Mutation Characteristics of inhA and katG Genes in Isoniazid-Resistant Mycobacterium Tuberculosis Patients in Xinjiang

Objective:To analyze the mutation characteristics of inhA and katG genes in isoniazid-resistant Mycobacterium tuberculosis in Xinjiang.Methods:The katG and inhA in 148 strains of isoniazid-resistant Mycobacterium tuberculosis were amplified through fluorescence quantitative PCR,and the amplified products were sequenced and compared.Results:The inhA gene mutation rate of 148 strains of isoniazid-resistant mycobacterium tuberculosis was 13.51%(20/148),among which the inhA gene mutation rate among patients of Han,Uygur,and Kazakh ethnicity were 15.87%,13.21%,and 17.65%,respectively.There was no significant difference in the inhA mutation rate among nationalities(c^(2)=2.897,P>0.05).The mutation rate of the katG gene was 84.46%(125/148),among which the mutation rates of patients of Han,Uyghur,and Kazak ethnicities were 82.54%,84.91%,and 76.47%,respectively.The Hui and other ethnic groups were all affected by the katG gene mutation.There was no significant difference in the mutation rate of the katG gene among different ethnicities(c^(2)=3.772,P>0.05).The mutation rates of the inhA gene in southern Xinjiang,northern Xinjiang,and other provinces were 18.60%,9.28%,and 37.50%,respectively.The mutation rates of the inhA gene in different regions were statistically different(c^(2)=6.381,P<0.05).There was no significant difference in the inhA mutation rate between patients from southern and northern Xinjiang(c^(2)=2.214,P>0.05)and between southern Xinjiang and other provinces(c^(2)=1.424,P>0.05).However,the mutation rate of the inhA gene in patients from other provinces was higher than that in northern Xinjiang(c^(2)=5.539,P<0.05).The mutation rates of the katG gene in southern Xinjiang,northern Xinjiang,and other provinces were 81.40%,87.63%,and 62.50%,respectively.There was no significant difference in the mutation rates of the katG gene among different regions(c^(2)=3.989,P>0.05).Conclusion:katG gene mutation was predominant in isoniazid-resistant tuberculosis patients in Xinjiang Uygur Autonomous Region,and inhA and katG gene mutation were no different among different ethnic groups.

Completion of 6-mo isoniazid preventive treatment among eligible under six children:A cross-sectional study,Lagos,Nigeria

BACKGROUND Nigeria is one of the thirty high burden countries with significant contribution to the global childhood tuberculosis epidemic.Tuberculosis annual risk for children could be as high as 4%particularly in high tuberculosis(TB)prevalent communities.Isoniazid(INH)Preventive Therapy has been shown to prevent TB incidence but data on its implementation among children are scarce.AIM To determine the completion of INH among under six children that were exposed to adults with smear positive pulmonary TB in Lagos,Nigeria.METHODS This was a hospital-based retrospective cross-sectional review of 265 medical records of eligible children<6 years old enrolled for INH across 32 private hospitals in Lagos,Nigeria.The study took place between July and September 2020.Data was collected on independent variables(age,gender,type of facility,TB screening,dose and weight)and outcome variables(INH outcome and proportion lost to follow up across months 1-6 of INH treatment).RESULTS About 53.8%of the participants were female,95.4%were screened for TB and none was diagnosed of having TB.The participants’age ranged from 1 to 72 mo with a mean of 36.01±19.67 mo,and 40.2%were between the ages of 1-24 mo.Only 155(59.2%)of the 262 participants initiated on INH completed the six-month treatment.Cumulatively,107(41.0%)children were lost to follow-up at the end of the sixth month.Of the cumulative 107 loss to follow-up while on INH,largest drop-offs were reported at the end of month 2,52(49%)followed by 20(19%),17(16%),11(10.2%)and 7(6.5%)at months 3,4,5 and 6 respectively.The analysis showed that there was no significant association between age,gender,type of facility and completion of INH treatment(P>0.005).CONCLUSION This study demonstrated suboptimal INH completion rate among children with only 6 out of 10 children initiated on INH who completed a 6-mo treatment in Lagos,Nigeria.The huge drop-offs in the first 2 mo of INH calls for innovative strategies such as the use of 60-d INH calendar that would facilitate reminder and early engagement of children on INH and their caregivers in care and across the entire period of treatment.

