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Asif M, Qusty NF, Alghamdi S. An Overview of Various Rifampicin Analogs against Mycobacterium tuberculosis and their Drug Interactions. Med Chem 2024; 20:268-292. [PMID: 37855280 DOI: 10.2174/0115734064260853230926080134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/14/2023] [Accepted: 08/12/2023] [Indexed: 10/20/2023]
Abstract
The success of the TB control program is hampered by the major issue of drug-resistant tuberculosis (DR-TB). The situation has undoubtedly been made more difficult by the widespread and multidrug-resistant (XDR) strains of TB. The modification of existing anti-TB medications to produce derivatives that can function on resistant TB bacilli is one of the potential techniques to overcome drug resistance affordably and straightforwardly. In comparison to novel pharmaceuticals for drug research and progress, these may have a better half-life and greater bioavailability, be more efficient, and serve as inexpensive alternatives. Mycobacterium tuberculosis, which is drugsusceptible or drug-resistant, is effectively treated by several already prescribed medications and their derivatives. Due to this, the current review attempts to give a brief overview of the rifampicin derivatives that can overcome the parent drug's resistance and could, hence, act as useful substitutes. It has been found that one-third of the global population is affected by M. tuberculosis. The most common cause of infection-related death can range from latent TB to TB illness. Antibiotics in the rifamycin class, including rifampicin or rifampin (RIF), rifapentine (RPT), and others, have a special sterilizing effect on M. tuberculosis. We examine research focused on evaluating the safety, effectiveness, pharmacokinetics, pharmacodynamics, risk of medication interactions, and other characteristics of RIF analogs. Drug interactions are especially difficult with RIF because it must be taken every day for four months to treat latent TB infection. RIF continues to be the gold standard of treatment for drug-sensitive TB illness. RIF's safety profile is well known, and the two medicines' adverse reactions have varying degrees of frequency. The authorized once-weekly RPT regimen is insufficient, but greater dosages of either medication may reduce the amount of time needed to treat TB effectively.
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Affiliation(s)
- Mohammad Asif
- Department of Pharmaceutical Chemistry, Era College of Pharmacy, Era University, Lucknow, 226003, Uttar Pradesh, India
| | - Naeem F Qusty
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al‒Qura University, Makkah, 21955, Saudi Arabia
| | - Saad Alghamdi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al‒Qura University, Makkah, 21955, Saudi Arabia
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Akhtar J, Singh S, Verma AK, Pal R, Nath R. A prospective observational study to evaluate Glutathione S-transferase gene polymorphism and its association with Antitubercular drugs induced liver injury in tertiary hospital. Indian J Tuberc 2022; 69:341-346. [PMID: 35760484 DOI: 10.1016/j.ijtb.2021.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/09/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Anti-TB drugs are most common cause of idiosyncratic hepatotoxicity worldwide. Reactive metabolite formed during drug metabolism has been involved in a clinical toxicity are described as 'idiosyncratic' drug induce liver injury (DILI). We have observed the distribution of glutathione S -transferase (GST) gene polymorphism & its association with drug-induced liver injury in patients taking anti-tubercular treatment. METHODS A prospective observational study including 96 patients receiving anti-tubercular treatment. Blood sample was collected for LFT and gene extraction after ruling out other cause of liver injury. DNA extraction for GST gene was done follow by polymerase chain reaction to identify homozygous null mutation at GSTM1 and GSTT1 loci. Association of GSTM1 and GSTT1 gene with DILI was seen. RESULTS Out of 96 tubercular patients under treatment, drug induced liver injury was found in 21 (21.9%) patients and 75 does not develop DILI, GST M1 gene null mutation was observed in 14 (66.7%), GST T1 gene null mutation was observed in 9 (42.9%), Both GST gene null mutation was observed in 8 (38.1%) in DILI group. CONCLUSION The GSTM1 gene null mutation and both GSTM1 and T1 gene null mutation were a risk factor for the development of DILI. But there is no significant association between GSTT1 gene null mutation and DILI in TB patients.
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Affiliation(s)
- Javed Akhtar
- Department of Pharmacology & Therapeutics, King George Medical University, Lucknow, U.P, India
| | - Sarvesh Singh
- Department of Pharmacology & Therapeutics, King George Medical University, Lucknow, U.P, India
| | - Ajay Kumar Verma
- Department of Respiratory Medicine, King George Medical University, Lucknow, U.P, India
| | - Rishi Pal
- Department of Pharmacology & Therapeutics, King George Medical University, Lucknow, U.P, India
| | - Rajendra Nath
- Department of Pharmacology & Therapeutics, King George Medical University, Lucknow, U.P, India.
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Batalha IL, Bernut A, Schiebler M, Ouberai MM, Passemar C, Klapholz C, Kinna S, Michel S, Sader K, Castro-Hartmann P, Renshaw SA, Welland ME, Floto RA. Polymeric nanobiotics as a novel treatment for mycobacterial infections. J Control Release 2019; 314:116-124. [PMID: 31647980 PMCID: PMC6899522 DOI: 10.1016/j.jconrel.2019.10.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 09/10/2019] [Accepted: 10/03/2019] [Indexed: 12/17/2022]
Abstract
Mycobacterium tuberculosis (Mtb) remains a major challenge to global health, made worse by the spread of multi-drug resistance. Currently, the efficacy and safety of treatment is limited by difficulties in achieving and sustaining adequate tissue antibiotic concentrations while limiting systemic drug exposure to tolerable levels. Here we show that nanoparticles generated from a polymer-antibiotic conjugate (‘nanobiotics’) deliver sustained release of active drug upon hydrolysis in acidic environments, found within Mtb-infected macrophages and granulomas, and can, by encapsulation of a second antibiotic, provide a mechanism of synchronous drug delivery. Nanobiotics are avidly taken up by infected macrophages, enhance killing of intracellular Mtb, and are efficiently delivered to granulomas and extracellular mycobacterial cords in vivo in an infected zebrafish model. We demonstrate that isoniazid (INH)-derived nanobiotics, alone or with additional encapsulation of clofazimine (CFZ), enhance killing of mycobacteria in vitro and in infected zebrafish, supporting the use of nanobiotics for Mtb therapy and indicating that nanoparticles generated from polymer-small molecule conjugates might provide a more general solution to delivering co-ordinated combination chemotherapy.
