anti-TB Drug-induced Hepatotoxicity Research Articles

Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity.

Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium which causes tuberculosis (TB). TB control programmes are facing threats from drug resistance. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains need longer and more expensive treatment with many medications resulting in more adverse effects and decreased chances of treatment outcomes. The World Health Organization (WHO) has emphasised the development of not just new individual anti-TB drugs, but also novel medication regimens as an alternative treatment option for the drug-resistant Mtb strains. Many plants, as well as marine creatures (sponge; Haliclona sp.) and fungi, have been continuously used to treat TB in various traditional treatment systems around the world, providing an almost limitless supply of active components. Natural products, in addition to their anti-mycobacterial action, can be used as adjuvant therapy to increase the efficacy of conventional anti-mycobacterial medications, reduce their side effects, and reverse MDR Mtb strain due to Mycobacterium's genetic flexibility and environmental adaptation. Several natural compounds such as quercetin, ursolic acid, berberine, thymoquinone, curcumin, phloretin, and propolis have shown potential anti-mycobacterial efficacy and are still being explored in preclinical and clinical investigations for confirmation of their efficacy and safety as anti-TB medication. However, more high-level randomized clinical trials are desperately required. The current review provides an overview of drug-resistant TB along with the latest anti-TB medications, drug-induced hepatotoxicity and oxidative stress. Further, the role and mechanisms of action of first and second-line anti-TB drugs and new drugs have been highlighted. Finally, the role of natural compounds as anti-TB medication and hepatoprotectantshave been described and their mechanisms discussed.

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

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. 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. 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. Our study suggests that silymarin use has the potential for the reduction of anti-TB drug-induced hepatotoxicity.

Prevalence and Onset of Hepatotoxicity Caused by Anti-Tuberculosis Drugs on Pulmonary TB Patients in Wangaya General Hospital Denpasar – Bali in 2016

Introduction: As tuberculosis (TB) endemic country, TB becomes a community health problem in Indonesia. Data from the Global TB Report in 2016 showed that Indonesia is the second most country with TB burden after India. WHO and the Ministry of Health issue a TB prevention program based on the End TB Strategy aimed to reduce morbidity, mortality, and disability due to TB. One of the challenges faced in the management of TB is the side effects of the anti-tuberculosis drug. Hepatotoxicity is the most common side effect. Aims: This study aims to determine the prevalence and onset of anti-TB drug-induced hepatotoxicity in TB patients after receiving the anti-TB drug in Wangaya Hospital Denpasar Bali. Method: This study used a cross-sectional method by obtaining secondary data of pulmonary TB patients visiting the pulmonary clinic in Wangaya General Hospital from January to December 2016. Result: Of 77 subjects, fifty-six percent of them were men. The highest prevalence was found in the 41-50 years age group (26.9%), while the lowest was found in the 81-90 years age group (1.2%). Anti-TB drug-induced hepatotoxicity occurred in 6.5% of subjects. The most frequent onset of hepatotoxicity occurred within the second week of medication. Anti-TB drug-induced hepatotoxicity occurred in 6.5% of subjects. The most frequent onset of hepatotoxicity occurred within the second week of medication. Conclusion: Based on this study, we suggest a liver function test before and after two weeks of an anti-TB drug.

Drug selection for simultaneous treatment of tuberculosis combined with hepatitis C virus infection

Clinically, patients with tuberculosis (TB) combined with hepatitis C virus (HCV) infection often require simultaneous treatment. Consequently, when anti-HCV and TB drugs are used in combination drug-drug interactions (DDIs), anti-TB drug-induced hepatotoxicity, and liver disease states need to be considered. This paper focuses on discussing the metabolic mechanisms of commonly used anti-TB and HCV drugs and the selection options of combined drugs, so as to provide rational drug use for TB patients combined with HCV infection.

The efficacy of Jujube syrup on the prevention of drug-induced hepatotoxicity in pulmonary tuberculosis patients: A pilot randomized double-blind placebo-controlled clinical trial.