Crystal Structure and Characterization of Bis(4-isoniazidylthioformyl) Disulfide Hydration Sodium Coordination Polymer:n[(4-Pyridyl-CONHNCS_2)_2^(2-)]·[Na_2(H_2O)_8^(2+)]_n

The title compound has been prepared and characterized by elemental analysis, infrared spectra, NMR and thermal analyses, and its crystal structure was determined by X-ray diffraction method. The crystal crystallizes in the monoclinic system, space group C2/c with a = 2.3066（5）, b = 0.53320（ 11）, c = 2.3236（5） nm,β= 102.76（3）°, V = 2.7872（ 10） nm^3, Mr = 612.67, Z = 4, Dc = 1.460 g/cm^3, R = 0.0570 and wR = 0.1271. In the title compound, two 4-isoniazidylthioformyl units are bridged by S-S bond （0.2037（3） nm）. The Na ions are linked by O（4）, O（4A）, O（1） and O（1A） to form a one-dimensional hydration sodium coordination polymer. The Na ion is coordinated by a meridional arrangement of the six O atoms to assume a slightly distorted octahedron as a result of intermolecular hydrogen bonds. The thermal analytical data indicate that it decomposes completely at the temperature of 609.26 ℃.

Hepatoprotective potential of ethanolic extract of Ziziphus oenoplia(L.)Mill roots against antitubercular drugs induced hepatotoxicity in experimental models

Objective:To evaluate the hepatoprotective potential of ethanolic(50%) extract of Ziziphus oenoplia(L.) Mill(Z.oenoplia) root against isoniazid(INH) and rifampicin(RIF) induced liver damage in animal models.Methods:Five groups of six rats each were selected for the study.Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin(100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups.The serum levels of glutamic oxaloacetic transaminase(SGOT),glutamate pyruvate transaminase(SGPT),alkaline phosphatase (SALP),and bilirubin were estimated along with activities of superoxide dismutase,catalase, glutathione S-transferase,glutathione peroxidase,and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver.Result:The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase,glutamate pyruvate transaminase,alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards norma) in a dose dependent manner after the treatment with ethanolic extract of Z.oenoplia roots.Meanwhile,the decreased activities of superoxide dismutase,catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependency.In addition,ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections.Conclusions:The results of this study slrongly indicate that ethanolic extract of Z.oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats.

Naringenin protects against isoniazid- and rifampicininduced apoptosis in hepatic injury

