mycobacterium tuberculosis via an as yet undefined mechanism. An M. tuberculosis...
Pyrazinamide (PZA) is a first-line tuberculosis drug that inhibits the growth of Mycobacterium tuberculosis via an as yet undefined mechanism. An M. tuberculosis laboratory strain that was auxotrophic for pantothenate was found to be insensitive to PZA and to the active form, pyrazinoic acid (POA). To determine whether this phenotype was strain or condition specific, the effect of pantothenate supplementation on PZA activity was assessed using prototrophic strains of M. tuberculosis. It was found that pantothenate and other β-alanine-containing metabolites abolished PZA and POA susceptibility, suggesting that POA might selectively target pantothenate synthesis. However, when the pantothenate-auxotrophic strain was cultivated using a subantagonistic concentration of pantetheine in lieu of pantothenate, susceptibility to PZA and POA was restored. In addition, we found that β-alanine could not antagonize PZA and POA activity against the pantothenate-auxotrophic strain, indicating that the antagonism is specific to pantothenate. Moreover, pantothenate-mediated antagonism was observed for structurally related compounds, including n-propyl pyrazinoate, 5-chloropyrazinamide, and nicotinamide, but not for nicotinic acid or isoniazid. Taken together, these data demonstrate that while pantothenate can interfere with the action of PZA, pantothenate synthesis is not directly targeted by PZA. Our findings suggest that targeting of pantothenate synthesis has the potential to enhance PZA efficacy and possibly to restore PZA susceptibility in isolates with panD-linked resistance.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Niacinamide; Pantetheine; Pantothenic Acid; Pyrazinamide; beta-Alanine
PubMed: 25246400
DOI: 10.1128/AAC.04028-14 -
Zhonghua Jie He He Hu Xi Za Zhi =... Mar 2012
Review
Topics: Antitubercular Agents; Microbiological Techniques; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 22781157
DOI: No ID Found -
The Pediatric Infectious Disease Journal Aug 1997This prospective study was performed to evaluate the tolerance of pyrazinamide in short course chemotherapy in children.
BACKGROUND
This prospective study was performed to evaluate the tolerance of pyrazinamide in short course chemotherapy in children.
METHODS
A total of 114 children ages 6 months to 15 years (4.5 +/- 3.4 years) with diagnosed pulmonary tuberculosis from 1985 to 1995 entered the trial. A 2-month regimen of isoniazid, rifampin and pyrazinamide, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to all children. Clinical adverse effects specifically investigated were gastrointestinal disturbances, rash, signs of hepatotoxicity and arthralgias. Laboratory toxicity data (number of leukocytes, erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and serum uric acid) were collected before treatment and 1, 3 and 5 months after the beginning of chemotherapy.
RESULTS
Clinical adverse effects were mild in all cases. Three children (2.6%) had fever and 5 (4.4%) had gastrointestinal disturbances. Aspartate aminotransferase and alanine aminotransferase mean values showed no differences along time and no patients had clinical signs of hepatotoxicity. Only 11 children (19.6%) showed a slight increase in alanine aminotransferase (< 194 units/l). Serum uric acid increased in 92.2% of the children compared with pretreatment values. This increase remained within the normal range in all but 9.8% of patients. There was a significant increase in uric acid mean concentrations after 1 month of therapy (from 3.7 +/- 0.7 mg/dl to 5.7 +/- 1.6 mg/dl, P < 0.05), which fell again (4.0 +/- 1.1) 1 month after pyrazinamide was stopped. There were no signs of gout or arthralgias. In no case was the treatment interrupted.
CONCLUSION
The addition of pyrazinamide in chemotherapy for pulmonary tuberculosis in children was found to be safe. The slight increase in uric acid concentration during its administration had no recognized adverse consequences.
Topics: Adolescent; Antitubercular Agents; Blood Sedimentation; Child; Child, Preschool; Drug Tolerance; Female; Humans; Infant; Male; Prospective Studies; Pyrazinamide; Tuberculosis, Pulmonary; Uric Acid
PubMed: 9271037
DOI: 10.1097/00006454-199708000-00006 -
Kekkaku : [Tuberculosis] Mar 2015In the 1950s, high doses (40-70 mg/kg/day) of pyrazinamide were reported to cause drug-induced liver injury (DILI). It remains unclear whether adding pyrazinamide (Z) at...
BACKGROUND
In the 1950s, high doses (40-70 mg/kg/day) of pyrazinamide were reported to cause drug-induced liver injury (DILI). It remains unclear whether adding pyrazinamide (Z) at the currently accepted low dose (20-25 mg/kg/day) to a regimen of isoniazid (H), rifampicin (R), and ethambutol (E) increases the risk of DILI.
METHOD
We reviewed adult patients admitted for smear-positive tuberculosis who were treated with a daily HRE or HRZE regimen. A Cox model was used to analyze the impact of pyrazinamide on the occurrence of DILI.
