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Thomas L, Chaithra, Batra Y, Mathur M, Kulavalli S, SV CS, Dutt N, Bhardwaj P, Varma M, Saravu K, Banerjee M, Rao M. Pharmacogenomic heterogeneity of N-acetyltransferase 2: a comprehensive analysis of real world data in Indian tuberculosis patients and from literature and database review. Ann Med 2025; 57:2478316. [PMID: 40138446 PMCID: PMC11948353 DOI: 10.1080/07853890.2025.2478316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/06/2025] [Accepted: 01/31/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Isoniazid is primarily metabolized by the arylamine N-acetyltransferase 2 (NAT2) enzyme. Single nucleotide polymorphisms (SNPs) in the NAT2 gene could classify an individual into three distinct phenotypes: rapid, intermediate and slow acetylators. NAT2 SNPs and the slow acetylator phenotype have been implicated as risk factors for the development of antitubercular drug-induced liver injury (AT-DILI) in several tuberculosis (TB) populations. PATIENTS AND METHODS We conducted a prospective observational study to characterize and compare the NAT2 SNPs, genotypes and phenotypes among patients with TB and AT-DILI from the Southern and Western regions of India. The NAT2 pharmacogenomic profile of patients from these regions was compared with the reports from several geographically diverse TB populations and participants of different genetic ancestries extracted from literature reviews and the 'All of Us' Research Program database, respectively. RESULTS The TB patients of Southern and Western regions of India and several other geographically closer regions exhibited near similar NAT2 MAF characteristics. However significant heterogeneity in NAT2 SNPs was observed within and between countries among AT-DILI populations and the participants of different genetic ancestry from the 'All of Us' Research Program database. The MAF of the NAT2 SNPs rs1041983, rs1801280, rs1799929, rs1799930 and rs1208 of the TB patients from Southern and Western Indian Sites were in near range to that of the South Asian genetic ancestry of 'All of Us' Research Program database. About one-third of the total TB patients from the Southern and Western regions of India were NAT2 slow acetylators, among whom a relatively higher proportion experienced AT-DILI. CONCLUSION Further studies exploring the risk of NAT2 SNPs in different AT-DILI patients with larger sample sizes and a population-specific approach are required to establish a policy for NAT2 genotyping as a pre-emptive biomarker for AT-DILI monitoring for personalized isoniazid therapy in clinics.
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Affiliation(s)
- Levin Thomas
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Chaithra
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Yashi Batra
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, USA
| | - Mitali Mathur
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Shrivathsa Kulavalli
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | | | - Naveen Dutt
- Department of Pulmonary Medicine, All India Institute of Medical Sciences, Jodhpur, India
| | - Pankaj Bhardwaj
- Department of Community Medicine and Family Medicine, All India Institute of Medical Sciences, Jodhpur, India
| | - Muralidhar Varma
- Department of Infectious Diseases, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Kavitha Saravu
- Department of Infectious Diseases, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
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Kumar R, Kumar A, Kumar S. Acute liver failure from anti-tuberculosis drug-induced liver injury: An update. World J Hepatol 2025; 17:106618. [DOI: 10.4254/wjh.v17.i5.106618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 04/01/2025] [Accepted: 05/10/2025] [Indexed: 05/27/2025] Open
Abstract
Tuberculosis (TB) is still a major public health issue in developing countries, where it causes a heavy disease burden. Although current anti-TB treatment regimens demonstrate high efficacy, the hepatotoxic potential of first-line anti-TB drugs (ATDs) - particularly isoniazid, rifampicin, and pyrazinamide—poses a considerable risk, as these agents are associated with a significant incidence of ATD-induced liver injury (AT-DILI). The clinical presentation of AT-DILI can range from asymptomatic elevations in serum transaminases, which may resolve spontaneously due to hepatic adaptation, to acute liver failure (ALF), a potentially life-threatening condition. A recent meta-analysis reported a global incidence of AT-DILI of 11.5%, with rates varying from 2% to 28%. Approximately 7% of patients with AT-DILI progress to ALF, a condition characterized by a poor survival rate with medical therapy. ATD-induced ALF (AT-ALF) is clinically indistinguishable from ALF due to other causes and disproportionately affects young female patients, typically within eight weeks of treatment initiation. Emergency liver transplantation has become an effective therapeutic option for AT-ALF, although outcomes are generally poorer compared to elective transplantation. This minireview provides a comprehensive overview of AT-ALF, covering its epidemiology, risk factors, clinical presentation, prognosis, and treatment options.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Abhishek Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Munshi R, Panchal F, Desai U, Utpat K, Rajoria K. A study of N-acetyltransferase 2 gene polymorphisms in the Indian population and its relationship with serum isoniazid concentrations in a cohort of tuberculosis patients. Monaldi Arch Chest Dis 2024. [PMID: 39704240 DOI: 10.4081/monaldi.2024.3181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/16/2024] [Indexed: 12/21/2024] Open
