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Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist.

Objective To compare the expression levels of pncA gene in pyrazinamide （PZA）-resistant and multidrug-resistant Mycobacterium tuberculosis before and after PZA drug stimulation， and to explore the relationship between PZA-resistant Mycobacterium tuberculosis and pncA gene expression. Methods PZA-resistant and multidrug-resistant Mycobacterium tuberculosis was cultured， and the minimal inhibitory concentration （MIC） of rifampicin and PZA was detected. The strains were cultured in medium containing 0 and 50 μg/mL PZA， and the expression level of pncA was detected by real-time fluorescence quantitative PCR. Results The MIC of PZA of 21 strains of Mycobacterium tuberculosis was ≥ 1 600 μg/mL，400-800 μg/mL for 12 strains， and 100-200 μg/mL in 5 strains，and their corresponding PZA resistance levels were defined as high，medium and low，respectively. The median MIC of rifampicin was 128， 128 and 64μg/mL， respectively. Chi-square test showed that there was no significant difference between any two groups （all P > 0.05）. According to the relative quantitative 2-ΔΔCt method， the expression levels of pncA in the high，medium and low levels of PZA drug-resistant Mycobacterium tuberculosis was 0.904（0.202， 2.653）， 1.157（0.658， 1.511） and 1.147（0.372， 1.347）， and 1.544（0.611， 3.191）， 0.846（0.421， 1.237） and 0.726 （0.225， 3.017） in the 50 μg/mL treatment group，respectively. There was no significant difference in pncA gene expression between the control and PZA drug-containing culture groups（P > 0.05）. Conclusion No significant changes are observed in the expression levels of pncA in multidrug-resistant and PZA-resistant Mycobacterium tuberculosis before and after PZA drug stimulation.

Sequential C−H functionalization of molecules containing multiple C−H bonds can efficiently lead to structural diversity. Herein we present the first chelation‐assisted sequential α‐/β‐C−H functionalization of E‐styrenes with simple alkenes and alkynes in excellent regio‐ and stereo‐selectivity. The process involves α C−H functionalization by six‐membered exo‐cyclopalladation to result in tri‐ and tetrasubstituted 1,3‐dienes and β C−H functionalization through seven‐membered endo‐cyclopalladation to produce tetra‐ and pentasubstituted 1,3,5‐trienes in up to 97 % yield with up to >99/1 E/Z selectivity, both enabled by the chelation assistance of pyrazinamide. The protocol is demonstrated to be widely applicable, tolerant to a wide range of functional groups and bioactive fragments, and suitable for gram‐scale synthesis as well as one‐pot and two step preparation of trienes. Mechanistic experiments and density functional theory (DFT) calculations were performed to elucidate the selectivity and reactivity. [ABSTRACT FROM AUTHOR]

Equilibrium solubility of antitubercular agent pyrazinamide in mixed solvents is scarce in the literature. Thus, the mole fraction solubility of this drug in aqueous-cosolvent mixtures of 1,4-dioxane or ethanol has been determined at 298.15 K by means of flask shake and UV–Vis analysis. Solubilities were adequately correlated with the modified Nearly Ideal Binary Solvent/Redlich–Kister model. Moreover, some expressions for the local mole fraction of cosolvents and water around the pyrazinamide molecules in solution were derived on the basis of the inverse Kirkwood Buff integrals. Pyrazinamide is preferentially solvated by water in water-rich mixtures and cosolvent-rich mixtures, but preferentially solvated by cosolvent in mixtures with intermediate compositions. [ABSTRACT FROM AUTHOR]

Background and Objectives Pyrazinamide is one of the effective drugs for treating tuberculosis. Inclusion of this drug in the treatment regimen shortens the duration of tuberculosis treatment. The mutation in pncA gene causes loss of pyrazinamidase activity, the most important resistance mechanism in Mycobacterium tuberculosis isolates. Therefore, the purpose of this study is to investigate the phenotypic and genotypic resistance to pyrazinamide antibiotic in multidrug-resistant (MDR) Mycobacterium tuberculosis isolates in Khuzestan province between 2017 and 2022. Subjects and Methods This study was conducted on 40 isolates of Mycobacterium tuberculosis in Ahvaz TB Regional Laboratory. Drug sensitivity of the isolates was determined by the relative method in the antibiotic pyrazinamide in the isolates. Then, the frequency of pncA gene mutations related to pyrazinamide resistance in MDR isolates was determined using sequencing. Results According to the results of the drug sensitivity to rifampin and isoniazid antibiotics, there were 25 isolates, of which 16 strains were resistant to two drugs, namely isoniazid and rifampin (MDR-TB), and 9 were single-drug resistant isolates (8 isolates resistant to rifampin and 1 isolate resistant to Isoniazid). Of the 17 samples that had the pncA gene and were resistant to pyrazinamide, 13 had mutations in the pncA gene while 4 did not have any mutations. The most common mutation was a non-synonymous mutation in which the amino acid Val had changed to Phe. Conclusion According to the results of this study, there is a high frequency of resistance to pyrazinamide in MDR strains. Also, there is a high percentage of single-resistance mutations in the pncA gene, while there is lower prevalence of mutations in the panD and rpsA genes, which provide quick and accurate information about the sensitivity to pyrazinamide for MDR-TB and mono-resistant isolates. Therefore, the best method for detecting resistance to pyrazinamide is sequencing and whole pncA DNA sequence to confirm pyrazinamide resistance instead of the usual methods covering mutated hotspots. [ABSTRACT FROM AUTHOR]