AIM To explore the protective effects and mechanisms of naringenin(NRG) on hepatic injury induced by isoniazid(INH) and rifampicin(RIF).METHODS Male mice were randomly divided into four groups and treated for 14 d as follows: normal control group was administered intragastrically with normal saline solution alone; model group was administered intragastrically with INH(100 mg/kg) and RIF(100 mg/kg); lowand high-dosage NRG pretreatment groups were administered intragastrically with different doses of NRG(50 or 100 mg/kg) 2 h before INH and RIF challenge. Mice were killed 16 h after the last dose of drug treatment to determine activity of serum transaminases. Oxidative stress was evaluated by measuring hepatic glutathione(GSH) and superoxide dismutase(SOD) and malondialdehyde(MDA) levels. Histopathological changes in hepatic tissue were observed under the optical microscope. Hepatocyte apoptosis was measured by TUNEL assay and caspase-3 activation. Expression of Bcl-2 and Bax in liver was determined by western blot.RESULTS Both low- and high-dosage NRG pretreatment obviously alleviated serum levels of alanine aminotransferase and aspartate aminotransferase, liver index, hepatic MDA content, and increased hepatic GSH content and SOD activity compared with the INH and RIF-treated group(44.71 ± 8.15 U/L, 38.22 ± 6.64 U/L vs 58.15 ± 10.54 U/L; 98.36 ± 14.78 U/L, 92.41 ± 13.59 U/L vs 133.05 ± 19.36 U/L; 5.34% ± 0.26%, 4.93% ± 0.25% vs 5.71% ± 0.28%; 2.76 ± 0.67 nmol/mgprot, 2.64 ± 0.64 nmol/mgprot vs 4.49 ± 1.12 nmol/mgprot; 5.91 ± 1.31 mg/gprot, 6.42 ± 1.42 mg/gprot vs 3.11 ± 0.73 mg/gprot; 137.31 ± 24.62 U/mgprot, 148.83 ± 26.75 U/mgprot vs 102.34 ± 19.22 U/mgprot; all P < 0.01 or 0.05). Histopathological evaluation showed obvious necrosis and inflammatory cell infiltration in liver of mice administered INH and RIF; however, mice pretreated with NRG showed minor hepatic injury. In addition, INH and RIF resulted in hepatocyte apoptosis, and NRG pretreatment dramatically suppressed INHand RIF-induced hepatocytes apoptosis. Furthermore, NRG-mediated anti-apoptotic effects seemed to be in connection with its regulation of Bax and Bcl-2 protein expression in hepatic tissue.CONCLUSION NRG might attenuate INH- and RIF-induced hepatic injury via suppression of oxidative stress and hepatocyte apoptosis.

Evaluation of antihepatotoxic potential of Solanum xanthocarpum fruit extract against antitubercular drugs induced hepatopathy in experimental rodents

Objective:To assess the hepatoprotective effect of Solanum xanthocarpum(S. xanthocarpum) fruit extract against antitubercular drug-induced liver toxicity in experimental animals.Methods:Ethanolic(50%) fruit extract ofS. xanthocarpum(100, 200 and 400 mg/kg bw) was administered daily for 35 days in experimental animals. Liver toxicity was induced by combination of three antitubercular drugs [isoniazid(I) 7.5 mg/kg, rifampicin(R) 10 mg/kg and pyrazinamide(P) 35 mg/kg] given orally as suspension for 35 days in rats. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatise(ALP), total bilirubin(TBL), albumin(ALB), total protein(TP), lactate dehydroginase(LDH), and serum cholesterol(CHL). Meanwhile,in vivoantioxidant activities as lipid peroxidation(LPO), reduced glutathione(GSH), superoxide dismutase(SOD) and catalase(CAT) were measured in rat liver homogenate. The biochemical observations were supplemented by histopathological examination.Results:The results demonstrated that treatment withS.xanthocarpumsignificantly(P<0.05-P<0.001) and dose-dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore,S. xanthocarpumsignificantly(up toP<0.001) reduced the LPO in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels. Histopathology of the liver tissue showed that S. xanthocarpumattenuated the hepatocellular necrosis and led to reduction in inflammatory cells infiltration.Conclusions:The results of this study strongly indicate the protective effect of S. xanthocarpumagainst liver injury which may be attributed to its hepatoprotective activity, and thereby scientifically support its traditional use.

Application of Near Infrared Diffuse Reflectance Spectroscopy with Radial Basis Function Neural Network to Determination of Rifampincin Isoniazid and Pyrazinamide Tablets