Abstract
The N-acetyltransferase 2 (NAT2) gene exhibits substantial genetic diversity, leading to distinct acetylator phenotypes among individuals. In this study, we determine NAT2 gene polymorphisms in tuberculosis (TB) patients and analyze serum isoniazid (INH) concentrations across the various genotypes. An observational prospective cohort study involving 217 patients with pulmonary or extrapulmonary TB was carried out. The NAT2 genotypes were identified using real-time polymerase chain reaction technology. INH concentrations at baseline and 2 hours post-dosing were estimated using high-performance liquid chromatography. The association between the acetylator status and INH concentrations was evaluated using odds ratios (OR) and the occurrence of adverse events across the different patient genotypes was also assessed. The genotype frequency of fast, intermediate, and slow acetylators was 7.37%, 39.17%, and 53.46%, respectively, while allele frequency was 27% for fast acetylators and 73% for slow acetylators. All the alleles followed the Hardy-Weinberg equilibrium. Patients with slow acetylator status had significantly increased serum INH concentrations 2 hours post-drug administration, followed by intermediate acetylators as compared to fast acetylators. 69 (31.8%) patients developed adverse drug reactions post-therapy. Patients with slow acetylator status had the highest (OR: 9.66) risk of developing drug-induced hepatoxicity, especially those with raised serum INH concentrations (OR: 1.34). Understanding the correlation between genetics and serum antitubercular drug levels in antitubercular drug-induced hepatotoxicity will provide valuable information to the medical community, minimizing the risk of adverse reactions and hospitalizations.
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Affiliation(s)
- Renuka Munshi
- Department of Clinical Pharmacology, Topiwala National Medical College And Bai Yamunabai Laxman Nair Charitable Hospital, Mumbai
| | - Falguni Panchal
- Department of Clinical Pharmacology, Topiwala National Medical College And Bai Yamunabai Laxman Nair Charitable Hospital, Mumbai
| | - Unnati Desai
- Department of Pulmonary Medicine, Topiwala National Medical College And Bai Yamunabai Laxman Nair Charitable Hospital, Mumbai
| | - Ketaki Utpat
- Department of Pulmonary Medicine, Topiwala National Medical College And Bai Yamunabai Laxman Nair Charitable Hospital, Mumbai
| | - Kirti Rajoria
- Department of Clinical Pharmacology, Topiwala National Medical College And Bai Yamunabai Laxman Nair Charitable Hospital, Mumbai
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Mahajan R, Tyagi AK. Pharmacogenomic insights into tuberculosis treatment shows the NAT2 genetic variants linked to hepatotoxicity risk: a systematic review and meta-analysis. BMC Genom Data 2024; 25:103. [PMID: 39639188 PMCID: PMC11622454 DOI: 10.1186/s12863-024-01286-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Tuberculosis (TB) patients undergoing anti-tuberculosis treatment often face serious adverse drug reactions, such as hepatotoxicity. Genetic variants of the N-acetyltransferase 2 (NAT2) gene have been linked to an increased risk of these toxic events. OBJECTIVE This study aims to provide a comprehensive evaluation of the evidence linking NAT2 genetic variants to anti-tuberculosis drug-related hepatotoxicity (ATDH). METHOD A comprehensive review and meta-analysis was performed by accessing databases such as PubMed, Scopus, and Web of Science. A total of 24 articles were incorporated into the dataset. Meta-analyses were conducted to gather estimates of the association between the slow acetlylators (SA) genotype and ATDH. The studies were stratified by ethnicity, regimen, genotyping methods, criteria for liver toxicity, and dosage. Also, meta-analysis for the specific SA type that was most likely responsible for the ATDH was also conducted. RESULTS The included studies showed individuals with a slow NAT2 acetylator had a significantly greater risk of experiencing hepatotoxicity ATDH (odds ratio [OR] 2.52 (95% CI: 1.95-3.27; p value < 0.001) compared to individuals with other types of acetylator (i.e., rapid and immediate). Among individuals with slow acetylator NAT2*5/7, NAT2*5/6, and NAT2*6/6 genotypes, there is a greater likelihood of association compared to other variations. CONCLUSION Our meta-analysis confirms a significant association between slow NAT2 acetylator and increased hepatotoxicity risk. The findings from the present underscore the potential of pharmacogenomic testing to improve TB treatment outcomes. By identifying patients with the slow acetylator NAT2 genotype, healthcare providers can predict an increased risk of anti-tuberculosis drug-induced hepatotoxicity. This allows for personalized treatment strategies, such as adjusting drug dosages or selecting alternative therapies, to minimize adverse effects and optimize efficacy.
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Affiliation(s)
- Rashmi Mahajan
- Dr. Bhimrao Ramji Ambedkar Government Medical College, Kannauj, India
| | - Anuj Kumar Tyagi
- Dr. Bhimrao Ramji Ambedkar Government Medical College, Kannauj, India.