Liver injury is the most common complication of anti‐tuberculosis drugs that can cause significant problems. The study aimed to determine the effectiveness of Jujube syrup on the prevention of antituberculosis drug‐induced hepatotoxicity (DIH). This pilot randomized double‐blind study was conducted based on a placebo‐controlled design in patients with tuberculosis (TB). The patients were divided into two groups based on the block random allocation method and received 10 cc of jujube or placebo syrup per day. The liver enzyme levels were assessed as primary outcomes, and the severity of cough, anorexia, and nausea along with the quality of life (QOL) was assessed as secondary outcomes. Finally, eight and nine patients in the jujube and placebo groups completed the study, respectively. In the second week of the study, 27.3% of the patients in the placebo group developed hepatotoxicity. Moreover, there was no liver toxicity in the jujube group. This difference between the two groups was statistically significant (p = .037). Furthermore, the severity of cough in patients in the jujube group decreased significantly during weeks 2 and 4. The QOL significantly improved in the jujube group, compared to the placebo group. This study suggested that Jujube syrup could prevent anti‐TB DIH. It can also improve the severity of cough and the QOL in pulmonary TB patients.

Extrapulmonary tuberculosis

Introduction: Tuberculosis (TB) is a major cause of morbidity and mortality globally. Extrapulmonary TB (EPTB) constitutes about 15%-20% of all TB patients but accounts for 50% among HIV-coinfected. Confirmation of microbial diagnosis of EPTB is usually challenging. Areas covered: Availability of newer imaging modalities like 18FDG-PET-CT, PET-MRI, has facilitated precise anatomical localization of the lesions and mapping the extent of EPTB. The use of image-, endoscopy-guided invasive diagnostic methods has made procurement of tissue/body fluids for diagnostic testing possible. With the advent of universal drug-susceptibility testing, a rapid diagnosis of drug-resistance is now possible in EPTB. Drug-susceptible EPTB usually responds well to first-line anti-TB treatment; TB meningitis, bone and joint TB and lymph node TB often require longer duration of treatment. Expert opinion: Adjunctive use of corticosteroids in the initial period is recommended in central nervous system and pericardial TB. Surgical intervention is helpful to obtain tissue samples for diagnosis. Adjunctive surgical treatment along with medical treatment is useful in treating complications like hydrocephalus, Pott’s spine. Follow-up of EPTB patients is crucial as treatment is usually longer, requires recognition of development of immune reconstitution and inflammatory syndrome (IRIS), monitoring of adverse events, serious adverse events like anti-TB drug-induced hepatotoxicity, organ-related complications and treatment adherence.

A validation study of the UGT1A4 rs2011404 variant and the risk of anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population.

Anti-tuberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. A recent study found that the rs2011404 variant of uridine 5'-diphospho-glucuronosyl-transferase 1A4 (UGT1A4) is a marker of susceptibility to ATDH. The present study aimed to validate this relationship in an Eastern Chinese Han anti-TB treatment population. A 1:4matched case-control study was conducted among anti-TB treatment patients in four regions of Jiangsu. ATDH was diagnosed based on the criteria from the Chinese Society of Hepatology and the updated Roussel Uclaf Causality Assessment Method. A conditional logistic regression model was used to estimate the association between rs2011404genotypes and the risk of ATDH using odds ratios (ORs) with 95% confidence intervals (95% CIs) and smoking, drinking, hepatoprotectant use and liver diseases as covariates. A total of 202 ATDH cases and 808 controls were matched according to age, sex and treatment history. After correcting for potential confounding factors, conditional logistic regression analysis indicated no significant differences in genotypes between the two groups (CC vs. TC: OR=0.933, 95% CI: 0.457-1.905, p=0.849). Subgroup analysis suggested that patients carrying the CC genotype at rs2011404 in UGT1A4 were at a reduced risk of moderate or severe liver injury (OR=0.293, 95% CI: 0.093-0.921, p=0.036). Based on a 1:4 individual matched case-control study, possessing the CC genotype at rs2011404 of the UGT1A4gene reduces the risk of moderate or severe liver injury in Eastern Chinese Han patients receiving anti-TB treatment. Further research is warranted to explain the role of the UGT1A4gene and its contribution to individual differences in susceptibility to ATDH.