Partial least squares（PLS）,back-propagation neural network（BPNN）and radial basis function neural network（RBFNN）were respectively used for estalishing quantative analysis models with near infrared（NIR）diffuse reflectance spectra for determining the contents of rifampincin（RMP）,isoniazid（INH）and pyrazinamide（PZA）in rifampicin isoniazid and pyrazinamide tablets.Savitzky-Golay smoothing,first derivative,second derivative,fast Fourier transform（FFT）and standard normal variate（SNV）transformation methods were applied to pretreating raw NIR diffuse reflectance spectra.The raw and pretreated spectra were divided into several regions,depending on the average spectrum and RSD spectrum.Principal component analysis（PCA）method was used for analyzing the raw and pretreated spectra in different regions in order to reduce the dimensions of input data.The optimum spectral regions and the models＇ parameters were chosen by comparing the root mean square error of cross-validation（RMSECV）values which were obtained by leave-one-out cross-validation method.The RMSECV values of the RBFNN models for determining the contents of RMP,INH and PZA were 0.00288,0.00226 and 0.00341,respectively.Using these models for predicting the contents of INH,RMP and PZA in prediction set,the RMSEP values were 0.00266,0.00227 and 0.00411,respectively.These results are better than those obtained from PLS models and BPNN models.With additional advantages of fast calculation speed and less dependence on the initial conditions,RBFNN is a suitable tool to model complex systems.

Mixed Binder Carbon Paste Electrode for Quantitation of Isoniazid in Serum

This paper covers the construction and behaviour of a mixed binder carbon paste electrode system appropriate for the cathodic stripping voltammetric quantitation of iso-niazid. The mixed binder consisted of glycerol and liquid paraffin. At the mixed binder carbon paste electrodes in a pH 3.0 buffer solution, isoniazid showed two sensitive cathodic stripping voltammetric wave at-0. 75 V (p1) and-0. 88 V (p2) , respectively. The p2 can be used for the determination of trace amounts of isoniazid, the linear range of the peak current to the isoniazid concentration being from 5. 0×10-7 to 5.0×10-5 mol/L, and the limit of detection being 1. 0×10-7 mol/L with a relative standard deviation of 6. 0%(n=10). The proposed method was directly used to determine the drug in blood serum without the pretreatment of blood serum.

Evaluation of Antimycobacterial Activity of Higenamine Using Galleria mellonella as an In Vivo Infection Model

The Phytochemical investigation on MeOH extract on the bark of Aristolochia brasiliensis Mart.&Zucc(Aristolochi-aceae)led to the isolation of major compound(1)as light brown grainy crystals.The compound was identified as 1-(4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol(higenamine)on the basis of spectroscopic analysis,including 1D and 2D NMR spectroscopy.The compound was evaluated for its antimycobacterial activity against Mycobacterium indicus pranii(MIP),using Galleria mellonella larva as an in vivo infection model.The survival of MIP infected larvae after a single dose treatment of 100 mg/kg body weight of higenamine was 80%after 24 h.Quantitatively the compound exhibited a dose dependent activity,as evidenced by the reduction of colony density from 10^(5) to 10^(3) CFU for test concentrations of 50,100,150 and 200 mg/kg body weight respectively.The IC50 value for higenamine was 161.6 mg/kg body weight as calculated from a calibration curve.Further analysis showed that,a complete inhibition of MIP in the G.mellonella could be achieved at 334 mg/kg body weight.Despite the fact that MIP has been found to be highly resistant against isoniazid(INH)in an in vitro assay model,in this study the microbe was highly susceptible to this standard anti-TB drug.The isolation of higenamine from the genus Aristolochia and the method used to evaluate its in vivo antimycobacterial activity in G.mellonella are herein reported for the first time.

Protective Effects of Total Glucosides of Paeony against the Liver Injury Induced by Anti-tuberculosis Drugs

[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony （TGP） against the liver injury induced by isoniazid （INH） and rifampicin （RFP）, and to provide experimental evidence for rational use of anti-tuberculosis drugs.[Methods] Liver injury in mice was induced by the combination of INH and RFP in mice. After the mice were given different doses of Total Glucosides of White Paeony Capsules （TGP） for 10 d, the hepatosomatic index, biochemical indices in serum and liver homogenate were measured, and histopathological changes in liver tissue were observed. Glucurolactone was used as the positive control, and 0.9% sodium chloride was used as the negative control in the experiment.[Results] TGP reduced the activities of alanine transaminase （ALT） and aspartate transferase （AST） in serum and the level of malondialdehyde （MDA） in liver tissue, and increased the level of glutathione （GSH） and the activity of superoxidase dismutase （SOD） in liver tissue.[Conclusions] TAP has a protective effect against the liver injury induced by INH and RFP.