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Affiliation(s)
- Iris L Batalha
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom
| | - Audrey Bernut
- Dept. of Infection, Immunity & Cardiovascular Disease, Bateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, United Kingdom; Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom
| | - Mark Schiebler
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom
| | - Myriam M Ouberai
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom
| | - Charlotte Passemar
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom
| | - Catherine Klapholz
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom
| | - Sonja Kinna
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom
| | - Sarah Michel
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom
| | - Kasim Sader
- Cambridge CryoEM Pharmaceutical Consortium, Thermo Fisher Scientific, Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom
| | - Pablo Castro-Hartmann
- Cambridge CryoEM Pharmaceutical Consortium, Thermo Fisher Scientific, Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom
| | - Stephen A Renshaw
- Dept. of Infection, Immunity & Cardiovascular Disease, Bateson Centre, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, United Kingdom; Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom
| | - Mark E Welland
- Nanoscience Centre, Department of Engineering, University of Cambridge, 11 J.J. Thomson Avenue, Cambridge, CB3 0FF, United Kingdom.
| | - R Andres Floto
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, CB23 3RE, United Kingdom.
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Kar P, Karna R, Ruttala R, Arora S, Chakravarty A, Kumar S. Clinical and Molecular Risk Factors of Anti-tubercular Therapy Induced Hepatitis. J Clin Exp Hepatol 2019; 9:200-206. [PMID: 31024202 PMCID: PMC6477131 DOI: 10.1016/j.jceh.2018.06.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND This is a case-control study aimed at evaluating clinical as well as molecular risk factors for occurrence of ATT induced hepatitis in Northern Indian population. METHODS 100 patients of tuberculosis were recruited from both Outdoor patient department and wards of Lok Nayak Hospital, New Delhi. 40 out of 100 patients who developed ATT induced hepatitis were taken as test group and 60 out of 100 patients who didn't develop liver dysfunction on ATT were taken as controls and studied and compared for clinical factors such as age, gender, nutritional status, HBsAg carrier, chronic hepatitis C and HIV infection. Molecular factors i.e. NAT2 acetylator status, GSTT1 and M1 null mutations were also determined in all of the patients in each group and compared. RESULTS Mean body weight and serum albumin were significantly lower in the ATT induced hepatitis patients as compared to the control group. No preferential association was observed between age and gender with ATT induced hepatitis. HBsAg carrier (OR-6.5; P = 0.03), HIV infection (OR-5.1; P = 0.01), slow acetylator phenotype (OR-3.85; P = 0.02), GSTM1 null mutation (OR-2.72; P = 0.02) and GSTT1 null mutation (OR-3.12; P = 0.02) were found to be positively co-related to ATT induced hepatitis according to the univariate analysis. HBsAg carrier (OR-23.18; P = 0.01), HIV infection (OR-16.92; P = 0.02), Slow acetylator phenotype (OR-70.90; P = 0.001), GSTM1 null mutation (OR-37.03; P = 0.002) and GSTT1 null mutation (OR-8.19; P = 0.014) were also found to be independently increasing the risk of ATT induced hepatitis using multivariate analysis. CONCLUSION The present study established a positive co-relation between malnutrition, HBsAg carrier, HIV infection, NAT2 slow acetylators, GSTM1 null mutation, GSTT1 null mutation and ATT induced hepatitis.
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Key Words
- ALT, Alanine Aminotransferase
- AST, Aspartate Aminotransferase
- ATD, Anti-tubercular Drugs
- ATT induced hepatitis
- ATT, Anti-tubercular Therapy
- GST, Glutathione-S-transferase
- GSTT1
- HAV, Hepatitis A Virus
- HBV, Hepatitis B Virus
- HBsAg, Hepatitis B Surface Antigen
- HCV, Hepatitis C Virus
- HEV, Hepatitis E Virus
- HIV, Human Immunodeficiency Virus
- NAT2
- pulmonary tuberculosis
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Affiliation(s)
- Premashis Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi-02, India,Premashis Kar, Former Director Professor, Department of Medicine, Maulana Azad Medical College, University of Delhi, E23 Nivedeta Kunj, Sector 10 R.K. Puram, New Delhi 110022, India. Tel.: +91 011 23230132.
| | - Rahul Karna
- Maulana Azad Medical College, University of Delhi, New Delhi-02, India
| | - Rajesh Ruttala
- Maulana Azad Medical College, University of Delhi, New Delhi-02, India
| | - Shilpa Arora
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi-02, India
| | - Anita Chakravarty
- Department of Medical Microbiology, Maulana Azad Medical College, University of Delhi, New Delhi-02, India
| | - Suresh Kumar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi-02, India
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Muyaya LM, Young T, Loveday M. Predictors of mortality in adults on treatment for human immunodeficiency virus-associated tuberculosis in Botswana: A retrospective cohort study. Medicine (Baltimore) 2018; 97:e0486. [PMID: 29668628 PMCID: PMC5916691 DOI: 10.1097/md.0000000000010486] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Mortality in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly in sub-Saharan Africa. This study aimed to compare mortality and predictors of mortality in those who were antiretroviral therapy (ART) naïve to those with prior ART exposure.This retrospective cohort study was conducted in Serowe/Palapye District, Botswana, a predominantly urban district with a large burden of HIV-associated TB with a high case fatality. Between January 1, 2013 and December 31, 2013, patients confirmed with HIV-associated TB were enrolled and followed up. Kaplan-Meier and Cox proportional hazard modeling was undertaken to identify predictors of mortality, with ART initiation included as time-updated variable.Among the 300 patients enrolled in the study, 131 had started ART before TB diagnosis (44%). There were 45 deaths. There was no difference in mortality between ART-naïve patients and those with prior ART exposure. In the multivariate analysis, no ART use during TB treatment (hazard ratio [HR] = 5.6, 95% confidence interval [CI] = 2.9-11; P < .001), opportunistic infections other than TB (HR = 8.5, 95% CI = 4-18.4; P = .013), age ≥60 years (HR = 4.8, 95% CI = 1.8-13; P = .002), hemoglobin <10 g/dL (HR = 2.4, 95% CI = 1.3-4.5) and hepatotoxicity (HR = 5, 95% CI = 1.6-17; P = .007) were associated with increased mortality. In the subgroup analysis, among ART-naïve patients, no ART use during TB treatment (HR = 8.1, 95% CI = 3.4-19.4; P < .001), opportunistic infections other than TB (HR = 16, 95% CI = 6.2-42; P < .001), and hepatotoxicity (HR = 8.3, 95% CI = 2.6-27; P < .001) were associated with mortality. Among patients with prior ART exposure, opportunistic infections other than TB (HR = 6, 95% CI = 2.6-27; P < .001) were associated with mortality.Mortality in patients with HIV-associated TB is still high. To reduce mortality, close clinical monitoring of patients together with initiation of ART during TB treatment is indicated.