Determinants of Drug-Induced Hepatotoxicity Among Patients with Human Immunodeficiency Virus Taking a High Dose of Rifapentine Plus Isoniazid Drugs at the All Africa Leprosy Tuberculosis Rehabilitation and Training Center in Addis Ababa, Ethiopia.

PurposeThe drugs for the treatment of latent Tuberculosis are potentially hepatotoxic and can lead to drug-induced hepatotoxicity. The current study aimed at identifying the determinants of anti-tuberculosis drug-induced hepatotoxicity among patients living with Human Immunodeficiency Virus taking Isoniazid and rifapentine at All Africa Leprosy Tuberculosis Rehabilitation and Training Center in Addis Ababa, Ethiopia.MethodsAn unmatched case–control study was conducted from March, 21, to April 21, 2020, at All Africa Leprosy Tuberculosis Rehabilitation and Training Center. A total of 65 cases and 130 controls were interviewed. Data were collected using a data extraction tool from clinical reporting forms, follow-up charts, and patients’ logbooks. Binary and multiple logistic regressions were conducted to check the association between independent and dependent variables. Adjusted odds ratios and the corresponding 95% confidence intervals were estimated to assess the strength of association. P-values <0.05 were used to declare statistical significance.ResultsThe prevalence of anti-TB drug-induced hepatotoxicity was 8%. Body mass index <18.5 Kg/m2 (AOR = 5.8 [95% CI: 2.2–8.9]), low CD4 count (AOR = 4.9 [95% CI: 1.6–15.8]), and the presence of comorbid illnesses (AOR = 3.9 [95% CI: 1.7–8.9]) were identified as independent predictors of drugs-induced hepatotoxicity among Human Immunodeficiency Virus positive patients taking Isoniazid and rifapentine.ConclusionThe prevalence of anti-TB drug-induced hepatotoxicity was higher compared to standard references. BMI<18 kg/m2, low CD4 count, and comorbid illness were positively associated with anti-tuberculosis drug-induced hepatotoxicity among patients with HIV.

Prevalence and Risk Factors Associated with First-Line Anti-Tuberculosis Induced Hepatotoxicity in Suratthani Hospital, Thailand

ackground: Tuberculosis (TB) is a major public health problem, including Thailand. Anti-TB drugs are very effective treatment, but they can cause hepatotoxicity. Data on the prevalence of anti-TB drug-induced hepatotoxicity (DIH), as well as the contributing risk factors, are scarce in Thailand. Objective: To measure the prevalence and identify risk factors associated with first-line drugs (FLD) induced hepatoxicity in TB patients. Materials and Methods: The present study was a retrospective study design in TB clinic of Suratthani Hospital, in Southern Thailand. All patients diagnosed with TB and received FLD between January and December 2017, were eligible for the study. Hepatoxicity defined as the following criteria: serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels &gt;5x upper limit of normal (ULN) without symptoms, or AST or ALT &gt;3x ULN with clinical symptoms. Results: Of all the 198 TB cases, 18 were identified as DIH. Prevalence of DIH was 9.1%. Hepatitis after FLD was independently associated with age&gt;60 years (adjusted OR [aOR] 28.49, 95% CI 2.68 to 302.95, p=0.005) and serum albumin &lt;3.5 g/dL (aOR 20.97, 95% CI 2.11 to 208.51, p=0.009). Conclusion: Age of more than 60 years and low serum albumin of less than 3.5 g/dL were significant risk factors associated with first-line anti-TB drugs induced hepatoxicity. Keywords: Hepatoxicity, Anti-tuberculosis drug, Risk factor, Thailand