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Mondal S, Roy V, Meshram GG, Khanna A, Velpandian T, Garg S. Pharmacokinetics-pharmacodynamics of first-line antitubercular drugs: a comparative study in tuberculosis patients with and without concomitant diabetes mellitus. Eur J Clin Pharmacol 2024; 80:1945-1958. [PMID: 39287783 DOI: 10.1007/s00228-024-03754-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/30/2024] [Indexed: 09/19/2024]
Abstract
PURPOSE To observe the variability in the plasma concentrations and pharmacokinetic-pharmacodynamic (PK-PD) profiles of first-line antitubercular drugs in pulmonary tuberculosis (TB) patients with and without diabetes mellitus (DM). METHODS Newly diagnosed pulmonary TB patients aged 18-60 years with or without DM were included in the study. Group I (n = 20) included patients with TB, whereas group II (n = 20) included patients with both TB and DM. After 2 weeks of therapy, plasma concentrations and other PK-PD parameters were determined. Improvements in clinical features, X-ray findings, sputum conversion, and adverse drug reactions (ADRs) were assessed after 2 months of therapy. RESULTS Isoniazid displayed non-significantly higher plasma concentrations in diabetic patients, along with a significantly (P < 0.05) longer elimination half-life (t1/2). Rifampicin plasma concentrations at 4, 8, and 12 h were significantly (P < 0.05) lower, and it displayed significantly (P < 0.05) lower area under the curve (AUC0-12 and AUC0-∞), shorter t1/2, higher clearance (Cl), and a lower AUC0-∞/MIC ratio in diabetic patients. Pyrazinamide and ethambutol showed non-significantly higher plasma concentrations, AUC0-12, AUC0-∞, and t1/2 in diabetic patients. The improvements in clinical features, X-ray findings, sputum conversion, and ADRs were comparable in both groups. CONCLUSIONS The presence of DM in TB patients affects the PK-PD parameters of isoniazid, rifampicin, pyrazinamide, and ethambutol variably in the Indian population. Studies with a larger number of patients are required to further elucidate the role of DM on the PK-PD profile of first-line antitubercular drugs and treatment outcomes in TB patients with concomitant DM. TRIAL REGISTRATION CTRI/2021/08/035578 dated 11/08/2021.
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Affiliation(s)
- Sourav Mondal
- Department of Pharmacology, Maulana Azad Medical College, New Delhi, 110002, India
- Department of Clinical Pharmacology, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, 400012, India
| | - Vandana Roy
- Department of Pharmacology, Maulana Azad Medical College, New Delhi, 110002, India.
| | - Girish Gulab Meshram
- Department of Pharmacology, Maulana Azad Medical College, New Delhi, 110002, India
| | - Ashwani Khanna
- TB and Chest Clinic, Lok Nayak Hospital, New Delhi, 110002, India
| | - Thirumurthy Velpandian
- Department of Ocular Pharmacology and Pharmacy Division of Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sandeep Garg
- Department of General Medicine, Maulana Azad Medical College, New Delhi, 110002, India
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Bhargava A. The 3 HP regimen for tuberculosis preventive treatment: safety, dosage and related concerns during its large-scale implementation in countries like India. THE LANCET REGIONAL HEALTH. SOUTHEAST ASIA 2024; 31:100422. [PMID: 39957776 PMCID: PMC11827095 DOI: 10.1016/j.lansea.2024.100422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/21/2024] [Accepted: 04/26/2024] [Indexed: 02/18/2025]
Abstract
The 3-month once-weekly isoniazid-rifapentine (3 HP) regimen for tuberculosis preventive treatment recommended by WHO is being rolled in countries including India. It has higher completion rates and lower risk of hepatotoxicity than isoniazid preventive treatment, but trials also showed higher frequency of systemic drug reactions (SDRs) including flu-like syndromes and dizziness, and also uncommon Grade 3 or 4 adverse events like hypotension, syncope, bronchospasm. Low BMI is a risk factor for SDRs. Available data on safety of 3 HP in the Asian region is limited, heterogeneous, but points to a higher frequency of SDRs suggesting a need for caution in its large-scale implementation. 19% (118/614) of household contacts initiated on 3 HP in Delhi reported dizziness. Multiple lines of evidence including pharmacokinetic data suggest that the SDRs may be related to isoniazid and its plasma concentration. WHO and national guidelines for the 3 HP regimen currently recommend a fixed dose of once-weekly 900 mg isoniazid in adults regardless of body weight that poses a risk of SDRs for lower weight adults, amplified by the acetylator status and the lack of co-administration of pyridoxine. Weight based dosing, co-administration of pyridoxine and pharmacovigilance studies should accompany the roll out of 3 HP to ensure its safe and successful implementation.
