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Bioorganic & Medicinal Chemistry Letters Aug 2011Pyrazinamide (PZA), an essential component of short-course anti-tuberculosis chemotherapy, was shown by Saturation Transfer Difference (STD) NMR methods to act as a...
Pyrazinamide (PZA), an essential component of short-course anti-tuberculosis chemotherapy, was shown by Saturation Transfer Difference (STD) NMR methods to act as a competitive inhibitor of NADPH binding to purified Mycobacterium tuberculosis fatty acid synthase I (FAS I). Both PZA and pyrazinoic acid (POA) reversibly bind to FAS I but at different binding sites. The competitive binding of PZA and NADPH suggests potential FAS I binding sites. POA was not previously known to have any specific binding interactions. The STD NMR of NADPH bound to the mycobacterial FAS I was consistent with the orientation reported in published single crystal X-ray diffraction studies of fungal FAS I. Overall the differences in binding between PZA and POA are consistent with previous recognition of the importance of intracellular accumulation of POA for anti-mycobacterial activity.
Topics: Bacterial Proteins; Binding Sites; Binding, Competitive; Crystallography, X-Ray; Enzyme Inhibitors; Fatty Acid Synthases; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; NADP; Pyrazinamide; Stereoisomerism; Structure-Activity Relationship
PubMed: 21775138
DOI: 10.1016/j.bmcl.2011.06.055 -
Fundamental & Clinical Pharmacology Oct 2009Pyrazinamide can have adverse effects such as hepatic toxicity, hyperuricemia or digestive disorders. In rare cases, alterations in taste and smell function have been...
Pyrazinamide can have adverse effects such as hepatic toxicity, hyperuricemia or digestive disorders. In rare cases, alterations in taste and smell function have been reported for pyrazinamide when combined with other drugs. We report a case of reversible olfactory disorder related to pyrazinamide in a woman, with a positive rechallenge. The patient presented every day a sensation of smelling something burning 15 min after drug intake. Dysosmia disappeared completely after pyrazinamide withdrawal and recurred after its rechallenge. The case was reported to the Tunisian Centre of Pharmacovigilance.
Topics: Antitubercular Agents; Female; Humans; Middle Aged; Olfaction Disorders; Pyrazinamide; Recurrence
PubMed: 19674115
DOI: 10.1111/j.1472-8206.2009.00736.x -
Antimicrobial Agents and Chemotherapy Jul 2022Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve...
Pyrazinamide is one of the first-line antituberculosis drugs. The efficacy of pyrazinamide is associated with the ratio of 24-h area under the concentration-time curve (AUC) to MIC. The objective of this study was to develop and validate a limited sampling strategy (LSS) based on a population pharmacokinetic (popPK) model to predict AUC. A popPK model was developed using an iterative two-stage Bayesian procedure and was externally validated. Using data from 20 treatment-naive adult tuberculosis (TB) patients, a one compartment model with transit absorption and first-order elimination best described pyrazinamide pharmacokinetics and fed state was the only significant covariate for absorption rate constant (k). External validation, using data from 26 TB patients, showed that the popPK model predicted AUC with a slight underestimation of 2.1%. LSS were calculated using Monte Carlo simulation ( = 10,000). External validation showed LSS with time points 0 h, 2 h, and 6 h performed best with RMSE of 9.90% and bias of 0.06%. Food slowed absorption of pyrazinamide, but did not affect bioavailability, which may be advantageous in case of nausea or vomiting in which food can be used to diminish these effects. In this study, we successfully developed and validated a popPK model and LSS, using 0 h, 2 h, and 6 h postdose samples, that could be used to perform therapeutic drug monitoring (TDM) of pyrazinamide in TB patients.
Topics: Adult; Antitubercular Agents; Bayes Theorem; Drug Monitoring; Humans; Pyrazinamide; Tuberculosis
PubMed: 35727060
DOI: 10.1128/aac.00003-22 -
International Journal of Infectious... Mar 2018Pyrazinamide is a key drug in the first-line treatment regimen for tuberculosis, with a potent sterilizing effect. Although low pyrazinamide peak serum concentrations...
OBJECTIVES
Pyrazinamide is a key drug in the first-line treatment regimen for tuberculosis, with a potent sterilizing effect. Although low pyrazinamide peak serum concentrations (C) are associated with poor treatment outcomes, many resource-constrained settings do not have sufficient laboratory capacity to support therapeutic drug monitoring (TDM). The objective of this study was to determine whether a colorimetric test of urine can identify tuberculosis patients with adequate pyrazinamide exposures, as defined by serum C above a target threshold.