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Affiliation(s)
- Ley Muyaya Muyaya
- Division of Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, Stellenbosch University
- Palapye District Health Management Team, Ministry of Health, Palapye, Botswana
| | - Taryn Young
- Division of Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, Stellenbosch University
- Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University
| | - Marian Loveday
- Health Systems Research Unit, South African Medical Research Council, Cape Town, South Africa
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Mirlohi MS, Ekrami A, Shirali S, Ghobeishavi M, Pourmotahari F. Hematological and liver toxicity of anti-tuberculosis drugs. Electron Physician 2016; 8:3005-3010. [PMID: 27790357 PMCID: PMC5074763 DOI: 10.19082/3010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 08/24/2016] [Indexed: 01/16/2023] Open
Abstract
Introduction Tuberculosis (TB) is a major global health problem, and anti-tuberculosis drugs can cause severe adverse reactions. The aim of this study was to determine hematological and biochemical changes and associated risk factors in smear positive pulmonary tuberculosis patients undergoing treatment with standard protocols. Methods In a descriptive study, a total of 40 tuberculosis patients aged between 15–60 years were collected from hospitals in Khuzestan Province (Iran) from March 2013 to March 2014. The patients were treated with drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) during the initial two months, followed by isoniazid and rifampicin for the next four to six months. Activities of liver enzymes (ALT, AST, and ALP) and hematological parameters were recorded before and after treatment. Data were analyzed using paired samples t-test and Wilcoxon test by SPSS 16. Results After using drug treatments, hematological parameters (RBC, Hb, HCT, MCV, MCH, and MCHC), except platelet count, were changed significantly (p ≤ 0.001). Liver enzyme activities (ALT, AST, and ALP) were decreased significantly (p ≤ 0.001) after treatment. Conclusion In this study, changes of hematological and biochemical parameters have been observed in patients with pulmonary tuberculosis. It can be concluded that the anti-tuberculosis treatment is associated with changes of hematological parameters and liver enzymes.
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Affiliation(s)
- Maryam-Sadat Mirlohi
- M.Sc. of Biochemistry, Student Research Committee, Department of Clinical Biochemistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Alireza Ekrami
- Ph.D. of Microbiology, Faculty Member, Health Research Institute, Infectious and Tropical Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed Shirali
- of Biochemistry, Faculty Member, Research Center of Thalassemia and Hemoglobinopathy, Department of Laboratory Sciences, School of Paramedical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehdi Ghobeishavi
- Graduate Degree of Laboratory Sciences, Student Research Committee, Department of Clinical Biochemistry, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fatemeh Pourmotahari
- M.Sc. of Biostatistics, Department of Biostatistics Sciences, Dezful University of Medical Sciences, Dezful, Iran
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Awodele O, Momoh A, Awolola N, Kale O, Okunowo W. The combined fixed-dose antituberculous drugs alter some reproductive functions with oxidative stress involvement in wistar rats. Toxicol Rep 2016; 3:620-627. [PMID: 28959585 PMCID: PMC5615933 DOI: 10.1016/j.toxrep.2016.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 06/27/2016] [Accepted: 06/30/2016] [Indexed: 12/02/2022] Open
Abstract
The reproductive toxicity of combined fixed-dose first-line antituberculosis (CFDAT) regimen was assessed in rats. Thirty-two (32) Wistar rats weighing 168.1 ± 8.0 g were divided into four groups of eight rats per group. Two groups of male and female rats were administered oral distilled water (1.6 ml) and CFDAT drugs containing rifampicin, isoniazid, pyrazinamide and ethambutol (RIPE, 92.5 mg/m2 per body surface area) respectively for forty-five days. Serum follicle stimulating hormone, luteinizing and testosterone were reduced significantly (p < 0.05) in the treated male rats. Similarly, sperm count levels were decreased by 27.3% when compared with control. RIPE elevated serum oestrogen (p < 0.05), progesterone (p < 0.05) as well as prolactin (p > 0.05) levels in the treated females. In addition, RIPE reduced (p < 0.05) total proteins levels and increased (p < 0.05, 53%) catalase levels in male but not female animals. Superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, reduced glutathione levels as well as lipid peroxidation were unaltered in all rats respectively. Histopathological studies revealed congested peritesticular vessels and no changes in the ovary when compared with control. Overall, our results demonstrate reproductive toxicity potentials of RIPE in the rat, thus, suggesting that these reproductive parameters be monitored during antituberculous chemotherapy.
