The biotin synthesis pathway in Mycobacteria tuberculosis is a new target for the development of anti-tuberculosis drugs / 药学学报

italic>Mycobacterium tuberculosis, responsible for tuberculosis (TB), remains a major health problem worldwide and is one of the infectious diseases causing increased morbidity and mortality worldwide. Biotin, namely vitamin H, is an important cofactor necessary for fatty acid biosynthesis, gluconeogenesis and amino acid metabolism in organisms including Mycobacterium tuberculosis. Due to its inability to ingestion biotin from outside, Mycobacterium tuberculosis can only obtain biotin through biotin biosynthesis. Different from the classical BioC-BioH, BioI-BioW and non-classical BioZ pathways, Mycobacterium tuberculosis synthesized biotin by "BioC-BioH(2)" pathway in the early stage. This review focuses on the unique biotin synthesis pathway of Mycobacterium tuberculosis and its key genes, especially the response of this pathway and biotin-dependent carboxylase to tuberculosis first-and second-line drugs, as well as inhibitors and natural products targeting biotin synthesis.

Pharmacokinetics of rifampicin, isoniazid & pyrazinamide during daily & intermittent dosing: A preliminary study

Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (Cmax) of RMP was significantly higher (RMP: 8.5 ?g/ml vs. 5.5 ?g/ml; P=0.003) and Cmax of INH was significantly lower (INH: 4.8 ?g/ml vs. 10.9 ?g/ml; P<0.001) in case of daily dosing compared to thrice-weekly ATT. Cmax of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP Cmax (8.0 ?g/ml) during thrice-weekly compared to daily ATT (78% vs. 36%; P=0.004). Multiple linear regression analysis showed that Cmax of RMP was significantly influenced by the dosing rhythm, pulmonary TB and Cmax of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.

Clinical characteristics of liver injury caused by anti-tuberculosis drugs in newly treated pulmonary tuberculosis patients co-infected with hepatitis B virus / 公共卫生与预防医学

Objective To investigate the clinical characteristics of drug-induced liver injury caused by anti-tuberculosis drugs in newly treated pulmonary tuberculosis patients with hepatitis B virus (HBV). Methods A total of 133 patients with pulmonary tuberculosis and HBV who were treated in Zhuzhou Central Hospital from January 2018 to early January 2022 were selected, and all were treated with conventional anti-tuberculosis 2HRZE/4HR regimen. According to the liver injury, the patients were divided into liver injury group and no liver injury group. Univariate analysis was used to analyze the related factors of liver injury caused by anti-tuberculosis drugs, and multivariate logistic regression analysis was used to analyze the independent risk factors of liver injury caused by anti-tuberculosis drugs. Results Among 133 cases of newly treated pulmonary tuberculosis patients with HBV, 24 cases had liver injury caused by anti-tuberculosis drugs, accounting for 18.05%; 109 patients had no liver injury caused by anti-tuberculosis drugs, accounting for 81.95%. Univariate analysis showed that there were significant differences in smoking history, drinking history, diabetes history, hypertension history, anti-tuberculosis treatment plan, malnutrition, and use of hepatoprotective drugs between the liver injury group and the no liver injury group (P<0.05). Multivariate logistic regression analysis showed that smoking history, drinking history, diabetes history, hypertension history, PZA-containing regimen, malnutrition, and no use of hepatoprotective drugs were independent risk factors for liver injury caused by anti-tuberculosis drugs. Conclusion Smoking history, drinking history, diabetes history, hypertension history, PZA-containing regimen, malnutrition, and no use of hepatoprotective drugs are the risk factors for drug-induced liver injury caused by anti-tuberculosis drugs in newly treated pulmonary tuberculosis patients with HBV.

Nutritional status of patients with pulmonary tuberculosis and anti-tuberculosis treatment effect / 中国热带医学