METHODS
In the derivation study of healthy volunteers, three dose sizes of pyrazinamide were evaluated, and intensive pharmacokinetic blood sampling was performed over an 8-h period, with a timed urine void at 4h post-dosing. Pyrazinamide in urine was isolated by spin column centrifugation with an exchange resin, followed by colorimetric analysis; the absorbance peak at 495nm was measured. The urine assay was then evaluated in a study of 39 HIV/tuberculosis patients in Botswana enrolled in an intensive pharmacokinetic study. Receiver operating characteristics (ROC) curves were used to measure diagnostic accuracy. The guideline-recommended pyrazinamide serum C target of 35mg/l was evaluated in the primary analysis; this target was found to be predictive of favorable outcomes in a clinical study. Following this, a higher serum C target of 58mg/l was evaluated in the secondary analysis.
RESULTS
At the optimal cut-off identified in the derivation sample, the urine colorimetric assay was 97% sensitive and 50% specific to identify 35 of 39 HIV/tuberculosis patients with pharmacokinetic target attainment, with an area under the ROC curve of 0.81 (95% confidence interval 0.60-0.97). Diagnostic accuracy was lower at the 58mg/l serum C target, with an area under the ROC curve of 0.68 (95% confidence interval 0.48-0.84). Men were less likely than women to attain either serum pharmacokinetic target.
CONCLUSIONS
The urine colorimetric assay was sensitive but not specific for the detection of adequate pyrazinamide pharmacokinetic exposures among HIV/tuberculosis patients in a high-burden setting.
Topics: Adult; Botswana; Colorimetry; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Monitoring; Female; HIV Infections; Humans; Male; Non-Randomized Controlled Trials as Topic; Pyrazinamide; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; Tuberculosis; Young Adult
PubMed: 29253711
DOI: 10.1016/j.ijid.2017.12.017 -
Lancet (London, England) Feb 1982
Topics: Humans; Liver; Pyrazinamide; Tuberculosis
PubMed: 6120379
DOI: 10.1016/s0140-6736(82)91428-3 -
The Indian Journal of Medical Research Nov 2008As the dosages recommended for children are based on weight, empirical and derived by extrapolation from the studies in adults, pyrazinamide (PZA) pharmacokinetics in...
BACKGROUND & OBJECTIVE
As the dosages recommended for children are based on weight, empirical and derived by extrapolation from the studies in adults, pyrazinamide (PZA) pharmacokinetics in children is likely to be different from adults. Limited information exists regarding the pharmacokinetics of PZA in paediatric patients of primary progressive disease (PPD) of lungs. This study aims to look at the changed pharmacokinetics of pyrazinamide in children with PPD of lungs by using reverse phase high-pressure liquid chromatography (HPLC).
METHODS
A total of 40 children (age range 5 to 13 yr) of PPD were receiving pyrazinamide (30 mg/kg/day). On 11(th) day of short course antitubercular therapy, blood samples (two per day from 11(th) to 13(th) day) were collected at 0 h (pre-dose), 1, 2, 3, 4, 8 and 24 h after pyrazinamide administration and concentration of pyrazinamide was estimated by reverse phase high-pressure liquid chromatography. The mean peak serum concentration, the time to reach mean peak serum concentration, total clearance, concentration at time zero, volume of distribution, terminal elimination rate constant, elimination half-life, total area under serum concentration-time curve were measured.
RESULTS
The mean serum concentrations of pyrazinamide were found higher than its minimum inhibitory concentration (20 microg/ml) required to inhibit the growth of tubercle bacilli from 1 to 8 h continuously.
INTERPRETATION & CONCLUSION
Our results suggest that a dose of 30 mg/kg/day achieves much higher concentration of pyrazinamide as compared to its minimum inhibitory concentration (20 microg/ml). Therefore, lowering of pyrazinamide dosage is suggested in children for better patient compliance along with reduction in cost, side-effects and toxicity without compromising its efficacy.
Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Female; Humans; Male; Microbial Sensitivity Tests; Pyrazinamide; Tuberculosis, Pulmonary
PubMed: 19179681
DOI: No ID Found -
Praxis Und Klinik Der Pneumologie Dec 1981
Review
Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rats; Tuberculosis, Pulmonary
PubMed: 6808484
DOI: No ID Found -
Molecules (Basel, Switzerland) Jan 2019Vibrational modes of pyrazinamide (PZA), 3-hydroxybenzoic acid (3-hBA), and their cocrystal were characterized using terahertz time-domain (THz-TDS) and Raman...
Vibrational modes of pyrazinamide (PZA), 3-hydroxybenzoic acid (3-hBA), and their cocrystal were characterized using terahertz time-domain (THz-TDS) and Raman vibrational spectroscopic techniques. In experimental THz spectra, the cocrystal has characteristic absorption bands at around 0.81, 1.47, and 1.61 THz, respectively, meanwhile the raw materials are absolutely different in this region. Raman spectra also show similar results about differences between the cocrystal and corresponding starting parent materials. Density functional theory (DFT) was used to simulate both optimized structures and vibrational modes of the cocrystal formed between PZA and 3-hBA. The vibrational modes of such cocrystal are assigned through comparing the simulation DFT frequency results with experimental vibrational spectra. The calculation of the theoretical THz spectrum shows that the hydrogen bonding effect established between H11⁻N12⁻H13 and the carboxyl group -COOH makes contributions to the formation of absorption peaks in 0.49, 0.62, 0.83, and 1.61 THz, which agrees pretty well with experimental results. The theoretical Raman result also matches well with experimental observations. The results provide a fundamental benchmark for the study of pharmaceutical cocrystal formation and also inter-molecular hydrogen bonding interactions between active pharmaceutical ingredients and various cocrystal coformers based on Raman and terahertz vibrational spectroscopic techniques combined with theoretical simulations.