Tuberculosis treatment with the first-line agents becomes ineffective due to multidrug resistance. Therefore, the importance of the second-line drugs, including p-amino-salicylic acid, is steadily increasing. The parenteral administration of p-aminosalicylic acid in the form of a sodium salt is compromised due to its partial decomposition by gastric juice and liver. The inhalation delivery, which provides rapid administration of both topical and systemic drugs, is a promising alternative approach. At the same time, creating an amorphous form of the active pharmaceutical ingredient by forming solid dispersions makes it possible to further increase the rate of its dissolution. In the present work, microspherical particles of solid dispersions of p-aminosalicylic acid with polyvinylpyrrolidone of various molecular weights were prepared. For all formulations, physicochemical characteristics and dissolution profiles were obtained. The results of this study enable development of a technique for creating microspherical particles of solid dispersions of drugs suitable for inhalation administration. [ABSTRACT FROM AUTHOR]

Novel 8-Benzyloxy-5-[2-(substituted-phenyl)-thiazol-4-yl]-1H-quinolin-2-one derivatives are synthesized by the cyclocondensation of substituted thiobenzamide and in-situ generated 8-benzyloxy-5-(2-bromo-acetyl)-1H-quinolin-2-one in the ethanol using simple one-pot multicomponent protocol under catalyst-free reaction conditions. All the products were screened for anti-tuberculosis (TB) activity against Mycobacterium tuberculosis H37Rv stains using L. J. medium conventional method and Compound 4h show good and Compound 4a, 4c, 4e, 4g, 4i, and 4j are also showing significant activity against M. tuberculosis. [ABSTRACT FROM AUTHOR]

Preclinical evidence is needed to assess drug-metabolite behaviour in compromised liver function for developing the best antitubercular treatment (ATT) re-introduction regimen in drug-induced liver injury (DILI). The pharmacokinetic behavior of rifampicin (RMP) and its active metabolite des-acetyl-rifampicin (DARP) in DILI's presence is unknown. To study the pharmacokinetic behavior of RMP and DARP in the presence of carbon tetrachloride (CCl4) plus ATT-DILI in rats. Thirty rats used in the experiment were divided equally into six groups. We administered a single 0.5 mL/kg CCl4 intraperitoneal injection in all rats. Groups II, III, IV, and V were started on daily oral RMP alone, RMP plus isoniazid (INH), RMP plus pyrazinamide (PZA), and the three drugs INH, RMP, and PZA together, respectively, for 21-days subsequently. Pharmacokinetic (PK) sampling was performed at 0, 0.5, 1, 3, 6, 12, and 24 h post-dosing on day 20. We monitored LFT at baseline on days-1, 7, and 21 and sacrificed the rats on the last day of the experiment. ATT treatment sustained the CCl4-induced liver injury changes. A significant rise in mean total bilirubin levels was observed in groups administered rifampicin. The triple drug combination group demonstrated 1.43- and 1.84-times higher area-under-the-curve values of RMP (234.56±30.66 vs. 163.55±36.14 µg h/mL) and DARP (16.15±4.50 vs. 8.75±2.79 µg h/mL) compared to RMP alone group. Histological and oxidative stress changes supported underlying liver injury and PK alterations. RMP metabolism inhibition by PZA, more than isoniazid, was well preserved in the presence of underlying liver injury. [ABSTRACT FROM AUTHOR]

In the present study, an LC-MS/MS method allowing to quantify pretomanid and pyrazinamide simultaneously in rat plasma was developed. Chromatographic separation was achieved on an Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 μm; Agilent, USA) and maintained at 30 °C. Multiple reaction monitoring (MRM) using positive-ion ESI mode to monitor ion transitions of m / z 360.1 → m / z 175.1 for pretomanid, m / z 124.1 → m / z 81.0 for pyrazinamide, m / z 172.1 → m / z 128.1 for metronidazole (IS). The calibration curves showed good linear relationships over the concentration range of 50–7,500 ng mL−1 for pretomanid and 500–75,000 ng mL−1 for pyrazinamide. The precision and accuracy were below 15% and within ±15% of the nominal concentrations, respectively. The selectivity, recovery and matrix effect of this method were all within acceptable limits of bioanalytics. The method was applied to the analysis of plasma samples from pharmacokinetic studies in rats. The results show that the main pharmacokinetic parameters of pyrazinamide, namely, T max, t 1/2, and AUC(0–t), decreased in the combined group than in the alone group. [ABSTRACT FROM AUTHOR]

–Several natural products extracted from trees exhibit significant anti-cancer activity. However, the efficacy of these products varies depending on the type of cancer, as well as the pathways involved, such as mitochondrial pathways, ROS pathways, p53 pathways, and nuclear factor-κB signaling pathways. Therefore, it is essential to comprehend the diverse anticancer pharmacological mechanisms of these products on specific tumor cells to determine their therapeutic windows, optimize treatments, and develop new anticancer drugs. This review paper discusses the structure-activity relationship, pharmacological effects, and applications of paclitaxel, betulic acid, and camptothecin in various cancers. Additionally, their potential in tumor treatment and the delivery system of new effective anticancer drugs are discussed in detail, providing a comprehensive understanding of the latest progress of paclitaxel, betulic acid, and camptothecin anticancer drugs. [ABSTRACT FROM AUTHOR]

