Diagnosis, prevention and risk-management of drug-induced liver injury due to medications used to treat mycobacterium tuberculosis.

INTRODUCTION: Many of the first line medications for the treatment of active and latent M. tuberculosis are hepatoxic and cause a spectrum of anti-tuberculosis drug induced liver injury (ATLI), including acute liver failure (ALF). Despite advances in recognition of and prevention of ATLI, isoniazid remains one of the leading causes of DILI as well as drug-induced ALF. AREAS COVERED: A literature search of the incidence, risk factors, current societal guidelines, monitoring, and prophylactic medication usage in ATLI was performed using PubMed and institutional websites. Relevant articles from 1972 to 2024 were included in this review. EXPERT OPINION: Current societal guidelines regarding ATLI monitoring are mixed, but many recommend liver enzyme testing of high-risk populations. We recommend liver test monitoring for all patients on multi-drug therapy as well as those on isoniazid therapy. Precision medicine practices, such as N-acetyltransferase-2 polymorphism genotyping, are thought to be beneficial in reducing the incidence of ATLI in high-risk populations. However, broader implementation is currently cost prohibitive. Hepatoprotective drugs are not currently recommended, although we do recognize their potential. In patients who develop ATLI but require ongoing anti-TB treatment, strategies to restart the same or less hepatotoxic regimens are currently being followed.

Drug-Resistant Tuberculosis Case-Finding Strategies: Scoping Review.

BACKGROUND: Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown. OBJECTIVE: We therefore assessed the available literature on DR-TB case-finding strategies. METHODS: We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp). RESULTS: We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information. CONCLUSIONS: Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.

The hsa_circ_0082152 maintains NF-κB mRNA stability by binding to MTDH to promote anti-tuberculosis drug-induced liver injury.

Anti-tuberculosis drug-induced liver injury (ADLI) is a common adverse reaction during anti-tuberculosis treatment and often leads to treatment interruptions. Circular RNAs (circRNAs) have been identified as key modulators in liver diseases. CircRNAs is a special class of noncoding RNAs that have been found to have significant impacts on the progression of inflammation via various mechanisms. In the serum of ADLI patients, upregulation of the circular RNA hsa_circ_0082152 (derived from the host gene snd1) was observed, along with increased ALT and AST levels, as well as alterations in the levels of inflammation-related factors such as NF-κB, IL-1ß and TNF-α. To elucidate the underlying mechanisms, we established an HL-7702-ADLI cell model and confirmed similar upregulation of hsa_circ_0082152. Downregulation of hsa_circ_0082152 significantly inhibited inflammatory injury in ADLI cells, while upregulation had the opposite effect. RNA immunoprecipitation showed that hsa_circ_0082152 functions by interacting with metadherin (MTDH). Our study further verified that the interaction of hsa_circ_0082152 with the MTDH protein binding to NF-κB mRNA to maintain NF-κB mRNA stability, which increases the expression of NF-κB and its targets IL-1ß and TNF-α. Conversely, depletion of MTDH rescued the promotive effect of hsa_circ_0082152 overexpression on ADLI inflammation. Therefore, hsa_circ_0082152 overexpression promotes ADLI progression via the MTDH/NF-κB axis.

The effect of statins on the risk of anti-tuberculosis drug-induced liver injury among patients with active tuberculosis: A cohort study.

BACKGROUND: Tuberculosis (TB) remains prevalent worldwide, and anti-TB drugs are associated with drug-induced liver injury (DILI). Statins have pleiotropic effects which may decrease inflammation and achieve immunomodulation. However, few studies have investigated the pleiotropic effects of statins on the risk of DILI. The purpose of this study was to investigate whether statins prevent anti-tuberculosis DILI among active TB patients on standard anti-TB drug therapy. METHODS: We conducted a hospital-based retrospective cohort study using claims data from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD). Patients with a positive TB culture were included. The use of statins was defined as a daily equivalent dose >0.5 mg of pitavastatin. Deterioration in liver function was evaluated according to elevated liver enzyme levels. The primary and secondary endpoints were the DILI and the severe DILI. The prognostic value of statins was evaluated by Kaplan-Meier analysis, and Cox proportional hazards models. RESULTS: A total of 1312 patients with a diagnosis of TB and receiving anti-TB treatment were included. During the study period, 193 patients had the DILI and 140 patients had the severe DILI. Kaplan-Meier analysis showed a significant difference between the usual statin users and controls in the DILI. In multivariable Cox proportional hazards analysis, statins showed a protective effect against the primary and secondary endpoints. In addition, the protective effect of statins showed a dose-response relationship against the DILI. CONCLUSION: Statin treatment had a protective effect against the risk of anti-TB DILI with a positive dose-response relationship.