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Affiliation(s)
- O. Awodele
- Department of Pharmacology, Therapeutics and Toxicology, College of Medicine, PMB 12003, Idi-Araba Campus, University of Lagos, Nigeria
| | - A.A. Momoh
- Department of Pharmacology, Therapeutics and Toxicology, College of Medicine, PMB 12003, Idi-Araba Campus, University of Lagos, Nigeria
| | - N.A. Awolola
- Department of Anatomic and Molecular Pathology, College of Medicine, Idi-Araba Campus, University of Lagos, Nigeria
| | - O.E. Kale
- Department of Pharmacology, Therapeutics and Toxicology, College of Medicine, PMB 12003, Idi-Araba Campus, University of Lagos, Nigeria
- Department of Pharmacology, Benjamin Carson (Snr.) School of Medicine, Babcock University, Ilisan Remo, Ogun Nigeria, Nigeria
| | - W.O. Okunowo
- Department of Biochemistry, College of Medicine University of Lagos, PMB 12003, Lagos, Nigeria
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Sharma SK, Mohan A, Sharma A. Miliary tuberculosis: A new look at an old foe. J Clin Tuberc Other Mycobact Dis 2016; 3:13-27. [PMID: 31723681 PMCID: PMC6850233 DOI: 10.1016/j.jctube.2016.03.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 03/08/2016] [Accepted: 03/10/2016] [Indexed: 11/03/2022] Open
Abstract
Miliary tuberculosis (TB), is a fatal form of disseminated TB characterized by tiny tubercles evident on gross pathology similar to innumerable millet seeds in size and appearance. Global HIV/AIDS pandemic and increasing use of immunosuppressive drugs have altered the epidemiology of miliary TB. Keeping in mind its protean manifestations, clinicians should have a low threshold for suspecting miliary TB. Careful physical examination should focus on identifying organ system involvement early, particularly TB meningitis, as this has therapeutic significance. Fundus examination for detecting choroid tubercles can help in early diagnosis as their presence is pathognomonic of miliary TB. Imaging modalities help in recognizing the miliary pattern, define the extent of organ system involvement and facilitate image guided fine-needle aspiration cytology or biopsy from various organ sites. Sputum or BAL fluid examination, pleural, pericardial, peritoneal fluid and cerebrospinal fluid studies, fine needle aspiration cytology or biopsy of the lymph nodes, needle biopsy of the liver, bone marrow aspiration and biopsy, testing of body fluids must be carried out. GeneXpert MTB/RIF, line probe assay, mycobacterial culture and drug-susceptibility testing must be carried out as appropriate and feasible. Treatment of miliary TB should be started at the earliest as this can be life saving. Response to first-line anti-TB drugs is good. Screening and monitoring for complications like acute respiratory distress syndrome (ARDS), adverse drug reactions like drug-induced liver injury, drug-drug interactions, especially in patients co-infected with HIV/AIDS, are warranted. Sparse data are available from randomized controlled trials regarding optimum regimen and duration of anti-TB treatment.
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Affiliation(s)
- Surendra K. Sharma
- Department of Medicine, All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Alladi Mohan
- Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati 517 507, India
| | - Animesh Sharma
- Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110 060, India
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9
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Chitosan-isoniazid conjugates: Synthesis, evaluation of tuberculostatic activity, biodegradability and toxicity. Carbohydr Polym 2015; 127:309-15. [DOI: 10.1016/j.carbpol.2015.03.060] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 03/02/2015] [Accepted: 03/14/2015] [Indexed: 02/05/2023]
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10
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Hassan HM, Guo HL, Yousef BA, Luyong Z, Zhenzhou J. Hepatotoxicity mechanisms of isoniazid: A mini-review. J Appl Toxicol 2015; 35:1427-32. [DOI: 10.1002/jat.3175] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 04/17/2015] [Indexed: 12/25/2022]
Affiliation(s)
- Hozeifa M. Hassan
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Department of Pharmacology, Faculty of Pharmacy; University of Gezira; Wad-Medani Sudan
| | - Hong-li Guo
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
| | - Bashir A. Yousef
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Department of Pharmacology, Faculty of Pharmacy; University of Khartoum; Khartoum Sudan
| | - Zhang Luyong
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Jiangsu Center for Pharmacodynamics Research and Evaluation; China Pharmaceutical University; Nanjing China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research; China Pharmaceutical University; Nanjing China
| | - Jiang Zhenzhou
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University); Ministry of Education; Nanjing China
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing China
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11
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Amir M, Khan MA, Ahmad S, Akhtar M, Mujeeb M, Ahmad A, Khan SA, Al-Abbasi FA. Ameliorating effects of Tamarindus indica fruit extract on anti-tubercular drugs induced liver toxicity in rats. Nat Prod Res 2015; 30:715-9. [DOI: 10.1080/14786419.2015.1039001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Mohd Amir
- Bioactive Natural Product Laboratory, Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-62, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi-62, India
| | - Sayeed Ahmad
- Bioactive Natural Product Laboratory, Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-62, India
| | - Mohd Akhtar
- Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, New Delhi-62, India
| | - Mohd Mujeeb
- Bioactive Natural Product Laboratory, Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-62, India
| | - Aftab Ahmad
- Health Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Shah Alam Khan
- Department of Pharmacy, Oman Medical College, Muscat, Oman
| | - Fahad A. Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
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12
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Kargar M, Mansouri A, Hadjibabaie M, Javadi M, Radfar M, Gholami K. Anti-tuberculosis drugs adverse reactions: a review of the Iranian literature. Expert Opin Drug Saf 2015; 13:875-91. [PMID: 24935479 DOI: 10.1517/14740338.2014.925443] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Tuberculosis (TB) treatment, in particular therapy for multidrug-resistant TB (MDR-TB), is associated with toxicities and adverse drug reactions (ADRs). AREAS COVERED This paper reviews Iranian literature reporting ADRs which occurred during tuberculosis treatment. English language papers were sourced from PubMed, ScienceDirect, Wiley, Ovid and Proquest, with Google Scholar searched for Persian language articles. Reported ADRs, proportion of patients with ADRs, risk factors and determinants, as well as the characteristics of the studies were reviewed. 21 articles were included; about 60% of them were in English and three included patients with MDR-TB. The ratio of ADR per capita was 1.9 (in 6 studies) and 33.63% of patients developed an ADR (in 7 studies). Hepatitis (2.5 - 45.3%) was reported in nearly all of the studies. The mean time from initiation of medication to development of hepatitis ranged from 4.67 to 25.25 days (in 6 studies). Most cases of mortality were due to hepatotoxicity. Except for comorbidities and female gender, other risk factors such as HIV and length of hospitalization were only reported in one article. EXPERT OPINION The pattern of ADRs in Iranian articles was found to be similar to many other studies in the present review. We suggest that future studies resolve the confounding factors in this area that are mentioned in this review.
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Affiliation(s)
- Mona Kargar
- Research Center for Rational Use of Drugs, Tehran University of Medical Sciences , Tehran , Iran
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Jeong I, Park JS, Cho YJ, Yoon HI, Song J, Lee CT, Lee JH. Drug-induced hepatotoxicity of anti-tuberculosis drugs and their serum levels. J Korean Med Sci 2015; 30:167-72. [PMID: 25653488 PMCID: PMC4310943 DOI: 10.3346/jkms.2015.30.2.167] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 10/01/2014] [Indexed: 11/21/2022] Open
Abstract
The correlation between serum anti-tuberculosis (TB) drug levels and the drug-induced hepatotoxicity (DIH) remains unclear. The purpose of this study was to investigate whether anti-TB DIH is associated with basal serum drug levels. Serum peak levels of isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) were analyzed in blood samples 2 hr after the administration of anti-TB medication. Anti-TB DIH and mild liver function test abnormality were diagnosed on the basis of laboratory and clinical criteria. Serum anti-TB drug levels and other clinical factors were compared between the hepatotoxicity and non-hepatotoxicity groups. A total of 195 TB patients were included in the study, and the data were analyzed retrospectively. Seventeen (8.7%) of the 195 patients showed hepatotoxicity, and the mean aspartate aminotransferase/alanine aminotransferase levels in the hepatotoxicity group were 249/249 IU/L, respectively. Among the 17 patients with hepatotoxicity, 12 showed anti-TB DIH. Ten patients showed PZA-related hepatotoxicity and 2 showed INH- or RMP-related hepatotoxicity. However, intergroup differences in the serum levels of the 4 anti-TB drugs were not statistically significant. Basal serum drug concentration was not associated with the risk anti-TB DIH in patients being treated with the currently recommended doses of first-line anti-TB treatment drugs.