Alanine transaminase and hemoglobin appear to predict the occurrence of antituberculosis medication hepatotoxicity; findings and implications in Botswana

ABSTRACT Objective Tuberculosis (TB) remains a global health problem, with medications having adverse effects including drug-induced hepatotoxicity. We determined the prevalence of anti-tuberculosis drug-induced hepatotoxicity and associated risk factors. Methods Retrospective cross-sectional study in Botswana including TB patients admitted from 1 June 2017 to 30 June 2018. Anti-TB drug-induced hepatotoxicity was categorized according to WHO criteria whereas causality assessment was made according to the updated Roussel Uclaf Causality Assessment Method (RUCAM) scale. The association between hepatotoxicity and included variables was undertaken by binary logistic regression. Results Out of 112 patient files, 15 (13.4%) developed hepatotoxicity after an average of 20.4 days from the start of treatment. Grade 3 and 4 hepatotoxicity was found in 66.7% of the cases. According to the updated RUCAM tool, 86.7% of patients were categorized as having possible anti-TB-associated hepatotoxicity. Patients with elevated baseline alanine transaminase (ALT) were more likely to develop hepatotoxicity (OR = 3.484, 95% CI = 1.02–11.90). Patients with normal hemoglobin (Hb ≥ 12 g/dl) were also more likely to develop hepatotoxicity (OR = 4.413, 95% CI = 1.160–14.8). Conclusion Overall, normal hemoglobin and elevated baseline ALT levels were significantly associated with anti-TB drug-induced hepatotoxicity. Additional research is needed to explore this association further.

Incidence and associated risk factors of antituberculosis drug-induced hepatotoxicity among hospitalised patients in Wuhan, China

ObjectiveTo analyse the incidence and risk factors of hepatotoxicity induced by antituberculosis (anti-TB) drugs in Renmin Hospital of Wuhan University, and to provide evidence for clinical prevention and treatment of...

Bile acids, lipid and purine metabolism involved in hepatotoxicity of first-line anti-tuberculosis drugs

ABSTRACT Objectives Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination. Methods UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway. Results In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR-/- mice. Additionally, the purine and lipid metabolic pathways were involved in ATDH. Conclusion ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.

Association of FAM65B, AGBL4, and CUX2 genetic polymorphisms with susceptibility to antituberculosis drug-induced hepatotoxicity: validation study in a Chinese Han population.

Antituberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism has not been elucidated thoroughly to date. A recent genome-wide association study reported that seven single-nucleotide polymorphisms (SNPs) in the family with sequence similarity 65, member B gene (FAM65B), ATP/GTP-binding protein-like 4 gene (AGBL4), and cut-like homeobox 2 gene (CUX2) were associated strongly with ATDH in Ethiopian patients. We validated this relationship in a Chinese Han anti-TB treatment population. A 1 : 2 matched case-control study was carried out of 235 ATDH cases and 470 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by odds ratios with 95% confidence intervals, and weight and hepatoprotectant use were used as covariates. Patients with a polymorphism at rs10946737 in the FAM65B gene were at an increased risk of moderate and severe liver injury under the dominant model (adjusted odds ratio=2.147, 95% confidence interval: 1.067-4.323, P=0.032). No other genotypes or genetic risk scores were found to be significantly related to ATDH. This is the first study to explore and validate the relationships between seven SNPs in the FAM65B, AGBL4, and CUX2 genes and ATDH in a Chinese population. On the basis of this case-control study, SNP rs10946737 in FAM65B may be associated with susceptibility to ATDH in Chinese Han anti-TB treatment patients. Further research is warranted to explain the role of the FAM65B gene and its contribution toward individual differences in susceptibility to ATDH.

The A/A Genotype of XPO1 rs4430924 Is Associated With Higher Risk of Antituberculosis Drug-Induced Hepatotoxicity in Chinese Patients.