Puzzling Clinical Appearance of a Pancreatic Tuberculosis Case.

Tuberculosis (TB) is generally known as an infectious disease caused by Mycobacterium tuberculosis. Not only the lungs, TB can also infect various other organs. Pancreatic TB is a rare manifestation of extrapulmonary TB infection accounting for only 0-4.7% of the total TB cases worldwide. It's still intricating for clinicians to diagnose pancreatic TB due to the extremely rare prevalence and non-specific clinical signs and symptoms. Herein we report a 71-year-old male patient complaining of jaundice and weight loss. Clinical condition, laboratory and tumor markers, also MRI imaging showed no abnormality. We made the diagnosis through histopathological examination of tissues extracted from bypass biliodigestive procedure, showing granulomas, along with confirmed bacteriological analysis with Ziehl Nelsen staining. This patient received Fixed Drug Combination (FDC) of anti-tuberculosis therapy for 6 months. The patient gained weight, had an improvement of serum bilirubin level and had no remaining lesion in abdominal CT scan.

Guided discovery of hepatoprotective polyhydroxy cembrane-type diterpenoids from the gum resin of Boswellia carterii by MS/MS molecular networking.

Seven previously undescribed polyhydroxy cembrane-type diterpenoids, olibanols A-G (1-7) were obtained from the gum resin of Boswellia carterii by means of MS/MS molecular networking. Compound 2 possessed four hydroxy groups, 1, 3, 4, 5, and 6 had three hydroxy groups, 7 with one hydroxy group, among which 1 and 4 were a pair of epimers with double bond at C-3 and hydroxy at C-8. Structures of these previously undescribed compounds were determined by NMR analysis and ECD calculations. All the polyhydroxy cembrane-type diterpenoids obtained were assayed for their hepatoprotective effects against the anti-tuberculosis drug-induced hepatic damage to the HRZ-induced HepG2 cells. As results indicated, compounds 3, 4, and 6 showed significant hepatoprotective effects against the hepatic damage via the Nrf2 signal pathway, which could be developed as potential hepatoprotective agents against the anti-tuberculosis drug-induced hepatic damage.

Nutritional intervention is promising in alleviating liver injury during tuberculosis treatment: a review.

Liver injury is a main adverse effect of first-line tuberculosis drugs. Current management of tuberculosis-drug-induced liver injury (TBLI) mainly relies on withdrawing tuberculosis drugs when necessary. No effective treatment exists. Various nutrients and functional food ingredients may play a protective role in TBLI. However, a comprehensive review has not been conducted to compare the effects of these nutrients and functional food ingredients. We searched Pubmed and Web of Science databases from the earliest date of the database to March 2023. All available in-vitro, animal and clinical studies that examined the effects of nutritional intervention on TBLI were included. The underlying mechanism was briefly reviewed. Folic acid, quercetin, curcumin, Lactobacillus casei, spirulina and Moringa oleifera possessed moderate evidence to have a beneficial effect on alleviating TBLI mostly based on animal studies. The evidence of other nutritional interventions on TBLI was weak. Alleviating oxidative stress and apoptosis were the leading mechanisms for the beneficial effects of nutritional intervention on TBLI. In conclusion, a few nutritional interventions are promising for alleviating TBLI including folic acid, quercetin, curcumin, L. casei, spirulina and M. oleifera, the effectiveness and safety of which need further confirmation by well-designed randomized controlled trials. The mechanisms for the protective role of these nutritional interventions on TBLI warrant further study, particularly by establishing the animal model of TBLI using the tuberculosis drugs separately.

N-acetyltransferase 2 genetic polymorphisms and anti-tuberculosis-drug-induced liver injury: a correlation study.