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Affiliation(s)
- Anurag Bhargava
- Department of Medicine, Yenepoya Medical College, Mangalore, Karnataka, India
- Center for Nutrition Studies, Yenepoya (Deemed to be University), Mangalore, India
- Department of Medicine, McGill University, Montreal, Canada
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Thomas L, Raju AP, Chaithra S, Kulavalli S, Varma M, Sv CS, Baneerjee M, Saravu K, Mallayasamy S, Rao M. Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients. Expert Rev Clin Pharmacol 2024; 17:263-274. [PMID: 38287694 DOI: 10.1080/17512433.2024.2311314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 01/24/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). RESEARCH DESIGN AND METHODS A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. RESULTS NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators. CONCLUSION The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.
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Affiliation(s)
- Levin Thomas
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Arun Prasath Raju
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - S Chaithra
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shrivathsa Kulavalli
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Muralidhar Varma
- Department of Infectious Diseases, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | - Mithu Baneerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Kavitha Saravu
- Department of Infectious Diseases, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Surulivelrajan Mallayasamy
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Woodland JG, Basarab GS, Mogwera K, Winks S, Chibale K. The 2022 H3D Symposium: Celebrating over a Decade of African-Led Infectious Disease Drug Discovery to Enhance Global Health. ACS Infect Dis 2023; 9:389-393. [PMID: 36762950 DOI: 10.1021/acsinfecdis.3c00041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Affiliation(s)
- John G Woodland
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7700, South Africa.,South African Medical Research Council Drug Discovery and Development Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Gregory S Basarab
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7700, South Africa
| | - Koketso Mogwera
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7700, South Africa
| | - Susan Winks
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7700, South Africa
| | - Kelly Chibale
- Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7700, South Africa.,South African Medical Research Council Drug Discovery and Development Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
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Misra UK, Warrier S, Kalita J, Tripathi A, Kumar S. Treatment response and complications during management of Pott's spine. J Neuroimmunol 2022; 373:577979. [PMID: 36270077 DOI: 10.1016/j.jneuroim.2022.577979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/05/2022] [Indexed: 11/07/2022]
Abstract
The global incidence of TB in 2016 was 10.4 million and India accounts for a quarter of the global burden of TB. It is estimated that there are 2.79 million people with TB in India. About 10% of extra pulmonary TB involves bone and joints. Spinal TB accounts for half the cases of skeletal TB. The incidence of spinal TB is 1-4% of total TB cases, then it is estimated that only in India approximately 60,000 spinal TB cases exist. To report the pattern of recovery and predictors of outcome of Pott's spine. The intervention comprised of four drug antitubercular treatment, rest, immobilization, and ultrasonography or computerized tomography guided aspiration or biopsy as indicated outcome measures were six months Nurick grade, and mRS and complications like drug induced hepatitis (DIH) and paradoxical worsening. Seventy-three patients with Pott's spine, median age 36 (11-73) years, 32 (43.8%) females were included. The neurological signs were present in 44 (64.4%) patients. At six months, median Nurick grade improved from 4 to 2 and;and 70% patients had a good outcome as defined by mRS.The predictors of poor outcome were weight loss, non-ambulatory state on admission and paradoxical worsening. It is concluded that neurological involvement in Pott's spine was present in 64% patients, paradoxical worsening (deterioration in symptoms after one month of ATT) in 11% and DIH in 16%. Weight loss, non-ambulatory state on admission and paradoxical worsening predicted poor outcome.
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Affiliation(s)
- Usha K Misra
- Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India.
| | - Siddharth Warrier
- Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Jayantee Kalita
- Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Abhilasha Tripathi
- Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
| | - Sunil Kumar
- Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India
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Masiphephethu MV, Sariko M, Walongo T, Maro A, Mduma D, Gratz J, Alshaer M, Peloquin CA, Mduma E, Mpagama SG, Thomas T, Houpt ER, Traore A, Bessong P, Heysell SK, Operario DJ. Pharmacogenetic testing for NAT2 genotypes in a Tanzanian population across the lifespan to guide future personalized isoniazid dosing. Tuberculosis (Edinb) 2022; 136:102246. [PMID: 35961094 PMCID: PMC9884397 DOI: 10.1016/j.tube.2022.102246] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 07/12/2022] [Accepted: 08/03/2022] [Indexed: 01/31/2023]
Abstract
Despite updated recommendations for weight-based isoniazid dosing in children with drug-susceptible tuberculosis (TB) and higher dose isoniazid in regimens for adults with drug-resistant TB, individual pharmacokinetic variability can lead to sub-target isoniazid exposure. Host pharmacogenetics and isoniazid exposure remain understudied, especially in the East African population. We therefore employed a real-time polymerase chain reaction (qPCR) assay system to test genomic DNA extracted from saliva samples targeting the NAT2 gene responsible for isoniazid metabolism to describe the frequency of human single nucleotide polymorphisms in NAT2 within populations of children and adults in Tanzania, ascribe those polymorphisms to acetylator phenotype, and correlate to serum isoniazid exposures. In adults treated with higher dose isoniazid, genotypes with a predicted allelic phenotype of slow or intermediate acetylation were able to achieve a 0.41 μg/mL higher Cmax (p = 0.018) and a 2.9h*μg/mL higher AUC0-12 (p = 0.003) per mg/kg increase in isoniazid dosage versus adults with rapid acetylation phenotype. A similar relationship was not found in the younger age population as predicted by timing of NAT2 maturation. This saliva based qPCR assay was fieldable to guide personalized isoniazid dosing in adults but not young children that may not have full NAT2 maturation and activity.