@#Abstract: Objective To investigate the nutritional status of patients with pulmonary tuberculosis and its effects on conventional anti-tuberculosis treatment, so as to provide a basis for improving the efficacy of conventional treatment of pulmonary tuberculosis. Methods The relevant data of 168 patients with pulmonary tuberculosis admitted to Suining Central Hospital from April 2020 to April 2022 were retrospectively analyzed. Nutritional status of the patients before treatment was investigated using the Mini Nutritional Assessment (MNA) score, and the influencing factors of nutritional status before treatment were analyzed. Therapeutic effects of anti-tuberculosis drugs in the non-nutritional risk group and the nutritional risk group were comparatively analyzed. Results Among the 168 patients, 64 were assessed as having good nutritional status before treatment, 59 had the risk of malnutrition and 45 were malnourished according to the MNA score. Univariate analysis and linear regression analysis showed that age, underlying diseases, and clinical symptoms were factors affecting the MNA score before treatment (t=3.173, 3.718, 2.018, P all<0.05); whereas gender and education level were not factors affecting MNA score before treatment (t=0.065, 0.059, P all>0.05). According to the MNA score before treatment, the patients were dividedinto a non-nutritional risk group (MNA score > 23.5) and a nutritional risk group (MNA score ≤23.5). The negative conversion rate of sputum bacteria, effective rate of focal absorption in the non-nutritional risk group were 92.19% (59/64)and90.63% (58/64) , respectively, which were significantly higher than corresponding 79.85% (82/104)and76.92% (80/104) in the nutritional risk group. The drug resistance rate, adverse reaction rate, and average treatment cost of the no nutritional risk group and nutritional risk group were 7.81% (5/64) and 21.15% (12/104), 15.63% (10/64) and 31.73% (33/104), (0.62±0.13) million yuan and (0.89±0.26) million yuan, respectively, with significant differences (χ2=5.228, 5.071, 7.685, 5.396, 7.728, P all<0.05). Conclusions Patients with pulmonary tuberculosis exhibit poor nutritional status before treatment. The patients’nutritional status is easily affected by age, underlying diseases, and clinical symptoms, thereby affecting the effect of anti-tuberculosis treatment. Therefore, early nutritional intervention for tuberculosis patients should be recommended in order to prevent malnutrition and enhance the effectiveness of anti-tuberculosis treatment.

Transcriptional analysis on biomarkers of liver injury induced by anti-tuberculosis drugs / 上海预防医学

ObjectiveThe study utilized human transcriptome microarray to explore biomarkers for diagnosing drug-induced liver injury （DILI） caused by anti-tuberculosis drugs. MethodsA 6-month follow-up study was conducted on 152 patients treated with anti-tuberculosis drugs in designated hospitals in Shanghai. The blood samples were collected at the 0， 2， 4， 8， 12 and 24 weeks after treatment. According to the clinical biochemical indicators， the research subjects were divided into DILI cases （34 cases） and Control cases （118 cases）. Single factor analysis was conducted on the influencing factors between the two groups. In a 1∶1 matched DILI-control study， RNA samples of 13 pairs of cases were sequenced by the whole transcript expression mRNA array. Differentially expressed genes （DEGs） were screened by Hotelling's T2 value sequencing and the expression trend analysis of genes by STEM （short-time series expression miner）， and the functional enrichment and pathway analysis of DEGs were carried out. ResultsIn total 152 clinical cases， weight of patients was a risk factor for the occurrence of hepatotoxicity caused by anti-tuberculous drugs. Based on the analysis results of mRNA array， 513 DEGs were screened by Hotelling's T2 value sequencing method， which were enriched in 32 annotations of GO （Gene Ontology） analysis and 10 pathways of KEGG （Kyoto encyclopedia of genes and genomes） analysis. One differential expression pattern was screened by STEM， which was enriched in 2 biological process notes of GO. Among them， the key genes AIM2， CD86， CXCL10 and non-coding RNAs SCARNA10， SNHG10 and SNORD105 are potential biomarkers of DILI caused by anti-tuberculosis drugs. ConclusionIn this research for biomarkers conducted on cases with liver injury caused by anti-tuberculosis drugs， biological pathways associated with hepatotoxicity are identified and a series of key genes related with drug-induced liver injury are found， which provides the basis for mechanism study and searching for earlier and more sensitive biomarkers.

Drug resistance surveillance in Mycobacterium tuberculosis in Jiaxing City / 预防医学

Objective@#To investigate the resistance of Mycobacterium tuberculosis to first-line anti-tuberculosis drugs in Jiaxing City, Zhejiang Province from 2017 to 2019, so as to provide insights into improvements of the therapeutic effect of pulmonary tuberculosis. @*Methods@#Data pertaining to pulmonary tuberculosis in Jiaxing City from 2017 to 2019 were collected from the Tuberculosis Surveillance System of Chinese Disease Prevention and Control Information System, including demographics, treatment classification, sputum culture and drug resistance. The spectrum, types and prevalence of drug resistance in M. tuberculosis to four first-line tuberculosis drugs, including isoniazid (INH), rifampicin (RFP), streptomycin (SM) and ethambutol (EMB), was analyzed using a descriptive epidemiological method.@*Results@#A total of 1 310 M. tuberculosis isolates were cultured from pulmonary tuberculosis patients in Jiaxing City from 2017 to 2019, and there were 259 M. tuberculosis isolates that were resistant to anti-tuberculosis drugs, with an overall drug resistance rate of 19.77%. The prevalence rates of drug resistance to INH, SM, RFP and EMB were 13.36%, 11.83%, 5.50% and 3.59%, respectively. The prevalence of drug resistance was lower in M. tuberculosis isolates from treatment-naïve patients than from retreated patients (18.45% vs. 34.58%, P<0.05). M. tuberculosis isolates presented high resistance to SM (4.50%) and INH alone (4.35%), the highest resistance to INH-SM combinations (3.28%), and the highest resistance to INH+RFP+SM combinations (1.83%). Sixteen isolates were resistant to all the four drugs, with a drug resistance rate of 1.22%. The proportions of resistance to a single drug, RFP resistance, multidrug resistance and resistance to two and more drugs were 10.31%, 5.50%, 4.73% and 4.73%, respectively. In addition, the prevalence of RFP resistance among all patients and treatment-naïve patients both showed a tendency towards a rise from 2017 to 2019 (P<0.05). The prevalence of RFP resistance (7.01% vs. 3.76%) and resistance to two and more drugs (6.01% vs. 3.25%) was both higher among interprovincial mobile tuberculosis patients than among local non-mobile patients (P<0.05). @*Conclusions@#The overall prevalence of drug resistance was lower in M. tuberculosis isolates in Jiaxing City from 2017 to 2019 than in Zhejiang Province, with INH and RFP resistance as predominant types.