Random amplified polymorphic DNA analysis of Mycobacterium tuberculosis isolates resistant to Isoniazid in Indonesia

Background: M. tuberculosisis the most important etiological factor of tuberculosis. One of the factors that make TB hard to eradicate is the emergence of M. tuberculosisdrug resistance. Drug resistance in M. tuberculosisis attributed primarily to the accumulation of mutations in the drug target gene. Objectives: to analyze profile of Random Amplified Polymorphic DNA (RAPD) in M. tuberculosisisolates resistant to Isoniazid and found RAPD marker. Methods: seven Isoniazid resistant isolate of M. tuberculosisfrom Ma kassar, Indonesia strain were analyzed by RAPD method using primers OPN 02, OPN 09, OPN 20, BG 65, N 9, that amplification fragment DNA than as molecular marker. Results: The results of the present study showed high degree of polymerphism in theM.tuberculosisstrains in the population, and found that specific DNA fragment at Isoniazid resistant isolates using primer N 9 is 1450 bp as a marker. Conclusion: This study gives information about RAPD marker of M. tuberculosis strain to Isoniazid resistant.

Hepatoprotective Activity of Yigan Mingmu Oral Liquid against Isoniazid/Rifampicin-Induced Liver Injuries in Rats

Background: To explore the hepatoprotective effect of Yigan mingmu oral liquid (YGMM) on isoniazid-rifampicin induced liver injury in rats. Methods: Total 38 SD rats were randomly divided into 6 groups including control group, model group, silymarin positive control group, and three YGMM treatment groups. Model group was administered intragastrically with INH (100 mg/kg) and RIF (100 mg/kg) for 14 days. Silymarin group and YGMM treatment groups were administered intragastrically with silymarin (100 mg/kg) and different doses of YGMM (1, 2.5, 5 mg/kg) 2 hours before INH and RIF administration from day 4 to day 14.?Results: Rats were sacrificed 16 hours after the last day treatment to determine the activities of serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), as well as total bilirubin (TB) content. Oxidative stress was evaluated by measuring total superoxide dismutase (T-SOD) and malondialdehyde (MDA) levels. Histopathological changes in liver tissues were observed under an optical microscope by using hematoxylin and eosin staining. The mice?in model groups showed significantly (p < 0.05) increased levels in AST, ALT, ALP, TB and MDA compared to their control groups;and showed significantly (p < 0.05) decreased level in T-SOD. These changes were significantly (p < 0.05) reversed by the YGMM treatments in a dose-dependent manner. Hepatic pathological changes were attenuated or even reversed by silymarin or YGMM treatments. Conclusions: YGMM has a good hepatoprotective activity on isoniazid-rifampicin induced liver injuries in rats.

Cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on QSG-7701 hepatocytes

Objective:To investigate the cellular toxicity of isoniazid together with rifampicin and the metabolites of isoniazid on cultured QSG-7701 cells lines.Methods:Isoniazid,rifampicin, mixture of rifampicin and isoniazid,acetylhydrazine,hydrazine were added in cultural media of QSG-7701 cells and cultured for 48 hours.The survival rate of cells was determined by MTT method.The cultural media and cells were collected and the activity of lactate dehydrogenase was detected by chromatometry.Results:Compared with control group,the survival rate decreased significantly and the lactate dehydrogenase released from cell increased significantly in cells treated with isoniazid,rifampicin,acetylhydrazine,hydrazine.Hydrazine,the metabolite of isoniazid produced significant damage on hepatocytes in low concentration.Conclusions: Rifampicin together with rifampicin and metabolites of isoniazid produce cellular toxic effects and hydrazine may be the most toxiferous metabolite.