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Affiliation(s)
| | - Margaretha Sariko
- Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical College, Moshi, Tanzania
| | | | - Athanasia Maro
- Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical College, Moshi, Tanzania
| | - Dorcus Mduma
- Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical College, Moshi, Tanzania
| | - Jean Gratz
- University of Virginia, Charlottesville, VA, USA
| | | | | | | | | | - Tania Thomas
- University of Virginia, Charlottesville, VA, USA
| | - Eric R Houpt
- University of Virginia, Charlottesville, VA, USA
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Hernández-González O, Herrera-Vargas DJ, Martínez-Leija ME, Zavala-Reyes D, Portales-Pérez DP. The role of arylamine N-acetyltransferases in chronic degenerative diseases: Their possible function in the immune system. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119297. [PMID: 35588943 DOI: 10.1016/j.bbamcr.2022.119297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 06/15/2023]
Abstract
Since their discovery, arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2, respectively) have been associated with the metabolism of xenobiotics. NAT2 is the main factor in the therapeutic success of tuberculosis treatment due to its role in the biotransformation of isoniazid. However, researchers have started to investigate the possible participation of NAT1 and NAT2 (NATs) in carcinogenesis, although the mechanisms have not been elucidated fully. NATs enzymatic activity is essential in some types of cancer, such as breast cancer and acute lymphoblastic leukemia. Whether NAT1 and/or NAT2 participate in insulin resistance level in diabetes mellitus or in the immune system remains to be explored. Therefore, it is clear that its role in cell physiology has more implications than just metabolizing compounds.
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Affiliation(s)
| | | | - Miguel Ernesto Martínez-Leija
- Faculty of Chemical Sciences, Autonomous University of San Luis Potosí, Mexico; Research Center for Health Sciences and Biomedicine, Autonomous University of San Luis Potosí, Mexico
| | - Daniel Zavala-Reyes
- Research Center for Health Sciences and Biomedicine, Autonomous University of San Luis Potosí, Mexico
| | - Diana Patricia Portales-Pérez
- Faculty of Chemical Sciences, Autonomous University of San Luis Potosí, Mexico; Research Center for Health Sciences and Biomedicine, Autonomous University of San Luis Potosí, Mexico.
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Kralj T, Brouwer KLR, Creek DJ. Analytical and Omics-Based Advances in the Study of Drug-Induced Liver Injury. Toxicol Sci 2021; 183:1-13. [PMID: 34086958 PMCID: PMC8502468 DOI: 10.1093/toxsci/kfab069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1-1.5 million patients annually, and remains a major challenge during drug development-toxicity and safety concerns are the second-highest reason for drug candidate failure. The future prevalence of DILI can be minimized by developing a greater understanding of the biological mechanisms behind DILI. Both qualitative and quantitative analytical techniques are vital to characterizing and investigating DILI. In vitro assays are capable of characterizing specific aspects of a drug's hepatotoxic nature and multiplexed assays are capable of characterizing and scoring a drug's association with DILI. However, an even deeper insight into the perturbations to biological pathways involved in the mechanisms of DILI can be gained through the use of omics-based analytical techniques: genomics, transcriptomics, proteomics, and metabolomics. These omics analytical techniques can offer qualitative and quantitative insight into genetic susceptibilities to DILI, the impact of drug treatment on gene expression, and the effect on protein and metabolite abundance. This review will discuss the analytical techniques that can be applied to characterize and investigate the biological mechanisms of DILI and potential predictive biomarkers.