Objective: This study explores vitamin drug conjugates, linking drugs to targeting moieties (Niacin and Pantothenic acid), aiming to enhance TB drug efficacy, reduce dosing frequency, and minimize toxicity. Methods: Isoniazid-Niacin (INH-NIA), Isoniazid-Pantothenic Acid (INH-PA), and Pyrazinamide-Niacin (PYZ-NIA) conjugates were synthesized. Their anti-mycobacterial activity against Mycobacterium smegmatis was evaluated. Molecular docking and molecular dynamics simulations assessed binding affinity and stability with MTb proteases. Drug-likeness and ADME properties were examined. Results: INH-NIA and PYZ-NIA demonstrated significant anti-mycobacterial activity, while INH-PA showed lower activity. Docking and simulations confirmed strong binding with MTb proteases. Drug-likeness and ADME properties supported their potential as antitubercular agents. Discussion: Combining antitubercular drugs with specific vitamins in vitamin drug conjugates offers a promising approach to enhance drug efficacy and reduce resistance. These conjugates provide targeted delivery and improved bioavailability, addressing critical challenges in TB treatment. Molecular dynamics simulations validate the stability of drug-target complexes, reinforcing their potential as antitubercular agents. Conclusions: Vitamin drug conjugates, especially INH-NIA and PYZ-NIA, hold significant promise in combating TB. Their innovative approach may revolutionize TB treatment by addressing drug resistance and improving patient outcomes. Further research is warranted to explore and develop these conjugates as effective tools in the fight against TB. This study underscores the importance of innovative strategies in addressing drug-resistant MTb strains and advancing TB treatment options. [ABSTRACT FROM AUTHOR]

DRESS related to first-line antituberculosis drugs (ATD) is a challenging diagnosis. With a long-lasting combined treatment of 4-concomitantly administrated drugs, identification of the culprit drug remains difficult and may expose patients to treatment interruption and affect their outcome. A 42-year-old female, treated with isoniazid, rifampicin, pyrazinamide and ethambutol for multifocal tuberculosis, developed, 40 days later, hyperthermia, facial edema, cervical lymphadenopathy and generalized exanthema. Biological test results revealed eosinophilia, atypical lymphocytes, and liver injury. DRESS was suspected, and ATD were withdrawn. As patch tests for the 4 ATD showed negative results, we decided to reintroduce pyrazinamide, ethambutol and rifampicin separately with a 3-day interval. Pyrazinamide and rifampicin were tolerated. However, after receiving ethambutol, she developed fever and generalized rash, with no biological abnormalities. Since ethambutol was claimed to be the culprit drug, isoniazid was added, and 10 hours later, the patient developed fever, facial edema, generalized rash, eosinophilia and liver injury. This clinical and biological pattern resolved 2 weeks later. This report suggests a hypersensitivity relapse to ethambutol after isoniazid-induced DRESS. [ABSTRACT FROM AUTHOR]

Background: Pyrazinamide is a Biopharmaceutical Classification System class III antibiotic indicated for active tuberculosis. Methods: In the present work, pyrazinamide-loaded biodegradable polymeric nanoparticles (PNPs) based dry powder inhaler were developed using the double emulsion solvent evaporation technique and optimized using design of experiments to provide direct pulmonary administration with minimal side effects. Batches were characterized for various physicochemical and aerosol performance properties. Results: Optimized batch exhibited particle size of 284.5 nm, % entrapment efficiency of 71.82%, polydispersibility index of 0.487, zeta potential of −17.23 mV, and in vitro drug release at 4 hours of 79.01%. Spray-dried PNPs were evaluated for drug content, in vitro drug release, and kinetics. The particle mass median aerodynamic diameter was within the alveolar region's range (2.910 μm). In the trachea and lung, there was a 2.5- and 1.2-fold increase in in vivo deposition with respect to pure drug deposition, respectively. In vitro drug uptake findings showed that alveolar macrophages with pyrazinamide PNPs had a considerably higher drug concentration. Furthermore, accelerated stability studies were carried out for the optimized batch. Results indicated no significant change in the evaluation parameters, which showed stability of the formulation for at least a 6-month period. Conclusion: PNPs prepared using biodegradable polymers exhibited efficient pulmonary drug delivery with decent stability. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is notorious as the leading cause of death worldwide due to a single infectious entity and its causative agent, Mycobacterium tuberculosis (Mtb), has been able to evolve resistance to all existing drugs in the treatment arsenal complicating disease management programs. In drug discovery efforts, natural products are important starting points in generating novel scaffolds that have evolved to specifically bind to vulnerable targets not only in pathogens such as Mtb, but also in mammalian targets associated with human diseases. Structural diversity is one of the most attractive features of natural products. This review provides a summary of fused-nitrogen-containing heterocycles found in the natural products reported in the literature that are known to have antitubercular activities. The structurally targeted natural products discussed in this review could provide a revealing insight into novel chemical aspects with novel biological functions for TB drug discovery efforts. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains one of the leading global causes of mortality. Several methods have been established to detect anti-TB agents in human plasma and serum. However, there is a notable absence of studies analyzing TB drugs in urine. Thus, our objective was to validate a method for quantifying first-line anti-TB agents: isoniazid (INH), pyrazinamide (PZA), ethambutol (ETH), and rifampicin (RIF), along with its metabolite 25-desacetylrifampicin, and degradation products: rifampicin quinone and 3-formyl-rifampicin in 10 µL of urine. Chromatographic separation was achieved using a Kinetex Polar C18 analytical column with gradient elution (5 mM ammonium acetate and acetonitrile with 0.1% formic acid). Mass spectrometry detection was carried out using a triple-quadrupole tandem mass spectrometer operating in positive ion mode. The lower limit of quantification (LLOQ) was 0.5 µg/mL for INH, PZA, ETH, and RIF, and 0.1 µg/mL for RIF's metabolites and degradation products. The method was validated following FDA guidance criteria and successfully applied to the analysis of the studied compounds in urine of TB patients. Additionally, we conducted a stability study of the anti-TB agents under various pH and temperature conditions to mimic the urine collection process in different settings (peripheral clinics or central laboratories). [ABSTRACT FROM AUTHOR]

Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07–1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06–1.16), treatment success (aRR, 1.07; 95% CI, 1.03–1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14–1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC0–24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens. [ABSTRACT FROM AUTHOR]

Bullous lung disease caused by tuberculosis is rare, and complications have a poor prognosis with uncertain pathophysiologic mechanisms. We describe a 29-year-old male patient who was admitted to the emergency department due to bilateral tension pneumothorax, which was complicated by bronchopleural fistula. This was managed with the placement of chest tubes, continuity of anti-TB drug treatment, and Heimlich valve placement. [ABSTRACT FROM AUTHOR]

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Copyright of Salud, Ciencia y Tecnología is the property of Fundacion Salud, Ciencia y Tecnologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundTreatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.MethodsendTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.DiscussionThe lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.Trial registrationClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10-35 mg·kg-1), pyrazinamide (range 20-30 mg·kg-1), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK-PD) and pharmacokinetic-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (Cmax) was associated with shorter time to culture conversion (TTCC) and higher probability of 2-month culture conversion (p-value4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with grade 3 or higher liver function tests (LFT)), and no relationship was seen between pyrazinamide Cmax and LFT levels.Pyrazinamide's microbiological efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.

Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7- and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose escalation study in treatment-naive adult smear-positive patients with TB. Patients received, in consecutive cohorts, 40 or 50 mg·kg-1 rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between days 8 and 14. In the 40 mg·kg-1 cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg-1 cohort (n=17), all patients experienced adverse events during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. Adverse events were mostly mild/moderate and tolerability rather than safety related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinaemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean area under the plasma concentration-time curve from time 0 to 12 h (AUC0-24 h) for 50 mg·kg-1 compared with 40 mg·kg-1; 571 (range 320-995) versus 387 (range 201-847) mg·L-1·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg-1 (11% (range 8-17%)) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (Spearman's ρ=0.670 on day 3, p

Background Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM® was used to analyze the data. Results Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin’s absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid’s clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide’s clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusions We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.

Movement disorders associated with tubercular meningitis have been reported, ranging from tremors to chorea. Stereotypy is a rare manifestation following tubercular meningitis. Here we report a rare case of a 29-year-old man who developed stereotypy and parkinsonism following tubercular meningitis. The stereotypy was in the form of rotatory movements of the right upper limb, which were repetitive, purposeless, non-goal directed, present for most of the day, and partially suppressible. In addition, it was associated with severe generalized parkinsonism. This report expands the spectrum of movement disorders seen in tubercular meningitis. [ABSTRACT FROM AUTHOR]

Pancreatic tuberculosis (TB) is extremely rare and has similar clinical and radiological findings compared to pancreatic malignancy. Challenges in detecting individuals with pancreatic TB, especially in rural areas with limited supporting resources, are the reasons for a more complete care strategy. We report a case of pancreatic TB in a 25-year-old woman admitted to the emergency department (ED), who was initially suspected of having a pancreatic tumor. Her chief complaints were fever, fatigue, and abdominal pain, while she also experienced weight loss. Exploratory laparotomy and further pathological evaluation suggested pancreatic TB. Subsequently, the patient was given anti-TB drugs and showed clinical improvement. In conclusion, this case report highlighted that pancreatic TB could mimic pancreatic cancer; however, it is a treatable condition. Thus, it is important for physicians to consider this as a differential diagnosis, especially in high-risk populations and in rural areas with limited diagnostic tools. [ABSTRACT FROM AUTHOR]

The antibiotic pyrazinamide (PZA) is a cornerstone of tuberculosis (TB) therapy that shortens treatment durations by several months despite being only weakly bactericidal. Intriguingly, PZA is also an anti-inflammatory molecule shown to specifically reduce inflammatory cytokine signaling and lesion activity in TB patients. However, the target and clinical importance of PZA's host-directed activity during TB therapy remain unclear. Here, we identify the host enzyme Poly(ADP-ribose) Polymerase 1 (PARP1), a pro-inflammatory master regulator strongly activated in TB, as a functionally relevant host target of PZA. We show that PZA inhibits PARP1 enzymatic activity in macrophages and in mice where it reverses TB-induced PARP1 activity in lungs to uninfected levels. Utilizing a PZA-resistant mutant, we demonstrate that PZA's immune-modulatory effects are PARP1-dependent but independent of its bactericidal activity. Importantly, PZA's bactericidal efficacy is impaired in PARP1-deficient mice, suggesting that immune modulation may be an integral component of PZA's antitubercular activity. In addition, adjunctive PARP1 inhibition dramatically reduces inflammation and lesion size in mice and may be a means to reduce lung damage and shorten TB treatment duration. Together, these findings provide insight into PZA's mechanism of action and the therapeutic potential of PARP1 inhibition in the treatment of TB. The mode of action of the tuberculosis antibiotic pyrazinamide is poorly understood. Here, Krug et al show that pyrazinamide inhibits the immune regulator PARP1 and demonstrate PARP1 inhibition as a host-directed therapy. [ABSTRACT FROM AUTHOR]