Difficultés diagnostiques de la tuberculose cérébrale / Diagnostic difficulties of cerebral tuberculosis

La tuberculose est une des maladies infectieuses les plus répandues dans le monde .Elle représente un problème de santé publique majeur dans les pays en voie de développe ment, y compris l'Algérie . À l'échelle mondiale et parmi tous les cas de tuberculose, l'OMS rapporte 14 % de tuberculose extra-pulmonaire (TEP) sans atteinte pulmonaire concomitante. Dans notre pays et durant ces dernières années, une recrudescence de la tuberculose extrapulmonaire a été observée. L'objectif de cet article était de présenter un cas atypique de tuberculose cérébrale dont le diagnostic a été tardif, posé par l'examen anatomopathologique avec une revue de la littérature. C'est le cas d'une jeune patiente hospitalisée dans le cadre de l'urgence pour un syn drome d'hypertension intracrânienne avec troubles neurologiques. La tomodensitomé trie cérébrale a objectivé de multiples localisations cérébrales avec une hydrocéphalie active. Le bilan d'extension était sans anomalie. La patiente avait bénéficié d'une inter vention chirurgicale, les suites opératoires ont été favorables. L'examen anatomo-pa thologique était en faveur d'une lésion inflammatoire spécifique granulomateuse faite de larges plages de nécrose caséeuse. La patiente a répondu au traitement antituber culeux. Le problème diagnosticque et les résultats seront discutés avec une revue de la littéra ture. La tuberculose cérébrale est une forme rare de la tuberculose extra-pulmonaire. Le tableau clinique ainsi que la neuro-imagerie (TDM, IRM) sont atypiques. Le diagnostic était postopératoire, reposant sur l'examen anatomopathologique. Le pronostic dépend de la précocité du diagnostic, du siège de la lésion et de la réponse au traitement antituberculeux.

Tuberculosis is one of the most widespread infectious diseases in the world. It constitutes a major public health problem, especially in developing countries, including Algeria. Globally and among all tuberculosis cases, WHO reports 14% extra-pulmonary tuberculosis (EPT) without concomitant pulmonary involvement. In our country and in recent years, an upsurge in extrapulmonary tuberculosis has been observed. The objective of this article was to present an atypical case of cerebral tuberculosis whose diagnosis was late, made by anatomopathological examination with a review of the literature. We report the case of a young patient hospitalized in emergency for an intracranial hypertension syndrome with neurological disorders. Cerebral computed tomography revealed multiple brain locations with active hydrocephalus. The extension assessment was without anomaly. The patient underwent a surgical intervention, the operative consequences were favorable. The pathological examination was in favor of a specific inflammatory granulomatous lesion made up of large areas of caseous necrosis. The patient was cured under anti-tuberculosis treatment. The diagnostic problem and the results will be discussed with a review of the literature. Cerebral tuberculosis is a rare form of extrapulmonary tuberculosis. The clinic as well as the neuroimaging (CT, MRI) are atypical. The diagnosis is postoperative, based on the pathological examination. The prognosis depends on the early diagnosis, the site of the lesion and the response to anti-tuberculosis treatment.

Drug-induced liver injury after anti tuberculosis drugs administration, how to diagnose? a case report

Drug-induced liver injury (DILI) is a liver injury caused by various drugs, herbs, or other xenobiotics, which causes abnormalities in liver tests or liver dysfunction in the absence of other causes of liver damage. The most common causative drugs are antituberculosis drugs (ATDs), anti-infective drugs, and natural herbal medicines. The diagnosis of DILI can be difficult due to the lack of specific signs, symptoms and tests and is partly a diagnosis based on exclusion. In this case report, we will discuss how to diagnosis DILI TB and causative assessment using RUCAM score. A male, 64 years old, has complained of weakness since 1 week ago and worsened since 1 day ago. The patient also felt persistent nausea for 1 week, so his eating and drinking decreased. Besides, he complained getting abdominal pain, especially in the upper right region and heartburn. The patient has been on first category of TB treatment since 20 days ago. Chest X-ray showed Lung TB with infiltrate inmultiple cavities. Abdominal ultrasound showed no abnormality. The patient was discharged from our hospital after 6 days of hospitalization. DILI remains a diagnosis of exclusion based primarily on a detailed history and judicious use of blood tests, hepatobiliary imaging, and liver biopsy. TheRoussel Uclaf causality assessment method (RUCAM)system is an assigning point for clinical, biochemical, serologic and radiologic features of liver injury. We use RUCAM score to make an assessment that show the likelihood of the hepatic injury due to a specific medication.