Antituberculosis (anti-TB) drug-induced hepatotoxicity may be related to the excessive reactive oxygen species induced by hepatotoxic metabolites. Antioxidant activity involves the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The BTB domain and CNC homologue 1 (Bach1) may compete with Nrf2 for binding to transcriptional enhancers. Elimination of Bach1-mediated transcriptional repression depends on nuclear exporter exportin 1 (Xpo1). Thus, Xpo1 may indirectly affect antioxidant activity. The present study aimed to examine the role of tag single-nucleotide polymorphisms in XPO1 in Chinese anti-TB treatment patients. A 1:2 matched case-control study was conducted using 314 anti-TB drug-induced hepatotoxicity cases and 628 controls. After correcting for weight and hepatoprotectant use, conditional logistic regression analysis showed that patients carrying the AA genotype of rs4430924 in XPO1 were at higher risk of anti-TB drug-induced hepatotoxicity than those carrying the GG genotype based on the subgroup of probable cases (adjusted OR, 1.938; 95%CI, 1.035-3.628; P = .039), and marginally significant differences were also found under the recessive model (P = .048) and the additive model (P = .047). Based on this 1:2 matched case-control study, the AA genotype of rs4430924 in XPO1 may be associated with higher risk of anti-TB drug-induced hepatotoxicity in Chinese anti-TB treatment patients. Further studies in larger and more varied populations are required to validate this relationship.

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity

A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.

Assessment of hepatotoxicity of first-line anti-tuberculosis drugs on Wistar rats.

Adverse drug reactions are inevitable risk factors associated with use of modern medicines. First-line anti-tuberculosis drugs contribute to diverse pathological complications, and hepatotoxicity is one of them. This study investigated the effects of anti-TB drugs in combination (rifampicin [RIF] + isoniazid [INH] + pyrazinamide [PZA]) on Wistar rats. Rats were grouped as control group (saline), toxicant group that was given (30.85mg/kgb.wt., INH + 61.7mg/kgb.wt., RIF + 132.65mg/kgb.wt. PZA in dosage extrapolated from dose that is used in human). Different anti-oxidant enzymes were measured in the liver along with histopathology, hematology, genotoxic effect on bone marrow chromosomes, and DNA fragmentation. In addition, gene and protein expression of CYP2E1, NR1I2, NAT, and CYP7A1 was measured by qPCR and western blot. After administration of anti-TB drugs to Wistar rats for 28days, there was an increase in thiobarbituric acid reactive substances and a decrease in anti-oxidant enzymes. Marked changes in histopathology, hematology, DNA fragmentation, chromosomes, and in gene expression were observed. Results of the study proved increased hepatotoxicity due to combinational treatment of anti-TB drugs and also that CYP2E1, NR1I2, NAT, and CYP7A1 genes play a vital role in anti-TB drug-induced hepatotoxicity.

THE IMPACT OF ANTITUBERCULOSIS DRUG-INDUCED HEPATOTOXICITY TO SUCCESFUL TUBERCULOSIS TREATMENT IN INDONESIA

Objective: This study aimed to evaluate the impact of antituberculosis (anti-TB) drug-induced hepatotoxicity (DIH) to outcome TB treatment.Methods: A cohort retrospective study conducted at a tertiary hospital in Jakarta - Indonesia, from the period of 2013-2016. A total of 76 samples of TB patient with and without anti-TB DIH were analyzed.Results: Successful outcome TB treatment for TB patient with anti-TB DIH is 47.4% compared to TB patient without anti-TB DIH is 78.9%. Relative risk (RR) analysis showed that risk of unsuccessful TB treatment for TB patient with anti-TB DIH is 2.50 fold higher (95% confidence interval: 1.259- 4.960) than TB patient without anti-TB DIH. Age, sex, and comorbidities are not statistically significant to outcome TB treatment. For TB patient with anti-TB DIH, onset anti-TB DIH and recurrence anti-TB DIH also not statistically significantly influence outcome TB. The mean duration of treatment for a successful outcome for TB patient with and without anti-TB DIH was statistically significant (p&lt;0.05), respectively, 8.44±1.85 and 6.52±0.93 months.Conclusion: Anti-TB DIH increases the risk of unsuccessful and prolonged duration TB treatment.