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Affiliation(s)
- Thomas Kralj
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569, USA
| | - Darren J Creek
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
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Bakshi S, Kaur M, Saini N, Mir AA, Duseja A, Sinha SK, Sharma S. Altered expressions of circulating microRNAs 122 and 192 during antitubercular drug induced liver injury indicating their role as potential biomarkers. Hum Exp Toxicol 2021; 40:1474-1484. [PMID: 33729026 DOI: 10.1177/0960327121997975] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Drug induced liver toxicity is a serious health complication leading to high mortality rates and post marketing withdrawal of drugs. Although considered to be the gold standard biomarkers; aspartate aminotransferase, alanine aminotransferase, total bilirubin and alkaline phosphatase have been found to have specificities beyond liver, therefore more specific and predictive markers for the detection of antitubercular drug mediated liver damage are required. Unfortunately, the effectiveness of currently used first line antitubercular drugs namely isoniazid, rifampicin, pyrazinamide is often accompanied with liver injury, impeding the cure of patients. Keeping in view, the prognostic and diagnostic applications of microRNAs in various diseases, we tried to assess the importance of microRNAs 122 and 192 in antitubercular drug associated liver injuries. The study included subjects having tuberculosis of any type with antitubercular drug induced liver injury; naïve or newly diagnosed tuberculosis patients, tuberculosis patients on drugs not having toxicity and healthy controls. Observations from this study revealed that expression levels of miR-122 and miR-192 were significantly decreased in the serum of antitubercular drug induced liver injury patients only. Therefore, these microRNAs or the pathways associated with them can be used as a tool to predict or cure antitubercular drug associated liver injury in future.
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Affiliation(s)
- S Bakshi
- Department of Biochemistry, 29751Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - M Kaur
- Department of Biochemistry, 29751Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - N Saini
- Department of Biochemistry, 29751Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - A A Mir
- Department of Biochemistry, 29751Postgraduate Institute of Medical Education and Research, Chandigarh, India.,Department of Biochemistry, All India Institute of Medical Sciences, Raebareli, Uttar Pradesh, India
| | - A Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - S K Sinha
- Department of Gasteroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - S Sharma
- Department of Biochemistry, 29751Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis. Antimicrob Agents Chemother 2020; 65:AAC.00487-20. [PMID: 33139294 PMCID: PMC7927832 DOI: 10.1128/aac.00487-20] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 10/13/2020] [Indexed: 11/20/2022] Open
Abstract
Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs and to simulate different dosing strategies. The pharmacokinetic properties of rifampin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while those of isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. Cerebrospinal fluid (CSF) penetration of rifampin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampin, were sufficient to achieve target exposures. The ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampin dosing at 50 mg/kg of body weight/day would be required to achieve the target exposure. Moreover, low rifampin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.
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Ungcharoen U, Sriplung H, Mahasirimongkol S, Chusri S, Wichukchinda N, Mokmued P, Wattanapokayakit S, Chongsuvivatwong V. The Influence of NAT2 Genotypes on Isoniazid Plasma Concentration of Pulmonary Tuberculosis Patients in Southern Thailand. Tuberc Respir Dis (Seoul) 2020; 83:S55-S62. [PMID: 33138342 PMCID: PMC7837378 DOI: 10.4046/trd.2020.0068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 11/03/2020] [Indexed: 01/16/2023] Open
Abstract
Background Isoniazid (INH) is metabolized by polymorphic N-acetyltransferase 2 (NAT2) enzyme, which noticeably alters INH plasma concentration. We aimed to determine the distribution of NAT2 genotype in Thai tuberculosis (TB) patients and correlate their genotype with plasma INH concentrations. Methods Blood samples from 55 newly diagnosed pulmonary tuberculosis participants from three hospitals were collected to classify the subject by NAT2 genotype performed by the Multiplex haplotype-specific polymerase chain reaction method. Patients were grouped into three acetylators (fast, intermediate, and slow). On day 14 of tuberculosis treatment, the second blood sample was taken to estimate the peak plasma concentration at 2 hours after oral administration. INH plasma concentration was analyzed by liquid chromatography‒tandem mass spectrometry/mass spectrometry method. Results The NAT2 genotype distribution of fast, intermediate, and slow acetylator was 10.9%, 36.4%, and 52.7%, from six, 20, and 29 patients, respectively. The median (interquartile range) of INH plasma concentration at 2 hours post drug administration for these three genotypes were 0.75 (0.69–0.86), 2.56 (2.12–3.97), and 4.25 (3.56–5.50) µg/mL from four, 14, and 12 cases, respectively. The INH plasma concentration at 2 hours after administration was significantly associated with body weight and NAT2 acetylator. Conclusion The INH plasma concentration was found lower in fast than intermediate and slow acetylators. Body weight and NAT2 acetylator influenced INH plasma concentrations at 2 hours after drug administration. Therefore, the NAT2 genotype should be known before starting TB treatment to maximize therapeutic outcomes.