Body piercing has been practiced for centuries in Asian and African countries as a part of religious and cultural ceremonies. Complications like bleeding, pyogenic bacterial infections like staphylococcal and pseudomonas, viral infections like hepatitis B virus, allergic reactions, scarring, granuloma formation, and sarcoid-like foreign body formation have been reported. Thaipusam is a traditional religious festival observed in Asian countries, commonly in India and Malaysia. During the celebration, devotees allow their bodies to be pierced and decorated with needles, hooks, and skewers (Alagu kuthuthal) on cheeks, tongue, chest, and back, followed by "holy ash" (Vibhuthi). We report a case of cutaneous tuberculosis because of the body piercing during this traditional festival. The patient was started on anti-tubercular therapy, and the lesions disappeared within 2 months of ATT. [ABSTRACT FROM AUTHOR]

Application of ultrasound has several beneficial effects on both crystallization process and product crystal properties. This work focuses on experimental study and population balance modeling of ultrasound-assisted unseeded batch cooling crystallization of an important polymorphic pharmaceutical. The δ -polymorph of pyrazinamide, a drug for mycobacterium tuberculosis, exhibits plate-like morphology, and such crystals are best described by atleast two dimensions: length and width. A multi-dimensional population balance model for batch cooling sonocrystallization of pyrazinamide from its 1,4-dioxane solution is developed and validated. A series of experiments are performed with different ultrasound amplitudes (silent, 10%, and 50%) to study the effect of ultrasound on nucleation rate, crystal size, and polymorphism. The ultrasound is applied till the point of nucleation and an enhanced nucleation rate is introduced in the model in the presence of ultrasound irradiation. The various kinetic parameters are estimated following a systematic methodology based on uncertainty quantification and sensitivity analysis using experimental observations related to solute concentration and crystal size distribution. The Polynomial Chaos Expansion (PCE) is used to quantify the uncertainties in model prediction due to kinetic parameter uncertainties and sensitivity analysis is performed using total order Sobol's sensitivity indices derived from PCE model. The kinetic parameters are estimated in two steps. First, a global search technique is used to simultaneously estimate all the kinetic parameters. Next, the less sensitive parameters are kept fixed and the more significant parameters are fine-tuned using a gradient-based local optimizer. Out of total nine kinetic parameters, only four parameters appeared to be significant for both silent and sonicated cases. The high-resolution finite volume scheme is used to solve the multi-dimensional population balance model and the simulation results agree very well with experimental data related to both concentration and crystal size distributions. The results revealed that compared to silent cases, sonication increased the nucleation rate by 102 times and 104 times for 10% and 50% amplitude, respectively. The growth rate was also enhanced significantly with increase in ultrasonic amplitude. All the experiments yielded the desired δ -polymorph of pyrazinamide. [Display omitted] • A multi-dimensional population balance model for sonocrystallization is developed. • The polymorphic pharmaceutical pyrazinamide is used as a model compound. • The effect of ultrasound on nucleation, crystal size and polymorphism is studied. • Kinetic parameters are estimated using uncertainty and sensitivity analysis. • Polynomial Chaos Expansion is used for uncertainty quantification. [ABSTRACT FROM AUTHOR]

In this study, new benzothiazole–pyrimidine hybrids (5a–c, 6, 7a–f, and 8–15) were designed and synthesised. Two different functionalities on the pyrimidine moiety of lead compound 4 were subjected to a variety of chemical changes with the goal of creating various functionalities and cyclisation to further elucidate the target structures. The potency of the new molecules was tested against different tuberculosis (TB) strains. The results indicated that compounds 5c, 5b, 12, and 15 (MIC = 0.24–0.98 µg/mL) are highly active against the first-line drug-sensitive strain of Mycobacterium tuberculosis (ATCC 25177). Thereafter, the anti-tubercular activity was evaluated against the two drug-resistant TB strains; ATCC 35822 and RCMB 2674, where, many compounds exhibited good activity with MIC = 0.98–62.5 3 µg/mL and 3.9–62.5 µg/mL, respectively. Compounds 5c and 15 having the highest anti-tubercular efficiency towards sensitive strain, displayed the best activity for the resistant strains by showing the MIC = 0.98 and 1.95 µg/mL for MDR TB, and showing the MIC = 3.9 and 7.81 µg/mL for XDR TB, consecutively. Finally, molecular docking studies were performed for the two most active compounds 5c and 15 to explore their enzymatic inhibitory activities. [ABSTRACT FROM AUTHOR]

