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Nature Communications Jun 2017Ethylene is an important phytohormone that promotes the ripening of fruits and senescence of flowers thereby reducing their shelf lives. Specific ethylene biosynthesis...
Ethylene is an important phytohormone that promotes the ripening of fruits and senescence of flowers thereby reducing their shelf lives. Specific ethylene biosynthesis inhibitors would help to decrease postharvest loss. Here, we identify pyrazinamide (PZA), a clinical drug used to treat tuberculosis, as an inhibitor of ethylene biosynthesis in Arabidopsis thaliana, using a chemical genetics approach. PZA is converted to pyrazinecarboxylic acid (POA) in plant cells, suppressing the activity of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO), the enzyme catalysing the final step of ethylene formation. The crystal structures of Arabidopsis ACO2 in complex with POA or 2-Picolinic Acid (2-PA), a POA-related compound, reveal that POA/2-PA bind at the active site of ACO, preventing the enzyme from interacting with its natural substrates. Our work suggests that PZA and its derivatives may be promising regulators of plant metabolism, in particular ethylene biosynthesis.
Topics: Amino Acid Oxidoreductases; Arabidopsis; Biosynthetic Pathways; Ethylenes; Flowers; Pyrazinamide
PubMed: 28604689
DOI: 10.1038/ncomms15758 -
Kekkaku : [Tuberculosis] Feb 1994To 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... (Clinical Trial)
Clinical Trial Review
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.
Topics: Clinical Trials as Topic; Female; Humans; Male; Pyrazinamide; Surveys and Questionnaires; Tuberculosis
PubMed: 8126986
DOI: No ID Found -
The Journal of Antimicrobial... Sep 2014To identify the pyrazinamide MIC above which standard combination therapy fails. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To identify the pyrazinamide MIC above which standard combination therapy fails.
METHODS
MICs of pyrazinamide were determined for Mycobacterium tuberculosis isolates, cultured from 58 patients in a previous randomized clinical trial in Cape Town, South Africa. The MICs were determined using BACTEC MGIT 960 for isolates that were collected before standard treatment with isoniazid, rifampicin, pyrazinamide and ethambutol commenced. Weekly sputum collections were subsequently made for 8 weeks in order to culture M. tuberculosis in Middlebrook broth medium. Classification and regression tree (CART) analysis was utilized to identify the pyrazinamide MIC predictive of sputum culture results at the end of pyrazinamide therapy. The machine learning-derived susceptibility breakpoints were then confirmed using standard association statistics that took into account confounders of 2 month sputum conversion.
RESULTS
The pyrazinamide MIC range was 12.5 to >100 mg/L for the isolates prior to therapy. The epidemiological 95% cut-off value was >100 mg/L. The 2 month sputum conversion rate in liquid cultures was 26% by stringent criteria and 48% by less stringent criteria. CART analysis identified an MIC breakpoint of 50 mg/L, above which patients had poor sputum conversion rates. The relative risk of poor sputum conversion was 1.5 (95% CI: 1.2-1.8) for an MIC >50 mg/L compared with an MIC ≤ 50 mg/L.
CONCLUSIONS
We propose a pyrazinamide susceptibility breakpoint of 50 mg/L for clinical decision making and for development of rapid susceptibility assays. This breakpoint is identical to that identified using computer-aided simulations of hollow fibre system output.
Topics: Adolescent; Adult; Antitubercular Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; South Africa; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult
PubMed: 24821594
DOI: 10.1093/jac/dku136 -
Revista Espanola de Quimioterapia :... Apr 2022
Topics: Antitubercular Agents; Exanthema; Humans; Isoniazid; Pyrazinamide
PubMed: 35229590
DOI: 10.37201/req/157.2021 -
International Journal of Pharmaceutics Apr 2020Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility...
Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility problems as the case of ritonavir has clearly demonstrated; however, polymorphs also provide opportunities to improve pharmaceutical formulations, in particular if the stable form is not very soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate the usefulness of metastable forms and their stabilization. However, despite the existence of a number of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditions between the polymorphs appear to be lacking. The main objectives of this paper are to establish the temperature and pressure equilibrium conditions between the so-called α and γ polymorphs of pyrazinamide, its liquid phase, and vapor phase and to determine the phase-change inequalities, such as enthalpies, entropies, and volume differences. The equilibrium temperature between α and γ was experimentally found at 392(1) K. Moreover, vapor pressures and solubilities of both phases have been determined, clearly indicating that form α is the more stable form at room temperature. High-pressure thermal analysis and the topological pressure-temperature phase diagram demonstrate that the γ form is stabilized by pressure and becomes stable at room temperature under a pressure of 260 MPa.
Topics: Crystallization; Drug Stability; Phase Transition; Pressure; Pyrazinamide; Ritonavir; Temperature; Thermodynamics
PubMed: 32199962
DOI: 10.1016/j.ijpharm.2020.119230 -
British Medical Journal Sep 1960
Topics: Humans; Hyperuricemia; Pyrazinamide; Uric Acid
PubMed: 14443204
DOI: 10.1136/bmj.2.5202.830 -
The Pediatric Infectious Disease Journal Mar 2011Pyrazinamide plasma concentrations were determined in 34 children (median age, 3.32 years) 1 month after commencing antituberculosis treatment. The median (interquartile...
Pyrazinamide plasma concentrations were determined in 34 children (median age, 3.32 years) 1 month after commencing antituberculosis treatment. The median (interquartile range) peak concentration was 30.7 (25.5, 35.0) mg/L after a median dose of 23 mg/kg. Peak concentrations < 20 mg/L were found in 5 children (15%) and such low concentrations were particularly likely after doses < 20 mg/kg.
Topics: Antitubercular Agents; Child; Child, Preschool; Female; Humans; Infant; Male; Plasma; Pyrazinamide; Tuberculosis
PubMed: 21416694
DOI: 10.1097/inf.0b013e3181fbefe1 -
European Journal of Pharmaceutics and... Aug 2015We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the...
We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the different components occurring during the spray drying process and to obtain homogeneous LPPs, spray drying parameters were modified to decrease the drying speed. As a result, good aerodynamic properties for lung delivery were obtained with a fine particle fraction (FPF) of 40.1±1.0%, an alveolar fraction (AF) of 29.6±3.1%, a mass median aerodynamic diameter (MMADaer) of 4.1±0.2μm and a geometric standard deviation (GSD) of 2.16±0.16. Plasma and epithelial lining fluid (ELF) concentrations of pyrazinamide were evaluated after intratracheal insufflation of PZA-LPPs (4.22mgkg(-1)) into rats and compared to intravenous administration (iv) of a pyrazinamide solution (5.82mgkg(-1)). The in vivo pharmacokinetic evaluation of PZA-LPPs in rats reveals that intratracheal insufflation of PZA-LPPs leads to a rapid absorption in plasma with an absolute bioavailability of 66%. This proves that PZA-LPPs dissolve fast upon deposition and that PZA crosses efficiently the lung barrier to reach the systemic circulation. PZA concentrations were 1.28-fold higher in ELF after intratracheal administration than after iv administration and the ratio of ELF concentrations over plasma concentrations was 2-fold greater. Although these improvements are moderate, lung delivery of PZA appears an interesting alternative to oral delivery of the molecule and should now be tested in an infected animal model to evaluate its efficacy against Mycobacterium tuberculosis.
Topics: Administration, Inhalation; Animals; Antitubercular Agents; Biological Availability; Drug Carriers; Drug Compounding; Injections, Intravenous; Lung; Male; Microscopy, Electron, Scanning; Particle Size; Porosity; Powders; Pyrazinamide; Rats, Sprague-Dawley; Surface Properties
PubMed: 26036447
DOI: 10.1016/j.ejpb.2015.05.021 -
Journal of Clinical Microbiology Jan 2022Pyrazinamide is an important component of both drug-susceptible and drug-resistant tuberculosis treatment regimens. Although approximately 50% of rifampin-resistant...