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Affiliation(s)
- Ina Jeong
- Department of Internal Medicine, National Medical Center, Seoul, Korea
| | - Jong-Sun Park
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young-Jae Cho
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ho Il Yoon
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Junghan Song
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Choon-Taek Lee
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae-Ho Lee
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
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Liu F, Jiao AX, Wu XR, Zhao W, Yin QQ, Qi H, Jiao WW, Xiao J, Sun L, Shen C, Tian JL, Shen D, Jacqz-Aigrain E, Shen AD. Impact of glutathione S-transferase M1 and T1 on anti-tuberculosis drug-induced hepatotoxicity in Chinese pediatric patients. PLoS One 2014; 9:e115410. [PMID: 25525805 PMCID: PMC4272297 DOI: 10.1371/journal.pone.0115410] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 11/22/2014] [Indexed: 01/22/2023] Open
Abstract
Background Anti-tuberculosis drug induced hepatotoxicity (ATDH) is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S-transferases (GST) plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy. Methods Children receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction. Results One hundred sixty-three children (20 cases and 143 controls) with a mean age of 4.7 years (range: 2 months-14.1 years) were included. For the GSTM1, 14 (70.0%) cases and 96 (67.1%) controls had homozygous null mutations. For the GSTT1, 13 (65.0%) cases and 97 (67.8%) controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD. Conclusion Ourresults did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study.
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Affiliation(s)
- Fang Liu
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - An-xia Jiao
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xi-rong Wu
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Wei Zhao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
- Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France
- Clinical Investigation Center CIC1426, INSERM, Paris, France
- EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France
| | - Qing-qin Yin
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Hui Qi
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Wei-wei Jiao
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jing Xiao
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Lin Sun
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Chen Shen
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jian-ling Tian
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Dan Shen
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Evelyne Jacqz-Aigrain
- Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France
- Clinical Investigation Center CIC1426, INSERM, Paris, France
- EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France
| | - A-dong Shen
- Key Laboratory of Major Diseases in Children and National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China
- * E-mail:
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Ghaffari H, Venkataramana M, Nayaka SC, Ghassam BJ, Angaswamy N, Shekar S, Sampath Kumara KK, Prakash HS. Hepatoprotective action of Orthosiphon diffusus (Benth.) methanol active fraction through antioxidant mechanisms: an in vivo and in vitro evaluation. JOURNAL OF ETHNOPHARMACOLOGY 2013; 149:737-744. [PMID: 23933497 DOI: 10.1016/j.jep.2013.07.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 06/24/2013] [Accepted: 07/27/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Preparations of Orthosiphon diffusus (Benth.) have been used by folk medicinal practitioners in the Western Ghats of India for treating inflammation, hepatitis and jaundice for many years and their effectiveness is widely acclaimed among the tribal communities. AIM OF THE STUDY To evaluate the mechanisms behind the antioxidant and hepatoprotective potential of Orthosiphon diffusus methanol active fraction (MAF) using in vivo (rat) and in vitro (cell culture) models. MATERIALS AND METHODS Neutralization of CCl4-induced hepatotoxicity by MAF was evaluated in rats. Towards this, serum levels of hepatic injury markers (lactate dehydrogenase and alkaline phosphatase), antioxidant enzymes in the liver homogenates, and histological examination were performed. In in vitro studies, mechanisms of neutralization of H2O2-induced toxicity by MAF using MTT, Comet assay and up-regulation of antioxidant enzymes at genetic level (RT-PCR) was performed in HepG2 cells. RESULTS Rats pre-treated with Orthosiphon diffusus MAF demonstrated significantly reduced levels of serum LDH (1.3-fold, p<0.05) and ALP (1.6-fold, p<0.05). Similarly, multiple dose MAF administration demonstrated significantly enhanced levels (p<0.05) of antioxidant enzymes in the liver homogenates. Histological analysis revealed complete neutralization of CCl4-induced liver injury by the extract. The in vitro studies demonstrated that, pre-treatment of MAF effectively prevented H2O2-induced oxidative stress, genotoxicity and significantly enhanced (~6-fold, p<0.01) expression of genes for antioxidant enzymes. CONCLUSIONS Orthosiphon diffusus MAF demonstrated significant hepatoprotection against CCl4-induced hepatotoxicity by antioxidant mechanisms comparable to silymarin. H2O2-induced oxidative stress was completely neutralized by MAF through enhanced expression of genes for antioxidant enzymes. Therefore, this study validates the use of Orthosiphon diffusus by folk medicinal practitioners in India. Further, MAF of Orthosiphon diffusus can serve as a strong candidate for the development of herbal hepatoprotective agents.