Isoniazid (INH) and pyrazinamide (PZA) are both the first-line anti-tuberculosis drugs in clinical treatment. It is notable that there are serious side effects of the drugs along with upregulation of reactive nitrogen species, mainly including peripheral neuritis, gastrointestinal reactions, and acute drug-induced liver injury (DILI). Among them, DILI is the most common clinical symptom as well as the basic reason of treatment interruption, protocol change, and drug resistance. As vital reactive nitrogen species (RNS), peroxynitrite (ONOO-) has been demonstrated as a biomarker for evaluation and pre-diagnosis of drug-induced liver injury (DILI). In this work, we developed a red-emitting D-π-A type fluorescence probe DIC-NP which was based on 4′-hydroxy-4-biphenylcarbonitrile modified with dicyanoisophorone as a fluorescent reporter and diphenyl phosphinic chloride group as the reaction site for highly selective and sensitive sensing ONOO-. Probe DIC-NP displayed a low detection limit (14.9 nM) and 60-fold fluorescent enhancement at 669 nm in the sensing of ONOO-. Probe DIC-NP was successfully applied to monitor exogenous and endogenous ONOO- in living HeLa cells and zebrafish. Furthermore, we verified the toxicity of isoniazid (INH) and pyrazinamide (PZA) by taking the oxidative stress induced by APAP as a reference, and successfully imaged anti-tuberculosis drug-induced endogenous ONOO- in HepG2 cells. More importantly, we developed a series of mice models of liver injury and investigated the hepatotoxicity caused by the treatment of anti-tuberculosis drugs. At the same time, H&E of mice organs (heart, liver, spleen, lung, kidney) further confirmed the competence of probe DIC-NP for estimating the degree of drug-induced liver injury, which laid a solid foundation for medical research. [ABSTRACT FROM AUTHOR]

We describe the development and validation of a new high performance liquid chromatography (HPLC) method for analysis of a combination of the first-line anti-tubercular drugs isoniazid, pyrazinamide, and rifampicin together with clofazimine. This is a unique challenge since clofazimine and rifampicin are relatively highly lipophilic drugs, whereas isoniazid and pyrazinamide are considerably more hydrophilic. Thus, clear separation of peaks and quantification of four individual drugs can present difficulties during the development of an analytical method. Detection was established at two wavelengths—254 nm for isoniazid and pyrazinamide and 320 nm for clofazimine and rifampicin. Gradient elution was employed using 0.1% aqueous formic acid (A) and acetonitrile (B); clear separation of the four drugs was achieved within 10 min. A linear relationship was indicated by a correlation coefficient (r2) of 0.9999 for each anti-tubercular drug, respectively. The limit of detection (LOD) for the individual drugs was 0.70 µg/mL (isoniazid), 0.30 µg/mL (pyrazinamide), 0.20 µg/mL (rifampicin) and 0.20 µg/mL (clofazimine). Precision experiments rendered a mean recovery percentage of 101.25% (isoniazid), 98.70% (pyrazinamide), 99.68% (rifampicin) and 97.14% (clofazimine). This HPLC method was validated and is reliable, repeatable, and accurate for the purpose of conducting simultaneous HPLC analyses of the four anti-tubercular drugs. [ABSTRACT FROM AUTHOR]

The long journey of tuberculosis (TB) from exposure to latent or progressive TB infection, from primary stage to second stage of illness with or without infectious status, and then to chronic post-TB sequelae is very complex and still unclear, including a various spectrum of stages and manifestations. A case report of a 55 year-old woman with personal history of pleural effusion, in her youth, 2 previous episodes of COVID-19 infections, having no exposure to active smoking but occupational exposure to wood dust, hot steam, barbeque smoke, was admitted to Constanta Clinical Pneumology Hospital in October 2022 for hemoptysis and fatigue. Clinical and paraclinical investigations highlighted an acute evolutive episode of Pulmonary TB with metastatic bilateral nodular pattern, negative smears, positive cultures and positive QuantiFERON TB Gold in Tube (QFT-GIT). TB standard regimen of therapy was started, based on QFT-GIT positivity, and after it ended, chronic obstructive pulmonary disease was detected by spirometry and small airways dysfunction by impulse oscillometry. TB illness does not stop after directly observed therapy ends. So, systematical screening of pulmonary, bronchial or pleural sequelae should be performed and identified syndromes need to be treated, as well as reintegration in the job process by a careful monitoring. [ABSTRACT FROM AUTHOR]

This research aimed to discover novel isoniazid (INH) derivatives as anti-tubercular (anti-TB) agents. The chemical structures of isoniazid-based pyridazinone (IBP) derivatives were designed, and their toxicity and pharmacokinetic properties were predicted using the ProTox II and Swiss-ADME databases. The molecular docking of non-toxic IBPs was also performed concerning INH, pyrazinamide (PYZ), ethionamide (ETH), macozinone (MCZ), and BTZ043 utilizing DprE1 enzyme's proteins (PDB IDs: 4F4Q, 4NCR and 6HEZ). Based on the in silico study results, IBP19, IBP21, IBP22, and IBP29 were selected for their synthesis, and the spectral analysis confirmed their chemical structures. In vitro, anti-TB activity against Mtb H37Rv strain and MTT assay (against HepG2 and Vero cell lines) of IBP19, IBP21, IBP22, and IBP29 were also carried out. A total of eleven non-toxic IBPs were identified with promising pharmacokinetic parameters. The docking score (DS in kcal/mol against 6HEZ protein) of IBP19 (-9.52), IBP21 (-8.78), IBP22 (-9.07), and IBP29 (-9.99) was better than MCZ (-8.76) and BTZ043 (-8.56) revealing their DprE1 enzyme inhibitory action. The in vitro anti-TB activity evaluation (MIC values) confirmed that IBP19 (1.562 µg/ml), IBP21 (1.562 µg/ml), IBP22 (1.562 µg/mL), and IBP29 (1.562 µg/mL) had almost double potency than INH (3.125 µg/mL), and PYZ (3.125 µg/mL). IBP19, IBP21, IBP22, and IBP29 also displayed a CC50 value of > 300 µg/mL against HCL and VCL cell lines. This effect was better than INH (> 200 µg/mL), ETH (> 150 µg/mL), and PYZ (> 200 µg/mL). Accordingly, IBP19, IBP21, IBP22, and IBP29 provide a new template for developing safe and effective novel DprE1 inhibitors. [ABSTRACT FROM AUTHOR]