Background: Considering the genetic characteristics of people with anti-tuberculosis (TB)-drug-induced liver injury (ATDILI), genetic factors and their consequences for treatment need to be studied. Objective: The correlation between N-acetyltransferase 2 (NAT2) genetic polymorphisms and ATDILI was analysed. Methods: In this study, the liver and coagulation functions of 120 patients with TB were monitored dynamically for at least 3 months. The genetic polymorphisms of patients were detected by pyrosequencing, and the acetylation types of liver damage and the distribution of NAT2 genetic polymorphisms were compared and analysed. Results: The results showed that there were significant differences in the distribution of alleles and acetylation types among different groups (p < 0.05). In patients with grade 4 liver injury (liver failure), any two alleles were included, i.e., *6 and *7. Specifically, patients with fast acetylation genotypes accounted for 42.4% (14/33), those with intermediate acetylated genotypes accounted for 55.2% (32/58), and patients with slow acetylation genotypes accounted for 65.5% (19/29). Conclusion: Patients with slow acetylation genotypes had higher rates of liver failure and liver injury than those with intermediate and fast acetylation genotypes, and patients with slow acetylation genotypes containing any two alleles (*6 and *7) had a higher rate of liver failure than those with other alleles. In summary, the time of liver injury in patients with slow acetylation genotypes was earlier than the total average time, and the time of liver function recovery in patients with fast acetylation genotypes was shorter than the total average time.

The Effectiveness of Silymarin in the Prevention of Anti-tuberculosis Drug-induced Hepatotoxicity: A Randomized Controlled Clinical Trial.

Background: Several animal studies have shown the protective effect of silymarin (the extract of Silybum marianum seeds) against anti-tuberculosis drug-induced hepatotoxicity (ATDH). However, the knowledge of ATDH of silymarin in humans is scarce. In this study, we aimed to clinically evaluate it. Methods: During this randomized controlled clinical trial, 36 new cases of tuberculosis (TB) were enrolled to receive either silymarin 150 mg twice daily for two weeks along with a standard anti-TB therapeutic regimen (experimental group; n = 16) or standard anti-TB therapeutic regimen alone (control group; n = 21). Liver function tests (serum AST, ALT, ALP, and total bilirubin) at the end of weeks 1 and 2 as well as the rate of ATDH during the study were determined and compared between the groups. Results: No significant differences between the experimental and control groups were observed at the end of the first week regarding liver function tests; However, at the end of the second week, the mean serum levels of AST (P = 0.03) and ALP (P = 0.04) were significantly lower in the experimental group. ALT (P = 0.016) and ALP (P = 0.027) levels in the experimental group significantly decreased during the study, while the changes in the control group were not significant. Two patients in the control group (9.5%) developed ATDH, while no one in the experimental group manifested this adverse effect. Conclusions: Our study suggests that silymarin use has the potential for the reduction of anti-TB drug-induced hepatotoxicity.

Inoculum-dependent bactericidal activity of a Mycobacterium tuberculosis MmpL3 inhibitor.

Indolcarboxamides are a promising series of anti-tubercular agents, which target Mycobacterium tuberculosis MmpL3, the exporter of trehalose monomycolate, a key cell-wall component. We determined the kill kinetics of the lead indolcarboxamide NITD-349 and determined that while kill was rapid against low-density cultures, bactericidal activity was inoculum-dependent. A combination of NITD-349 with isoniazid (which inhibits mycolate synthesis) had an increased kill rate; this combination prevented the appearance of resistant mutants, even at higher inocula.

Skin infiltrating T-cell profile of drug reaction with eosinophilia and systemic symptoms (DRESS) reactions among HIV-infected patients.