Pyrazinamide is an important component of both drug-susceptible and drug-resistant tuberculosis treatment regimens. Although approximately 50% of rifampin-resistant isolates are also resistant to pyrazinamide, pyrazinamide susceptibility testing is not routinely performed due to the challenging nature of the assay. We investigated the diagnostic accuracy of genotypic and phenotypic methods and explored the occurrence of pyrazinamide heteroresistance. We assessed pyrazinamide susceptibility among 358 individuals enrolled in the South African EXIT-RIF cohort using Sanger and targeted deep sequencing (TDS) of the gene, whole-genome sequencing (WGS), and phenotypic drug susceptibility testing. We calculated the diagnostic accuracy of the different methods and investigated the prevalence and clinical impact of heteroresistance. True pyrazinamide susceptibility status was assigned to each isolate using the Köser classification and expert rules. We observed 100% agreement across genotypic methods for detection of fixed mutations; only TDS confidently identified three isolates (0.8%) with minor variants. For the 355 (99.2%) isolates that could be assigned true pyrazinamide status with confidence, phenotypic DST had a sensitivity of 96.5% (95% confidence interval [CI], 93.8 to 99.3%) and specificity of 100% (95% CI, 100 to 100%), both Sanger sequencing and WGS had a sensitivity of 97.1% (95% CI, 94.6 to 99.6%) and specificity of 97.8% (95% CI, 95.7 to 99.9%), and TDS had sensitivity of 98.8% (95% CI, 97.2 to 100%) and specificity of 97.8% (95% CI, 95.7 to 99.9%). We demonstrate high sensitivity and specificity for pyrazinamide susceptibility testing among all assessed genotypic methods. The prevalence of pyrazinamide heteroresistance in Mycobacterium tuberculosis isolates was lower than that identified for other first-line drugs.
Topics: Amidohydrolases; Antitubercular Agents; Genomics; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Tuberculosis, Multidrug-Resistant
PubMed: 34757831
DOI: 10.1128/JCM.01907-21 -
Spectrochimica Acta. Part A, Molecular... Mar 2020Pyrazinamide and isoniazid, as two first-line anti-tuberculosis drugs, are investigated by terahertz time-domain spectroscopy (THz-TDS). Both pyrazinamide and isoniazid...
Pyrazinamide and isoniazid, as two first-line anti-tuberculosis drugs, are investigated by terahertz time-domain spectroscopy (THz-TDS). Both pyrazinamide and isoniazid have three absorption peaks, at 0.50, 0.71, 1.42 THz and 1.16, 1.46, 1.56 THz, respectively, which can be used as the basis for qualitative identification of these two drugs. In order to gain insight into the origin of the characteristic absorption peaks, density functional theory (DFT) based on single molecular, dimer, and crystalline structures of pyrazinamide and isoniazid are performed. The purpose of the calculation based on the single molecular structure is to understand the intramolecular interaction, while those based on the dimer and crystalline structures are to investigate the intermolecular interactions in PNZ and INZ. Comparing the theoretical results of the dimer and crystalline based structures reveals that the crystalline structure leads to vibrational spectra that are closer to the experimental values in terms of the number of absorption peaks and the positions of the absorption peaks. Vibrational mode assignments can be summarized as that the characteristic absorption peaks of pyrazinamide mainly come from intermolecular interaction, and the characteristic absorption peaks of isoniazid originate from both the intramolecular and intermolecular interactions. Our experimental and theoretical results indicate that the combination of THz-TDS with DFT is an effective approach for identification of molecules with pharmaceutical significance.
Topics: Crystallization; Density Functional Theory; Dimerization; Isoniazid; Molecular Conformation; Pyrazinamide; Quantum Theory; Terahertz Spectroscopy; Vibration
PubMed: 31761544
DOI: 10.1016/j.saa.2019.117591