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Affiliation(s)
- Hadi Ghaffari
- Department of Studies in Biotechnology, University of Mysore, Mysore, Karnataka, India
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Evaluation of hepatoprotective potential of ethanolic extract of Ixora pavetta against isoniazid and rifampicin induced hepatotoxicity in rats. ACTA ACUST UNITED AC 2013. [DOI: 10.1016/j.dit.2013.06.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Padilha EC, Pires RV, Filho MAFN, de Pontes Machado DV, Baldan HM, Davanço MG, Campos ML, Brunetti IL, Peccinini RG. Pharmacokinetic and safety evaluation of the use of ciprofloxacin on an isoniazid-rifampicin regimen in rabbits. Biopharm Drug Dispos 2012; 33:501-9. [DOI: 10.1002/bdd.1817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 08/29/2012] [Accepted: 09/18/2012] [Indexed: 11/10/2022]
Affiliation(s)
- Elias Carvalho Padilha
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Rodrigo Vieira Pires
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Marco Antonio Ferraz Nogueira Filho
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Diego Vinicius de Pontes Machado
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Helen Mariana Baldan
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Marcelo Gomes Davanço
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Michel Leandro Campos
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Iguatemy Lourenço Brunetti
- Department of Clinical Analysis, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
| | - Rosângela Gonçalves Peccinini
- Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences; São Paulo State University; Araraquara; SP; Brazil
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Arpha K, Phosri C, Suwannasai N, Mongkolthanaruk W, Sodngam S. Astraodoric acids A-D: new lanostane triterpenes from edible mushroom Astraeus odoratus and their anti-Mycobacterium tuberculosis H37Ra and cytotoxic activity. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2012; 60:9834-9841. [PMID: 22957940 DOI: 10.1021/jf302433r] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Tuberculosis (TB) is one of the chronic infectious diseases caused by Mycobacterium tuberculosis that causes about 2-3 million deaths per year. Isoniazid and rifampicin are examples of first line drugs used for TB treatment; however, they are potentially hepatotoxic. More effective and safer drugs are urgently needed, especially from natural products. Basidiomycete mushrooms are known as important sources of pharmaceutically active metabolites including an anti-TB agent. In this work, the chemical constituents of the edible mushroom Astraeus odoratus were isolated and investigated for antibacterial activity against M. tuberculosis H(37)Ra. The cytotoxic activity against cancerous cell lines was also evaluated. Four new lanostane triterpenes, astraodoric acids A-D, and new 5-hydroxyhypaphorine have been isolated together with four known compounds. The structures were elucidated by NMR spectroscopic methods, HR-ESI-MS results, and X-ray crystallographic analysis. Astraodoric acids A and B exhibited moderate antibacterial (MICs of 50 and 25 μg/mL) and cytotoxic activities (IC(50) values of 34.69 and 18.57 μg/mL against KB and 19.99 and 48.35 μg/mL against NCI-H187), respectively. The results of this study show that A. odoratus could be a significant natural source for safer antitubercular and anticancer agents.
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Affiliation(s)
- Kittibhorn Arpha
- Natural Products Research Unit, Centre of Excellence for Innovation in Chemistry (PERCH-CIC), Department of Chemistry, Faculty of Science, Khon Kaen University , Khon Kaen, 40002, Thailand
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Lee CH, Wang JD, Chen PC. Case-crossover design: an alternative strategy for detecting drug-induced liver injury. J Clin Epidemiol 2012; 65:560-7. [PMID: 22445086 DOI: 10.1016/j.jclinepi.2011.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Revised: 10/31/2011] [Accepted: 11/08/2011] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Our observational study was conducted to assess if the case--crossover design could be applied to detect the risk of hepatoxic drugs on liver injury in the automated databases. STUDY DESIGN AND SETTING The study was conducted on approximately 22 million people enrolled in Taiwan's National Health Insurance database from 1997 to 2004. We applied case--crossover and case--control designs to assess the estimated risks of liver injury related to well-known hepatoxic drugs, including isoniazid, rifampicin, erythromycin, and diclofenac. Using case--crossover and case--control designs, we analyzed to explore the association between hospitalization and our target drugs through a conditional logistic regression model. RESULTS The adjusted odds ratios (ORs) of isoniazid, rifampicin, erythromycin, and diclofenac showed 24.4 (confidence interval [CI] =10.7-55.5), 30.8 (CI=14.1-67.1), 2.1 (CI=1.4-3.1), and 2.9 (CI=2.4-3.5) among 4,413 hospitalized liver injury patients during the 30-day exposure window by the case--crossover designs. Most adjusted ORs by case--crossover design were more conservative than ORs by case--control design. CONCLUSIONS In addition to a case--control design, the case--crossover design is a suitable method, for detecting the potential hepatotoxicity of drugs.
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Affiliation(s)
- Chang-Hsing Lee
- Department of Public Health, Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Room 733, 17 Syujhou Road, Taipei, Taiwan
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Ehtesham NZ, Nasiruddin M, Alvi A, Kumar BK, Ahmed N, Peri S, Murthy KJR, Hasnain SE. Treatment end point determinants for pulmonary tuberculosis: human resistin as a surrogate biomarker. Tuberculosis (Edinb) 2011; 91:293-9. [PMID: 21606003 DOI: 10.1016/j.tube.2011.04.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2011] [Revised: 04/18/2011] [Accepted: 04/23/2011] [Indexed: 12/20/2022]
Abstract
Treatment of tuberculosis (TB), which takes one human life every 15 s, globally, requires a prolonged (>6 months) antitubercular treatment (ATT) which, is known to have hepatotoxic side effects. This study was designed to explore the utility of human resistin, a proinflammatory hormone, as a sensitive biomarker to determine TB treatment end points. Patients for pulmonary tuberculosis enrolled under the directly observed treatment, short-course (DOTS) program were followed-up for six months and were monitored by sputum analysis, body weight and ELISA-based serum resistin and C-reactive protein (CRP) levels at 0, 2, 4 and 6 months, along with close family contacts of TB patients and healthy controls. The mean circulating resistin levels were found to be significantly higher (P < 0.001) in patients (n = 48, 25.74 ± 9.45 ng/ml) reporting for the first time for treatment (T0) as compared to healthy subjects (n = 45, 7.18 ± 2.40 ng/ml). Resistin levels in contacts (n = 48, 19.61 ± 7.88 ng/ml) also were found to be significantly (P < 0.001) elevated as compared to healthy controls. Significant increase in body weight after four months (P = 0.006) and at 6 months (P < 0.001) of treatment inversely correlated with resistin levels. Our data suggest resistin could be a surrogate marker for TB treatment in addition to its utility as an early prognostic biomarker for monitoring TB disease onset.
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Affiliation(s)
- Nasreen Z Ehtesham
- Institute of Life Sciences, University of Hyderabad Campus, Prof C.R. Rao Road, Hyderabad, India.