Cholestatic drug induced liver injury in active pulmonary tuberculosis patient: a case report

Drug induced liver injury (DILI) has been a long-standing concern in the treatment of tuberculosis. Anti-tuberculosis therapy (ATT) is known to have hepatotoxicity effect. DILI is diagnosed clinically using liver biochemical test, such as alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin. Calculating ratio (R) of ALT over ALP, is useful to classify types of injury pattern in DILI. Roussel Uclaf causality assessment method (RUCAM)scaleserves as a method to assess the causality agents for DILI. Here we report a case of 59 years old male who developed cholestatic DILI on fourth weeks of ATT. Patient came in with loss of consciousness, jaundice, nausea, pruritus, and abdominal tenderness. Patient抯 ALT level was normal, but ALP and total bilirubin was significantly elevated, with R values less than 2, indicating a cholestatic type of injury. Patient sputum was positive for tuberculosis bacteria, showing an active infection. Patient was admitted and ATT was discontinued. Patient showed improvement, but eventually fall into sepsis and developed respiratory distress on sixth day of admission despite adequate treatment and close monitoring. Despite most of the cases resolves spontaneously upon cessation of the toxic agents, in the severe form, it may fall into chronic liver injury, acute liver failure, and eventually death. Preventing DILI is readily important by educating, screening for risk factors, and routine evaluation of liver enzymes in patient under ATT. Early diagnosis and prompt treatment are needed to avoid poor prognosis in the course of the disease.

Cien años de vacuna BCG / One hundred years of BCG vaccine

Resumen La vacuna BCG fue administrada por primera vez en 1921, en París, a un recién nacido de madre tuberculosa. Entre 1924 y 1960, el Instituto Pasteur entregó cultivos de BCG a más de 50 labora torios de todo el mundo. En 1925, el Dr. Andrés Arena lo introdujo en Argentina, donde se comenzó a producir y aplicar la vacuna a recién nacidos por vía oral. La cepa original sufrió múltiples cambios genéticos que no parecen haber afectado su eficacia protectora, establecida aun sin que se conociera el mecanismo de acción. En Argentina, un estudio (1978-1985) demostró que la BCG previene la TB primaria en general, y en un 100% la meningitis y otras localizaciones extrapulmonares. Su efecto es independiente de las medidas de control de la TB (detección de casos y tratamiento). Además, BCG provee protección inespecífica contra diversas enfermedades infecciosas y se la usa en el tratamiento del cáncer de vejiga. En 2020 ya se habían establecido por lo menos cinco tecnologías para el desarrollo de vacunas anti-TB: vacunas celulares, de subunidades proteicas, de ácidos nucleicos, con vector adenovirus, y con virus influenza recombinante como vector. Actualmente hay más de 20 vacunas candidatas anti-TB en evaluación. La historia enseña, y la pandemia de COVID-19 ha confirmado que la vacunación es un instrumento fundamental para el control de las enfermedades infecciosas. Y hasta que haya disponible otra más eficaz, BCG seguirá figurando en el Calendario de Vacunación Nacional, para ser aplicada al recién nacido.

Abstract The BCG vaccine was given for the first time in 1921, in Paris, to a newborn of a mother with tuberculosis. Between 1924 and 1960, the Pasteur Institute delivered BCG cultures to more than 50 laboratories around the world. In 1925, Dr Andrés Arena introduced the BCG seed to Argentina, where the vaccine began to be produced and applied orally to newborns. The original strain underwent diverse genetic changes in different parts of the world, which did not seem to affect its protective efficacy. In Argentina, a study (1978-1985) showed that BCG prevents primary TB in general, and has 100% ef ficacy in meningitis and other extra-pulmonary TB locations. BCG effect is independent of TB control measures (case detection and treatment). Furthermore, BCG provides nonspecific protection from various infections and is used in the treatment of bladder cancer. By 2020, at least five technologies had already been established for the future development of anti-TB vaccines: cellular vaccines, protein subunits, nucleic acids, with adenovirus vector, and with recombinant influenza virus as a vector. There are currently more than 20 TB vaccine candidates under evaluation. History teaches, and the COVID-19 pandemic has confirmed, that vaccination is a fundamental instrument for the control of infectious diseases. Until a more effective vaccine becomes available, BCG will continue to be included in the Argentine National Vaccination Calendar for application to newborns.