RESULTS
We reviewed 195 patients (123 men [63%], 72 women [37%], average age 65 ± 19 years, 65 HRE patients [33%], 130 HRZE patients [67%]). The incidence of DILI in the first two months was 15% (29/195). The HRZE regimen was not associated with DILI (hazard ratio 0.55, P = 0.263).
CONCLUSION
Addition of low-dose (20-25 mg/kg/day) pyrazinamide to the HRE regimen does not appeared to be associated with increased DILI incidence during the first two months of treatment.
Topics: Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Pyrazinamide
PubMed: 26477109
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Jul 2010Antimicrobial pharmacokinetic-pharmacodynamic studies suggest that pyrazinamide doses higher than those currently recommended may be more efficacious. However, high... (Meta-Analysis)
Meta-Analysis
Antimicrobial pharmacokinetic-pharmacodynamic studies suggest that pyrazinamide doses higher than those currently recommended may be more efficacious. However, high pyrazinamide doses are believed to be hepatotoxic. Searches for clinical trials in MEDLINE, EBSCOHOST, and the Cochrane Controlled Trial Register were made. Studies that employed pyrazinamide dose scheduling and pharmacokinetic analysis design were examined. Population pharmacokinetic modeling methods were utilized to identify parameters associated with toxicity. At an equivalent area under the concentration-time curve, the time that concentration persisted above some thresholds was associated with overall adverse events (P = 0.032), arthralgia (P = 0.089), and an elevated serum aspartate aminotransferase level at 3 months (P = 0.067). Next, a meta-analysis was utilized to compare rates of adverse events (i) between different pyrazinamide doses, (ii) between different dosing schedules, and (iii) between pyrazinamide-containing and non-pyrazinamide-containing antituberculosis regimens. The 29 studies selected were heterogeneous (Cochrane Q statistic P value of <0.001; I(2) of >95%). For the once-a-day dosing schedule, arthralgia was dose dependent (r(2) = 0.996). However, arthralgia was less common with intermittent dosing, consistent with the time concentration persisted above the threshold. Arthralgia was generally clinically inconsequential. The frequencies of hepatotoxicity were 0.057 (95% confidence interval [CI], 0.021 to 0.141) for pyrazinamide monotherapy, 0.044 (CI, 0.033 to 0.059) for pyrazinamide-containing combination regimens, and 0.040 (CI, 0.023 to 0.040) for non-pyrazinamide-containing combination regimens. The frequencies of hepatotoxicity were 0.042 (CI, 0.026 to 0.067) for 30 mg/kg of body weight, 0.055 (CI, 0.031 to 0.094) at 40 mg/kg, and 0.098 (CI, 0.047 to 0.193) at 60 mg/kg of pyrazinamide. Thus, high-dose pyrazinamide did not significantly increase hepatotoxicity. This suggests that a considerable portion of hepatotoxicity rates may be idiosyncratic.
Topics: Antitubercular Agents; Controlled Clinical Trials as Topic; Drug Administration Schedule; Humans; Liver; Pyrazinamide
PubMed: 20439617
DOI: 10.1128/AAC.01567-09 -
The Pediatric Infectious Disease Journal Nov 1991The stability of monosuspensions, cosuspensions and multisuspensions of isoniazid (INH), pyrazinamide (PZA) and rifampin (RIF) has been evaluated by high pressure liquid...
The stability of monosuspensions, cosuspensions and multisuspensions of isoniazid (INH), pyrazinamide (PZA) and rifampin (RIF) has been evaluated by high pressure liquid chromatography over a period of 28 days both with and without the addition of vitamin C (20 micrograms/ml) and at ambient temperatures of 4 degrees C, 24 degrees C and 40 degrees C. At the end of 28 days greater than 90% of initial concentrations of INH, PZA and RIF in monosuspensions remained unchanged irrespective of ambient temperature as was the case with INH and PZA in cosuspension. The addition of RIF to either INH or PZA in cosuspension or together in multisuspension led to a marked fall in the concentration of one or more of the agents, an effect that was accentuated by the addition of vitamin C. In the case of a multisuspension of INH + RIF + PZA with vitamin C added, 41.7% (4 degrees C), 24.1% (24 degrees C) and 20.3% (40 degrees C) of initial INH concentrations and 1.9% (4 degrees C), 1.3% (24 degrees C) and 0.0% (40 degrees C) of initial RIF concentrations remained detectable after 28 days. The addition of vitamin C to monosuspensions of INH and PZA led to a marked decline in the amount of drug detectable and only in the case of RIF was greater than 90% of initial concentrations of the drug detectable after 28 days. The dispensing of cosuspensions or multisuspensions of antituberculosis agents containing RIF is inadvisable as is the addition of vitamin C in any form.
Topics: Ascorbic Acid; Child; Chromatography, High Pressure Liquid; Drug Stability; Humans; Isoniazid; Pyrazinamide; Rifampin; Suspensions; Temperature; Tuberculosis
PubMed: 1749695
DOI: 10.1097/00006454-199111000-00007