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Yamada S, Tang M, Richardson K, Halaschek-Wiener J, Chan M, Cook VJ, Fitzgerald JM, Elwood RK, Brooks-Wilson A, Marra F. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics 2009; 10:1433-45. [PMID: 19761367 DOI: 10.2217/pgs.09.66] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
AIMS TB is a serious global public health problem. Isoniazid, a key drug used to treat latent TB, can cause hepatotoxicity in some patients. This pilot study investigated the effects of genetic variation in NAT2 and CYP2E1 on isoniazid-induced hepatotoxicity in TB contacts in British Columbia, Canada. MATERIALS & METHODS DNA re-sequencing was used to establish the spectrum of genetic variation in the exons, promoter and conserved regions of NAT2 in all subjects. For CYP2E1, the CYP2E1*1C polymorphism was genotyped by PCR-RFLP. Association tests of NAT2 variants and haplotypes, as well acetylator types were performed. RESULTS We enrolled 170 subjects on isoniazid treatment (23 cases and 147 controls). Systematic re-sequencing of NAT2 revealed 18 known and 10 novel variants. CONCLUSION No single genetic variant of NAT2 and CYP2E1 showed a significant association with isoniazid-induced hepatotoxicity in this highly heterogeneous population. There was evidence of a trend for increasing hepatotoxicity risk across the rapid, intermediate and slow acetylator groups (p = 0.08).
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Affiliation(s)
- So Yamada
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
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Eminzade S, Uras F, Izzettin FV. Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals. Nutr Metab (Lond) 2008; 5:18. [PMID: 18601745 PMCID: PMC2491620 DOI: 10.1186/1743-7075-5-18] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2008] [Accepted: 07/05/2008] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The first line anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) continues to be the effective drugs in the treatment of tuberculosis, however, the use of these drugs is associated with toxic reactions in tissues, particularly in the liver, leading to hepatitis. Silymarin, a standard plant extract with strong antioxidant activity obtained from S. marianum, is known to be an effective agent for liver protection and liver regeneration. The aim of this study was to investigate the protective actions of silymarin against hepatotoxicity caused by different combinations of anti-tuberculosis drugs. METHODS Male Wistar albino rats weighing 250-300 g were used to form 6 study groups, each group consisting of 10 rats. Animals were treated with intra-peritoneal injection of isoniazid (50 mg/kg) and rifampicin (100 mg/kg); and intra-gastric administration of pyrazinamid (350 mg/kg) and silymarin (200 mg/kg). Hepatotoxicity was induced by a combination of drugs with INH+RIF and INH+RIF+PZA. Hepatoprotective effect of silymarin was investigated by co-administration of silymarin together with the drugs. Serum biochemical tests for liver functions and histopathological examination of livers were carried out to demonstrate the protection of liver against anti-tuberculosis drugs by silymarin. RESULTS Treatment of rats with INH+RIF or INH+RIF+PZA induced hepatotoxicity as evidenced by biochemical measurements: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities and the levels of total bilirubin were elevated, and the levels of albumin and total protein were decreased in drugs-treated animals. Histopathological changes were also observed in livers of animals that received drugs. Simultaneous administration of silymarin significantly decreased the biochemical and histological changes induced by the drugs. CONCLUSION The active components of silymarin had protective effects against hepatotoxic actions of drugs used in the chemotherapy of tuberculosis in animal models. Since no significant toxicity of silymarin is reported in human studies, this plant extract can be used as a dietary supplement by patients taking anti-tuberculosis medications.
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Affiliation(s)
- Sude Eminzade
- Department of Pharmacology, Marmara University, Faculty of Pharmacy, Haydarpasa, Istanbul, Turkey
| | - Fikriye Uras
- Department of Biochemistry, Marmara University, Faculty of Pharmacy, Haydarpasa, Istanbul, Turkey
| | - Fikret V Izzettin
- Department of Pharmacology, Marmara University, Faculty of Pharmacy, Haydarpasa, Istanbul, Turkey
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Abstract
Antimycobacterial chemotherapy is the mainstay of treatment for the majority of patients with genitourinary tuberculosis (GUTB). A large body of evidence from clinical trials suggests that short-course chemotherapy regimens, employing four drugs including rifampicin and pyrazinamide, achieve cure in most of the patients with tuberculosis (TB) and are associated with the lowest rates of relapse. Standard six-month regimens are adequate for the treatment of GUTB. Directly observed treatment, short-course (DOTS) is the internationally recommended comprehensive strategy to control TB, and directly observed treatment is just one of its five elements. DOTS cures not only the individual with TB but also reduces the incidence of TB as well as the prevalence of primary drug-resistance in the community. Corticosteroids have no proven role in the management of patients with GUTB. Errors in prescribing anti-TB drugs are common in clinical practice. Standardized treatment regimens at correct doses and assured completion of treatment have made DOTS the present-day standard of care for the management of all forms of TB including GUTB.
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Affiliation(s)
- Tamilarasu Kadhiravan
- Department of Medicine, All India Institute of Medical Sciences, New Delhi - 110 608, India
| | - Surendra K. Sharma
- Department of Medicine, All India Institute of Medical Sciences, New Delhi - 110 608, India
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Roblot F, Besnier JM, Giraudeau B, Simonnard N, Jonville-Bera AP, Coipeau P, Choutet P, Autret-Leca E, Le Guellec C. Lack of association between rifampicin plasma concentration and treatment-related side effects in osteoarticular infections. Fundam Clin Pharmacol 2007; 21:363-9. [PMID: 17635174 DOI: 10.1111/j.1472-8206.2007.00490.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The aim of this study was to assess the frequency of gastrointestinal side effects (GSE) and hepatotoxicity in patients treated with rifampicin for an osteoarticular infection and to determine if there is an association between rifampicin plasma concentrations and side effects. Rifampicin plasma concentrations were prospectively measured before (trough concentration, C(0)) and 2 +/- 0.5 h (peak concentration, C(2)) after drug intake. The presence of GSE, the alanine transferase (ALT) value, and concomitantly administered medications were recorded on the day rifampicin concentrations were measured. C(0) and C(2) were compared for differences regarding the presence or absence of side effects. Multivariate analysis was performed, with associated medications being taken into account. Seventy C(0) and 57 C(2) values were measured in 46 adults after a median treatment of 8 days (range, 1-179). Wide inter-individual variability was observed for C(0) and C(2). Thirteen (28%) patients reported GSE at least once. When GSE occurred, C(0) (median, 1 mg L(-1); range, 0.1-9.9 mg L(-1)) and C(2) (median, 10.3 mg L(-1); range, 1.8-40.3 mg L(-1)) were similar to C(0) (median, 0.6 mg L(-1); range, 0.1-10.3 mg L(-1)) and C(2) (median, 10.9 mg L(-1); range, 2.9-29.0 mg L(-1)) without GSE. The ALT value was more than normal in only three patients (6.5%) after rifampicin treatment began. The patients received no different associated medications whether or not GSE were present. Multivariate analysis showed no association between rifampicin plasma concentrations and GSE. GSE occur frequently in patients receiving rifampicin for osteoarticular infection but without an association with rifampicin plasma concentrations. Thus, therapeutic drug monitoring of rifampicin is irrelevant in the management of GSE.