STANDARDIZATION OF MODEL OF INDUCTION OF HEPATOTOXICITY WITH ANTI-TUBERCULOSIS DRUGS IN WISTAR ALBINO RATS

Objective: The objective of the study to standardize the model of hepatotoxicity induced by ATT drugs in Wistar Albino rats. Isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), the first line drugs used in the treatment of tuberculosis (TB) associated with the potential adverse effect. Numerous animal studies were reported endeavoring induction and cure of anti-TB (ATT) drug-induced hepatotoxicity using herbal and chemical drugs. However, the previous reported study failed to replicate where Wistar albino rats were treated with INH, RMP, and PZA and had shown the significant development of liver injury. Hence in present paper, aimed to develop a standardize model of induction of hepatotoxicity with ATT drugs.Methods: Wistar rats were treated with ATT drugs in combination in various doses up to 4-8 weeks. Total nine experiments were conducted to achieve successful hepatotoxicity. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were the biochemical parameters of assessment. Histopathological changes in the liver were also examined.Results: No evidence of any liver injury or an inflammatory infiltrate has been observed as had been reported in the previous studies. Rather decrease in serum ALT levels has been observed by researcher. In short, hepatic injury cannot be developed with the doses used in previous reported papers. The successful attempt to induce hepatotoxicity can be achieved with the doses of INH - 100, RMP - 300, PZA - 700 mg/kg. The findings were confirmed by the raised ALT, AST, and ALP levels compared with baseline. The histopathological changes also support the findings.Conclusion: The dose of INH - 100, RMP – 300 and PZM - 700 mg/kg. Succeeds to induce hepatotoxicity in Wistar albino rats and Swiss albino mice as well.

Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB) drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF) were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.

Prevalence of hepatitis C virus and human immunodeficiency virus in a group of patients newly diagnosed with active tuberculosis in Porto Alegre, Southern Brazil.

BACKGROUND Porto Alegre is the Brazilian state capital with second highest incidence of tuberculosis (TB) and the highest proportion of people infected with human immunodeficiency virus (HIV) among patients with TB. Hepatitis C virus (HCV) infection increases the risk of anti-TB drug-induced hepatotoxicity, which may result in discontinuation of the therapy.OBJECTIVES The aim of this study was (i) to estimate prevalence of HCV and HIV in a group of patients newly diagnosed with active TB in a public reference hospital in Porto Alegre and (ii) to compare demographic, behavioural, and clinical characteristics of patients in relation to their HCV infection status.METHODS One hundred and thirty-eight patients with TB were tested for anti-HCV antibody, HCV RNA, and anti-HIV1/2 antibody markers. HCV RNA from real-time polymerase chain reaction (PCR)-positive samples was submitted to reverse transcription and PCR amplification. The 5′ non-coding region of the HCV genome was sequenced, and genotypes of HCV isolates were determined.FINDINGS Anti-HCV antibody, HCV RNA, and anti-HIV antibodies were detected in 27 [20%; 95% confidence interval (CI), 13-26%], 17 (12%; 95% CI, 7-18%), and 34 (25%; 95% CI, 17-32%) patients, respectively. HCV isolates belonged to genotypes 1 (n = 12) and 3 (n = 4). Some characteristics were significantly more frequent in patients infected with HCV. Among them, non-white individuals, alcoholics, users of illicit drugs, imprisoned individuals, and those with history of previous TB episode were more commonly infected with HCV (p < 0.05).MAIN CONCLUSIONS HCV screening, including detection of anti-HCV antibody and HCV RNA, will be important to improving the management of co-infected patients, given their increased risk of developing TB treatment-related hepatotoxicity.