Topics: Crystallization; Hydrogen Bonding; Hydroxybenzoates; Models, Molecular; Molecular Structure; Pyrazinamide; Spectrum Analysis, Raman; Terahertz Spectroscopy
PubMed: 30704029
DOI: 10.3390/molecules24030488 -
Progress in Biophysics and Molecular... May 2020Drug induced degradation of a target protein is a novel concept in drug discovery. Traditionally drugs modulate activity, as opposed to abundance, of their targets.... (Review)
Review
Drug induced degradation of a target protein is a novel concept in drug discovery. Traditionally drugs modulate activity, as opposed to abundance, of their targets. Degradation inducing ligands act catalytically. Thus, one advantage of target degradation over the classical on-target mechanism is that lower drug concentration may be sufficient to cause the desired cellular effects. The first promoters of target degradation were discovered unintentionally: it turned out that some drugs 'accidently' promote degradation of their target by the cellular proteolytic machinery. Elegant methods were developed to target specific proteins of interest for degradation, thus enabling the rational discovery of degradation inducers. The application of targeted degradation has so far been limited to human cells. Recently, we discovered that an antibacterial drug, the anti-tuberculosis antibiotic pyrazinamide, functions as a promotor of degradation of its bacterial target. Increasing antimicrobial resistance makes the discovery of novel antibiotics more urgent than ever. Can rational target degradation be applied for the discovery of anti-bacterials? Here, we first discuss briefly some historic examples and then recent approaches in rational target degradation for human diseases. Then, we describe how the first anti-bacterial target degradation promoter pyrazinamide triggers removal of its target. Efforts are under way to exploit this specific mechanistic knowledge for the discovery of next generation pyrazinamide. We end with the big - and open - question whether targeted protein degradation as an approach to anti-bacterial drug discovery can be generalized, similar to what has been achieved in the area of drug discovery for human diseases.
Topics: Antibiotics, Antitubercular; Bacterial Proteins; Drug Discovery; Drug Resistance, Bacterial; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Targeted Therapy; Protein Binding; Proteolysis; Pyrazinamide; Tuberculosis
PubMed: 31738980
DOI: 10.1016/j.pbiomolbio.2019.11.005 -
Clinical Pharmacology in Drug... Apr 2022A single-dose, open-label, randomized-sequence, 2×2 crossover study was conducted in healthy Chinese adults, after fasting and postprandial, to evaluate the... (Randomized Controlled Trial)
Randomized Controlled Trial
Bioequivalence and Pharmacokinetic Evaluation of 2 Pyrazinamide Formulations in Healthy Chinese Adults: A Single-Dose, Open-Label, Randomized-Sequence, 2×2 Crossover Study.
A single-dose, open-label, randomized-sequence, 2×2 crossover study was conducted in healthy Chinese adults, after fasting and postprandial, to evaluate the bioequivalence of 2 pyrazinamide (PZA) formulations. Fasting and postprandial tests were conducted in 24 cases. Test-reference and reference-test were randomly divided into 2 sequence groups, with 12 cases in each group. The concentration of PZA in plasma was determined after 0.5 g single oral PZA test and reference formulations by the high-performance liquid chromatography-tandem mass spectrometry method. In the fasting group, the 90% confidence intervals (CIs) of the 2 formulations maximum plasma concentration (C ), area under the plasma concentration-time curve (AUC) from time 0 to last detectable plasma concentration, and AUC from time 0 to infinity after logarithmic conversion were 104.8% to 121.9%, 97.7% to 101.6%, and 97.7% to 101.6%, respectively. In the postprandial group, the 90%CIs of the 2 formulations' C , AUC from time 0 to last detectable plasma concentration, and AUC from time 0 to infinity after logarithmic conversion were 86.4% to 100.2%, 96% to 102%, 95.8% to 102.3%, respectively. The 90%CIs of the test/reference C ratio and AUC ratio were within the acceptable range of 80.00% to 125.00% for bioequivalence under both fasting and postprandial conditions. No serious adverse events occurred during treatment with the test formulation or the reference formulation.
Topics: Adult; China; Cross-Over Studies; Humans; Pyrazinamide; Tablets; Tandem Mass Spectrometry; Therapeutic Equivalency
PubMed: 34784108
DOI: 10.1002/cpdd.1035