Study on the Prevention Mechanism of Anti-tuberculosis Drug-induced Liver Injury with Orazamide Based on HMGB1-RAGE Signaling Pathway / 中国药房

OBJECTIVE：To prelimi narily investigate the possible mechanism of orazamide to prevent anti-tuberculosis drug-induced liver injury （ATB-DILI）. METHODS ：A total of 60 Kunming mice were randomly divided into blank group ，model group，positive control group [diammonium glycyrrhizinate 60 mg/（kg·d）]，orazamide low-dose ，medium-dose and high-dose groups [ 80，160，320 mg/（kg·d）]，with 10 mice in each group. Except for blank group ，other groups were given isoniazid [ 75 mg/（kg·d）]+rifampicin [ 75 mg/（kg·d）] for 14 days intragastrically to induce ATB-DILI model. At the same time ，administration groups were given relevant medicine intragastrically ，blank group and model group were given normal saline intragastrically. The administration volume was 20 mL/（kg·d），once a day ，for consecutive 14 days. The general conditions of the mice were observed and recorded every day ，such as growth and development ，mental and diet state. After last medication ，liver index was calculated ， and HE staining was adopted to observe pathological changes of liver tissue of mice. The positive expression of high mobility group protein B 1 （HMGB1） and NF-κ B in liver tissue were detected by streptavidin biotin-peroxidase complex （SABC） immuno- histochemistry. The serum levels of liver function indexes in serum ，the protein expression of advanced glycation end product receptor（RAGE）and TNF-α in liver tissue were detected by ELISA. RESULTS：Compared with blank group ，the growth and development of mice in the model group were slow ，and their appetite and spirit were poor. The liver index ，serum levels of TBIL ， DBIL，ALT，AST，ALP，TBA and γ-GT were increased significantly （P＜0.05）. Structural disorder of liver lobules ，degeneration and necrosis of liver cells and inflammatory cell infiltration were observed. The expression of HMGB 1，NF-κB，RAGE and TNF-α in liver tissue were elevated significantly （P＜0.05）. Compared with model group ，the general condition of mice were all improved to different extents in orazamide low-dose ，medium-dose and high-dose groups ，positive control group ，while liver index and above serum indexes were all decreased significantly （P＜0.05）. The pathological changes of liver tissue were all improved to different extents ，while the protein expression of HMGB 1，NF-κB，RAGE and TNF-α were all decreased significantly（P＜0.05）. The improvement of above indexes in orazamide high-dose group were all significantly better than orazamide low-dose and medium-dose groups （P＜0.05）；the levels of ALP and TBA in orazamide high-dose group were significantly lower than positive control group （P＜0.05）. CONCLUSIONS ：Orazamide can prevent ATB-DILI induced by isoniazid combined with rifampicin in mice，the mechanism of which may be associated with down-regulating the protein expression of HMGB 1 and RAGE in liver tissue and inhibiting the secretion of inflammatory factors.

Changes of Anti-tuberculosis Herbs Formula During Past Three Decades in Contrast to Ancient Ones / 中国结合医学杂志

OBJECTIVE@#To investigate the evolution of herbal medicine in treating tuberculosis (TB) and encourage anti-TB drug discovery and development.@*METHODS@#In this study, 477 ancient traditional Chinese medicine formulae were collected from the Dictionary of Traditional Chinese Medicine Prescriptions and 172 modern Chinese medicine formulae (from 1986 to 2016) were collected by searching 4 databases: WanFang Data Knowledge Service Platform, China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP) and Chinese Bio-medical Literature and Retrieval System (SinoMed) in Chinese. We restricted the search to publications in Chinese. Further data analysis was done using the Traditional Chinese Medicine Inheritance Support System version 2 Software.@*RESULTS@#There were 425 herbs in the 477 ancient formulae and 257 herbs in the 172 modern formulae. Half of the top 30 herbs were shared by both modern and ancient prescriptions. They are Radix Ophiopogonis, Astragalus membranaceus, Fritillaria cirrhosa, Dried rehmannia glutinosa, Poria cocos, Angelica sinensis, Prepared rehmannia glutinosa, Platycodon Root, Radix paeoniae alba, Schisandra chinensis, Bighead atractylodes rhizome, Rhizoma anemarrhenae, Cortex lycii radicis and Radix Scutellariae. Only two groups of herbs with a high correlation coefficient were found in both modern and ancient prescriptions, the Dried rehmannia glutinosa with Radix ophiopogonis, and Radix ophiopogonis with Prepared rehmannia glutinosa. There were 9 and 15 core herb combinations in modern and ancient prescriptions, respectively, but no one was found simutaniously in both modern and ancient prescriptions.@*CONCLUSIONS@#Although there were wide variations in the herb groups and herb combinations in the formulae, half of the top 30 herbs were found in both modern and ancient prescriptions. The core herb combinations in modern and ancient prescriptions could help us to improve the priscription for treatment of TB.