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Affiliation(s)
- France Roblot
- CHRU de Tours, Service des Maladies Infectieuses, 2 boulevard Tonnellé, 37044 Tours Cedex, France
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Aouam K, Chaabane A, Loussaïef C, Ben Romdhane F, Boughattas NA, Chakroun M. Les effets indésirables des antituberculeux: épidémiologie, mécanismes et conduite à tenir. Med Mal Infect 2007; 37:253-61. [PMID: 17336011 DOI: 10.1016/j.medmal.2006.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2006] [Accepted: 12/11/2006] [Indexed: 01/22/2023]
Abstract
Tuberculosis, what ever its localization, is an infectious disease which can be totally cured by combining antitubercular drugs. Current therapeutic regimens with isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin have proved successful in treating tuberculosis. However, they are associated to a high rate of adverse effects that can lead to therapeutic failure. Understanding the nature and the severity of these adverse effects allows for their appropriate management. Toxic neuropathy and hepatitis are the most common adverse reactions to isoniazid. Rifampicin is generally well tolerated but some severe immuno-allergic reactions may occur in case of intermittent regimen. Pyrazinamide-induced liver injury is rare but sometimes lethal. Joint affections, usually due to hyperuricemia, are more frequent but easily manageable. The major adverse effect related to ethambutol is ocular optic neuropathy. It occurs dose-dependently and can be irreversible. Finally, administration of streptomycin is potentially associated with renal and cochleo-vestibular toxicity that might be milder than when induced by other aminoglycosides. The management of antituberculosis-induced adverse effects depends on parameters related to the adverse effect itself and to the administrated drug.
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Affiliation(s)
- K Aouam
- Laboratoire de pharmacologie, faculté de médecine, 5019 Monastir, Tunisie
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Abstract
Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.
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Affiliation(s)
- Wing Wai Yew
- Tuberculosis and Chest Unit, Grantham Hospital, Hong Kong, China.
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Baldan HM, De Rosa HJ, Brunetti IL, Ximenes VF, Machado RGP. The effect of rifampicin and pyrazinamide on isoniazid pharmacokinetics in rats. Biopharm Drug Dispos 2007; 28:409-13. [PMID: 17828712 DOI: 10.1002/bdd.570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Tuberculosis chemotherapy involves combination of the drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) for a 6-month period. The present work investigated the influence of RMP and PYR on the pharmacokinetic parameters of INH when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg+RMP 100 mg; INH 100 mg+PYR 350 mg; INH 100 mg+PYR 350 mg+RMP 100 mg. It was found that the co-administration of PYR caused an increase in the INH distribution volume (V(d)/F), half-life of elimination (t(1/2beta)) and clearance (Cl(T)/F), and a decrease in the area under curve 0 to 24 h (AUC). Co-administration of RMP caused an increase in the Cl(T)/F and a decrease in the AUC. The combination INH+PYR+RMP caused an increase in the Cl(T)/F and a decrease in the AUC. These significant pharmacokinetic interactions between the tuberculostatic drugs might be related to differences in the therapeutic and toxic effects.
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Affiliation(s)
- Helen M Baldan
- Departamento de Princípios Ativos Naturais e Toxicologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP, Brasil
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Chen J, Raymond K. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob 2006; 5:3. [PMID: 16480505 PMCID: PMC1395332 DOI: 10.1186/1476-0711-5-3] [Citation(s) in RCA: 205] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2005] [Accepted: 02/15/2006] [Indexed: 12/19/2022] Open
Abstract
Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex.
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Affiliation(s)
- Jiezhong Chen
- School of Pharmacy, Faculty of Science, Technology and Engineering, La Trobe University, Bendigo, Vic 3550, Australia
| | - Kenneth Raymond
- School of Pharmacy, Faculty of Science, Technology and Engineering, La Trobe University, Bendigo, Vic 3550, Australia
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Pal R, Vaiphei K, Sikander A, Singh K, Rana SV. Effect of garlic on isoniazid and rifampicin-induced hepatic injury in rats. World J Gastroenterol 2006; 12:636-9. [PMID: 16489682 PMCID: PMC4066101 DOI: 10.3748/wjg.v12.i4.636] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the hepatoprotective effect of garlic on liver injury induced by isoniazid (INH) and rifampicin (RIF).
METHODS: Wistar rats weighing 150-200 g were treated orally with 50 mg/kg of INH and RIF daily each for 28 d. For hepatoprotective studies, 0.25 g/kg per day of freshly prepared garlic homogenate was administered orally half an hour before the INH+RIF doses. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin were estimated on d 0, 14, 21, and 28 in all the rats. Histological analysis was carried out to assess the injury to the liver. Lipid peroxidation (LPO) as a marker of oxidative stress and non-protein thiols (glutathione) for antioxidant levels were measured in liver homogenate.
RESULTS: The treatment of rats with INH+RIF (50 mg/kg per day each) induced hepatotoxicity in all the treated animals as judged by elevated serum ALT, AST, and bilirubin levels, presence of focal hepatocytic necrosis (6/8) and portal triaditis (8/8). Garlic simultaneously administered at a dose of 0.25 g/kg per day prevented the induction of histopathological injuries in INH+RIF co-treated animals, except in 4 animals, which showed only moderate portal triaditis. The histological changes correlated with oxidative stress in INH+RIF treated animals. The group which received 0.25 g/kg per day garlic homogenate along with INH+RIF showed higher levels of glutathione (P < 0.05) and low levels of LPO (P < 0.05) as compared to INH+RIF treated group.
CONCLUSION: Freshly prepared garlic homogenate protects against INH+RIF-induced liver injury in experimental animal model.
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Affiliation(s)
- Ravinder Pal
- Department of Gastor PGIMER, Chd, House No. 137, Sector 15-A, Chandigarh 160015, India
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