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Background: Tuberculosis is an air-borne contagious disease caused by slow-growing Mycobacterium tuberculosis (Mtb). According to Global Tuberculosis Report 2022, 1.6 million people were infected by tuberculosis in 2021. The continuing spread of drug-resistant tuberculosis (TB) is one of the most difficult challenges to control the tuberculosis. So new drug discovery is essential to the treatment of tuberculosis. This study aims to develop a QSAR model to predict the antitubercular activity of tetrahydronaphthalene derivatives. The QSARINS was used in this study to develop the QSAR predictive model. Results: A number of tetrahydronaphthalene derivatives with MIC90 values were obtained from the literature to develop the QSAR predictive model. The compounds were divided into two sets: a training set consisting of 39 compounds and a test set containing 13 compounds. The best predictive Model 4 has R2: 0.8303, Q2LOO: 0.7642, LOF: 0.0550, Q2-F1: 0.7190, Q2-F2: 0.7067, Q2-F3: 0.7938 and CCCext: 0.8720. Based on the developed QSAR equation, the new compounds were designed and subjected to molecular docking, molecular dynamics and ADMET analysis. Conclusion: In the QSAR model, the molecular descriptors of MATS8s, Chi4, bcutv8, Petitjeant and fr_aniline were highly influenced the antitubercular activity. The developed QSAR model helps to predict the antitubercular activity of tetrahydronaphthalene derivatives. [ABSTRACT FROM AUTHOR]

Pyrazinamide is an important medicine used for the treatment of tuberculosis(TB). The preparation of pyrazinamide via catalytic hydration of 2‐cyanopyrazine is of great economic interest with high atomic economy. Heterogeneous non‐precious transition metal‐catalyzed hydration of nitriles under neutral reaction conditions would be rather attractive. Herein vanadium‐nitrogen‐carbon materials were fabricated and employed for selective hydration of nitriles using water as both the solvent and reactant. 2‐Cyanopyrazine could be smoothly converted into to pyrazinamide with unique substrate specificity. Additives with different N and O atoms could significantly affect hydration of 2‐cyanopyrazine due to competitive adsorption/coordination in the reaction system. This work provides a new approach for non‐precious metal catalyzed hydration of nitriles. [ABSTRACT FROM AUTHOR]

By utilizing the sulfamethizole component via the diazo‐coupling approach by electrophilic substitution process, an unprecedented series of four mono‐azo sulfonamide molecules were synthesized in good yield. Spectroscopic investigation unambiguously confirmed the structures of the newly synthesized mono‐azo sulfonamide derivatives, including FT‐IR, NMR (1H and 13C), HRMS, Uv‐Vis, and Photoluminescence (PL). In a variety of organic solvents, the 3‐diethylaminophenol coupled azo‐sulfonamide T3 showed a maximum bathochromic shift of λmax in the range 462–479 nm and in the region of 88–142 nm, a derivative of 2‐hydroxy‐1,4‐naphthoquinone T4 coupled azo colourant showed a significant Stokes shift. Conceptual density function theory was also used to build a new family of high energy density energetic mono‐azo sulfonamides. Frontier molecular orbitals (HOMO‐LUMO) and global reactivity descriptors were identified to analyze how molecules interact with one another. Further, the potency of the anti‐tubercular activity of the colorants was examined with the standards such as Isoniazid, Ethambutol, Pyrazinamide, Rifampicin, and Streptomycin. The results indicated that‐ Lawsone pigment (2‐hydroxy‐1,4‐naphthoquinone) incorporated azo molecule T4 displayed the sensitivity at 3.12 μg/mL compared with other the three mono‐azo molecules. [ABSTRACT FROM AUTHOR]

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants. [ABSTRACT FROM AUTHOR]

Scrofuloderma can be rarely find in children. The condition needs to be considered as a differential diagnosis if we find a characteristic skin lesions in lymph node regions with associated systemic manifestations suggestive of TB. Late diagnosis and inappropriate treatment can lead to poor prognosis and antimicrobial resistance. In this report, we present a case of a severely malnourished 1-yearold girl with srofuloderma. [ABSTRACT FROM AUTHOR]