Antimicrobial and anti-tubercular potential of Streptomyces lomondensis SACC 63 isolated from soil samples in Himachal Pradesh, India

Aim: The antimicrobial and anti-tubercular potential of Actinobacteria isolated from soil in Himachal Pradesh, India, was examined in this study.Methodology: The bioactive metabolites produced from five selected Actinobacterial cultures SACC-63, SACC-75, SACC-76, SACC-77 and SACC-N10 by agar surface fermentation were tested for their antimicrobial and anti-tubercular efficacy in in-vitro. The taxonomy of SACC-63 was identified as Streptomyces lomondensis using 16S-rRNA sequence analyses. Results: The ethyl acetate extract of strain SACC-63 showed broad spectrum activity against wide range of bacterial and fungal pathogens at 250 µg per disc concentration. In anti-tubercular screening by luciferase reporter phage (LRP) assay, four actinobacterial strains showed more than 65% inhibition against the standard strain Mycobacterium tuberculosis H37Rv and multi drug resistant (MDR) M. tuberculosis strain at 100 µg ml-1 and 500 µg ml-1 concentrations, except the strain SACC-N10. The MIC values of SACC-63 against microbial pathogens ranged between 62.5 µg ml-1 and 250 µg ml-1. The strain SACC-63 showed 99% similarity with Streptomyces spp. Further, phylogenetic analysis based on 16S rRNA revealed a close relationship between SACC-63 and S. lomondensis. Interpretation: The present study suggested that S. lomondensis SACC-63 isolated from Himachal Pradesh region in India could be a promising source for the production of bioactive molecules.

In vitro anti-tuberculosis effect of chitosan-gelatin/poly(lactic acid co-glycolic acid) combined with drug-loaded hydrogel / 中国组织工程研究

BACKGROUND: Anti-tuberculous chemotherapy is the main method for treating bone and joint tuberculosis. However, systemic administration hardly maintains the effective drug concentration in the focus area, and the therapeutic efficacy is unsatisfactory. OBJECTIVE: To prepare a chitosan-gelatin/poly(lactic-co-glycolic acid) combined with drug-loaded hydrogel, which can release anti-tuberculosis drugs in situ for a long time and promote osteogenesis. METHODS: Isoniazid, a hydrophilic anti-tuberculosis drug, and a hydrophobic stromal cell derived factor-1 were loaded into poly(lactic-co-glycolic acid) by double emulsion method to prepare drug-loaded poly(lactic acid co-glycolic acid) microspheres, which were then mixed into chitosan gelatin/poly(lactic acid co-glycolic acid) combined with drug-loaded hydrogel. The ability of drug delivery and anti-tuberculosis of poly(lactic acid co-glycolic acid) microspheres and chitosan gelatin/poly(lactic acid co-glycolic acid) combined with drug-loaded hydrogels in vitro were tested. MC3T3-E1 cells were inoculated on the surface of microspheres and hydrogel respectively. The biocompatibility was detected by cell counting kit-8 assay. The osteogenetic activity was detected by alkaline phosphatase activity. RESULTS AND CONCLUSION: (1) The burst release of isoniazid in the microspheres was about 23.3% in 1 hour, 42.6% in 2 days, and then it entered the sustained-release stage in the later 25 days. The burst release of stromal cell derived factor was about 19.8% in 1 hour, 44.7% in 2 days, and then it entered the sustained-release stage in the next 25 days. The release of isoniazid and stromal cell-derived factor in the combined drug-loaded hydrogel was 8.3% and 8.5% in the first hour, respectively. The cumulative release rates on the second day were 15.2% and 17.6%, respectively, which were much lower than that of poly(lactic acid co-glycolic acid) microspheres. (2) After 4 weeks in vitro, the antibacterial diameter of the combined drug-loaded hydrogel was much larger than that of the drug-loaded microspheres, and the antibacterial rate was higher than that of the drug-loaded microspheres (P < 0.05). (3) The combined drug-loaded hydrogel and the drug-loaded microspheres had good cytocompatibility and cell viability was about 100%. (4) After 5 and 10 days of culture, there was no significant difference in the activity of alkaline phosphatase on the surface of drug-loaded hydrogel and drug-loaded microspheres. (5) These results show that the in situ chitosan-gelatin/poly(lactic acid co-glycolic acid) combined with drug-loaded hydrogel can be used for treating tuberculosis and other bone and joint infections.