Introduction: Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) is more common in persons living with HIV (PLHIV), and first-line anti-TB drugs (FLTDs) and cotrimoxazole are the commonest offending drugs. Limited data is available on the skin infiltrating T-cell profile among DRESS patients with systemic CD4 T-cell depletion associated with HIV. Materials and methods: HIV cases with validated DRESS phenotypes (possible, probable, or definite) and confirmed reactions to either one or multiple FLTDs and/or cotrimoxazole were chosen (n = 14). These cases were matched against controls of HIV-negative patients who developed DRESS (n = 5). Immunohistochemistry assays were carried out with the following antibodies: CD3, CD4, CD8, CD45RO and FoxP3. Positive cells were normalized to the number of CD3+ cells present. Results: Skin infiltrating T-cells were mainly found in the dermis. Dermal and epidermal CD4+ T-cells (and CD4+/CD8+ ratios) were lower in HIV-positive vs. negative DRESS; p < 0.001 and p = 0.004, respectively; without correlation to whole blood CD4 cell counts. In contrast, no difference in dermal CD4+FoxP3+ T-cells was found in HIV-positive vs. negative DRESS, median (IQR) CD4+FoxP3+ T-cells: [10 (0-30) cells/mm2 vs. 4 (3-8) cells/mm2, p = 0.325]. HIV-positive DRESS patients reacting to more than one drug had no difference in CD8+ T-cell infiltrates, but higher epidermal and dermal CD4+FoxP3+ T-cell infiltrates compared to single drug reactors. Conclusion: DRESS, irrespective of HIV status, was associated with an increased skin infiltration of CD8+ T-cells, while CD4+ T-cells were lower in HIV-positive DRESS compared to HIV-negative DRESS skin. While inter-individual variation was high, the frequency of dermal CD4+FoxP3+ T-cells was higher in HIV-positive DRESS cases reacting to more than one drug. Further research is warranted to understand the clinical impact of these changes.

Gut microbiota characteristics of Mongolian and Han populations in anti-tuberculosis drug-induced liver injury: a population-based case-control study.

BACKGROUND: The pathogenesis of anti-tuberculosis (TB) drug-induced liver injury (ADLI) is complicated and remains unclear. We aimed to analyse the relationship between the characteristics of gut microbiota and ADLI in Mongolian and Han patients with pulmonary TB and identify the most notable bacteria related to the occurrence of liver injury in those populations. METHODS: Patients with concurrent liver injury (LI) and no liver injury (ULI) before receiving first-line anti-TB drug treatment (T1) from the Han population in Tangshan and the Mongolian population in Inner Mongolia were selected as research subjects. At the time of liver injury (T2), stool samples were measured by bacterial 16S rRNA gene high-throughput sequencing to analyse and compare the differences in the gut microbiota of the LI and ULI Mongolian and Han patients at T1 and T2 and identify the differences between those patients. RESULTS: A total of 45 Mongolian and 37 Han patients were enrolled in our study. A dynamic comparison from T1 to T2 showed that the microbiota of the LI and ULI groups changed significantly from T1 to T2 in both the Mongolian and Han populations. However, there were commonalities and personality changes in the microbiota of the two ethnic groups. CONCLUSION: Differences in gut microbes in ADLI were found among the Han and Mongolian patients in our study. Ekmania and Stenotrophomonas were related to the occurrence of ADLI in Mongolian patients, while Ekmania and Ruminococcus__gnavus_group were related to the occurrence of ADLI in the Han population.

Study of drug interaction, mutant frequency and mutant prevention concentration of DFMBT against Mycobacterium tuberculosis H37RV.

In the present study 7,7-Dimethyl-4-(4-trifluoromethyl-phenylamino)-2,4,4a,6,7,8-hexahydro-benzo[d] [1,3]thiazin-5-one (DFMBT) was synthesized and evaluated for in vitro activity against Mycobacterium tuberculosis (M.tb) H37RV. Results demonstrated that at 64x MIC, DFMBT completely sterilized the TB culture from day 4 of the incubation whereas at 32 and 16x MIC, it sterilized the TB culture from day 8. The bacterial cultures were completely sterilized by DFMBT at 8x MIC from day 16 of incubation. DFMBT showed 1.5 µg/mL MIC value as compared to the standard anti-tuberculosis drugs using broth macro-dilution method. The MBC value of DFMBT was found to be 6.0 µg/mL whereas for INH, RIF, AMK and LVX the values were found to be 0.312, 0.156, 5.0 and 5.0 µg/mL, respectively. The DFMBT in combination with INH/RIF or AMK showed the ∑FIC value of 0.258, 0.252 and 0.453, respectively indicating synergistic interaction. Moreover, the value of ∑FIC for the combination of DFMBT with LVX was found to be 1.33 suggesting and additive interaction. The post antibiotic effect of DFMBT at 1x and 64x MIC was found to be 29.89 ± 10.12 and 158.75 ± 17.50 h, respectively. The DFMBT showed an MPC value of 150 µg/mL which was intermediate between INH and RIF. In summary, DFMBT exhibits bacteriostatic as well as bactericidal effect on Mycobacterium tuberculosis H37RV. It has synergistic interaction with INH, RIF and AMK anti-TB drugs, descent post antibiotic effect, mutation frequency and mutant prevention concentration. Thus, DFMBT may be developed as an effective agent as anti-TB compound.