Avant de choisir un schéma thérapeutique antituberculeux initial, les cliniciens devraient évaluer les facteurs de risque de TB pharmacorésistante chez tous les patients. Des tests moléculaires rapides visant à estimer une résistance à la rifampicine (et, dans l'idéal, à l'isoniazide) devraient être réalisés chez chaque patient et les résultats devraient servir à orienter le traitement. Ces tests sont particulièrement importants pour les patients ayant des facteurs de risque de TB pharmacorésistante. Pour une prise en charge optimale de la TB pharmacorésistante, en particulier de la TB multirésistante (TB-MR), les dispensateurs de soins de santé devraient disposer de ce qui suit: (i) de tests de sensibilité à tous les antituberculeux qui seront utilisés; (ii) d'un approvisionnement ininterrompu en antituberculeux de première et de deuxième ligne à qualité assurée; (iii) d'un traitement sous observation directe et d'autres composantes d'un programme de prise en charge complète axé sur le patient; et (iv) d'une équipe expérimentée dans la prise en charge de la TB pharmacorésistante composée, entre autres, de médecins, de personnel infirmier et de pharmaciens. Les isolats de tous les patients atteints de TB résistante à la rifampicine ou multirésistante doivent être soumis à des tests phénotypiques de pharmacosensibilité de tous les antituberculeux recommandés actuellement dans le traitement de la TB-MR. Les organismes gouvernementaux fédéraux et provinciaux ainsi que les entreprises pharmaceutiques exerçant leurs activités au Canada devraient faciliter l'accès aux antituberculeux de deuxième ligne pour la tuberculose multirésistante (TB-MR) et la tuberculose ultrarésistante (TB-UR). Chez les patients présentant une monorésistance à l'isoniazide, un schéma thérapeutique comprenant notamment une fluoroquinolone de génération ultérieure (la levofloxacine de préférence), la rifampicine, l'éthambutol et le pyrazinamide devrait être appliqué pendant 6 mois. Pour ce qui est du traitement de la TB résistante à l'isoniazide, chez les patients atteints de tuberculose moins étendue (par exemple, non cavitaire) et en particulier s'il y a un risque accru d'hépatotoxicité, le pyrazinamide devrait être administré seulement pendant les 2 premiers mois de traitement. Pendant les 4 autres mois, la rifampicine, l'éthambutol et la fluoroquinolone devraient être administrés. Le traitement de la TB-MR devrait comprendre, entre autres: l'administration de schémas thérapeutiques comprenant notamment la bédaquiline, pour tous les patients; l'administration de schémas thérapeutiques comprenant notamment le linézolide, pour tous les patients; et l'administration de schémas thérapeutiques comprenant notamment la lévofloxacine ou la moxifloxacine, pour tous les patients. Concernant le traitement de la TB-MR, il ne faudrait pas utiliser les antituberculeux auxquels la résistance de la souche infectante est confirmée par des tests de pharmacosensibilité. Dans ce cas, le schéma thérapeutique initial devrait comprendre notamment la lévofloxacine ou la moxifloxacine ET la bédaquiline ET le linézolide ET la clofazimine ET la cyclosérine. Dans le cadre du traitement de la TB-MR, le nombre total d'antituberculeux peut être réduit à quatre au bout de 5 à 7 mois suivant la négativation de la culture. Un traitement de la TB-MR d'une durée totale de 18 à 20 mois qui peut varier selon la réponse au traitement est approprié. En ce qui concerne le traitement de la TB pré-UR ou de la TB-UR ou dans les cas où un ou plusieurs antituberculeux des groupes A et B ne peuvent pas être administrés en raison des effets indésirables, des contre-indications, de l'indisponibilité ou de la résistance, un ou plusieurs antituberculeux du groupe C peuvent être ajoutés afin de veiller à ce que le schéma thérapeutique soit composé d'au moins 5 antituberculeux. L'ordre de préférence pour l'ajout des antituberculeux du groupe C est le suivant (par ordre décroissant): éthambutol, pyrazinamide, délamanide, amikacine, imipénème-cilastatine ou méropénem (plus acide clavulanique), éthionamide et acide p-aminosalicylique. Chez les patients atteints de TB-MR, la résection pulmonaire partielle (lobectomie, segmentectomie ou résection cunéiforme) chez des patients soigneusement choisis peut s'avérer un complément utile dans le cadre d'un traitement médical optimisé. Le meilleur moment pour pratiquer la résection chirurgicale semble être une fois que la négativation de la culture est confirmée. [ABSTRACT FROM AUTHOR]

Background: The plasma concentrations of the four most commonly used firstline anti-tuberculosis (TB) drugs, isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and pyrazinamide (PZA), are often not within the therapeutic range. Insufficient drug exposure could lead to drug resistance and treatment failure, while excessive drug levels may lead to adverse reactions. The purpose of this study was to identify the physiological parameters influencing anti-TB drug concentrations. Methods: A retrospective cohort study was conducted. The 2-h plasma concentrations of the four drugs were measured by using the highperformance liquid chromatography-tandem mass spectrometry method. Results: A total of 317 patients were included in the study. The proportions of patients with INH, RMP, EMB, and PZA concentrations within the therapeutic range were 24.3%, 31.5%, 27.8%, and 18.6%, respectively. There were positive associations between the concentrations of INH and PZA and RMP and EMB, but negative associations were observed between the concentrations of INH and RMP, INH and EMB, RMP and PZA, and EMB and PZA. In the multivariate analysis, the influencing factors of the INH concentration were the PZA concentration, total bile acid (TBA), serum potassium, dose, direct bilirubin, prealbumin (PA), and albumin; those of the RMP concentration were PZA and EMB concentrations, weight, α-L-fucosidase (AFU), drinking, and dose; those of the EMB concentration were the RMP and PZA concentrations, creatinine, TBA and indirect bilirubin; and those of the PZA concentration were INH, RMP and EMB concentrations, sex, weight, uric acid and drinking. Conclusion: The complex correlations between the concentrations of the four first-line anti-TB drugs lead to a major challenge in dose adjustment to maintain all drugs within the therapeutic window. Levels of TBA, PA, AFU, and serum potassium should also be considered when adjusting the dose of the four drugs. [ABSTRACT FROM AUTHOR]