Should pyridoxine be given to breastfed infants whose mothers are on isoniazid?

A mother was recently started on isoniazid and rifampicin for latent tuberculosis infection.She was breastfeeding her 1-monthold infant.There was no indication to treat the child with antituberculous therapy.As isoniazid can be present in breast milk,question was raised whether the baby should receive pyridoxine supplementation to prevent peripheral neuropathy or seizures.There were variable views in the management approach due to uncertainties of evidence in this topic.

Fast Evaluation of Oxidative DNA Damage by Liquid Chromatography-Electrospray Tandem Mass Spectrometry Coupled With Precision-cut Rat Liver Slices

Objective To establish a fast and sensitive method for the detection of 8-hydroxy-2’-deoxyguanosine （8-OHdG） in precision-cut rat liver slices by HPLC-MS/MS and to investigate isoniazid （INH） -induced oxidative DNA damage. Methods Precision-cut liver slices （300 μm） were prepared from male rats, and incubated with INH （0.018 mol/L） for 2 h after 1 h preincubation. DNA in the slices was extracted and digested into free nucleosides at 37℃ . The samples were injected into HPLC-MS/MS after the proteins were removed. The level of oxidative DNA damage was estimated using the ratio of 8-OHdG to deoxyguanosine （dG）. Results The limit of detection of 8-OHdG was 1 ng/mL （S/N=3） and the intra-assay relative standard variation was 3.38% when one transition 284.3/168.4 was used as a quantifier and another two transitions 284.3/140.2, 306.1/190.2 as qualifiers. 8-OHdG and dG were well separated, as indicated by elution at 10.02 and 7.37 min, respectively. INH significantly increased the ratio of 8-OHdG to dG in rat liver slices （P〈0.05）. Conclusion 8-OHdG in precision-cut liver slices could be sensitively determined by HPLC-MS/MS. HPLC-MS/MS coupled with precision-cut tissue slices is a fast and reliable analytical technique to evaluate oxidative DNA damage of target tissues caused by procarcinogens and cytotoxins.

Synthesis, Crystal Structure and Luminescence Property of a 2D Mn(Ⅱ) Coordination Polymer Based on Isoniazid

A novel 2D Mn（II） coordination polymer [Mn（CH3COO）2（INH）]n （INH = isoniazid） has been synthesized in DMF solution with isoniazid and Mn（CH3COO）2. The polymer was characterized by single-crystal X-ray diffraction analysis, FTIR and X-ray powder diffraction （XRPD）. The crystal belongs to the monoclinic system, space group P2flc with a = 9.3251 （18）, b = 16.340（3）, c = 8.8096（17） A, β = 94.747（3）°, V = 1337.7（4） A3, Z = 4, μ（MoKa） = 1.006 mm-1, F（000） = 636, R = 0.0754 and wR = 0.1375 （I 〉 2σ（I））. In the complex, each Mn（II） atom is coordinated to three CH3COO groups and two INH ligands. The Mn（II） atoms locate in a distorted coordination octahedron and are bridged by CH3COO＂ ions to form a 1D S shaped chain extending along the c direction. The INH molecules act as bridges to link the Mn（II） atoms of adjacent chains and further construct a lamellar polymer. The remaining coordination site is occupied by an O atom of the other CH3COO. The experimental results show that the title complex has good luminescence property and could be used as potential optical materials.

Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation

AIM To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid(INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.METHODS INH was conjugated with N-acetyl cysteine(NAC) and N-(2)-mercaptopropionyl glycine using the SchottenBaumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.RESULTS Prodrugs were found to be stable in acidic(pH 1.2) and basic(pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly(59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially. CONCLUSION The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.