Adjunctive Integrated Stress Response Inhibition Accelerates Tuberculosis Clearance in Mice.

Despite numerous advances in tuberculosis (TB) drug development, long treatment durations have led to the emergence of multidrug resistance, which poses a major hurdle to global TB control. Shortening treatment time therefore remains a top priority. Host-directed therapies that promote bacterial clearance and/or lung health may improve the efficacy and treatment duration of tuberculosis antibiotics. We recently discovered that inhibition of the integrated stress response, which is abnormally activated in tuberculosis and associated with necrotic granuloma formation, reduced bacterial numbers and lung inflammation in mice. Here, we evaluated the impact of the integrated stress response (ISR) inhibitor ISRIB, administered as an adjunct to standard tuberculosis antibiotics, on bacterial clearance, relapse, and lung pathology in a mouse model of tuberculosis. Throughout the course of treatment, ISRIB robustly lowered bacterial burdens compared to the burdens with standard TB therapy alone and accelerated the time to sterility in mice, as demonstrated by significantly reduced relapse rates after 4 months of treatment. In addition, mice receiving adjunctive ISRIB tended to have reduced lung necrosis and inflammation. Together, our findings identify the ISR pathway as a promising therapeutic target with the potential to shorten TB treatment durations and improve lung health. IMPORTANCE Necrosis of lung lesions is a hallmark of tuberculosis (TB) that promotes bacterial growth, dissemination, and transmission. This process is driven by the persistent hyperactivation of the integrated stress response (ISR) pathway. Here, we show that adjunctive ISR inhibition during standard antibiotic therapy accelerates bacterial clearance and reduces immunopathology in a clinically relevant mouse model of TB, suggesting that host-directed therapies that de-escalate these pathological stress responses may shorten TB treatment durations. Our findings present an important conceptual advance toward overcoming the challenge of improving TB therapy and lowering the global burden of disease.

The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study.

AIM: Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc., while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients. METHODS: A 1:4 matched case-control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls. RESULTS: The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P=0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR=0.79, 95% CI: 0.66-0.94, P=0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend=0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P=0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model. CONCLUSION: This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study.

Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is one of the most common adverse reactions that brings great difficulties to the treatment of tuberculosis. Thus, early identification of individuals at risk for ATB-DILI is urgent. We conducted a prospective cohort study to analyze the urinary metabolic and microbial profiles of patients with ATB-DILI before drug administration. And machine learning method was used to perform prediction model for ATB-DILI based on metabolomics, microbiome and clinical data. Methods: A total of 74 new TB patients treated with standard first-line anti-TB treatment regimens were enrolled from West China Hospital of Sichuan University. Only patients with an updated RUCAM score of 6 or more were accepted in this study. Nontargeted metabolomics and microbiome analyses were performed on urine samples prior to anti-tuberculosis drug ingestion to screen the differential metabolites and microbes between the ATB-DILI group and the non-ATB-DILI group. Integrating electronic medical records, metabolomics, and microbiome data, four machine learning methods was used, including random forest algorithm, artificial neural network, support vector machine with the linear kernel and radial basis function kernel. Results: Of all included patients, 69 patients completed follow-up, with 16 (23.19%) patients developing ATB-DILI after antituberculosis treatment. Finally, 14 ATB-DILI patients and 30 age- and sex-matched non-ATB-DILI patients were subjected to urinary metabolomic and microbiome analysis. A total of 28 major differential metabolites were screened out, involving bile secretion, nicotinate and nicotinamide metabolism, tryptophan metabolism, ABC transporters, etc. Negativicoccus and Actinotignum were upregulated in the ATB-DILI group. Multivariate analysis also showed significant metabolic and microbial differences between the non-ATB-DILI and severe ATB-DILI groups. Finally, the four models showed high accuracy in predicting ATB-DILI, with the area under the curve of more than 0.85 for the training set and 1 for the validation set. Conclusion: This study characterized the metabolic and microbial profile of ATB-DILI risk individuals before drug ingestion for the first time. Metabolomic and microbiome characteristics in patient urine before anti-tuberculosis drug ingestion may predict the risk of liver injury after ingesting anti-tuberculosis drugs. Machine learning algorithms provides a new way to predict the occurrence of ATB-DILI among tuberculosis patients.