Association of adverse drug reaction to anti-tuberculosis medication with quality of life in patients in a tertiary referral hospital

Abstract INTRODUCTION: Adverse drug reactions can develop when using anti-tuberculosis medication, and the effects of the drugs can also significantly hinder the treatment of patients. METHODS: A cross-sectional survey was conducted in 73 patients using two standardized questionnaires and the World Health Organization Quality of Life-Bref. RESULTS: All patients reported the presence of adverse drug reactions, 71.6% of which are minor and 28.3% both major and minor. The global quality of life analysis showed that patients with tuberculosis have a good average (67.3%). CONCLUSIONS: There is an association between quality of life and adverse drug reaction, educational level, and vulnerability.

Efficacy and Safety of Linezolid Combined with Routine Anti-tuberculosis Drugs for Tuberculous Meningitis ： A Meta-analysis / 中国药房

OBJECTIVE：To systematically evaluate the efficacy and safety of linezolid （LZD）combined with routine anti- tuberculosis drugs in the treatment of tuberculous meningitis （TBM），so as to provide evidence-based reference for clinical medi- cation. METHODS ：Retireved from PubMed ，Cochrane Library ，Embase，CNKI and Wanfang database ，randomized controlled trials（RCT）of LZD combined with routine anti-tuberculosis drugs （trial group ）versus routine anti-tuberculosis drugs （control group）were collected from the inception to Jan. 2020. After literature screening and data extraction ， the quality of the included literature were evaluated with bias risk assessment tool recommended by Cochrane system evaluator handbook 5.2. Meta-analysis was conducted by using Rev Man 5.3 software，and sensitivity analysis and publication bias analysis were performed. RESULTS ： Totally 9 RCTs involving 602 patients were included. Meta-analysis showed that total response rate [OR ＝4.05，95％CI（2.26，7.26）， P＜0.000 01]， changes of protein content of cerebrospinal fluid [MD ＝0.48，95％CI（0.20，0.77），P＝0.000 8]，changes of white blood cells count of cerebrospinal fluid [MD ＝44.43，95％CI（20.06，68.81），P＝0.000 4]，changes of cerebrospinal fluid glucose/ synchronous blood glucose [MD ＝0.09，95％CI（0.05，0.14），P＜0.000 1] of trial group were significantly higher than those of control group. There was no statistical significance in the changes of chloride content of cerebrospinal fluid [MD ＝8.08，95％CI（－0.64， 16.80），P＝0.07] and the incidence of ADR [OR ＝1.34，95％CI（0.57，3.11），P＝0.50] between 2 groups. The results of sensitivity analysis showed that there were significant differences comparison with before exclusion when the change of protein content in cerebrospinal fluid and the change of glucose/synchronous blood glucose in cerebrospinal fluid were taken as indexes ，and there was no significant difference comparison with before exclusion when the changes of white blood cell count and chloride content in cerebrospinal fluid were taken as indexes. The results of publication bias analysis showed that there was a certain publication bias in this study. CONCLUSIONS ：LZD combined with conventional anti-tuber culosis drugs is effective and safe for TBM. Because the inconsistent results of sensitivity analysis and publication bias exists in publication bias analysis ，the conclusions need to be further confirmed by more large sample and multi-center studies.

Study on CYP2E1 gene polymorphism and the relationship between methylation level of its promoter region and liver injury induced by anti-tuberculosis drugs in Mongolian tuberculosis patients in Inner Mongolia / 医学研究生学报

ObjectiveThere are few studies on whether the occurrence of anti-tuberculosis drug-induced liver injury (ADIH) is associated with the polymorphism of CYP2E gene and methylation level. This study aims to CYP2E1 gene polymorphism and the relationship between the methylation level of the promoter region and ADIH in Mongolian tuberculosis (TB) patients.Methods A total of 135 Mongolian TB patients who received standardized treatment at the Tuberculosis Research Institute of Tongliao City, Inner Mongolia from November 2015 to June 2018 were selected. According to the ADIH criteria, TB patients with liver injury were selected as the ADIH group (n=45), and TB patients without liver injury were matched as the control group based on a ratio of 1∶2 (n=90). DNA extraction and polymerase chain reaction (PCR) were performed to amplify the CYP2E1 gene to determine the CYP2E1 rs2031920 genotype, and to analyze the CYP2E1 gene polymorphism and relationship between ADIH and promoter methylation level.Results There were no significant differences in the distribution of CYP2E1 rs2031920 genotype, C1 and C2 gene frequencies between the ADIH group and the control group (P>0.05). The overall methylation level in the promoter region of CYP2E1 gene in ADIH group (0.711±0.085) was significantly lower than that of the control group (0.759±0.062). Results of Logistic regression showed that the overall methylation level in the promoter region of CYP2E1 gene was the influencing factor for the occurrence of ADIH (P<0.005). For each 0.1 unit increase of methylation level, the risk of ADIH occurrence reduced by 0.388 times, and the OR (95% CI) value was 0.388 (between 0.204 and 0.739).Conclusion The overall methylation level in the promoter region of CYP2E1 gene was reduced in Mongolian ADIH patients, but the polymorphism of CYP2E1 gene was not related to the occurrence of ADIH. These results suggested that CYP2E1 methylation could be applied to the prevention and treatment of ADIH in patients with tuberculosis.