Genetic Polymorphisms and Toxicities of First-Line Antituberculosis Drugs: Systematic Review of the Literature

Introduction: Polymorphisms are the main genetic factors associated with toxicities of antituberculosis drugs. This literature review summarizes the polymorphisms of the genes that code for the enzymes of the metabolism of antituberculosis drugs and their transmembrane transporters. Some mechanisms of drug-associated toxicities and strategies for their management have also been described in this review. Methods: The bibliographic searches were exclusively carried out in PubMed, over a period of ten years (2010-2020). The search terms were the words “toxicity + antituberculosis drug + one or two word(s) among the following: polymorphism, genetics, mutation, SNP, HLA or haplotype”. Publications in English or French, relating to the various toxicities associated with first-line anti-tuberculosis drugs (Rifampicin, Isoniazid, Ethambutol and Pyrazinamide) administered to patients with pulmonary tuberculosis, extrapulmonary tuberculosis or co-infected with TB/HIV were included in this review. Duplicates, in vitro, in silico or drug-induced toxicity studies other than antituberculosis drugs and genetic mutations of Mycobacteria strains were not included. Results: The studies selected and included were case reports, cohort studies, original research, systematic reviews and meta-analyses on human subjects of different ethnic origins. Hepatotoxicity is the most common toxicity associated with NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms in patients on antituberculosis drugs. Other forms of toxicity, less frequent, occurring in certain patients under concomitant treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), antiretrovirals (ARVs), antibiotics or antiepileptics have also been identified. Conclusion: The genetic polymorphisms associated with the toxicities of antituberculosis drugs concern both the main enzymes of the metabolic pathways (NAT2, CYP2E1, GST) and the transmembrane transporters (SLCO1B1 and ABCB1). Other genetic polymorphisms (TXNRD1, SOD2, TYMP) have been suspected but their mechanisms are not yet well understood.

Diagnosing Drug-Resistant Tuberculosis with the Xpert^®MTB/RIF. The Risk for Rifampin Susceptible Cases

Setting: Tuberculosis clinic in México. Objective: Since the Xpert&reg;MTB/RIF does not detect resistance to isoniazid, our objective was to emphasize the need for additional drug susceptibility testing. Design: A prospective study. All patients with an Xpert&reg;MTB/RIF and a positive tuberculosis culture with drug susceptibility testing were included. Results: 70 patients were included. Forty-two (60%) had a history of previous treatment for TB. Fourteen patients (20%) had a strain resistant to isoniazid (H), twelve of them (85.7%) with a history of TB treatment in the past vs. 2 (7.1%) among new cases (p = 0.028). Four patients (5.7%) had resistance to rifampin (R);three of them were previously treated cases. Additionally, six patients with a negative Xpert test (8.6%) had a positive MGIT culture;three of them were resistant to H (the 3 were poly-resistant). Two patients with a positive Xpert&reg;MTB/RIF test without R resistance were phenotypically multidrug-resistant. Conclusion: Isoniazid resistance is associated with overall increased treatment failure, relapse, and acquired multidrug resistance in patients treated with regimens containing only first-line tuberculosis drugs. It is urgent that national TB programs implement the necessary infrastructure to complement the Xpert&reg;MTB/RIF results with DST either by phenotypic or genotypic methods.

Spectrum of Atypical Presentation of Tubercular Infections of Central Nervous System—Case Series and Review of Literature

Tubercular infections of central nervous system commonly present with hydrocephalus, basal exudates, infarcts, tuberculomas, etc. However, rarely there are atypical lesions which can pose greater difficulty in differentiating from other lesions like tumors. This case series describes the spectrum of such lesions, with review few individual reports found in literature. Clinical presentations were weakness of limbs, slurring of speech and underlying primary tubercular focus. The age group ranged from 16 - 60 years with M:F ratio being 1:1. Spectrum of such lesions is discussed here with emphasis on the role of magnetic resonance imaging in prompt diagnosis. Thus initiating an early conservative line of management and its follow up with aversion of neurointervention which has its own inherent complications, the final outcome is a reduction in morbidity and mortality (as noted in the follow up) as well as patient cost care.