Combined electronic medical records and gene polymorphism characteristics to establish an anti-tuberculosis drug-induced hepatic injury (ATDH) prediction model and evaluate the prediction value.

Background: Anti-tuberculosis drug-induced hepatic injury (ATDH) lacks specific diagnostic markers. The characteristics of gene polymorphisms have been preliminarily used for the risk classification of ATDH, and the activation of Pregnane X receptor/aminole-vulinic synthase-1/forkhead box O1 (PXR/ALAS1/FOXO1) axis is closely related to ATDH. Therefore, we consider combining general clinical features of the electronic medical record, laboratory indications, and genetic features of key genes in this axis for predictive model construction to help early clinical diagnosis and treatment. Methods: The general characteristics derived from the Hospital Information System (HIS) medical record system, the biochemical tests and hematology tests were detected by Roche automatic biochemical immunoassay analyzer cobas8000 and Sysmex automatic hemocytometer XE2100. The single nucleotide polymorphisms (SNPs) genotyping work was conducted with a custom-designed 48-plex SNP scan® TM Kit. A total of 746 cases were included which were divided into training set and validation set according to the ratio of 3:2 randomly. Taking the occurrence of confirmed ATDH as the outcome variable, lasso regression and logistic regression were used to identify the predictors preliminarily. alanine aminotransferase, aspartate aminotransferase, monocyte, uric acid, albumin, fever, the polymorphisms of rs4435111 (FOXO1) and rs3814055 (PXR) were chosen from all variables to combine the predictive model. The goodness of fit, predictive efficacy, discrimination, and consistency, and clinical decision curve analysis was used to assess the clinical applicability of the models. Results: The best model had a discriminant efficacy C-index of 0.8164, a sensitivity of 34.25%, specificity of 97.99%, a positive predictive value of 78.13% and negative predictive value of 87.69%, the two-tailed value of Spiegelhalter Z test of consistency test S:P =0.896, maximum absolute difference Emax =0.147, and average absolute difference Eave =0.017. In the validation set, performance was close. The clinical decision curve showed the clinical applicability of the prediction model when the prediction risk threshold was between 0.1 and 0.8. Conclusions: The ATDH prediction model was constructed using a machine learning approach, combining general characteristics of the study population, laboratory indications, and SNP features of PXR and FOXO1 genes with good fit and certain predictive value, and has potential and value for clinical application.

Chromatographic Methods for the Determination of Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, and Main Metabolites in Biological Samples: A Review.

Bioanalytical methods are used to quantify drugs and their metabolites in biological samples in order to determine bioequivalence, perform pharmacokinetic and bioavailability studies, and complete therapeutic drug monitoring. The objective of this review paper is to describe bioanalytical methods based on Liquid Chromatography that are used to quantify antitubercular drugs and their metabolites in different biological samples, utilizing scientific literature from 1992 to 2021.

1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis.

Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in Mycobacterium tuberculosis (Mtb). Mutations in compound 1-resistant Mtb mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC. The compounds effectively inhibited the HadAB and HadBC enzyme activities and affected mycolic acid biosynthesis in Mtb, in a concentration-dependent manner. Unlike known 3-hydroxyl-ACP dehydratase complex inhibitors of clinical significance, isoxyl and thioacetazone, 1,3-diarylpyrazolyl-acylsulfonamides did not require activation by EthA and thus are not liable to EthA-mediated resistance. Further, the crystal structure of a key compound in a complex with Mtb HadAB revealed unique binding interactions within the active site of HadAB, providing a useful tool for further structure-based optimization of the series.