Study on CYP2E1 gene polymorphism and the relationship between methylation level of its promoter region and liver injury induced by anti-tuberculosis drugs in Mongolian tuberculosis patients in Inner Mongolia / 医学研究生学报

ObjectiveThere are few studies on whether the occurrence of anti-tuberculosis drug-induced liver injury (ADIH) is associated with the polymorphism of CYP2E gene and methylation level. This study aims to CYP2E1 gene polymorphism and the relationship between the methylation level of the promoter region and ADIH in Mongolian tuberculosis (TB) patients.Methods A total of 135 Mongolian TB patients who received standardized treatment at the Tuberculosis Research Institute of Tongliao City, Inner Mongolia from November 2015 to June 2018 were selected. According to the ADIH criteria, TB patients with liver injury were selected as the ADIH group (n=45), and TB patients without liver injury were matched as the control group based on a ratio of 1∶2 (n=90). DNA extraction and polymerase chain reaction (PCR) were performed to amplify the CYP2E1 gene to determine the CYP2E1 rs2031920 genotype, and to analyze the CYP2E1 gene polymorphism and relationship between ADIH and promoter methylation level.Results There were no significant differences in the distribution of CYP2E1 rs2031920 genotype, C1 and C2 gene frequencies between the ADIH group and the control group (P>0.05). The overall methylation level in the promoter region of CYP2E1 gene in ADIH group (0.711±0.085) was significantly lower than that of the control group (0.759±0.062). Results of Logistic regression showed that the overall methylation level in the promoter region of CYP2E1 gene was the influencing factor for the occurrence of ADIH (P<0.005). For each 0.1 unit increase of methylation level, the risk of ADIH occurrence reduced by 0.388 times, and the OR (95% CI) value was 0.388 (between 0.204 and 0.739).Conclusion The overall methylation level in the promoter region of CYP2E1 gene was reduced in Mongolian ADIH patients, but the polymorphism of CYP2E1 gene was not related to the occurrence of ADIH. These results suggested that CYP2E1 methylation could be applied to the prevention and treatment of ADIH in patients with tuberculosis.

Advances in the research of anti-tuberculosis drugs / 中国药科大学学报

@#Tuberculosis(TB)treatment is currently falling into a gigantic dilemma-particularly with the increased frequentcy TB resistance, so the development of new anti-tuberculosis drugs is imperative and has received extensive attention. In the past decade, significant progress has been made in this field. Bedaquiline, delamanid and pretomanid have been approved for the clinical use. In addition, many other drugs and combination protocols are undergoing clinical trials. This review focuses on the new chemical entities for TB treatments from multiple perspectives, including the mechanisms of action, in vitro and in vivo pharmacological activities, pharmacokinetic properties and clinical results. Anti-tuberculosis drug research is prospected to provide a reference for drug deve-lopment.

Assessment of adherence to anti tuberculosis medication for successful implementation of revised national tuberculosis programme at a tertiary care hospital, Shimoga: a cross-sectional observational study

Background: This study assessed level of non-adherence to anti tuberculosis (TB) therapy among pulmonary TB patients, compares various factors among adherent and non-adherent TB patients, stressing on reasons for non-adherence at a tertiary care hospital.Methods: This institution based observational and cross-sectional study was conducted interviewing patients with pulmonary TB and assessed using Moriskys medication adherence scale-8 (MMAS-8), a pre- tested structured questionnaire based scoring system of patients treated for pulmonary TB at district TB centre SIMS, Shimoga. Descriptive statistics were employed.Results: Among 70 cases analysed, 57 were males and 13 females, with mean age group of 41.32�63 and mean MMAS score of 2.23�87. 53.33% patients were on continuous phase of treatment. The level of non-adherence were as follows, high= 18%, medium= 38% and low= 44%. The common cause for non-adherence was forgetfulness (66%) reasons being: betterment of symptoms (54%), sickness after taking medication (31%), distance of travel: far (15%). Many were labourers (62%), with low literacy rate, also chronic alcoholics (72%) and smokers (73%). Female with moderate literacy and not addicted to alcohol/smoking showed high adherence compared to males (p<0.05%).Conclusions: As prevalence of non-adherence is high, especially Patients on continuous phase of TB treatment, there arises immense need for continuous and effective health education to patients� and their family regarding the adverse effects and the need for high level of adherence to treatment for the complete cure of disease. Patients who are addicted to alcohol/smoking should be targeted with interventions to quit the same, provide free transport facility to RNTCP centres and prompt treatment of ADR, will improve adherence to medication.