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Affiliation(s)
- Usanee Ungcharoen
- Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Hutcha Sriplung
- Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Surakameth Mahasirimongkol
- Division of Genomic Medicine and Innovation Support, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
| | - Saranyou Chusri
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand
| | - Nuanjun Wichukchinda
- Division of Genomic Medicine and Innovation Support, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
| | - Phongpan Mokmued
- Division of Genomic Medicine and Innovation Support, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
| | - Sukanya Wattanapokayakit
- Division of Genomic Medicine and Innovation Support, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
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Shetty P, Panchal F, Munshi R, Sundar U, Darole P. A case series of three patients presenting with isoniazid induced toxicity and N-acetyl transferase 2 gene mutation: A management conundrum for programmatic therapy of tuberculosis in India. Indian J Tuberc 2020; 67:407-410. [PMID: 32825881 DOI: 10.1016/j.ijtb.2020.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 09/26/2019] [Accepted: 01/06/2020] [Indexed: 10/25/2022]
Abstract
Isoniazid is an essential drug in the management of tuberculosis but there is a high degree of variation in the Indian population's capacity to acetylate or inactivate isoniazid to the inactive metabolite acetyl isoniazid, and they can be distinctly characterized phenotypically as being either slow or rapid inactivators (the concentration of the enzyme being higher in rapid inactivators). Several mutations in the N-acetyl transference 2 (NAT2) gene account for majority of the slow acetylator genotypes in the human population (NAT2*5A, NAT2*5B, and NAT2*6A). Such individuals are at a greater risk of drug-induced adverse reactions due to reduced drug elimination, compared to those possessing the wild type allele. Here we discuss two cases of Isoniazid induced peripheral neuropathy and one case of Isoniazid induced hepatotoxicity confirmed as having heterozygous or homozygous NAT2 gene mutation. In all 3 cases, the presence of NAT2 gene mutation was associated with the adverse events and the adverse events subsided on stopping or reducing the dose of isoniazid. However, due to lack of guideline-based management of adverse events occurring due to isoniazid, the drug was either abruptly stopped or dosage lowered based only on clinical expertise, which could potentially lead to further resistance to Mycobacterium tuberculosis (as occurred in one of our cases). Further studies of the relationship between NAT2 genotypes, isoniazid concentrations and adverse drug events are required to make genotyping a helpful tool for optimizing isoniazid's therapeutic response and minimizing adverse drug reactions, particularly in countries with a high burden of tuberculosis.
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Affiliation(s)
- Parvan Shetty
- Department of Clinical Pharmacology, TN Medical College & BYL Nair Charitable Hospital, Mumbai, India
| | - Falguni Panchal
- Department of Clinical Pharmacology, TN Medical College & BYL Nair Charitable Hospital, Mumbai, India
| | - Renuka Munshi
- Department of Clinical Pharmacology, TN Medical College & BYL Nair Charitable Hospital, Mumbai, India.
| | - Uma Sundar
- Department of Medicine, LTM Medical College & LTM General Hospital, Mumbai, India
| | - Pramod Darole
- Department of Medicine, LTM Medical College & LTM General Hospital, Mumbai, India
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Valodara AM, SR KJ. Sexual Dimorphism in Drug Metabolism and Pharmacokinetics. Curr Drug Metab 2020; 20:1154-1166. [DOI: 10.2174/1389200220666191021094906] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/27/2019] [Accepted: 10/04/2019] [Indexed: 12/11/2022]
Abstract
Background:Sex and gender-based differences are observed well beyond the sex organs and affect several physiological and biochemical processes involved in the metabolism of drug molecules. It is essential to understand not only the sex and gender-based differences in the metabolism of the drug but also the molecular mechanisms involved in the regulation of drug metabolism for avoiding sex-related adverse effects of drugs in the human.Method:The articles on the sex and gender-based differences in the metabolism of drug molecules were retrieved from the Pub Med database. The articles were classified into the metabolism of the drug molecule, gene expression regulation of drug-metabolizing enzymes, the effect of sex hormones on the metabolism of drug, expression of drugmetabolizing enzymes, etc.Result:Several drug molecules are known, which are metabolized differently in males and females. These differences in metabolism may be due to the genomic and non-genomic action of sex hormones. Several other drug molecules still require further evaluation at the molecular level regarding the sex and gender-based differences in their metabolism. Attention is also required at the effect of signaling cascades associated with the metabolism of drug molecules.Conclusion:Sex and gender-based differences in the metabolism of drugs exist at various levels and it may be due to the genomic and non-genomic action of sex hormones. Detailed understanding of the effect of sex and related condition on the metabolism of drug molecules will help clinicians to determine the effective therapeutic doses of drugs dependingon the condition of patient and disease.
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Affiliation(s)
- Askhi M. Valodara
- Department of Zoology, Biomedical Technology and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, India
| | - Kaid Johar SR
- Department of Zoology, Biomedical Technology and Human Genetics, School of Sciences, Gujarat University, Ahmedabad, India
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Pérez-González MZ, Macías-Rubalcava ML, Hernández-Ortega S, Siordia-Reyes AG, Jiménez-Arellanes MA. Additional compounds and the therapeutic potential of Cnidoscolus chayamansa (McVaugh) against hepatotoxicity induced by antitubercular drugs. Biomed Pharmacother 2019; 117:109140. [PMID: 31387195 DOI: 10.1016/j.biopha.2019.109140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/14/2019] [Accepted: 06/14/2019] [Indexed: 01/16/2023] Open
Abstract
Previously non-isolated compounds (scopoletin and β-D-Glucopyranoside, (1R)-O-isopropyl 6-O-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-2,3,4-triacetate) were isolated from an organic extract of the Cnidoscolus chayamansa stem. Also, lupeol acetate (main compound, 49.7 mg/g of dry extract) and scopoletin (0.19 mg/g of dry extract) were quantified by HPLC analysis from this organic extract. The protective activity of the C. chayamansa organic extract against hepatotoxicity induced by antitubercular drugs [Rifampicin (50 mg/kg), Isoniazid (50 mg/kg), and Pyrazinamide (100 mg/kg)] are reported. The extract was tested at 200 and 400 mg/kg in Balb/C mice during 85 days, using silymarin (2.5 mg/kg) as positive control. Liver damage was determined using biochemical parameters (AST, ALT, ALP, CHOL, HDL TG, Urea, and CREA), histological analysis, and evaluation of oxidative stress (SOD, CAT, Gpx, Lpx and POx). The extract at both doses favored body weight gain with respect to the anti-TB group; the dose of 200 mg/kg was better. Also, the extract at both doses decreased the values of transaminases (AST, ALT) enzymes (p < 0.05) vs. anti-TB group. In oxidative stress parameters, the SOD value was decreased, as were the levels of peroxidation of lipids and oxidative protein in the group with C. chayamansa extract at 200 and 400 mg/kg vs. the anti-TB group. Histological analyses from liver showed the absence of steatosis in the extract group at 400 mg/kg, and moderate steatosis in the silymarin and extract (at 200 mg/kg) groups with respect to anti-TB group, which demonstrated a steatosis. It should be noted that during the study period, none of the treated mice died. In conclusion, the CHCl3: MeOH extract of C. chayamansa has a hepatoprotective effect against hepatotoxicity induced by anti-TB drugs.
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Affiliation(s)
- Mariana Z Pérez-González
- Unidad de Investigación Médica (UIM) en Farmacología, UMAE Hospital de Especialidades, CORSE 2º piso, Centro Médico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtémoc 330, Col. Doctores, 06720, Ciudad de México (CDMX), Mexico
| | - Martha L Macías-Rubalcava
- Instituto de Química (I.Q.), Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Alcaldía Coyoacán, 04510, CDMX, Mexico; Departamento de Productos Naturales, I.Q., UNAM, Ciudad Universitaria, Alcaldía Coyoacán, 04510 CDMX, Mexico
| | - Simón Hernández-Ortega
- Instituto de Química (I.Q.), Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Alcaldía Coyoacán, 04510, CDMX, Mexico; Laboratorio de Rayos X, UNAM, Ciudad Universitaria, Alcaldía Coyoacán, 04510 CDMX, Mexico
| | - A Georgina Siordia-Reyes
- División de Histopatología, UMAE Hospital de Pediatría, CMN-SXXI, IMSS, Av. Cuauhtémoc 330, Col. Doctores, 06729, CDMX, Mexico
| | - María Adelina Jiménez-Arellanes
- Unidad de Investigación Médica (UIM) en Farmacología, UMAE Hospital de Especialidades, CORSE 2º piso, Centro Médico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtémoc 330, Col. Doctores, 06720, Ciudad de México (CDMX), Mexico.
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McIlleron H, Chirehwa MT. Current research toward optimizing dosing of first-line antituberculosis treatment. Expert Rev Anti Infect Ther 2018; 17:27-38. [PMID: 30501530 PMCID: PMC6364307 DOI: 10.1080/14787210.2019.1555031] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Drug concentrations in tuberculosis patients on standard regimens vary widely with clinically important consequences. Areas covered: We review the available literature identifying factors correlated with pharmacokinetic variability of antituberculosis drugs. Based on population pharmacokinetic models and the weight, height, and sex distributions in a large data base of African tuberculosis patients, we propose simplified weight-based doses of the available fixed dose combination(FDC) for adults with drug susceptible tuberculosis. Emerging studies will support optimized weight-based dosing for children. Other sources of important pharmacokinetic variability include genetic variants, drug-drug interactions, formulation quality, and methods of preparation and administration. Expert commentary: Optimized weight band-based dosing will result in more equitable distribution of drug exposures by weight. The use of high doses of isoniazid in patients with drug-resistant tuberculosis would be safer and more effective if a feasible test was developed to allow stratified dosing according to acetylator type. There is an urgent need for more suitable formulations of many second-line drugs for children. The adoption of new technologies and efficient FDC design may allow further advances for patients and treatment programs. Lastly, current efforts to ensure adequate quality of antituberculosis drug products are not preventing the use of substandard products to treat patients with tuberculosis.
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Affiliation(s)
- Helen McIlleron
- a Division of Clinical Pharmacology, Department of Medicine , University of Cape Town , Cape Town , South Africa
| | - Maxwell T Chirehwa
- a Division of Clinical Pharmacology, Department of Medicine , University of Cape Town , Cape Town , South Africa
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